Wave Life Sciences Ltd. Stock

Hi, everyone. Just wanted to come on to welcome everyone to this session of our SMID Cap Executive Insights Virtual Event. So I'm Jill Hall, head of Small and Mid-Cap Strategy here at Global Research. So we're very happy to host this event for another year. Great opportunity to hear from corporates across the small and mid-cap space. Our analysts have great coverage in the space, about 1,000 small and mid-cap companies in the U.S. So fortunate to hear from almost 20 of them between today and tomorrow. So feel free to reach out to me or to the Corporate Access team if you need help registering for any other sessions. We can definitely still add people and -- or if you need the schedule as well as if you need help connecting with any of our analysts afterward or getting on to distribution for their research, our small and mid-cap research, we also do a fundamental compilation of small and mid-cap research each day. So with that, I'll pass it over to Alec.

Awesome. Thanks, Jill. So my name is Alec Stranahan. I'm a senior analyst covering biotech here at BofA. I cover 29 companies ranging from $40 billion to $400 million on the market cap scale. And I'd say Wave is probably one of the more interesting stories in my coverage, and it's my pleasure to be joined today by Paul Bolno, who is the President and Chief Executive Officer of Wave Life Sciences. Paul has been with the company since just about the beginning and I know you'll be able to feel his passion about their RNA platform and opportunities in obesity and elsewhere. So Paul, thanks so much for doing this with us.

No, thank you, Alec. Excited to be here.

Yes. Great. Great. So I've got some questions to run through here to sort of lead the discussion. But for those dialed in, if you do have a question, you can utilize the raise hand feature via Zoom or you can e-mail me separately, I've already gotten a couple of questions come in, and I'll be sure to relay those on your behalf. So Paul, maybe just to start, Wave has clinical validation for the RNA interference and RNA editing aspects of your technology. But maybe just starting at a high level for those less familiar, with the story and the technology platform, maybe you can run through what Wave was created to do and sort of what's going on at the company currently?

No. It's a wonderful place to start because as you said, when we kind of look at where we are today, it's easy to become fixated on some programs and clinical validation, and we talk about RNAi as if it's almost commoditized and we talk about RNA editing as this innovation on the platform. But as you pointed out, if I reflect kind of back on now in over a decade investment that we've been making at Wave, it's fundamentally off of chemistry. And at the core essence of Wave has always been about how do we design differentiation on chemistry that can ultimately unlock the potential of RNA medicines. And I say this both on the investment we made in stereochemistry and so making single molecules where we could really understand the fundamental pharmacology of how these medicines work to the ability to extrapolate new modifications that continue to drive potency, durability and differentiation as we see with our obesity program INHBE.

And so when I step back and say, RNA medicines, we've got a ubiquitous chemistry capability across all RNA therapeutics across the different modalities. And what's really exciting about that, and I think this is the opportunity that sits ahead of us, both with the pipeline that we're currently developing. And as we have R&D Day later this year, really extrapolating on where we can take this forward is the convergence between what you can do when you have differentiated chemistry and how that translates to the intersection with novel genetic targets. And that's really enabling us to really approach new areas.

So case in point, INHBE, a novel genetic target in obesity that really addresses what we see as kind of the fundamental future of the next generation of obesity therapeutics. Alpha-1 antitrypsin, the first RNA editing program that's an important program for alpha-1 patients but also unlocking the power of RNA editing more broadly with PNPLA3 coming behind it. And again, here's an opportunity where silencing as we predicted a little over a year ago, where we were saying that if you knock down this enzyme, you could make the disease worse. The idea that in editing that could actually treat the underlying disease, we were seeing that play out with some of the recent clinical data updates on RNAi and PNPLA3.

And so again, differentiated target, differentiated approach. And I think as we think to the future, the opportunity we have in front of us beyond the existing pipeline to use the platform to unlock differentiated targets that really address new biology is pretty exciting.

Yes. No, definitely a lot going on at the company. And maybe just to level set here in the beginning, what's the benefit of RNA editing versus DNA editing, which I think is maybe a little bit more mainstream for generalist investors. And I mean you're also competing against some DNA editing companies [Cyagen and ACB]. So maybe you can just speak at a high level on kind of the benefits of editing the RNA.

Yes. I mean, I think when we step forward, we say what is the target product profile for these patients who are living with a disease. In this case, we're talking about alpha-1 antitrypsin deficiency and how do we best address that? And the opportunity we always say is, we have different modalities and different ways to address diseases. So if we don't think that that's the best way to do it. We don't have to be doing it. And so really, RNA editing came about because our view fundamentally is that a redoseable medicine that doesn't permanently mutate DNA and put patients at potential risk for off-target edits and separate, when we talk about this space, in particular, alpha-1 antitrypsin deficiency.

When we talk about off targets, people tend to immediately go to just, well, is it bystander editing? Can you address that through specificity? The real risk to off-target editing that could lead to editing of cancer-associated genes that could take decades to materialize. In addition to what happens when you get bystander edits that create different proteins. So specificity is important. So can you redose it and get an access to new cell types? Can you get specificity that is exquisite? And we've seen that in our preclinical characterization. We see that clinically, which is beautiful crossing of our M protein and Z protein.

So we know we're functionally converting that Z misfolded protein to M. And durability, so being able to do so in a way that's not putting a dosing burden on patients and then when we think about access and market access to these patients. On the other side, how accessible do we make it when you work with payers?

And when we think about the idea of -- and I don't think we've ever seen the concept of a true one and done therapy. But if you take durability you need over a decade of durability on a DNA editor with safe, durable like no loss of editing to just break even from a payer on what you would get in terms of treating a patient with an RNA editor. And so when we think about being able to provide that, so potency, safety, durability and access. We see RNA editing is providing those features. And it's not dissimilar to what we're seeing in other therapeutic spaces. I mean, I think TTR has just been another great example of watching where RNA medicines have really unlocked the potential for an indication and maintain a competitive position. So I think we see that same opportunity in front of us for alpha-1 antitrypsin deficiency.

Great. And Wave, I think, has a distinct advantage that within RNA, you can silence, you can edit, you could do a splicing. How do you decide which approach is best for a given disease? And I guess, where does your proprietary chemistry maybe create the clearest competitive advantage?

So I think the wonderful thing about the chemistry is we can see that advantage whether we're talking about editing or RNAi or splicing. So the opportunity that the chemistry provides gives us, to your point, and I think it's a very good one that we can think about to hammer everything as a nail, with the wonderful thing about having optionalities as we think about these tools as we can select, to your point, the right tool for the right job. And I think there's no better example of that, frankly, than the program that will be going into the clinic later this year, which is PNPLA3. So there's 9 million patients who have this genetic mutation. You can find it in 23andMe, so it's commercially available and people can find out that they have the PNPLA3 mutation. And those patients are at a substantial higher risk of all-cause liver disease mortality. So the ability to actually provide a fix to that is important.

I say a fix because for a while, people said, okay, there's this mutation. If you can silence it, you can treat the underlying disease. And as we, as to your point, we can make RNAi and we can make editor. So what do we do? And we shared some of these data last year at R&D Day. When we looked at the comparison between silencing the enzyme versus fixing the enzyme, there were differences in outcome measurements. We saw differences in the cell's ability to dispose of the fat that was inside as we think about MASH. We also saw differences, and we'll be sharing more on this on the inflammatory component of the disease. And so when we look back and said, well, do you want to silence or turn off this enzyme, but frankly, you need it, right?

This is a disease where a heterozygous phenotype. So 50% correction basically restores functionality back to those patients in terms of their survival advantage. The idea that we had was, well, yes, absolutely. Here's a case where actually the correction actually fixes the disease. And I think not only do we see that in our preclinical studies, but watching multiple clinical programs start to read out on the silencing front is conferring that same advantage that we've been seeing that there's actually the real advantage in fixing and correcting that underlying mutation back to a normal functioning enzyme as opposed to silencing and then taking that enzymatic function away. And so we're excited as that goes forward to be able to think about this really in redefining liver diseases. Here's a PNPLA3 mutation. We can look at it for these different indications, but really what underlies this is protecting these patients very early on from a substantial risk. And 9 million patients is not an insignificant number of patients that can be addressed.

Right, right. And you've mentioned a few of the internal pipeline assets, and I want to go through them one by one. But I think maybe a good question just to sort of lead into that is I think WVE-007, which is your obesity asset got a lot of attention or a lot of attention to the company when we saw the really encouraging early human data a few months ago. But I guess which program kind of has the best or the greatest potential to change how the market values Wave over the next 12 to 18 months?

Yes. I mean I think over the next year, I think it's the wonderful aspect of these 2 programs, right? I think they have -- if we think about alpha-1 antitrypsin and we think about 007, each has the ability to be transformative in its own way, right? I think in the case of the next near-term period on 007, I think a lot of the -- what people will say is the initial enthusiasm, I still think sustains our enthusiasm in the program. I think the biology is really well understood.

We have genetic data. We have human data, and we have the bridging between human genetics of patients. We have the bridging to treated patients, and we have the models in between. And the medicine is doing exactly what it's supposed to be doing in a way that's differentiated as we've watched other silencing programs come forward. That reinforces our differentiated chemistry. And we're still looking at durability as we think about a once to twice a year dosing.

We still see the only clinical data set in patients who are otherwise healthy, so Phase I patient population in low fat who sees substantial reductions in visceral fat that are clinically relevant, substantial reductions in total body fat. So we think about what's going to drive ultimately weight loss in general is total body fat and change in waist circumference, which is actually a measurably meaningful way of looking at the impact of this medicine. And so I think as we think about the early data from the Phase I population, and even that is being compared to Phase II/III. I think we're highly encouraged that with dosing underway in the IIa monotherapy in the patient population that is the intent to treat, right? These are patients with higher BMIs, higher levels of visceral fat, higher levels of total body fat, with and without diabetes. There's 2 other cohorts so that we can really elucidate kind of the broader cardiometabolic areas for treatment, meaning diabetes, MASH and others, it's pretty exciting. And I think we're poised now without running to be able to accelerate and deliver the new data.

And then shortly from now initiate the combination study and then where I think there's probably an underappreciated application because everybody is so focused on the frontline and how are we going to win a monotherapy, and I think the opportunity is very much there, and I think this is going to be a meaningful medicine in combination. Do you have to keep pushing incretins in order to get a benefit or the add-on? And I think we're seeing examples of add-on being really great opportunity. But I think the most underappreciated aspect long term for treatment of these patients who are living with obesity have been treated are at steady state on regardless of what therapy they came into treatment on. I think the conversation we hear time and again against clinicians and patients and payers, for that matter is, what does maintenance now start to look like in this population?

And to date, maintenance is really like a titrating back on incretin levels and how much regain can you stave off in order to kind of keep people on a level. And I think that really fascinating opportunity of maintenance for INHBE is actually just shifted of how do you lock in and prevent fat regain? That's the challenge, right? If you titrate back your incretin, the weight that comes back is actually fat. And as you come back, you imagine a patient going back to baseline actually has more fat than they actually started their therapy with.

So the idea that we could shift to a maintenance therapy that could be once to twice a year, prevent that regain of fat back and really stabilize patients now has us not segmenting a market, but really thinking about how do you take any incretin patient and actually think about a forward-looking vision where they don't have to sustain on that and run all of the complicating risks to being on a sustained injectable or frankly, oral. Where we'll see whether or not the oral is in a real-world setting, actually sustain the levels that they're seeing now. But we think maintenance is a really exciting way. And at this moment in time, I don't think it's still getting the attention that we think it should. And I think as we start that clinical study this half, I think that's going to be an exciting news part of the story. So that's kind of how we think about unlocking obesity. And we saw that there is a lot of value there.

On the other side, alpha-1 antitrypsin is we're poised to have regulatory feedback on a path to accelerated approval, I think, accelerates a different conversation with Wave, right, which is one of how do we move into a commercial stream for a substantial number of patients, 200,000 patients in U.S. and Europe. Would be the first RNA editing program, we think, as we laid out as your first question in a way that's differentiated, I think, from others and as we test that profile amongst the medical community, patient community and payers. We think that's an exciting component in Wave that gets unlocked again in the second half as we think about going into next year and having this pathway to potential accelerated approval.

And so I really do think we're in a position as we look forward that the next 12 months is incredibly exciting across both assets. And I don't think -- I think both have the potential to contribute substantially to a higher value than we're seeing today. With then PNPLA3 coming behind that as a supportive asset that will continue to generate data in the next 12 months that unlocks that opportunity and as people will learn at R&D Day. The opportunity we have with bispecifics and other targets that sustainably deliver on that pipeline beyond the existing 007 and 006, I think is a really strong foreseeable future.

Yes. Yes, great. Those tend to be the 2 assets that I get most focused on from investors as well. So maybe we can touch on those, and then I do hope we get time to talk about PNPL3 -- sorry, PNPLA3 as well at the end because I know that's a large unmet need as well. But maybe starting on 007 in obesity and cardiometabolic disease. And I think you kind of covered a lot of it. But maybe we could just talk a little bit about the lessons learned so far from the Phase I data.

I mean you showed reductions in total and visceral fat with muscle preservation, which is kind of the holy grail when you think about maintenance or even an upfront therapy, like a lot of the total weight loss is actually from muscle and not fat with incretins. So if you're able to strike that balance with convenient dosing, like it seems like a pretty actionable profile. But I guess how did investors sort of interpret those results through the dose escalation? I think we're going to get a higher dose as well later this year and what have you learned about baseline BMI, the relationship between Activin E reduction and clinical benefit that's sort of helping you inform next steps for your clinical program.

Yes. I mean I think one from -- and I think this is great from a platform perspective, from preclinical data to human data, I think we're seeing strong correlations and translations of target engagement editing. And as we predict our dose going forward, I mean the fact that we're seeing that once to twice a year sustained at the lowest dose that we're going into, I think, continues to speak to what we expect to see from where we think we would need to be from a dose. And we're seeing 88% to 85% reduction in Activin E. So we're -- knowing that we've seen preclinically that once you cross the 70% threshold and sustain it, you start to see that reduction. So we're well in excess of that.

I think that's an important nuance too because I think what it also affirms for us is this differentiation on chemistry. So what we have seen in our preclinical data is it's the only preclinical data set that's seen single dose reduction in body weight. Not prevention of weight gain or slowing of fat regain, but true reduction in body weight. And I think that was important because it does demonstrate that with sustained reduction, and it's important to remember that the DIO mouse is an obese mouse model with excess fat. So I think it's affirming for us that where there's fat that can be stored, you'll see that reduction and lipolysis occur. And I think that's exactly what we saw in the humans. And in fact, to your point on the dose response was really interesting.

And we have to go back to these data and remind ourselves because I also think people tend to become, let's say, fixated on BMI and forget you can be a body builder with a higher BMI and you can be overweight or obese with higher BMI. And the main difference there is the amount of fat. And so I think what we've seen, which has been affirming for the mechanism is where there's higher fat, we see higher rates of decline, right? And so that played out actually in the clinic.

If we think about the dose response, the update we provided at the 400 was actually probably one of the clearest data sets to prove this principle. Once patients had a higher level of visceral fat and total fat, those patients had reductions on par with where we saw the substantial decline in the 240-milligram dose. So I think what's key in this early study, and I think it's hard because obesity is an area. And I do appreciate that those who are evaluating these kind of from the other side are looking at kind of the incretin pathway, right?

People come out and they're like, here's our IIa data. Here's how it looks in the IIa population. And if we look at our peers who share data for INHBE around us, they're all looking at the IIa. We never saw the early Phase I data. I think it was compelling as our Phase I data was competitive where we were starting to benchmark our Phase I population with the IIa population. We were like, "Oh, look, Wave saw a 14-point whatever reduction in visceral fat that looks similar to these other companies reduction in visceral fat." And a reminder, when we kind of step back is, yes, but if you look at -- because these patients had different starting rates of fat, our patients only had 1 liter of fat to lose, and yet they could lose it remarkably in comparison to a comparator with 5 liters of fat because they were a much larger population, which, again, will speak to what's next and why we have conviction in the program.

But I think it really taught us that the medicine is doing exactly what we had modeled to do it. It targets the cells, it's durable. It's potent, it's safe, and I think that's really important as we think about durability and potency in this population. So safety and tolerability looks exquisite. So I think that opportunity on top of that is translating very well.

Now the next question that everybody has is what about 600? And I think we've been saying time and time again that, yes, 600 should see -- we're probably at the blunter end of the curve. It will probably be -- I would anticipate more Activin E reduction, but I wouldn't expect that the baseline characteristics of those patients would be any different. And we know we've already suppressed that.

So I think we'll see what we'll continue to see around PK/PD. I think the most exciting and we've been very clear on this, is now seeing what the medicines do in the patient population with higher BMI, higher total fat, higher visceral fat and comorbidities. And that's that comorbidities piece that allows that fat to be larger. And I think if we think about our modeling, and we've shared this with a number of folks, if you look at the baseline characteristics, which are pretty much good baseline surrogates for baseline characteristics of patients into obesity studies, they have much higher total fat, much higher visceral fat.

And if you look at where our studies started in relation to those studies, and I should kind of give that, I don't know, it's like, but we started at a body composition profile that looked like where those patients end after a year on therapy and still saw that we could continue to bring that down. So what's encouraging is, as soon as we go to that population where we get to a higher fat to lose with the comorbidities, we model that we're not in any way kind of going, do we think we're going to see greater than 5% changes in body weight.

I think what's most important, and you pointed it out, is being able to see that improvement in body composition. And I think that's an exciting conversation that's also happening this half, where we're going to engage regulators around that more broadly. We know the other obesity patient groups are as well. And I think there's a big conversation to be had really on starting to reframe a focus on body composition that irrespective of the 5%, and we're not trying to change the regulatory paradigm there. But we do think from a label perspective and a forward-looking perspective, that changing the narrative from pounds on the scale, as you point out, you can have up to 40% reduction in your muscle mass in that early time point that's really accounting for weight loss with incretins. That's not a benefit.

Those patients are losing an organ that has -- plays a big role in insulin sensitivity, further weight loss and muscle mass and stabilization. So the ability to really frame what long term is providing health benefits as we think about improvements in body composition, I think, is going to be an exciting part of the story as we go through this year and into next year.

Right. Yes. And we know that in patients with higher BMI that have been exposed to other INHBE assets. You do see better activity, which is probably not inherent to that -- those other compounds. It's probably just where you start determines where you can end up. And to your point, Paul, the Phase IIa INLIGHT study, I think that's a BMI of 35 to 50, right, with or without type 2 diabetes. And you're going to be measuring the whole gamut, body weight, body composition, visceral fat, liver fat, HbA1c, lipids. I guess which of these endpoints kind of matters the most for establishing 007 and which could actually open up expansion opportunities into say, MASH or even diabetes?

I think they're all important in their own way, right? I mean I think in general, looking at that continued shift in body composition, right? Reductions in total body fat, reductions in visceral fat are going to be very important. I think ultimately, that translates to body weight because by stabilizing muscle, you're going to see weight as a function of losing fat, right? And so I think that's going to be a surrogate to looking at what we're going to have in addition to the drivers of what's causing that, which we want to see the weight reduction, but coming off of total body fat.

Then to add to your point, I think what's really important about this mechanism and frankly, it was also driving, I think, the patient disposition at the beginning of the study is the concept that these patients can have comorbidities, right? And so when you start thinking about prediabetics and diabetics as 2 different cohorts, the ability to look and track hemoglobin A1c and we go back to these humans who are walking around with a protective loss of function, they have improvements in hemoglobin A1c. They have better type 2 diabetes outcomes and cardiovascular outcomes. Why? Well, because of this improvement, they have lower triglycerides, they have higher HDL, right, in addition to these improvements in hemoglobin A1c.

So I think we're going to look and be able to elucidate some of those cardiometabolic endpoints as we think about looking at those 2 different cohorts, and we'll have the biomarkers to measure that. And as you point out, by having MRI-PDFF in this study, particularly the diabetic patients that have comorbidities and higher BMI, the likelihood, right, of having higher levels of liver fat as we've seen in the other studies is quite substantial. And therefore, the improvements that we can see if we look at our peers who have looked at liver MRIs, 44% reduction in liver fat is consequential. I mean that's substantially as large as, if not actually larger than some of the MASH studies.

So I think the opportunity we're going to have here is there's the unlocking the obesity perspective in a differentiated program with a differentiated pharmacology and we're going to have the opportunity to open up the broader cardiometabolic endpoints that are all part of the study.

Okay. Great. And with the approval of oral incretins I'd say, the field is moving pretty quickly. Although we haven't seen maybe as much progress as the clinical pipeline would have led one to believe 2 or 3 years ago. I guess where do you expect 007 to kind of fit into this evolving landscape? Like do patients get an injectable and then oral maintenance or would INHBE asset compete against an oral or would it be complementary in combination? How are you sort of thinking about these kind of synergizing together ultimately 5,10 years down the road?

Yes. I think if we don't think about the method of delivery, then we know that incretins are compatible and orthogonal to INHBE, right? So the same features apply your point of whether it's monotherapy at the front end, in combination with the oral which is an interesting way of thinking about it because the whole goal is to minimize patient number of injections and you could be talking about 1 or 2 a year on INHBE and then on oral and that could take down the frequent -- injection frequency from a weekly injectable down to once or twice a year in combination with an oral.

As I start thinking about maintenance and where we are, I think the difference is you talk to patients where you go into your physician's office and you get a shot and then you don't have to think about it for the year without the tolerability challenges and frankly, you don't -- it doesn't negate all of the other safety and tolerability complications on the incretins, whether we're talking about oral or injectables. The idea that you still go to a once-a-year injectable, we think is highly competitive with that as we talk to, again, physicians, payers and patients.

I think what's going to be interesting as the data continues to evolve and looking at some of the orals is what the impact ultimately is, right? I mean here's a medicine that you got to take every day. Some, depending on time based, some take whenever you like. But we know from other orals that are required daily. I mean, I think cholesterol and statins are just a great example of what adherence looks like on a medicine that doesn't have the same tolerability challenges causing nausea and vomiting.

And you start thinking yourself in the real world setting, when somebody is not calling you, you don't have an app, you're not kind of in a trial where you're taking it on this frequent basis. The evolution of what real-world data looks like when people miss a dose or missed 2 doses to start adjusting their doses titratable versus how that looks in a maintenance concept versus you go in, you get your shot. And you know you're covered for the period of time that your Activin E is suppressed. We think that the INHBE profile is highly competitive against orals in that maintenance setting.

Yes. Okay. That makes sense. Maybe I'll pause for a moment. We're about 30 minutes in, and I'll see if anyone on the line has any questions on obesity and then we can shift to the AATD and the rest of the pipeline. Again, if you have a question, feel free to raise your hand. I can see it through our platform, and we can unmute you. Maybe while we wait, I did get an e-mail question here on obesity. And the question is kind of around the partnership opportunity, right? Obesity is a large market. There's a lot of potential here for you guys to go alone or to leverage kind of the capabilities to run some of these large studies. Pharma has been focused on post GLP-1 maintenance, and that's not just U.S. pharma, also in the EU and areas like Japan as well. So what's sort of your outlook on partnerships? And would you look to develop this on your own? Or would you want to be strategic to run it with a partner?

I think we always want to make good strategic decisions with any program that we're investing in. And I think near term, what we feel is, again, with a once to twice a year therapeutic study, I think there's value to be unlocked with the current data set, right? I mean, we've got the ability to show duration, safety and efficacy in the patient population. I think as we think long term and as you point out, and I think some of this to your earlier question about how do we think about the interplay between programs where AATD could be a program that has the potential pathway now to, let's say, accelerated approval in a commercial transition. How these assets start to interplay as we think over the next 12 months with data and value being able to think about those strategic decisions. We do have interesting opportunities after value becomes unlocked on this program.

There is, as you point out, continued strategic interest in this program. It's orthogonal. I think it's enticing when people think about combinations. And I think the fact that we don't have to add to the injection burden, we don't have to add to the safety and tolerability burden. So as people think about combinations, which we're seeing in the obesity space, it is critical that this program is not adding the burden both on the administration or on the safety tolerability profile and in fact, may actually improve that in combination if you can come down in lower doses of some of the other therapies. So we're seeing people kind of proactively come and have that conversation about how to think about combination.

We're having conversations with folks, particularly maintenance as well, where there are a number of companies that have been interested in obesity and their whole debate is always how to get in front of it. And having the ability to come in and say, "Well, you don't have to build the market, you just have to move the market," opens up a pretty attractive set of discussions. So I think INHBE does provide that. I think the focus is also not losing sight that accruing and accreting data is critical. And so the focus of the company is making sure that we can deliver the data sets that are going to deliver a differentiated profile against the current programs.

But I think equally important, and we're seeing this in a really nice way in our partnering discussions is, I think, a real recognition that with INHBE, people didn't think about Wave for years as an siRNA company, right? I mean just I think INHBE has opened up conversations about the access that we've had as an siRNA therapeutic company, where we've been years ahead of, I think, who people would view as a best-in-class siRNA company that's kind of defined the field. I think the ability that we accelerated a clinical program for a massive indication ahead in a way that's sustainably differentiated, I think, has really solidified our place as both an RNAi capability company platform or broadly in addition to what we can do with INHBE specifically.

Okay. Okay. So partnerships could, sort of reading between the lines, it could span the in-house pipeline and it could also be kind of a discovery platform type?

Exactly, particularly the work that we've already shown at Research Day last year on extrahepatic siRNA. And so I think we're already there on that with durability. And then continued share updates on bispecifics, the idea of like, can you dual target, and that's exciting as well.

Yes. Okay. Very good. I want to shift gears now and talk about alpha-1 for a little bit. Here with the rights wholly owned to the program, you guys can kind of run with it. You've shown some deepening data, acute phase response, both Z and M protein production, which is important. And I think we're expecting some additional data in the second half. So I guess how should investors sort of be thinking about this program and kind of the path to a pivotal study as you approach the regulator?

Yes. I mean I think the key for us is that the current data is supporting that. This is doing exactly what it's supposed to be doing. It's going to the right cell type. It's converting Z to M in a -- I think there's always times when you look at it and you're like, "Oh, wow, there isn't this kind of concern that some patients are better responders than others." And I think the clarity of really showing the data that every patient is seeing this really nice conversion, I think, is really important as we think about positioning this going forward. And then I think the opportunity that we've seen preclinically where we have longer follow-up and being able to really show what's happening, which, as we saw in the humans, not just this M to Z, but that reduction in Z is consequential, right?

We oftentimes are always in our minds thinking about alpha-1 antitrypsin in the lung side of the equation. Liver is really important. And I think when those data were also shared at EASL, we got a lot of interest from the hepatologists who are -- so as we think about kind of bringing together the alpha-1 treatment community on both the pulmonologists and the hepatologists who are thinking about reduction in liver burden and improvement in lung. I think both of those features become crucial.

And that's important because as you continue to treat, and this is the preclinical data we showed. And so you take that burden of that misfolded protein off the liver, you actually see liver regeneration. And the beauty of liver regeneration is now you've got fresh hepatocytes that you can continue to correct. And I think this is one of the underappreciated sides that repeat administration is actually a feature in this disease, right? Because as you begin to correct the liver and as the liver repairs itself and gets healthier, you've got the ability to continue to access new hepatocytes that are continuing to get fixed, continuing to be able to produce more protein. And over time, we saw that in the animal model where we often get the question of why do we think there's this kind of continued uptick as it gets later. And clearly, we went back and saw a reduction in that burden on those aggregates in the liver and that transition, you're seeing more protein get made. So I think that really longitudinal piece of continuing to treat these patients is important.

So what to expect? I think the key for us as we come through this kind of regulatory window, and we'll provide those updates when they come is really what we would imagine, and we wouldn't have any reason to believe otherwise, is that there's a path to potential accelerated approval based on biomarkers, that's how we foresee it. I think the opportunity, as you lay out ahead of us is how do we think about the design of that study. And I think we don't have to look to the design that others have because there's features we don't have to evaluate, right, that we don't have to concern ourselves with.

So can we do that whether it's with different number of patients or more importantly, a different time horizon with which we can look to evaluate that from what could be an interim endpoint for a biomarker-driven, but are there opportunities for us to run a larger, longer study over time so we don't have to run two studies, one confirmatory and one that's an accelerated registration that gets us to a potential pathway to full approval faster, but not forgoing that you can have that interim look to get to the market faster.

And I think that's where we want to be creative in our discussions and that will be part of an ongoing conversation. But I think that's what we look at as we think about the design and update to the next trial.

Okay. Okay. So powering for early success at an interim, but having like a longer tail on the follow-up for -- to check the box.

That's right. And so the discussions around, and we know the advocacy organizations have been having C-PATH discussions on CT densitometry. So as we think about kind of aligning on what those potential endpoints could be, I think there's really a unique opportunity to be thinking about that long term that ultimately could potentially contract the time to full approval.

Okay. Okay. And I think data from the 600 mg monthly multi-dose cohort is also expected here in the second half?

That's right.

I guess what should investors focus on from the update versus what we already know about the asset? And how would that cohort reading out kind of influence your study design either way?

Yes. I think our plan is we look at the kinetics of our current -- I mean, we're getting high potency than we could get -- if we think about over 20 micromolar protein, right, like shortly after the lowest single dose, right? Like 2 weeks after that dose a patient could get to 20 micromolar during an acute phase response. So what we do know is that editing happens, it's happening pretty quickly in terms of that response rate. It's potent. And as we look at PK, I don't know if there's much more on that potency side, we'll see. We'll have, as we said, the 400 and the 200 were similar in terms of total exposures because one was biweekly and one was monthly.

We'll be able to look at some of that PK, which will probably inform more for us how do we think about dosing intervals. So what do we think the infrequency of administration needs to be? But we'll learn more about the PK. And I think what we'll see in terms of the translation of more time once you have cells that are exposed, is the impact more on time to generating protein than necessarily more drug. But clearly, we're in the MZI phenotype. So we have what we believe we need to have for a biomarker discussion as we go into those discussions.

Okay. Okay. Great. Looking forward to that. And another update that you have in the second half will be putting 008 into the clinic. That's your PNPLA3 asset. And this is not one that I get a ton of questions on, but when I was making up our model, and we do have a build for this indication, it was actually kind of interesting to see what actually the prevalence of I148M variant is, and just how important this is and actually the genetic validation that's already there in the literature, like it's a pretty obvious application for your technology with a large end market.

So it feels like next year, this could actually become more part of the conversation as people look at Wave. So I guess, what are you sort of thinking about this program? How do you approach the initial clinical study here in the second half? And what is sort of the first in-human derisking that you'd be looking for from the study?

Yes. I think, one, to your point, I mean, it is -- we had liver patient come in recently and walk through her PNPLA3 journey. And so I think what's wonderful is it's an opportunity to grow. Like patients are finding out that they have the mutation. There were experimental therapeutics on silencing. And I think what we're seeing was particularly after EASL, a big shift from some of the clinicians that have been kind of the voices of the silencing community shifting and saying, well, actually, we need to shift our focus to editing.

And so I think it's a great opportunity for us to engage that community as we're getting this trial forward-looking ready. And with the patient population, as you point out, that can be diagnosed just based on genetics, and those tests are already readily available. So I think there's a lot that we can do in this case well before we get to the trial that actually gets things ready to go so that we can accelerate things pretty quickly.

We'll share more on the trial design typically when we start the study, but I think the opportunity ahead of us, given that we know the patients, there's physician engagement to get these sites up and running and they're excited about this potential opportunity is we'll have the ability to look at biomarkers in that study.

So to your point, being able to get early reads on that target engagement and profile well in advance of seeing as we think about a MASH study later, being able to look at more near-term endpoints that tell us that this is doing what it's supposed to be doing. And I think on the heels of alpha-1 and the pharmacology learnings, I think we're able to take this very quickly over to PNPLA3, where we know a 50% correction actually fixes the mutation and opportunity for these patients. So I think that's -- and we don't have this acute phase -- this is not an acute phase protein. So what's really nice is an enzyme, you correct it to 50%, you repair the disease.

So I think on some basis, it's a little bit more simplistic in its understanding of the disease biology. And I think as we design the study, we've designed it in a way that we can derisk it, we think, pretty quickly. So I think as we think about 2027, while it seems like it's on the horizon and farther out. As we think about the back half of this year, getting this into the clinic and getting ready so that 2027, I think, does become an unlocking period for this particular program.

Okay. And maybe last question, Paul, as we run up on time here. And I think this will kind of help wrap everything up as well. And it's just around the cash balance, right? And it takes money to make money, especially in biotech. So how are you thinking about capital allocation, your cash runway, which I think is into the second half of '28 and what does that sort of carry you through in terms of derisking for the pipeline?

Yes. I mean, as we said, we -- I mean, on our last earnings call, we have nearly $500 million in cash. So that capital takes us into Q3 of '28. But the most important thing is as you lay out, it takes us through these inflections, right? We're going to continue to drive 006 or alpha-1 into the clinic on that pathway. We're going to deliver important data across monotherapy in the high BMI with and without diabetes, that cash covers the combo study and data there that unlocks that potential value and maintenance. So we'll see that data set. In addition to all of that opens up, and I think it is important to your point on what are we going to see in the other biomarkers? I know there's a lot of questions that people always have about what about all the other cardiometabolic indications.

Those are all in that. And I think that's the wonderful thing about this IIa design that we did say, and as you mentioned, it's an investment, but we invested in those biomarkers so that we don't have to run separate studies to be able to look at liver fat reduction, hemoglobin A1c reductions, lipid profile shifts, insulin sensitivity. And so those will all be unlocked as part of the IIa study. And so I think as we think about those in addition to bringing PNPLA3 into the clinic and delivering that data set, that again differentiates that program.

I think we've made the right investments in a very focused and deliberate way, and we came into the year with a resolute focus that these would be the 3 programs that we would be allocating capital to. And I think we've stayed very disciplined on ensuring that we can deliver the data sets across each of those. So we're excited to deliver the data.

Yes. Great. We're looking forward to seeing the data. So thanks for the updates here and the great conversation. I think we'll have to end it there for the sake of time. But Paul, really appreciate you joining us here for our conference, and thanks, everyone, who dialed in for your interest.

Thank you for having me, and thank you, everybody, for dialing in.

Thank you. Take care.

Hello, and welcome to Wave Life Sciences Second Quarter 2026 Earnings Call. [Operator Instructions] Also, as a reminder, this conference is being recorded today.

I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator, and good morning to everyone on the call. Earlier this morning we issued a press release outlining our second quarter 2026 earnings update. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Erik Ingelsson, Chief Scientific Officer; Dr. Chris Wright, Chief Medical Officer; and Kyle Moran, Chief Financial Officer.

The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statements for any reason. I'd now like to turn the call over to Paul.

Thanks, Kate, and good morning to everyone joining us on today's call. At Wave, we are focused on harnessing the convergence of deep genetic insights with our proprietary chemistry to rapidly advance the pipeline of transformational RNA medicines. Over the past decade, we have built the most sophisticated and broadly enabled oligonucleotide platform in the industry. Multiple clinical data sets now demonstrate our ability to rapidly advance programs from novel genetic target to proof of mechanism in the clinic. Our proprietary chemistry is what differentiates our pipeline and distinguishes our molecules from others in the field.

In the first half of 2026, we delivered multiple positive data sets across our RNAi and RNA editing pipeline, led by WVE-007 for obesity and WVE-006 for AATD, positioning us to advance both programs to the next stage of development. We also continue to progress our second RNA editing candidate, WVE-008 for PNPLA3 liver disease and remain on track for a CTA filing later this year.

In March, we shared positive data from the single-dose Phase I portion of the INLIGHT trial of 007 in obesity. These data fortified our conviction in a best-in-class siRNA design with robust and extremely durable silencing demonstrated in the clinic, supporting potential dosing of once or twice a year. Also, even in this otherwise healthy population, a single dose of 007 led to substantial reductions in visceral fat and subcutaneous fat without muscle loss or other adverse events associated with incretin therapy.

We have 3 opportunities to explore in the next phase of development for this program. First, evaluate WVE-007 in a Phase IIa population with higher BMI and comorbidities typical of other obesity trials to demonstrate 007's potential in obesity as well as evaluate biomarkers to unlock other cardiometabolic indications, including MASH and type 2 diabetes. Second, evaluate combination with incretin, which has the potential to deepen weight loss and enhance metabolic benefits. Third, and perhaps one of the most exciting and unique opportunities, evaluate maintenance therapy, which represents an entirely new commercial frontier, enabling patients an off-ramp for their GLP-1s.

We often hear from patients about the fear of weight regain post cessation of incretins. Up to 70% of patients discontinued GLP-1 therapy within the first year of treatment. And for many, it's due to challenges that WVE-007 may address, including tolerability issues, treatment burden or anhedonia, loss of joy, among others. In this maintenance setting, 007 would have the potential to enable individuals and payers to realize the sustained health benefits of fat loss and improve body composition for the long term.

Over the past quarter, the FDA accepted the Phase IIa INLIGHT trial amendment and dosing is now underway. The Phase IIa is enrolling individuals living with obesity with BMIs between 35 and 50 and comorbidities with and without diabetes. These patients are expected to have higher total body fat and higher levels of visceral fat than the Phase I otherwise healthy patients. With this multi-dose clinical trial, we are evaluating our target patient population and have the potential to deliver further improvements in body composition, meaning weight loss driven off of fat loss without muscle loss as well as other improvements in cardiometabolic biomarkers, including liver fat and HbA1c.

We are also working expeditiously to initiate the additional Phase II trials of 007 in combination and maintenance settings this year. Collectively, our development program has the potential to redefine the treatment landscape in obesity. In RNA editing, we delivered data supporting 006 potential to offer a new standard of care for individuals living with AATD by treating both lung and liver manifestations of the disease and restoring the dynamic AAT protein response with convenient, infrequent subcutaneous dosing.

We are planning to engage the FDA as the agency has granted our request for a meeting to discuss a potential accelerated approval pathway for WVE-006. This meeting is expected at the end of summer and will help inform our registrational plans and path toward bringing a much needed new treatment option to the 200,000 individuals in the U.S. and Europe living with homozygous ZZ AATD. As a scalable, infrequent subcutaneously dosed oligonucleotide therapy, 006 would offer a potentially differentiated value proposition for both health care providers and payers. Current IV augmentation standard of care does not have any impact on liver manifestations of the disease, while investigational DNA editing in addition to any safety concerns would be associated with payer challenges for onetime costly therapy with uncertain durability and multiyear enrollee retention.

Building on our RNA editing success, we are advancing our second RNA editing candidate, WVE-008 toward the clinic this year for PNPLA3 liver disease. 008 aims to address an area of high unmet need with 9 million individuals living with homozygous PNPLA3 I148M liver disease. Human genetic data demonstrates these homozygous individuals have about a ninefold higher risk of dying from liver disease as compared with noncarriers. The landscape of therapies and development for this target has been narrowed by recent clinical demonstration that silencing approaches do not address the disease and may actually exacerbate it. An RNA editing approach is the only way to restore the functional protein and offers a potential for a novel infrequently dosed therapy with strong support from human genetics.

Beyond our lead RNAi and RNA editing programs, we continue to push the boundaries of innovation with our proprietary chemistry. We are planning to host our Annual Investor Day in the fall to shed more light on our latest platform advancements and work on our bifunctional modality. At the start of the year, we outlined our pipeline priorities, WVE-007, 006 and 008, demonstrating our core focus on RNAi and RNA editing as well as our intent to seek partnership opportunities for HD and DMD. Given the evolving regulatory and commercial landscape in DMD, we are exploring potential partnerships in advance of filing an NDA for N531. We continue to believe in N531 and 003's potential as best-in-class treatment options and look forward to continuing our partnering discussions.

With our continued success in the clinic and robust balance sheet, we are well positioned and well capitalized to bring our pipeline of potential first and best-in-class candidates to the next stage of development as we reimagine what's possible for patients.

Now I'd like to turn the call over to Erik, who will discuss 007 and how we are leveraging our proprietary chemistry and human genetic insights to advance the transformative approach for obesity and other cardiometabolic diseases. Erik?

Thank you, Paul. I'll start today by discussing our INHBE GalNAc-siRNA, WVE-007, and how our program aims to fill a large unmet need with a differentiated approach grounded in human genetics. Today, there are over 1 billion individuals living with obesity globally, including 175 million in the U.S. and Europe alone. These individuals face markedly higher risks of a range of diseases such as MASH, type 2 diabetes and other cardiometabolic diseases. Excess body fat, in particular, visceral fat is a key driver behind this elevated risk of disease.

While there are several therapeutic options available for weight loss and countless more in clinical development with similar modes of action to those already on the market, these therapies come with several limitations. Current standard of care therapies reduce body weight through both fat loss and muscle loss, and they carry high discontinuation rates due to the GI side effects, limiting potential for long-term health benefits. The loss of muscle also with current weight loss therapies is substantial with up to 40% of the total weight loss. This has significant health implications as skeletal muscle in addition to muscle strength and function also plays a key role in metabolism by sustaining basal metabolic rate, glucose disposal and insulin sensitivity. Muscle also prevents weight regain, which occurs mostly from fat in a majority of individuals at discontinuing incretin therapies. Remember, as much as up to 70% of individuals discontinuing incretin within the first year of treatment.

An ideal obesity therapy should instead selectively reduce excess fat, including harmful visceral fat, the fat surrounding one's organs that is most strongly linked to MASH, type 2 diabetes and other cardiometabolic diseases, while also lowering subcutaneous fat and liver steatosis and critically preserve skeletal muscle. It's well established that a 5% to 10% reduction in visceral fat mass is associated with positive health outcomes by reducing risk of multiple preventable metabolic diseases and preserving patient function and quality of life.

All these benefits can be delivered by 007's mechanism of action. Rather than acting on appetite, 007 silences INHBE and lower serum Activin E, a liver-derived peptide that signals adipocytes to put the brakes on lipolysis. Removing those brakes drives fat loss without calorie restriction without the muscle loss seen with incretin-based therapies. Our INHBE approach is strongly grounded in human genetics that carriers of heterozygous INHBE loss of function variant, nature's own knockdown experiment exhibit a healthier overall metabolic profile.

As Paul discussed earlier, 007's unique ability to durably suppress INHBE is driven by our proprietary chemistry and SpiNA sRNA design. Our next-generation SpiNA designs enhance interactions with AGO2, stabilize the loaded risk complex and improve liver exposure, all of which contribute to dramatically improved silence and potency and durability when compared with industry-leading sRNA designs, something we have shown repeatedly for INHBE and other targets.

While RNAi is a well-established therapeutic modality and there are extensive human genetics data supporting INHBE as a target, we believe our proprietary chemistry distinguishes us from others attending a similar approach.

Our interim Phase I INLIGHT data sets from lower BMI, otherwise healthy individuals confirm that this proprietary chemistry and the underlying human genetics are already translating in the clinic. We have observed consistent durable and dose-dependent serum Activin E reductions of up to 88%, which were sustained through at least 7.5 months, supporting 007's potential for once or twice yearly dosing. Notably, we observed the translation of target engagement to substantial improvements of cardiometabolic risk factors with preservation of lean mass and clinically meaningful reductions in total fat, visceral fat and weight circumference after just a single dose.

To provide context for our results of this early development stage, we calculated the visceral fat-to-muscle ratio or VMR, which is a measure of body composition that integrates harmful visceral fat and beneficial lean mass into a single index. Lower VMR is associated with a decreased risk of MASH, type 2 diabetes and cardiometabolic disorders.

With a single dose of 007 in our Phase I population, we already observed a 16.5% improvement in VMR, which is more than 12.2% achieved with weekly semaglutide in the Phase II BELIEVE study and approached the 18.8% observed with bimagrumab.

We believe VMR has the potential to serve as a novel composite biomarker that captures body composition improvements more holistically than BMI and that may better predict long-term clinical benefits. Together with the patient community and KOLs, we're working to engage with the regulators on the importance of improving body composition, including decreasing excess fat and preserving muscle consistent with their recent guidance.

What makes the comparison with the BELIEVE study particularly exciting is that our INLIGHT participants had substantially lower baseline BMI, lower visceral fat and lower total fat compared to Phase II and Phase III obesity studies, including the BELIEVE study. Clinical experience also highlights the importance of baseline adiposity. Early Phase I studies in leaner individuals typically show more modest fat reductions, while studies of individuals with higher baseline obesity demonstrate substantially larger decreases in total and visceral fat mass. Early follow-up from our 400-milligram cohort, which included a substantially higher proportion of individuals with low levels of body fat also confirmed that higher baseline visceral fat led to greater visceral fat reductions overall.

As Chris will speak to shortly, we've been working expeditiously to advance 007 into participants with higher BMI and comorbidities in the Phase IIa portion of INLIGHT, where existing science predicts a larger effect. Activin E binds to ALK7 on all adipocytes and visceral fat being more metabolically active and better perfused mobilizes first, exactly what we have observed in Phase I. With more excess fat to lose, we expect both visceral and total fat loss with 007 to be substantially more pronounced in higher BMI participants in the IIa study. For further detail on our 007 development plans and our RNA editing programs, I'd now like to turn the call over to Chris.

Thanks, Erik. As we recently announced, we're excited to have advanced 007 to a population well suited to its mechanism of action. We would expect even more pronounced effects on visceral and subcutaneous fat loss. Dosing is currently underway in the Phase IIa multi-dose portion of INLIGHT. This global placebo-controlled trial will enroll individuals with higher BMIs in the range of 35 to 50 and comorbidities across 2 dose levels, 240 milligrams and 400 milligrams and 2 study populations with and without type 2 diabetes for a total of 4 cohorts of 40 patients each.

Assessments in this multi-dose portion are like those in the single-dose portion with additional inclusion of body composition measured by MRI, liver fat content as measured by MRI-PDFF, HbA1c, lipid levels and other measures. The design and study population enables enhanced evaluation not only of improved body composition and weight loss, but also informs additional opportunities for 007 in MASH, type 2 diabetes and cardiometabolic diseases. Participants will be given 2 doses of 007, one at day 1 and at day 85 and followed for 12 months with the first key assessments occurring at day 85. We believe that 007's orthogonal mechanism, ability to drive fat reductions while preserving muscle and favorable safety profile are also aptly suited to combination and maintenance approaches.

Our preclinical data provides compelling support for both use cases. We've observed approximately twofold greater weight loss as an add-on to incretin versus incretin alone in obese mice and have demonstrated the ability to curtail weight regain following cessation of incretin. Planning is well underway for clinical studies addressing incretin combination and post- incretin maintenance and remain on track to initiate this year. We also expect to share additional data from the Phase I portion of INLIGHT this year, including data from our 600-milligram cohort, which will further inform the durability of 007.

Turning to our ongoing RestorAATion-2 clinical trial of WVE-006 for AATD. AATD is a uniquely compelling disease for RNA editing. It is a monogenic disorder caused by a single well-characterized genetic variant in the SERPINA1 gene. This leads to misfolded Z-AAT protein and an absence of healthy circulating M-AAT protein, which normally protects the lung during inflammation or infectious events. Without dynamic production of functional AAT protein, individuals with alpha-1 are at risk for lung damage and ultimately developing emphysema and bronchiectasis, which is characterized by chronic cough, recurrent infections and shortness of breath. In parallel, misfolded Z-AAT accumulates in hepatocytes and causes progressive liver injury and increased risk of liver disease.

Approximately 200,000 individuals in the U.S. and Europe live with homozygous PiZZ-AATD. Currently, the only approved treatment for AATD is weekly IV plasma-derived augmentation therapy, which carries several limitations. With a fixed scheduled dose, there's no restoration of dynamic response, leaving individuals with alpha-1 at risk if AAT protein levels fall too low during an infectious or inflammatory event. IV therapy is time-consuming and often requires inpatient visits and does nothing to lower Z-AAT to address the risk of liver disease.

Investigational therapies in development also come with several limitations. DNA-based editing approaches target both lung and liver, but they introduce permanent DNA modifications, carry bystander editing risk and rely on LNP delivery, which is associated with liver enzyme elevations. The risk of irreversible off-target effects is particularly notable as genomic DNA editing has been connected to editing in cancer-associated genes. Also in development are AAT siRNA approaches, which reduce Z-AAT. However, they do not restore M-AAT, potentially exacerbating lung disease through chronic AAT knockdown. 006 has the potential to be the first treatment for AATD that enables individuals with alpha-1 to produce protective AAT protein when needed most and address the root cause of the disease with a convenient and infrequent subcutaneously dosed therapy.

With 006, our goal is to recapitulate an MZ-like phenotype as it's well established that heterozygous individuals have low risk of both lung and liver disease. MZ individuals compared to ZZs have reduced levels of Z-AAT, which protects the liver from damage and are able to protect the lung with basal AAT levels above 11 micromolar, of which at least 50% is wild-type and AAT.

And most importantly, are able to mount a dynamic AAT response during an acute infection. That combination, Z-AAT reduction, protective basal levels with a meaningful proportion of wild-type M-AAT and a preserved acute phase response is the bar we set for 006. As we shared in May, this is exactly the profile we've consistently achieved. WVE-006 delivered a compelling therapeutic profile following only 3 months of treatment across both 200-milligram biweekly and 400-milligram monthly dosing.

Importantly, 006 RNA editing -- the 006 RNA editing approach produces only wild-type canonical MAAT and does not include bystander edited isoforms as seen with DNA editing. This specificity is crucial as bystander edits not only introduce functional activity risk, but may also render patients ineligible for future base editing or RNA editing therapies. Enrollment and dosing are now complete in the 200-milligram, 400-milligram and 600-milligram cohorts of RestorAATion-2, and we remain on track to share data from the 600-milligram monthly dosing cohort in the second half of this year, which will help inform an optimal dose regimen.

With the compelling profile of 006 we've observed to date, we're continuing to engage with the AATD community, key opinion leaders and advance our discussions with regulators. We're excited to announce today that the FDA granted our request for a meeting, which is planned for the end of this summer. During this, we intend to discuss a potential accelerated approval pathway for 006 in AATD. Feedback from this meeting will help inform our potential registration study design and our plans to efficiently advance 006 for ZZ individuals with alpha-1 who are in urgent need of new treatment options.

Building on our success with 006, we are advancing our second RNA editing clinical candidate, WVE-008 for homozygous PNPLA3 I148M liver disease. Similar to 006 and 007, our approach to 008 is deeply grounded in genetics. The PNPLA3 variant is a well-established driver of MASH and liver diseases more generally, yet there are no approved medicines that directly address this biology. There are an estimated 9 million homozygous PNPLA3, I148M carriers across the U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers.

Currently, the only treatment options are nonprecision medicines aimed at reducing liver steatosis and early fibrosis with limited efficacy for these IL-48M carriers. Silencing PNPLA3 can only partially address disease biology. It's likely to leave residual pathology since it knocks down all PNPLA3 protein without restoring healthy wild-type protein, which has important physiologic functions in the liver. As a result, silencing partially addresses steatosis, but inflammation and fibrosis remain unaddressed or worse. Recent clinical trials of PNPLA3 silencing support this notion as dose-dependent increases in liver enzymes were observed. By contrast, with 008, we aim to correct the I148M variant using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid mobilization, reversing steatosis and fibrosis and improving liver health.

In May, we shared preclinical data supporting our approach at EASL, the European Association for the Study of the Liver Congress. We demonstrated that our PNPLA3 AIMers delivered substantial editing of the I148M transcript, exceeding the 50% threshold expected to lower risk for liver disease, achieved concentrations in the liver expected to support substantial editing and decreased lipid droplet density more than siRNA. In our upcoming first-in-human study of 008, we plan to leverage previously genotype populations to efficiently identify homozygous I148M carriers and accelerate enrollment. We will evaluate target engagement with circulating biomarkers and assess early signs of efficacy using noninvasive imaging. We remain on track for a CTA submission in 2026. With that, I'll turn the call over to Kyle to provide an update on our financials. Kyle?

Thanks, Chris. Our revenue for the second quarter of 2026 was $2.3 million compared to $8.7 million in the prior year quarter and relates to our ongoing collaboration agreement with GSK. Research and development expenses were $51.3 million in the second quarter of 2026 as compared to $43.5 million in the same period in 2025. The increase particularly reflects -- primarily reflects continued investment in advancing our clinical programs, including preparation for the Phase IIa portion of INLIGHT and continued progress on our RNA editing pipeline.

Our G&A expenses were $24.8 million for the second quarter of 2026 as compared to $18 million for the prior year quarter. The increase primarily reflects costs associated with supporting our expanding pipeline and preparing for the next stages of development. As a result, our net loss was $69.4 million for the second quarter of 2026 as compared to a net loss of $50.5 million in the prior year quarter. We ended the second quarter with $490.6 million in cash, cash equivalents and marketable securities, which we expect to be sufficient to fund operations into Q3 2028. While we expect to receive milestone payments from GSK in the second half of 2026, it's important to note the potential future milestones and other payments to us under our collaboration are not included in our cash runway. I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. As we look to the second half of 2026, we believe we are well positioned to unlock value across our pipeline. With 007, our Phase IIa trial in individuals with obesity is underway, and we are rapidly working to advance incretin combination and post- incretin maintenance studies later this year. With 006, we are on track to meet with regulators on a pathway to accelerated approval. And we are also working to bring our second RNA editing candidate into clinical development for PNPLA3 liver disease in the second half of this year. Before turning to questions, I want to thank our team for the progress we've made and for their continued commitment to reimagining what's possible for patients. I'll now turn the call over to the operator. Operator?

[Operator Instructions] We'll take our first question from Yun Zhong with Wedbush.

So the question is on the 007 program for obesity. And I wanted to confirm that for the ongoing Phase IIa portion, the goal is to confirm that you are able to achieve 5% weight loss as compared to placebo at 12 months to support the advancement for this program into the indication of obesity. And then on combination therapy, I believe other programs have reported or will report data. And given the same mechanism of action, what would be your expectation on data from your own program? Do you think you will potentially be able to show any differentiation? Thank you.

I'll start with the second question, then we'll work backwards to the first question because I think the answer to the second question is, we do believe that I think it's valuable to see what others have been generating in that space, not just for the potential for increasing fat loss. And remember, these other data sets that people have seen in combination were in Phase IIa, high BMI, high visceral fat, high total fat patient populations. And that we're able to see, as you point out, substantial reductions in both fat, visceral fat in particular, and liver fat, we should remind that the liver fat was pretty substantial. I think given that in comparison, both on preclinical ED50, where we're about threefold more potent and in our preclinical data where we've seen increased potency, I think we would expect to see those data as affirming and that we would continue to expect to see with greater, more durable knockdown, potentially better data. So I think it's great to see that the field sees that in the combination setting.

I think we're also excited about maintenance because I think where we've generated data there and where the human genetics outlie, I think maintenance is an incredibly interesting opportunity for us in differentiation. Getting back to your first question, which I think is critical for people to hear, the Phase IIa is designed, as you point out, to be able to elicit that regulatory and cross that regulatory threshold of 5%.

I think as we've been pretty consistent with looking at other studies like BELIEVE trial of bimagrumab, where there was less fat loss in this healthy population than we saw out there. Actually, those that medicine had a greater lean mass gain than what we have. If we think about that equation and put our medicine into this population, we would expect to see no different, we should see weight loss. I mean, bimagrumab had greater than 5% weight loss in that treatment setting.

I think it's also important to point out that the Phase IIa design is more consequential than just looking and hitting that target. Remember, we built into the study intentionally by looking at diabetics and nondiabetics adding MRI-PDFF, the opportunity to expand this more broadly in cardiometabolic disease beyond just the obesity threshold in terms of looking at the treatment of MASH, where, again, we look at the comparators in this population, that ability to see substantial liver fat reduction is consequential in the field of MASH. And so we want to see that data. We'd want to see the data on hemoglobin A1c. And we also want to see the data on lipid. So I think in the totality of this is a cardiometabolic drug, including obesity. I think this study is designed and poised to unlock that opportunity.

We'll take our next question from Samantha Semenkow with Citi.

This is Ben on for Sam. I guess maybe following up on the first question. In the Phase IIa INLIGHT trial, what metrics are you focused on? And what magnitude of improvement do you need to see to support specific expansion into MASH or type 2 diabetes or the other cardiometabolic diseases?

Thank you. And I'll let Chris talk about the endpoints that we're looking at and then can affirm. Chris, can you talk about, the what we're evaluating.

Sure, sure. So we're looking at MRI-PDFF, so looking at liver fat in the Phase IIa study. And so I know that there are other compounds in the same mechanism in the same area that have shown substantial decreases in liver fat that really are highly competitive with what's out there in the MASH space. And then we'll also be looking at hemoglobin A1c. We are looking at both nondiabetics and diabetics, and that's a measure that can change over a relatively short time frame and can be utilized as a registration endpoint. So we're excited to see what types of benefits you would have there.

And then lastly, we'll be looking at a number of different lipid profiles to understand if there's a potential there as well for -- to move forward into a lipid registration type study since there's very tight connections between lipid levels and cardiovascular outcomes.

Just to add on, I mean, that in connection additionally with the other measurements. So being able to look at both depth and MRI, which will give us that opportunity to assess visceral fat volume and total fat. That's important because if we -- I know a lot of people want to always step back and kind of put these data sets of our Phase I up against other Phase II, III data sets and create tables.

And I appreciate the need for folks to do that. I think what is important is to remember in that low fat, low BMI, low visceral fat population that even when we do compare that against comparator studies where people said, oh, your visceral fat reductions look relatively similar. Our visceral fat compartment was a liter versus 5 liters, almost 5x as much visceral fat where we're seeing that reduction. So the ability that we've seen in this Phase I otherwise healthy population is highly encouraging. And so we do want to be able to -- for that comparator work, have MRI imaging to be able to set the comparators up where we have a high-resolution imaging system to be able to do that.

In addition, we'll look at other measurements like grip strength and others and be able to look at muscle retention because I do think when we do step back and think about this therapy in the context from a particular payer perspective and a patient perspective, yes, we want the cardiometabolic health benefits associated with that disease. But this muscle retention, as Erik pointed out, is critically important. I think we oftentimes think about muscle strength. We can be able to assess that, but muscle is also a metabolic organ. And so the ability to look at that ability to retain and sustain muscle in the setting of that fat reduction are endpoints we'll look at as well, like weight circumference and total body weight. So again, there's a number of endpoints that we'll be assessing as part of the study broadly that encompass both obesity and cardiometabolic indications in totality.

Our next question comes from Steve Seedhouse with Cantor Fitzgerald.

This is Nick on for Steve. We just wanted to clarify in the FDA meeting end of summer. Have you already received some feedback on an accelerated approval pathway and subsequently requested a meeting to discuss? Or do you not yet have any feedback yet on a proposed accelerated pathway and this meeting in the end of summer will constitute the first feedback from the FDA?

Thank you for the question. This would be the first meeting with the FDA. So when we submitted for the meeting, they granted that, and this is when it's scheduled. So we would expect after that meeting to provide an update after we have written feedback. So we do appreciate the clarifying question that this is the first request for meeting. And we're excited that instead of a written response, the FDA granted a face-to-face discussion on an accelerated approval pathway.

Our next question comes from Joe Schwartz with Leerink Partners.

I was wondering if you could give us some more insight into how enrollment is progressing in the higher BMI Phase IIa cohorts for 007 and what you're seeing in terms of screen failure rates and baseline characteristics? And when investors should expect the first meaningful data from these cohorts?

Yes. So we're currently making really great progress on enrollment. We're in the process of opening additional sites. And once we have everything up and running well, we'll be able to comment more on kind of the timing. But so far, it's been -- there's been really great interest in the study, and it's enrolling extremely well.

Yes. Just I mean, echo Chris' sentiment like momentum coming off the last data set high, both ex U.S. but also importantly on this study, U.S. So as we think about this study having actually the expansion for -- expand the number of sites and accelerate it. Also to Chris' point, remember, this study has 3-month time points and other assessments. We'll continue to look at the rate of enrollment to guide. While the potential is there for 2026, we have to see how we're progressing in the study ultimately to provide that guidance.

Our next question comes from Whitney Ijem with Canaccord Genuity.

This is Angela on for Whitney. So maybe just another one on 007. Looking at the human genetic data, INHBE loss of function does demonstrate the improved fat distribution as you've discussed, but not necessarily correlated with BMI as we understand it. So I guess like what gives you confidence that we'll be able to see BMI improvement with monotherapy in the Phase IIa?

Yes. I think the correlation, and it's interesting, and I'll move back and forth with Erik on this one. But I think what's interesting when we go back, there was a poster that we shared and actually, Alnylam has done the work on a large -- I think it was 300 patients is kind of a natural history cohort in nondiabetics. And actually showed Activin E, if we think about the actual ligand itself, actually a strong correlation with BMI, insulin sensitivity and truncal fat. So the data and correlation between the ligand and BMI is well correlated. I think the challenge in trying to -- and I think you bring up a very good point on the assessment and why BMI in itself is not a great indicator of body composition is you could be a body builder and have higher BMI.

So I think the context of really thinking about the addition of comorbidities where you get higher subcutaneous fat, higher visceral fat in addition to that becomes an important criteria and characteristic as we think about improvements in body composition. But I think what's encouraging is, again, even in the setting in the Phase I otherwise healthy patients, we did see substantial reductions in subcutaneous fat, visceral fat 3.3% reduction of waste circumference. And so I do think the ability to see those changes even in the lower BMI setting sets us up for encouraging changes to move to high BMI.

But again, with comorbidity, those patients, when you look at their characteristics and disposition are also high subcu fat, high visceral fat. And obviously, that's mechanistically what we've seen in reduction in the animal models. Erik, I don't know if there's anything or if you want to just add additional comments to that.

Yes. I think you covered most of it, but maybe just to add a few things. So the phenotype in the genetic studies were adjusted for BMI. So just to design when we set that up now 20 years ago, those type of phenotypes look at body composition. We wanted to adjust out like an overall body size. So just by design, it won't be associated with BMI. That's the first thing.

The second thing is that human genetic carriers, they have 50% reduction, and we think we need to get to kind of over 70% based on what we see in our animal data, where we definitely do see total weight loss. And then I guess the last thing is that we already see total body fat reduction with one single dose at the 240-milligram cohort. So we're pretty confident about that now as we're rolling into higher BMI with much more excess fat to use and multiple doses that we will get to the real weight loss as well, just based on the total fat loss that will accumulate in the Phase II.

Our next question comes from Salim Syed with Mizuho.

Paul, maybe just one from us on the DMD side. Can you just provide a little bit more color exactly what caused the shift here to, I guess, now evaluate potential partnerships in advance of filing the NDA for 531? And if you don't get the partnership, is there any scenario here where you still plan to file the NDA?

Thank you. I think we've been clear at the start of this year that we were going to seek a partnership for N531. And I think we remain consistent in discussions on partnering with N531. I think to the point of -- and the last part of the question of would we file absent the partner and advance file in advance of a partnership, I think we're going to continue to evaluate the space. I think what's evolved in this space, particularly with the update that the existing PMO 53 Golodirsen is going to file for potential full approval early in the year, and there'll be regulatory feedback around that, I think, in advance of recognizing that you need to fully enroll or have well underway a confirmatory study in advance wouldn't be prudent at this point in time until we understand that pathway and continue to have the discussions that are ongoing around potential partnerships and collaborations. So I think we've just evaluated all of that relative to where the current funds are invested and that was the decision we made.

Our next question comes from Alec Stranahan with Bank of America.

Maybe one for Paul. Curious if after regaining the rights to 006, whether the pace or the nature of the FDA interactions have changed within AATD. And I guess looking ahead to the meeting this summer, is your expectation kind of in line with endpoints and study size based on recent precedents or any sort of unique aspects of your data set that could warrant say, an even smaller study, for example?

No, thank you for the question. And I think the short answer to your first part of your question is yes. Obviously, by regaining the rights means that we can control the pace of regulatory interactions and with that, could obviously accelerate them. So that's obviously wonderful. I think to the second point, we wouldn't expect differences in terms of biomarker-driven approaches for potential pathway, but I think it's again incumbent upon us and which is why we want to have a face-to-face meeting to get alignment, not just on that biomarker-driven pathway to potential accelerated approval. But as you point out, just because others have requirements in terms of duration of study and numbers of patients, may not be equivalent for us. If we're doing a repeat administration, it may not have to run as long a period of time. And one of the other nature of the conversation that we're interested in is being able to open and explore what the full approval pathway looks like and how we might be able to more efficiently design a study that could have an interim analysis for a biomarker-driven accelerated approval with the potential to sustain those patients on for full approval. So we expedite the time and pathway to get there. So all of this will be the nature of the discussions with the agency, and we're excited to have that.

Our next question comes from Madison El-Saadi with B. Riley.

So what MRI-PDFF liver fat reduction would the team consider a meaningful cross read to MASH? Is this something we would benchmark against Rezdiffra, which I think was around a 30% relevant reduction? Or is there a population difference we should be aware of? And then maybe if you could just touch on your fall Investor Day, this is something that's really anchored by 006 regulatory update, obesity progress? Or is this really more about the broader earlier-stage platform?

Thanks, Madison. I think at a high level, I mean, look, as you point out, we've already seen from others in the field in a high BMI, high fat setting that they could achieve 44% reduction. So greater than existing therapies and products that are approved in MASH. So I think the potential is out there. I think the signals, I think we're going to look for similar signals and potentially the opportunity for more robust signals that we have a more potent drug, but also the ability to have a therapy to achieve that, which could potentially be, as a reminder, we have still the potential for once a year dosing.

So as we think about the opportunity in the field for once or twice a year dosing to be able to achieve that alongside beyond just the treatment of liver fat, all of the other potential cardiometabolic benefits that come with INHBE silencing, we think there's a tremendous opportunity in it as a differentiated product for the treatment of MASH, but we need to generate that data.

And I think it's important, as Chris outlined, that the current Phase IIa study beyond obesity is designed to elicit these signals so that we can look at the data, evaluate that and evaluate a potential path forward. As it relates to our fall research Day or Investor Day as it's evolved to, that's pretty consistent. I think you all have attended, we've done these now for nearly a decade. And so we try to do that consistent piece of understanding what's coming. I mean, if you think about the history over the last couple of years, it was INHBE introduction and then pass the clinic. Last year PNPLA3 passed the clinic. So I think there's an opportunity to learn about future programs. I think as we talked about, bispecific is an important deal that we're opening up and so the opportunity to continue to see more there.

We'll always guide if that's the best place for where data is coming or where updates are coming. As you also know, historically, if there's a meaningful update, we'll provide that absent having an intent to hold that for. So again, it's always been an opportunity for us to share whether that's data preclinically or clinically, we have that opportunity coming up. And we'll share more on what's going to be that schedule in the very near future.

Our next question comes from Catherine Novack with JonesTrading.

I just wanted to drill down on expectations for monotherapy body weight loss for 007 in patients with type 2 diabetes. We've seen combination data with incretins showing INHBE knockdown might help some size patients to therapy. But what do you exactly expect to see with monotherapy in type 2 diabetes relative to what you've seen in the healthy overweight patients?

Yes. No, thank you for the question because I think early on there were a lot of discussions that I think confounded this field into diabetic, nondiabetics and that, that would be different around thinking about combinations. And I think it's important as we think about how we bifurcated it. And again, as we shared on the prior question, the work that's encouraging is that there doesn't appear to be for INHBE in BMI and insulin sensitivity and truncal fat. That observational study that was run was in nondiabetics. So this correlation is not tied to a diabetic subcohort of population. It's the whole population that would be amenable to that.

So when we step back and look at it, we're not going to miss an opportunity. If there's a signal either in one versus the other, we'll have both. The real opportunity we have in bifurcating and studying the diabetic population is because we have hemoglobin A1c, we'll be able to look at what's seen in human genetics and the ability of INHBE or Activin E reduction to actually improve insulin sensitivity and improve hemoglobin A1c levels potentially. So we'll be able to see that signal.

But the study design, as we said, is designed to capture body weight reduction in a total -- in a patient population that has higher BMI, higher subcu fat, higher visceral fat, look for those cardiometabolic improvements more broadly. But again, not tied specifically to a subpopulation. And I think that was kind of a red herring like a year ago that I know spiraled into this being a diabetic subpopulation for effect. But actually, the data in human genetics and in the population studies that have been run don't demonstrate that to be an effect, but we'll have the study elicit that.

Our next question comes from Ben Burnett with Wells Fargo.

I wanted to ask about the 008 program as this is now moving towards the clinic, the PNPLA3 liver disease program. I think you mentioned that a 50% editing, you would expect to see sort of a positive clinical effect. How did you arrive at that threshold? And is that the threshold that you might expect in patients?

Erik, you want to speak to the genetics and the driver?

Yes. Thanks for the question. So this is anchored on the human genetics observations where it's known that individuals that are homozygous for this variant, they have a 9x higher risk of dying from liver disease during follow-up versus the heterozygous that are just mildly increased risk. And so the risk reduction, if you go from homozygous state to heterozygous state is more than 80%. So that's kind of what drives this 50%. That's the bar that we want to try to achieve. Getting higher than 50% is also better, but at 50%, we would expect to have the therapeutic effect. So that's kind of at the center of what. And yes.

And then just to follow on to that because I think as we spend more time on this program, I do think it's an exciting one. I think the confounding data too that's coming out on the siRNA silencing of that enzyme is equivalently important, right? So we're talking about now fixing it and repairing it and bringing it up to 50%. I think the human experiments that have shown that decreasing that continually actually leads to potential worsening in liver disease. And we just to think about this not just in the fat accumulation, but in the inflammatory aspect and fibrotic aspect, which is actually this particular enzyme works on both where the fat is located and on that anti-inflammatory antifibrotic effect. And so I think on both sides, the data continues on human genetics, why 50%, but also why silencing it is potentially detrimental.

Next question comes from Cha Cha Yang with Jefferies.

This is Cha Cha on for Roger. Mostly just a question on timing for your Phase II. Can you just let us know what we can expect for your data releases? Are you still going to be doing updates for 3 months, 6 months, 9 months, et cetera? And then just a sense on timing for that.

Thanks. As we've said previously, the study is initiating. Recruitment is going extraordinarily well, all things moving. And so once we have a cadence for when we can expect that we don't have to provide multiple updates on guidance, we'll have a good sense of patients and timing, and we'll provide that updated guidance as soon as we have a sense of the enrollment. Chris, is there anything you want to add to that?

No I think you covered it. We're just bringing on some new sites and just trying to accelerate it as much as possible, and there's a lot of interest. And so once that's kind of at a steady state, we'll be able to provide guidance.

Our next question comes from Danielle Brill with Truist Securities.

This is Alex on for Danielle. Question on AATD. I know it's a little bit early to talking about the potential commercial question. But as we think about the opportunity, any initial market research or anecdotes about physician or patient preference for a mechanism that is not a gene therapy, whether that's hesitation or awareness of off-target permanent editing potential of gene therapeutics. Just curious what your current temperature checks are from patients and clinicians.

Thank you, Alex. And yes, I mean, we're doing our market research and analysis, obviously, in preparation for feedback from the agency on potential pathways to accelerated approval. And they include not just as you outlined, patients and clinicians, but also payers. And I think as we're engaging around this, I think we're seeing a lot of support across all 3 constituencies. To your point, hesitancy on permanent genetic mutations with the potential for editing cancer-associated genes and what that risk factor looks like to be discharged over time, the risk that maybe you might not be able to get -- be amenable to other editing therapies if you were to come on, not to mention, as you point out, the potential safety risk. So as we're seeing that, we're seeing a lot of support for RNA medicines and not dissimilar to other therapeutic spaces like TTR, where people are seeing if you can get through a redosable durable. So pushing potential monthly dosing or less frequent, that ability to see that play out with correction, we're seeing a lot of support for that.

And as we think about the payer conversations, I think the idea that you need like over a decade of safe durability to breakeven on an RNA medicine, we're seeing a lot of support on that side. So again, as we're testing the constituencies, we're continuing to see a lot of support for RNA medicine approach to ATP.

Our next question comes from Ananda Ghosh with H.C. Wainwright & Co.

Continuing on the diabetic question, historically, the impact of incretins on the body weight in T2D patients has been always lower compared to pure obese patients. So given the differentiated MOA of incretins, what are your thoughts? Like what do you think the 007 might have an impact on in the diabetic patients differentially? And then I have 2 follow-up questions.

Yes, Erik, I'll let you start, and then I'll join.

Yes. So I think that's a great question. It's actually kind of at the center of why we think it's important to look at diabetics and nondiabetics separately because we know that weight loss mechanisms are different mechanistically. For a mechanism like this that is directly driving weight loss through fat loss, we do think it has a lot of potential for diabetics. But to Paul's point, we also know based on both human genetics and observational studies that this effect is also important in nondiabetics. So that's why we're going to study both in the Phase IIa trial.

I don't have anything to add to that.

Our next question comes from Cassie Yuan with RBC Capital Markets.

Maybe Chris, on your PNPLA3 program, can you just elaborate how RNA editing of I148M variant is expected to be superior to siRNA silencing. But meanwhile, Madrigal recently in-licensed an siRNA. You did mention preclinical data showing [ Amer ] reduced, is it accumulation more effectively than siRNA and given evidence that PNPLA3 silencing may also lead residual pathology in inflammation and fibrosis. So just curious how you would articulate the potential clinical differentiation of 008 to patients and potential partners and how you're thinking about patient enrichment and selection for first-in-human study.

No, thank you. And one, I think there's a lot to unpack there. I think on one hand, as you point out, it is a commonly detected mutation. So when we think about the ability for PNPLA3, it's in consumer genetic tests. So since we had a patient here even just a week ago kind of discussing the disease from one of the liver foundations and she found out to have PNPLA3 liver disease through one of her consumer genetic tests like that and her kind of starting to diagnosis, she knew she had liver disease, was getting evaluated.

And I think the drive to actually drive genetic testing there is increasing. So I think that's encouraging. And there's work that we're doing, obviously, in preparation for the clinic about enriching and identifying these patients in advance. So again, work that can be done that Chris and the development team are doing to enhance the enrollment and speed with which we can generate human data sets.

I think to your point, the growing body of evidence, both in preclinical and clinical data on silencing versus editing is continuing to accumulate. We shared at the last -- our Investor Day last year where we provided some of the preclinical data, yes, we see that there's a shift in terms of silencing where we can do SI, so we can knock it out if we wanted to. Editing was much more efficient in terms of driving not just that reduction, but also improvements in other inflammatory biomarkers. I think more we can end up sharing there as we think ahead.

I think what's encouraging as well as we think about this distinction is recent presentations at EASL on siRNA therapies that did show dose-dependent worsening in the liver disease. So I think the clinical data is continuing to accumulate on what happens if you knock out that important enzyme and the data is continuing to obviously amass preclinically and with us going into the clinic in June 1, we'll demonstrate human data, the ability to show that by restoring the function of this enzyme as the human genetics suggest we should be able to make efficiently not just the treatment for what happens with fat, but the reason that enzyme may be at the center of so many different liver diseases beyond just MASH is a function of its impact on this reactive oxygen system, kind of this pro-inflammatory system. And it's been seen time and time again that if you can increase this, you can improve the fibrotic side.

I don't know, Erik, if there's anything to add on the preclinical data and Chris, on the Erik, if there's anything to add on the preclinical.

No, I think you were very comprehensive. The bottom line is that you want to restore it to a function. It has an important wild-type function. So if you knock it out, you can exacerbate some aspects of the disease, and that's really where we -- by using an RNA editing approach, we're restoring it back to normal.

Our last question comes from Mara Goldstein with Clear Street.

I know it's late in the call, but I'm just curious if you can provide some color as you're thinking about sort of the cardiometabolic signals that you're looking for, for 007 in the trial, sort of how do you weigh that and -- or rank order what you'd be looking at and what the threshold might be?

Thank you. I'll step back from rank ordering. I think they're all important as we think about cardiometabolic diseases. They're all different, right? As we have elucidated like the ability, and I think this all stems as Erik shared during the remarks earlier, visceral fat drives -- we think about what's so important ultimately in this disease process is visceral fat as you go 5% to 10%, that difference, that increase in visceral fat, just 5% to 10% drives a whole bunch of different cardiometabolic output.

So this ability to see that substantial reduction in the output of that becomes important as we think improvement, as we said, we've already seen 14% reduction, 15% reduction in visceral fat. So we're consequentially changing that now in an otherwise healthy population. And again, being able to evaluate that in the IIa population is interesting for us, right, because it's going to allow us to look at each of these markers, what happens with hemoglobin A1c as a function, not just in stratifying patients, diabetic not, but really the impact on hemoglobin A1c, which by itself is a marker for registration in type 2 diabetes. What's happening with lipid levels and improvement in lipid levels as seen in the human genetics, but also potentially for insulin sensitivity as we think about HDL triglyceride ratios.

And then the ability to look at that in its compendium of obviously, fat loss and weight loss and obesity in more general. So I think -- and MASH with liver fat. So I think we're looking at all of these independently and in their global association with each other in the context of obesity and cardiometabolic disease. I don't know, Chris or Erik, if there's anything to add to that.

No, I would just say we'll look at the data and see where we're best differentiated and where we can move forward the fastest. And you can think about MASH, for example, where you can get an accelerated approval, that could be attractive if we're seeing strong effects on lipids there in the liver. So that's sort of how we're looking at it, just following the data and taking the best things forward into the most accelerated path we can to get this approved, yes.

Erik, anything to add?

No, I think you covered it. I think they're all -- I guess the only thing I would add is that it all comes back to the mechanism as in driving fat loss and decreasing visceral fat and that mechanism is really linked to all of these outcomes. So there are a lot of opportunities here.

Thank you. There are no further questions at this time. I'll now hand the call back over to Paul Bolno for closing remarks.

Thank you for joining our call this morning. We appreciate your continued support. Have a great day.

This concludes today's call. Thank you, everyone, for joining. You may now disconnect.

Welcome.

Thanks, Rob.

Welcome to the inaugural session of the 47th Annual Goldman Sachs Healthcare Research Conference. Pleased to be joined by Wave Life Sciences, and Paul.

So first, Paul, for those in audience and listening, who may be less familiar with Wave today specifically, what do you think is the most important thing for investors to understand about the company and where it stands today?

Well, thanks for having us. And it's a great time to be connecting as we kind of hit the midpoint of 2026. We're kind of at, what I would call, a strategic inflection point on operating against what we set out as a strategy as we began 2026, which is: one, we see our platform chemistry translating into potentially meaningful therapies, starting with WVE-007 for Inhibin E coming off of our initial clinical data seeing again in the siRNA space, our chemistry uniquely translate to a meaningful improvement in body composition in a Phase I healthy volunteer study and excited for the updates as we transition to the Phase IIa high BMI study, which should be starting shortly, so we'll spend more time, I'm sure, talking about that, but that's obviously a very critical component in our evolution.

Second is the growth of our RNA editing platform, which is exciting, led by alpha-1 antitrypsin deficiency and the work we have there. And this summer being a key inflection as we engage with regulators and a potential pathway to accelerated approval, being able to differentiate that program in the RNA editing field from other therapies for alpha-1 antitrypsin deficiency and critically unlocking the platform capability for RNA editing, where we'll have WVE-008, the first RNA editing program for PNPLA3, so a disease of 9 million patients, that will come into the clinic as we end this year.

So again, lots of progress across siRNA, RNA editing. And we're excited to continue to do the work on the platform, and we're well resourced to execute on those clinical trials.

That's great. We'll get into individual programs here in a sec, but maybe before doing so, investors often debate the value of a platform in breadth versus depth. You obviously have a few different RNA modalities. How do you think about the benefit of having RNAi or any editing, splicing and emerging by functional modalities all under one roof?

Yes. I think when we step back and say -- I think there's lots of different ways to define platform companies, right? You can become a platform company off of biology. When you build a platform company off of chemistry, the main value there is to really demonstrate that, that capability is translatable. And so when we think about building an RNA medicines company, the goal and the premise has always been how do you unlock the power of emerging clinical genetics, right? How can you find? Because I do think, for our field and our industry, the biggest challenge is how do you find high-value, high-impact targets to make medicines for patients. The value of a chemistry platform is how do you unlock those genetics so that when those interesting, compelling, high-impact, high-value targets become accessible that you can be poised to translate those innovations. So case in point, Inhibin E going after a validated genetic target in the UK Biobank for obesity and cardiometabolic disease is intriguing on the RNAi side and we'll talk about our differentiation on chemistry where we're seeing that not just translate preclinically, but now in the clinic given our unique and proprietary chemistry.

Equally important, as we think about alpha-1 antitrypsin deficiency, PNPLA3-driven mutations for disease and liver, these are all opportunities not on the silencing side, but where actually -- and we'll talk about PNPLA3 specifically given some of the presentations at EASL that are reaffirming that siRNA is not the approach to take down the mutation, but correction is to be poised to have a platform that can correct an enzyme, lets us jump on that opportunity for those 9 million patients and have a potential therapy.

So I think the key on the platform is really how do you drive differentiation. I'll step back and say, when we talk about Inhibin E, I think the uniqueness of, again, the work that the team has done in that is special, and we'll see that later R&D Day this year as we talk more about, to your point, this bifunctional capability, which is how do we interplay these modalities of either dual silencing targets or silencing and upregulation editing in one molecule.

That's great. Maybe now turning to 007, before getting into study design data, can you talk more broadly about biological rationale of Inhibin E as a target in cardiometabolic, and maybe also what you've learned about it over the course of the last little bit?

Yes. I mean, one of the very important points as we said is, we like targets where there is human clinical validation for those entrants so that when we're working on a program that there is clinical support that if you interrogate that target with a medicine that you have a higher probability of that medicine translating in the clinic for patients. Inhibin E is a wonderful example of that. It's kind of like the PCSK9 for obesity in the sense that the UK Biobank data set has shown that there is very good translation of this target. People walking around with a 50% loss of function of this target have low abdominal visceral obesity. They have more lean mass. They have lower lipid levels, so lower triglyceride levels, higher HDL levels. And most importantly, the human outcome study has been run. They have a low risk of cardiovascular disease and a lower risk of type 2 diabetes.

So if we think about the totality of the evidence that says this is an important medicine for cardiometabolic disease, including obesity, the clinical genetics tell us that. I think stepping back and saying the translation from human clinical genetics to a medicine often entails the pathway of not having to be born with it, which is a great maintenance study, but ultimately, how do you create a therapeutic. And so this was our opportunity to really start to say, can we answer a fundamental question on our platform capability, opening up an opportunity unique to Wave, meaning can we take advantage of a target that the body has just a little bit of more biology of the target is a target that's the ligand is produced in the liver and hepatocytes and uniquely targets a receptor on adipocytes, ALK-7, and we can talk more because there's always a lot of conversations around ALK-7, but the unique mechanism is actually the ligand communicating with that receptor. So the target is the ligand.

What it does is it actually kind of puts the brake on lipolysis. So evolution was always about fat storage when calories were not plenty, and so therefore, the desire was how do you build and store fat. When you take the breakoff lipolysis, you see that breaking down, oftentimes starting with highly vascularized fat like visceral fat and then proceeding into the subcutaneous compartment, and we'll talk more about the ability of this in both subcutaneous and visceral fat.

So the key when you're developing a therapy is always will this translate? Can we uniquely translate this? And so far, we've been unique in the sense that our chemistry has translated to the only single dose reduction in body weight in the I/O animal model so we could give a single injection of drug. We could see weight loss comparable to the GLP-1s all driven off of fat, so preserving lean mass. And I think that's important as we talk, not just about the importance of muscle as a stabilizer, a functional component of muscle, but muscle is an insulin sensitizing organ. So as we talk about cardiometabolics, this idea of fat reduction, lean mass preservation then ultimately translate into healthier outcomes.

So we demonstrated that in the mouse model monotherapy can show monotherapy reduction in fat leading to weight loss. We did a combination study, and we know with the evolution, and we'll talk more about that clinically, but the idea that you could get even more weight loss when you combine these with GLP-1s with that weight loss coming off of just fat. So it gives you the opportunity to think about how do you preserve muscle sparing in the context of incretins.

And the last, which we think is a very compelling opportunity that we've demonstrated preclinically is maintenance. And as I said, that's also the compelling opportunity that's been seen in the UK Biobank clinical genetics, which is that if you knock the target out prior to cessation of incretins, you prevent rebound weight gain even in the setting of higher caloric consumption. So this idea that if you want to transition from incretins onto a muscle preservation, but not lose or drive that weight regain, and remember, that weight regain that patients experience where the body weight comes back usually 2 or above where they started is driven off of fat. So these patients, from a health standpoint, actually accrete more fat after they stop than they had at the beginning of the study.

So the ability to think about this is a therapy where you can give a once to twice a year injection that sustains patients. And I think when we think about these 3 use cases, it's a prime opportunity that we've been able to see that chemistry platform that you were referring to uniquely translate to Wave in seeing that. And we've seen these data both in the preclinical studies now translate to humans, where a single dose in a Phase I healthy volunteer study we could recapitulate that biology with a substantial reduction of visceral fat, about 15%, reduction in subcutaneous fat, about over 5.4%, and most importantly, a reduction in waist circumference of 3.3%, which is tightening of belt loop. When we think about that in the healthy setting, which is a very different setting than people historically look at obesity studies, that data was, in our minds, very compelling in the translation of moving into obesity studies that look like other larger obesity studies.

Makes sense. Maybe on -- you mentioned a little bit about this, but the unique chemistry platform that you have, this is a target that many others, including some of the largest names in RNA, have tried and frankly, haven't even been able to get a molecule into the clinic let alone continue through clinical development. Maybe just briefly in terms of what allowed you to bring something potentially very compelling to the clinic.

Absolutely. I mean getting back to that concept of platform chemistry, and it's -- we appreciate the question because oftentimes, as portfolios mature, we spend more time saying, what's unique about the clinical data and driving the clinical opportunities in it, forgetting that probably one of the most fundamental criteria of Wave is an oligonucleotide chemistry company. And I would say Inhibin E is giving us the opportunity to truly say that we have the potential of best-in-class in siRNA in this category is Wave's unique chemistry, meaning with the phosphoryl guanidine and our stereochemistry and control, the ability that -- and we published this paper probably about 3.5 years ago in NAR, we were able to compare it to, as you pointed out, some of the best oligonucleotides that are translating in the clinic and do head-to-head comparisons where we could see improvements in potency and improvements in durability.

I think at the time where we were generating that work in the target space, a lot of the targets we're kind of exploring of what more would you gain? You could gain more in terms of decreasing dosing frequency. And those are all -- I'm not discounting that, those are important and interesting. But it was really when we saw Inhibin E where we said, here's a target that is under pressure, to your point, is eluding others because it needs that suppression. This would be a wonderful target actually to translate those chemistry innovations into strong differentiation in the clinic. And so this is a target that needs to be suppressed.

And so again, to your point, the ability to suppress that target didn't just translate into preclinical animal obese models, but translated well even in the healthy volunteer studies and recapitulating that fat reduction, lean muscle sparing and durability to the point where, again, in this space, it's competitive now where we can have a once to twice a year subcutaneous injection that can drive really meaningful improvements in body composition.

Yes. Makes sense. Maybe on the data you've generated to date, obviously, reduction in lean mass, stabilization, there's a lot of focus on overall body weight. Like how do you interpret the data that you've had today, and maybe a little bit more detail than you've given as well as what do you think it means moving forward for the molecule?

Yes, I think when we step back and really say, what does it mean? What does it mean in obesity treatment? I think we are seeing an evolution. We actually just came to this conference from our time at ADA. And I think in the meetings there and in the settings before it, I think there's a real fundamental shift in how we talk about therapies for obesity. So we have had this compelling discussion about what does healthy weight loss mean? It means improving body composition. It means sustaining lean muscle mass, which does weigh more than fat, and shifting the narrative to pounds on a scale to what does improvement in body composition look like overall in terms of improving human health.

And so when we think about that, and I'm often reminded -- many people have heard this, but I just think it's the right way to visualize this. One of the key opinion leaders in this space, I'll give her credit, Angela Fitch, she has a very great analogy in her clinics where patients who come in, they may weigh 250 or more pounds and they come in and they say, I want to lose weight. I want to be 170 pounds. She is like, why? What is it about? And I think it's because, for a long time, that's the only way we had to measure what's happening to our bodies, right? You stand on a scale and you watch the weights on pounds go down. And remember, those pounds are often driven by lean muscle mass loss. And we saw that when we analyzed the BELIEVE data on the incretin comparator arm, in 3 months, 50% of that reduction was lean mass loss. So that's the tool people have to see that.

And so when these patients come in and say, I want to be 170 and she'll hold up a picture of Michael Phelps and say, if I told you, you're going to be over 200 pounds, but this is what you were going to look like, would you want that? They go yes. And I think it really changes the narrative visually of what people are really looking for and how important that lean muscle mass preservation is ultimately to human health.

So we moved the conversation past pounds on a scale driven off of weight loss and really reframed the discussion to what does healthy weight loss look like? It is substantial. It means you need to lose substantial amounts of fat to drive that body composition. And I think -- hands down, I think the tools for that are getting better and more distributed. I mean we're seeing scales now that people have in their homes that cost as much as body weight scales that actually enable people to measure their body composition. And it will be really interesting in the evolution of some of the incretins as people watch on that scale and see not the weight go down, but the lean mass changes that correspond to that, I think it will allow us to kind of reframe and refocus the narrative on what's important, which is fat reduction.

So to your point, coming into that framing, recognizing that the clinical trial that we delivered first was healthy volunteers. So I think it is important we oftentimes use BMI, and coming out of ADA, I can say BMI is uniformly viewed as not an ideal way to be talking about this space because you can be a bodybuilder with a high BMI or you could be obese with -- an unhealthy with high BMI. And so it is important to think about not just high BMI, but our study excluded patients with comorbidities. And it's the comorbidities that drive increase in fat, visceral fat and subcu fat. And that is what you ultimately want to see.

So in the Phase I, even in these healthy patients, we saw substantial reductions in visceral fat, 15%, just to put that in context because I think we always talk about numbers. An increase in 5% to 7% in visceral fat drives a number of diseases. So we can talk about cardiovascular disease risk, risk of diabetes. And as you kind of cross up to that like near 10%, you're talking about MASH. And so if we think about that change and seeing a 15% reduction in visceral fat in a healthy population, that is a really consequential shift for human health.

We also saw, and I think it's important when we get beyond what drives health outcomes is the reduction in subcutaneous fat and recognizing that, that's what drives change in body weight. That's the larger compartment. We saw a shift in declining subcutaneous fat by 5.4%, and again, in these patients who did not have a substantial amount of fat to lose. And that translated -- I always say, what does that translate to as we think about what's meaningful to patients is that 3.3% reduction in waist circumference, meaning this was translating.

Additionally and very important in the obesity therapeutics landscape is, this came with a safety profile that was extraordinarily clean. So for these medicines, the only AEs were mild irritations at the injection site in some patients without dose dependency. So again, the important piece is safe and driving these meaningful changes in body composition. And again, reinforcing for us, I mean, the lowest dose, 7.5 months after that injection, we were still suppressing Activin E. So the notion that you've got durability and then frequency, safety, but most importantly, those improvement in body composition in this Phase I population, I think is incredible as we kind of make that transition to the Phase II high BMI patients with comorbidities, with and without diabetes, where the setting is more fat and will look more similar to other trials that have been run in this space, and I think we're poised there to see meaningful differentiation.

Yes. Maybe along those lines, and as you're going into that patient population, any expectations for what you're going to further learn about the program in terms of dose optimization, et cetera., as well as kind of key differences in overall study design versus your Phase I?

Yes. So I mean first is very different in terms of Phase I. So this shift is a shift in the population. So this will be high BMI patients with comorbidities with and without diabetes. And as we model what that delivers and with all the waist circumference parameters that other studies have, that sets up the population where we would expect substantially increased levels of visceral fat and substantially a level -- increased levels of subcutaneous fat. And we've put it in baseline characteristics with other obesity trials. This study does have MRI and MRI-PDFF, and we'll talk shortly about liver fat reduction. But by having MRI in the study does give us a way to ascertain a baseline, whether or not we're meeting the body composition similarity. So again, the study will be poised to deliver that change.

I think with and without diabetes is equally important. So what do we want to see in this study, we'll have 2 different doses that we'll be looking at, the 240 and the 400. So that will let us have the ability to discern how do we optimize that infrequency of administration in those settings. We'll be able to explore that on the PK side. But on the PD side, one of the opportunities we have, so if we think about endpoints in this study, beyond just obesity and weight loss. So we're obviously going to measure body weight reduction, body composition by DEXA and MRI, but we're going to have other endpoints in this study with which we can evaluate other opportunities given that obesity is a metabolic disease, but what are the other cardiometabolic diseases that are approached with this mechanism.

So one, the reduction in fat, which we've seen from others who have developed their assets. We still think we have a threefold improvement in ED50, but it was highly encouraging to see in this setting post a number of about a 44% reduction in liver fat. I mean, that's substantial compared to other MASH drugs. So the ability to have that opportunity in the study to discern our own data set and what we can see is compelling as an end point. Two, hemoglobin A1c. So again, looking at the diabetic patients, let us evaluate what the impact would be on other biomarkers. Hemoglobin A1c is an endpoint that doesn't require an outcome study in diabetes. So we'll have that. And we'll also be able to look at lipid levels, which, again, the human genetics shows those improvements. So we'll be able to discern those endpoints in addition to things like insulin sensitivity looking at HDL triglyceride ratio.

So I think in totality, this monotherapy study is really poised to unlock the potential for Inhibin E in obesity and other cardiometabolic diseases as a single agent, realizing that there's 30 million patients in the U.S. who are at risk of lean mass loss that need an approach to body composition improvement and fat loss and is uniquely poised to do that.

I think the settings that will start beyond this, so there's 3 trials that will start on the heels of that, so this study will initiate this quarter, next study will be the combination study. So this will give us the opportunity to really look at directly with an incretin, and it's safe to say, given that others have looked at the combination with tirzepatide that, that would be a fair way to view this combination study. And the ability there is really not to drive weight maxing at the risk of lean mass, but ultimately, how do these 2 features intertwine. So the ability potentially is something like the low clinical dose of tirzepatide to see that you can maximize fat loss without having to push the incretin from a tolerability perspective and a lean mass loss perspective. And if we think about the idea that 70% of patients are intolerable to their incretin beyond a year, how do we think about these as keeping patients on meaningful medicines and maximizing body composition improvements.

The third opportunity, which we're excited about is maintenance, and that's recapitulating exactly what we did in the animal model and showing that we could dose Inhibin E prior to cessation of the incretin and be able to have a way to sustain that weight reduction that patients have achieved, but do so without continuing the incretin to suppress lean mass, again, tolerability and have, I think, a unique way to drive adherence, which is we speak to. Payers is something that everybody is focused on is the investment to get to a certain body composition, and what's the risk to staying there? We know patients, they're investing financially and trying to stay there. And so the ability to work with patients on maintenance to be able to have an off-ramp to incretins is pretty exciting.

Great. Maybe just briefly, you talked liver fat reduction, obviously, looking at in T2D, but potential outside of just obesity [indiscernible] of broader cardiometabolic opportunities?

[indiscernible] broader metabolic opportunities, in particular, as you mentioned, diabetes, MASH, what was formerly called PCOS and going through evolution, there's lots of ways to think about metabolically driven diseases that are driven off of importantly, visceral fat. And so the opportunity where we have a potent reduction of visceral fat drives a whole host of cardiometabolic inflammatory diseases. And so again, a unique approach where we're doing that, where the biomarkers are part of the study. And I can't emphasize that enough that when one runs studies in obesity, people kind of have in their mind the classic body composition, DEXA and weight. And I think the ability that we haven't missed the opportunity as part of the study to embed these other biomarkers and tools of measurement are going to give us that opportunity to unlock that potential as part of the study that's initiating. So that will continue to generate data over time in a number of indications that we can unlock.

Great. Turning to 006, several different approaches for AATD. I guess, maybe briefly before getting the data and what you've seen to date, why do you think RNA editing is a compelling approach here? And maybe also briefly on your RNA editing platform?

Yes. So I mean, RNA editing in general, we think, is an interesting platform. It's compelling in that we don't have to work at the DNA level with permanent mutation. So the ability to have a way to either correct a transcript or upregulate a transcript opens up the potential to explore a number of therapeutic opportunities. AATD is the unique one in the context of correction, meaning you've got a single mutation on the transcript that if you can correct you can restore the production meaningfully of healthy wild-type protein. Focusing on the ZZ patients, which is where we do, these patients make no N proteins. So it gives you [indiscernible] to evaluate how your medicine works, whether it's [indiscernible] one. And first and foremost is reducing the Z protein, right? These patients may have 2 copies of Z protein, and that's what's produced. That protein gets stuck in the liver, it's also secreted, but it's the toxic folding of that protein, which damages the liver, and therefore, by reducing that toxic protein, you ultimately enable liver repair.

And I say this because as we talk about editing versus other approaches, protein replacement therapy, we have to remember that alpha-1 antitrypsin patients are both lung and liver patients. So these patients have both higher risk of liver disease as well as lung disease. When we think about lung disease, and we'll talk about this shortly, it is a chronic disease of acute exacerbation. So what happens are, we all have kind of steady-state levels because it's an acute reactive protein that sit in the background. What really happens when we're exposed to an irritant is that UC or pneumonia, cold, kidney stone, that the body increases IL-6 and CRP, that's the acute inflammatory response. That increases the transcripts that produce the protein, the protein then gets produced to protect damage from occurring. And it's that chronic damage that happens over those acute exacerbations that injures tissues.

So the approach that editing has actually is to recapitulate changing these patients. So if we think about patients on the spectrum of ZZ to SC to MZ to healthy MM, as these patients have less Z and the ability to produce more M, they are protected in their various tissues. So that's exactly what we saw preclinically, and that's exactly what we saw in the clinic is that as we treated with 006, we saw, and it was actually really beautiful when you think about the curves that all patients were responding and you could look at an individualized patient level and actually see that their Z protein substantially reduced and they end up producing more M protein. And we expect that, as the liver continues to get better, those can continue to increase to higher levels.

What's nice is we can recapitulate getting to that MZ like phenotype, meaning reduction of Z, production of M, and importantly, having that acute phase response. So for example, we did see that when patients had an acute phase response, they could produce total protein levels greater than 20 micromolar. And so this idea that you could generate that protection when you need it is really the fundamental aspect of what editing is supposed to do, do that safely in a way that you could redose it. And as we know from clinicians and patients, reverse it, that if you stop the medicine, you haven't permanently altered the DNA of those patients.

I think it's important because sitting on the other side, as you asked the question on replacement, there is the replacement concept, which is really focused on just the lung. So that's infusing a protein in the background setting [ still ] of a ZZ patients to try to be there to protect that tissue. The challenge there is, these patients, when they have those events, it's consumptive proteins. So that protein goes away. So I guess the best way to think about these 2 as we do in either end of the pendulum is one is depleting the protein during the event, the other is producing the protein into the event, which we think is a core advantage of editing in general. And it's nice to see other editors also demonstrating those same features and phenomena. So I think that's a core component of editing.

We think about DNA editing versus RNA editing, again, I do emphasize that the idea in liver patients to not have to use LNPs that can be pro-inflammatory in liver is an advantage. And we saw that as clinicians reporting patients with more advanced liver disease, F1s, F2s on the studies as the study progressed is important. And as I said, not being able to off-target edit. That's not about bystander editing. There's a whole concept still around creating the M protein versus bystander M protein, which is kind of thinking about that as an on-target, off-target, but then there's also the risk of permanent off-target editing that's irreversible, and that's a very real risk. And so as we think about this balance having a reversible approach in RNA editing, we think, is highly compelling.

Great. Over the course of RestorAATion-1 and 2, what have you learned about PK/PD profile of the molecule and how it informs kind of go-forward plan here?

Yes. I think as we know and said in the last trial, the 200 biweekly was looking at that dosing versus 400 monthly. And so it did give us the potential for, as we said, monthly dosing in this. I think what we'll continue to look for is whether or not there are opportunities on that dosing regimen. And if you look at the curves at the end of these studies, we do see duration. So as it's loaded on to cells and as we're continuing to see that activity, the potential for less frequent administration or other dosing regimens is in the evaluation. I think the key for us right now is staying focused on this potential for monthly dosing and whether or not -- where that sits in, generate those data and continue to evaluate it.

Great. You mentioned 008 earlier. What initially drew you to PNPLA3 as a target? And why do you think RNA editing is the right approach here?

Yes. So PNPLA3 mutation, this is -- as we said, we like targets that have validation. So it's got very strong genetics on the mutation of this enzyme drives an increase of disease. There's also very good genetic epidemiology data that shows that if you can correct it back to 50%, you improve the survival of some of these patients, so their risk of volatile liver disease goes down. So very strong genetics in shifting these patients from the homozygous state to the heterozygous state.

The question is, and there's been a number of RNAi approaches, we demonstrated this work. We shared it in an R&D Day in the past that if you take this enzyme away, you can actually increase the risk of disease in these patients, meaning you could see increases in potential for liver fat, you could see increases in inflammatory response that aren't addressed, and that's really the ability of correcting the enzymes so they can do its' function, expel fat, improve the inflammatory response.

So when we did our own comparisons between these 2, and I think we're pretty good at making siRNAs given what we did with Inhibin E, we could really do that kind of cross comparison and modality to say, well, what's the right modality to treat this? I think recently and coming off of EASL very shortly ago, I think what we're continuing to see is that the siRNAs are doing that. They are actually, as they're dose-dependent, potentially worsening of the disease. So really shifting and reaffirming, frankly, from the human clinical data on the RNAi front, that correction is the right way to pursue this. And so we're excited to bring that data from our preclinical data that shows that potential now to the clinic where we can address this. And it is a very consequential size. And it's all for liver disease, while we're starting and looking at things like MASH and others are doing that, there's a whole variety of diseases that these patients are exposed to. And oftentimes, it goes undiagnosed in the context that these patients go on to have liver diseases for other consequences, whether it's alcoholic cirrhosis and hepatitis to other liver diseases from infection that they just have an exacerbated response. And this is an identifiable mutation, it's in 23andMe. So this is not an exotic mutation to look for and evaluate.

Great. Maybe in our final minute, what do you think is the most underappreciated aspect of Wave today?

Yes. I think when we go back, within each of these diseases we're talking about, there is that desire to see the next step. So I think what's underappreciated is how important body composition is ultimately to the obesity landscape, and we're -- how we believe we're best poised to address that with Inhibin E both with our existing human data, again, remembering that the underappreciated fact is that was a Phase I study and delivered results that very meaningfully should translate into the Phase IIa, and we're going to do that.

We're resourced to deliver that IIa study and the subsequent combo and maintenance. Additionally, AATD is an asset. We'll deliver those data and then with the upcoming regulatory discussions for that pathway and continue with PNPLA3 to unlock a very broad indication in the editing space. So I think collectively, we're resourced to deliver a portfolio that's translating across platforms, across mechanisms to deliver high-impact, high-value diseases.

Great. Well, that concludes our time today. Thank you, Paul. Thank you for coming. Great to have you.

Thank you very much. We appreciate it. Thanks.

Hello, and welcome to the Wave Life Sciences RestorAATion-2 Clinical Data Update Conference Call. [Operator Instructions] Also, as a reminder, this conference is being recorded today.

I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator. This afternoon, we issued a press release announcing a positive update from our ongoing RestorAation-2 trial of WVE-006 in alpha-1 antitrypsin deficiency. Our press release can be found in the Investor Relations section of our website, www.wavelifesciences.com. The slide presentation to accompany this call will be available on the website following the prepared remarks.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2025. We undertake no obligation to update or revise any forward-looking statements for any reason.

Joining me today in Orlando is Dr. Paul Bolno, President and Chief Executive Officer, who will begin with opening remarks. Next, Dr. Kyle Hogarth, Professor of Medicine and Director of the Alpha-1 Clinical Research Center, University of Chicago will provide an overview of the current AATD landscape and unmet need for PIDV individuals. Dr. Chris Wright, Chief Medical Officer, will then present the RestorAATion-2 clinical data update before turning the call back over to Paul for closing remarks. Dr. Erik Ingelsson, Chief Scientific Officer, is also here with us today and will be available to answer questions.

I'd now like to turn the call over to Paul.

Thanks, Kate. Good afternoon, and thank you for joining us for an update on RestorAATion-2, our clinical program for WVE-006, the first GalNAc-conjugated subcutaneously delivered RNA editing oligonucleotide for AATD. We're excited to be speaking to you from the ATS conference, where there is a significant appreciation for the limited treatment options available for the hundreds of thousands of individuals living with TIZZ-AATD.

Through our engagement with the Alpha-1 community, we have heard many accounts of the challenges of living with AATD. One individual described it as a full-time, full body and full life disorder. Every set of stairs, every fragrance candle store, every emptying a vacuum bag is uncomfortable and potentially dangerous. Our discussions with KOLs and advocacy groups have also shed light on their work to improve detection of AATD liver disease, which can ultimately lead to cirrhosis in these patients.

Our work at Wave is to help these individuals breathe easier and reclaim their lives. There is a clear and urgent need for new therapies, which address both the liver and lung manifestations of AATD and restore dynamic AAT production with a convenient and safe regimen, recognizing these patients have underlying liver disease.

Earlier today, data from our RestorAATion-2 clinical trials were highlighted for the first time in a major medical meeting, and there is broad enthusiasm for the transformational potential of our RNA editing approach. By correcting the mutant transcript in the liver, 006 aims to address the root cause of both the lung and liver manifestations of the disease. RNA editing with 006 enables the production of endogenous native wild-type MAAC protein, which reaches the lung and protects against the protease damage that drives lung disease.

Importantly, with RNA editing, we avoid creating bystander edits, meaning unintended base edits in the target SERPINA-1 transcript that creates a nonnative protein and avoid permanent off-target edits like indels, which could silence the protein altogether or has potentially other severe consequences. Publicly available data on DNA editing approaches also confirms that these off-target edits risk changes that include cancer-associated genes.

Designed using our proprietary PRISM chemistry, which drives potency, specificity, stability, distribution and delivery, 006 has the potential to be the first treatment for AATD that enables patients to produce protective AAT protein when needed and address the root cause of the disease with a convenient and infrequent subcutaneously dosed therapeutic.

With 006, our goal is to recapitulate an MZ-like phenotype as it's well established that heterozygous PIMZ individuals has significantly lower risk of both lung and liver disease. And the individuals have reduced levels of Z-AAT, which protects the liver from damage and are able to protect the lung with basal AAT levels above 11 micromolar, of which at least 50% is wild-type M-AAT and most importantly, are able to mount a dynamic AAT response during an acute infection. That combination Z-AAT reduction, protective basal levels with a meaningful proportion of wild-type M-AAT and a preserved acute phase response is the bar we set for 006.

We are pleased to share today this is exactly the profile we consistently achieved. With only 3 months of treatment, 006 continues to deliver a compelling therapeutic profile, achieving all of our key treatment goals with both 200 milligrams biweekly and 400 milligrams monthly dosing. Z-AAT, the misfolded protein that drives liver pathology was reduced by approximately 70% with 200 milligrams biweekly dosing and 400 milligrams monthly dosing.

Total levels of AAT reached 11.9 micromolar with biweekly dosing and 13.6 micromolar with monthly dosing, both above the 11 micromolar bar that has historically defined the proceptive level. Wild-type M-AAT reached 64% of total protein with biweekly dosing and 59% with monthly dosing, which recapitulates the M-AAT proportion seen in MZ heterozygous. This wild-type M-AAT is all canonical M-AAT and does not include bystander edited isoforms as seen with DNA editing. And we continue to see MZ-like dynamic AAT production with now 3 acute phase responses observed and a strong correlation supporting that AAT rose dynamically with CRP even in minor elevations throughout the study.

006 continues to be generally safe and well tolerated with no liver toxicities. Durability of editing remains impressive and supports the potential for monthly self-administered subcutaneous dosing. As Chris will elaborate on later, we are on track for regulatory feedback on an accelerated approval pathway for 006 in mid-2026.

Now to speak more to the unmet need and treatment gaps remaining for individuals living with AATD, I would like to introduce Dr. Kyle Hogarth. Dr. Hogarth is a Professor of Medicine in the section of Pulmonary Critical Care Medicine at the University of Chicago. He is the Director of Bronchoscopy and is heavily involved in the field of advanced bronchoscopy and interventional pulmonology. He also runs the Alpha-1 antitrypsin deficiency Clinical Resource Center, one of the largest in the Midwest with over 250 patients and helps write the 2016 Alpha-1 antitrypsin deficiency clinical practice guidelines.

Without further ado, I'll turn the call to Dr. Hogarth.

Thanks so much. I really appreciate this opportunity and bring everyone kind of up to speed on the broad understanding of what this disease is about and why a therapy like this is so interesting. As you know, alpha-1 is part of the SERPINA-1 family and the mutation in this, in particular, the Z mutation, which is our focus, can lead to both liver disease and lung disease, but both like completely different mechanisms.

As the schematic that you are the drawings that you see on your slides, the healthy phenotype of M, you make plenty of alpha-1 protein. It leaves the liver with no difficulty. And the little scale picture on the side shows you make way more alpha than we need. It's actually the second most common protein the liver makes, implying its importance. And that's all to counter the amount of inflammation that goes on in the lungs from just your daily breathing.

Now the ZZ phenotype leads to a misfolded protein that polymerizes and accumulates within the liver. And over time, that puts patients at risk for both fibrosis and cirrhosis. And it's unclear as to specifically which double Zs will develop this. So it represents a profound unmet need because we have at the moment, 0 therapeutics for alpha-1-related double Z genes in the liver and a lifelong fear of these patients for what level of liver disease they're going to develop.

But because of that mutation and the accumulation in the liver, there's a reduction of the amount of alpha circulating and then you get flipped the scale, you get this balancing act problem of not nearly enough protection and then way too much destructive forces going on within the lung from the inflammation. And that manifests then as damage to all different parts of the lung, including the airways where you'll get more asthma COPD predominant phenotype, but then also, of course, emphysema with the direct parenchymal destruction.

So when we look, of course, there's actually about 260 described mutations and counting, but the M and the S and the D are the big players, M is the normal. So hopefully, everyone's double M who's on this call. But the double Zs where our focus are the ones that are obviously of most importance. And as you will note, as you get worsening mutations present, the level of alpha-1 continues to decline. It's a broad range of levels within these proteins or within these mutations. But the double Zs are obviously consistently well below normal, but also importantly, well below the protective threshold of 11 micromolar.

And that even in an acute phase response, the double Zs can never get into the normal level. This actually matters even less because the Z mutation has got a double problem of being less -- having less ability to bind to neutrophil elastase. So the Z protein by itself is a dysfunctional protein on top of being a low level and it further polymerizes in the lung is another additional risk. And when you look across survival curves, we move this little thing off to the side.

I can see the curve better. speaking to the people directly. You'll notice the survivals of MMCs versus MM versus SZs versus MMs and then, of course, you doubleZs. And so looking at these slides, I think it becomes very clear that being a carrier has a beyond mild risk, and that's usually associated only with smoking. So carriers who don't smoke really have little to no increased risk for lung disease as opposed to people that start to accumulate mutations and reduce levels.

And then, of course, looking at our double Zs, double Zs who have a much worse survival probability than our double Ms than normal population. This represents, obviously, from a disease perspective, the unmet need of trying to alter this natural history of this disorder. Now when you look again, there's lots of different ways to slice and dice this data looking at both MZs, SS, SCs and Zs. What I think you'll see on this -- this is obviously a slide with a lot of data -- but when you compare, obviously, everybody to MM and look at the risk for liver disease and the risk for chronic bronchitis and emphysema, and they're called out in the boxes, your MZs are barely above the odds ratio.

The majority of that, again, is related to external factors such as smoking, vaping, et cetera. And then look at your double Zs where everything is shifted to the right in regards to the odds ratio for risk of fibrosis cirrhosis, risk of obstructive lung disease and emphysema. Double Zs have a profound increased risk for the problem -- both these problems developing as opposed to the MZ population, which barely has an increased risk and in some cases, actually crosses over the a no risk.

And so this is all simplicity aside, this is what you remember from high school biology. Carriers are carriers. They're not interesting. It's only people that have 2 mutations that are going to be at increased risk. And of course, we've got both disorders. And by various estimates across the U.S. and Europe, there's about 200,000 people that are CZ, but less than 10%, that's roughly -- it's actually less than 10% are diagnosed and managed.

So there's a profound unmet need on the diagnostic side, some of which is held back because of a perception of inadequate therapeutics related to plasma-derived therapy. That's been one of the biggest holdups when you talk to a lot of physicians about why they don't test. They don't feel like there's a management. There's no way to treat. So why bother? That leads to a problem of people developing lung disease typically at a younger age and on average, having to see 8 different physicians -- or excuse me, 3 different physicians over 8 years.

And then because alphas as our COPD meds have gotten better are living a little bit longer, we are seeing an adult onset of liver disease now roughly at around 60 years, what has traditionally been a disease of children. And so there is an overlap. you look across the Alpha-1 International Registry, lung disease being the predominant phenomenon, but then obviously, liver disease, both in isolation and in the setting of lung disease being present. That is our problem. And it's a profound issue of both unmet need, like I already stated on the liver side with no therapeutics and then on the lung side, very limited treatment options.

And so to put it into context because you're on this call saying, this is just a rare disease, not a rare disease. If you put it into the same rate of, say, that 100,000 double disease that are estimated to be the American numbers, again, that's an underestimate, but we'll stick to it. It's actually more common in both sickle cell and cystic fibrosis diseases that are usually something that people are quite familiar with and have seen.

Now the key difference here is that both of those are extremely clinically obvious. They present in a very specific way, and then you draw the blood to determine that you are clinically correct. Alpha-1 presents is a disease that every lung doctor on earth sees every single day, which is COPD and asthma. So it's been hiding in the noise as part of the problem that it's had. There's been a lot of discussions about making sure people follow the guidelines appropriately and actually work up these lung diseases. This is not a rare disorder. It's just been rarely tested for.

And going back to the core of the Z mutation, these folks actually on one level, make plenty of alpha-1. It's just all stuck in the liver. This is a biopsy of the liver of built up accumulated polymerized gumming up the system, if you will, alpha-1 protein stuck there. And the fibrosis is very common and often asymptomatic and then progresses on from F0 through F3, which is the worst form and you'll see where then you get clinically associated liver disease, both liver function abnormalities as well as a particular damage to the liver. And of course, if there's an additional insult, an inability to recover and continue to manufacture all the other things that the liver also needs to take care of.

And this is, of course, by itself as a double Z regardless of any other external liver insults, whether that's various meds, whether that's alcohol, et cetera. And this obviously impacts quality of life. I don't think it should come as any surprise that having lung disease, I think it was already stated talking to patients who gave you very specific examples. But these are folks who do suffer from obstructive lung disease, asthma, emphysema, chronic bronchitis, bronchiectasis, basically the entire obstructive phenomenon. They get short of breath, they get winded doing exercise.

On the liver disease side, obviously, there is this ongoing damage to the liver and actually an increased risk for hepatocellular carcinoma. There's also a rare manifestation within the skin and also an associated vasculitis. The issue is, is that we, I guess, technically do have a therapy for alpha-1, and it involves for the patient's rest of their life, every week getting a needle put into their vein and having someone else's plasma infused, and that's it. And if you have liver disease, I got nothing for you.

And on the lung side, you just take inhalers and then every week forever, chain to an IV. And that's been the state ofthe-art for a very long time. And why do we do this? Because obviously, when we look at the 60 milligrams per kilogram dosing intravenously, it kept patients above the protective threshold. And this became the standard of care. This became what we treat currently.

There's 4 plasma-derived products currently available in the United States based off of this. That's great. imagine from a patient's perspective, desiring something maybe a little bit better. And of course, the idea of going back to that scale where there's this deficiency of alpha-1, the imbalance where you have a whole lot more destructive forces. The idea, of course, of replacing it makes sense, built the scale back, right? So it's all about not just increasing alpha-1 levels generically, but it's increasing the amount of M protein.

But you'll notice when you look at this little graph, you don't see anything reducing the Z protein, right? The Z protein is still the same levels, and it's still got its own issues of not being able to avidly bind to neutrophil elastase and it's still got its issues of polymerizing. So alpha-1, a huge component of the acute phase response. the bodily response to injury of any kind, whether that's an infection, whether that's a kidney stone, it doesn't matter.

You get multiple elevations across multiple different proteins to essentially think about it as rallying the forces, if you will, if you want to make it very humanized. And obviously, lots of different things go up. But if you track the C-reactive protein is there in the red box, you'll obviously see that goes way up. That is a measure of inflammation. And you'll notice that alpha-1 also shoots up dramatically to help regulate all the inflammation going on because neutrophil elastase is one of the main responses to any amount of damage inside the lung.

And as the name implies, elastin, elastase, the lung is made of elastin, you now have unregulated enzymes quite literally digesting the lung. Through multiple other inflammatory markers. And of course, this is why you have this acute phase response. Now what you'll see right here is that's in a normal person. if I'm an alpha-1 patient who was infused on a Monday and I, Friday afternoon have pneumonia, true pneumonia and have a ridiculous amount of inflammation going on in my lung, I'm depleting the alpha-1 that I got on Monday rapidly. And I have no ability to respond. I only got a meager amount of Z protein as a response. That's not good for our patients. And that's seen right here in this schematic.

Again, when we give IV dosing, the levels go up, they come back down, they go up, they go back down. This is why it's weekly, and we've got lung protection. But now when I have that acute phase problem, I've already gotten rid of it, and I have this gap of time where I don't have any protection. This is also important. I mean, I used the example of the infused Monday and pneumonia on Friday, but alpha-1 is broken down in a one-to-one capacity to take down neutrophil elastase.

So if there's a ton of neutrophil elastase, I said pneumonia, but even an exacerbation is going to increase neutrophil elastase. You're going to have this profound and rapid imbalance. And while the liver is trying to churn out a little bit more Z protein, which again isn't very good at binding and is also going to continue to do potentially more damage to the lung. These people are literally getting kicked while they're down. And the problem is there's a 0 indication to give extra infusions. So this has been our problem.

And again, this represents state-of-the-art, the best we've had historically. So this is, of course, where other options come in. And this is where, of course, the excitement from today's data for people like me who are busy reviewing it and thinking about how we're going to be dealing with our patients, unbelievably excited. Now there's a lot happening across this whole space, as you're aware.

On the lung side, there's a recombinant form of augmentation therapy, less infusions, higher levels, but conceptually the same as what we're already doing. There's a liver-only therapy, except to shut down that Z mutation are going to essentially make our patients a double null. And so yes, you'll help the liver, blood, you're going to leave the lungs completely naked. And then, of course, on the genetic-based side and potentially 2 birds stone here, our ability to modify the RNA and as the data is obviously was presented, ability to do it easily and monthly and subcutaneously.

And then obviously, the potential for DNA-based editing, which has raises both some concerns and excitement all at the same time from a clinician's perspective. But I think this represents, obviously, for us in the alpha-1 world, an exciting time that people are finally interested in our disease. So thanks.

Let me turn it back over to Chris.

Thanks, Dr. Hogarth. We appreciate you joining and sharing your perspectives today and truly grateful for all the work that you do for the alpha-1 community. As a reminder, WVE-006 is a subcutaneously dosed GalNAc-conjugated A toy editing oligonucleotide or AIMer, designed to correct the single G2A mutation in the SERPINA-1 transcript that causes ZZ-AATD. The corrected transcript translates into the healthy wild-type M-AAT protein, the same protein the cell would have produced if the patient did not carry the Z mutation.

Two benefits follow. First, the cell makes less Z-AAT, allowing clearance of the misfolded protein aggregates that drive liver pathology. Second, the cell produces wild-type M-AAT, which is secreted into circulation and reaches the lungs where it performs its physiological role, inhibiting neutrophil elastase and related proteases that could otherwise damage lung tissue. Here, you can see serum AAT levels across the 4 major AATD genotypes. ZZ individuals, the people we hope to treat, produce only mutant Z-AAT and no M-AAT.

Their serum AAT sits below the 11 micromolar threshold and they are at high risk for both lung and liver disease. Notably, levels of misfolded Z-AAT for ZZ individuals are underrepresented by turbidimetry assays, which have lower limits of quantification as high as 6 micromolar. In our RestorAATion-2 trial, we use a highly specific LC-MS assay with lower limits of quantification of 0.03 micromolar. With 006, our goal is to shift these ZZ individuals towards an MZ range with reduced Z-AAT, production of wild-type M-AAT and a dynamic acute phase response.

Heterozygous MZ-AATD individuals have low risk of lung or liver disease and circulating M-AAT levels ranging from 57% to 71% of total with a mean of 64% based on an analysis of natural history study samples measured using the same validated assay as RestorAATion-2. Here, you can see the impact of RNA editing visualized. On the left is the same population we're treating in RestorAation-2, the ZZ genotype, producing exclusively Z-AAT, accumulating Z aggregates in the liver and not mounting a meaningful AAT response in the lung.

On the right is the MZ-like profile we are aiming to achieve with greater than 50% M-AAT as a proportion of total, AAT levels that rise in response to acute inflammatory events and CRP elevations and with the potential for higher serum AAT over time as Z aggregates resolve and hepatocyte health improves. When a ZZ individual, as shown on the left, encounters an inflammatory stimulus, CRP levels rise. However, these individuals have a limited ability to increase circulating AAT levels when it's most needed. The result is that lung damage accumulates during exacerbations, the moments when protection is most critical.

When an MZ individual, as shown on the right, encounters an inflammatory stimulus like a respiratory infection, 2 things happen in concert. CRP rises sharply and in close approximation, circulating AAT protein levels also substantially increase. That coordinated rise is one of the body's natural defense mechanisms, yielding more circulating AAT precisely when neutrophil elastase activity is highest.

One of the best ways to limit exacerbations and the associated damage that drives disease progression would be to enable ZZ individuals to respond like an MZ or healthy individual, increasing circulating protective AAT protein when it's needed most. Even with augmentation therapy, individuals with ZZ-AATD experienced acute exacerbations on an average of 1 or 2 times per year. When this occurs, a rapid increase in AAT is needed to maintain a healthy protease activity balance.

Healthy individuals, including MZ, mount that response within 24 to 72 hours of the stimulus. ZZ individuals on augmentation therapy may not be able to mount this response as they receive exogenous AAT on a fixed schedule. Between doses, levels decline and exacerbations further deplete tissue AAT. The result is that patients on augmentation therapy may be left at risk from the very events that drive lung damage over time. WVEs 006 mechanism allows the dynamic regulation of AAT. Endogenous AAT levels can rise during the acute phase response without the need for additional dosing, restoring the natural protective rhythm that healthy individuals exhibit.

Now turning to the clinical results. RestorAATion-2 is our ongoing Phase I/II trial of WVE-006 in adults with ZZ-AATD. Our restoration program began with healthy volunteers in RestorAATion-1. This was a safety, tolerability and PK dose escalation study that proceeded through single and multiple ascending dose phases, ultimately evaluating up to 3 600-milligram doses of WVE-006 administered every other week. These data informed the starting dose of RestorAATion-2, our open-label dose escalation study of individuals with AATD who have the homozygous ZZ genotype.

In RestorAATion-2, each cohort was designed to enroll 8 participants who began with a single dose of WVE-006 and then continued into a multi-dose cohort. Today's update includes data from both the single and multi-dose portions of the 200-milligram and 400-milligram cohorts, which have completed dosing as well as data from the 600-milligram single-dose cohort. Our 600-milligram multi-dose cohort is ongoing and data is anticipated in the second half of this year.

Baseline characteristics in RestorAATion-2 were similar between cohorts with some minor differences in gender and liver fibrosis levels as reflected by elastography. Participants mostly had no or mild evidence of liver or lung disease as required by protocol with 1 participant having moderate liver disease. All participants were required to be between 18 and 70 have a ZZ genotype and be non-smokers for at least 1 year prior to screening. WVE-006 continues to be generally safe and well tolerated across all dose cohorts. There were no serious adverse events.

All treatment-emergent adverse events were mild to moderate in severity. There were no treatment-related clinically relevant changes in laboratory parameters, including liver function tests and no clinically relevant changes in ECG or vital signs. This absence of treatment-related changes in liver function test is particularly notable as it is a key differentiator from approaches requiring LNPs for delivery.

One participant in the 400-milligram cohort completed the single-dose portion and withdrew prior to the multiple dose phase. This individual experienced a moderate injection site reaction and had a history of multiple allergies. There were no other discontinuations due to TEAEs across the study. Before walking through the biomarker data, it's important to reflect on what we set out to achieve with 006.

As we've discussed today, AATD is a multifaceted disease, impacting both the liver and the lung. An ideal AATD therapy should aim to address both manifestations of the disease, protecting the liver by reducing Z-AAT and protecting the lung by restoring M-AAT and its dynamic production during inflammation. Our results today support that these key program goals were achieved. Starting with the changes in M-AAT and Z-AAT at an individual level, you can see just how rapid and consistent the effects of 006 were across participants with everybody responding to treatment following just a single dose.

On the top, you see substantial increases in M-AAT protein with corresponding decreases in Z-AAT on the bottom of the slide, consistent with the presence of significant RNA editing. We also observed significant increases in neutrophil elastase inhibition or FAAT across all 3 cohorts. Here, we show the substantial mean reductions in Z-AAT across doses and regimens. On the left are mean maximum reductions of serum Z-AAT from baseline across 3 single-dose cohorts. Following a single dose, we achieved dose-dependent Z-AAT reductions of 47% at 200 milligrams, 50% at 400 milligrams and 59% at 600 milligrams.

With repeat dosing, these reductions deepened in the 200-milligram multi-dose cohort where participants received 7 total doses, 1 every other week. Z-AAT reductions reached 71%, up from 47% in the single-dose panel, as shown in the middle. Effects were similar with monthly dosing in the 400-milligram cohort where participants received 4 total monthly doses, Z-AAT reductions reached 68%, up from 50% following a single dose, as shown on the right.

These robust reductions in Z-AAT across dosing regimens are particularly notable as our preclinical data support that Z-AAT reductions of greater than 50% improve liver outcomes, including reductions in Z-protein aggregation in the liver, which is the central driver of ATV liver pathology.

Turning to mean M-AAT. We again see dose-dependent effects across our single-dose cohorts. On the left are mean maximum M-AAT percentages of total protein in the single-dose portion of our trial. Following a single dose, M-AAT as a percentage of total AAT reached 44% at 200 milligrams, 48% at 400 milligrams and 52% in 600 milligrams. In our multi-dose cohorts with just 3 months of treatment, we're delivering M-AAT as a percent of total AAT in the MZ range.

With extended dosing, both our biweekly 200-milligram and monthly 400-milligram delivered similar M-AAT levels that were within the MZ natural history cohort range of 57% to 71% as outlined earlier. Importantly, these are percentages of wild-type healthy M-AAT, which is not included bystander edits.

Looking at the individual responses and M-AAT percent of total on the top and the reduction of Z-AAT from baseline at the bottom, we again see consistent and durable responses. For the 200-milligram cohort, both single dose and biweekly on the left and for the 400-milligram cohort, both single dose and monthly on the right, we see editing sustained out to at least 3 months post dose. M-AAT as a percentage of total remains elevated and Z-AAT reductions persist well into the follow-up phase. This durability supports monthly dosing with data from our 600-milligram multi-dose cohort expected to further inform the dosing regimen.

A long-standing goal in the community has been to ensure individuals living with AATD are protected with sufficient circulating AAT during exacerbations. In September, we showed data demonstrating that we've already achieved these goals with 006 as we were able to restore a ZZ participant's ability to respond to an acute inflammatory event with total AAT levels of greater than 20 micromolar, just 2 weeks after a single dose. Encouragingly, the magnitude and the 4-week duration of this response are also proportional to the levels anticipated for an MZ individual based on natural history.

Today, we're excited to share a growing body of evidence supporting 006's ability to systemically restore dynamic production of AAT. In addition to the acute phase response we shared in September, we've observed 2 additional acute phase responses, which were driven by mild upper respiratory tract infections. These events once again resulted in dynamic elevations of AAT with proportional increases of 58% and 60% from pre-event. Furthermore, across our entire study, we see that CRP increases are strongly and statistically significantly correlated with AAT increases even in events of smaller magnitudes.

What's particularly important here is what these events represent. Not every inflammatory event escalates to clinical attention, but these events are happening in the background, consuming AAT protein and driving cumulative tissue damage over time. That is why a dynamic endogenous AAT response matters. It protects patients not only during major acute phase responses, but also during the minor inflammatory events that accumulate.

Collectively, our data support 006 as a differentiated potential new medicine for individuals living with AATD. We've observed robust RNA editing with Z-AAT reductions of up to 71% and restoration of M-AAT to an MZ-like range, potentially supporting both liver and lung health benefits with durability favoring a convenient monthly dosing regimen. We have a growing body of evidence supporting that 006 enables the natural inflammatory response with 3 acute phase responses observed and a strong correlation of CRP increases in circulating AAT increases.

Importantly, 006 continues to be safe and well tolerated across all doses with no clinically meaningful liver toxicities observed to date. With the urgent need for better treatment options for patients and the compelling profile we've observed to date with 006, we're excited to advance our discussions with regulators and expect feedback on an accelerated approval pathway for 006 in mid-2026.

We also plan to share data from the 600-milligram monthly cohort in the second half of this year. This will further help inform the optimal dosing regimen. In tandem with our clinical and regulatory progress, we're actively collaborating with global advocacy partners to increase awareness of AATD, shorten the diagnostic journey and incorporate community feedback in study protocols, consent forms and educational materials.

With that, I'll turn it back to Paul for closing remarks. Paul?

Thanks, Chris. With our update today, we are generating a growing body of data, which support 006 as a fundamentally differentiated treatment option for individuals living with PiZZ AATD. With the ability to reduce the midfolded Z-AAT driving liver disease, restore wild-type M-AAT to protect the lungs and enable dynamic AAT response with a favorable safety and convenience, 006 has the potential to offer a differentiated proposition for people living with alpha-1, the physicians who treat them and for the payers to reimburse their care.

AATD remains an area of high unmet need. Currently, only 10% of the 200,000 PiZZ individuals are diagnosed. Standard of care is weekly IV augmentation therapy, which only addresses lung disease and is not reimbursed in many markets outside the United States. And there are no therapies for liver disease. Despite the limitations of augmentation therapy and low diagnosis rates, the global AATD market today is approximately $1.7 billion.

This market is expanding and projected to grow to $5 billion globally by 2031, driven by increasing rates of diagnosis, broader treatment uptake, including earlier intervention and better ex U.S. access as more effective therapies become available. WVE-006 is positioned to be a meaningful driver of [indiscernible] addressing both lung and liver disease with a safe and more convenient administration profile that extends the addressable population.

Against the landscape of approved and investigational therapies for AATD, WVE-006 has the potential to be best-in-class. Approved augmentation protects the lung but requires weekly intravenous infusion does not address liver disease and cannot deliver a dynamic AAT response. Recombinant augmentation and development extends dosing intervals, but operates on the same protein replacement principle. Investigational therapies in development also come with several limitations.

DNA base editing approaches target both lung and liver, but they introduce permanent DNA modifications, carry bystander editing risk and rely on LNP delivery, which is associated with liver enzyme elevation. The risk of irreversible off-target effects is particularly notable as DNA editing has been connected to editing in cancer-associated genes. Also in development are AAT siRNA approaches, which reduce Z-AAT.

However, they do not restore M-AAT, potentially exacerbating lung disease through chronic AAT knockdown. 006 has the potential to offer individuals living with PiZZ AATD, a compelling treatment option, which addresses both lung and liver, restores dynamic AAT production, safe and well tolerated and is delivered subcutaneously with infrequent monthly dosing. For over a decade, we've been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health.

Today's results accelerate the already strong momentum of our potentially best-in-class pipeline and strength and differentiation of our platform driven by our lead RNA editing and RNAi programs. Building on our success in RNA editing, we're advancing our next candidate, WVE-008 to the clinic this year, which has the potential to address the 9 million individuals living with PNPLA3 liver disease. In RNAi, we are rapidly advancing multiple studies of WVE-007 across treatment settings, which are strategically designed to unlock its full potential in obesity and other cardiometabolic diseases.

This quarter, we expect to initiate our high BMI Phase IIa trial, followed shortly thereafter by trials investigating 007 in combination data. Beyond our lead RNAi and RNA editing programs, we are continuing to push the boundaries of innovation through our bifunctional modality that allows us to both silence and/or upregulate or edit to treat diseases with a single construct in a single dose. We're also advancing a growing pipeline of new hepatic and extrahepatic candidates.

With the substantial progress we've made, we believe we are well positioned and well capitalized to advance our pipeline of transformational therapies for patients. Before turning the call over to questions, I'd like to take a moment and thank all the individuals participating in our restoration clinical program, the clinicians involved in the study site staff. The Alpha-1 community inspires the work we do every day. And from everyone at Wave, we'd like to express our sincerest gratitude.

With that, I'll turn it over to the operator for Q&A. Operator?

[Operator Instructions] Our first question will come from Samantha Semenkow with Citi.

Congratulations on all the progress. My question is for Dr. Hogarth. I wanted to expand a little bit on perhaps the last slide you shared in your presentation, Dr. Hogarth. I'm wondering how you're thinking about the emerging efficacy and safety profile that we're seeing here today for WVE-006 and comparing that to the emerging data from DNA editing therapies and the recombinant AAT replacement therapies. Just wondering how you're thinking about potentially utilizing these for your patients.

Sam, it's a wonderful question. However, I must say Dr. Hogarth is in the middle of 2 other -- he's actually going to an alpha-1 back and just stepped out. We're trying to see if we can bring him back in for questions. But if not, we're happy to find him. I think he's already gone to the alpha-1 foundation recept but I apologize. But we'll get -- we'll connect him with you.

Your next question will come from Steve Seedhouse with Cantor.

Yes, I'll ask you a question then Paul in that case. So it looks to me like the biweekly dosing does, in fact, make a difference compared to monthly dosing. And my question is, do you agree? Is that what you see in the data? And do you think it's, therefore, worth exploring 600 mg biweekly to maximize efficacy and sort of close the efficacy gap with DNA editing? Or is there sort of a safety tolerability concern with doing that going forward?

Thank you for the question, Steven. So on one hand, the short answer to the last question is no. So if you think about the safety study we ran up through 600, there's no questions. So going up to 600 biweekly, which is what we studied in the Phase I portion of healthy volunteer study. So there's not a question of safety. What's interesting, and again, the 600-milligram monthly cohort will teach us a lot in terms of exposure is, to your point, there's -- on the dosing, we actually had a nice dose response as we gave doses to that kind of initial period of continuing to build and grow and see that shift from Z to M.

We also saw, and I think what you're looking at is a window early where biweekly looked that it was smoothing that line out and then continued. But when you stop and you look at the biweekly, it stays pretty relatively flat for well over a month and beyond after that period. So I think we're going to learn a lot about what happens on the monthly basis, particularly with what levels of exposure and how to balance those.

And I think the 600-milligram monthly data will teach us a lot. I think to the question of what does one need, I think we have to step back and realize 2 weeks after a single dose, we could get 20 micromolar protein. And even in -- as Chris pointed out, the cases now of what we call mild upper respiratory that's a common cold. And what we saw though is we could get up to 16 micromolar. So what we've seen even at these doses is the ability to mount an impressive response to meet the needs of the patient. So I think the question is ultimately going to be what's that optimized dosing regimen. And I think we're in a good position to explore that.

Your next question will come from Samantha Semenkow with Citi.

Apologies for the -- so based on the data, it seems like the 600-milligram single dose is tracking a little bit below what we saw for the 400-milligram single dose. So I'm wondering if you think that's going to be a plateauing effect in that 400 milligram is maybe the go-forward dose? Or do you think in the multi-dose when we see it, there's a possibility we could continue to see a dose-dependent effect ongoing?

Yes. I think the -- actually, it was really nice that we did see a dose-dependent effect. 600 was more in the reduction of Z and more M. So 600 was higher. So we did see a dose response at 600. I think the question ultimately comes down to once you reach a steady state inside the cell, how much more benefit is extracted from that. And I think that, again, as we look at the 600 monthly, where we'll be able to look at the 400 monthly and look at that exposure relationship.

Again, I think it will help us on that dosing regimen. I think as Steve pointed out earlier, 200 is interesting once it reaches a steady state, and it may very well be an interesting dose and frequency. But the last, I think, 600 monthly will be just one last piece in the puzzle in terms of modeling that dosing regimen. But we definitely infrequently is nice. And as we've been wonderful to be here at a conference and spend time with clinicians and as we've tested this thesis, this idea of really shifting these dosing intervals out has been well received.

Your next question will come from Yun Zhong with Wedbush.

And my question is also related to dosing. So while in the study, you only followed patients for 12 weeks. From the PD profile, do you think -- well, in reality, people will probably receive chronic treatment. Do you think more doses will eventually lead to higher editing efficiency and higher AAT -- total AAT protein being produced?

No, thank you. And it's a wonderful question because it's exactly what we saw both in preclinical models. It's well understood. To your point, this is only 3 months of dosing. And so as hepatocytes become healthier, they become more functional. We're actually rescuing hepatocytes and they'll continue to turn over and generate more protein. And with more protein and more editing comes the continued -- that sustained effect. I think that's coupled and importantly driven by, as both Chris and Dr. Hogarth mentioned, a profound reduction in Z protein.

So with the reduction in Z protein very quickly and removing those aggregates, those cells are now -- that toxic insult to hepatocytes is now removed, so these cells can become healthier and those cells turn over. I think that's a valuable component in RNA editing where we think about durability with the ability to continue to get access to these cells as they're turning over so that you can begin to capture them and again, be able to recruit more cells that can get healthier and generate that over time.

Your next question will come from Salim Syed with Mizuho.

Great. Congrats on the data. Paul or Chris, maybe just one for us on the 2 additional patients in the 400-milligram multi-dose cohort that saw an increase in AAT. Could you quantify the 57.8% and 59.8% increase? Could you quantify that in terms of total protein so that I believe you guys said 20.6 for the 200 milligram. Could you give us a similar number for the 2 patients? What was the M-AAT in those patients as well?

Yes. So that was the update that I gave, which is we see about a 16 micromolar increase. So those are the examples that we continue to see that increase in that relative proportion, as we said, of M and Z, is the same.

Your next question will come from Joe Schwartz with Leerink Partners.

Great. I guess I wanted to ask about the 3 dynamic response events. They look very compelling, but still anecdotal. So I was wondering how important is it to make this a labeled feature in your view? And if so, how might you do this? And then the CRP-AAT correlation is pretty strong with an R of 0.73, but I think this means that around half the variance is unexplained. Do you have any thoughts on what's driving the rest of this data?

Yes. break these into 2 parts. They're very much related in terms of the question of like anecdotal and continuing to look at what's happening. So I mean, to your point, I think we were the first to show it last year. I think there were a lot of questions of is it anecdotal. It was robust. It was exactly as we'd expect. I think what was encouraging in the interim is we saw that happen in DNA editing. So an editing approach as we think about protein replacement therapy and editing is driving this adaptive response. That's what's supposed to be happening.

And I think it's encouraging is we engage regulators as well on a path of, are you recapitulating an MZ-like phenotype with that responsiveness. That's a critical component across that because that is the response. Seeing 2 more, again, in the case of these were much more mild. These were cases of cold, and we see the 16 micromolar total. It had the same features to it. So again, the body of evidence is growing from an anecdotal response to it's behaving like it should.

I think to your point on the correlations, that was something we were looking for levels where patients weren't kind of at the level because when patients have a kidney stone, they're coming to their physician for an evaluation of that problem. Being able to look across the study for patients who aren't coming in and having those fluctuations, it's doing exactly essentially what Dr. Hogarth drew for everybody and where we should see that in those responses at a low level, when we see those correlations, it gives us the conviction and confidence that, again, the body is being restored to what it can do in a normal situation.

I mean there's always a degree of some variability to your point on that, which could be just around functional sampling. But I think when we step back and say, is it really achieving the key objective for these patients to mount the responses that they need to, to prevent lung injury. I think the answer is yes. And I think it gives us a lot of conviction going into the upcoming regulatory discussions around...

Your next question will come from Alec Stranahan with Bank of America.

Just a quick one for me. I guess as you're looking to gain regulatory alignment for the pivotal for 006, is your baseline expectation going in a biomarker-driven primary? And I guess, do you think functional AAT or total AAT would be more important here? And then maybe when you're thinking about future studies, given the good tolerability profile today, do you think there's room to go beyond the 600 mg dose, maybe to say, an 800 mg monthly or even bimonthly cohort?

Yes. So yes, I mean, the first question is a biomarker-driven approach principally driven as we think about that transition from M to Z, which is the hallmark of what an MZ phenotype is supposed to be with other biomarkers that will continue to look alongside. And to the last question that came up, the ability to see that relationship between CRP, AATD -- sorry, total AAT and AAT levels as it relates to those acute phase responses.

So again, putting together the picture and the totality of the biomarker data that really recapitulates the MZ phenotype. I think the question you're asking in terms of doses, there's a certain level of exposure that, again, we can get to 20 micromolar, which is like where we talk about with the IV protein replacement therapy trying to have somewhat of a native to protect. And as Dr. Hogarth said, deplete the protein when they have the event at 200 milligrams, 2 weeks post a single dose, we could get to 20 micromolar protein.

So I think we have to step out from the more phenomena that really is exemplifies what IV replacement therapy is supposed to do, right, pouring water into bucket with holes in the bottom and the hope that as you're depleting it, you're going to constantly fill it back up, versus editing where when you have that acute phase response, you mount the response that you need into the event for the period of time. And again, I think it's encouraging that when that's happened in places that we could mark in the study, we've actually seen the body rise to meet those occasions.

So I think that dynamic event is well within the dose cohorts that are already being studied. What we're really going to optimize is a couple of the other questions came up is what the dosing interval could be that we could push that out more conveniently to patients. And if we think about a convenient subcu potentially self-administered therapy for these patients, that's monumental in terms of transforming how we care for them. And if we can do that safely without causing liver injury in patients who are susceptible to liver injury and exposing them to other risks, I think we're putting together, I think, a very important proposition for patients and their caregivers.

Your next question will come from Catherine Novack with Jones.

Just wondering, is it possible for us to back into the mean max M-AAT using the percentages given? Or are the mean max total and the percentage of proportion of M to Z taken at, I guess, multiple different time points. How should we be thinking about that?

It's dynamic. I don't know if you could.

Yes. So because each individual has a sort of different time course, that's why the mean max makes sense in terms of trying to understand kind of the effects of the drug. So you can't really do the bowel calculation, as you mentioned, just because it's not at a specific time point. It's the max value for any individual subject over the course of the treatment duration.

But it's reasonable to think in totality about the percent M over time.

Your next question comes from Madison El-Saadi with BRS.

Congrats on the data. Just wondering, what do you think is new here that is most likely to incrementally influence the FDA on their conclusion on the accelerated regulatory requirements? And then somewhat related to that, is it -- do you think that the required frequency of administration of the drug could actually decrease over time, as you pointed out, as new hepatocytes are generated?

Yes. I think on the last question is, yes, with the caveat that we have to study that. But the data suggests like as we look at where -- that was what was interesting about the 200 biweekly where we stopped and you could see the durability continuing. It does suggest that there's some level of -- as drug gets on board and over time, you've got that exposure. And then to your point, as we get more cells that are healthier, but then are getting dosed that, that could continue to extend that range. And we'll continue to look at that dynamic range.

In terms of the agency and biomarkers, again, I think it's the range of biomarkers that support the MZ phenotype. So again, it will be that transition from showing we can move Z to M at the same levels that MZ patients have. And it will be this dynamic response. I think the dynamic response is so important in this because ultimately, that is the disease, right? It's a chronic disease of acute exacerbations. And so being able to mount those needs when patients have them at the appropriate levels that the patients need are great ways for us again to show that the biomarkers are doing kind of -- are possibly doing what they're supposed to do. And so I think relative to the approval pathway, I think we have the component there, and we're excited to engage.

Your next question will come from Cheng Li with OpCo.

Congrats on the results. So probably just going back to the dosing discussion. I'm just wondering if there's a scenario you can probably do like induction periods where you have slightly more frequent dosing followed by maintenance period where you can have like more extended dosing beyond monthly injection. Is that something like you can potentially consider for the pivotal study? And if I can just squeeze in one commercial question. I'm wondering how you're thinking about like patients already on like augmentation therapy and if you can encourage patients to switch to 006 once approved? And what is required for such like switching for patients?

Yes. No, thank you for the questions. And to the first question, I think the answer is yes. And I think the data suggests that. And as we think about that's something that's been done with other therapies, particularly in the siRNA space for a while to get to exposures. I think stepping back, I think this is where the 600 exposure question is going to get us a lot of learning in terms of those dynamics.

But you're absolutely right that, that opportunity, as we look at the modeling following the 600 monthly will give us opportunities to think about how infrequent. We maybe had to push it out actually substantially longer with a certain level of exposure. So that's going to help inform those dosing regimens. In terms of commercial, we spend a lot of time with that because I think as we think forward, and it was a good portion of a number of our meetings today with the community, physicians and others associated with alpha-1.

I think there's a lot of enthusiasm for thinking about kind of transforming this care from a hospital IV setting, to your point on augmentation to really transferring this back to patients where it could be self-administered and that they could have a subcu versus IV and now really thinking about how do you deploy that to patients with augmentation and Dr. Hogarth being a great example, but several other physicians who we've been working with do see this as a shift where augmentation protects you at that threshold, but we've got this ability to continue to provide that level of protection that's seen with augmentation in a way that's adapted.

And I think what's so critical, and we hear this a lot, we heard it a lot over the course of this meeting, is really the fact that these patients are all underlying liver patients. I mean it's interesting we're talking to the foundation today, and they brought up a really great point that as patients -- as hospitals started to do liver scans both patients who are coming in for pulmonary issues, the underdiagnosis rate of liver disease was astounding, the patients that were just being picked up on fibro scanning.

And so I think as we think about this as both a liver and a lung disease, it comes down and physicians are realizing that just because you infuse the protein, you're not protecting liver. In fact, you're keeping those patients exposing and making toxic Z protein. So the ability really to see physicians gravitate towards the shift in protecting both lung and liver is important. I will say to the prior question, there was a question on biomarkers. And I do think it's important as we do engage with the agency that the specificity of knowing that what we're calculating is truly wild-type M-AAT protein.

We know with others, particularly in the DNA space that the vast majority of protein being made is actually a variant of the native protein. So we think about being able to have those conversations about a wild-type protein and levels of editing that are exquisitely specific, I think that's going to factor in a lot to the discussion as well.

Your next question will come from Ben Burnett with Wells Fargo.

I wanted to ask about the discontinuation case that occurred. I think you mentioned that there was an injection site reaction that led to that discontinuation. Was that the only adverse event that the patient received? And any other color you can provide about that?

That's correct. So the person had the irritation at the injection site. And because they had a lot of allergies, the sense was that it was best for them not to proceed with the multiple injections. But -- so that was sort of the long and short of it. There wasn't really much more going on there.

Your next question will come from Whitney Ijem with Canaccord Genuity.

Sorry if I'm being dense here, but I just want to follow up and make sure I'm thinking about this correctly. I guess as we think about longer-term dosing, I understand that there is a potential for kind of higher total levers over time as the cells turn over. Is there also a potential for higher percent M over time? Or should we be thinking about that as kind of a fixed percentage, but with higher AAT levels? And then second part of that is just, are you continuing to dose the monthly doses for 7 doses to match the 7 doses and the biweekly? And should we expect longer-term updates from those cohorts?

So the next update will be the 600-milligram monthly cohort, and that will be our update. To your point on longer follow-up, it doesn't just clear total -- if you think about it, to your point, it will -- you should continue to see more M. So as you free up cells that can release more M protein and free out dose, you can continue to drive that. I think what's encouraging, and I know the question is so hard because we're in this mindset of augmentation therapy of like can you give out more?

Again, patients met 20 when they needed 20 micromolar total protein. And so I think we have to remember that so long as there's exposure inside the cell and to this point, if we push that frequency out as long, patients will be able to make protein that they need when they need it. And that's really, I think, probably the most important feature of editing in totality. And when we look at the levels that we're seeing, we're seeing levels that are in the MZ range.

So the ability to correct these patients both at their baseline, but also to see them meet those dynamic responses, again, as we go to regulators. So really a combination of the profile that we're excited to take forward.

Your next question comes from Cassie Yuan with RBC CM.

Congrats on the progress. And Paul, you have already nicely pointed out and other analysts have alluded to that going from flat to MAD at each level or going up on single dose escalation, circulating in serum constantly improve, but it's also notable that total AAT does not always increase. So how should we rationalize the biology there? Or is it mostly correlated with individual baseline level of so more of arithmetic experimentation than biological? And related to that, with Sanofi inhibit data update also at the conference is showing every 3-week IV can now get us to steady-state trough functional AAT above 24 micromolar. Does that raise the bar for any player in the editing space?

No, thank you. And I think the last question is, no, I think the challenge on this kind of where -- what is raising the bar is remember, that's the threshold with which patients now get exposed to Dr. Hogarth's important point seeing these patients is that's kind of the threshold where they had an event that they'd be depleting the protein. So again, being able to flip the narrative that actually with editing, and it's really a critical component to editing, you actually increase the exposure into those events.

Again, we could raise the 20 micromolar into the event, which is actually what the patient needed, right? And that could stay out over a month to provide that protective ability and then come back to baseline. And so the dynamic effect is really the underlying component of editing. I think as we think about the ability to do that infrequently, it also have the liver, right? So by pushing out the intervals so now it's, call it, monthly as a number of people have raised the potential for thinking about regimens that could be longer.

You have to remember that, that protein replacement doesn't raise the bar, as we said, not just because it's broken down, but because it's still not protecting the liver. These patients are still exposed and still during those acute events are actually producing Z protein into that event, which is causing further injury to the liver. So the ability really to shift to cascade, to shift, and that's really the driver of editing, to shift Z protein to M protein. That dynamic is the dynamic that you see in MZ is a shift from Z protein to M protein. That's the critical feature. That's what we do. And I think that's why it provides a really competitive differentiation from the protein replacement therapies.

Your next question will come from Michael King with Rex Biomed LLC.

It's Mike from Rodman. I don't know how we got signed in as Rex Biomed, apologies. Pretty much all of my questions -- sorry about that, Paul. I'm not trying to throw a curveball here. Most of my questions about the dosing and pharmacodynamics have been answered. I'm just curious from the animal modeling that you've done, do we know how long it would take to begin to either stabilize or even reverse liver or lung damage. Could you move patients from F3 to F2, could you reverse the lung damage, et cetera, over time?

Yes. I think -- I mean it's been interesting here to spend time with folks who've been looking at various ways of measuring lung injury. It's not easy to do in the animal model, but the levels of exposure and the levels of correction we get to, to the point on creating the MZ phenotype lead on lung. I think what is important to this pharmacodynamic modeling is we are able to look, as Chris alluded to on the call, at what level of Z protein reduction actually starts reversing aggregate damage where you see that reduction in liver aggregates and liver globules.

And in a 50% reduction in Z protein, we started to see that those dynamics shift in our preclinical models. So again, encouraging that we're seeing in excess of 70% reduction in Z. And so that ability both in the production of M, but really importantly for these patients because they're at risk of liver disease, being able to substantially reduce that Z protein should continue to shift that. And the advantage in that is, again, you now start making healthier hepatocytes, you start getting that turnover kinetics now with new hepatocytes that are corrected and aren't kind of saddled with decades of Z protein aggregation, you now get healthier cells that can make more protein.

So it's highly encouraging as we continue to think about this profile over a longer period of time. I think the other thing that was encouraging, too, in the liver baseline characteristics is that physicians were more comfortable putting patients on who were at more advanced stages of liver disease as the study progressed. And I think the notion that people were feeling comfortable versus, again, I think LNP background, patients with liver disease who occupy a substantial component of alpha-1 antitrypsin felt comfortable putting liver patients into the study. And I think it's important as we think about long-term treatment of both liver and lung patients.

Your next question will come from Cha Cha Yang with Jefferies.

This is Cha Cha on for Roger Song. Congrats on your update. I was hoping that you can share more about what we can expect from your FDA feedback update in mid-2026, assuming this is alignment on using AAT as a biomarker, but anything else we should expect there?

I think that's right. We're looking to have some agreement around using the biomarker to move forward. And again, it's not just total, but it's also how much M you have and how much Z you can decrease because you want to impact both liver and lung. And so we're excited to have those discussions with the agency.

Yes. I mean, I guess the key for us is much like others coming out with a very strong plan for what the path looks for the filing so that we could actually start guiding to the subsequent studies, right? I mean the goal for us is to think about this as a commercial program. So the goal is what's that path look like to commercialization, both on an accelerated approval pathway, but importantly, how we think about continuing to make sure that we address both lung and liver on the path forward. So I think this will be the beginning, and we're excited to provide that feedback.

Your next question comes from Alex Nackenoff with Truist Securities.

This is Alex on for Danielle. Congrats on the update. Just a detailed question from us. Can you explain the discrepancy in the reporting of the 400-milligram SAD data? I believe in the last cut, you reported the mean value was 12.8 micromolar. And today, you're indicating it's 14. Does that include additional patients, which drove the mean higher or removing the 400-milligram discontinuation? Just curious if these numbers were calculated differently and how to rectify those.

You've hit it because we've included a fuller data set with more patients for this particular analysis, everything up until the date of the data cut versus before.

So we didn't remove -- last part, we didn't take any -- just to be clear, we didn't take...

Yes, we didn't take any patients out. The one discontinuation completed their entire single ascending dose portion and then stop before the multiple ascending dose. So there was no patients that were removed. Go ahead.

Your next question will come from Michael King with Rex Biomed (sic) [ Rodman & Renshaw Research ].

Just a follow up on the previous question about the FDA interaction. Can you -- and it goes back to my question about the clinical benefit. The accelerated approval could come on the -- potentially on the biomarkers, but is there a clinical endpoint or endpoints that you think you might have to achieve over time to flip that to a full approval? Or do you think the biomarkers could allow for a full approval under the regs?

Yes. I think what's interesting, I mean, obviously, the focus right now is the accelerated approval based on biomarkers. I think the work that's happening around other tools in terms of CT densitometry, being able to do noninvasive imaging of liver, both give us opportunities. And you'd imagine that the discussions continue around those. And what's wonderful is those aren't just Wave having those discussions. So the clinical community, the alpha-1 community is engaged too through CPAP and other channels about really thinking about alternative endpoints that do and demonstrate benefits to long term.

Thank you. There are no further questions at this time. I will now turn the call back over to Paul Bolno for closing remarks.

Thank you, everyone, for joining the call. I'm grateful to every employee for their dedication and focus on our mission and on the patients and families we serve. And thank you again to the ATD community for your continued support and partnership. Have a great night.

Hello, and welcome to Wave Life Sciences First Quarter 2026 Earnings Call. [Operator Instructions]. Also, as a reminder, this conference call is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our first quarter 2026 earnings update. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Eric Ingelsson, Chief Scientific Officer; Dr. Chris Wright, Chief Medical Officer; and Kyle Moran, Chief Financial Officer. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Thanks, Kate, and good morning to everyone joining us on today's call. Coming into the year, we outlined our key priorities for 2026, accelerating development of WVE-007, our INHIBNE GalNAc siRNA program for obesity and rapidly advancing our RNA editing portfolio led by WVE-006 for AATD and followed by WVE-008 for PNPLA3 liver disease.

Today, I'm pleased to share an update on the significant progress we've made towards these goals. We are rapidly advancing 007, which has the potential to be transformational in the treatment of cardiometabolic diseases, including obesity. Using our best-in-class chemistry, 007 continues to demonstrate a highly differentiated profile.

Clinical data, even in a Phase I population continues to demonstrate improvement in body composition with fat loss, importantly, visceral fat loss and muscle preservation, impressive durability with potential for once or twice a year dosing and a clean safety profile. We're accelerating 007 to the next stages of development where we have the opportunity to unlock its full potential across multiple treatment settings, beginning with our Phase IIa trial in participants with higher BMI and with and without diabetes.

We are preparing to initiate our Phase IIa trial this quarter as the FDA has recently accepted the multi-dose portion of INLIGHT. Closely following the initiation of our Phase IIa trial in higher BMI participants, we plan to initiate studies evaluating 007 in combination with incretins and maintenance post cessation of incretin treatment.

In RNA editing, we continue to lead the field with 006. Clinical data from our ongoing RestorA-2 trial has already demonstrated the potential for 006 to provide a much-needed novel therapeutic option to individuals living with AATD, including generating over 20 micromolar of AAT protein during an acute phase response. It's important to note that these acute phase responses are the drivers of lung damage in AATD. We look forward to highlighting these data during the ATS conference and hosting an investor webcast to share our monthly 400-milligram multiple dose as well as single-dose 600-milligram data.

Having already achieved therapeutically relevant AAT restoration with our interim data, we are on track to receive regulatory feedback on a potential accelerated approval pathway in mid-2026. We're also building on our success in RNA editing to advance our next candidate, WVE-008 towards the clinic this year, which has the potential to address the 9 million individuals living with PNPLA3 liver disease.

Beyond our lead RNAi and RNA editing programs, we are continuing to push the boundaries of innovation through our bifunctional modality that allows us to both silence and/or edit to treat diseases with a single construct at a single dose. We're also advancing a growing pipeline of new hepatic and extrahepatic candidates. With the substantial progress we've made, we believe we are well positioned and well capitalized to advance our pipeline of transformational therapies for patients.

Now I'd like to turn the call over to Erik, who will discuss how we are leveraging our proprietary chemistry and human genetic insights to advance WVE-006 for AATD and WVE-007 for obesity. Erik?

Thank you, Paul, and thank you to everyone joining us on the call today. I'll start with WVE-006, our GalNAc-siRNA editing oligonucleotide or AIMer for alpha-1 antitrypsin deficiency. ATD is a uniquely compelling disease for RNA editing. It's a monogenic disorder caused by a single well-characterized genetic variant in the SERPinA1 gene, which leads to misfolded alpha-1 antitrypsin or AAT protein teredZ-AAT. Healthy circulating AAT turned MAAT protects the lungs during inflammatory or infectious events. ATD is sometimes referred to as genetic COPD for a reason.

Without dynamic production of functional AAT, patients are at risk of lung damage and ultimately developing emphysema and bronchiectasis, which is characterized by chronic cough, recurrent infections and shortness of breath. In parallel, Z-AAT accumulates in hepatocytes and causes progressive liver injury and risk of liver disease. By correcting the mutant transcript in the liver, RNA editing addresses the root cause of both the lung and liver manifestations of the disease.

Approximately 200,000 individuals in the U.S. and Europe live with homozygous PICV-AATD. It's a devastating disease, impacting the ability of patients to work, play with their children or even walk to the mailbox. Currently, the only approved treatment for AATD is weekly IV plasma-derived augmentation therapy, which carries several limitations. With a fixed scheduled dose, there is no restoration of dynamic response, leaving patients at risk if AAT protein falls too low during an acute space reaction as a result of infectious or inflammatory events. IV therapy is time consuming and often required in patient visits and IV therapy does nothing to lower AAT to address development of liver disease in these patients.

RNA editing is designed to restore heterozygous emptT-like phenotype, including AAT production that drives to meet the demand during acute space response. This is a particularly important distinction between RNA editing and the current augmentation standard of care that we continue to hear echoed in our conversations with physicians and patients as there is uncertainty that there is adequate lung protection when patients experience infections between infusions. Such acute exacerbations, the sudden worsening of a patient's respiratory symptoms that often require urgent treatment occurs roughly twice per year on average, even on weekly augmentation therapy. 006 is a highly specific and efficient GalNAc AIMer.

Unlike DNA editing therapies in development, RNA editing does not modify DNA and 006 does not require delivery with lipid nanoparticles or LNPs that may be as with systemic and liver inflammation, potentially inducing hepatocellular stress and activating a hepatic acute phase response. 006 also avoids reversible collateral bystander edits and inults, which are associated with DNA editing.

With 006, our goal is to recapsulate the emptylike phenotype as it is well established that heterozygous PINC individuals at significantly lower risk of both lung and liver disease. T individuals maintain basal AAT levels above the protective threshold of 11 micromolar, wild-type MAAT above 50% of total AAT and most importantly, they retain the ability to mount a dynamic AAT response during an acute infection. That combination, protected beta levels and meaningful proportion of authentic MAAT and a preserved acute face response is the bar we set for 006 and that we cleared in the interim readout of our RestorAATion-2 trial in the fall.

We demonstrated that 200-milligram biweekly dosing of 006 can restore endogenous MAAT protein to therapeutically meaningful levels and reduce mutant AAT correspond. This will lead to improved liver health and potentially even higher MAAT production over time, in line with what we have observed preclinically and ultimately lead to improved lung and liver outcomes in AAT.

Crucially, we have shown that 006 reestablishes the body's physiological response to inflammatory stress, something that is not possible with IV augmentation. Now with upcoming data from our 400-milligram multi-dose cohort, we look to continue to recapsulate the MC-like phenyat but at a more convenient monthly dosing interval. Moving on to our INHBE GalNAc-siRNA program for obesity WVE-007. Individuals living with obesity face markedly high risk of a range of diseases such as NASH, type 2 diabetes and cardiovascular disease.

Excess body fat, in particular, visceral fat is a key driver behind this elevated risk of disease. Current standard of care therapies reduce body weight through both fat and muscle loss and carry high discontinuation rates, limiting potential for long-term health benefits. An ideal obesity therapy would instead selectively reduce harmful visceral fat, the fat surrounding once organ that is most strongly linked to MASH type 2 diabetes and cardiovascular disease, while also lowering subcutaneous fat and liver steatosis and critically preserving skeletal muscle.

Muscle preservation matters. Why? Because muscle sustains based on metabolic rate, glucose disposal and insulin sensitivity. Also it prevents weight regain, mostly from fat, which occurs in the majority of individuals that discontinue increasing therapies. And remember, as much as up to 70% of individuals discontinue incretin within a year. Preserving muscle while decreasing total and in particular, visceral fat is the ideal profile for an obesity medicine and is well established at already a 5% to 10% reduction in visceral fat mass associated with direct health outcomes by reducing risk of multiple preventable metabolic diseases and preserving patient function and quality of life. All these benefits can be delivered by 007's mechanism of action.

Rather than acting on appetite, it silences in the knee and lower serum actin, a liver-derived hepatokine that signals adocytes put the brakes on lipolysis. Removing those brakes drives fat loss without calorie restriction and without the muscle loss seen with incretin-based therapies. This approach is also strongly grounded in human genetics as carriers of heterozygous in loss of function variants, nature's own knockdown experiments exhibit a healthier overall metabolic profile, driven by lower visceral fat as evidenced by lower waste-to-hip ratio and lower visceral lose volume as well as downstream effects with lower triglycerides, ApoB and HbA1c and higher HDL cholesterol.

These carriers also have favorable associations with liver traits such as ALT, a measure of liver damage and CT1, a measure of liver inflammation and fibrosis and importantly, lower risk of developing type 2 diabetes and coronary heart disease. And as we have said on prior calls, targets supported by human genetics carry a 2 to 4x higher probability of success in drug development. IvenE a textbook example of this opportunity.

We chose to target the activin E ligand through IBE silencing over its receptor ALK 7 for several reasons. Turning off protein production in hepatocytes to upstream source with GalNAc-siRNA is the most efficient and durable way to impact this pathway. Also suppressing activin E rather than disabling a receptor that induces signals via multiple ligands across different tissues is a more selective approach with lower risk of unintended consequences. This selectivity is especially important for long-term safety and for clinical translation. CER-07's unique ability to durably suppress IE is driven by our proprietary chemistry and SNAiRNAign.

While RNAi is a well-established therapeutic modality and there are extensive human genetic data supporting IBE as a target, we believe our proprietary chemistry distinguishes us from others attending a similar approach. 007 is highly differentiated by Wave's proprietary pheno design, including backbone serrochemistry and PN chemistry, which enhances interactions with AVO2, stabilizes the loaded risk complex and improves liver exposure. This contributes to dramatically improved potency and durability when compared with industry standard siRNA science. Our interim Phase I ENLIGHT data sets from lower BMI, otherwise healthy individuals confirm that this proprietary chemistry and the underlying human genetics are already translating with preservation of lean mass and clinically meaningful reductions in total fat, visceral fat and waster complement after just a single dose.

As Chris will discuss further in a moment, we're rapidly advancing 007 into patients with higher BMI and comorbidities in the Phase IIa portion of INLIGHT, where a scientific rationale predicts a larger effect. Activin E binds AP7 on allocytes and visceral fat being the more metabolically active and better pursued mobilizes first, exactly what we have observed in Phase I. Together, this means that we expect both visceral and total fat loss with 007 to be substantially more pronounced in higher BMI participants with more excess fat.

To review our clinical progress with 007 and our RNA editing programs in further detail, I'd now like to turn the call over to Chris.

Thanks, Erik. I'll begin by discussing our recent data and plans to accelerate development of WVE-007. In March, we shared interim data from the Phase I portion of our ongoing in-LI clinical program, placebo-controlled single ascending dose study designed to measure safety, tolerability and PK/PD. Participants were healthy individuals living with overweight or Class I obesity with an average BMI of 32, a population with less fat and lower BMI than those included in Phase II and Phase III obesity studies.

The safety and tolerability profile of WV007 remains encouraging, and we continue to observe robust, highly statically significant dose-dependent and durable active E reductions through at least 7 months. This combination of tolerability and durability supports a convenient dosing interval of once or twice a year that may allow for enhanced patient adherence, more persistent fat loss and better health outcomes.

Having reached 6 months of follow-up in our 240-milligram cohort, we observed further improvements in body composition following a single subcutaneous dose. This included placebo-adjusted visceral fat reductions of 14.3% well above the established threshold to deliver improved cardiovascular outcomes. Total fat reductions were 5.3% and lean mass was stable. There were also improvements across clinical measures, including a clinically meaningful 3.3% reduction in weight circumference. These results are particularly encouraging given this is a Phase I study of otherwise healthy participants with an average BMI of 32 and no dietary or exercise restrictions.

As Erik just spoke to, reducing fat, particularly harmful visceral fat while also preserving muscle is critically important for the treatment of obesity, including overall functional improvement and cardiometabolic health benefits. The current standard of care pushes the limits on high percentage weight reductions, but it comes at a cost of substantial muscle loss.

To provide context for our results at this early development stage, we calculated the visceral fat to muscle ratio or VMR, which is a measure of body composition that integrates harmful visceral fat and beneficial lean mass into a single index. Lower VMR is associated with decreased risk of NASH, type 2 diabetes and cardiometabolic disorders. We believe VMR has the potential to serve as a novel composite biomarker as compared to BMI alone that more holistically captures the body composition improvements driven by INHBE knockdown and that may better predict long-term clinical benefit.

With a single dose of 007 in our Phase I population, we've already observed a 16.5% improvement or greater reduction in BMR which was more than the 12.2% achieved with weekly semaglutide in BELIEVE and approached the 18.8% observed with vimanrimab. What makes this comparison particularly exciting is that our INLIGHT participants had substantially lower BMI, visceral fat and total fat compared to Phase II or Phase III obesity studies. Clinical experience highlights the importance of baseline adiposity.

Early Phase I studies in leaner subjects show modest fat reductions, while studies of individuals with higher baseline obesity demonstrate large clinically meaningful losses in total and visceral fat mass.

Early follow-up from our 400-milligram cohort, which included a substantially higher proportion of individuals with lower levels of visceral fat also confirmed that higher baseline visceral fat leads to greater visceral fat reductions overall.

Collectively, these data emphasize the impact of baseline body composition on therapeutic effect and support the potential to deliver even more pronounced improvements in body composition in the Phase IIa portion of INLIGHT, given participants higher excess fat at baseline and 007's mechanism of targeted lipolysis.

Following the FDA's recent acceptance of our protocol amendment, we remain on track to initiate the Phase IIa multiple dose portion of INLIGHT this quarter. This global placebo-controlled trial will enroll individuals with higher BMIs in the range of 35 to 50 and comorbidities across 2 dose levels, 240 milligrams and 400 milligrams and 2 study populations with and without type 2 diabetes for a total of 4 cohorts of 40 patients each.

Assessments in the multi-dose portion are similar to those in the SAD portion with additional inclusion of body composition measures by MRI, liver fat content measured by MRI-PDFF, HbA1c, lipid levels, CRP and muscle function. The design and study population enables enhanced evaluation not only of improved body composition and weight loss, but also informs additional opportunities for 007 in NASH, type 2 diabetes and cardiovascular disease.

Participants will be given 2 doses of 007 at day 1 and day 85 and followed for 12 months with the first main assessment occurring at day 85. As Paul discussed earlier, we are also planning to initiate trials evaluating 007 in combination with incretins and as maintenance post incretin this year. We believe that 007's orthogonal mechanism, ability to drive reductions in fat while preserving muscle and favorable safety profile are actively suited to combination and maintenance approaches.

Our preclinical data provides compelling support for both use cases. Planning is well underway for studies addressing incretin combination and post incretin maintenance, and these will initiate this year. We also expect to share additional data from the Phase I portion of INLIGHT this year, including data from our 600-milligram cohort, which will further inform the durability of 007.

Turning to our ongoing RestorAATion-2 clinical trial of WVE-006 for AATD. We continue to advance this study while engaging with key opinion leaders and patient organizations who are eager to be involved. As we speak to key opinion leaders, there are several aspects of our data that excite them. one, restoring a dynamic AAT response to address acute lung infections; two, decreasing harmful Z protein to address liver disease; and three, offering a safe, well-tolerated infrequent nonintravenous treatment for patients that avoids permanent genetic modifications.

We look forward to presenting an expanded data set during ATS on May 18, which includes data from the 400-milligram monthly cohort as well as the 600-milligram single-dose cohort. Continuing to recapitulate our prior interim results with a less frequent dose would strengthen the overall profile of 006 as a differentiated patient-friendly therapy for AATD. In addition, we plan to share from the 600-milligram multi-dose cohort in the second half of this year.

Now turning to our second RNA editing clinical candidate, WVE-008 for homozygous PNPLA3 I148M liver disease. This PNPLA3 variant is a well-established driver of NASH pathology. Yet there are no approved medicines that directly address this biology. There are an estimated 9 million homozygous PNPLA3 I148M carriers across the U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers.

With 008, we aim to correct the I148M variant using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid metabolism, reversing steatosis and fibrosis and improving liver health.

In our upcoming first-in-human study of 008, we plan to leverage previously genotype populations to efficiently identify homozygous I148M carriers, evaluate target engagement with circulating biomarkers and assess early signs of efficacy using noninvasive imaging. We remain on track for a CTA submission in 2026.

With that, I'll turn the call over to Kyle to provide an update on our financials. Kyle?

Thanks, Chris. Our revenue for the first quarter of 2026 was $38.2 million compared to $9.2 million in the prior year quarter. The year-over-year increase primarily relates to recognizing the full amount of revenue associated with WVE-006 as a result of regaining full rights to that program, along with the progression of work in our ongoing GSK collaboration.

Research and development expenses were $47.4 million in the first quarter of 2026 as compared to $40.6 million in the same period of 2025. The increase primarily reflects continued investment in advancing our clinical programs, including preparation for the Phase IIa portion of INLIGHT and continued progress across our RNA editing pipeline. Our G&A expenses were $22.1 million in the first quarter of 2026 as compared to $18.4 million in the prior year quarter. This increase primarily reflects costs associated with supporting our expanding pipeline and preparing for the next stages of development.

As a result, our net loss was $26.1 million for the first quarter of 2026 as compared to a net loss of $46.9 million in the prior year quarter. We ended the first quarter with $544.6 million in cash and cash equivalents, which we expect will be sufficient to fund operations into the third quarter of 2028.

I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. As we look ahead, we believe we are well positioned and well capitalized to continue delivering on our clinical development plans. We are rapidly advancing multiple studies of 007 across treatment settings, which are strategically designed to unlock its full potential in obesity and other cardiometabolic diseases. We're delivering new 006 data in May that will continue to inform its potential to provide a differentiated treatment option to individuals living with AATD.

And we are progressing 008 towards the clinic for the 9 million individuals living with liver disease. With our proprietary chemistry translating in the clinic and an emerging pipeline of next-generation candidates, we are committed to translating powerful human genetic insights into potentially transformational RNA medicines for people who need them. We look forward to keeping you updated on our progress.

And with that, I will turn it over to the operator for Q&A. Operator?

[Operator Instructions]. We'll take our first question from Joe Schwartz from Leerink Partners.

Congrats on all the progress. It seems like a treatment approach targeting INHBE biology could be somewhat sensitive to baseline patient characteristics. So I was wondering, how are you thinking about optimizing for that in future trial design? Are there any screening or enrichment strategies you could implement to enhance signal detection?

Yes, Joe, and we appreciate the question. I think first and foremost, in the obesity study, as you point out, is particularly, as Chris mentioned on the study, a mechanism that's driven on hypolysis is excess fat, the requirement to have not just large BMI, but have fat to lose in order to have a reduction in fat, which is typical in most Phase I to Phase II transition. So if we look at the BELIEVE study, we actually haven't updated those who look at the 8-K today on the corporate deck on Slide 24, the realization that as you shift patients from a low BMI, low fat setting to a higher BMI, high fat setting, meaning the shift that you see from where our study started, which is where the BELIEVE patient ended to where the BELIEVE patient started both on semaglutide and bimagrumab.

There's an elevation not just in visceral fat, but on the left panel that slide, an increase in total fat. And so when we see those changes, we do expect, as you said, to see that reduction. Now what can we do to actually assure that as we enroll patients in that study that the patients exhibit the phenotype, meaning in an obese study are not just large in BMI, but large in visceral fat and in total fat.

And I think there, we've seen pretty consistently that if you use other metrics like weight circumference, allowing comorbidities, those patients do tend to fall into that range. One other opportunity we have to assure this as the study is enrolling is we are, as Chris mentioned, doing baseline MRI imaging on these patients as we start. So we will have the opportunity to look at baseline images to ensure that patients are collecting in that region.

We will take our next question from Steve Seedhouse.

I wanted to ask about the regulatory interactions in AATD and just get your thoughts on if the FDA -- or really just the discussions you've had, if the FDA is looking for specific MAAT levels, if that's part of the thinking here or if like the degree of MAAT increase that would support approval or accelerated approval is going to be more of a review issue. And then I'm also curious if you know yet if the primary analysis in a pivotal study here is going to be more of like a responder analysis on a certain threshold or if it's more of like a mean change in MAT or total AAT in the entire population?

Yes. No. Thanks, Steven. I'll start and then turn it over to Chris for further comments. But I think one is, obviously, we don't comment on individual interactions, but we will have feedback as we get to midyear. So it's safe to assume we're preparing and engaging in those conversations. I think in general, it's about the dynamic response, right? So it is this kind of shift from -- and based actually on comments that the FDA has made actually publicly, specifically as it relates to AATD and patient meetings, they did refer to AATD as an ideal example of a plausible mechanism pathway, meaning that there's the opportunity that we can see that editing translates these patients from a ZZ phenotype to an MZ phenotype.

So I think that we -- as we move past this kind of just threshold concept of what does it take to be an MZ patient, well, greater than 11. But we need to step back and remember that actually, the 11 micromolar, as people discuss that threshold level increasing is one of protein replacement therapy, this idea with a consumptive protein that you need to put more in, in order to have that when it gets depleted during an acute event be there. I think the context of not just Wave, but as we've seen B as well, seeing that when you do edit, you see this restoring of this dynamic response and what is the ability of that dynamic response to actually protect patients.

I think those are the best examples of the plausible mechanism meaning if you're at that greater than 11 micromolar and over 50% of that being N protein, then you're in the position that when you have a proportionate CRP or inflammatory response, you can mount that proportionate response in both total protein and in N protein. And that's exactly what we saw. We saw actually, if you model the CRP exposure that we saw, we saw an MZ level response both in total protein exceeding 20 micromolar and over 10 micromolar of protein in that individual. So that dynamic response is what's required being demonstrating the total both on threshold and percent M, we think is important. And those will be the nature of the conversations that we'll be having with the agents. And I'm sorry, the last -- you...

Last, I think responders versus me and the like. I think those are exactly the types of questions that we'll be engaging with the FDA on the pivotal studies. So more on that as we have those discussions.

Yes, it's important to note, remember that these patients are coming in with 0 and protein. So the idea that this is all de novo functional from editing to those responses is crucial. And I think the agency has been receptive...

We'll take our next question from Cheng Li with Opp &Co.

Congrats on the update. I'm just curious about the 007 like future clinical path, recognizing the body composition is an important feature for this mechanism. And also you mentioned several measures, including BMR. I'm just curious about which one you think can be incorporated into the clinical trial to support registration that you think has the best chance.

Yes. I mean I think as Chris mentioned, we're going to have a number of endpoints in this study that independently help us build the cardiometabolic profile. So obviously, we'll have body composition measures anddexXa looking at total fat, visceral fat. We'll have MRI imaging as well. And importantly, MRI-PDFF to look at liver fat. I mean I think that's going to be interesting as these patients would be expected to have increases.

In addition to that, as we think about just why when you have -- and I think about Phase I studies where you exclude comorbidities of why you end up seeing this lower level of total fat, but importantly, visceral fat, visceral fat is harmful fat, and it's responsible for a number of these other cardiometabolic risk factors, including diabetes and cardiovascular disease. So one of the opportunities we have in removing the cardiometabolic -- sorry, the comorbidities in addition to allowing patients with and without diabetes is we're going to have the ability to see what's played out in human genetics with reduction in IHIB-E, which is reductions in hemoglobin A1c.

Well, that's a registrational endpoint in the treatment of diabetes. We'll be able to look at ratios of triglycerides and HDL in terms of insulin sensitivity, and we'll be able to look at other measures like CRP from an inflammatory standpoint. So it really is important as we think about this study as being able to open up, one, how do we think about the treatment of obesity and what's really important, and we are seeing a big shift, particularly in the last quarter on finally discussions about body composition being what target and what should be targeted for these patients with an ability to tie that to an impactful measurement that will be in the appropriate Phase IIa.

And as Chris said, I mean, we'll have a 160-patient study across doses, across disease states that really will let us fully exploit the mechanism and shortly thereafter. So again, accreting the data to where I do think there's a substantial opportunity for INHBE which is in the maintenance setting. This idea that 70% of people can't stay on incretins. And if we think about the therapy for obesity with incretins being like the treatment of hypertension, we're seeing patients who need a lifelong treatment to stay in this range of body composition that they achieve.

I think we're also going to have the opportunity as we think about the Phase II studies that we will be initiating the concept of being able to have and lock in, in a maintenance setting an infrequent way of treating patients and preserving and locking in the benefits from a cardiometabolic outcome position that's been achieved with other weight loss therapies. So I think the totality of data that we'll be generating to unlock the full mechanism of is both in this Phase IIa study in the multi-dose, but also in the subsequent studies that we will be initiating.

We'll take our next question from Samantha Lynn Semenkow with Citi.

Just one for me on AATD. I think your explanation around the dynamic nature of the mechanism makes a lot of sense. I just wonder from a competitive landscape, we're seeing the DNA base editors get up to a mean of about 16 micromolar total in MAT. We've seen at least one patient from another competitor go up to 20. Do you think optically you need to achieve some sort of threshold in order to entice both patients and physicians to use an RNA editing approach? Or have you done any market research around this? Just curious your thoughts there on what the actual profile could end up being and how competitive that would be?

Thank you. And I mean this is where we spent a lot of time with clinicians as again, in preparation as we think about ATS coming. And I think there's a lot of enthusiasm from this community RNA editing. And I say that for a couple of reasons. I mean, one, the idea of being able to -- and we'll talk about kind of the thresholds and numbers in a minute. But I think the most important thing is that if we think about the ability to be able to infrequently redose patients, it's important because over time, the liver does regenerate.

And the idea that as these cells that are on a pathway to dying and becoming fibrotic are actually now rescued and saved because you're able to, through editing, deplete protein, take those toxic aggregates out of the liver, restore liver health, those cells are now right to be able to be dosed and have actually correction and actually become productive in their responses and producing healthy M protein.

And so as we talk to clinicians, that notion of infrequent repeat dosing is actually viewed as actually favorable as opposed to the risks and potential outcomes from permanent DNA mutations. I think the other thing that as we think about patients who have liver disease and ZZ patients, where they are on the spectrum will have liver disease is the notion of not using LNPs. We have to remember that LNPs activate IL-6 and the CRP immune response and in and of themselves are immunogenic.

And if we think about that as being a causing and inducing an acute phase response could also elevate 1 antitrypsin and a protective response to that. And so the notion that in patients with liver disease, we want to avoid things that are going to irritate the liver is also important as we think about the totality of the therapeutic modality that clinicians are thinking about in terms of their treatment of patients. Now while all of that is wonderful, at the same time, what we want to see is the ability to actually drive the correction. And so as we think about the production of protein and what RNA editing is designed to do is entirely specific.

So when we talk about protein and oftentimes, these things get inflated with numbers, when we say M protein numbers or M protein percentage, we are talking about purely the actual isoform of AATD. So this is the native M-AAT protein. And as the prior question suggested, that's something we're discussing as part of our regulatory interactions, which is that we make only the native M-AAT protein. We don't create bystanders. We don't create indels. But importantly, those bystander edited proteins have different ranges of function. So we can be assured that the protein we're creating behaves like the native natural protein.

So as we kind of shift back to the beginning of your question, which is what's going to be important as we think about this, I think where we've also seen clinicians is not being able to make that switch to thinking about. And actually at ATS, it's going to be interesting because it will be wave on presenting on editing and then there will be the updates on protein replacement therapy. It's really this shift from having to say, well, more is more to baseline because that is a protein replacement narrative that's you have to put more protein in because the patient can actually produce more.

And so therefore, it's a race to put more protein in that gets depleted. We'll have the opportunity to continue to say, with editing, you can now create that dynamic response. And as we said, we can create a dynamic response that's proportionate to a CRP response up to 20 when the patient needed 20 and could have easily generated more if the patients needed more.

So I think if we think about the range of both total and protein, we are very much convinced that we can create the baseline levels that serve as the biomarker to demonstrate that these patients are able to go out, live a healthy functional normal life and have the appropriate responses to these acute phase events as they happen. And I think one of the most interesting things when we went back and kind of looked at that initial patient wasn't just the spike the patient had that got up to 20, but it was the realization and every went back to those slides that are there on this dynamic response that over the multi-dose, these patients had small elevations in CRP.

And what was really compelling is every time they had those adjustments, they were generating an increased response to total protein that met that. So I think by restoring this dynamic response, that's ultimately how you prevent the chronic injury that happens for the 1 to 3 times a year that these patients needed.

Our next question comes from Alec Stranahan from Bank of America.

Just a couple of quick ones on the Phase IIa portion of INLIGHT. Could you walk us through how you're thinking about the dose selection given the Phase I portion is still ongoing? And will GLP-1 use be allowed in this population for enrollment? Or is this maybe a population you'll reserve for future studies? And in terms of cadence of data from the Phase IIa, is your plan to share regular interim updates like the Phase I, maybe, say, at the first 3-month assessment following the first dose?

I'll take the last question and then hand it over to Chris. But in terms of the cadence of data at this point, yes, it's possible that we could deliver the initial, as you pointed out, 3-month time point. We'll give a more concrete update on milestone cadence when the study initiates and as that study launch. But yes, there's a possibility of data as we think about this year. Chris, do you want to take the first question?

Sure. So in terms of the doses chosen, so this is really based on -- I mean, it is ongoing, but we clearly have interesting data on 240 as well as 400. And so based on the data that we've seen in terms of the level of knockdown, PK/PD modeling and the degree of efficacy that we saw even at 240, we felt that we could move forward in the multi-dose with the 240 and 400 and that these should be the range of doses that are expected to be efficacious also based on the modeling. So it kind of all falls together, modeling from preclinical. So it all kind of falls together from that perspective, and that's how those 2 initial doses were chosen.

In terms of incretin in this particular study amendment, it's a monotherapy amendment. So we're not allowing incretence. However, we're in the throes of combination study design, which would include incretN and we'll provide more information on that shortly as well.

Just to follow up on the last point. I mean, as Chris mentioned, I mean, we do see substantial reductions in the 2 dose cohorts that we're taking forward with very tight ranges between patients. And so I think a lot of what we're going to learn is not just getting more efficacy from that, but the impact of time, durability and which dose is going to allow for the most less frequent interval while not losing any efficacy signal.

Our next question comes from Yun Zhong with Wedbush.

So the question is on the Phase IIa portion of the obesity study. On the second dose, do you have any expectation on the potential impact on gene and protein expression? And in terms of the clinical outcome, would you expect the benefit to be on durability or the magnitude of fat reduction or both because you're changing the patient baseline characteristics. So I just wonder, will you be able to tell whether that's -- and any potential better outcome will be from repeat dosing or from the more higher BMI or both? Will you be able to tell the difference, please?

Yes.

I can just say our the way that it is designed and what we know about the pharmacokinetics and pharmacodynamics, we expect a very substantial knockdown with the 2 doses that would be very persistent over time. So we think that, that's a great approach to identify the right doses and understand the duration better and to optimize our likelihood of efficacy.

And then to that point, and you also mentioned it, the patient characteristics are different. And so the dose response could also be slightly different in people that have higher levels of obesity or higher BMIs. And so it's important to look at a number of doses in that context as well. But we would expect that we should see stronger results there, as we outlined earlier in the sense that this is a drug that increases fat metabolism. And so the more you have to metabolize the bigger the effect should be.

Just to add one more thing as well. The design here, the 0 and 3 months dosing is really to accelerate the Phase IIa trial. It's not because we do think we need to give the dose that frequent. So all of our PK modeling indicates that it's once a year or at most twice a year. So it's a way to kind of accelerate and facilitate data readouts fast.

And to that point, I mean, if you look at our 240, I mean, past 7 months, we're still seeing suppression of activin E. So again, with 400, we expect that to be larger. But you also bring up an interesting question on just -- and I heard you mention genetics. I mean I think we have to go back to the genetics and realize that activin E is a biomarker. Hence, we're able to look at the impact of the reduction on the actual protein biomarker over time. And when one looks at that interaction, there were the discussions that had come up a while ago about diabetes, nondiabetes.

And I think the data that has been shared to date doesn't demonstrate that these patients should be different in disposition, whether they have diabetes or not. Actually, the data that was run in that, I think it was an over 300-patient observational study from Alnylam clearly showed that acne correlated with high BMI, insulin sensitivity and truncal fat in nondiabetic patients. So I think the implication here is really that if you can dial back a protein that drives hypolysis, then you're going to see that impact.

Now we're going to be able to be in a position where we're going to look at that in different settings. So we'll have it in the nondiabetic setting, the diabetic setting will look at how that plays a role, particularly on endpoints like hemoglobin A1c. So if we think about the implications for broader cardiometabolic disease beyond obesity, we'll be able to look at what happens with insulin sensitivity, what happens with hemoglobin A1c for diabetes and other measurements in lipids and inflammatory markers as we think about cardiovascular disease.

So I think the study is really stepping back and letting us look at the broad range of cardiometabolic diseases in those different patient settings.

Our next question comes from Salim Syed with Mizuho.

Congrats on the progress, guys. Paul, Chris, maybe one for us on the data coming out on 006 and ATS. So is it possible to just kind of give us high level kind of what people should expect here or look out for? I mean, obviously, the data that was presented in September of last year, the 200 single and 200 multi, there wasn't much of a dose response or even got to the 40 milligram single that you guys continued progress here with the 400 multi and then we'll be getting 600 single and then I guess, in the second half of this year, 600 multi. So is there any reason here people should be expecting some sort of threshold effect as you break through the higher doses that we get more efficacy?

Yes. I mean... No, it's a great question. I think if we went back to September, there's actually a dose response if we think about M protein. It went from 0 to like 44% to 65%. So I mean, I think if we think about the context of where patients start and how that builds over time, I think editing can continue to grow. I think with the question of is more going to drive more in the absence of an acute phase response, that's really the distinction that we're separating, which is once you hit a point where you can catalytically edit, the transcripts that are necessary. It's really a function of time. You deplete Z protein, the Z protein continues to come down and clear from the liver, the cells get better. And you should, over time, as we've seen with MZ patients who actually don't have liver disease over their lifespan, they can actually generate more protein.

And so I think that notion of correction over time is important. But I think our guidance is we were able to mount a response that could generate a lot of proteins, 20 micromolar if you had the right event. So it's not substrate limited to the effect that people will say, is the enzyme exhausted or there is substrate limitation in the context that if you're not having an acute phase response and the body is not producing or needing to produce protein that it won't produce more. And so I think that's been the example we've seen and others have seen.

I think what we're able to do is look at this without the conflation of LNP irritation, which can also create kind of a inflationary signal of inflammation. In a signal where you have GalNAc, you can go directly to the target site, we do see that when you have these elevations of acute phase responses that you can meet those dynamics. So I think stepping back, if we could see that we could produce the same levels, meaning you could create stable levels of very micromolar, we were 13. So edited protein that's M that's above, again, the MZ threshold, so again, above 50% protein and be in a position where you can protect patients from a dynamic response, but now no longer have to deliver biweekly injections to get there, but demonstrate we can do it monthly or less frequently. I think that puts us in a very good position in terms of the regulatory context and ultimately, most importantly, to treat patients with alpha-1 antitrypsin.

Our next question comes from Roger Song with Jefferies.

Also on the INHBE. So understanding you will have a poster at the ADA. So just curious what kind of incremental data we will -- we should expect to see? And then regarding the FDA interaction, have you had any discussion around the 5% is coming to the total body weight reduction versus we can look at a total fat or even visceral fat reduction threshold moving away from the overall body weight given the novel mechanism?

Thank you, Roger. And I mean, to your first question, yes, we will have a poster at ADA. As it relates to new data cadence, we haven't provided any updates other than 2026, we'll be providing continued updates on 007. To your second question, as it relates to kind of regulatory thresholds and 007, I think it is important that there is a broader range of discussions beyond a flat 5% change in total body weight.

Nonetheless, it's why I think Slide 24 in the new corporate deck is important because I think the notion of -- and I know people were kind of trying to think about with visceral fat, it's kilogram.5 k and if you lose that, and everybody is trying to figure out where body weight reduction comes from. But if you look at the parallel side of what happens to total fat in that population, you've got about 48 kilos of total subcutaneous body fat that gets produced that ultimately delivers weight loss.

So I don't think we're needing to necessarily have a different conversation around how in a Phase II/III obesity study in patients with excess fat, how you can deliver on that 5% threshold. Nonetheless, I think there is a very robust conversation that we're preparing for with the agency, where I think there's a lot of alignment, particularly in this administration, thinking about the impact of pharmacovisceral fat. I mean there's 2 decades of literature on elevations of visceral fat driving NASH, driving cardiovascular disease, driving diabetes. quantitatively, meaning a 10% change in visceral fat changes outcomes that are clinically. And what do payers pay for? They pay for outcomes.

And so as we think about the endpoint of visceral fat reduction as actually being the driver of what makes patients unhealthy, that focus on being able to reduce visceral fat is important. As Chris pointed out, it doesn't -- there's not a lot of complicated mathematics to take BMR and look at the impact of visceral fat and lean mass preservation. There's literature around that. So this is not a new metric of identifying how you can change body composition in a positive way. And very much, we do plan to have a conversation with the agency that specifically focuses on looking at other metrics like BMR and visceral fat as an endpoint, not just to the exclusion of the 5%, but even in addition to that, being able to build in the real impact of improving body composition, which is what's required for the treatment of obesity is important.

And I think we all need to remember that obesity is a cardiometabolic disease. And so ultimately, a lot of the endpoints that we're measuring hemoglobin A1c, insulin sensitivity driven off of visceral fat reduction are going to be important. So yes, it will be very much a topic of conversation this year as we think about the path forward.

Our next question comes from Bill Maughan with Clear Street.

So I wanted to just mix things up and actually ask about your exon skipper program. While obviously not as massive a market as obesity, it is a fairly near-term opportunity and a potential significant revenue driver, yet there seems to be a bit of a lack of, I guess, emphasis just around discussions around Wave on the exon skipper. So I just wanted to get your most recent kind of thoughts on how big that could be commercially and whether or not there's potential for that to surprise a bit and get a little more credit than it's being given currently.

Yes. No, thank you for the question. As we think about DMD, I mean, we have delivered a differentiated approach with the clinical data update we gave. As we said, we were in the process of delivering and putting together that studies continuing to get to the monthly dosing regimen, which we believe would be, again, differentiated and required for an NDA filing. So that work continues to remain on track.

I think as you also point out, as we think about the opportunities of allocation of capital in terms of building out to commercialization, we have said that we do plan to engage in strategic partnering discussions as it relates to that transition and commercialization.

And we continue to look for several things evolving. One, the evolution of the commercial landscape as we look at the product dispositions that are out there and two, the regulatory environment. So I think over the course of this year, there's going to be a lot of opportunities for us to make those assessments in commercial landscape, the regulatory landscape as we can continue to deliver on that pathway.

Our next question comes from Ben Burnett with Wells Fargo.

Our next question comes from Danielle Brill with Truist Securities.

Our next question comes from Luca from RBC.

This is Cassie on for Luca. Congrats on all the progress and a quick one on the competitive landscape for obesity. Your competitor is moving into combination approaches relatively earlier on in development. Could you -- maybe could we take that as maybe signaling that monotherapy alone has inherent limitations in obesity treatment for INHBE? Paul, you already gave some color on this, but do you believe there's a feeling what INHBE alone can achieve? And are you concerned that waiting until Phase II or later to explore combinations may put you in a competitive disadvantage versus competitors already testing combo strategies? Sorry for the long question, but any color would appreciate.

I think it's a wonderful question because I do think already, if we look at where we were relative to just our Phase I population with our single-dose data, we are competing with visceral fat reductions that were in multi-dose of others, right? And as we think -- including combination. So I think if we think about what we have is differentiated, and I think Eric shared that during his update on the call, our chemistry is giving us a high degree of potency and durability. And if we think about the INHBE target itself, it requires not just potent reduction, but requires stable suppression.

And so this notion of being able to keep that target low despite any desire of the body to upregulate it is a key differentiator. We saw that in preclinical data that differentiated us from our competitors where they to do repeat dosing of a GalNAc siRNA to drive weight loss. Remember, these are obese mice. So the mice that we're all talking about in these studies were mice that would be much more representative of your Phase II/III high BMI mice. And what do we see? We saw that if we could give a single dose and suppress activin E, we could see weight loss in that model, driven off of fat reduction, visceral fat reduction, subcutaneous fat reduction.

So I think we're seeing strong clinical translation on potency and durability distinction from our competitors, such that absolutely, I think we will see continued fat loss substantially with muscle preservation in this high BMI setting. So I don't think that there's necessarily the ceiling effect as much as it is the treatment effect in the appropriate population.

As we said a number of times last year, it was always going to be about treating the patients with the right disease setting, meaning the Phase II/III population of obesity, high fat with the right dose over the right amount of time. So I think we're set up to see that. Nonetheless, I think the power, as you point out, in combinations is very real. So if we stay in the monotherapy, we do believe that, that's going to be a segmented marketplace. We think about the opportunity for -- I think there's nearly 30 million people in the U.S. who are at risk of lean mass reduction who need weight loss.

And so as we think about segmentation, I think there is a substantial population monotherapy that's going to need fat reduction without the risk of lean mass loss. Combination nonetheless is a very interesting place to be. I don't think we're losing our lead there.

As Chris alluded to, we're actually accelerating the combination studies. And so already at a monotherapy piece, we have a distinction from our competitors. And again, we believe that in combination, we should see a more robust effect by being able to add INHBE onto existing inreatment therapies. And so the opportunities there are twofold. I know on one hand, we tend to think about giving more and trying to drive even more weight loss, importantly, fat loss, which comes from INHBE.

I think we've got another distinction, which is the ability, frankly, not to have to kind of push incretin to the edge of tolerability, but being able to think about actually in this environment, particularly as we watch that space evolve, being able to actually have to give less incretin therapy in combination to exert a maximal effect. And so I think there's a big piece on titration where INHBE can add to that combination strategy to ultimately drive profound visceral fat loss, subcutaneous fat loss along and coincidentally with incretin.

And then ultimately, where we have generated data uniquely, I think for Wave with INHIBN-E, I think this maintenance setting is actually a wonderful place to be. We were just on calls recently where there's a lot of thought going into what does the evolving treatment landscape look like in a world where like antihypertensive, obesity treatment is now going into a place where you have patients who have BMI reductions.

And frankly, now you have payers saying, now that you're no longer meet the BMI criteria, you might need to come off therapy. And so there's actually now discussions on the payer side of saying, actually, you're going to lose those benefits and actually build a maintenance setting.

So as that maintenance concept evolves, so what does a lifelong therapy look like that preserved outcomes, I think this maintenance opportunity is pretty substantial for us that if people invest, payers invest in getting to that healthy, stable outcome, how do you sustain that in a way that's going to be tolerable is not going to help drive additional complication side effects, tolerability effects and the potential for now a once to twice a year maintenance therapy is consequential. So I think all 3 settings are set up for us to be uniquely differentiated. And as we said, all 3 studies are pulled into this year and being accelerated. So we'll be generating human data in the right population in all 3 of the settings.

Maybe just to add one more thing. So since this is new biology as well, I think it's important to really try to understand the potential across a lot of ways, and we have so many ways of winning this year, like we're going to look at the 5% threshold for weight loss. We're looking at body composition with a focus on fat loss. We're looking at potential cardiometabolic protection across lipids, HbA1c with diabetes and fat in liver for MASH.

And then in addition, the combo and maintenance. There are a lot of opportunities, and we're accelerating. So we're going to get all of that data and starting everything this year.

Our next question comes from Catherine Novack with Jones.

I just have one on the 006 multi-dose regimen. I guess knowing that successive dosing can push mean max AAT higher, how should we be thinking about mean max AAT achievable with monthly versus biweekly dosing that was used for a multi-dose regimen prior readout? And how do we think about the delta between the single dose and the multi-dose when we're switching to monthly?

Yes. I mean I think one -- and I'll take the second part first. I think that will be interesting, right, as we look about what's the difference in terms of the on rate, if we think about it between the 200 to 400 and the 600. So we'll have the opportunity to look at what do those kinetics look like as you point out. And then the difference between biweekly dosing versus again, monthly and then the impact on those rates. And I think, again, -- our framing today is that if we assume that we are getting a biweekly 200 to near steady state in the sense that it's not substrate limited, but in the absence of an acute phase response where you're producing more transcript that you're not going to necessarily get more without the benefit of time, right, the ability of cells to clear out the cells to get healthier producing hem. That's going to be the chief driver of seeing those increases. And so we'll be able to look at what happens on the repeat dosing of monthly versus biweekly.

But I think that's the big shift in the dosing regimen. I think 600, as Chris alluded to later this year, 600 monthly would give a better sense of keeping the kinetics and the timing of those dosing intervals coupled with dose to get better. But this is really to see can we see that we get to that same steady state, the ability to balance acute phase responses of as much protein as patients need, they can produce, but do that in a monthly I think that's going to be the driver for this next update.

Our next question comes from Whitney Ijem with Canaccord Genuity.

I think just to quickly follow up on the last question. I think you've answered it, but just to put a finer point on it, is what you're saying that given the time frame of the next update, we shouldn't necessarily expect to see a dose response on either total or M protein at steady state at ATS in particular, but that dose response could come over time or maybe in the setting of an acute phase response later. Is that the right way to think about it?

I think the way to see it is when we should -- it is going to be that. We'll see what the driver is of more. But again, I think our demonstration to date, even looking at the early data is we got to more, right? We got to 20 micromolar in the setting of an acute phase response where you actually generate more substrate, more transcript to be edited. So I think at a certain point, there's going to be this concept of steady-state editing where as much transcript is being edited, you can clear Z. I think that's going to be what we clearly want to see as Z protein continuing to come down. And then there's a function of time. And so I think it's more than thinking about dose at the time of what -- how much duration is there for the body over time to clear Z, get healthier hepatocytes that can produce more protein. I don't know if there's...

Our next question comes from Madison Wynne El-Saadi with B. Riley.

Just looking at the Phase IIa MAD design, I mean, it's certainly looking like a CV MAT versus, say, pure obesity study. I'm curious if -- did the FDA acceptance include any commentary on body comp as a kind of co-primary -- or was it more of a kind of protocol discussion?

And then relatedly, what's the magnitude of MRI-PDFF reduction in Phase IIa in lGHT that management would view as supporting a stand-alone MASH development versus, say, a subsegment of the obesity program?

Yes. I mean I think to your first point in general, I do think it's just important, we can't say this enough that obesity is a cardiometabolic disease. So running a study that fully interrogates the cardiometabolic implications of a target that comes out of human genetics that is a cardiometabolic target. So I think being able to fully extrapolate all of the value of what does that mean for a patient beyond just as you said, at classic obesity, which is the classic studies are looking at weight loss at the expense really of muscle and muscle drives the predominant early reduction in that body weight.

So being able to shift the narrative to not just reduction of fat that will be important in the treatment of obesity, but all of the other advantages that come to patients and frankly, are recognized by, again, what payers pay for, which is the cardiometabolic improvement is what this study is designed to elucidate.

So yes, we'll be able to look at body composition, and that's part of the endpoints as we said, as part of an obesity study in addition to body weight. But all the important metrics, as you point out, are critical for us because they are all part of the development paradigm here. The last piece is, I mean -- and we've seen this with others and competitors who've done monotherapy reduction of liver fat, and they saw consequential reductions in liver fat that pretty much surpassed other match programs and reduction of again, fat in the liver.

So given our potency, durability, given that we wouldn't expect this mechanism to be differentiated, we should see in terms of like reduction in liver fat because of what we're doing, we would expect to see substantial reductions and that target engagement there, reduction of fat on imaging would guide us to say that MASH would be a target to pursue a dependent.

Maybe I add one more thing, and that is that these cardiometabolic risk factors and liver fat are very strongly correlated with obesity and visceral fat. So it's not so much that we're not requiring -- it's not an inclusion criteria. It's more that we're removing the exclusion criteria from the Phase I, which hampered us in terms of looking at those things. So again, we -- just based on the normal distribution of liver fat in this obesity class, we expect that there is liver fat that we can look...

Our next question comes from Michael King with Rodman & Renshaw.

This is [indiscernible] on for Mike. Congrats on the updates. Just a quick question on the DMD program. So Novartis was just talking about the drugs they got from Avidity that they're using antibodies to deliver oligos to the muscle. Do you think you have the best tissue penetration you can get with N 531? And how are you thinking about the competitive dynamic as you head towards the NDA filing?

Yes. I mean I think in general, it's a wonderful question because, again, in the absence of conjugates, if you look at the muscle exposure, our muscle exposure was pretty extraordinary even in comparison to muscle targeted ligand. So when we think about distribution to the tissue without having to add that, that was consequential nonlimiting. And we saw for the first time actually real measurements of muscle regeneration.

So when we think about getting into stem cells and regenerating muscle and think about more broadly the platform implications for being able to treat the disease in the muscle, both with splicing oligonucleotide, siRNA and others, we talk about extrahepatic. I think there was not a requirement as we think to have to create the complexity of that to get exposure. So the landscape is something we continue to look at as it evolves. But in terms of being able to access the tissue and what would be required to do that, I think our platform delivers exquisitely muscle....

Our last question comes from Ananda Ghosh with H.C. Wainwright & Co.

When you look at the genetics of the actin and when you talk to the academic community, one aspect of the biology, which they all stress about is that Iin probably works best in the negative energy balance, which you see when you add actin knockdown approach with GLP-1s, which also Arrowhead has already shown. The question is what happens when you take off the GLP-1s during the maintenance phase when probably the patient energy balance either neutralizes or probably goes to a positive energy balance. Then what happens to those liberated free fatty acids? Do you actually think that you will see a stability in the weight gain? And if you do see where does those 3 fatty acids go, which are liberated when you don't have GLP-1s, in which tissues do they accumulate?

And probably in the same as they did in the first point, right, when we saw it go to muscle. And if you actually a beautiful experiment that we had run in this was the preclinical data where when you stabilize these obese mice on GLP-1 exactly to your point, their caloric consumption declines dramatically, they lose weight, they hit their steady state. And interestingly enough, and I think it does speak to the mechanism of action when you predose and the timing of that was critical, not after you dose before the cessation to get the on-ramp of active suppression before turning off the GLP-1. When you stop the GLP-1, you actually saw caloric consumption increase in both arms of the study. the placebo arm and the INHBE treatment arm. So again, the energy balance while going up wasn't changed.

Now what you did do in advance of putting those excess calories on is actually turn off exactly what the body wants to do and actually what's really damaging in weight cycling with GLP-1s and it's a real problem in patients who chronically come on and off of them is that when the weights regain, it's regained its fat, fat is position in a variety of tissues, and that's unhealthy. And so what we did see is when you actually take the brakes off lipolysis, the body is now not able to store new fat. So you don't see that reaccumulation of fat.

What you do see is -- and we kind of see this slight -- much like probably what we saw in the slight increase in the monotherapy arm, which is it goes to muscle. So you end up with the free fatty acids and the muscle, muscle can then actually build. And so we don't expect -- that will be interesting to see whether or not that plays out that people who have actually been losing muscle over time might gain some muscle back when at the same time, but not restore that as fat and hence stay at steady state.

So again, as we said on the call, that study is going to initiate this year, we're going to be generating that human data to recapitulate what we saw in the animal model. But I do think if we think about what the best human genetic evidence is for INHBE, it's maintenance. These are people who go over a lifetime without thinking about their caloric consumption and have low abdominal visceral fat, have an improved metabolic profile in terms of risk of diabetes and cardiovascular disease and lipid profile. And so actually the setting where there's the most human genetic data for, and we're excited to run that human clinical trial.

There are no further questions at this time. I'll now turn the call back over to Paul Bolno for closing remarks.

Thank you for joining our call this morning. We look forward to speaking with many of you later today and during the ATS conference next month. Have a great day.

Hello, and welcome to Wave Life Sciences Positive Interim Phase I Clinical Data from INLIGHT Trial of WVE-007 for Obesity Call. [Operator Instructions] Also, as a reminder, this conference is being recorded today.

I will now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs.

Thank you, operator. This morning, we issued a press release announcing Positive Interim Clinical Data from our ongoing Phase I INLIGHT Trial of WVE-007 in otherwise healthy individuals living overweight or obesity. Our press release can be found in the Investor Relations section of our website, www.wavelifesciences.com. The slide presentation to accompany this call will be available on the website following the prepared remarks.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2025. We undertake no obligation to update or revise any forward-looking statement for any reason.

Today, Dr. Paul Bolno, President and Chief Executive Officer, will begin with opening remarks. Next, Dr. Erik Ingelsson, Chief Scientific Officer, will discuss WVE-007, our INHBE GalNAc-siRNA; and Dr. Chris Wright, Chief Medical Officer, will present the INLIGHT clinical trial interim data and Phase IIa update. Next, Paul will review next steps and anticipated milestones before turning it over to Q&A. Dr. [ Sandra Barges ], Chief Technology Officer, will also be available to answer questions.

I'd now like to turn the call to Paul.

Thank you, Kate. At Wave, our goal has been to harness the power of human genetics to develop transformational medicines, leveraging our best-in-class chemistry. Today, we're pleased to share with you significant progress towards this goal with the continued clinical translation of WVE-007, our GalNAc-siRNA for obesity. 007 is a potentially transformational treatment for obesity that improves body composition by reducing fat, in particular, harmful visceral fat while preserving muscle.

There are 3 key takeaways I'd like to highlight from today's update. First, our best-in-class siRNA for obesity continues to demonstrate an industry-leading and highly differentiated profile in the clinic. Potent, dose-dependent and durable reductions of active [indiscernible] and a very clean safety profile. Second, 007 continues to translate in the clinic and demonstrate its potential as a novel transformative therapy to deliver fat loss and muscle preservation. In a Phase I study with low BMI and a generally healthy population, we are already seeing substantial improvements in body composition, including a clinically meaningful 14% reduction in visceral fat and a 3.3% reduction in waist circumference in 6 months following just a single dose. The continued fat loss we're observing a concurrent stabilization of muscle also led to weight loss of 1%.

And third, as planned, we are quickly advancing 007 to the Phase IIa portion of INLIGHT in a higher BMI population that includes individuals with comorbidities, which is consistent with other Phase II or Phase III obesity studies. These study populations carry more excess fat and will enable demonstration of higher fat loss with continued muscle preservation leading to greater weight loss as well as demonstration of clinical biomarkers to inform development in MASH, type 2 diabetes and cardiovascular disease.

Today, Erik will first remind you of the unique and compelling biology and human genetic evidence that support 007, and Chris will then cover our Phase I Interim Data update and next steps for Phase IIa development. Erik?

Thank you, Paul. Before diving further into today's results, it's important to reflect on the current obesity treatment landscape and why we believe that 007 is well positioned to deliver a truly differentiated novel therapeutic approach. Individuals living with obesity face markedly higher risk of a range of diseases such as MASH, type 2 diabetes and cardiovascular disease. Excess body fat, in particular the dangerous visceral fat is a key driver behind this elevated risk of disease.

Current standard of care with GLP-1s and other incretins is focused on caloric restriction by reducing appetite and slowing gastric emptying and carry many limitations such as muscle loss, frequent dosing and tolerability challenges, resulting in high discontinuation rates as well as weight cycling due to individuals coming on and going off therapy. The consequence of muscle loss is particularly important to emphasize that skeletal muscle plays an important role in metabolism and weight maintenance.

Taken together, there is a large unmet need for therapies that leverage an orthogonal approach to induce fat loss while preserving muscle, enhance efficacy of incretins as an add-on and maintain weight loss and metabolic improvements after cessation of incretins. 007 improves body composition by decreasing excess fat through adipose lipolysis and retaining muscle and does not lead to or require caloric restriction to achieve these results. With a favorable safety profile that we have observed to date and the potential for infrequent once or twice yearly dosing, we believe that 007 could offer a transformational approach to obesity treatment.

007 is designed to silence Inhibin E to lower serum Activin E and compelling human genetic data support our confidence in this mechanism of action. In the UK [ Biobank ] and other population-based studies, heterozygous Inhibin E loss of function variant carriers, individuals living naturally with 50% less Inhibin E exhibited a healthier overall metabolic profile, driven by lower visceral fat as evidenced by lower waste-to-hip ratio and lower visceral adipose volume as well as downstream effects with lower triglycerides, [ ApoB ] and HbA1c and higher HDL cholesterol. These carriers also have favorable associations with liver traits, such as ALT, a measure of liver damage and CT1, a measure of liver inflammation and fibrosis and importantly, lower risk of developing type 2 diabetes and coronary heart disease.

By silencing Inhibin E mRNA, we aim to recaptulate the protective phenotype seen in these heterozygous loss of function carriers. Inhibin E is produced in the liver where it dimerizes as the [ hepatokine ] Activin E. Activin E is released into circulation where it binds to ALK7 receptors on adipocytes. This blocks adipose lipolysis to break down of triglycerides, promoting fat storage, increasing risk for obesity and cardiometabolic disease. By reducing hepatic Inhibin E mRNA with a GalNAc-siRNA, we lower circulating Activin E, leading to a decreased ALK7 signaling in adipose tissue and releasing the brake on lipolysis or in other words, increasing metabolism of excess fat, which is ultimately expected to lead to weight loss and lower cardiometabolic risk.

Although there is human genetic evidence for both Inhibin E and ALK 7, further supporting the importance of this mechanism in regulating body composition, we chose to target Activin E through Inhibin E silencing over its receptor ALK7 for several reasons. Turning off protein production in hepatocytes, the upstream source with the GalNAc-siRNA is the most efficient and durable way to address this mechanism. Further, suppressing the Activin E ligand rather than disabling the ALK7 receptor is a more selective approach with lower risk of unintended consequences since ALK7 has multiple ligands across different tissues, including reproductive organs. This selectivity is especially important for us as we think about long-term safety as well as clinical and commercial translation.

007 is highly differentiated by our proprietary chemistry, which makes us well positioned to deliver a potentially best-in-class approach. 007 is a GalNAc-siRNA using Wave's [indiscernible] design, including backbone [ serochemistry ] and [ PN ] chemistry, which enhances interaction with [ A02 ], stabilizes the loaded risk complex and improves liver exposure, all of which contributes to dramatically improved silencing potency and durability when compared with industry standard siRNA designs, something we have shown repeatedly for Inhibin E and other targets.

In addition to strong evidence from human genetics, there is also robust evidence showing that higher circulating Activin E levels are associated with a range of cardiometabolic measures, providing further evidence of the importance of this mechanism in development of obesity and cardiometabolic disease in humans. In an observational study of 324 nondiabetic participants, Activin E levels were strongly correlated with increased BMI, abdominal fat and fasting insulin. This, together with the genetic evidence from the general population, our preclinical data and our data from the INLIGHT study all support that the associations of Inhibin E and Activin E with body composition are not restricted to individuals with diabetes, but that Inhibin E suppression can result in fat loss regardless of diabetes status.

Importantly, the strong correlations of Activin E levels with BMI highlight the opportunity for larger effects of 007 when we move to higher BMI individuals in our Phase II studies, which Chris will speak to in more detail momentarily. 007 is designed to improve body composition while -- by decreasing fat while preserving muscle. We expect effects on both subcutaneous and visceral fat as Activin E binds to ALK 7 on all adipocytes. Generally, any weight loss regimen will have a proportionately larger effect on visceral fat, especially at the earlier time points since this type of fat is more metabolically active, better supplied with blood and more sensitive to fat mobilizing hormones. We expect this phenomenon to be even more pronounced with 007 as it acts directly on light policies. We expect both visceral and total fat loss with 007 to be substantially larger when studied in higher BMI populations with more excess fat.

Visceral fat, which is around your organs, is strongly linked to insulin resistance, MASH, type 2 diabetes and cardiovascular disease. There is robust evidence supporting that 5% to 10% lower visceral fat is associated with decreased risk of a number of cardiometabolic diseases. Wave's circumference is an easily accessible clinical proxy for visceral fat that has also been shown to be strongly associated with cardiometabolic diseases in many large studies. We are already observing more than 14% reduction in visceral fat and more than 3% reduction in weight circumference after 6 months in our 240-milligram dose despite low baseline levels of visceral fat and BMI.

While it tends to get less attention in obesity, muscle also plays a crucial role in metabolic health in addition to preserving strength, function, bone density and longevity and reducing risk of sarcopenia and frailty. For context, with incretin therapy, up to 40% of the weight loss is driven by muscle loss, meaning that the health benefits delivered from fat loss are partially offset by muscle loss. Skeletal muscle increases basal metabolic rate, the number of calories you burn as your body performs all basic life-sustaining functions, making up about 70% of the calories we burn. Further, higher muscle mass with higher glucose disposal, better insulin sensitivity and improved over energy balance which helps reducing visceral fat and preventing weight regain.

Visceral fat and skeletal muscle are the 2 components of body composition that are most important for cardiometabolic health. As most obesity treatments drive fat loss at the expense of muscle loss, using a metric such as visceral fat to muscle ratio or VMR is a good composite measure of body composition to integrate both the harmful visceral fat and the beneficial lean fat into a single index. This metric has been used in many scientific publications and a lower VMR has been shown to be strongly associated with the decreased risk of MASH, type 2 diabetes and cardiovascular diseases.

Our comprehensive preclinical studies underscore our conviction in our potentially best-in-class therapeutic approach that leverages a completely orthogonal mechanism from incretins by inducing fat loss with lean mass preservation. We have shown that our molecules reducing Inhibin E [ RNA ] and circulating Activin E levels, increase adipocyte like policies and lead to reduction of adipocyte sizes and fat loss, in particular, visceral fat. This, in turn, results in a reduction of inflammation and fibrosis in adipose tissue as well as improved insulin sensitivity, changes that are likely to contribute to a lower risk of cardiovascular disease in type 2 [ diabetes ].

In our studies in [ DIO ] mice, a model that represents severe obesity with an abundance of excess fat, weight loss within Inhibin E sRNA was similar in magnitude to semaglutide but occurred more gradually. A potential explanation for the initially slower weight loss could be that the preservation of lean mass is offsetting weight loss early on, but that over time, the substantial fat loss is translating to weight loss as the lean mass stabilizes.

The early clinical translation of 007 in INLIGHT fortifies our excitement in other treatment settings, such as add-on to incretins, where we have observed approximately twofold greater weight loss as an add-on to semaglutide versus semaglutide alone in DIO mice. We have also shown an ability to curtail weight regain upon cessation of semaglutide within Inhibin E, providing powerful data for its utility in the maintenance setting.

With that, I'll now turn it over to Chris to walk through the INLIGHT clinical data in more detail.

Thanks, Erik. Good morning to everybody on the call. As a reminder, the Phase I portion of INLIGHT is a placebo-controlled single ascending dose study, randomized 3:1 active placebo with potential to escalate up to 5 single dose cohorts. It's designed as a safety tolerability PK/PD study. Participants are healthy individuals living with overweight or Class I obesity with key inclusion criteria of HbA1c less than 5.9 and BMI between 28 and 35. The study does not require diet or exercise modifications or counseling.

In addition to safety, tolerability, PK and Activin E levels, the study has exploratory endpoints of body composition by DEXA, biomarkers and body weight. [indiscernible] is currently ongoing at multiple trial sites, including in the U.S. We began testing WVE-007 at our lowest subtherapeutic dose of 75 milligrams in 8 participants, which did not include DEXA. We next evaluated the 240, 400 and 600-milligram ascending dose cohorts, including DEXA and other measures. Today's update primarily covers 6-month follow-up data from our 240-milligram cohort as well as observations from our 400-milligram cohort.

In addition, further updates on safety and PK for the 75 through 600-milligram cohorts are provided. We will describe the design of our Phase IIa multiple dose amendment to INLIGHT in more detail as well. Participants were in their late 30s to early 40s on average with a mix of men and women in each cohort, with a somewhat higher proportion of females in the 75-milligram group and males in the 240 and 400-milligram cohorts. Mean baseline BMI was approximately 32 across the treatment cohorts, consistent with the participants having healthy overweight or Class I obesity. Baseline characteristics show differences between our 240 and 400-milligram cohorts with the 400-milligram cohort having lower baseline BMI, lower weight circumference, lower body weight, total fat and visceral fat with higher lean mass.

The difference in baseline visceral fat was particularly notable as it was 30% lower in the 400-milligram group compared to the 240-milligram group. Overall, the differences suggest that the 400-milligram cohort had a healthier baseline body composition relative to the 240-milligram cohort.

To put these baseline characteristics into perspective, here you see a graph showing the U.S. general population distribution of BMI on the X-axis and visceral fat on the Y-axis. The dark blue contour represents where 50% of the U.S. population falls for these measures and the light blue contour indicates 95% of the population. On this background, we show the baseline BMI and visceral fat levels for our 240 milligram, that's purple dot and 400 milligram in the pink dot Phase I INLIGHT cohorts. And the baseline BMI and visceral fat levels, the open dots typical for Phase II and III obesity studies using the BELIEVE study as an example.

As you can see, consistent with Phase I obesity studies, baseline BMI and visceral fat and INLIGHT are markedly lower than the baseline levels of Phase II and III studies. The Phase II BELIEVE study provides a good example of this with baseline BMI and visceral fat primarily outside of the 95% population contour in light blue, meaning that the baseline BMI and visceral fat are in the most extreme 5% of the population. Further, baseline levels in the 400-milligram cohort are even closer to a healthy population with average BMI and visceral fat levels near the 50% population dark blue contour.

We continue to observe a favorable safety profile across all cohorts, which is of critical importance for a potential new medicine designed to treat millions of people living with obesity. There were no treatment discontinuations, serious TEAEs or deaths. All study-related AEs were mild. There were no clinically meaningful changes in lipids, glucose or other clinical laboratory measurements, including liver function tests through 600 milligrams.

Following our update in December, we continue to see robust and durable reductions in Activin E. In this chart, the percentage reduction of Activin E from baseline is shown on the Y-axis with days on study on the X. We're pleased to show highly statistically significant dose-dependent active decreases across all 007 dose levels with a mean max reduction of up to 88%. Notably, over 70% suppression of Activin E was still observed out to at least 7 months, supporting a highly convenient dosing interval of once or twice a year. With this durable Activin E suppression, we're now excited to show a pronounced improvement in body composition observed over time following a single 240-milligram subcutaneous dose.

Visceral fat mass decreased from a 7.8% placebo-adjusted reduction at 3 months to a statistically significant 14.3% placebo-adjusted reduction at 6 months. Total fat reduction reached 5.3% at 6 months and lean mass stabilized. There were also improvements across clinical measures, including a 3.3% reduction in waste circumference and a 0.9% reduction in body weight. Overall, these data demonstrate that a single dose of WVE-007 can shift body composition towards best visceral and total fat while preserving muscle mass, consistent with our preclinical findings and the underlying human genetics. These results are encouraging as we're starting to see evidence of improvements in clinical measurements such as waste, circumference and weight at 6 months, even after a single dose of 007 in a Phase I study of otherwise healthy participants with an average BMI of 32 and no dietary or exercise restrictions.

As Erik previously discussed, we believe improvements in body composition will drive meaningful health outcomes. A key indicator of these improvements is the visceral fat to muscle ratio or VMR, which is an established measure of body composition. As Erik described, low VMR is associated with a wide range of health benefits, including increased risk of MASH -- sorry, decreased risk of MASH, type 2 diabetes and cardiometabolic disorders. To benchmark and contextualize our results at this early development stage, we calculated the change or improvement from baseline in BMR for our 240-milligram dose of 007 and estimated this for the treatment arms of the Phase II BELIEVE study investigating weekly semaglutide and [ IV bimaglimab ], a myostatin inhibitor in participants with a BMI of 37.

As you can see, a single 240-milligram dose of 007 is outperforming both high and low semaglutide at the 3-month and 6-month time points, even in the context of otherwise healthy participants with BMI of 32. This is due to the substantial reductions in lean mass by semaglutide, which adversely impacts its BMR score. The BMR 007 is on par with [ bamaglimab ] with convenience of potential once yearly dosing and favorable safety profile.

What's particularly impressive about these results is that we're able to achieve these improvements in body composition in a Phase I study of otherwise healthy participants with mean BMI of 32 compared to Phase II and III obesity studies with BMIs of 35 or higher in metabolic comorbidities. On this graphic, when we add the baseline and post-treatment BMI and visceral fat values from the BELIEVE Phase II trial, as shown in the green arrows. You see that the INLIGHT baseline BMI and visceral fat are at a level where the BELIEVE study ends after 48 weeks of treatment.

Turning to the 400-milligram cohort of INLIGHT. We observed placebo-adjusted changes from baseline that were lower than what we observed in the 240-milligram cohort at the 3-month time point. For example, the visceral fat reduction was 5%. As I previously shared, the 400-milligram cohort had a notably healthier body composition profile. To understand this impact, we performed a post-hoc analysis, categorizing participants by baseline visceral fat levels of greater or less than 500 grams. 500 grams is an established threshold for healthy levels of visceral fat. Importantly, we saw similar statistically significant reductions in visceral fat at 3 months in both cohorts where the baseline visceral fat was greater than 500 grams.

The key takeaway is this, these data are highly supportive that baseline BMI and excess visceral fat will drive treatment response magnitude and reinforce our expectation that with high BMI and visceral fat, effects of 007 on body composition and weight should be even greater.

Now I'd like to reorient you back to this chart and mention why the data I've just shared with you are encouraging when we think ahead to the Phase IIa portion of our ongoing INLIGHT trial. As this trial will enroll participants with BMI and visceral fat at levels comparable to other Phase II and III obesity studies, we expect greater fat loss and total weight loss like what is observed in other Phase II and III obesity studies.

Turning to the Phase II portion of the INLIGHT study. Our teams are actively working to initiate this study in the second quarter of 2026. This Phase IIa portion will enroll individuals with BMIs in the range of 35 to 50 and comorbidities with a 3:1 active placebo randomization. Assessments in this multi-dose portion are expected to be similar to those in the SAD portion with additional inclusion of body composition measured by MRI, liver fat content as measured by [ MRI-PDFF ], HbA1c, lipid levels, CRP and muscle function. The design and study population enables enhanced evaluation not only of improved body composition and weight loss, but also informs additional opportunities for 007 in MASH, type 2 diabetes and cardiovascular diseases.

The study will enroll 2 different populations with high BMI with and without type 2 diabetes, with the diabetic cohort initiating after the start of the first 2 high BMI cohorts. Participants will be given 2 doses of 007 at day 1 and at day 85 and follow-ups for 12 months, with the first major assessment occurring at day 85.

Finally, in addition to investigating 007 in individuals with high BMI and comorbidities, including diabetes, 007's favorable safety profile and ability to drive reductions in fat while preserving muscle with an orthogonal mechanism may support the use of 007 as an add-on to [indiscernible]. Within the community, there's excitement about 007's potential as a maintenance therapy, which would allow people to transition off infant therapies while at the same time preventing rebound weight gain, preserving muscle and sustaining cardiometabolic health. Planning for this new Phase II program is actively progressing, and we remain on track to initiate trials investigating 007 as an incretin add-on and as a post-incretin maintenance in 2026.

I'll now turn the call back to Paul.

Thanks, Chris. We are extremely excited about the profile we have observed with 007 in this study population with low BMI. We've demonstrated clinically meaningful improvements in body composition, favorable safety and tolerability and durability supporting once to twice a year dosing, and we're moving quickly to advance 007 into the next phase of development.

In addition to initiating new trials investigating 007's potential as an add-on and maintenance post incretin therapy in 2026, we're on track to initiate the Phase IIa MAD portion of our ongoing INLIGHT study next quarter in individuals with higher baseline BMI and comorbidities. Here, we'll have an opportunity to evaluate further improvements in body composition in a population with higher BMI, which is much more representative of typical Phase II and III obesity studies with participants having a lot of excess fat to lose. Therefore, we believe this study population will achieve even greater effects on body composition with substantial fat loss, lean mass retention leading to the regulatory threshold of at least 5% weight loss. In addition to measures of body composition, we'll also be evaluating improvements on imaging and clinical biomarkers, which will inform 007's potential to impact across additional indications.

As a reminder, reducing visceral fat by at least 5% is strongly associated with improving broader cardiometabolic diseases. Therefore, the over 14% reduction in visceral fat 6 months after a single dose of 007 is highly encouraging. We will be evaluating a number of measures in the Phase IIa portion of INLIGHT, including MRI-PDFF, hemoglobin A1c, lipid levels, CRP and muscle function, which will have the potential to unlock indications beyond obesity, including MASH, type 2 diabetes, cardiovascular disease, PCOS and more.

With 007's ability to improve body composition through reducing fat and preserving muscle, we believe 007 will offer a transformative approach for obesity in combination, maintenance and as monotherapy, particularly individuals who are not able to tolerate incretins or muscle loss as well as for a range of metabolic diseases. With over $600 million in year-end cash and cash equivalents, we are well capitalized and well positioned to deliver on multiple milestones with both WVE-007 and WVE-006. We remain on track to initiate the Phase IIa portion of INLIGHT in individuals with higher BMI next quarter as well as to initiate new trials of WVE-007 as an incretin add-on and as post-incretin maintenance in 2026.

Also this year, we plan on sharing additional data from INLIGHT, including data from the 600-milligram cohort of our Phase I study. In the second quarter, WVE-006 remains on track to deliver data from the 400-milligram multi-dose cohort and the 600-milligram single-dose cohort of [ Restoration-2 ] at the ATS conference in May, and we expect to receive regulatory feedback mid-2026 on a potential accelerated approval pathway.

Before turning the call over to questions, I would like to take a moment to thank everyone participating in INLIGHT, the clinicians involved and the study site staff. They continue to inspire the work we do every day. And from everyone at Wave, we'd like to express our sincerest gratitude.

With that, I will turn it over to the operator for Q&A. Operator?

[Operator Instructions] Our first question comes from Steve Seedhouse from Cantor Fitzgerald.

It's a multipart one on the dose selection going forward. I was just hoping you could expand on the rationale for the chosen doses given what you're seeing in this initial data set for the Phase IIa, including if you could clarify how frequent you're going to be dosing. It wasn't clear if the day 85 visit includes the second dose or if it's going to be less frequent.

And then last part of that question is just was the dose selection informed at all by any insight into the efficacy of the 600-milligram cohort?

No, thank you for the question. So the dose selection is informed by 2 important criteria. One is obviously Activin E reduction. So if we think about the dose response, the whole mechanism, as Erik laid out fundamentally at the beginning, is potent durable suppression of Activin E. So we see a dose-dependent suppression. But what's interesting is we get to the 240 and 400, the PK is looking incredible for 240. I mean, as we said, we're out now past 7 months with suppression. With 400 continuing to accrete behind it.

So we do believe we have the suppression we need to stay below that 70%, 75% threshold across both the 240 and 400. The biggest question is ultimately going to be what ultimately gives us the potential for once a year dosing. So we'll understand does 240 sustain that? Is it once a year or is it twice a year? And is 400 give us that opportunity for longer duration. So we do believe we've got the Activin E suppression necessary for the dose selection.

Safety as well. I mean, we're cleared through 600. So safety is clean across all of the dose cohorts. In terms of the dosing regimen, as you point out in the Phase IIa, with durability out past 12 months, we know we've been talking to a number of you about the fact of how long -- how can we accelerate this MAD study. So our view is we're actually truncating that at day 0, day 85. And so there'll be those 2 doses in that regimen.

So remember, the Phase I study, as we think about PK follow-up, follows these patients over a year. So we'll be continuing in this current Phase I INLIGHT to be monitoring Activin E levels over that period of time to look at durability, while in the MAD study, be able to truncate the distance between those 2 dose regimens. So the MAD will have that shorter interval. And that combined with the Phase I will inform the subsequent dosing regimen. But again, we continue to see active durable suppression. And I think to step back one other piece on dose selection to activity.

When we go back to the observational study in over 300 patients where there's a correlation between Activin E, BMI and truncal obesity, it informs us really well that if we stay at this level of suppression and go into, as Chris showed, that high BMI, higher excess visceral fat population, we do expect substantial continued decreases in both visceral fat from where we already are at over 14% total fat and importantly, body weight.

Sorry, 600. So we will have, as we said, we'll look at the 600 data later. But no, the dose selection is not informed by the 600. We will look at that data to see where that goes subsequently.

Our next question is from Joe Schwartz from Leerink Partners.

So I have a 2-part question. In a landscape where most therapies drive weight loss broadly, how confident are you that preferential visceral fat reduction will be valued by regulators, physicians and payers as a differentiated benefit?

And then is there a specific patient population such as high visceral adiposity, insulin resistance or sarcopenic obesity, where this mechanism and profile is particularly compelling if total weight loss remains more modest relative to visceral fat loss? And can you quantify any good base case opportunities for us, recognizing that most investors are not underwriting broader use at this point?

Yes. I mean I think to step back, as you just define the obesity population in the commercial setting, that's studied in patients with high abdominal adiposity and high excess visceral fat. If we go back to every 2, 3 study. And I think stepping back, we have to remember, we're all looking now, as Chris nicely laid out, at a Phase I population.

So to your point, the population that we'll be going into as we think about an obesity therapy has high abdominal adiposity, high visceral fat. And in that reduction, you'd expect to see continued drop in body weight, which is why, again, we've always said in the right dose at a year in the right population, meaning the obese population, we would expect to see the regulatory thresholds.

I think moving down the regulatory thresholds and thinking about reimbursement and what payers pay for, payers pay for outcomes. And so if we think about what's driving health benefits of obesity therapies, it's driven exactly, as Erik said, on the danger of visceral fat. Visceral fat is what drives cardiometabolic risk, diabetes risk. And so again, the fact that we're seeing levels in a Phase I study, low BMI, lower visceral fat than in Phase II obesity studies that are exceeding those like we should be able to have that health benefit play out as part of that therapeutic landscape.

That said, to your last question of are there unique populations as we think beyond monotherapy -- sorry, beyond combo maintenance, that for monotherapy, there's over 30 million people living with obesity who are at risk for muscle loss. So just as a distinct population within the monotherapy setting, there's people who can't afford to lose muscle from a metabolic standpoint in addition to frowsy. And so the ability to still achieve high levels of important reductions in fat with muscle preservation is unique to that. But I think it is really important to say that's assuming that locking in the profile currently on substantial visceral fat in the current study, which is not the study that you do in obesity, which will be in high abdominal fat. So again, we do anticipate in that higher population, the data suggests, the genetics suggest that we'll see substantially larger...

Just to add one more thing as well. As Paul said, when we move into the Phase II/III trial with a higher BMI population, we expect that both the visceral and the subcutaneous fat will continue to go down. The Inhibin E [indiscernible] binding is happening on all types of adipocytes, and we have already seen effects on both visceral and subcutaneous. We do see that both will continue to deepen in the larger BMI population with more fat excess.

Our next question is from Cheng Li from Oppenheimer.

Just maybe 2 parts. I'm just wondering what is the -- what may be the best predictor for 007 efficacy, whether it is like baseline visceral fat or is BMI or maybe baseline Activin E level? And just a follow-up question is, just wondering if BMR can be validated as like a predictor for a clinical outcome that can be used as part of the registration endpoint.

Thank you. And I think you pointed out the important access because if you actually look at the correlation, it's very nice between exactly what you laid out, which is that Activin E levels correlate with higher BMI. So the higher BMI as we move into, there are higher active levels. And I will say, we see very similar data to the population data in our study. Her BMI correlates to higher Activin E levels. So again, higher BMI, higher Activin E. And if you look at the -- that also correlates to higher abdominal truncal obesity and so higher visceral fat. And so again, when you put those metrics together and you look to where Phase II/III obesity studies run, you improve the metric that's hence the X and Y axis on both BMI. BMI is a reflection of abdominal adiposity, hence, visceral fat and in that setting of higher excess fat.

I do think it's just really important to level set coming into this study, which is why I think people kind of are going, how does this compare? Is that when we have the healthy Phase I study with patients living with obesity and overweight, the criteria that caps any of these other effects limits because visceral fat drives additional comorbidities, limits the ability to explore that. So I do think based on actually the response in the 400 and the 240 that this point on visceral fat thresholds and what an excess visceral fat threshold does is actually really validated. We see higher levels of visceral fat tied to those comorbidities driving larger effect size. And so again, going to the Phase II study in that higher BMI, higher visceral fat population would be expected to drive further efficacy.

Our next question is from Alec Stranahan from Bank of America.

This is Matthew on for Alec. Two from us. First, can you explain how you think about the kinetics of total fat loss, which remained relatively flat between month 3 and 6 and visceral fat loss, which doubled in that same time frame? Just maybe thinking about how we view that in the higher BMI population, whether we expect the kinetics or magnitude of these changes to be different?

And then maybe a second quick one, I guess, looking at HbA1c lipid levels, CRP muscle function, have you been tracking these in Phase I data? And any comments on how those have looked so far?

We'll take the last question first, and then we'll focus on the first. But the last one is those were actually part of the exclusion criteria to be a healthy overweight obese study. Patients had to be excluded with changes in hemoglobin A1c, serum lipids or not. So most -- there's not an ability to see a dynamic effect, hence, the subsequent study where we'll have patients with comorbidities where we will be able to see those dynamic effects. I think what's encouraging on the lipid profile on the safety side was despite the changes, there were changes in lipid profiles that would suggest any concern. So I think we could use that in that context in the Phase I study. But obviously, as we said, that's a core part of the Phase IIa assessment.

As we think about the dynamics on fat, as you point out, that's absolutely going to be driven on where you start from. the more excess fat you have subcutaneous or visceral, the larger the effect size and impact. And so if you shift the curve up, I would expect the continuation of that distribution, if you look at percentage of fat, the impact on visceral versus subcutaneous fat. That will continue to be and you imagine that ratio in an outsized effect percentage-wise on visceral fat. That said, subcutaneous fat, which is a larger proportion of the body, when you lose that will be responsible for further weight loss.

So if you imagine going up that curve from -- again, we started at the end of where the BELIEVE study was and saw these data. When you pull that back up to a starting BMI that's greater than 35 and that study, average BMIs in all of the recently reported studies in obesity around 37. So you go up to that BMI benchmarking to that level of visceral fat, we would expect to see the magnitude even on visceral fat, which is impressive as it is after a single dose now to actually get steeper and deeper.

Our next question is from Madison El-Saadi from B. Riley.

Maybe if you can comment, just curious what the percentage of treated patients in the 240 mg arm at 6 months may have reached, say, 3% body weight. Just trying to understand maybe what that distribution looks like behind that 0.9% number. And then if we could maybe take a step back and try to understand the path to 5% weight loss that we know investors want to see. What's the dose, the duration, the population BMI that can get us there? And then what is the earliest data set you think could demonstrate it?

Yes. I'll take the last question. I mean I do think this is why we're accelerating the IIa as we announced going into this year that from the beginning of the study, we've always said this is a Phase I safety PK/PD study to look at the impact of 007, Activin E levels, dose suppression. And then because we're going to be studying it in patients who are living with overweight and obesity, we'd be able to look and measure the impact of fat and reduction and obviously, body weight, but being able to look at DEXA. I think what these data continue to affirm is we've got a very powerful medicine that reduces fat and preserves muscle. I think to your point of where that efficacy is going to be drawn, and that's, again, the announcement we made coming into this year was that's going to be seen like every other obesity medicine in a II/III study where patients have high BMI, high visceral fat, and they're in a setting where they have excess fat to deplete.

And so I think, again, we're set up and we're poised to be able to see that. Within the individual weight metrics, I mean, that is the number for the cohort, and we haven't broken and looked at that into the dynamic range to be able to look at the placebo response. So that is the number. And I think what's encouraging, it's consistent. So if we look at the change as we think about fat reduction between 3 months and 6 months, there's continued progress. So it does speak to what we thought, which is going to be important as we go into the high BMI setting that the initial lean mass plateaus, so you hit that. And as long as you have excess fat to lose, we'll continue to remind you excess fat is what obesity is. This medicine's mechanism of action is reduction of excess fat, visceral or subcutaneous. So you need to put patients into a setting where they can have excess fat to lose, which is what's planned for the IIa study.

Our next question is from Roger Song from Jefferies.

I found this high visceral fat post-hoc analysis very interesting, maybe very informative. Just curious, you see higher visceral fat reduction in this high population. Did you look at the total fat and the weight between the high and the low visceral fat population? And then how should we think about the dose dependence here between 240 and 400, 2-part question.

Yes. No, thank you. And so we take the second part of the question. The challenge in any obesity study is always powering, having enough sample to look at. And the most sensitive measure on a medicine that reduces fat, as we know from all of it is visceral fat is the first index. So as you point out, 500 is not an arbitrary threshold. So just to be clear, 500 is the threshold of kind of what defined as excess visceral fat. So by crossing into the excess visceral fat threshold, i.e., having more excess fat to lose, that's where that separation occurs. But once you get past that, it's very hard to pull out with the noise, other signals beyond where we have sensitivity.

What it does tell us, and this again, forms the IIa study is if you look at that graph that we put out on BMI and visceral fat, once you get up to the BMIs and in that study, you'll see that it's well in excess of the 500-gram threshold of where you need to see to see a reduction in fat.

Yes. Maybe just to add, Roger, you mentioned that you found it interesting. We also found it very interesting and encouraging because it really emphasizes that this approach and this therapeutic really works as supposed to do, right? Like if you have excess fat, there is an opportunity to burn that through increased light policies. So it's highly encouraging as we now move into the IIa study with higher BMI and much more excess fat to act on.

And your question on dose dependency, I think we have to think about what -- how do we define dose dependency. So the first part of dose dependency on a medicine whose mechanism of action is the reduction of Activin E, right, the central ligand in all of this is we do see a dose-dependent reduction. What we see is that as you compress because of potent durable selection, we're right at that inflection point across doses. So we do see the dose dependency. But what we see is that the determination ultimately comes down to fat and the ability to have excess fat.

So therefore, if we think about the dose dependency on excess fat, the more excess fat you have to lose, the greater effect size you're going to see across the cohorts without having to necessarily push the dose. So I think, again, the benefit of the IIa study where we are going to take 240 and 400 both forward is we'll be able to look at that effect size on a duration construct between those 2.

Our next question is from Salim Syed from Mizuho Securities.

Apologies, he seems to have lowered his hand. We will go to Luca Issi from RBC Capital Markets.

Congrats on the progress. This is Cassie for Luca. For weight loss, could you help us characterize what's happened in the placebo arm just on the weight loss part? We know in other obesity trials, patients can be receiving lifestyle management instructions and that might help them lose weight there. Any color on how we see that is very helpful.

And if we can ask another one on the visceral fat, the impact of baseline body composition makes a lot of sense. And going forward, do you anticipate that sort of minimal visceral fat threshold in your inclusion criteria? And what is the thinking on the proportion of obese patients have visceral fat over 500 and above overall? Is the profile closer to the 60% that you see in your 400 mg or it can be higher? Any color there much appreciated.

No, thank you. I'm going to work backwards on that. So what's interesting is if we -- and it's a very good question because it's the one where we put our head on, on making sure that when we design the IIa study in a medicine that reduces fat, how sure are we going to be that we've captured that population. And actually, the data and the analysis we did on both BMI and waist circumference inclusion criteria will put us in the same box as others. So we do fully expect that the study will look like other Phase II/III studies. And when you look at the disposition of patients in those II/III studies, they're well in excess of that 500-gram of visceral fat. And again, it's why we kind of put the graph there because it's a nice way to get a sense visually of where we expect these patients to cluster on that study.

And if you imagine that patient population would high abdominal adiposity, there's a big impact for visceral fat reduction beyond the over 14% we're seeing. But importantly, on subcutaneous fat and ultimately, with muscle preservation, that leads to weight loss. So again, the conviction is high based on the patient population. That's -- we see across studies. We don't just -- there are no diet and exercise requirements in this study. So again, placebo that placebo-adjusted weight is the best way to visualize the study because there are dynamics in that. And again, it was important for us that we do see that weight loss is coming because I know there were a lot of questions coming up, what's happening with lean mass? Is lean mass going to stabilize and is fat loss going to eventually lead to weight loss, not just for this study, but importantly, how would we imagine the impact of that back in the Phase IIa study.

And absolutely, I mean, consistent with what we've been saying for a very long time now in the patient population, which is reflected in that right box of an obesity patient population where we can substantially reduce fat and preserve lean muscle, we would anticipate weight loss in the regulatory framework and lens. So I think we would expect the majority and not really all the patients in the obesity study when you look at baseline characteristics from other studies to have high degree of abdominal adiposity and visceral fat, where we would expect to see an effect size.

Our next question is from Salim Syed from Mizuho Securities.

Hopefully, you can hear me this time. Paul, just one from us. I know you're talking about the framework of the 5% that the regulators want to see, but I presume you're also speaking to the regulators about body composition and trying to get them to be perhaps more vocal about why that matters. And I think that would certainly help Wall Street with the body composition lens. Is that something that you're actively speaking to them on? And do you have any sense on the path and when they could perhaps get more vocal? What are they looking for to get more vocal?

So we don't comment on direct interactions with the agency, but I will say you are correct. I mean the agency is focused on body composition. Even in the most recent guidance that they put out last year, there was this reflection on weight loss with the caveat is the recognition that it's really body composition changes they want to see. I mean this race to the bottom where weight loss is driven off of lean mass is recognized to that. And there's a focus on building muscle building protein, and that's very important amongst the current administrators and health and human services. So I think there's a lot of alignment between what's driving benefit.

And I think it's super important to remember that visceral fat when we talk about obesity and the driver and obesity, it's visceral fat that drives the complications in health and health outcomes. And again, that's what payers are paying for. When CMS what do we pay for? It's paying for outcomes. And so the advantage that we expect to see where we already are in this low BMI, low setting, which is kind of incredible, a single dose, 240, 6 months later, we're taking visceral fat back down to levels that exceed kind of the 5% to 10% threshold that you'd want to see to see change in outcomes, we see that.

So we are encouraged to have those conversations with regulators on what's going to ultimately drive it, but also not having to concede the fact that with substantial reduction in visceral fat and on subcu fat in that Phase II population, greater than 5% weight loss to hit a weight loss threshold is not taken off the table, but where the conversation should be if we put weight loss aside, we know clinicians and patients want to see leaner, not lighter. Scale weight is less important than body composition. We're having a huge impact on the area that people are focused on and including the regulators. And we're excited to bring these data where, again, we're already exceeding what's in the literature for now over decades of 5% to 10% visceral fat being tied to bad outcomes, bring these data and have these discussions with them on subsequent studies.

Our next question is from [ Bill Mallon ] from Clear Street.

So just to put a finer point on that, how firm do you expect the 5% weight loss to be the eventual registrational endpoint? I know in your previous answer, you talked about what patients and regulators want to see, but could that convert into an actual registrational pivotal study endpoint?

And second, on the 3 use cases that you discussed, mono, add-on or maintenance, is monotherapy now probably the least likely eventual commercial presentation? Or do you still see that as sort of a beachhead in the market?

No, thank you. I mean I'll take the last question first because I just think it's really important. So I think the obvious, which is, I think, what you're reflecting on is combination and maintenance are 2 key aspects of this medicine, right? The ability to see, particularly given the safety profile, so you're not adding on additional safety on top of the existing therapies. So we don't see changes in good safety tolerability.

So I think those become obvious. We've had companies suggest maybe you start with Inhibin E and then you can actually titrate incretins depending on what patients need. And so there are a variety of ways of thinking about add-on maintenance, and we think that's interesting. I think as we pull back and say, what does mono mean? I think to understand where we're going to be is why we're running the Phase IIa monotherapy study. I think these data don't -- again, these are Phase I data. Everyone, including some of our peer companies in biotech who've shared recent Inhibin E data are sharing patients with BMIs of 37. So again, these data are low BMI patients in a healthy study, and this is an early obesity study.

So I think we need to wait and see what IIa obesity data looks like, where we do inspect larger impact on visceral subcu fat impact on weight loss to really define the profile. And within that profile, we do recognize within monotherapy, like I said, there's about 30 million patients who are living with obesity who are intolerant to or can't tolerate that potentially 40% reduction in muscle mass. So that population is already thought to be segmented at a certain point in time. And I think a profile with substantial fat reduction and particularly visceral fat will find a place in that monotherapy market. But I think we need to wait until we have IIa obesity data in order to define where that sits relative to other obesity products.

And on the registrational endpoint?

No. So that -- to Salim's question, I mean, that is an area that you would imagine that we're very focused on. So again, putting the 5% and not taking that off the table, I do think that that's an arbitrary number. The most important thing when you're -- and truly, I think part of the reason people are throwing up 5% is there's a back calculation of fat reduction that's tied to that, what the impact on these therapies might be to visceral fat.

And so this is where, as both Chris and Erik alluded to, the VMR and being able to look at an index that is correlated to cardiovascular management and diabetes, which really looks at the impact of both visceral fat, so bad fat, harmful fat, excess fat and lean mass preservation actually gives a tool, and we've had several clinicians that we've been speaking with recently who actually think that's a really viable way because it's not a complicated measurement to look at somebody's visceral fat, which is already calculated and their lean mass to determine some sort of comparable ratio of how patients are doing on a weight loss journey that ultimately protects body composition. And we think that conversation in the setting with supported in literature with regulators would actually be a really powerful way to actually codify and quantify the impact on body composition.

Our next question is from Michael King from Rodman & Renshaw.

I think we pretty much covered everything. But Paul, just in the answer to your last question, I think I know the answer to this, but just want to get confirmation from you, which is what are the gating factors or factor that you'll need to proceed past to get -- start combination studies with incretins?

Yes. I think we're already -- that planning is underway. And the way we've designed our submission protocol on the IIa will get us some feedback that will inform how quickly we can get that started. So I think our conviction is high, obviously, on the IIa study starting soon, but I also have good conviction on the combo maintenance study. And so I think all 3 of those this year become important components to really address the prior question, which is how to think about this in the 3 treatment settings, monotherapy, add-on combination where there's a powerful way of thinking about this given the impact on visceral fat and where we think the payers will be on that and maintenance.

And if I could just quickly follow up on that. Do you feel like you want to be sort of agnostic to which incretin you combine with? Or do you want to go with the most powerful one? Do you want to go with the orals, the injectables? There's a lot of different permutations that one could envision here.

We've been having that conversation internally, and there are a lot of folks who've been talking to us about ways of which incretins they would prefer us to work with. So I think in general, we're going to make that determination when we share the ultimate study. I think there's a lot of options, particularly on the injectable side. I mean I think that there's an opportunity there because I think they're well validated. So again, we run a study. We want to have the data to be able to be reflective on where the experience and particularly when you're looking at the effect of 2 medicines together, where there's a very good understanding of the impact of what you're combining with so that signals aren't overlapped and you can really discern the impact of your product. So again, you'd imagine we're spending a lot of time with folks on that.

Our next question is from Whitney Ijem from Canaccord Genuity.

Can you hear me?

Yes.

Just a couple of quick points of clarification. For the additional data we'll be getting later this year, should we be expecting like 9-month data from 240 and 6 months from 400, et cetera, like assuming every 3-month cadence? This is the first question.

And then the second question is, have you looked at the baseline characteristics for the 600 mg dose and have any comments, I guess, on BMI and visceral fat there relative to the 400 mg cohort?

Yes. So I'll take the last question. So again, we haven't evaluated the 600-milligram cohort yet. But given the inclusion criteria and how patients are dispositioned across the study, I wouldn't expect it to look differently than the current disposition across patients. So we'll see that data. So again, to your point on data updates and cadence, the 600-milligram data will come as will other updates. I think our guidance right now is these data continue to accrete, and we'll provide opportunities over the course of '26 to share those data because I think it will be informative to us and others.

The most important data, which is kind of where I don't want to reflect is we've just seen -- we're getting super high levels of fat reduction in patients who don't have a lot of fat to lose, right? These patients don't have excess fat. So the most informative data in INLIGHT is going to be the second portion of INLIGHT, which is the Phase IIa. And that's where we're going to be able to provide updates on when that study gets up and running to and when we expect data, again, in those higher BMI patients, which is going to be much more reflective of all of the great questions that we're being what happens in that setting, we're going to have the answers to those. And based on all of the modeling and prediction, it all net gets better when you have excess fat.

So I think we're going to have a lot of data over the course of 2026 that are going to continue to inform the profile of Inhibin E with the realization that we're talking about a potent durable medicine on Activin E. I think -- well, it's easy to kind of stay focused on, and I get it, we focus there a lot too on what the downstream effect is on fat. The most important starting point is, do you have a potent, durable suppression of the Activin E ligand with which to see that effect. And I think there were a lot of questions over a year ago is what does Activin E suppression look like? It's a challenging target for a number of companies to keep durably suppressed.

So I think we kind of go back to the most fundamental and foundational part of the data set. We've got safe, durable suppression of Activin E. So then we can look forward and say, what's the impact in this low BMI setting, that checks the box that we feel very confident about going to the high BMI setting, and that's where we should be able to create the comparisons to other obesity therapies.

Our next question is from Samantha Semenkow from Citi.

Just in the Phase IIa, with the addition of the second dose, is the expectation there to drive further reduction in Activin E with that dose? Or is it longer durability of that initial reduction? And then I guess you've already talked about the 70% to 75% that you want to stay under. Is there a target Activin E dose that you believe will maximize the fat and weight loss with this potential mechanism?

No, thank you. One, I think we're there. I mean I think the key here is getting to higher excess fat and then that's where we're going to see the change. I think the dosing regimen, as you're pointing out, is going to teach us just a lot about the suppression. I mean if you look at the curves, as soon as we give the single dose, that there's a rapid decline in Activin E levels. We'll see. I mean that it's going to -- I'd say any time you study something, you're going to have an opportunity to really look at the impact of that on Activin E suppression. But really, it's going to help us as we think about long-term dosing regimens and again, focus on the potential for once a year, what that ultimately looks like.

So between the continued 12-month follow-up of the current dose cohorts, we're going to learn a lot there, particularly on Activin E suppression. And then in the MAD, that will continue to inform us in between those 2 studies, that will ultimately define a dosing regimen for a Phase III registrational study.

Our next question is from Catherine Novack from JonesTrading.

Can you hear me now?

Yes.

All right. Sorry if I missed this, but can you just give us an explanation for the change between December reporting and today's reporting the 3-month reductions in visceral fat and total fat mass. Is that a change in the pool placebo comparator? And then just one more on timing. Do you anticipate that 3-month Phase IIa data could be achievable within 2026, given a 2Q '26 start?

I'll let Chris take the first, but the short answer is yes, to your full placebo, yes.

So it is the full placebo and also that goes into like an overall model of all the data. So we have all the data since December in the model, MMRM and which includes additional placebo participants that were recruited at that time. So that's the reason.

Which is an important way to do the statistics on the study as you treat new placebo patients to make sure they're incorporated.

To your last question, mean it's highly encouraging. So again, if we get the study up, as you noticed when Chris presented, we'll have that 3-month follow-up time. And so we do see that to the prior question on the dosing regimen, we do think that single dose initially is sufficient, right, as we think about potential once a year, twice a year therapy. So we will have an opportunity within the IIa study at an earlier time point to be able to assess the impact on higher BMI patients as it relates to body composition and weight.

Our final question comes from [ Melinda Ghosh ] from H.C. Wainwright & Co.

One question regarding the VMR comparison, I just wanted to know how comparable is the BELIEVE and INLIGHT Trial to do a head-to-head comparison?

Yes. It gets back to the -- and it's a wonderful way to, I think, to reflect back again on we've got BMIs of 32, right? If we think about where our patients are proportionately. Again, it's the direct comparison of where we're starting where those BELIEVE study patients are ending on their treatment. And when you compare our patients and where they're starting after treatment to the BELIEVE patients, recognizing that they have more abdominal visceral fat, they have more subcutaneous fat, they have higher BMIs. We're still outperforming semaglutide on the VMR index, right, which does speak to this improvement in body composition in a Phase I study in low BMI patients. And so -- and on par with [ bamagrimab ].

Again, hence, not the equivalency, we think, long term because when you take our patient population and you bring them back up to the top of the curve where there would be comparison, we'd expect to see even larger impacts on visceral fat and subcutaneous fat with that higher starting point. So it is really important that while these comparisons are done, they're being done from a different patient disposition. So our patients, lower BMI, healthy, no comorbidities, no diet exercise as part of the study. And again, I just kind of reflect on these patients got a single shot and in 6 months without a diet exercise regime that's put on them, lost visceral fat in a consequential way and began to lose body weight. So these patients and most importantly, the 3.3%, we spent a lot of time with questions on body circumference. I mean this is patients also able then to tighten the belt buckle.

So just to put the visualization into what's happening in this low BMI healthy population. Again, we're highly encouraged going into the IIa study, which everyone else is looking at to see an outsized effect.

Thank you. There are no further questions at this time. I will now turn the call back over to Paul Bolno for closing remarks.

Thank you, everyone, for joining the call this morning. I'm grateful to every Wave employee for their dedication and focus on our mission and on the patients and families we serve. Have a great day.

Good morning, and welcome to the Wave Life Sciences Fourth Quarter and Full Year 2025 Earnings Conference Call. [Operator Instructions] As a reminder, this call is being recorded and webcast.

I'll now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations. Please go ahead.

Thank you, Sophie, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our fourth quarter and full year 2025 earnings update. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Chris Wright, Chief Medical Officer; and Kyle Moran, Chief Financial Officer. Dr. Eric Ingelsson, Chief Scientific Officer, will be available for questions after the call. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason.

I'd now like to turn the call over to Paul.

Thanks, Kate, and good morning to everyone joining us on today's call. 2025 was a tremendous year for Wave, marked by positive clinical data sets in obesity and AATD that further demonstrated the broad potential of our unique differentiated RNAi and RNA editing capabilities. Entering 2026, we are building on the strong momentum with a focus across two priorities: accelerating development of our WVE-007 and INHBE GalNAc siRNA program for obesity and rapidly advancing our RNA editing portfolio led by WVE-006 for AATD, followed closely by WVE-008 for PNPLA3 I148M liver disease.

Today, I will start with WVE-007, which is designed to address the substantial need for better next-generation treatment options for individuals living with obesity. While GLP-1s have clearly defined the market and raised awareness of the disease, they require frequent dosing, carry tolerability challenges, induce muscle loss and result in high discontinuation rates as well as weight cycling with patients coming on and off therapy. INHBE silencing with WVE-007 aims to lower serum activin E levels and improve body composition by reducing fat while preserving muscle. Compelling human genetic data support our confidence in this mechanism of action. Activin E is a liver-derived hepatokine that signals adipocytes to slow or put the brakes on lipolysis. By removing these brakes, 007 aims to unleash fat burning without calorie restriction and without concurrent muscle loss. The current obesity treatment paradigm is focused on total body weight loss, which is not the best way to improve overall health and longevity. An ideal obesity treatment should primarily focus on improvements in body composition, meaning decreasing metabolically harmful fat tissue and preserving healthy functional muscle tissue.

Next-generation obesity therapeutic strategies must first and foremost, reduce harmful visceral fat and also be able to decrease subcutaneous and liver fat while preserving muscle. This profile is exactly what 007 aims to achieve. Visceral fat is strongly linked to multiple metabolic disorders, including type 2 diabetes, cardiovascular disease, NASH and others. It is well documented that lowering the mass of visceral fat by more than 5% is associated with reduced risk of developing many metabolic diseases. Additionally, total fat loss has been shown to improve glucose tolerance, insulin sensitivity and overall lipid profile, while simultaneously attenuating adipose inflammatory state and decreasing hepatosteatosis, which is the first step in the development of NASH. Preservation of skeletal muscle is not just about strength. Rather, muscle plays a central role in maintaining basal metabolic rate through higher glucose disposal, better insulin sensitivity and improved overall energy balance. All of these benefits can be delivered by silencing of INHBE.

We chose to target the activin E ligand through INHBE silencing over its receptor ALK7 for several reasons. Turning off protein production in hepatocytes, the upstream source with a GalNAc siRNA is the most efficient and durable way to impact this pathway. Suppressing Activin E rather than disabling a receptor that transduces signals via multiple ligands across different tissues is a more selective approach with lower risk of unintended consequences. This selectivity is especially important for us as we think about long-term safety as well as clinical and commercial translation. 007's unique ability to durably suppress INHBE is driven by our proprietary chemistry and SpiNA siRNA design. While RNAi is a clinically and commercially proven mechanism, there are extensive human genetic data supporting INHBE as a target. We believe our proprietary SpiNA designs distinguish us from others attempting a similar approach. With SpiNA designs, we've demonstrated an unprecedented tenfold improvement in Ago2 loading and several fold increase in exposure versus industry benchmarks. Together, these improvements drove substantial increases in potency and duration of activity.

WVE-007 is our first SpiNA design and our preclinical data for WVE-007 remains differentiated from any other competitor. Most importantly, we are now seeing our preclinical data translate in the clinic. In December, we shared interim data from INLIGHT study. In our lowest therapeutic dose cohort just three months after a single dose of 007, we observed fat loss similar to semaglutide without the associated muscle loss. These improvements in body composition included substantial reductions in fat, including reductions in both total body fat and visceral fat and importantly, muscle preservation.

I want to remind you, this is a Phase I study in otherwise healthy individuals with overweight or obesity and average BMI of these participants was 32, meaning this population has less visceral fat and subcutaneous fat than typical obesity studies. The trial also didn't include any diet or exercise modification. Already at our single lowest therapeutic dose, we observed that 007 demonstrated robust and durable suppression of activin E, supporting once or twice a year dosing, and we shared a clean safety profile through our 600-milligram cohort. The INLIGHT study is fully dosed through the 600-milligram cohort, and we are on track to announce six-month follow-up data from the 240-milligram single-dose cohort as well as three-month follow-up data from the 400-milligram single-dose cohort later this quarter. With continued fat loss and with stabilization of muscle or lean mass, we are looking to see continued improvements in body composition and fat loss beginning to drive weight loss.

As mentioned earlier, the INLIGHT population has lower fat to begin with, versus typical obesity studies, and thus, a better comparison will be made of individuals with higher BMI who have greater fat mass, both visceral and subcutaneous, which is exactly what we will be looking at in the Phase IIa multi-dose portion of INLIGHT. This MAD portion will enroll patients with higher BMI and comorbidities and is on track to initiate in the first half of this year. Chris will speak more on that later.

We are also excited about the potential for this molecule as both an add-on to incretins as well as for maintenance post as an incretin offering. We have generated a compelling body of preclinical evidence supporting these use cases, and we remain on track to initiate new clinical trials evaluating 007 in these settings in 2026. There is widespread recognition of the need for novel obesity mechanisms and therapeutics beyond ingredients. A once to twice a year treatment, which can reduce fat and preserve muscle with a favorable safety and tolerability profile has the potential to shift the obesity landscape.

In RNA editing, we continue to lead the field with WVE-006, our GalNAc RNA editing oligonucleotide for alpha-1 antitrypsin deficiency. AATD is a uniquely compelling disease for RNA editing because it is a single gene disorder where correcting the mutant RNA transcript in the liver directly addresses the root cause of both the lung and liver manifestations of the disease. There are approximately 200,000 individuals in U.S. and Europe living with homozygous ZZ AATD with high risk of disease. AATD is a debilitating disease that impacts multiple aspects of daily life from their ability to work and play with their children to even just walking to the mailbox. These individuals living with alpha-1 have been underserved and remain in urgent need of an effective therapeutic option. Current treatment options are limited to IV augmentation therapy that aims to address the lung with nothing currently approved for AATD liver disease. With our highly specific and efficient GalNAc AIMer design for RNA editing, we do not modify DNA, and we do not require delivery with lipid nanoparticles or LNPs that may be associated with systemic and liver inflammation, potentially inducing hepatocellular stress and activating a hepatic acute phase response. We also avoid the irreversible collateral bystander edits and indels, which are associated with DNA editing.

With 006, we have shown that RNA editing can restore endogenous M-AAT protein to therapeutically meaningful levels, reduce mutant Z-AAT and reestablish the body's normal physiologic response to inflammatory stress, something that is not possible with the current standard of care. Remember, AAT protein plays a protective role during inflammation or acute phase responses when it's rapidly consumed. A patient on IV augmentation risk lung injury if AAT protein levels fall too low during an event. In contrast, RNA editing is designed to restore an MZ-like acute phase response where AAT production rises to meet the demand. With our data demonstrating already over 11 micromolar protein greater than 50% editing and acute phase response at our lowest dose, we're advancing our regulatory engagement with full control of the program. We expect to receive regulatory feedback on a potential accelerated approval pathway in mid-2026. Additionally, we are on track to report data from the 400-milligram multi-dose cohort of the ongoing RestorAATion-2 clinical trial this quarter and report single and multi-dose data from the 600-milligram cohort in 2026.

Building on our clinical success in RNA editing, we are advancing our second RNA editing clinical candidate, WVE-008, a GalNAc-conjugated AIMer for homozygous PNPLA3 I148M liver disease, and we are on track for CTA submission in 2026. In DMD, we remain on track to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen. In addition, our research collaboration with GSK continues to progress, and GSK has now selected a fourth program to advance the development candidate following achievement of target validation, which carries an associated milestone payment that was received in the first quarter. Under the collaboration, GSK can advance up to eight programs leveraging our PRISM platform with target validation work ongoing across multiple therapeutic areas. Wave is eligible for up to $2.8 billion in initiation, development, launch and commercialization milestones as well as tiered royalties, and we expect to continue to receive milestone payments in 2026 and beyond.

With that, I'd like to turn the call over to Chris to review our clinical progress with 007 and our RNA editing programs.

Thanks, Paul. Starting with our INLIGHT clinical trial of WVE-007. The ongoing portion of INLIGHT is a Phase I randomized placebo-controlled single-dose study in otherwise healthy individuals living with overweight or obesity. The study is active at multiple clinical trial sites, including in the U.S. and is fully enrolled through four dose levels. Our three therapeutic dose cohorts are fully expanded with 32 participants in each cohort. Individuals received a single dose of WVE-007 and are then followed for up to 12 months with key assessments, including safety, tolerability, PK, activin E, body composition as measured by DEXA, biomarkers and body weight. The average BMI in the study is low compared to what is observed in typical obesity studies, and there are no diet or exercise modifications.

With this backdrop, we are particularly excited with the positive interim data we shared last year. At three months in the lowest therapeutic cohort, a single 240-milligram dose of 007 led to an improvement in body composition, characterized by a placebo-adjusted 4% reduction in total fat, 9.2% reduction in visceral fat and preservation of muscle as evidenced by a 0.9% increase in lean mass. Notably, 007's placebo-adjusted reduction in total fat mass was on par with semaglutide at 12 weeks, while simultaneously preserving lean mass and driving greater reductions of visceral fat. The safety profile was favorable and there were durable reductions in serum activin E, supporting potentially once or twice yearly dosing.

Overall, these data demonstrate that a single dose of 007 can shift body composition towards less visceral and total fat while preserving muscle consistent with our preclinical findings and with the underlying human genetics. We look forward to evaluating the impact of this mechanism at a higher dose and over a longer duration later this quarter. With this data, we anticipate that the continued fat loss and stabilization of muscle mass will drive further improvements in body composition and weight loss.

We are preparing to initiate the Phase IIa multi-dose portion of INLIGHT in which we expect to enroll individuals with higher BMI and comorbidities. Assessments in this multi-dose portion are expected to be like those in the single-dose portion with additional inclusion of body composition measured by MRI and liver fat content as measured by MRI-PDFF. We're excited to evaluate not only body composition to demonstrate fat loss with lean mass preservation in the study, but also better understand the impact on liver fat, which could read positively for a NASH indication. Finally, we remain on track to initiate new clinical trials evaluating 007 as an incretin add-on and as a post-incretin maintenance therapy in 2026.

Now turning to our ongoing RestorAATion-2 clinical trial of 006 for AATD. Our goal is to achieve three criteria: one, keeping basal protein levels at or above 11 micromolar. Two, driving circulating M-AAT protein above the 50% heterozygous MZ threshold with corresponding decreases in the mutant Z-AAT protein and most importantly, three, restoring the physiologic response of serum AAT protein to acute inflammatory events.

Last September, we delivered data from our RestorAATion-2 trial, demonstrating that we have achieved these goals with 006. Most notably, we were able to restore a ZZ participant's ability to respond to an acute inflammatory event with a total AAT levels of greater than 20 micromolar, just two weeks after a single dose of 006. We are accelerating our regulatory engagement time lines now that we have full control of the program. We anticipate receiving feedback mid-2026, which will guide our path towards an accelerated approval.

Now turning to our second RNA editing clinical candidate. We are advancing WVE-008 for homozygous PNPLA3 I148M liver disease. This PNPLA3 variant is a well-established driver of NASH pathology, yet there are no approved medicines that directly address this biology. There are an estimated 9 million homozygous PNPLA3 I148M carriers with liver disease across the U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers. With 008, we aim to correct the I148M variant using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid mobilization, reversing steatosis and fibrosis and improving liver health.

In our upcoming first-in-human study of 008, we plan to leverage previously genotype populations to efficiently identify homozygous I-148M carriers, evaluate target engagement of circulating biomarkers and assess early signs of efficacy using noninvasive imaging. We remain on track for a CTA submission in 2026.

With that, I'll turn the call over to Kyle to provide an update on our financials. Kyle?

Thanks, Chris. Our revenue for the fourth quarter was $17.2 million compared to $83.7 million in the prior year quarter. For the full year 2025, revenue was $42.7 million as compared to $108.3 million in the prior year. The quarter-over-quarter and year-over-year decreases were attributable to revenue recognized upon the termination of the Takeda collaboration in October 2024. These decreases were partially offset by increases in revenue recognized under our collaboration agreement with GSK.

Research and development expenses were $52.8 million in the fourth quarter of 2025 as compared to $44.6 million for the same period in 2024. Research and development expenses for the full year of 2025 were $182.8 million as compared to $159.7 million in 2024. These increases were primarily driven by our rapidly advancing INHBE program and RNA editing programs as well as compensation-related expenses, including share-based compensation.

Our G&A expenses were $20.9 million in the fourth quarter of 2025 as compared to $16.1 million in the prior year quarter, and $75.3 million for the full year of 2025 as compared to $59 million in 2024. These increases were primarily related to compensation-related expenses, including share-based compensation. Our net loss was $53.2 million for the fourth quarter of 2025 as compared to net income of $29.3 million in the prior year quarter. Net loss for the full year of 2025 was $204.4 million as compared to net loss of $97 million in 2024. We ended the year with $602.1 million in cash and cash equivalents, which we expect will be sufficient to fund the operations into the third quarter of 2028. It's important to note that potential future milestone and other payments to us under the GSK collaboration are not included in our cash runway.

I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. 2026 will be a year of strategic focus aimed at accelerating development of 007 for obesity and rapidly advancing our RNA editing portfolio. We are excited to build on our positive momentum and are energized now more than ever to unlock the full potential of our RNA medicines pipeline to transform human health. Looking ahead, we expect our next update to be data from our INLIGHT clinical trial of WVE-007 for obesity and additionally, expect this to be followed by data from our RestorAATion-2 clinical trial of WVE-006 in ATD. We look forward to keeping you updated on our progress. And with that, I'll turn it over to the operator for Q&A. Operator?

[Operator Instructions] We'll take our first question from Joseph Schwartz with Leerink Partners.

This is Jenny on for Joe. I guess just one on AATD. One of your major competitors recently aligned with the FDA on their biomarker-based accelerated approval framework. How closely does your regulatory strategy mirror what they've laid out for their biomarker-driven path? And are there any key differences? And have you had comparable alignment discussions with the FDA?

No. Thank you, Jenny. And I think what we all heard in the feedback from one of our recent peer companies from the agency is very much aligned with our thought process in AATD in the beginning and frankly, fairly well aligned with the existing therapies that have been developed for AATD, which is a biomarker approach in a disease where the protein is the measurement therapeutically active substrate. And so we wouldn't anticipate a distinct or different conversation. I think for us, recognizing that the only protein we're making is the M-AAT protein, and we don't have to deal with bystander edited proteins and the functionality of that, I think we're in very good shape for a discussion on active protein and meeting the requirements that we see as the therapeutic threshold. So we are engaging with them. Obviously, we don't comment on individual conversations with the agency, but we do fully anticipate feedback by mid-2026 on a registrational pathway. I think it was also highly encouraging recently, and I'm sure many of you heard on the plausible mechanism pathway, comments made by the head of the FDA as well as CEDR on using those pathways specifically for ATV. So I think it's a very good time for us to be approaching regulators on a pathway for alpha-1.

Our next question comes from Salim Syed with Mizuho Securities.

Maybe just one for us on just the second quarter data. I think at JPMorgan, you guys mentioned that we should be expecting the 400-milligram multi and 600-milligram single in the second quarter of this year for INHBE. It doesn't seem like it's listed in the slide or the press release. Has there been a change? Are we going to get that data? Or what caused you to remove it from the catalyst slide?

Yes. No, the data is on track. I mean, as we always say, the beauty of a single-dose study with exquisite durability is all the patients are dosed. So data just continues to accrete. So we'll focus on the upcoming data, looking at the impact of time on 240 and the 400. And there's opportunities again for data cadence over the course of the year. We're not guiding to each individual update. But as you said, all these data time lines are all on track given that all the patients in the study have been dosed. I mean we have now over 100 patients on the study across multiple dose cohorts. So it does create a unique opportunity over the course of this year.

Okay. So we'll still get that data then, Paul, or something that we -- you're still sort of...

Data included by the next update in Q1, and then we'll provide subsequent updates on Catalysts at each time we provide the update. So the next update on INHBE is this quarter.

Our next question comes from Steve Seedhouse with Cantor Fitzgerald.

I wanted to actually expand on the alpha-1 antitrypsin deficiency expectations. So assuming you get alignment on an accelerated approval pathway and some AAT marker either M or total. What are you hoping that the confirmatory trial requirement will be there? Or what are you expecting? Do you already have sort of clarity on what the post-marketing requirements would be for full approval eventually?

It's a great question, Steve. I think that's the conversation that we want to have with the agency and align on. I think there's a number of ways of thinking about that, that can be efficient, particularly in the design of a subsequent studies that could roll into addressing some of those opportunities. And I think there's really two sets of development pathways. One is obviously respiratory. The other important feature of RNA editing, remember, is we see dramatic decreases in Z-AAT protein, which open up the opportunity for liver indications as well. So I think our goal is make sure that we focus on an accelerated approval pathway for AATD patients. These patients aren't liver and lung patients. These are AATD patients and then ultimately establish the right pathway as it relates for both labeling for lung and liver, and we'll align with the agency on those.

Our next question comes from Joon Lee with Truist Securities.

Do you have an internal weight loss bogey for the forthcoming six-month data for the 240 milligrams and three-month data for the 400 milligrams to feel confident on achieving the 5% weight loss bogey at 12 months? And what sorts of outcomes data are you planning to generate to minimize potential payer pushbacks?

Yes. Thanks for the question, Joon. I mean I think if we ultimately think about the pathway for a greater than 5% weight loss, remember, that threshold is after 12 months in patients that would be presumed to have an average BMI of 37 on an optimized treatment regimen. So in the low BMI Phase I otherwise healthy patient population at the doses we're in now, I think we'd like to see continued trajectory down on the weight loss curve. I mean we had about 0.9% decrease in body weight with increase in lean mass preservation and decrease -- substantial increase in fat. So with the expectation that total fat should continue to decline, we expect lean mass to stabilize, we would expect to see that change in total body mass. And that would just be a great indicator for us. And again, we continue to follow that, all of which would signal incredibly favorably that in the study, and as we mentioned on the call, I think this half of the year, getting that Phase IIa portion of the study in the MAD in patients with allowing for comorbidities, which means the expectation for higher BMIs that more aligned with other obesity studies would put us in a wonderful position to be able to have a regulatory pathway on weight loss.

I think the broader conversation that we all need to kind of be ready for, and I think this is what we're hearing too from our strategic partners as well, is that this addressing body composition piece is critically important. I mean what we hear time and time again, both from the clinicians, patient advocacy community and obesity, again, and strategic partners is scale weight versus body mass. And this notion that weight on a scale equating to actually healthy phenotype and actually what's driving obesity improvements in health outcomes is driven from fat reduction, lean mass preservation and ultimately seeing that forward. So I think it's important that we look at the benchmarking for weight loss to be, can we cross those criteria for an approval in obesity? And we do believe that we will use that pathway. But I think what's more important than that in terms of ultimately the therapeutic potential for INHBE in the obesity landscape is really driving this improvement of an overall body composition, and that's how you get healthy outcomes.

Our next question comes from Alec Stranahan with Bank of America Securities.

Good to see the progress. Maybe one on obesity. It was interesting to hear your thoughts on the various activin E strategies out there. Are there any specific AEs or other metrics you think we should pay attention to for, say, ALK7 or direct active modulators that you may be avoiding here with targeting INHBE? And I guess, longer term, given the better tolerability you're seeing so far, how does the duration of mass benefit that you could potentially achieve with 007 fit into your picture for addressing some of the comorbid conditions that these patients face.

No. Thank you. And I'll break the question into the first piece. I mean, as we think about, as you mentioned, some of the myostatin and other activin pathways. I think as we're looking at our safety profile versus safety profiles of other medicines in that space, I think they've been distinct. So I do think what we're seeing in terms of not just driving fat loss, and we'll talk about that in the context of your what's ultimately going to improve the outcome for patients in that status. I think we see a very differentiated safety profile and efficacy profile as it relates to fat loss.

As it relates to the -- as you pointed out, some of the potential risks and future looking at ALK7, I think we need to continue to watch those programs over time. I mean that's something that has to be evaluated is what is the downstream impact of this kind of multifaceted ligand strategy and what happens. And I think we'll be -- data will be accreting there and people will be able to observe what the impact of that is. I think it gets back to the very important point of why we selected INHBE, which is specificity. I think this has all learned over a long time in obesity that specificity and understanding pathways is important. And I think the INHBE access with ALK7 in terms of driving improvements in outcome is established both in genetics, following patients over time, so in clinical genetics and ultimately, as we're seeing translate in our human studies.

As you point out, and I think this is an incredible opportunity in thinking about areas for INHBE reduction and particularly active reduction. I do think this opportunity is it's very well established that a 5% or more change in visceral fat does change outcomes, cardiovascular outcomes, diabetic outcomes. And so when we do think long-term about what's actually driving the benefits of when people say weight loss, ultimately, what's driving those benefits is this reduction in visceral fat, which we've surpassed with now nearly 10% reduction in visceral fat at our lowest therapeutic dose at the earliest time point and reduction in total body fat. So I think with all of that, coupled with preservation of muscle, which ultimately as an endocrine organ is critical for sustaining, the profile of what's ultimately going to drive health outcomes is that benefit. And those outcomes are well established in the literature.

I think when people step back and say, what overall is important in medicine, I think those two things are really important. One, we have the health outcomes and for those who try to think about what's going to happen with that preservation. I don't think people raise their hand and say, I want a medicine that I'm going to lose 40% to 50% of my lean body mass at the expense of losing fat. And so I think ultimately, as an obesity therapy on health outcomes and other measurements, a reduction in substantial fat, particularly visceral fat and preservation of lean mass over time creates an optimal therapy in the space and with durability of once to twice a year as we think about the commercial prospects. You really can change the landscape in the current setting. So as we think about maintenance and the opportunity for once twice a year and the ease of administrating that. But we also think about the global 1 billion patients worldwide living with obesity and how they get access to therapies. And when you change that dynamic where patients aren't having to go in for a weekly or monthly injection of a protein or stay on a daily oral pill that has to be coincidental with eating and has all of the other tolerability challenges. We think it opens up the global obesity landscape, too.

Our next question comes from Madison El-Saadi with B. Riley Securities.

It's nice to see you're adding MRI-PDFF to your planned Phase II obesity trial. Just wondering what is the treatment delta you are expecting to get there, just recognizing that monotherapy semaglutide gets around 30% to 40%. So curious where you think you may land on that scale from, say, GLP-1 to the FGF21 mechanism.

Yes. I mean without at this point, running -- I mean, it was interesting in looking at comparator data, peer data on combinations where they were seeing nearly a 78% reduction in liver fat. I think there is a substantial opportunity, as Chris pointed out on the call, for MASH as a potential indication as a monotherapy. So I think by enrolling a study where we have patients that allow for comorbidities, I think there is going to be a substantial opportunity for us on imaging to look at monotherapy data by itself in recognizing that there really is a powerful signal that's been seen with INHBE reduction in weight loss. And I think it steps back into again, the overarching opportunity for an INHBE pathway and really thinking about the substantial active knee reduction and driving outcomes, both for MASH and reduction of liver fat. And as we were talking about the last call, as we think about just lipid levels in general, you should see with this reduction in these patients with comorbidity. And this is really, I think, again, speaking about long-term outcomes and benefits to patients in cardiovascular disease, reductions in lipid profile, meaning reductions in cholesterol, LDL, hemoglobin A1c and triglycerides.

Our next question comes from Catherine Novack with Jones Trading.

Just one for me on the dose response and relationship between activin E and fat loss. So clinically, you are seeing similar fat loss to a competitor with lower activin E knockdown. Is there anything we're missing or is it just small numbers? And then similarly, do you have preclinical modeling data that shows that going from 75% to 85% knockdown is going to lead to better fat loss?

Yes. I mean I think one of the things that we've seen, and as you pointed out, our study versus other studies that have come out is we actually have larger cohorts. So I think the dynamic effect that we're seeing with longer-term measurements of activin E, I think we feel really confident that both -- and we'll talk about the dose response second, that we do see really highly durable suppressed activin E levels over time. And I think that's the most important feature of speaking to activin E reduction is not just do you knock it down, it's keeping it chronically suppressed. And so we have the long-term data that, again, to your point, differentiates this from other programs in the space.

Secondly, going back to our preclinical data, yes, we have shared that we see a dose response on activin E reduction driving, again, with suppression, driving further weight loss. Remember, that was the measurements we were using in our preclinical experiments were reduction in weight loss and that weight loss driven by fat loss. So again, gives us continued support between the 240. And we've been consistent in saying the bookends that we think around the therapeutic activin E, we believe, are modeled into the 240 versus 400 as being opportunities to look at that dynamic range on weight loss as we saw preclinically and translate that into fat loss in the clinic. So yes, we would expect to see the impact of both time but also dose on fat reduction.

Our next question comes from Cheng Li with Oppenheimer.

Congrats on the quarter. Just wondering for the upcoming INLIGHT update, are you planning to share some additional like biomarker data for those like related to inflammation or maybe fibrosis? And also, are you planning to present the data at maybe a medical conference this year?

Yes. We haven't guided to where we're presenting. It will be this quarter. So I think that's the most important update for consistency. In terms of data, we'll present the data the expectation should be similar to last time in terms of looking at the key metrics of measurements. I think what's important and really where the opportunity sits, to Chris' point on the call for the IIa portion of the study is since these are otherwise healthy individuals, and that's really why the BMIs are in this range of around 32 is because we've cut out patients that have a lot of the other features that you're measuring because those wouldn't be considered otherwise healthy individuals, and they don't meet that criteria. And so therefore, being able to look at some of the other markers that one can see in the study does present more of a challenge because they're otherwise healthy. I think the opportunity as we get into the Phase IIa, where we allow patients with comorbidities being higher hemoglobin A1c, other lipid characteristics will give us more opportunity to be able to discern some of these other changes that are seen with INHBE in a clinical context, but that will be in the subsequent IIa portion of the study.

Our next question comes from Whitney Ijem with Canaccord Genuity.

This is Angela on for Whitney. Can you just maybe help us set expectations into the upcoming obesity and AATD readout? So for 007, how should we all be thinking about what is good in terms of body count or fat reduction from the 240-milligram cohort at six months and then 400 at three months? And then similarly for 006 in terms of what AAT levels would you want to see from 400 MAD? Thank you.

I mean I think the key criteria for us is we're already on that curve with the 240, where we're seeing fat loss similar to GLP-1s increased visceral fat, higher fat visceral fat reduction than GLP-1s and lean mass preservation versus remember, at that three-month time point, there was nearly a 50% reduction in lean mass on the GLP-1. So I think continue to see the profile of an improvement in body composition with, I think, continue to see the impact of that fat reduction. So that should happen over time and lean mass should be stabilizing over time, which should be driving that lean -- the total body mass curve down, so weight down. I think that will be the opportunity of looking at the impact of time at 240. And then it was brought up by one of the other questions, which I think is an important one is we're going to be able to look at the establishment of this dose response context. So what's the impact of time on that curve and what's the impact of dose on that curve? And so the 400 will be equally as important looking at that early time point. So that will be at the three-month time point because, again, we can compare it to the GLP-1s on the dose response at that early time point with a higher dose and suppression of activin E and potential decreasing in fat and be able to set the stage for what does that look like modeled over time based on the 240 six months. So I think we've got an opportunity really to continue to watch those kinetics play out.

And if we go back to our preclinical data, that was really the slope of that weight loss curve was driven by exactly what we believe we're seeing in humans, which is mice have substantial reductions in total body fat. They had a slight increase in lean mass. And overall, the mice lost weight similar to GLP-1s and their curve was continuing. So I think the opportunity is to actually be able to model between our preclinical data and clinical data based on the human evidence coming forward in obesity.

For 006 in AATD, I mean, I think it's important to remember that the arms race for more and more protein isn't necessarily what the requirement is if you're not doing IV protein replacement therapy. So I think the idea in editing has been to establish do you have the therapeutic threshold to say that these patients are corrected to an MZ phenotype so that ultimately -- and it is really important when we talk about editing to step back and say, it's a chronic disease of acute exacerbations. And therefore, the whole premise of this is how do you prepare a patient so that when they have that exacerbation, they can rise to meet that need. And as we saw, 20 micromolar, the lowest single dose meant that those patients actually in the event are protected at levels that we're talking about for IV protein replacement to hopefully prevent that where that nadir could actually be lower in the IV protein replacement space. So I think we've already seen that we're at that threshold. I think the question going forward is going to be both durability, time, so opportunity to continue to see as liver gets healthier, are we producing potential for more M protein over time, which we think based on our preclinical experience should be seen, so you can continue to see that protein get released to see increases in, but ultimately continue to sustain the portfolio. I mean, the pattern of increased editing efficiency.

So I think that's the notion. We're going to be able to look at that at the 400 and see again, duration. So is this -- this will be monthly? Do we think about the opportunity to think about a medicine that could be quarterly or less frequently. Being able to model that is going to be important ultimately as we think about a therapy. And so I think we're set up to be able to distinguish this as delivering on the profile that we believe is going to be requisite for the regulatory interactions for a potential accelerated registrational pathway.

Our next question comes from Ben Burnett with Wells Fargo.

This is Craig on for Ben. I appreciate the opportunity to ask you all a question today. So appreciating the fact that 007 is a liver-directed agent, I guess, based on your understanding of the biodistribution of that agent, would you expect any of it to find itself to muscles? And maybe just a quick second one here. Given that now you're exploring the benefit of 007 on liver fat, how do you see that coexisting with 008 over longer periods of time?

Yes. I mean I think to address the first one very simply, it's a GalNAc conjugated siRNA. So it's an active receptor-mediated uptake in the liver. So that is the target organ for delivery. And based on our preclinical data, that's where the drug is distributed and exerts its impact on a simple basis. And the second question was -- sorry, if you want to...

008.

008. So, how do these work? Yes. I mean I think what we have to think about in 008, and it's important to kind of step back separately from just thinking about 007 and the impact on liver fat and 008 in the constituency, MASH is one indication for 008. If we step back and think about the PNPLA3 indication, these patients are at risk of all told liver disease. So the best way to think about PNPLA3. And maybe, Erik, you can share and we should double-click back on the indication because I think it is important to really think about this as a genetic mutation for the liver disease in general and all to liver disease, not just NASH and where the ability to identify the mutations found in 23andMe, it's a genetic mutation that can drive a whole variety of diseases, of which NASH is one. But Erik, I don't know if you want to...

Yes. Just to build on that, I think this is the first approach that is directly -- or rather, there are no approved drugs that are directly addressing the pathology in these carriers. So it's kind of -- it really corrects back the disease driving variant in these carriers. And to Paul's point, it's not only MASH, it's across a whole set of different liver diseases. So it addresses directly the causal variant. So therefore, it's kind of a unique approach, we think.

We think about this as having kind of and we shared some more on this. So it's a good opportunity for us to go back to Research Day. There's this concept on lipid trafficking and when we think about MASH and where that application is, but there's also an inflammatory component in these PNPLA3 patients, which is why their response to injury drives this fibrosis and liver injury in general. And so the real opportunity in correcting this, and this is again why you want to correct it and not silence it is restoring the functionality of this enzyme so that what you're able to do now for these cells is actually repair them. So not thinking about kind of symptomatic treatments that improve kind of one aspect of the disease, but actually fix the underlying pathology that allows these patients to go forward, not just focus on liver fat, but actually prevent fibrosis and downstream sequelae, where these patients who are homozygous are at very high increased risk of really progressing to cirrhosis and ultimately new transplantation. So I think the opportunity we really have in fixing this disease at the source.

This is separate from thinking about how do we think about the opportunities beyond treating body composition as it relates to obesity therapies with 007. So if we think about 007, there are a whole host of things we can think about as we think about visceral fat reduction and what the impact long-term is on visceral fat reduction, improving outcomes to patients, not just thinking about obesity in general, but thinking about visceral fat reduction downstream, thinking about MASH as another indication because of the increased impact on reduction in liver fat. And so I think these medicines are very different in how they approach things. INHBE really focused on a pathway around fat reduction and the ability of 008 to focus on a pathology that's very uniquely driven off of a genetic mutation.

Our next question comes from Roger Song with Jefferies.

This is Cha Cha Yang on for Roger. I had two questions. One is, can you speak more to what you expect to see for 007's kinetics based on some preclinical PK data? And what we should expect to see for the rate of fat loss, weight loss and lean muscle mass change over the next six to nine months? And then just second question really quickly. Can you just remind us what trials and programs your 2028 cash runway will include?

Yes. I mean I think what we see on the curves, if you look at the animal modeling data, so you can follow where the GLP-1 curve on weight loss is, where that's heavily predominantly driven on lean mass loss at the beginning and then continued fat reduction kind of gives you this that increased slope and plateauing and then where you see INHBE, where you see this acceleration kind of into that curve. And so I think we're right on that tracking with the rate. We're all learning about the pathology -- say we're all learning about the rates of that curve together. I think it is tracking actually very nicely to our preclinical experience. I would say mouse kinetics to human, there's always a separation. So we just have to continue to watch that play out. But I think we have a very good benchmark in looking at the GLP-1 versus INHBE, and they're tracking as to be expected. So again, high degree of conviction that with more time, you see more fat reduction. With higher doses, you'll continue to see more fat reduction. And then as you point out, we'll have these periods at six months, nine months and out to the patient study allows for a follow-up out to a year. We're going to get the opportunity to really follow that in this lower BMI setting.

I think what's going to be exciting about bringing on earlier now this higher BMI setting is going to be that we're going to be able to look at these things in tandem, right, be able to track these together and be able to see, again, in that higher setting, which is more akin to the animal model, does that happen faster? And so we'll be able to look at that and track that. But again, very good correlation between the DIO mouse and what we're already seeing in the clinic. So again, drive that conviction, remembering that we did see weight loss in the preclinical models.

Your other point within this 2028 envelope is exactly, as we point out, delivering on our four strategic priorities. We're going to deliver the 006 data. We'll have our regulatory interactions in the middle of this year. It was and why we said last year, it was important for us to accelerate INHBE. It funds the Phase IIa studies so that we can continue to deliver the study in patients with a higher BMI. And it's inclusive of accelerating, as we said this year, the study on both add-on and maintenance. And what's been interesting in some of our strategic conversations is we are getting -- there are good conversations happening with the ability to access various incretin and various designs and studies. And so that isn't incorporated into those savings in those studies, but there's opportunities that exist as we think about those collaborations ways of thinking about retaining the asset, but ultimately continuing to drive clinical data sets off of that. So again, delivering in our runway, as we said at the beginning of this year, the core strategic principles of 007 in obesity, 006 for alpha-1 antitrypsin deficiency and bringing also forward the CTA submission and the clinical trial for 008. So that's in the envelope.

The next question comes from Michael King with [indiscernible].

I just want to maybe reflect more on 007. We're talking in very scientific terms. But if you think about the trajectory of the obesity space, I look at it as kind of a war of one upmanship that started between Lilly and Novo and then it's going to be, I think, joined by the likes of Pfizer and others just trying to focus on body mass index or loss of body weight. You see the consumerism aspect of it with Serena Williams and Charles Barkley losing 30-plus pounds or 50-plus pounds, respectively, of weight. So how does one communicate maybe -- and this may not be your problem to solve. It may be your strategic partner, but how does one communicate the benefit of loss of visceral fat and preservation of muscle apart from body weight when so much of the light in the obesity ecosystem is focused on body weight loss.

No, it's where we spend a lot of time, and it's frankly why we're extraordinarily excited about where INHBE fits into this because I think athletes is not aside, call it you're a normal person, right, who is going and wants to your point, there's a need or requirement in their minds, they're saying, I need to lose weight, right? They're worried about either being obese or overweight and they want to take a therapy. And if you look at this, I don't know anybody who is going to raise their hand and say, you know what, I wouldn't mind losing 30%, 40%, 50% of my lean body mass because I'm going to look at a scale and it's going to go down. When you could look -- and actually, I'm reminded this because I was actually talking to a KOL yesterday. And what she was reminding me of is we need patients who are leaner, not lighter. And the notion that she has patients to come into the office and she remind them, she's like, don't look at your scale. But if I told you, they're coming in because they're saying, look, I want to lose like 40 pounds. I want to lose this. And then she puts up a picture actually like Michael Phelps. And she's like, if I told you could be 200 pounds and look like that versus 150 pounds but have no lean mass, what would you -- and inevitably, when people think about it in real-world context, what they're really saying is they want to be leaner. They want to have high lean body mass low subcutaneous and visceral fat, but they don't want to do it at the expense of muscle, and they're thinking about it.

They can get their back.

It's just as important. And now -- but it doesn't mean -- so like -- and I don't want to take us into the swirly of, it doesn't mean you're not going to lose weight. If you lose subcutaneous fat and you preserve muscle, you will lose weight. So this notion that all of that has to not coexist with the regulatory pathway, I think, is a false pretense. So you can completely exist within the regulatory paradigm. But if I actually see where regulators are going as well, they're indexing this, right? The guidance last year was on body composition, bring us weight loss, but bring us body composition. Don't come where this race. You pointed out, the race that's happening in this other kind of or call it on the incretins. It's just like incremental loss of -- it's at the expense of muscle. There's tolerability, there's weight cycling. There's this notion of a whole generation of people who are on a therapy and it's switching from saying, well, we should think about this like hypertension, keep people on it for a long time. 70% of people can't stay on the incretins for a full year, right, with all of the other complications to it. So I think the notion of really reminding ourselves why are we doing this? A once to twice a year medicine that can drive substantial fat reduction, preserve lean mass. So you get that opportunity on both, as you said, the perception side, what do I look like kind of question. But most importantly, what's going to drive health outcomes benefit is the profile of what INHBE and activin E reduction brings, but does so at a scale where, again, safety, tolerability, I think, is highly differentiated from the growing incretin class. I think maintenance will be a really fundamental opportunity here, the idea of what does the off-ramp for a chronic therapy look like where somebody now has to look at the potential lifetime of sustaining themselves on an incretin therapy. It's why we're excited this year to get the maintenance study, which is give patients an off-ramp. You can have the sustained reduction in fat, you can prevent continued sustained loss of muscle. You can have a once to twice a year maintenance therapy. And so I think there's an enormous opportunity on the maintenance setting. And I think we're hearing this echoed by all of the strategics that we're talking about that truly recognize that this INHBE body composition, maintenance is crucial.

And not to be lost to realize that when we do talk about this as an obesity therapy, there are a substantial number of people who can achieve goal on the incretin therapy. They can't tolerate staying on. They can't tolerate being titrated up on it. And so we really do think about the therapeutic paradox. We have one strategic say, what would be really interesting is INHBE is the basal state and then titrate the incretins around it so that you can preserve better tolerability and safety. So I think this really does fit within this paradox. But as you point out, I think it really is important for people to remember in the real-world consequence, this really is delivering the profile that patients are looking for, reduction in fat, preservation of muscle, ultimately allowing patients to be leaner, not lighter.

We'll take our last question from Cassie Yuan with RBC Capital Markets.

On INHBE here, I appreciate that you're amongst the most advanced in clinic today for this target, but it also seems like some of your competitors are speeding up by following signals in comorbidities and subpopulations earlier in their studies. Could you maybe comment on how important is it to be the first pivotal data for INHBE? And ultimately, do you see activin E space accommodating multiple players? And what do you think is going to be the differentiating factors amongst the players here for activin E lowering therapies? Any color there on these dynamics is much appreciated.

Yes. I think, look, I mean, as you point out, obesity is a very large space, so it can accommodate multiple therapeutic companies. But as we've also seen in the space, it's helpful to be a leader. And I think within the INHBE access, I think Wave is well poised to be the leader for INHBE silencing. I think our chemistry is highly differentiated. We saw that from driving single-dose weight loss in our preclinical studies, which is the only preclinical data to date that's shown dramatic decreases in sustained activin E reduction tied to weight loss. So our chemistry translated to differentiated preclinical data, which ultimately, as we've seen, translate into the clinic in a highly differentiated way.

I think what we're seeing across the INHBE space with competitors are programs that look very similar across all of the peer companies. I mean if you look at all the posters that were sitting there on other INHBE programs at Obesity Week, they all looked remarkably similar. So I think there will be a separation between here's what Wave is bringing to the table in a highly differentiated way to look at INHBE with a once to twice a year therapy that drives a dramatic difference. And then there'll be everybody else. So I think it creates a very unique opportunity for us really to define the space and then sustain our leadership within that space. And I think it is important because I think we tend to think about siRNA as a commoditized space across indications. And I think we're hearing this from those who are experts in the field recognizing that what the team has done in driving new chemistries forward has created a very unique space for us here.

Now we need to sustain that leadership, really, as you pointed out, defining what success is going to look like. And so it's wonderful that we could see already this differentiation. Everybody is comparing us to GLP-1s at three months, other INHBE programs at these time points, that we're a little bit later. But we're doing this in a way where our BMI setting, to your point, we're looking at patients who are nondiabetics, right, who are low BMI, and we're already seeing these differences. We're excited to go into the higher BMI setting because I think that's going to give us the opportunity to see even greater weight loss and fat loss and then ultimately changes in other outcomes measurements. So I think we're really poised to not have to say we need to get into these settings to be able to see the efficacy. We can see it in this low setting and then only build on that from here, time, higher doses and also in patients with higher BMI and comorbidity. So the data should continue to mature as these studies move forward, both in the existing INLIGHT study, but also in the Phase III study.

Thank you. There are no further questions at this time. I will now hand the call back over to Paul Bolno for closing remarks.

Thank you for joining our call this morning. We appreciate your continued support, and have a great day.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the senior biotech analysts here at JPMorgan. Our next presenting company is Wave Life Sciences and presenting on behalf of the company, we have President and CEO, Paul Bolno. Paul, over to you.

Thank you, Tess, and thank you, everybody, for joining us today. Before we start, we'll obviously be making some forward-looking statements during this call, so I'd please ask you to refer to our SEC filings for updates. Taking a pause and thinking about entering 2026, we are energized now more than ever to unlock the broad potential of RNA medicines and open up the opportunity to transform human health. And what this really reflects back on as a journey on building a leading RNA medicines company and at the foundation. And this is going to be important as we speak to the evolution of the clinical portfolio is the foundational bedrock of Wave is in our RNA chemistry. So when we talk about what we've been able to build and differentiate from, we should be thinking about a proprietary chemistry engine, and we'll share more on that later. That enables us to rapidly take deep genetic insights and translate those into impactful medicines. And I say this because the speed with which now we can take chemistry and translate that into medicines is incredibly rapid. So to put this in context for the obesity therapy. It was 18 months from the time we generated mouse stated human clinical data and about 24 months from the time we had identified a genetic sequence to delivered clinical data. So rapid insights into rapid medicines. This is all built off of a foundational broad IP estate and importantly translates to the building that we've done in manufacturing. So therefore -- and so with our own in-house GMP manufacturing we've been able to rapidly translate medicines forward. And we'll talk about how that's been important as we advance in the clinic.

Taking forward in the clinical portfolio, the dominant program that we'll spend a lot of time talking about today is our innovative GalNAc-conjugated Inhibin E siRNA program. We've been able to see highly differentiated approach to treating obesity that's driven off of an improvement in body composition, meaning reduction in fat and muscle preservation. In addition to the ground baking work we've been doing at RNAi, we've been leading the field of RNA editing. And then pioneering that with our alpha-1 antitrypsin program, and we'll share more data on that program later as well as the advancement of the next program on our RNA editing platform, PNPLA3 for liver disease. Beyond what we've been doing with GalNAc conjugation for liver with siRNA and RNA editing, we've been able to advance extrahepatic set of programs, both in RNA editing and in siRNA, delivering the adipose tissue, muscle as well as CNS. And we'll share a little bit of data that we've built beyond our R&D Day on the novel bifunctional modality. And this really lets us think about taking these 2 opportunities in siRNA editing into a single oligonucleotide construct, let's just have one drug that can both upregulate and edit as well as silence a second target. So a lot happening, but a core focus that we'll share on obesity and alpha-1 antitrypsin and editing.

We're well capitalized, and we entered this year with now $602 million of cash, which will take us into the third quarter of 2028. So as we talk and pause about our innovation on chemistry, and it's really important to take this as a foundation because as we think about this field, there's others in this approach, who are talking about RNAi. And we need to think about how these approaches are different. Why is the chemistry different? So on the left-hand panel and on the far left, you'll see data that's represented from one of our paper that we shared several years ago. This is an NAR paper. And we shared in the paper is that black line and that teal line. And when you look at the paper, what we showed is that the innovation that we see on our siRNA chemistry is giving us about a 10- to 15-fold improvement in Ago2 loading, yielding a more potent and durable knockdown in SI. What we've shared an update on at our R&D Day is that actually with the innovations that we continue to push forward on our chemistries that we're actually seeing much deeper knockdown. So again, enhanced Ago2 loading, leading to deeper knockdown to the target but even more durable suppression of that target. This is going to be critical as we talk about Inhibin E and the opportunity in obesity where we can differentiate based on our siRNA formats between our chemistry and that of others that are moving forward. I should say that, that black reference compound represents the state-of-the-art siRNA chemistry as it stands today. So we'll talk about this again in the context of obesity.

In addition to the work that we're doing in siRNA, these chemistry innovations also apply to new modalities. So new modalities like RNA editing. And as we shared what we're able to do in highly potent, highly specific base editing. So this is ADAR editing. We can see these chemistries transition to more potent, durable editing and that translating ultimately into the portfolio.

As we said at the beginning, while we've built a deep and broad portfolio chemistry translating across programs in the clinic across different modalities, 2026 is a year of strategic focus. When we talk about strategic focus, that really means an emphasis on 2 areas. The first area is accelerating the development plans for WVE-007 across multiple treatment settings within obesity. And rapidly advancing our RNA editing portfolio of WVE-006 for AATT as well as 008 for PNPLA3. What does that mean? So in obesity, it means moving as we announced yesterday, to the Phase IIa portion of the INLIGHT study. So this is the multi-dose portion where we'll be exploring the ability to knock down Inhibin E in patients with higher BMI and with and without comorbidities. And we'll share more on that later. In addition, it also means that we're going to initiate new clinical studies in both a combo and add-on study to incretins as well as maintenance. We think 2 very important opportunities to explore the 007 program.

In RNA editing, it means delivering the data from the 400 and 600-milligram cohorts this year, the 400-milligram editing data for WVE-006 is coming this quarter and as well as filing the CTA and transitioning WVE-008 for PNPLA3 for the 9 million patients living with liver disease into the clinic.

So looking forward to obesity, we do believe that obesity is in need of a treatment paradigm shift. We know that the current standard of care for GLP-1s is limited by a loss of muscle mass, and this is consequential, and we'll share more on that later, not just in the case of thinking about frailty, but really thinking of muscle as an endocrine organ is character by frequent dosing, poor tolerability and discontinuation rates that are driven from that. When we think about the future of obesity therapy beyond in treatment therapies, we're thinking about what the possibility is when you can improve body composition. WVE-007 to flash forward ahead, we saw fat loss similar to GLP-1s at the 3-month time point. It preserves muscle mass. So very importantly, and we'll talk about the consequences of that preserving a muscle mass, has the potential for once to twice a year dosing, both in the preclinical data as well as our clinical data. And very importantly, for an obesity therapy was generally safe and well tolerated. And we say that, that was all the way through the 600-milligram dose cohort in the study. We believe that this principle of what we're bringing forward has the potential to change and improve body composition for the over 1 billion patients worldwide living with obesity. So we talk about body composition. There's often [indiscernible] what does that mean? How important is body composition. And we have to think about body composition as having 2 components. The first is a reduction in fat, in particular, visceral fat. That's critical to when we think about cardiovascular outcomes, inflammation, MASH and a number of diseases that are associated with obesity, those are driven by increasing levels of abdominal visceral fat. Inhibin E silencing does reduce subcutaneous fat, and that's obviously important as we think about the majority of body fat, which is tied to body weight reductions. So we will see a reduction in fat as well as a reduction in abdominal visceral fat. Equally important is thinking about muscle preservation. And we say this is important again beyond frailty because muscle is a very large endocrine organ that's responsible for improving insulin sensitivity. But as you maintain that and lose body weight, is also a feature in how you can continue to progress body weight reduction over time. So preserving muscle is crucial in a therapy for obesity. So how do we think about Inhibin E. Inhibin E Is a wonderful target in that it comes from the U.K. Biobank. So we like targets that have protective loss of function variants where essentially the human clinical trial has been run. This means that in the human population that's been studied in the U.K. Biobank, a 50% loss of function of Inhibin E has a genetic profile of low waste to hip ratio, so low abdominal visceral fat, has an improvement in lipid profiles, so low LDL, high HDL. And essentially, the clinical outcome experiment has been run, patients with a 50% reduction of Inhibin E have a low risk of Type 2 diabetes as well as cardiovascular disease. So an ideal way to come into a program is one where the human experiment has been run, the genetics are there. The question that always hums forward is can you induce a change in that phenotype? Well, how do we do that? So thinking about silencing Inhibin E. So this is a target that's produced in the liver. So an ideal target for a GalNAc siRNA construct, the liver target makes and forms a dimer of Inhibin E and that is the Activin E substrate. That is the protein of the ligand. We have assays that can measure activity in blood so that you actually have a great serum biomaker for efficacy, and you can measure the impact of silencing on that biomarker. Activin E binds to, and I'm sure people have heard of ALK7 is a receptor that's on the adipocyte so the fat cell, so this is highly characterized communication of a hepatokine from the liver that cross talks with receptors that are on the adipocytes. And if you silence that, so in a normal environment, I'd say before we silence, Activin E binds to ALK7, and that's actually the body's mechanism for storing energy, storing fat. And evolutionarily, that's how humans protected themselves. You store fat, you store energy and that protects you during times of famine. If you knock out Activin E, you remove the brakes on lipolysis from that receptor and you see a shrinkage of adipocyte fat cells and it goes through lipolysis and you lose that. So that's the mechanism between the 2. The efficiency and the reason we chose Inhibin E is the efficiency of taking a catalytic siRNA with GalNAc to a specific cell type that produces the ligand hepatocyte and being able to turn off the spigot and prevent Activin E from engaging with the receptor is a highly efficient way to target this pathway. Now there are other approaches of looking at Activin E in the periphery around the adipocytes, we do believe that targeting GalNAc the hepatocyte is the most efficient way to drive this process. Now this activin E is in circulation. And recently, there's been some discussions of whether or not Type 2 diabetes has a role to play in weight loss with Inhibin E therapies and others. We'll say that a very large prospective or I should say, observational study in 250 patients was presented in a poster at Obesity Week. And in this study of 250 nondiabetic patients, it was seen that Activin E levels correlated with increase in BMI, increase in truncal and abdominal fat and increasing in [indiscernible] insulin, all suggesting similar to the data that we'll share soon in our healthy overweight population without Type 2 diabetes that type 2 diabetes is not connected with the Inhibin E, Activin E pathway in terms of weight loss. But actually, BMI is highly correlated, and we'll talk about that in the context of moving into high BMI patients in the next study. So what did we see preclinically that drove our enthusiasm around this target is that we did see that with our chemistry being able to take a single dose and silence Inhibin E, it led to a potent durable reduction of Activin E levels. That reduction of Activin E below our threshold of 70 caused a reduction in fat, particularly visceral fat, preserved muscle and there was a slight increase in lean mass that we saw preclinically, and we'll talk about that in the context of the human data and ultimately resulted in body weight reduction in the DIO mouse at a similar level of weight reduction to GLP-1s. What you'll notice in that line on the far right, in terms of the Inhibin E weight loss curve versus the semaglutide weight loss curve is there's a shift in that rate of weight loss and weight decline. Originally, before our clinical data, it was thought that maybe lipolysis takes longer, and that might be accounting for that -- the change in that slope even though we reached the same standpoint and that sema moves pretty rapidly. I think what we're seeing both on our preclinical data and ultimately, as we'll share in our clinical data is that rapid weight decline in semaglutide is principally driven through a decline in loss of lean muscle mass. We'll share the 12-week data from the sema from the BELIEVE study. But at the 12-week time point, it's actually about 50% in humans lean mass loss at that early time point. And hence, why we think the steepness of that curve moves pretty rapidly. What's interesting with Inhibin E is we actually see that this weight loss while slower is principally driven because you have stabilization of lean body mass and then continued reduction in subcutaneous fat. And that continuous reduction in subcutaneous fat drives weight loss. And so that's an important characteristic as we think about the profile as we move forward.

Importantly, beyond monotherapy, so the idea that can you take down Inhibin E and does that drive weight loss similar to GLP-1s, we also saw the potential for combination. We've had a number of discussions with a variety of folks who've got differentiates across the treatment landscape of different ways to be thinking about how to drive the study as we think about our clinical study. But what was important is these approaches are completely orthogonal. So the idea that Inhibin E and its pathway is non-calorically driven, and we'll talk about that in the next slide when we look at the caloric comparisons on the maintenance study. But given that you have a throne approach of 1 being calorically driven or hedonically driven, which is the GLP pathway, one that's driven on lipolysis and the pathway for Inhibin E, they are combinable and synergistic, and we can think about approaches of titrating between GLP-1s as well as Inhibin E to drive weight loss. And what was really exciting to think beyond the combination is the opportunity for maintenance. And so this study, which we ran, where we track both calories and weight, what we could see is as you induce on a GLP-1 you see weight loss very similar. You have that anhedonic behavior, mice lose weight, both in the scope of muscle, lean muscle mass as well as in fat. And what we showed is if you pre-dose prior to cessation of GLP-1s, you curtail the rebound weight gain. This is independent from the fact that in both arms, the placebo arm and the treatment arm, caloric consumption resumed back above baseline. So essentially, what happened is that starvation phenotype of now eating and storing calories drove an increase in weight, all fat. But if you pretreat and took the brakes off lipolysis, you see a steady state of maintenance therapy. So these are the 3 treatment settings, mono, combo and maintenance that we've been looking at for Inhibin E preclinical data.

Transitioning to our clinical data. We ran a healthy overweight volunteer study. This Is a Phase I study. The criteria, while the BMI, as you could see, had a larger range, the criteria that restricted that was that these had to be healthy patients. So no comorbidities. And in that, the average BMI on the study was 32%. So substantially lower than that seen in other obesity trials. Additionally, there was no diet or exercise modifications required as part of the study. So this gave us a real-world setting where we could treat and see how patients actually low BMIs behaved on treatment. Cohort 1, because this was a Phase I healthy volunteer study, was a subtherapeutic dose and then the subsequent cohorts 240, 400 and 600 were at or above therapeutic expected threshold. I should say at the current time, all cohorts have been dosed. We've been cleared by the DSMB to go higher than 600, but as you'll see in the data, we don't believe that that's necessary. But it was important from us from a safety assessment when we did our first data cut, that the Safety Assessment included all cohorts on the study. So what do we see? We saw a highly durable reduction in Activin E levels. And I think this was incredibly important when we think about it in comparison to other Inhibin E programs that have been in development. We see an ED50 that's nearly threefold higher than other programs. So we're seeing potent, durable reduction of Activin E. Even at the subtherapeutic level, we're seeing that, that's sustained out months. And we believe, looking at the 240 and the 400 that, that should continue to support the once a twice-a-year dosing regimen. I will say that the time of the data cut, the 400 is still going down, and we'll share that we'll expect that data this quarter where we'll have the follow-up data on the 400 milligram. But we see that we're in the threshold, it's stable and it's durable. I'll also say that there's really good distribution into hepatocytes. So if we look at the error bars between the 6 patients that were on the 400 at the time of the cut and the 6 patients that were in the 75-milligram as we get that higher level of exposure, we're not concerned that there is lack of variability or distribution across patients. So again, highly encouraging as we think about therapeutic profile continuing to mature.

As we think about the clinical data, we saw much the recapitulation of that same data. So from human genetics to DIO mice. Now to humans with a substantial reduction in visceral fat, nearly 9.5%, a substantial reduction in total fat mass and a slight increase above placebo and lean mass, again, consistent with what we saw in our preclinical data. When we take these data and compare them to the only now published data, on 12 weeks with GLP-1s that include DEXA, so we can do points of comparison. We see that and have to recognize that the semaglutide study at this point had a BMI of 36. So it's nice that we're comparing from a BMI of 32 with no diet and exercise to study with a BMI 36 with diet and exercise. But in that study, we still see substantially decreased abdominal visceral fat when we compare that to GLP-1. We see about equivalent reduction in total body fat. So again, similar body fat reduction to GLP-1s at that time point. But importantly, that slight increase in lean mass versus substantial decrease. And what's interesting there is we said earlier, is at that time point, there's about a 50% reduction in lean body mass. So again, very important that what we're seeing at this time point is fat reduction and importantly, visceral fat reduction as well as retention of lean body mass. We do expect this study as it continues over time to continue to see like we saw preclinically, continued sustained reduction in fat, preservation and muscle. And when you put those 2 parameters together, that continued to drive reduction in total body weight. That's important because what we believe and continue to focus on is a regulatory pathway that follows the obesity guidance, which is a 12-month study looking at greater than 5% change in total body weight with an emphasis on body composition. So we do believe that these data continue to put us in the direction of an obesity study driven off of fat loss with muscle sparing.

One of the other things we can look beyond just generalized fat loss, driving subcu and ultimately, weight loss is the impact on visceral fat. And I think this is an important point of differentiation because what is seen is that a 7% to 10% decrease in visceral fat. Ultimately, you can play a role in cardiovascular outcomes. So as these studies continue, the ability to think about not just the impact on body weight through a reduction in subcutaneous fat as the dominant reducer, but actually visceral fat should point to an improvement in cardiometabolic outcomes.

So what's next for INLIGHT. Beyond the [indiscernible] INLIGHT Phase I portion, which will continue to accrete over time. This study allows 12-month follow-up at each cohort. So we'll continue, as I said, all patients have been dosed. So we'll continue to follow these patients out over time. The goal as we announced yesterday is to accelerate the Phase IIa portion, the multi-dose portion of the study. And that's going to enable us to change the criteria to have higher BMI individuals where we can then look in addition to having comorbidities, we do expect a larger impact on fat reduction with higher BMI, and therefore, a bigger impact in overall changes. And then, therefore, can look at that in comparison with similar BMI studies that have been done. We plan to initiate this study in the first half of this year. So focus on that study being the monotherapy. So building on our single dose, we do see a monotherapy application for weight loss with a once to twice a year drug that loses fat and preserves muscle. We do see the ability and we'll initiate this year at the combination study to look at the add-on effect. And I think as we've seen from other studies that have reported out recently, the power of the combination, particularly the liver fat reduction has been pretty consequential. And so we see Inhibin E in combination with incretin having a big impact on reduction of liver fat. So that's an important thesis to think about as we go forward. And then ultimately, where we see a very substantial portion and utilization of this is in maintenance. The idea that we can transition patients from a life of chronic incretin therapy to a once to twice a year maintenance drug. And the key that's there is thinking about -- as we think about the over 1 billion patients living worldwide with obesity, how can we move this beyond the United States and think about patients worldwide where you can get better access, better distribution if you only have to treat patients 1 to 2 times a year. So exciting. The value of this program continuing to go forward is now we'll continue to create data over time. And that data will really answer a question of how much does time play a role in continuation of body weight? How much is driven based on dose and Activin E reduction, and the study is already poised to deliver on both of these features as we look at data over the course of this year.

Beyond obesity, WVE-006, which is the first RNA editing program to go in the clinic, is moving forward and a quick update on that. For those who aren't familiar, AATD rare disease focused on about 200,000 patients in the U.S. and Europe who have a ZZ mutation. So these patients have 2 bad copies of a gene. This creates a misfolded protein. That protein is unable to be expressed and protect the lung and those patients go on to have lung injury, but also because of that protein is folding, go on to have liver injury due to the accumulation of that protein in the liver. There's no approved therapies that treat both the lung and liver manifestations of the disease. There is IV protein replacement therapy that's been approved to treat the lung conditions and to try to provide protein to protect that lung during periods of injury. There's no approved therapies yet to deplete the liver protein. So the approach that we have is grounded in genetics, Therefore, looking at the heterozygous patients. So these patients have 50% corrected M protein. So they are able to make a good copy of that protein. And when you look at these patients, they have greater than 11 micromolar protein that's able to circulate and protect the lung. They have 50% edited and protein. This is important because they're able to have a dynamic effect that can actually rise to meet that injury signal. And so these patients go on to have low risk of lung and liver injury. So the principal guiding feature in developing the AATD program is developing in a corrector that can correct over 50% of the transcript and therefore, deliver the restoration of this healthy phenotype. The other key dynamic effect, and this is important as the data came out, is thinking about augmentation therapy. So this replacement versus correction. And I think what's interesting, and you have to reframe a thought of what happens to these patients. So what happens in the case of AATD patients is it a chronic disease, but there's acute exacerbation. So these patients go through these intervals where they'll have a stimulus of inflammation that drives an increased protein response of damage. And normally, these patients would make alpha-1 antitrypsin protein to protect their organ in the lung. In the case of not having that, you get augmentation therapy, the challenge of augmentation therapy is you do this peak infusion. And then over time, as you can see on the graph, it's a consumptive protein, it declines. And actually, during that period of injury, patients are actually more exposed to that injury signal than they would be. So nobody knows kind of what happens in that interval as the protein is consumed, how much risk of injury there are. And it's a concern for clinicians. The difference of editing and correcting is actually the protein rises to meet the need of the body. So you reach a steady state at that heterozygous level that protects the body, and during that injury period where that stimulus is there, you actually see the increase in transcriptional activity and through correction can actually increase the expression of protein to protect an individual during that period of time, therefore, preventing the exacerbation from driving injury. The current design of the study had a healthy volunteer component that's been completed. We reported data from the 200 single and multi-dose study last year. We shared the single-dose data from the 400 last year, and the data this quarter will be from the 400 multi-dose cohort, looking at M-AAT levels, total AAT levels. What's important from the last time we repeated data is exactly what one would expect or want to see in that heterozygous genotype. We saw the lowest single dose of the study. We saw 13 micromolar protein at a steady state. We could see the actual correction and it was highly tight across patients in terms of that switch from Z protein to M protein. So we saw over 64, so well over 50% edited protein that could meet the need of that correction. And very importantly, we actually saw during the acute phase response when the patient needs it, they could produce over 20 micromolar proteins. So a patient had an actual event during the study. We could look at the CRP level during the study, it was a modest level but we could actually see that they could generate over 20 micromolar protein during the event. That's essentially where people are talking about where IV protein replacement should start before it actually starts to deplete. So when we think about the profile of delivering the heterozygous like phenotype, we were seeing that at the early parts of the study. As we said, we'll have the 400-milligram data in Q1.

Building off of this program and very quickly, a lot of the principles of editing and can we get to this 50% editing, highly efficiency, GalNac-conjugated subcu, a lot of the features that we like to see, coupled with generally being safe and well tolerated was, could we apply this to another indication. There's often a question that gets asked are, what are other large indications beyond alpha-1 antitrypsin. PNPLA3 is actually -- that mutation is a very interesting mutation. There's a strong foundation in human genetics. There's over 9 million patients that have in the U.S. and Europe that have this mutation, and it drives an increased incidence in liver disease. It's an enzyme, so it also has an approach where the 50% correction doesn't have this dynamic response event. So it's -- should I say, nothing is ever easy, but you can measure this and say that actually, you're just measuring can you correct this protein and allow it to restore its function. And the function really is about processing lipids as well as retinol, so be involved in fibrotic cascade. So when you think about that, given that it's involved in both lipid metabolism as well as fibrosis, you imagine that if you have that mutation, you can get a whole variety of liver diseases that come from this. So it's not restricted to MASH as an indication, although several companies talk about silencing in that approach. [ ALT or ] liver disease for PNPLA3 is how we think about this. And with that mutation, you have about -- if you can correct that to the heterozygous level, you have about an 80% risk reduction of disease. So very similarly, 50% correction drives an improvement ultimately in outcomes.

Why silence versus edit, it's been known that this is an enzyme that's really important again in lipid metabolism in fibrosis. So what we see in the control of the green -- the blue highlights or the nuclei of cells, the green is liver fat. And what you can see is if you can correct that protein and actually restores physiologic function to 50% or more, you actually see a better lipid traffic and you metabolize that fat, that's processed without the cell. We think this is why the siRNAs have had challenges, which is if you knock that enzyme out, you actually don't restore lipid metabolism. You don't [indiscernible] retinol metabolism, you can see fibrosis. So we think it's an ideal target. It's differentiated in the approach of why do editing and also attack disease that's consequential. We see continued and potent editing. We have the experience of translation from our preclinical models to clinical with alpha-1 antitrypsin. We see highly potent durable editing in our preclinical studies, highly specific, and this is a good point of differentiation as we think about the DNA editing constructs is that this editing is highly specific with no bystander edits, no off-target edits. And we see really strong tissue distribution, delivery and durability and expect to file a CTA in 2026.

Lastly, being able to put these 2 pieces together, we are working on bifunctional conjugates, we actually take the best of what we can do in RNA editing, the best of what we can do in siRNA and rather than making 2 molecules to drive therapeutics can actually create a single oligonucleotide construct that can do both editing and upregulation, coupled with silencing and have shown data preclinically at our last research day that you can think about targets like LDLR upregulation with PCSK9 silencing and think about applications where you wouldn't want to have 2 independent development plans, 2 commercial products to be co-administered. But think about it as 1 clinical trial with 1 product to transition to the market. So the key focus for Wave going forward is an emphasis in RNAi driven by obesity with 007 for Inhibin E, 006 in AATD and PNPLA3, with the ability to continue to drive those platforms and formats forward. Anticipated milestones, multiple data sets accruing on obesity over the course of this year with the next inflection being Q1, the 400-milligram 3-month data and the 240-milligram 6-month data. Additionally, 006, first quarter, we'll have the 400-milligram data, 008 moves into the clinic. We do expect to submit the NDA for N531 this year. However, we've been very clear on our strategic focus that we will look to find commercial distribution partners for that as opposed to invest the capital that we currently have allocated for advancing our siRNA program, particularly running those 3 trials that we mentioned in obesity, that we'll use those partnerships to drive the N531 study forward.

And with that, thank you for your time.

Great. Great. Thank you, Paul, for that presentation. So I thought I would just dive right in, in the time that we had and start with obesity. Can you speak in a little bit more detail to the size and the scope of the Phase 1 additional INLIGHT trial data that we will get this year? What is the type of profile you're looking to deliver in this trial overall? And what level of that loss and body composition results would you like to see with longer-term follow-up and higher doses?

Yes. That's we'll unpack that in a variety of ways. I think first and foremost, kind of stepping back to INLIGHT. INLIGHT right now has over 100 patients currently dosed in the study. So when we think about the magnitude of effect and being able to observe that over time, we have substantial number of patients that we can look at across the study over -- for both Activin E reduction and correlating that ultimately to therapeutic effect. So we do care about sample size and powering as we think about being able identify impact and effects from the study. In terms of what we want to see is we'd expect to see continuation of what we currently see, meaning we saw that if we potently and durably reduce Activin E, it translates to a reduction in fat. Emphasis on visceral fab, but that's not to say that we don't see substantial reduction in subcutaneous fat, which should continue to drive the potential for weight loss as well. So we see fat reduction and we see lean mass preservation. The profile that we'd expect to continue over time, both at that dose and then we'll talk about what happens as we go higher, is that we would expect to see that fat continue to decrease, but we would expect lean mass to stay stable. So again, when we think about what would drive the ultimate -- this is kind of the calculation for how to think about body weight reduction is that if you change body composition in that reduction in fat and you keep lean mass stable, you will lose body weight. And I think the important observational medicine to see that. And it was in the BELIEVE study is bimagrumab. So a totally different pathway, that's a myostatin medicine that makes lean mass go higher and actually has less an impact on fat, still sees weight loss over time. So again, we expect that profile of focus on fat reduction, lean mass sparing to drive that. I think what we're going to have the opportunity with this quarter is to see the impact of dose on the rate of change? Does a higher dose actually drive that transition faster? And ultimately, does it allow that to continue out longer. So we'll be able to look at both dose response as well as time response on body composition as the study continues to progress. And then the opportunity with the higher BMI Phase IIa portion is going to be able to see the impact of higher BMI on that rate of change.

Great. And you talked a little bit about the number of different treatment settings you can go -- could go into here. How do you think about overall Phase II development? And which of the pathways do you think are most derisked at this point versus where there may be a little bit more risk?

Well, derisking has 2 different components to it. I think on 1 hand, we do see on the monotherapy side, a derisking event that substantial reduction of Activin E causes substantial reduction in fat, which is tied mechanistically to both the animal model where we saw fat reduction similar to --- weight reduction similar to GLP-1 as well as the human clinical genetics. I think on the other side of the equation beyond monotherapy is actually there's substantial data on maintenance because if we think about the human heterozygous phenotype, there's a lifetime of maintenance essentially with a 50% reduction in the genotype that ultimately leads to an improved phenotype over time on maintenance therapy of what happens when you reduce Activin E, those patients don't gain weight. So when we think about the maintenance setting where persons at a set body weight from an incretin and you're dosing and withdrawing the incretin, that's probably the most correlative to when we think about the human clinical genetics but we'll be running that study as well.

And any further comments you want to make on kind of overall where you see this asset fitting into the treatment paradigm here? And also just how you see the evolving development landscape in the kind of the area that you're in?

Yes. There's a lot to discuss there. I think in each treatment setting, we see high need and impact. And if we work from the maintenance setting forward, I think in maintenance, keeping patients on a lifetime of a multi-dose incretin therapy has challenges. And I think we hear that from a number of individuals we talk to clinicians, patients, even strategic partners thinking about how do you continue to keep patients on incretins for a very long period of time. I think 1 approach that has been suggested is why we see the shift to oral medicines. But as we've learned from the statin community, trying to stay on an oral daily statin that actually has very low instant side effects, it's very hard to do consistently and compliance is a very difficult problem in keeping patients on therapy. Flash forward to an oral medicine that drives nausea, vomiting, and my guess is that, that real-world data as it emerges, we'll see how that continues to drive a maintenance therapy. So I think the idea of rapidly transition patients to a once to twice a year therapy that allows for sustained fat reduction, preservation of lean mass, and as a safety tolerability profile as we do, I think, is an ideal way of thinking long term about that opportunity. And we know what the current opportunity sits with that transitioning of those patients forward. Combination is real. We know patients who come in and talk about their journey with us and remind us that they could be looking at an advertisement on television that shows what the weight loss opportunity is in combination and says, even if they achieve that, they still wouldn't be at a treatment goal of healthy weight loss. And so therefore, the additional setting of being able to add this on to existing incretins to continue that weight loss journey is important because, again, because of the safety tolerability profile, the combination actually is not adding additional safety or tolerability events. We also have seen and had a number of [ strategics ] have discussions about how do we think about these interacting in terms of titrating back incretins and finding an optimized schedule between incretin therapy along with the combination. So that's intriguing. And I think there's a number of different ways to explore that. And then we're working our way back to monotherapy. And I think this is one of what is that rate of weight loss. And I think when people can have the conversation move from this being a pound for pound weight of weight reduction, which is principally driven off of lean mass. And I don't know many people are saying, I want to lose like 50% of my lean mass within 3 months have given an opportunity. The opportunity to reimagine what that looks like when you can have a monotherapy that you preserve your lean mass, you lose fat, weight loss will occur. But in terms of improved body composition, we think that is ideal. And as we talk to clinicians were saying, look, I've got patients who, I'll tell them, they've got to eat protein, but the anti-hedonic activity of the GLP-1s is having them not consume the protein that they need to retain that muscle. I think the treatment paradigm in monotherapy is ripe for migration. But we realize that, that with time for the community to adapt. And so I think all 3 treatment settings are an opportunity.

Okay. And I know it's such a tight amount of time here. So I'll just ask kind of an overall question to end us. Are there any other data milestones that you think matter most for Wave in 2026 that you would draw people's attention to?

I think the upcoming data, as we think about the continuation of 007 and driving improved body composition, again, is a paradigm shifting, it's probably the most watched, the most focused on opportunity. And the benefit we have is, as we roll forward, we're going to have ample opportunities to see that data continue to accrete both at each dose level over time, but also at the higher doses to see the continued improvement in body weight reduction.

Okay. Okay. Great. Thank you so much, Paul, and the entire Wave Life. Thank you.

Thank you. Appreciate it.

Hello, and welcome to Wave Life Sciences Positive Interim Clinical Data from INLIGHT Trial of WVE-007 and Obesity call. [Operator Instructions]. Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs.

Thank you, operator. This morning, we issued a press release announcing positive interim clinical data from our ongoing Phase I INLIGHT trial of WVE-007 in individuals living with overweight or obesity. Our press release can be found in the Investor Relations section of our website, www.wavelifesciences.com. The slide presentation to accompany this call will be available on the website following the prepared remarks.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2024. We undertake no obligation to update or revise any forward-looking statement for any reason.

Today, Dr. Paul Bolno, President and Chief Executive Officer, will begin with opening remarks. Next, Dr. Erik Ingelsson, Chief Scientific Officer, will highlight WVE-007 our INHBE GalNAc-siRNA, and Dr. Chris Wright, Chief Medical Officer, will present the interim INLIGHT clinical data. Last, Paul will conclude with next steps and anticipated milestones before turning it to Q&A. Dr. Chandra Vargeese, Chief Technology Officer, will also be available to answer questions. I'd now like to turn the call over to Paul.

Thank you, Kate. At Wave, our goal is to translate powerful human genetic insights into transformational medicines. And with WVE-007, we are addressing a significant unmet need individuals living with obesity. In particular, our focus has been on meaningfully improving body composition by reducing fat, in particular, harmful visceral fat and preserving muscle. And as you'll see, that's exactly what we did.

Today, we are excited to share a significant milestone towards this goal with the first clinical translation of 007 in our Phase I INLIGHT study, which has exceeded our expectations. We've long stated that our goal with a 3-month data from our 240-milligram cohort was to demonstrate that we are on the curve to deliver meaningful backlogs. And with today's update, after only 3 months, we're excited to be observing fat loss similar to GLP-1s without their associated impact on muscle. What was particularly remarkable was that this was despite in light investigating healthier participants without diet or exercise modifications.

Just 3 months after a single dose, 007 led to dramatic improvements in body composition, with substantial reductions in fact, including a 4.5% reduction in total body fat and a 9.4% reduction in visceral fat. Importantly, we observed clear evidence of muscle preservation with a 3.2% increase in lean mass. Our best-in-class SpiNA design is leading to robust and durable suppression of Activin E, supporting once or twice per year dosing, and we're seeing remarkably clean safety profile through our fourth 600-milligram cohort. As you'll hear today, these results support a potentially transformative profile and drive our excitement in advancing INLIGHT and further development of 007 across multiple settings. Now to provide further background on 007's differentiated approach and strong biological foundation. I'd like to turn the call over to Erik.

Thank you, Paul. Before diving further into today's results, it's important to reflect on the current obesity treatment landscape and why we believe WVE-007 is positioned to deliver a truly transformative novel therapeutic approach. Individuals living with obesity face markedly higher risks of a range of serious conditions, including cardiovascular disease, type 2 diabetes and several cancers. The key driver of this elevated disease risk is unhealthy body composition, with an excess of body fat in relation to lean mass.

While GLP-1 receptor agonist and other incretins have transformed obesity care, their impact is often limited by a substantial loss of muscle mass as well as tolerability challenges, especially GI side effects, frequent dosing and high discontinuation rates. The loss of muscle with incretins is particularly important to emphasize in this context due to the important role of muscle in metabolism and weight maintenance. We believe that an improved body composition is the key goal of any effective obese treatment strategy.

Body fat, in particular, excess of visceral fats, including fat around internal organs, is strongly linked to diseases like type 2 diabetes, fatty liver and cardiovascular disease, acting through chronic inflammation and insulin resistance. Additionally, skeletal muscle, which is the main component of lean mass is important for improved insulin sensitivity for sustaining a higher basal metabolic rates, which is critical for long-term weight maintenance, as well as for preservation of muscle strength and function and to reduce the risk of sarcopenia and frailty.

There's a lot of literature from over the last few decades, demonstrating the strong links of increased visceral fat with insulin assistance, MASH, type 2 diabetes and cardiovascular disease. As shown on the left, decreases of 5% to 10% visceral fat leads to substantial and clinically meaningful improvements across the number of cardio-metabolic disorders. As shown on the right, you can see that increasing levels of visceral fat are associated with the dramatically increased number of cardiovascular events. For these reasons, we're excited about the approach we're taking with 007 that leverages the completely orthogonal mechanism from gut, brain signaling and appetite suppression by inducing fat loss through lipolysis, breakdown of triglycerides, directly in adipocytes.

007 aims to improve body composition by reducing body fat, in particular visceral fat while preserving muscle to deliver a healthier cardiometabolic profile. 007 targets INHBE or Inhibin Subunit Beta E with a strong foundation in human genetics, which has been shown to increase the probability of successful drug development by up to two to fourfold, with coding variant evidence in the upper part of that range. In the U.K. Biobank and other cohorts, heterozygous Inhibin E loss of function variant carriers exhibited healthier metabolic profile with lower abdominal obesity by Waist-to-Hip ratio and lower visceral adipose volume, lower triglycerides, ApoB and fasting glucose and higher HDL cholesterol.

We also have favorable associations with liver trades, such as ALT and CT1, a measure of liver inflammation and fibrosis and lower risk of type 2 diabetes and coronary heart disease. Our therapeutic hypothesis is straightforward. By silencing INHBE mRNA, we aim to recapitulate to protect phenotype seen in these heterocycles loss-of-function variant carriers. Inhibin E is produced in the liver, where two of the subunits dimerize to form the hepatokine Activin E.

Activin E gets released into circulation where it binds in a specific manner to alpha-7 receptors on adipocytes. The resulting signaling blocks adipose like policies, promoting abdominal varicosity and increasing risk for cardio-vascular disease and type 2 diabetes. By reducing hepatic Inhibin E mRNA with a GalNAc-siRNA with lower circulating Activin E decrease ALK7 signaling adipose tissue and release the brake on life policies, which is expected to shrink adipocytes and reduce abdominal adiposity, thereby lowering cardiometabolic risk.

In addition to Inhibin's E, strong foundation in human genetics, we believe 007 is differentiated by our proprietary chemistry, which makes us well positioned to deliver a potentially best-in-class approach. 007 is a GalNAc-siRNA using Wave's SpiNA design, including backbone stereochemistry and [ PM ] chemistry to enhance interactions with Ago2 and to improve silencing potent and durability. We have demonstrated the dramatic improvement of Ago2 loading, which is a critical differentiator when trying to silence Inhibin E, a target that is hard to keep sufficiently and durably suppressed, presumably due to evolutionary pressure for the need to store energy efficiently. Based on observations from human genetics studies, we would expect that Inhibin E silencing and Activin E reductions should lead to meaningful improvements in body composition as well as cardio-metabolic health, which should be the main objectives of any obesity medication.

As we have shared in a number of previous presentations, our preclinical studies show that by reducing Inhibin E mRNA and circulating Activin E levels, increased adipocyte life policies leads to reduction of adipocytes sizes and fat loss, in particular, visceral fat. This, in turn, results in a shift from pro-inflammatory to anti-inflammatory macrophages and less fibrosis in visceral adipose tissue, as well as improved insulin sensitivity, changes that can contribute to lower risk of cardiovascular disease and type 2 diabetes.

As we also shared previously, our preclinical data in diet-induced obesity mice strongly support 007s ability to both potently and durably knockdown Inhibin E and reduce circulating Activin E, leading to substantial changes to body composition, with fat loss, in particular visceral fat while sparing muscle. Based on our preclinical data, we would expect reductions of Activin E levels of at least 70% to translate to improvements of body composition in clinical trial. As observed in the right figure when comparing the kinetics, weight loss within Inhibin E siRNA was similar in magnitude to Semaglutide, but occurred more gradually, potential explanation for the initially slower weight loss could be that the preservation of lean mass is offsetting weight loss early on.

But that over time, the substantial fat loss is translating to weight loss as lean mass stabilizes. As Chris will share in further detail momentarily, our results with 007 represent the first clinical data linking durable Inhibin silencing to meaningful changes in body composition in humans. With the clinical translation of 007, strong human genetics foundation and our robust preclinical data, we're incredibly excited to continue to evaluate 007 across cohorts and with longer follow-up in human light, where we expect to continue to see the loss of total and visceral fat with muscle preservation. With that, I'll now turn it over to Chris to walk through the INLIGHT clinical data in more detail.

Thanks, Erik. Good morning to everybody on the call. As a reminder, INLIGHT is a placebo-controlled single ascending dose study, randomized 3:1 active to placebo, with potential to escalate up to 5 single dose cohorts and plans for additional multiple dose cohorts. It's designed as a safety tolerability PK study. Participants are healthy individuals living with overweight and mild obesity.

With key inclusion criteria of HBA1c less than 5.9 and BMI between 28 and 35. The study does not require diet or exercise modifications or counseling. In addition to safety, tolerability, PK and Activin E levels, the study has exploratory endpoints of body composition by DEXA, biomarkers and body weight. INLIGHT is currently ongoing at multiple clinical trial sites, including in the U.S. We began testing WVE-007 at our lowest subtherapeutic dose of 75 milligrams in 8 participants, which did not include DEXA and was primarily to a firm early safety in PK/PD.

We next evaluated the 240 milligram, 400-milligram and 600-milligram ascending dose cohort, which are expected to be at or above our therapeutic threshold. We have expanded 2 and fully dosed 32 subjects in each of these cohorts based on the favorable safety profile. Today's update primarily covers 3-month follow-up data from our first potentially therapeutic 240-milligram cohort and equals 32. In addition, further updates on safety for the 75 through 600-milligram cohorts and PK from 75 milligrams to 400-milligram cohorts are provided. Baseline characteristics were generally well balanced across the treatment arms. Participants were in their late 30s to early 40s on average with a mix of men and women in each cohort, with a somewhat higher proportion of females in the 75-milligram group and males in the 240-milligram group compared to placebo.

Mean baseline BMI was approximately 32 kilograms per square meter in the treatment cohorts consistent with the participants having healthy overweight or mild obesity. In our cohorts from doses of 75 milligrams to 600 milligrams, including placebo, there were no discontinuations, serious TEAEs or deaths. All study drug-related AEs were mild. There were no clinically meaningful changes in lipids, glucose or other clinical laboratory measurements including liver function tests through 600 milligrams. Overall, we are very pleased with the favorable safety profile that WVE-007 continues to exhibit across a wide range of doses and our first-in-human trial to date.

Following our updated Research Day, we continue to see robust and durable reductions of Activin E. In this chart, we show the dose-dependent Activin E decreases over time across 3 single dose levels of WVE-007 and placebo. The percentage reduction of Activin E from baseline is shown on the Y-axis, with days on the study on the X-axis. As a reminder, at Research Day, we reported that at day 29, we saw statistically significant mean Activin E reductions of 56% at 75 milligrams, 75% at 240 milligrams and 85% at 400 milligrams. Activin E reductions in the 75-milligram cohort were sustained out to 6 months and reached a maximum reduction of 59%. Both the 240-milligram and 400-milligram dose levels still appear to be trending downward at day 29.

We are now pleased to show that these statistically significant reductions are enhanced and persist in the 240-milligram cohort at later time points with up to a 78% mean reduction in Activin E at day 43 and sustained [indiscernible] uses of greater than 75% out to day 85, which is approximately 3 months. These data continue to support a highly convenient dosing interval of once or twice a year. So what do these durable and robust reductions in Activin E translate into?

As I will now cover, we are seeing significant fat loss and meaningful improvements in body composition. Even at our initial 3-month time-point in our lowest therapeutic 240-milligram single-dose cohort, if you look from left to right, we observed significant reductions from baseline in visceral fat of 9.4%, total fat mass loss of 4.5% with increases in lean mass of 3.2% from baseline as measured by DEXA. Importantly, these changes were observed in otherwise healthy individuals with mild obesity and without any protocol mandated diet or exercise modifications. No significant changes from baseline were observed on any DEXA measure in the placebo arm. Overall, these data demonstrate that a single dose of WVE-007 can shift body composition towards less visceral and total fat, while preserving muscle consistent with our preclinical findings and with the underlying human genetics.

With this important and unique clinical proof of principle, we are looking forward to evaluating the impact of this mechanism with higher doses and over longer durations throughout 2026.

To help contextualize these body composition changes at the 3-month time point, we evaluated our results and examine those of the BELIEVE Phase II study, evaluating semaglutide and the myostatin inhibitor, bimagrumab, where DEXA scans were available at the 12-week time point. On the left are the placebo-adjusted changes from our INLIGHT study, with a single 240-milligram dose of WVE-007 at 3 months and participants with a mean BMI of around 32.

A 9.2% treatment effect was observed on visceral fat as well as on a 4% decrease in total fat mass. There were also small improvements in lean mass and decreases in total mass of 0.9%. In the center and on the right are the estimated placebo-adjusted changes from the BELIEVE Phase II trial, which investigated weekly semaglutide and intravenous bimagrumab and participants with BMIs around 36.5%. The total placebo-adjusted fat mass reductions for semaglutide were of a similar magnitude as for 007 at 4.2%, but there was substantial lean mass reduction of 3.5% or approximately 4.5 pounds. Visceral fat reduction was 5.7% and total mass reduction was 3.8%. Notably, 007 showed a placebo-adjusted reduction in total fat mass on par with semaglutide at 12 weeks, while simultaneously preserving lean mass and driving greater reductions of visceral fat.

When evaluating bimagrumab, which increases lean mass with reported safety limitations, there are modest reductions in visceral and total fat mass, along with increases in lean mass leading to small increases in total mass. It is particularly encouraging to see 007 driving total fat reductions on par with semaglutide or greater at the 3 month time point even in a lower BMI healthier population without diet or exercise modifications. Coupled with the convenience of once or twice yearly dosing, lean mass preservation and a favorable safety profile, we believe 007 has the potential to transform the obesity treatment paradigm. And we look forward to keeping you updated on our progress in INLIGHT. I'll now turn the call back to Paul.

Thanks, Chris. WVE-007 has demonstrated a potentially transformative therapeutic profile by improving body composition, specifically a loss of fat, including harmful visceral fat with muscle preservation. All of this is delivered with a single subcutaneous injection given only once or twice a year and a favorable safety and tolerability profile. Taken together, 007 has the potential to address the significant unmet needs that remain in obesity.

The clinical translation of WVE-007 in INLIGHT fortifies our excitement in other treatment settings, where we've demonstrated compelling preclinical evidence. As shown on the left, in mice, we've observed approximately twofold greater weight loss as an add-on to semaglutide versus semaglutide alone, and on the right, the ability of WVE-007 to curtail rebound weight gain following cessation of semaglutide, providing powerful data for its utility and maintenance setting. This translation now unlocks opportunities to investigate 007 in multiple treatment settings.

While INLIGHT is currently investigating otherwise healthy participants with a markedly lower BMI compared to other obesity trials, and no diet or exercise modifications, we believe 007's favorable safety profile and ability to drive reductions in fat while preserving muscle also support investigating 007 as a monotherapy in higher BMI populations with cardio-metabolic comorbidities. With it's orthogonal mechanism, we also see an opportunity to use 007 as an add-on to incretins -- and within the community, there is particular excitement about 007's potential as a maintenance therapy, which would allow people to transition off incretin therapies while at the same time preventing rebound weight gain, preserving muscle and sustaining cardio-metabolic health. Planning for these Phase II trials in these settings are now underway.

The substantial reductions in fat mass we've observed at this 3-month time point are already on par with semaglutide. And as we look ahead to the coming quarters, we have multiple opportunities to assess the impact of duration and dose on the continued improvement in body composition. Next quarter, we'll have 6 months of follow-up data from the 240-milligram cohort as well as 3 months of follow-up data from the 400-milligram cohort. And in the second quarter of 2026, we'll have 6-month follow-up data from the 400-milligram quarter as well as 3-month data from the 600-milligram quarter.

Before turning the call over to questions, I would like to take a moment to thank all the individuals participating in our INLIGHT clinical trial, the clinicians involved and the study site staff. They inspire the work we do every day and from everyone at Wave we'd like to express our sincerest gratitude. And with that, I'll turn the call over to the operator for Q&A.

[Operator Instructions] Our first question comes from Joon Lee at Truist Securities.

Congrats on the great data. It looks like there was a net weight gain in the placebo arm, driven by increase in lean mass. How do you explain that given most weight loss trials placebo arm loses weight, not gain. And bigger picture down the road, how are you looking at the potential labeling differentiation to compete against GLP-1s, which now just $300 to $600 per month?

No, thank you, Joon. And as you see, there was a gain in the placebo arm as well as in the treatment arm from baseline. Remember that this did not require diet and exercise and yet we still saw a statistically significant increase in lean mass. But if you look at the placebo adjusted data sets, it was about 0.9% increase. And we also saw, as you pointed out, a 0.9% decrease in total mass. So I think ultimately, we have a medicine that's driving weight loss down by losing fat. And this is very consistent with our preclinical data that demonstrated strong fat reduction, and over time muscle stabilization, both of which led to a total body weight decrease compared to semaglutide. So again, I think it's really a powerful medicine in a world that's really looking for improvements in body composition, long term.

To your point on the evolution of the commercial landscape with the pricing pressures on GLP-1. There are over 1 billion patients worldwide living with obesity. And I think the power of what we've shown today is that with a once to twice a year subcutaneous administration, one that can open up monotherapy to maintenance. I think it creates a powerful disruptor to the marketplace. So we're excited to accelerate it and to generate those data. And I think lastly, I think it's very much tied to the direction that the FDA is moving to obesity therapies. While they say in guidance that there's a 5% weight loss requirement for approval, it is very clear from the FDA that they want to see weight loss driven from fat loss and not from muscle explicitly. So I think this product definitely delivers within the realm of what the agency is looking for.

Joon, if I also can add, you asked about other trials. Remember that placebo loses weight is mostly from the Phase II and III trials where individuals are under intense lifestyle intervention. In this case, we didn't give any diet or exercise modifications. So it's hard to compare it in that case.

Great. And just a follow-up. Is weight loss going to be the regulatory hurdle that you guys are going to loop, I mean jump over? Or are you looking at something else as an approvable end point down the road?

Yes. We're not focused on creating new end points. I think the goal is that weight loss remains an approvable endpoint, and it remains a focus of what we see with Inhibin E human genetics, in our mouse models and ultimately, what we believe will continue to occur in humans. So very much a focus. But again, I think we're seeing momentum across the clinical community, the patient community and the regulatory community to drive a focus on body composition and driving that weight loss and preserving the mass and losing that. I mean, as Chris mentioned on the call, this is sounding at the first 3-month time point that actually a lot of that predominant weight loss driven off of the GLP-1 is fat, it was almost 4.5 pounds of fat that were lost at that early point in muscle. And so by preserving that muscle, that a lot of muscle to lose very early. And so we do see it as critical to loose fat, which is what we saw.

Our next question comes from Steve Seedhouse at Cantor Fitzgerald.

I wanted to first ask if you could comment on the precision and accuracy of the DEXA methodology that you're using in the study. I think it has a pretty good reputation, but I just wanted to confirm how much variance across patients in the study you'd expect to be just biological versus actually technical margin of error from the measurement? And I have a couple of follow-ups.

So from the DEXA perspective, we used a standard methodology and had a group that made sure that it was standardized across all the sites and all the data was analyzed in detail to ensure quality across the board.

Just relatedly, what was the -- if you have it handy, what was the highest percent fat loss and highest percent total weight loss that you saw in like any individual patient in the treatment, if you have that?

I mean, obviously, it was tight. This is the data that we're sharing in the means. We'll have more data coming in meetings in the future. But I think what's really important and what drives weight loss. And this is something that if you look at the Activin E data early on between the 75 and as we got to the 240, it's how tight the knockdown got. So if you look at the error bars in Activin E at the 75-milligram cohort, there was a lot more variation. And as you moved into higher doses, the expression and knockdown got tighter and tighter, and that translated to good tight fat loss and muscle preservation.

Got it. I'm just trying to get it basically as you follow through 6 months, your level of conviction that the true effect of the drug here with increasing fat loss over time that would be expected would sort of easily reveal itself.

And then the other question I want to ask is [ bimekizumab ] has an adverse event profile that includes like diarrhea, muscle spasms, I think, acne as well. Are you seeing any imbalance in those features specifically from 007?

I'll answer the last one first, simply, no. As you saw, it's a remarkably clean safety and tolerability profile. And so that obviously has us -- is an important feature. One, to your point around thinking about some of the evolving muscle sparing therapies. But importantly, as we think about other weight loss medicines and again, bodes well for a drug that focus on body composition, fat loss and muscle sparing.

I mean as we noted, we didn't really see any clinically meaningful changes in lipids or LFTs or glucose or any other clinical laboratory measure.

Okay. And just real quick, lastly, do you have data on any patients yet through 6 months in the 240 mg cohort or is that sort of batched and received altogether at some point in the first quarter?

Yes, it's batched and received together. But getting back to an earlier point we made of, how do we expect to see, and I think our forward-looking piece of trying to see variability. We have an extraordinary amount of confidence in what happens as we continue to run the study forward. That's driven on both the fact sustained durable knockdown of the Activin E expression and really the strong translation that we can continue to see in the preclinical models that is so long as you're suppressing Activin E, fat loss continues. So again, the data that we continue to expect as a function of the duration of time so as along with Activin E is suppressed, we do expect to see continued fat loss.

[Operator Instructions] Our next question comes from Samantha Semenkow at Citi.

This is Ben on for Sam. To start, can you talk about the slope of that loss and the increase in lean mass? Are you seeing any plateauing in the lean mass. And then from a genetic perspective, what is driving the increase in lean mass?

Yes. I mean I think we continue to see the slope of that loss. And lean mass, it's interesting in preclinical data it goes up and stabilizes. So if that continues to translate, we continue to expect to see, and that's been seen in other muscle medicine. So we expect to see sustained support in lean mass with continued suppression again and that's really the biology and the genetics along as Inhibin E and Activin E is expressed, you'll continue to see fat reductions. And we see that slope in kinetics in our preclinical experience compared to semaglutide, and we now see it in humans. And again, I think it's astounding when we go back to the comparator and mice and we go back to our comparator data looking across studies in humans, that impact on GLP-1s on muscle is profound, right? 4.5 pounds decline at the beginning versus our -- which is purely fat. And so again, we expect those characteristics to continue.

And to add to Paul's point there, that's the expectation based on our preclinical, but to be clear, from the clinical, we only have a DEXA from baseline 0 and then now at 3 months. So we only have these two. So it's not really kind of a trajectory at this, which is two time for us with the slope.

And then as a quick follow-up, maybe based on your preclinical models. Have you observed any kind of ceiling effects in either the fat loss or the muscle preservation just sort of thinking ahead through to the 400 and 600-milligram cohort?

Yes. Muscle stays stable, that's really a function of the fact that you're not shifting -- I think we're all used to a number [ increase ]. You're not shifting to a starvation phenotype where you break down muscle to provide energy and you break down fat. What's unique again about INHBE its purely a fat loss component. And actually, if you follow the mouse data out, which is pretty interesting is the total body weight kind of crosses the sem-arm, which means that it actually shows that actually as long as you have fat to deplete, you're able to continue to decrease your fat content.

And that's another reason why when we think about this study where we have particularly low BMI in comparison to the historical when all of you are looking at obesity studies, if you look at BELIEVE it was nearly 30 BMIs or nearly 37. So when we think about having larger fat subcutaneously in-visceral, the magnitude of effect should actually be potentially larger like it was in an animal model. So again, bodes well for future subsequent studies in an obese population with a higher BMI and comorbidities.

Our next question comes from Salim Syed at Mizuho Securities.

Paul, congrats on the data. I know you mentioned that the data here is pretty tight on the [indiscernible]. Could you give us just some quantification to how tight it was just given we don't have any sort of spider plot data here just on that -- maybe some of the measurements, the 9.2% and the 4% that you provided. How tight exactly is this data?

Yes. I mean we can share the data that we shared today, all the subsequent data would be at future presentations. But I think the key is that we're getting strong exposure, strong consistent knockdown of activity, and it's translating across statistically significant changes from baseline and fat and increasingly muscle. And so again, when we talked to a number of you going into this several months ago, I think our thought was we would be fortunate in a Phase I study without diet or exercise with all comers with low BMI, that will be really nice to start seeing trends on this. And so the fact that we're actually delivering statistically significant reductions in both fat and on lean mass, I think, speaks to the power of the data.

Okay. And then just a follow-up. The data that's coming into 1Q, could you maybe just review that for us? Like what are your expectations for the 6-month data and for the next cohort 3 months data?

Yes. I think what's clear, and we've said this a number of times that the goal is are we on that curve of fat loss. I think with today's data, we delivered -- we are on the curve of fat loss with GLP-1s with muscle preservation and we expect to continue based on our preclinical experience that's long again, as we have sustained Activin E suppression, that we would expect those findings to continue. So muscle preservation continuing and fat loss continuing.

And so I think it, again, quotes very, very well, for our Q1 data updates over a longer duration, so where we expect to see that impact continue. And we're also going to learn about dose impact. Did that accelerate the curve? Does that help us push the doing frequency? And so again, I think the power is going to be in both looking at both the dose as well as most importantly, duration. So we'll have multiple data sets as we move through not just first quarter, but beyond on really elucidating the power of Inhibin E.

Our next question comes from Ben Burnett at Wells Fargo.

Excellent. I just want to ask about -- so you mentioned that there's no diet or exercise modifications. How was that implemented in the study?

Sure. Yes. So this is a typical first-in-human study. So in that context, you don't generally limit diet and exercise in the way that you would for a Phase II weight loss study. So that was just part of a standard approach to first in-human studies when you're looking at safety and tolerability. We anticipate for our Phase II studies, we would, in fact, include similar criteria as others have as well.

Most interesting way to look at this is it's a real-world study. I mean, I think it's always been something that we've become enamored in looking at the genetics of Inhibin E, that this is a population that's walking around that has a protective loss of function that drives reductions in abdominal visceral fat that has better cardiovascular outcomes as Erik said, in better type 2 diabetes outcomes. And so -- and as part of living their normal lives. And so -- in a lot of ways, the Phase I portion of the study gives us kind of a real-world environment with which to assess that. Indeed, that's true.

I mean even in mice, what was fascinating on the prevention of rebound weight gain is when we stopped the GLP-1 and pre-dosed with Inhibin E despite an increase of hedonic eating with an increase in core consumption those mice did regain weight. And I think it's just really important as we reframe kind of thinking about obesity therapeutics and kind of a completely different paradigm shift is it's not about cohort restriction and essentially starvation. This is about resetting the metabolism to driving fat loss, which allows you to preserve muscle. So it's really exciting, I think, as we think about obesity therapeutics going forward.

Okay. That's great. And can I also ask, I mean, so the hypothesis is sort of playing out that we're -- you're seeing muscle sparing. I think a lot of us are kind of looking at the GLP-1s and what else is sort of coming down kind of the obesity pipeline as sort of comps for what to expect. I guess if you are indeed show that you could spare a muscle, like what -- would love to hear like what ultimate level of fat loss you want to see for this to be commercially competitive?

I think we want to continue to see where we are. I mean I think we're starting at this point, and we'll continue to follow a downward trend. And we're on par with GLP-1 as it states at this very, very early time point. So I think it bodes really well that we're competitive with GLP-1s on fat loss. We see that in our preclinical models as well. But not to underestimate the power of sparing muscle. I mean muscle is an endocrine organ as well in terms of insulin-sensitive outcomes. So -- And also drives energy consumption, which actually ultimately continues to drive better body composition.

So I think in profile, we're on that path already as it stands. But I think stepping back and thinking about, to your point, just the evolving landscape, I do think this idea of how do you put patients on medicines, right, that very early time point for majority to loose a massive amount of muscle at those early time points.

You retain it, you lose fat. And that's all kind of thinking about monotherapy settings. I think one of the very interesting applications is this maintenance concept. Ultimately, if we think longitudinally about how to keep the patients with a better body composition having a once to twice a year shot, where you continue to drive fat loss and preserve muscle, we think is a highly competitive profile.

Our next question comes from Yun Zhong at Wedbush Securities.

So the first question on the lipid profile, I believe that press release said there were no meaningful changes in lipid profile. But I thought heterozygous carriers, they do have a better lipid profile. So do you expect the treatment to maybe lead to any metabolic benefit as GLP-1 does to reduce the risk of other comorbidities?

Yes. Based on the human genetics, we would indeed expect that lipid levels, glucose and other metabolic parameters would improve. Now remember that this is -- these are otherwise healthy overweight and obese individuals. So you wouldn't really expect a lot of effect in this patient regiment. We -- that's also one of the reasons why we're very excited about the Phase II trials in higher BMI individuals with some of those like high triglycerides or prediabetics, where we definitely would expect this to be beneficial with decreasing levels.

I see. And then the second question, given the lean mass increase in both treatment cohort and the placebo cohort, I understand that there was no modification in diet, but are you collecting data on any potential impact on diet or calorie intake or maybe even exercise pattern?

No. So there's no requirement in this -- hence, it's people are going about their normal activities. So you're not incentivizing them that this is a weight loss study to participate in those activities.

Our next question comes from Cheng Li with Oppenheimer.

Just a couple from us. First, can you maybe comment on -- I mean, recognizing the small patient number, but curious if you can comment on any like baseline characteristics can predict the weight loss, for example, you see, the greater weight loss in female versus male or maybe higher BMI versus lower BMI. I'm also wondering if like baseline Activin E level can predict response to WVE-007?

Yes. I mean, first, I think your question was interesting, because if you set that up compared to all of the other comparator obesity studies that we were referring to on this call and people will I'm sure to others is actually in every one of those settings, this study had -- was essentially handicapped in the sense that the BMIs were lower. So to your point, we're starting with a lower BMI and seeing these data that are comparable with the 3-week data on GLP-1s, and then actually, as Chris pointed out, we actually had in this arm more males than females.

So if we look at kind of all of the -- as you point out on the obesity studies, things that would drive that to a different outcome, this medicine performed extraordinarily well in those settings. But stepping back, it is just to your point, a small study to be able to discern these features. But again, bodes really well. I mean I think while that separates, I think thinking about safety, convenience and opportunity. I mean, the profile is distinguishable again on all parameters.

Got it. And also, I think you are measuring some blood biomarkers, so any comments on those? Like biomarkers relevant to anti-inflammation or anti-fibrosis you can share?

Yes. I mean as part of the study, I mean, obviously, as we shared on what would be the first biomarker we looked at. We hoped DEXA was going to be a good biomarker to look at body composition changes and indeed it was. We are also collecting over the course of the study, different panels. But obviously, your point on Activin E, getting more samples. I mean we'll have over 100 patients worth of data as the study continues to progress. All patients are dosed in the study through 600 milligrams. So the study is now running. And as we accumulate that data both on Activin E on the biomarker, we'll be able to to assess that, both in duration -- so we want to look at the dynamics of those biomarkers over time as well as at higher doses. So we have to explore both the dose responsiveness as well as duration of biomarkers.

Our next question comes from Joseph Schwartz with Leerink Partners.

Congratulations on this really ground-breaking data. I guess I have a question on efficacy and also safety. So first of all, how would you expect the weight loss effects to differ in patients who are obese and are entitled to diet and exercise in a study like we might see in the next phase? And just conceptually, like why at a fundamental basis, would you expect the results to differ based on the mechanism? And then safety, it's really encouraging. You saw no discontinuations to 3 months. I think we do see some with the GLPs due to GI issues. So can you just dissect that for us a little bit?

Yes. I mean just take the first one. I mean what's interesting is we think about increased BMIs and to your point, as you get larger in patients with more subcutaneous fat as well as visceral fat, you have more opportunity to see substantial reduction. So I think we see that preclinically. The reductions are dramatic. And I think we'll have the opportunity in patients with larger BMIs to see both big impacts on both visceral fat as well as subcutaneous fat, as we actually move into those larger BMI patients as the last question was alluding to it. So I think there's a great opportunity in a forward-looking way that we de-risked the Inhibin E mechanism in the challenging population of a Phase I healthy overweight patient population with low BMI.

And I think this is a again exceeded our expectations to see this see this early. I think fat loss is happening extraordinarily quickly. And again, mirrors well to what we've seen in human genetics as well as in the diet induced obesity-loss model. So that's exciting. As far as safety, I'll let Chris answer that question.

Sure. So to your question around discontinuation, so we haven't really seen discontinuations as we show in the safety table just to comment on the overall duration. So it's not just 3 months. So the lower dose, 75-milligram is out to 6 months, and we saw no discontinuations there. And then for 240, we're also beyond the 3-month time frame at this point, the data cohorts is at 3 months, but those patients continue on and there's been no discontinuations today. And then from the GI perspective...sorry go ahead?

No, you're going to what I was going to ask.

Okay. Yes. I wasn't finished yet. I mean there's -- I was getting to your second question. So -- and as we also showed, there were no -- all the treatment related adverse events were mild, and there were no GI issues.

Our next question comes from Cha Cha Yang at Jefferies.

This is Cha Cha on for Roger Song. I was just hoping that you can speak to your decision to use BMI as a benchmark, especially as Lilly has halted that development of the product. And then also, if you could give some more color on time lines for potentially a maintenance trial and your thoughts on potentially starting that trial before INLIGHT [indiscernible]?

Yes. I'll take the first question first. It was intentionally to go benchmark against BMI in order to and find the study where we could look at 3-month DEXA data for semaglutide, that's in the BELIEVE II study, which was a combination study looking at what happened when you combined the bimagrumab with semaglutide. So in order to look at that data, obviously, bimagrumab was a component of that study and we needed to share the full data at that time point across the bimagrumab and sema. I think it's incredibly encouraging to your point that one, we delivered fat loss similar to GLP-1 in that setting. But when we also look at, to your point, bimagrumab, where we're seeing now preservation of lean mass with an incredible safety profile, right, and a convenience factor of a once to twice a year administration, I think when we look across both those settings, it really points to the potential of it Inhibin E to really become a distinguishing opportunity within the obesity space. So, yes. That was the rationale around that.

In terms of plans, because there are a number of opportunities to drive it forward. We are driving that. We don't believe 600 is necessary. So we don't have to complete the final stages of the INLIGHT study because those follow patients out for 12 months, right? So that's the opportunity to continue to look for further weight loss. But the start of the Phase II, particularly as we've been talking about a number of times in the call of being able to get this into a setting where we got a bit higher BMI patients to look at impact of effect and comorbidities and to be able to look at both maintenance and add-on, we do fully expect to start those studies, and we'll give further updates in the future when we'll start.

Our next question comes from Catherine Novack at Jones Trading.

I just had a question on the prioritization of the different potential Phase II studies. It seems like conversations at obesity, for example, a lot of expert opinion was that incretin discontinuation is the ideal setting for Inhibin E -- but given what you've seen today, it looks like there could be prioritization in other Phase II settings would make sense as well. Just given the resources that you have available and the potential size of some of these studies where do you think you'd want to focus your efforts in the next year?

Yes. I mean I think the interesting place, as you pointed out, is obviously seeing the opportunity in the high BMI comorbidity patient and what the opportunity is to change body composition. Again, with a convenient favorably safe medicine, I think, can be disruptive in that monotherapy setting and really seeing the full opportunity in those higher BMI patients is important.

I think the other is the off-ramp study. I mean as we think about the long-term duration of chronic loss of lean mass in addition to potential for anedonia and other tolerability issues where a substantial number of patients can't stay on therapy and then they're worried about gaining that weight back. I think as you've heard at the obesity week and we heard from a number of folks, that setting on the maintenance off-ramp is a very interesting study to do and is really defined and we've got a number of different potential incretins to run that study on to show that we can prevent that and the data is strong. So we'll continue to do that assessment. That will drive our prioritization strategy. But I think stepping back, the most important thing is I think we've got a profile that goes strongly into any one of those settings, and we'll be refining our go-to-market strategy around that.

Got it. And then given that there are multiple ligands at signal ALK7, is there any thought on compensatory signaling with sustained knockdown of Activin E. Would a view and others seen there long term?

So we don't. I mean I think it's a very interesting question that's coming up as we're seeing more literature ALK-7 and why we remain focused on Inhibin E is that there's a very clean cross communication between, as Erik pointed out at the very beginning the liver to adipose signaling. ALK-7 does is a receptor for some of the other Activins. And we've also seen literature now coming out that ALK-7 is on some other cell types beyond the adipocytes. And so I think opening up the risk factor for suppressing that where there is other mechanisms that ALK-7 signaling is involved in in other cell types. We like the cleanest path which we said from the very beginning and starting this program, which is you've got a hepatokine that has a very focused receptor and a very important job to do, and we can durably and productively and safely knock that out and in so doing, see a robust response. So I think we're very much focused on the Inhibin E pathway.

Our next question comes from Madison El-Saadi at B. Riley Securities.

A broader mechanistic question, we obviously have the animal data, and then we have data from a couple of human readouts. How long do you think patients need to be on drug before that top line weight loss crosses the GLP-1 weight-loss trajectory? And then related to that, it sounds like there are no plans to seek a Phase II endpoint on body composition?

Yes. I mean I think the key is, and I think the obesity field will move towards body composition isn't a negative word on body weight. I think as we had a KOL who runs a massive obesity clinic remind us that the goal of their patients is to help them get leaner. And I think if we imagine what happens when you drive weight loss to a number and lose lean mass and fat that doesn't create a healthier outcome, but that doesn't equate with not losing weight. And so I think really the focus has to continue to be a substantial reduction in fat, which does reduce body weight and preservation of lean mass. We do see that.

I mean that was the important data set in the DIO mouse model that tested the balance -- like this is not a medicine that plateaued and didn't show weight loss, similar to the GLP-1. It was how productive that weight loss was, which is a function of body composition, meaning losing fat preserving my muscle and yet the slope of the kinetics was slower.

But actually, that's a healthier outcome. And so I think if we think about that direction, there's nothing to suggest there's any plateauing effect and we should continue to see meaningful, durable, safe backlogs. As it relates to the regulatory endpoints, I think all of this is very much aligned with where regulators are trying to move things. I think seeing this kind of pound-for-pound weight loss competition where people are losing real lean mass is being viewed as detrimental. And therefore, there really is a focus on having that weight loss occur on fat, not muscle. And I think we're poised to deliver a robust data set into where we think the regulatory paradigm now is going.

Our last question comes from Luca Issi with RBC Capital Markets.

Maybe just a few questions here. Maybe circling back on a prior question. So would be the -- is this an asset that you're envisioning bringing all the way to finish line by yourself? Or is it the drug that you're maybe planning to partner at some point? Any context there, much appreciated.

And then maybe on competition, I think, again, your competitor will have data in early January. So I wonder if you can talk about differentiation versus them. And then maybe lastly on the data. Do you want to confirm is this entire data set that was presented today coming from a single site in Moldova? Or is this a data set that is coming from a broader number of sites and a broader number of geographies?

Yes, I'll take your last question first. It's coming from multicenter sites. So we've got sites across Europe, U.K. as well as the U.S. So there is -- it's a multicenter site. So I think you referred to where it started, but it's expanded since then.

As it relates to your first question, I think, absolutely, we intend to continue to drive this program forward. As we've seen and when we started, people like, do we need to partner at to go from our mouse to our human? This study when you have -- this development path in near term doesn't look any differently than any of our other medicines. We've got a strong biomarker, a genetically validated target, and we can measure outcomes in response to that.

And I think these data show us today that we can continue to demonstrate not only this in the Phase I, healthy overweight volunteer study, but really in patient populations with higher BMI, we can run off-ramp studies. So I think near term, the focus is deliver the next data sets and continue to deliver value to patients.

On the second one, which I think is another interesting question is it's brought up the competitor data and thinking about other siRNA approaches. And I think it's really critical to go back to Erik's introduction and actually go back to research day, where Chandra was sharing the incredible work the team has done on the innovation on chemistry differentiation using SpiNA designs for siRNA.

I feel like deja vu when we said for RNA editing that we have a differentiated approach delivering best-in-class editing. And everybody said, "Oh, well, chemistry doesn't matter." Well, I think those data played out. So if we think about the siRNA landscape, I think we're bringing innovation to chemistry that's driving better, more durable knockdown in seeing the only data preclinically in a weight loss setting that shows Activin E reduction.

So I think we've seen strong preclinical data showing that our SpiNA designs do potent, durable preclinical silencing -- that led to loss and fat and preservation of muscle in-vivo. And then ultimately, today's data, again, exceeding our expectations that -- those data translate when we bring a best-in-class chemistry forward. And now with the safety and convenience of a once to twice a year administration, I think we're really poised to disrupt and define the Inhibin E space.

Thank you. There are no further questions at this time. I will now turn the call back over to Dr. Paul Bolno for closing remarks.

Thank you, everyone, for joining the call this morning. I'm grateful to every Wave employees for their dedication and focus on our mission and on the patient's and families we serve. Have a great day.

Hello, and welcome to Wave Life Sciences Third Quarter 2025 Earnings Call. [Operator Instructions] Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our third quarter 2025 earnings update. Joining me today with prepared remarks is Dr. Paul Bolno, President and Chief Executive Officer; and Kyle Moran, Chief Financial Officer. Dr. Chris Wright, Chief Medical Officer; Dr. Erik Ingelsson, Chief Scientific Officer; and Dr. Chandra Vargeese, Chief Technology Officer, will be available for questions following the prepared remarks. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause our actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Thanks, Kate, and good morning to everyone joining us on today's call. I would like to first thank those of you who are able to join us for our 2025 Research Day on October 29, where we shared the first ever demonstration of activin E reductions in a clinical trial. Notably, with a single dose of WVE-007, our INHBE GalNAc siRNA, we were excited to show highly significant and durable human activin E reductions that exceeded levels needed in preclinical models to drive meaningful weight loss and prevent rebound weight gain following cessation of the GLP-1. In addition, we provided an in-depth overview of our recent progress in RNAi and RNA editing and how we are building on the successful clinical translation of our WVE-007 and WVE-006 programs to advance our pipeline, including our new RNA editing clinical candidate, WVE-008 for the treatment of the up to 9 million homozygous individuals living with PNPLA3 I148M liver disease in the U.S. and Europe.

We also unveiled how we're harnessing the power of both siRNA and RNA editing to advance an innovative new bifunctional single oligonucleotide construct that is designed to silence one target while simultaneously editing or upregulating another distinct target. All of these clinical and preclinical advancements are made possible by our unique and proprietary chemistry and platform innovations. Just last week, we had the privilege of sharing data on WVE-007 at Obesity Week, where we received significant attention from the patient community, key opinion leaders and companies with deep understanding of and strategic interest in the obesity space. There was a clear recognition for the need for non-incretin treatment approaches and overwhelmingly positive engagement on 007's potential to induce fat loss, preserve lean mass and improve cardiometabolic health, all without the negative GLP-1 class effects and with the convenience of once to twice a year dosing.

There is particular excitement in 007's potential as a maintenance therapy, which would allow patients to transition off chronic incretin therapies while at the same time preventing rebound weight gain, preserving lean mass and sustaining cardiometabolic health. Reflecting on the rapid progress we've made advancing 007 in our INLIGHT clinical trial, we have now enrolled over 70 participants and are well-positioned to deliver data on over 100 participants from the clinical trial sites in Europe and the U.S. in the first half of 2026. We began testing WVE-007 in INLIGHT at our lowest subtherapeutic dose cohort of 75 milligrams in 8 participants. Then for the subsequent cohorts, 240 milligrams, 400 milligrams and 600 milligrams, which are in the potential therapeutic range, we have expanded to 32 participants. WVE-007 was generally safe and well tolerated, and our independent data monitoring committee has approved further escalation to a next higher dose in Cohort 5.

At Research Day, we shared highly significant dose-dependent and durable activin E reductions 1 month post single dose of 007 in the first 3 cohorts of INLIGHT, including a 56% reduction for the 75-milligram cohort, 75% reduction for the 240-milligram cohort and an 85% reduction for the 400-milligram cohort compared to baseline. In addition, we had the opportunity to evaluate our lowest dose cohort out to 6 months. And throughout the 6-month follow-up period, we continue to see sustained reduction, supporting 007's potential for once or twice yearly dosing. The durability and potency we've observed thus far is particularly encouraging as we expect consistent and robust activin E reduction over time is necessary to achieve meaningful weight loss. As we shared at Research Day, Wave's unique Pena design and proprietary chemistry enabled the achievement of the potent and durable suppression needed for the INHBE target. In our DIO mouse model, we demonstrated that weight loss in the same range as semaglutide occurred when activin E was durably reduced by greater than 70% from baseline. The knockdown we've observed in the 240 and 400-milligram cohorts already exceed these levels.

In our preclinical studies, we have shown extensive data supporting 007's unique mechanism of action to drive weight loss in monotherapy as well as maintenance in combination settings. Specifically, we shared data that support 007's ability to double weight loss when added to semaglutide and prevent rebound weight gain following cessation of GLP-1 in DIO mice. Furthermore, we've shown that INHBE reduction led to adipocyte shrinkage, fewer pro-inflammatory macrophages, less fibrosis and improved insulin sensitivity in adipose tissues, highlighting mechanisms that could explain the risk reduction for type 2 diabetes and coronary artery disease observed in human genetic data. With robust and durable target engagement in the clinic and comprehensive preclinical data that support both the mechanism of action and impact of our proprietary chemistry, we're incredibly excited to build on this positive momentum. We plan to deliver multiple near-term updates that assess blood-based biomarkers of metabolic health, body composition and weight loss across multiple cohorts.

Beginning this quarter, we'll have the first opportunity to assess the early impact of INHBE reduction at 3 months in the 240-milligram cohort. And importantly, in the first quarter of 2026, we'll be able to assess 6-month follow-up data from the 240-milligram cohort as well as 3-month follow-up data from the 400-milligram cohort. In RNA editing, we continue to lead the field with WVE-006, our GalNAc RNA editing oligonucleotide for AATD. WVE-006 has the potential to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dosed therapeutic. WVE-006 does not require IV-administered LNPs or complex delivery vehicles like other investigational treatments in development. This profile supports treating individuals living with AATD, including those living with lung or liver manifestations of the disease or both. Since the approval of weekly IV augmentation therapies to help manage lung disease, the field has focused on keeping serum AAT levels above a minimum threshold of 11 micromolar, in part because ZZ individuals do not produce any M-AAT and have limited ability to increase serum AAT levels during an acute phase response or exacerbation.

However, with RNA editing, our goal is to restore the MZ phenotype by achieving 3 criteria: keeping basal protein levels at or above 11 micromolar, driving 50% or greater circulating M-AAT with corresponding decreases in Z-AAT protein and most importantly, restoring the physiological response of serum AAT protein to acute inflammatory events. In September, we delivered data from our RestorAATion-2 trial demonstrating that we have already achieved these goals with 006. We observed AAT levels of up to almost 13 micromolar. We showed 64% of AAT was wild-type M-AAT with a corresponding 60% decrease in mutant Z-AAT protein. And these effects were highly consistent and durable across individuals, supporting infrequent dosing of monthly or less. Most notably, we are able to restore a ZZ participants ability to respond to an acute inflammatory event with total AAT levels of greater than 20 micromolar, just 2 weeks after a single dose of 006. Encouragingly, the magnitude and 4-week duration of this response were also proportional to the levels you'd anticipate in an MZ patient based on natural history.

Following our September data, we've had multiple interactions with key opinion leaders in the field who expressed their excitement about these data. In particular, the ability of WVE-006 to restore physiologic AAT production represents a major paradigm shift from weekly IV augmentation therapies. As we look ahead to the remainder of our RestorAATion-2 trial, we are highly encouraged by our initial results progressing rapidly and excited to advance a potentially transformational new medicine to individuals living with AATD. Dosing is ongoing in the 400-milligram multi-dose cohort, and we remain on track to deliver data in the first quarter of 2026. We've also initiated the single-dose portion of our third and final 600-milligram cohort, and we look forward to delivering single and multi-dose data from the 600-milligram cohort in 2026.

Building on our success with 006, we are advancing WVE-008, a GalNAc-conjugated RNA editing program for PNPLA3 I148M liver disease as our next RNA editing clinical candidate. Like 006 and 007, PNPLA3 is a compelling target with strong human genetic evidence and a clear translational path to early clinical proof of concept. There are an estimated 9 million homozygous I148M carriers with liver disease across the U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers. The PNPLA3 I148M variant is a well-established driver of steatosis, inflammation, ballooning and fibrosis, and yet there are no approved medicines that directly address this biology. Emerging preclinical and clinical data indicate that simply knocking down PNPLA3 is not the right solution as loss of PNPLA3 function can worsen the very features we're trying to treat. By contrast, with 008, we aim to correct I148M using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid mobilization, reverse steatosis as well as improve inflammation, ballooning and fibrosis.

We've shared preclinical data that corroborate this approach. We've demonstrated that O08 restores functional PNPLA3 and decreases lipid accumulation. And importantly, we showed that we were able to achieve robust editing with no bystander edits or off-target signals and achieve high deliver tissue exposure, which supports infrequent dosing. Clinical planning is underway for our first-in-human study, where we will leverage previously genotype populations to efficiently identify homozygous I148M carriers, and we are on track for a CTA submission in 2026.

Turning to DMD and HD clinical programs. Earlier this year, we shared data from FORWARD-53 in DMD, which supported WVE-N531 as a potentially best-in-class and important new therapeutic option for individuals with exon 53 amenable DMD. We observed a statistically significant and clinically meaningful improvement of 3.8 seconds in time to rise versus natural history, which is the largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks. We also observed the first ever demonstration of substantial improvements in muscle health with exon skipping, including a statistically significant reduction in fibrosis and decreases in creatinine kinase and circulating inflammatory biomarkers. Moreover, we saw additional clinical evidence of myogenic stem cell or satellite cell uptake in N531 earlier in our trial, which supports the improvements in muscle health and muscle fiber maturation we observed at 48 weeks. WVE-N531 is also differentiated by supporting preclinical evidence, demonstrating even greater access to heart and diaphragms as compared to skeletal muscle. We remain on track to submit an IND in 2026 for accelerated approval of N531 with a monthly dosing regimen.

In HD, we are continuing to prepare for a global potentially registrational Phase II/III study of WVE-003 in adults with STP3 and HD using caudate volume as a primary endpoint, and we are actively engaged in discussions with prospective strategic partners. Developed using our platform's specificity of stereochemical control and best-in-class chemistry, we designed 003 to be the first allele-selective approach in HD. By reducing mutant Huntington at the mRNA and protein level, 003 addresses the underlying drivers of neurodegeneration. And by sparing wild-type Huntington protein, which is critical to central nervous system health, 003 is uniquely positioned to address the full spectrum of HD from early asymptomatic stage through the onset of symptoms and beyond. In SELECT-HD, we demonstrated potent and durable mutant Huntington reductions of up to an industry-leading 46% and preservation of wild-type Huntington with just 3 doses.

Importantly, we observed a statistically significant correlation between allele-selective mutant Huntington reductions and slowing of caudate atrophy, marking the first time this correlation has been observed in HD. As a reminder, our own internal analysis of natural history data sets, including Track and Predict-HD, showed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with a delay of onset of disability by more than 7.5 years. This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting the rate of caudate atrophy as a primary endpoint for an efficient clinical trial. These analyses, along with the complete clinical results from our SELECT-HD trial were both part of our engagement with FDA that led to supportive feedback. We remain on track to submit an IND application for this Phase II/III study in the second half of this year.

With that, I'd like to turn the call over to Kyle to provide an update on our financials. Kyle?

Thanks, Paul. Our revenue for the third quarter of 2025 was $7.6 million compared to negative $7.7 million in the prior year quarter. The year-over-year increase was attributable to the timing of revenue recognized under our collaboration agreement with GSK. Research and development expenses were $45.9 million in the third quarter of 2025 as compared to $41.2 million in the same period of 2024. This increase was primarily driven by our rapidly advancing INHBE program and RNA editing programs as well as compensation-related expenses, including share-based compensation. Our G&A expenses were $18.1 million for the third quarter of 2025 as compared to $15 million in the prior year quarter. The increase was primarily related to share-based compensation and other external expenses. As a result, our net loss was $53.9 million for the third quarter of 2025 as compared to a net loss of $61.8 million in the prior year quarter.

We ended the third quarter of 2025 with $196.2 million in cash and cash equivalents compared to $302.1 million as of December 31, 2024. Subsequent to quarter-end, an additional $72.1 million in ATM proceeds and committed GSK milestones extended our expected cash runway into Q2 2027. By contrast, it is important to note that potential future milestones and other payments to us under our GSK collaboration are not included in our cash runway.

I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. We are incredibly encouraged by the progress we've made across our pipeline. In the past 2 months alone, we've rapidly advanced INLIGHT and delivered robust and durable activin E reductions, and we have achieved the key treatment goals for 006 in RestorAATion-2. Looking ahead, we have a tremendous opportunity to build on our strong momentum as we continue to reimagine what's possible for patients. We look forward to keeping you updated on our progress. And with that, I'll turn it over to the operator for Q&A. Operator?

[Operator Instructions] We will take our first question from Joon Lee with Truist Securities.

And it's really great to see a nice dose response of activin E knockdown and weight loss in the DIO model. Have you looked into what happens to all the fat that's mobilized post activin E knockdown? Specifically, have you checked the liver fat deposits or looked at lipid panels for any LDL or triglycerides in these mice? And I have a quick follow-up on Huntington's.

Yes. Thank you, Joon. And yes, one, it was wonderful to see dose responses, as you pointed out, in the DIO mouse, -- it's even better when we got to see dose responses in humans, which is obviously incredibly encouraging. To the point that you're making on fat, I mean, I think we can comment on -- positively on multiple approaches. One, to your point, preclinically, we haven't observed any changes in increased lipids and deposits in the liver. That's both in the DIO studies we've done, but also in our preclinical toxicology studies. So, nothing to suggest that, that stat is finding its way to other tissues. I also point back to the clinical genetics, which show these patients actually have a decreased risk of NASH and liver disease. And then most importantly, as we look at the clinical study progressing, as we said on the last update that we're up to 600 milligrams with an FDA review so that we could start in the U.S. at 600. And they got to review all the safety data that preceded that. And so, at that point, again, encouraging, not just from a preclinical and mouse perspective, but also from a human perspective. And while we get this question, I mean, I think what we have to think about is lipolysis breaks up these free fatty acids and they're used as energy, energy and muscle, energy and heart. And so, these are positive findings that have been seen in other heart failure activities. So, nothing that we would -- that would suggest any concerns from our standpoint.

And on Huntington's, have you had a pre-IND meeting with the FDA? And any changes to their comments on the use of MRI as a reasonable surrogate for Huntington's? And any thoughts regarding recent backtracking by the FDA according to some of the companies that you -- in your peer group?

Yes. No, and we appreciate the question. I know there's a lot of discussions about HD recently. And yes, I mean, I think we have -- and we've shared this, have alignment with the FDA on the use of MRI as an imaging endpoint in connection with all of the other clinical data we're measuring. But it's important to note that we're running this as a placebo-controlled study as we're using that imaging endpoint as a primary endpoint. I think there is a lot of consternation over the agency's perceived changes of opinion. And to date, we haven't observed that or found that. I think it is important when we think about caudate. And I reflect on this relative to some of the discussions that are ongoing relating to utility of natural history studies in clinical trials. And I think it's important to note that when we use Track and Predict-HD as the natural history studies for comparison and supporting use of MRI imaging data, those 2 studies include MRI as a prominent feature.

And I do think -- the recognition is we just reminded people on the call today, and we've shared a number of times that a 1% change in caudate atrophy can translate to a 7.5-year delay in clinical disability really does set the stage that small meaningful changes in caudate can change clinical outcome measurements. And I think what's important there, if we think about other studies that have been done that haven't looked at propensity matching of caudate volume to patient sizes in natural history, some natural history roll don't include MRI imaging. Actually, if you have a larger caudate at the beginning of that study, that could actually be attributable to a delay in clinical disability on CHDURS and other clinical outcome measurements. So, I think it is important that while there's a lot of discussion about the agency, we feel very confident in both what's driving our decision on the utility of MRI imaging caudate, but also making sure we run a well-powered, well-designed clinical trial to determine that.

Paul, just a quick follow-up. How variable is the caudate volume within the same Huntington's stage, like Stage 2 and Stage 3 and et cetera. Within the same stage, are there variabilities in the caudate volume? And how much?

There can be -- I think what we've seen is very steady changes in caudate. And actually, with the shift in the staging criteria now, actually caudate is becoming a core component of that staging criteria. And so actually, you can assess stages and what patients have -- what change in caudate at each particular stage. And I think that's why it's helpful as we think about other studies that are done and trying to benchmark their size of caudate volume relative to that. We could assess that in looking at those data sets externally. And I think if you had to bias a study towards larger caudate, let's say, so that they would be accessible, that could be attributable to actually delaying and slowing clinical progression, not related to potential medicines. I mean I think what's critical about the data we've generated to date is we've seen the most substantial reductions in mutant Huntington.

I think looking at target engagement, coupled with changes in anatomical findings is important. We actually -- people remember, but at the HSG meeting back in October, even the oral small molecules showed a lower reduction in mutant Huntington. I mean, I think we looked at the data presented by Novartis on PTC, I mean they had less than 20% target engagement and actually had ventricular enlargement and brain volume reduction. So, I think looking at target engagement relative to outcomes is going to be critical. And I think we remain -- have high conviction on an allele-specific approach to mutant huntingtin lowering. And I think post all of this have been actively engaged with our potential partners in terms of accelerating the study.

We'll take our next question from Cheng Li with Oppenheimer.

Congrats on the progress. I have a question on the obesity we poster. It just seems like some gene expression changes actually happen pretty early, but some maybe happen later. So, I'm just wondering, by the time you report initial data in the fourth quarter, what kind of changes in those biomarkers related to metabolism, inflammation and fibrosis you would like to see and maybe which biomarkers are more important? And I have a quick follow-up.

Yes. I'll let Erik add his thoughts to this. But there is an induction over time. I think what we do see is the rapid engagement of both the target and suppression of protein happens fairly rapidly and is sustained. And as you point out, that change over time drives lipolysis as we saw in the DIO models. And then along that way, are going to be able to track various biomarkers of metabolic health that correspond with that. I don't know, Erik, if you want to add to that.

No, I think that's a good summary. There is a trajectory. I think maybe worth just pointing out that on the obesity week poster, those are from liver biopsies. And obviously, these are healthy individuals living with obesity and -- so there will not be any liver biopsies. But we -- as we have reported, we are able to look at some circulating biomarkers, but we haven't shared exactly what we're going to look at.

And just wondering, based on your like preclinical study, when do you think the weight loss can plateau with 007?

Yes. I think one of the encouraging findings is even out of that study where -- and everybody has that image in their head of the INHBE fat loss, which is weight loss, but all driven off of fat, similar to semaglutide's total body weight reduction. It doesn't appear at that point that we necessarily start to plateau versus the GLP-1 as it relates to fat loss. So, I think that's going to be -- while we talk about the early changes in kinetics, I think the opportunity is really to establish that floor. I mean I think people often talk about basically greater than a year on the GLP-1s plateauing. But I think what's nice is we haven't seen that point yet. So, I think we'll have an opportunity to continue to see what that curve looks like for INHBE over time, and the study is designed to assess that.

We'll take our next question from Salim Syed from Mizuho Securities.

Congrats on the progress, Paul and team. Just a couple from us. One on alpha-1 antitrypsin. Paul, just curious to get your thoughts around some of the DNA editor ATD programs that we've seen some recent preclinical data on some discussion there, obviously, being able to reduce 20 micromolar plus M-AAT, and just how does that framework you thinking all do you need to be in that sort of range for outside the acute phase response? And then the second question is just on DMD. I noticed in the press release, there's no more reference to the additional exon skipping program, CTAs for 2026. I'm wondering if that was removed, it's no longer the plan.

Yes. To start with the first one. I mean, I think as we've learned in trying to benchmark preclinical to clinical data, recognizing a lot of that's driven in the sort of A1 mouse model, that's high copy number. I think the absolute translation if we were to compare those data, let's say, DNA editing to DNA editing at beam, I think we've seen the corresponding changes that there's so much opportunity to edit transcript. But for that, that I don't necessarily think there's going to be substantially more editing than necessarily what we're seeing across potential other editors on the DNA editing side. I think what the opportunity is, is whether or not that changes the off-target potential, and we've seen that across a number of DNA editing constructs, both in AATD and not in AAT that off-target rates are consequential and can be detrimental. I think we see bystander edits that create apparent proteins, and that's challenging. And so, I think people are trying to work and address that. And with hepatic turnover, the potential to see that change.

So, I think all of that is to say, I think we need to see how those others translate, not from what data they're posting preclinically to differentiate and distinguish, let's say, them from being on the DNA editing side, but really how they ultimately translate into human clinical data. I mean I think at the end of the day; the most important feature is really can you get to MZ phenotype levels. And as we've seen, it's not about getting higher. I think the real misnomer in this space is applying the recombinant protein strategy, which is pour more protein into the body because it gets utilized as soon as there's an acute event. I think we have to all remember that alpha-1 antitrypsin is a chronic disease of acute exacerbations. And I think if we think about it in that context, it always comes down to what is the requirement to have enough protein so that you have this event, you don't deplete everything. I mean, theoretically, you could argue that maybe 11 micromolar was a questionable threshold for replacement because by the time you have an acute event, there's no protein left to actually protect your lung. And we've had a KOL recently remind us that his biggest fear is a patient who between infusions has an acute event, can't get infused and is now left exposed to the insult in the lung.

We have to reframe that whole narrative as we think about the paradigm shift for RNA editing, which is about rising to meet the need of what's required during those periods of acute inflammation. And as we've shown, we can achieve over 20 micromolar of protein during the acute exacerbation. So, I don't think this is a competition of like us because we're in RNA editing being limited to how we respond. We respond extraordinarily well. We respond with infrequent sub-Q administration. We have no by edits. We have no off target editing, no indels. And so, I think long-term, for treating a chronic disease, I think RNA editing and particularly our approach to RNA editing with our AMR designs, I think really meet the therapeutic need of patients with these diseases.

To your second question, I think on other exons, I don't think there's a fundamental change. We're ready to progress. I think what we want to see is the continued progress that we're making on exon 53 and where we're allocating capital to make sure that we progress on 53 and then continue to move other programs forward behind that. So, it's less about a formal change and more saying that as we reflect on guidance, I think the key is advancing exon 53, drive that forward and be prudent on the acceleration of other exons. I think as we look forward to '26, and we're going to share a lot more on this during the year, we are highly encouraged about the progress we're making in obesity space and with reflection that we're seeing from a number of parties, the work that we're doing on potential maintenance where we can wash patients off of GLP-1s and support them on a once to twice a year sub-Q therapy that actually prevents rebound weight gain, drives metabolic health and really becomes, I think, the standard for maintenance has us thinking about 2026 in a really positive way about studies that will continue to drive and support that. And we just have to think about the totality of where we're allocating capital, hence, why collaborations are important to us. So yes.

We'll take our next question from Steve Seedhouse with Cantor.

Congrats on all the recent progress. I wanted to ask in the AATD study, obviously, that is ongoing, and you have that one really profound example of the acute phase response. Are you able to maybe gather more examples of that by protocolizing AAT assessment if people get sick this winter or if they get their flu shots. Just curious if there's anything you can do in the study to supplement that finding.

It's an interesting question, Steve. It's one of the things that we obviously can identify. So, I think corresponding as we saw there, CRP levels with changes in AAT levels give us a way to be able to not miss those opportunities for assessment. We're not changing the protocol design on a prospective basis. But to your point, as we come into the winter season, the opportunities that we have to be able to capture those events. are there. I think what's highly encouraging is at a basal level, we recognize that we believe we are at an MZ phenotype editing capability. So, these patients, to your point, should be responding as such, and we'll be able to identify them.

And then just in INLIGHT, I was curious if you could clarify or just guide us what proportion of that study enrolled in the U.S. versus ex-U.S.? And even if it's sort of relevant, would you expect any difference in the patient demographics or something that would affect the results?

Yes, I'll let Chris join in. So obviously, the study started ex-U.S., and we provided the update during the last update that we now had the FDA IND acceptance to begin and begin at the highest dose, so at 600. So proportionately, obviously, in the early setting, it's proportionately ex U.S. with the opportunity to come here. I wouldn't expect any changes. Chris?

No, that's right. So as Paul said, we're just starting up in the U.S. now. So, we're going to be recruiting patients there going forward. And we haven't really changed our inclusion criteria based on region. So, we'd expect that all the subjects here would meet those criteria just like the ones in the ex-U.S.

I think it's important so that as we are able to, in the future, start analyzing data, I mean, there's the ability to look at the dose cohorts, but also to substantially power the ability to look at activity reduction related to body composition changes and other, which would allow us to work across cohorts as well as we get to the later data points. So, to Chris' point, it is important that we have cohesiveness amongst these patients so that we can do better analysis across the study.

Our next question comes from Madison El-saadi with B. Riley Securities.

A couple from us. On the single AATD patient that experienced the acute phase response, curious if there's any additional insights or observations from that patient that you could comment on? And then secondly, I actually wanted to ask about your bifunctional single nucleotide construct. Curious if you've optimized this construct to avoid any type of intermolecular interference and if you're seeing any off-target end, basically where you're at in the optimization phase.

Yes. I mean I think to the first one, there's no new insights other than, obviously, patient recovered, and we saw like very good corresponding relationship between that CRP exacerbation and down. I think it's important to this point, that is the disease. The disease of these infrequent, but they happen. There are these acute exacerbations. And so that response rate is what you expect to see in an MZ patient who is protected. But I think they responded exactly as you would anticipate an MZ patient response to occur. I'll look to Chandra just to confirm, but I mean, we did the work. We've shared some of those recent updates. And I think that was the piece that had me most excited about the fact that these bifunctional approaches to SI and editing could provide really compelling ways to treat diseases. I mean, as we shared the opportunity to think about things like the combinations and actually watching, PCSK9 reductions coupled with LDLR upregulation is a fascinating approach long-term to effectively treat cardiovascular disease and lipodystrophies. And so I think the opportunity is seeing each of those behave, and I think that was Chandra's compelling data on knockdown wasn't blocked by editing and editing wasn't blocked by knockdown shows that there wasn't steric hindrance across, and I don't -- we haven't seen any -- because AIMers are specific to the enzyme that they're working on in Dels or bystander edits, but I'll let Chandra. We haven't seen anything to that effect.

Yes. So, this is -- the platform provides us an opportunity to be highly specific for both enzymes. So that's the design principles, taking into consideration how our SpiNA react with our Ago2 highly specific and see specific knockdown and adding to that the AIMer that is also highly specific recruiting ADAR. And we found -- using our platform, we found a way to combine these 2 properties to give us exactly what we observed with single entity, but with one construct.

So, the best way to think about it is the uniqueness and specificity of each endogenous enzyme is able to observe its own unique endogenous function. So, the enzymes are highly specific for their approach.

Our next question comes from Bill Mohan from Clear Street.

I was hoping you could comment on the recent data from Sarepta's exon skippers that failed to confirm benefit in the confirmatory studies. Obviously, this highlights the unmet need in the space. But at the same time, do you expect any difficulties in maybe a changing FDA attitude towards dystrophin expression as a proper accelerated approval endpoint?

Yes. I think it's critical as we shared data very early on, on looking at consistent dystrophin expression across patients. If you remember, one of the key highlights, both 6-month and the 48-week data that we shared was not just an amplitude of how much protein. I think there's been a lot of discussions about mean protein levels. I think the narrative that was important for us to make sure people start pushing is how well distributed was that across patients? Because if patients don't have adequate amounts of protein level, then it shouldn't be unexpected if they don't continue to show benefit because they don't have adequate levels of protection. So, the highly consistent distribution we were seeing was important. I think what was most important to us was the fact that we actually did see that translate to statistically significant clinical meaningful improvements in time to rise. We saw those corresponding changes in muscle fibrosis. And I think that is really what was important and driving for us, and we're going to have the opportunity by the time we file in '26 to continue to follow those patients who are on the open-label extension study and additional patients being treated monthly to continue to see those clinical improvements. So, I think while we haven't seen any correspond from the FDA changing on dystrophin, I think we do recognize the importance of seeing clinical meaningful responses and being an important part of our decision.

And it might be a little early for this question. I know there's a lot of clinical derisking left in your INHBE program. But do you have a view on the pricing dynamic in the obesity market where there seems to be this sort of a sustained pricing pressure that we probably wouldn't expect to go away for a while.

No. And I think that's the unique opportunity that we have with INHBE and particularly the modality we're using to drive activin E reduction. So, we continue to see strong durability looking again beyond 6 months. So, we're through that at the lowest subtherapeutic dose. So again, highly supportive of once to twice a year sub-Q dosing. And if we think about the global greater than 1 billion people living with obesity, many of whom don't have access to GLP-1s. If we think about the markets more broadly, the ability to expand where we don't have to -- manufacturing, let's say, is not as big a challenge as with the protein therapies. The ability to really drive accessibility, we think, is a unique feature. And I think if we imagine a world where patients are even currently being able to transition to a once-a-year maintenance therapy where they still get the benefits in cardiovascular outcomes as we've seen with human clinical genetics and sustained weight loss. I think there's a really unique opportunity to think about the true global landscape for obesity. And I think actually a GalNAc siRNA approach with our chemistry that drives durability is highly disruptive as we think about the evolving obesity landscape, which is really dominated by similar increase.

I mean a shift from once a week to once a month still doesn't really radically change the environment and the landscape. And so, what does is the ability to do this with a once or twice a year drug. I think the other piece that's becoming more and more apparent to us coming out of the week is who's being treated. And as we think about the evolution of patients who -- and think about this with Medicare and other things picking up reimbursement, patients who really can't have sustained loss of lean muscle mass, loss of bone, loss of muscle as they continue to age and have to treat these diseases, the opportunity really to bring a medicine that drives fat loss, healthy outcomes, but retains lean muscle mass, I think, is both therapeutically relevant, but also as we think about the cost of transition.

Our next question comes from Roger Song at Jefferies.

Great to see you at the Obesity Week as well. So also, a couple of questions related to obesity inhibitor program. Just interested in learning a little bit more about the kinetics of the weight loss. I know you have the DIO model. And then -- so any reason you have to guide 6 months versus earlier or longer for the substantial weight loss similar to semaglutide? And maybe any insight from the human genetics can give us a little bit more color around that? And then also related to the dose response, yes, in the DIO, you see the dose response for the weight loss. Just curious about your human dose. How should we think about you step up from 240 to 400 and 600, what's the range of the corresponding dose to preclinical? And then if that possible, you can dose even higher than 600, is that necessary?

Yes. Thank you. And I'll have Erik chime in on the other side because I think he'll have some valuable thoughts about kinetics, too. But I think most importantly, we do look to the modeling of our models. The DIO models translated well for GLP-1. So, it's been great to see that corresponding positive control as we look to not just weight loss. And I think it's important to think about it as fat loss, so healthy weight loss. So, if we think about those kinetics, we achieved in the DIO mouse model up to similar levels of total body weight reduction of GLP-1s, but it's all fat. And so, there is a rate of kinetics on that curve that does appear to take more time. So that's something in that early time point as we think about these first 3 months into the 6 months, we're going to learn about the kinetics of INHBE reduction together. We know we potently lower it, and we're going to get to see what transpires during that window of time and whether or not the mouse model is reflective of that curve or is it similar both. I think what we feel more confident about is you get to 6 months and longer, the ability to see that continue to transition.

And I think the opportunity there is then whether or not that plateauing is what's seen because it does look like you can continue to drive fat loss beyond that point of where you have GLP-1 weight loss. So, I think the ability to kind of follow this over time, much like we all did with the GLP-1s is going to be critical as we understand what that journey looks like. The human clinical genetics gives us kind of a benchmark of what happens with a protective loss of function from birth. So, what happens when you have that. In a lot of ways, it both supports what we've seen in the DIO mouse model in the human study, but it's also really supportive of what we see with these revised maintenance therapies where you kind of have this weight loss and create a set point and then drive that forward. So, I think it's highly encouraging as we look at those genetics, both on initiation of weight loss, but also as we think about the potential future for maintenance therapy, which is incredibly exciting. So, I think that in totality, and Erik, I'd love your opinion on that. As it relates to dose, Roger, I think the ability that we do see this dose responsiveness in the animal models, I think we're going to get an opportunity to evolve that as we said on both -- Chris said on the past call at Research Day and as we reiterated on this call, we are approved to go higher than 600, whether or not we need to is a different story. But I think the ability to continue to drive a dose responsiveness of not just the totality of fat loss, but whether or not the kinetics happen faster in a dose responsive way is something we'll be able to study in humans over the course of the study. But with that, Erik, I don't know if you want to add on a couple of points.

Yes. I think you summarized it very nicely, but just, I guess, to double-click on a few things. So, from the human genetics, then obviously, we know that if you have a germline loss of function variant from birth, then you have a substantially better cardiometabolic profile and lower type 2 diabetes risk and cardiovascular risk. So that's 50%, right? And then we know from our in vivo models that if you can achieve more than 70% activin E reduction, we see that translate in the mouse models to weight loss and a better -- all driven from fat and especially as Paul pointed out, this double effect from semaglutide, the prevention of weight regain, cessation of GLP-1s, all of those effects. And we do observe that kinetics looks a bit slower than semaglutide. So that's why we're anchoring on the 6-month time point. But again, this is a novel mechanism we're learning together on the kinetics of this. But we're -- just to remind everyone, we're already in that range now in the 240 and the 400 mg cohort. We're in that range where we would expect this to translate to better cardiometabolic health and weight loss from fat loss.

Our next question comes from Joseph Schwartz with Leerink Partners.

This is Jenny on for Joe. For obesity, assuming you have positive early data, how do you envision the next steps in development beyond the INLIGHT study? What could these studies look like? And will you be able to do these on your own? Or would you consider strategic partnerships for this program? And would the GSK collaboration affect your ability to pursue anything if there are opportunities?

Thank you. I'll start with that last one because I think it's an important one to get out of the way. There is no inhibition for us to do anything related to INHBE with GSK. So INHBE is a wholly owned Wave program, and we have full control over that, not just clinically but commercially. So, it is a Wave asset. So, move past that one. As we think about the opportunities ahead, I think one of the things coming out of obesity, we enhanced our meetings with a number of KOLs who are incredibly excited about the profile, both not just the driver of fat loss without lean muscle mass loss and that profile as a monotherapy, particularly for a substantial number of patients with it. We're learning more and more, there is concern about anhedonia over time, hair loss, lean muscle mass, loss meaning muscle and bone and the ability to drive healthy weight loss with an infrequent injection and accessibility, I think, was highly encouraging. So, I think that, coupled with a huge amount of excitement for what maintenance could look like and a number of interested parties saying, how could we think about these things in conjunction, give us a number of opportunities as we think forward around what the right strategy is for running these studies.

Irrespective of partnering, we're committed to driving these studies forward. We think that there is a huge need for this in these therapies as we've seen with really the innovation coming in this space from more less frequent administration of incretins and other forms of incretins as opposed to really treating the underlying healthy fat loss and preservation of lean mass. So, with that, I think we're working on planning for running studies in obese patient populations and maintenance that we could drive and we'll give more updates as we think about these studies in 2026 that don't necessarily have us waiting to the completion of INLIGHT. I think INLIGHT is a study that we can envision ongoing as providing ample safety coverage. We're seeing that now with durability. But we don't have to look at these things in cession that INLIGHT needs to complete before we accelerate studies in obese patients and potentially, as we said, in maintenance. So, we're actively underway in that. We see that as a huge need, and we're working very quickly with a number of KOLs in the field to accelerate the studies.

Our next question comes from Yun Zhong with Wedbush Securities.

So first question on DMD program. I wanted to check if you have had any interactions with the FDA on your 48-week data and any additional clarity that you are able to provide in terms of how much monthly dosing data you will need to or you will be able to include in the package, please? And I have a follow-up question, please.

Yes. I mean, as we provided, we've had updates with the agency that we've discussed our plans as we think about filing. One, and as you point out, key was generating data, not just OLE data on a monthly basis, but ensuring that we have de novo patients that are treated on a monthly regimen with which we can study. We have, as we said on prior calls, enough patients, we believe, based on the existing approvals on both new patients as well as the existing patients to support that filing. And we'll continue to stay engaged with the agency as we advance those discussions towards that filing to avoid surprises.

Then on the Huntington's disease program, it's very encouraging to see or hear the FDA is open to accelerated approval pathway. But you commented on the capital allocation. So, I just wanted to ask, would you be able -- would you be open to moving the program independently even without a partner? Or would you prefer to have a partner before taking the next step?

No, thank you. And I think we've been consistent on this point. So, within HD, I think why we have conviction and why we have aligned with the agency is we're running a well-powered placebo-controlled study, and that's -- the design is advancing. I think what we're also having in conversations with potential strategic partners for the discussion is assuring that we're aligned on what that trial needs to look like to make sure it does meet the criteria, not just for the accelerated approval, but potentially in design the full approval of that study continues to progress. So, we don't have to go back. And so, as we get that alignment, that study, we would prefer to progress alongside another collaborator.

Our next question comes from Samantha Semenkow with Citi.

This is Ben on for Sam. Going back to obesity, you shared in the R&D slides, the placebo-adjusted benchmark based on semaglutide was approximately minus 2.5%. Are you expecting you'll see that in the upcoming data this quarter for the 240-milligram 3-month data? Or is it possible we'll need more time to reach that benchmark, just given what you kind of had described earlier about the kinetics?

Yes. And I think that's what we were -- I mean, if we go back to that slide on Research Day, it was really important that we're anchoring on is the 6-month data to that point. So that curve continues, remember about 4.4% out at the 5-month time point with fat loss for semaglutide. And I think that was key for us is we have the benchmark of fat loss following the GLP-1s over time. And I think what we're -- as we said before, what we're going to learn together is what happens on those rates of fat loss at the early time points. We now have benchmarks, as you said, of what we're benchmarking with GLP-1s. But I think it's really important as it relates to kind of a set point and what is a target range of fat loss to really get 6 months further than in the initial 6 months simply because, as we said, anchoring on preclinical data, there does appear to be a rate of kinetics that looks apparently different. And I think it's important for us to assess that in humans. So, it's why we're not guiding to a specific target number of fat loss in this first 3-month data set, but rather looking at continued engagement and reductions of activity, durability of activity, which is going to be critical and other biomarkers of metabolic health as well as body composition. So, we're going to have a number of features. We're measuring body weight, so it will be important to not miss but it really is important to look at that kinetics over time.

And if I may ask a follow-up question. What is other consideration for initiating the Cohort 5 given the IV MZ approved escalation?

Yes. I mean the only thing now is given how -- I mean, we are at 85% reduction at the 400-milligram cohort and now have a 600-milligram cohort. So, some of that is how much more utility we're going to get from going higher, and we'll have some of that biomarker data to assess. From a safety perspective, we can continue to go up substantially higher. But at the end of the day, it's still about understanding not again, leaving activin E in the efficacy on the table, what's going to drive durability, but also realizing what's going to be, frankly, necessary. And again, that's why we're highly encouraged and already planning what are the next subsequent Phase II studies start to look like as it relates to studying this in obese patients as well as men. So, we have the coverage beyond what we think we need currently, and it's why we are confident about the subsequent studies.

Our next question comes from Luca Issi with RBC Capital Markets.

This is Cassie on for Luca. Congrats on all the progress. And we have another one on INHBE, and this is circling back on the ex-U.S. versus U.S. You have a single site now in Moldova listed on clinicaltrial.gov. But you did mention that you have activated other sites, including the U.S. at 600-milligram. So, can we assume that the second quarter 2026 update in the 600-milligram cohort is when we will start seeing data from the U.S. patients? Or is that update still going to be data from the Moldova patients?

Yes. No, look, we appreciate the question. One, it's on -- just to make sure because at one point you mentioned, just to make sure that it's not confusing this is obesity, this is 007. And it's beyond Moldova. We have sites in U.K., Moldova, Europe, and the update was moving beyond Europe to starting in the U.S. So, there's a number of sites that will be generating patients. As we provided on the call, the real shift is from Europe to the U.S. And as we said, the U.S. is coming online at the 600-milligram cohort. That's what we shared at Research Day because one, the agency didn't have us restart at a lower dose. We could start at the subsequent cohort, which is 600. So, I think it's obvious from that, that we would expect that you wouldn't have U.S. patients not at 600. So, the U.S. contribution would come at 600.

Our last question comes from [indiscernible.

Just looking at your preclinical DIO mouse data you showed at Obesity Week, do you think the reduction in macrophages is simply due to reduction in adipocyte size? Or do you think there are other anti-inflammatory mechanisms involved?

Yes, I'll let Erik add, but it's not just reduction in that its shift to macrophage phenotype from an anti-inflammatory phenotype to anti-inflammatory. But Erik, I don't know if you want to add anything.

Yes. I mean exactly. So, it's a shift from less pro-inflammatory to more larger proportion anti-inflammatory, as Paul said. We also do see with the RNA-Seq data that we also see supportive evidence of that as well. There is less inflammatory -- inflammation in both the subcutaneous and visual fat. So, I think something is going on. It is probably partly driven by adipocyte size, but there could be additional mechanisms that are all related to the lipolysis.

And just a quick follow-up on DMD. Do you have any sense of the FDA's opinion on muscle content adjusted dystrophin versus unadjusted?

I think all of the conversations to date across a number of programs have been really exciting. I do think as we look at the new programs that have come in, looking at actually the production of dystrophin in muscle is important, realizing the high propensity for fat and making sure to look at that. So, there's been nothing from our standpoint that seems to change the agency's opinion on that.

Thank you. There are no further questions at this time. I will now turn the call back over to Paul Barno for closing remarks.

Thank you for joining our call this morning, and we appreciate your continued support. Have a great day.

Hello, and welcome to Wave Life Sciences 2025 Research Day. [Operator Instructions] Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Good morning, everyone, and welcome to Wave's 2025 Research Day. Spotlight on RNA editing and RNAi. The slides that accompany today's presentation will be available following the call in the Investors section of our website at www.wavelifesciences.com.

Before we begin, I'd like to remind you that management may make forward-looking statements during today's presentation. These statements are subject to risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in our SEC filings, including our most recent annual report on Form 10-K and our most recent quarterly report on Form 10-Q. We undertake no obligation to update or revise any forward-looking statement for any reason.

Today, we have an exciting agenda to cover, and our speakers will include Paul Bolno, President and CEO; Chris Wright, Chief Medical Officer; Erik Ingelsson, Chief Scientific Officer; and Chandra Vargeese, Chief Technology Officer. Following the presentations, all presenters will be available for Q&A. With that, let's get started. I'll turn the call over to Paul.

Thanks, Kate. Good morning, and thank you for joining us today. Our call this morning marks our seventh Annual Research Day. We dedicate this time each year to showcase our emerging pipeline and novel platform innovations. And today, we'll speak to how they're translating in the clinic.

Ultimately, all of the updates move us closer to our vision for Wave to deliver high-impact medicines and reimagine possible for oligonucleotide therapeutics and human health. For over a decade, we've been committed to innovation, leveraging our best-in-class chemistry and genetic insights to build a leading genetic medicines company. By combining human genetics, clinically validated chemistry and novel biology, we have built a multimodal pipeline of RNA medicines that continues to translate in the clinic. At Wave, we are leveraging AI from target discovery all the way through our development process to add efficiencies and unlock new targets to reach more diseases with our different modalities.

Today, we are spotlighting both emerging and clinical programs from two modalities, RNA editing and siRNA. In RNA editing, we are pioneering this field to continue to make history, most recently with our positive clinical data update from our ongoing RestorAATion-2 trial. In September, we shared exciting translation of RNA editing with WVE-006 from the first two cohorts of our RestorAATion clinical trial. These data included successful restoration of physiological or dynamic production of AAT protein at levels needed to prevent lung damage during an acute infection and represented a significant milestone for oligonucleotides. Building on this clinical success, today, we will introduce WVE-008, our PNPLA3 AIMer for liver disease. We are on track to submit a CTA filing for WVE-008 next year.

In RNAi, our first siRNA WVE-007 for obesity is rapidly progressing as a novel approach grounded in human genetics that is designed to drive fat loss and preserve muscle. As we had previously shared in our ENLIGHT clinical trial, the 75-milligram subtherapeutic cohort had substantial target knockdown, supporting our preclinical modeling that the second 240-milligram cohort would be expected to deliver a therapeutically relevant knockdown.

To confirm this, we plan to analyze all activin E biomarker data as well as safety once the full expanded Cohort 2 reached day 29.

Today, we are excited to share an activin E target engagement update from the ENLIGHT clinical trial. In the first 3 cohorts, we have observed highly significant dose-dependent activin E reductions following a single dose of WVE-007. These reductions in the clinic exceeded the active reductions that led to weight loss in our preclinical studies. The durability of effect supports the potential for once or twice a year dosing. We are incredibly excited about this program and its potential to disrupt the treatment paradigm for obesity by delivering fat loss while preserving muscle. Today's strong target engagement data sets us up for several clinical data updates with WVE-007 beginning later this quarter and throughout the first 2 quarters of 2026.

We'll then take you through the latest innovations on our platform with our novel chemistry. We are advancing our best-in-class siRNA, which builds on successful clinical translation of 007 as well as advancing our extrahepatic delivery capabilities to achieve both siRNA silencing and RNA editing.

We are also using our platform to innovate new modalities, including the capability to simultaneously silence and edit two unique targets with a single oligonucleotide structure. We are poised for significant sustained growth and based on our recent experience developing WVE-007, our GalNAc siRNA, it's clear that we can rapidly accelerate the time from target identification to clinical translation.

Across our entire portfolio, we are advancing a diverse, sustainable pipeline grounded in genetic insights with the potential to treat well over 100 million people in the U.S. and Europe. I will now turn the presentation to Chris for an update on WVE-006 in AATD. Chris?

Thanks, Paul. There are approximately 200,000 people in the U.S. and Europe living with PIZZ AATD, which is often misdiagnosed and progresses over time due to accumulated tissue injury from unchecked inflammation. While it is one disease, alpha-1 antitrypsin deficiency impacts multiple organ systems with a friction to impact lung and liver. AATD is caused by inheritance of a mutation in the SERPMA1 gene, which produces a protein alpha-1 antitrypsin. This AAT protein protects the lung during inflammatory or infectious events, preventing lung injury that could lead to emphysema and airway damage or bronchiectasis.

Damage in the lung occurs during exacerbations that induce an inflammatory acute phase response. Individuals who do not suffer from AATD produce increased levels of protective functional AAT protein during these events, thereby preventing lung damage. In the liver, mutant AAT protein, also called Z-AAT, tends to aggregate into deposits, which cause liver cell dysfunction and death, resulting in fibrosis, cirrhosis and liver cancer.

While therapeutics are advancing in development, the approved treatment options for AATD today are limited. There's an immense new need for more effective and convenient medicines. Weekly IV augmentation therapy is the current standard of care. This approach targets lung disease, providing healthy circulating protein, but it does not significantly impact liver disease as the mutant Z-AAT protein remains in the liver.

In addition, IV augmentation therapy does not provide the dynamic increases of AAT expression needed during an acute phase response resulting from a lung infection or other acute inflammatory events. In those with disease allele or healthy individuals, the AAT levels will increase to meet the need at the time of an infection. However, with IV augmentation therapy, there's no way to go down unless an additional IV dose of protein is delivered to the patient.

WAVE 006 is a first and potential best-in-class treatment, which aims to address both lung and liver manifestations of AAT. 006 is an RNA editing GalNAc oligonucleotide that contains Wave's proprietary chemistry, including PN and N3urium. It edits mRNA Ai in a highly specific manner to produce only wild-type M-AAT without by edits and is administered by a convenient subcutaneous injection with potential for monthly or less frequent dosing.

The goal of RNA editing is to increase wild-type M-AAT protein at its source and restore the physiological production of AAT needed to prevent lung damage during acute inflammatory adults, while enhancing liver health by reducing the production and aggregation of Z-AAT, thereby addressing both key disease manifestations. With RNA editing, you create a wild-type transcript, which leads to the production of M-AAT, the healthy AAT protein in the liver. M-AAT then circulates to reach and protect the lung. Its production in the liver also replaces AAT and allows for AAT reduction and clearance of harmful protein aggregates in the liver.

Across genotypes, those with two wild-type alleles have normal liver and lung disease risk and they respond to acute events by increasing their AAT levels to prevent inflammation-related tissue damage. Those with two disease alleles have high risk of liver and lung disease and are known to not increase AAT in the context of an acute phase response.

The MZ patients with healthy allele and Z allele have low liver and lung disease risk and are able to increase their AAT levels in the context of an acute phase response. Since the approval of weekly IV augmentation therapy to treat lung disease, the field is focused on keeping serum AAT levels above a minimum threshold of 11 micromolar. In part because ZZ individuals do not produce any M-AAT and have a limited ability to increase serum AAT levels during an acute phase response or exacerbation.

However, with RNA editing, if you edit by at least 50%, keep AAT protein above 11 micromolar and importantly, restore the acute phase response, the risk for liver and lung disease should be low as this will recapitulate the MZ phenotype and overcome key limitations of protein replacement therapy.

Typically in the disease state in patients with two mutant Z alleles, expression does not increase in the context of lung inflammation and the acute phase response. [ Z reactive peptide ] or ZRP, a measure of the acute phase response can be highly elevated in relation to an inflammatory insult such as pneumonia, but AAT does not correspondingly increase. In this context, inflammation remains unchecked and mainly lung damage causing emphysema and bronchiectasis. In the case of MZ or MM individuals that have a preserved acute phase response, AAT protein increases correspondingly to protect the lung against the undesirable consequences of inflammation, ensuring the lung stay.

With our recent data from RestorAATion-2, it was very encouraging that we already achieved the key goals of RNA editing by restoring the MZ phenotype even at the lowest single dose testing. Restoration of the MZ phenotype requires achieving three criteria. One, keeping basal protein levels at or above 11 micromolar; two, driving 50% or greater circulating M-AAT with corresponding decreases in Z-AAT protein and most importantly, three, restoring the physiologic response of serum AAT protein to acute inflammatory events.

In our September data readout, we observed AAT levels up to almost 13 micromolar. We showed 64% of AAT was wild-type M-AAT, while there was a corresponding 60% decrease in the mutant protein. These effects were highly consistent across individuals and persisted for up to 2 months after the last dose, supporting infrequent dosing of monthly or less.

Notably, we were able to restore a patient's ability to respond to an acute inflammatory event, in this case, a kidney. The participant exhibited a strong AAT response of greater than 20 micromolar. Dynamic effect was observed 2 weeks after a single dose of 006, supporting the rapid onset of the editing effect. Encouragingly, the magnitude and the 4-week duration of this response were also proportional to the levels we'd anticipate in an MZ patient based on natural history.

Following our data last month, we've had multiple interactions with key opinion leaders in the field who expressed their excitement about these data as the ability of WVE-006 to restore physiologic AAT production represents a major paradigm shift from protein replacement therapies.

IV augmentation therapy provides a bolus of AAT with the intention of keeping protein above the potentially therapeutic threshold until the next dose. If a patient experiences an acute inflammatory event, the circulating AAT is consumed without replenishment by normal physiology and interim dosing may be needed to protect against lung damage.

By contrast, with 006 RNA editing, the levels of AAT can increase and remain elevated to meet the need of the body to protect the lungs, potentially protecting lung tissue from inflammation-mediated damage in a dynamic fashion, consistent with the natural physiology of AAT and acute response.

Additionally, augmentation therapy do not have any impact on the liver manifestations of the disease, whereas 006 has demonstrated the ability to meaningfully increase levels of Z-AAT.

As we look ahead to the remainder of the RestorAATion-2 study, we're highly encouraged by our initial results and excited to advance the program, which is paradigm shifting and provides a potential new medicine to patients. With this goal in mind, we've made rapid progress through our RestorAATion-2 trial. We continue to dose patients in the 400-milligram MAD cohort and remain on track to deliver data in the first quarter of 2026. We've also initiated the single-dose portion of our third and final cohort based on the continued favorable safety profile to date and the desire to optimize our assessment of efficacy as well as dosing interval.

We selected 600 milligrams as our dose for this third cohort. 600-milligram SAD and MAD data are expected in 2026. In tandem with our progress on RestorAATion-2, we continue to have discussions with our partner, GSK, about next steps for the program and planned regulatory interactions. With that, I'd like to turn the floor to Eric to review our next RNA editing program, PNPLA3.

Thank you, Chris. Today, we're pleased to unveil WVE-008, our next wholly owned clinical candidate, which is a GalNAc-conjugated RNA editing program for genetically defined liver disease. 008 builds directly on learnings from WVE-006. As you heard from Chris, we have demonstrated clinically efficient and consistent RNA editing, restoration of dynamic physiological response to stimuli, durable effects supported in infrequent dosing and a favorable safety and tolerability profile.

PLNP3 is a compelling target with strong human genetic evidence and a clear translational path to early clinical proof of concept. There are an estimated 9 million homozygous I148M carriers with liver disease across the U.S. and Europe who are at a ninefold higher risk of dying from the liver disease compared to noncarriers.

As I will go over in the next few slides, we believe that our disease-modifying RNA editing approach to correct this variant to wild-type function is going to be superior, not only to PLNP3 silencing, but also to generic non-precision medicine approaches in NASH. The PLNP3 IL148M variant leads to a substantially higher risk of a range of liver diseases from MAFLD, NASH and [ alcoholxia ], to hepatitis to cirrhosis, liver cancer and liver failure.

Longitudinal data shows that heterozygous carriers have about 80% lower risk of liver-related death compared to homozygous carriers. Therefore, our therapeutic goal is to edit at least 50% of PLNP3 transcripts and hepatocytes, restoring a functional heterozygous state that is associated with a dramatically lower risk of liver complications and death.

Given the large addressable population and a clear genetic linkage, this is a setting where RNA editing is ideally suited to be both precise and disease modified. While MASH among noncarriers of the PLNP3 I-48 variant tends to be multifactorial and polygenetic to a large extent driven by obesity and type 2 diabetes, I-148M homozygous represent a distinct subset of MASH with more severe disease biology with fast progression to end-stage liver disease.

They're substantially enriched among lean NASH patients, that is they are more frequently abnormal weight, and they more often present with an advanced fibrosis. Up to 25% of NASH patients are homozygous for I-148M with even higher representation in lean and later-stage disease. The only treatment options are nonprecision medicines for obesity-related NASH aimed at [ skeocytosis ] and early fibrosis with limited efficacy for these I-148M carriers. Importantly, there are no approved genotype-directed disease-modifying therapies for PLNP3 I-148M homozygous. 008 is designed to directly address the genetic driver in these patients.

PLNP3 has an important role in the regulation of triglyceride storage and secretion, supporting the formation of triglyceride-rich VLDL particles that supply lipids to the peripheral tissues. PLNP3 expression on lipid droplets is dynamic. It increases in response to feeding and participate in lipid remodeling and mobilization to meet cellular energy and structural needs.

Additionally, PLNP3 has an important role in retinal metabolism by hydrolyzing retinal esters to release retinol. In short, PLNP3 is part of the liver's lipid metabolism machinery that determines whether fat is store in the liver are mobilized and exported as well as in retinal metabolism, disruptions of which can lead to inflammation and fibrosis.

The I-148M mutation impairs PLNP3'sos activity and exerts a gain of function effect that inhibits ATGL mediated lipolysis. This promotes hepatic triglyceride accumulation and stellate cell activation. Additionally, PLNP3 IL-148M suppresses retinol metabolism in hepatocytes and stellate cells, which increases liver fibrosis. Silencing PLNP3 can partially address disease biology, but is likely to leave residual pathology. ATGL activity is only partly rescued and silencing will not restore retinal metabolism. As a result, silencing can partially address steatosis, but inflammation, ballooning and fibrosis remain unaddressed.

By contrast, correcting I-148M is expected to restore PLNP3 activity in lipid mobilization, reverse steatosis as well as inflammation ballooning and fibrosis. And this is the key rationale for RNA editing over knockdown and would explain why PLNP3 siRNAs seem to have modest effect on steatosis, but no effect on later stages of NASH.

In line with this, multiple preclinical studies highlight potential liabilities of silence and PLNP3. In iPSC-derived human liver organoids, PLNP3 silencing worsens steatosis. In primary human hepatocytes, silencing increased ballooning and in cell cells, PLNP3 knockdown versus fibrotic responses.

Together, these findings support our strategy to restore PLNP3 function with RNA editing rather than removing, aiming to improve steatosis, inflammation, ballooning and fibrosis by preserving physiological roles important for liver health.

WVE-008 is a GalNAc-conjugated RNA editor designed for subcutaneous administration with potential for frequent dosing. It incorporates W's proprietary chemistry and builds on learnings from WVE-006. On the left, you can see a dose response curve showing robust editing with 008. In the middle, RNA-seq results from two donors at different doses yielded an ideal editing profile, strong on-target editing with no bystander edits and no off-target signals as evidenced by lack of any other transcripts than the main PLNP3 transcript, giving us confidence in editing efficiency and specificity of 008.

And on the right, we demonstrate high liver tissue exposure with 008 in preclinical studies, supporting the feasibility of a durable and frequent dosing. Collectively, these data provide a strong translational foundation, building on our clinical success with 008 as we advance towards with 008. Here, we compare lipid accumulation after treatment with our PLNP3 AIMer versus the PLNP3 clinical reference siRNA in two different in vitro models. On the top, in the hepatopa, a 3D human liver cell culture model, we observed significant decreases of lipid accumulation after editing, while the siRNA did not show a significant effect.

On the bottom, in a monolayer culture of primary hepatocytes, we again see substantial decrease of lipid accumulation increasing over time with our PLNP3 AIMer. In this model, we also see modest decreases with the PLNP3 siRNA. Taken together with prior literature, it shows the biological importance of keeping wild-type PLNP3 function and reinforces the biological rationale for correcting I-148M rather than silencing.

In summary, 008 meets our criteria for proceeding into clinical development. Strong evidence from human genetics, a large patient population with no treatment options, the best and first-in-class opportunity and an efficient path to clinical proof of concept. The PLNP3 I-148M variant is a well-established driver of steatosis, inflammation, ballooning and fibrosis, yet there are no approved medicines that directly address this biology. Emerging preclinical and clinical data indicate that simply knocking down PLNP3 is not the right solution. Loss of PLNP3 function can worsen the very features we're trying to treat.

Our approach is different. With 008, we'll edit not silence PLNP3, which will restore its important functions in liver lipid homeostasis. The goal is to reverse [ steatosis ] inflammation, ballooning and fibrosis by correcting the causal bar. 008 leverages Wave's proprietary clinically validated RNA editing platform, giving us an efficient path to proof of concept in a large genetically defined population with no current options.

Preclinically, our PLNP3 editing restores functional PLNP3 and decreases lipid uptake, and we have now selected 008 as our development candidate using Wave's proven chemistry and AIMer design. Clinical planning is underway for a first-in-human study where we will leverage previously genotype populations to efficiently identify homozygous I-148 carriers. In an initial first-in-human study, we will enroll homozygous carriers and assess safety, tolerability, pharmacokinetics and pharmacodynamic endpoints aligned to the mechanisms of PLNP3 I-148 [indiscernible].

Our objective is a clear early go/no-go readout for a precision medicine approach in this large population at high genetic risk. If successful, 008 has the potential to be a first and best-in-class treatment for homozygous PLNT3 I-148 [indiscernible] with liver disease. We're planning for CTA submission in 2026.

006 and 008 are two clinical RNA editing

programs, both targeting liver diseases, but our AIMer platform is broader. By building on our proprietary AIMer chemistry and design, we can modify our chemistry to see substantial RNA editing across a range of expertise tissues. As we shared last year's Research Day, our AIMers achieved substantial editing in lung, heart, adipose and pancreas, all without any ligands as well as region-wide editing in CNS after ICD or intrathecal dosing in rodents or nonhuman primates.

We continue to make progress on hepatic and extrahepatic editing, and we're currently building a diversified RNA editing pipeline, including a range of indications while advancing 008 towards the clinic.

Now I'm very excited to transition to our obesity program, WVE-007, a GalNAc siRNA that targets activin E. 007 offers a novel long-acting muscle-sparing approach to treat obesity and its metabolic complications. Individuals living with obesity face markedly higher risk of a range of serious conditions, including heart disease, type 2 diabetes and several cancers.

GLP-1 receptor agonists have transformed obesity care. However, their impact is often limited by a loss of muscle mass, tolerability challenges, especially GI side effects, frequent dosing and high discontinuation rates. Beyond GLP-1 agonists, other treatments that enable fat loss have been shown to curve metabolic diseases. There are still large unmet needs. Our approach is to focus on healthy weight loss with substantial loss of fat, in particular, visceral fat, which is a type of fat that contributes to the development of type 2 diabetes and cardiovascular.

We believe 007 can address important gaps in the current therapy for the more than 1 billion people living with obesity globally.

Our program has a strong foundation in human genetics, which has been shown to increase the probability of successful drug development by up to two to fourfold with coding variant evidence in the upper part of that range. In the UK Biobank and other cohorts, heterozygous NBE loss of function carriers exhibit a healthier metabolic profile with lower abdominal obesity by waste-to-hip ratio and lower visceral adipose volume, lower triglycerides, ApoB and fasting glucose and higher HDL cholesterol.

We also had favorable associations with liver traits such as ALT and CT1, a measure of liver inflammation and fibrosis and lower risk of type 2 diabetes and coronary heart disease. Our therapeutic hypothesis is straightforward. By silencing in mRNA by at least 50%. We aim to recalculate the protective phenotype seen in these heterozygous loss of function carriers.

Association of target engagement biomarkers with outcomes have also been shown to increase the probability of successful drug development. Therefore, we're very encouraged by evidence from multiple data sets showing that higher hepatic NBE expression is associated with greater adiposity, insulin resistance and MAPLD risk.

Taken together, these data support that reducing NVE mRNA should drive healthy weight loss and improve metabolic health.

[ IE or Iin subunit B ], which is the full name is produced in the liver, where two of the subunits dimerized to form the hepatkine activin. Activin E gets released into circulation where it binds in a specific manner to [indiscernible] receptors and adipocytes. Resulting signaling blocks adipose-like polysis, promoting abdominalosity and increasing risk for cardiovascular disease and type 2 diabetes. By reducing hepatic in the mRNA with a GalNAc siRNA, we lower circulating activin E, decrease alpha7 signaling in adipose tissue and release the grade from lipolysis, which is expected to shrink adipocytes and reduce abdominal adiposity, thereby lowering cardio metabolic risk.

007 uses Wave's best-in-class siRNA format that incorporates backbone serochemistry and PN chemistry designed to enhance interactions with AV2 and to improve silencing potency and durability. We have demonstrated the dramatic improvement of AV2 loading, which is a crucial differentiator for us when we're trying to silence, a target that is hard to keep sufficiently and durably suppressed, presumably due to evolutionary pressure or the need to store energy efficiently.

A bit later, Chandra will go deeper on our siRNA platform and how it underpins our broader hepatic and extrahepatic pipeline.

As we have shared previously, our preclinical data strongly support 007's ability to both potently and durably knock down INHBE E, leading to impressive reductions in body weight and visceral fat while sparing muscle. In diet-induced obesity or DIO mice, a single dose of INHBE GalNAc siRNA produces clear dose-dependent weight loss.

Importantly, the weight loss is all driven by fat reduction, especially visceral fat without any loss of muscle mass. As observed in the middle, the right panels, visual fat was reduced by 23% at 3 mg per kg and 40% at 10 mg per kg, while muscle was unchanged. These data support 007 as a single-agent option for healthy weight loss with visceral fat reduction in lean mass [ percedation ]. We also have robust preclinical data to support synergistic use cases with GLP-1 agonist. At a monotherapy, in siRNA achieves a similar magnitude of weight loss to semaglutide, but all coming from fat loss. When added on to semaglutide, we observed approximately two fold greater weight loss versus semaglutide alone.

In the right panel, you can see that when GLP-1 treatment is discontinued, in siRNA curtails typical weight regain seen in controls, supporting its use as an off-ramp and maintenance therapy.

In our DAO mouse models, a single in siRNA dose achieves more than 70% reduction of circulating activin E 1 month after dosing at dose levels where we observed a substantial fat loss, as I outlined in the previous two slides. When comparing the kinetics, weight loss within siRNA was similar in magnitude to semaglutide, but occurred more gradually. Based on these data, we would expect a similar degree of active reduction to translate to healthy weight loss in clinic over time.

In addition to weight loss, we expect meaningful improvements in cardio metabolic health, which is ultimately the main objective of any obesity medication. By reducing in the mRNA and active levels, we would anticipate increases in adipocyte-like polysis and reduction of adipose site size. This, in turn, would lead to fewer pro-inflammatory macrophages and less fibrosis in visceral adipose tissue as well as improved insulin sensitivity, changes that can contribute to lower risk of cardiovascular disease and type 2 diabetes.

On the next few slides, I'll show data demonstrating what we're seeing within siRNA treatment, supporting the link of increased light polysis with better cardio metabolic health. RNA sequencing for subcutaneous adipose tissue shows upregulation of genes and pathways related to insulin sensitivity, fatty acid utilization and basing of wide adipose tissue. Concurrently, pathways involved in adipose remodeling and fibrosis are down regulated. These changes indicate better cellular energetics with suppression of fibrotic remodeling. As we can see, in siRNA leads to an upregulation of genes supporting better insulin sensitivity, the acid utilization and being a wide adipose tissue while downregulating adipose and fibrotic pathways.

In vitreal adipose tissue, we observed upregulation of glucose utilization, armogenesis and lipid metabolism pathways, consistent with what we observed in subcutaneous fat and downregulating of innate immunity, cytokine release pathways and extracellular matrix remodeling. Together, these findings suggest increased glucose and fatty acid utilization, reduced inflammation and fibrosis in adipose tissue.

As we presented at the ADA scientific sessions in June, histology confirms that a single INHBE E GalNAc siRNA dose also leads to adipocyte shrinkage in day IO with a significant reduction in mean adipocyte diet.

Additionally, histology demonstrates a shift towards less inflammatory state in visceral fat. Total macrophage staining decreases with a strong suppression of pro-inflammatory M1 macrophages, while anti-inflammatory M2 macrophages are maintained at the same level.

Overall, this supports a transition from a pro to an anti-inflammatory state after silencing. Consistent with these immune cell changes, we see a 53% reduction of adipose fibrosis at day 56 after a single dose of INHBE E siRNA as shown by tr staining and quantified by image analysis. This decrease in fibrosis is likely the result of the shift towards a more anti-inflammatory state and will contribute to the improved insulin sensitivity and better cardio metabolic health.

To summarize, 007 has the potential to be a convenient therapeutic that drives healthy, sustainable weight loss while preserving muscle. Our approach is deeply rooted in human genetics, which strongly support that heterozygous loss of function carriers show less visual fat and healthier metabolic profiles with lower risk of type cardiovasases. Mechanistically, in silencing increases adipocyte-like polysis, shrinks adipocytes, reduces pro-inflammatory macrophages and fibrosis and improves insulin sensitivity, all hallmarks of better cardio metabolic health.

We've also shown that our clinical GalNAc siRNA -007 has the potential to be a best-in-class approach. 007 incorporates proprietary chemistry, including serochemistry and PN chemistry, which increases potency and durability of silence. And preclinically, we've demonstrated that a single dose of INHBE E siRNA achieves potent durable target engagement with more than 70% activin E reduction with a semaglutide equivalent weight loss, but all coming from fat loss, particularly the visual fat with no loss of muscle. Further, our preclinical data shows that our INHBE E siRNA can double the weight loss compared with GLP-1s alone and that it can curtail weight regain after GLP-1 session, supporting add-on and maintenance use cases. I'm now very excited to hand it over to Chris for an update on our ENLIGHT clinical study.

Thank you, Eric. As a reminder, ENLIGHT is a placebo-controlled single and multiple ascending dose study, randomized 3:1 active to placebo. with potential to escalate up to five single and three multiple ascending dose cohorts. It's designed as a safety, tolerability, PK/PD study, enrolling base cohorts of eight participants that can be expanded up to 32 subjects per arm. Participants are healthy individuals living with overweight with key inclusion criteria of A1c less than 5.9 and BMI between 28 and 35.

In addition to safety, tolerability, PK and activin E levels, the study has exploratory endpoints of body weight, body composition and biomarkers. Our ENLIGHT trial continues to progress rapidly through the single ascending dose portion of the study. ENLIGHT is currently ongoing at multiple trial sites, including in the U.S. as we recently opened an R&D.

We began testing WVE-007 at our lowest subtherapeutic dose cohort 75 milligrams and 8 participants. Then for subsequent cohorts, which are expected to be in the therapeutic range, we have the option to expand to 32 subjects as warranted by safety. With the favorable safety profile, we have fully expanded cohorts 2 and 3 to date and are currently expanding Cohort 4 at a dose of 600 milligrams.

Our independent data monitoring committee has also approved further escalation to a next higher dose in Cohort 5. Today, I'm excited to share the target engagement data with you from Cohorts 1, 2 and 3, which included doses of 75 milligrams, 240 milligrams and 400 milligrams, respectively. These data include time points out to 6 months from our 75-milligram cohort, which includes eight participants, six of whom received WVE-007 and two placebo. We also have 1-month follow-up data from our 240-milligram cohort, which includes 32 participants with 24 on 007 and 1 month of follow-up from our 400-milligram cohort, including eight participants with six on 007. I'm also pleased to note that to date, 007 continues to be safe and well tolerated with no discontinuations.

We are delighted to share the robust target engagement we have seen to date. In this chart, we show the results for activin E decreases out to 29 days across the 3 doses and placebo. The percentage reduction of active E from baseline is shown on the Y-axis, with days on study on the X-axis. We observed no change from baseline to day 29 for the placebo group. However, we observed highly significant dose-dependent decreases from baseline across all 3 doses, starting as early as day 8 all the way through to day 29. Each active dose also showed statistically significant activin E reductions compared to placebo at all time points from day 8 to day 29.

Across the three cohorts at day 29 compared to baseline, we observed a 56% reduction for 75 milligrams, a 75% reduction for 240 milligrams and an 85% reduction for 400 milligrams. Based on our preclinical data, a greater than 70% reduction is expected to be in the therapeutic range for fat loss. And these levels were achieved in both the 240-milligram and 400-milligram cohorts.

In addition to the highly significant and rapid dose-dependent activin E reductions we observed across our 3 cohorts, we had the opportunity to evaluate our initial 75-milligram subtherapeutic dose out to 6 months. I want to call your attention to this. Even out to 6 months, we continue to see sustained reduction at this low dose. As we look towards the future data from our 240 and 400-milligram cohorts, which are ongoing, we anticipate that this durability could extend even further given the continued downward trajectory of activin E levels over the first 29 days. These data support a convenient dosing interval of once or twice a year.

Our ENLIGHT trial data indicates that we have exceeded the reduction of activin E needed to show fat loss based on our preclinical studies. As Eric previously reviewed and as you see on the left, we demonstrated that meaningful weight loss in the DIO mouse model occurred when activin E was durably reduced by 70% from baseline. It's important to note that we expect consistent active reduction over time is necessary to achieve weight loss in the same range of semaglutide. This level of reduction in our clinical data is highlighted in the green on the right-hand graph. This substantial decrease with a long duration of effect will allow us to assess weight loss across multiple time points.

The ENLIGHT trial design allows evaluation of target engagement, blood-based biomarkers of metabolic health, body composition and weight loss across multiple cohorts with increased numbers of participants at higher doses as we expand each cohort. We look forward to following our cohorts as we progress with increasing doses and assessing these exploratory markers as well as weight loss over time. So what levels of weight loss do we expect to see in the ENLIGHT study? On the right are the semaglutide STEP 1 study results, where we separated the weight loss into fat in blue and lean mass in gray. From the fat mass loss perspective, which is most relevant to the INHBE E mechanism, there is a gradual weight loss over time with approximately 2.5% loss in fat mass by 3 months and 4.4% loss in fat mass around 5 months.

The aim of the WVE-007 program is to observe fat loss competitive with weekly semaglutide by 6 months post single 007 dose. With the robust and durable activin E reductions and favorable safety we are observing to date, we're incredibly excited to continue investigating 007 in ENLIGHT and look forward to sharing multiple data sets, including target engagement, body composition and weight loss over the coming quarters.

Later this quarter, we expect to share the data from the 240-milligram cohort with 3 months of follow-up. In the first quarter of 2026, we'll have 6 months of follow-up data from the 240-milligram cohort as well as 3 months of follow-up data from the 400-milligram cohort. Throughout 2026, we'll continue to have follow-up data for both these cohorts, and we'll also share data from the 600-milligram cohort.

With a mechanism focused on fat loss with muscle preservation, favorable safety and potential for once or twice yearly dosing, we believe WVE-007 has the potential to be a transformational approach for obesity, and we look forward to keeping you updated on our progress. Now to share an update on our platform innovations, including our best-in-class siRNA. I'd like to turn the call over to Chandra.

Thank you, Chris. For over a decade, Wave has been extending the frontiers of RNA therapies through advances in nucleic acid chemistry. Our foundations began with novel and proprietary backbone chemistry, enabling us to apply principles of rational design to oligonucleotides and define structural activity relationship to single. Since then, we have expanded our novel chemistry toolkit, which has provided step changes in potency, durability, delivery across hepatic and extrahepatic tissues. We have a clinically proven platform with unprecedented capabilities in silencing, splicing and RNA editing.

A hallmark of our platform is our ability to take shared learnings across modalities and apply these learnings to subsequent targets for rapid drug discovery and development.

Today, we are pleased to introduce Penna, a stereopure interfering nucleic acid design that enables RNAi-mediated silencing by further increasing Ago2 loading, leading to improved potency and durability compared to our earlier siRNA designs and industry benchmarks.

On the left panel here, you can see the dramatic difference in TTR mRNA silencing the GalNAc conjugated siRNA following a single dose at MPK. All siRNAs have the same sequence and 2-prime modification as the literature reference construct with state-of-the-art siRNA chemistry. Compared to reference and our previous published siRNA construct, sen designs have substantially improved the potency and duration of silencing, and we have observed up to 95% TTR mRNA reduction at least up to 8 weeks after a single dose. We see similar differences in TTR protein and see unprecedented increase in potency and duration of activity with sen designs following a single 0.5 mg per kg dose of GalNAc siRNA.

As a reminder, translation from preclinical experiments to the clinic is very well understood for RNAi. And we have just highlighted the exciting preclinical to clinical translation with WVE-007, our first design in the clinic with the potential for biannual or annual dosing. In our seminal NAR publication, we demonstrated that increase in potency and duration of activity compared to reference siRNAs was primarily driven by an AGO2 loading.

However, the dramatic shift in potency and duration of activity of Pena is driven by several fold increases in both Ago2 loading as well as PK with Pena driving up to tenfold improvement in Ago2 loading versus reference.

Now I'll turn to some examples with our design to highlight how PN variant allows us to access new extrahepatic tissues, which in turn expands the scope of targets and indications amenable to RNA therapeutics.

On this slide, we're showing results from a 3-month duration study with a single 5 mg per kg dose of three different tissue targeting Pena variants in mouse experiments to silence SOR1 gene expression. On the far left, we are highlighting silencing in adipose tissue and middle panel is silencing in the heart and the far right is in skeletal muscle.

In all three tissues, we observed approximately 75% knockdown after 1 month and the level of knockdown persisted for at least 3 months following a single dose. Additionally, as you may recall from last year, we shared that with siRNA designs, we are able to drive increases in potency and durability with tissue-specific delivery by optimizing physical chemical properties.

On this slide, we're showing results from an 8-week mouse experiment using siRNA designs to silence gene expression. On the far left, we highlight the well-described impact of using GalNAc to access hepatocytes in the liver. But this also highlights the limits of a conjugate and it is cell and tissue specific. So it does not enable silencing in other tissues of interest like Y [indiscernible] . To the middle and the right, we show how we can alternate designs with key enablements to enable access to various combinations of liver and adipose tissues in the absence of any targeting line.

Depending on the target and indication, we can deploy the designs that best fits the biology. Using PRISM, we can change the physical chemical properties of our oligos to deliver to numerous extrahepatic tissues and achieve potent and durable silencing with a single dose.

Now I would like to share with you an example of how we are applying these learnings and Pena to develop first and potential best-in-class programs, which addresses areas of high unmet need. In this case, we have been working on target with strong support by human genetics for a disease with high unmet need, high expression in liver and adipose and measurable biomarkers, which offer efficient path to proof of concept.

In this slide, we show that we can achieve robust and consistent target mRNA knockdown and protein levels in the liver and in different adipose compartments utilizing both variants. Also, the knockdown of this target reduces fasting serum triglyceride by 60% to 70% using the two Sena designs in a DAO model.

Next, we set out to investigate cellular access and silencing in the kidney using with PN variants. Oligonucleotide primarily accesses proximal tubule cells owing to its role in reabsorption. But this is usually a nonproductive delivery, meaning that oligonucleotides do not modulate targets in those cells. Our initial studies with a single 10 mg per kg subcutaneous dose of our Sena design achieved a durable 50% knockdown in mice with three different SOD1 constructs, which persisted for at least 4 weeks.

The panel on the right show all three constructs have broad distribution shown in red across various kidney cell types. Now to dig deeper into the cells that are accessible with Sena and to confirm silencing activity, we collaborated with our partners at GSK to conduct single cell RNA-seq analysis. This allowed us to map the knockdown effect at a cellular level, confirming broad knockdown across multiple cell types, including proximal tubules, distal tubules, endothelial cells and podocyte cells. Building on these early successes, SAR studies helped to identify sen variants, which demonstrated an impressive 75% mRNA knockdown with a sustained 50% reduction lasting up to 3 months after a single dose of 5 or 10 mg per kg. Protein reduction was also confirmed by immunohistochemistry and miRNAscope staining for oligo distribution. The knockdown was not only robust but also widespread, affecting primarily the cortex and outer medulla regions of the kidney.

High magnification images revealed broad distribution and substantial protein reduction, which was sustained at least up to 3 months following a single 5 mg per kg dose. Here, we see decreased levels of light blue representing knockdown of solvent protein in treated samples relative to control.

In red, we can also see broad cellular distribution of the oligos. In addition, we have demonstrated that AIMer optimization through AIMer optimization, we can achieve RNA editing in kidney. Following a single dose of AIMR 1 and 2, we see that we can achieve 50% editing of UGP2 transfer with broad distribution.

Finally, single-cell RNA-seq analysis was performed by GSK to assess editing efficiency. These data show efficient delivery and editing in multiple cell types in the kidney, including distal tubules, messenger, phodocytes, principal, optimal and transient cells.

Now I would like to discuss an example of how we are applying learnings and chemistry optimization from across our platform to uncover new modalities. By using PRISM platform, we found a unique way to combine RNA editing and silencing modalities into a single oligonucleotide construct. This enabled us to silence target while simultaneously cause editing or upregulating another distinct target with a single oligonucleotide construct.

Additionally, because this oligo is loaded on to A2, we believe that this has the potential to further extend the durability of editing compared to an AIMer alone. We confirm the ability of the single construct to engage in silencing and editing in vivo using a GalNAc conjugated oligo that is designed to edit UGP2 and silence TTR. As you can see in the graph on the left, in mouse liver, the single oligo construct shows a more durable level of editing shown in pink line compared to the UGP2 AIMer alone shown in light blue line up to 28 days following a single subcutaneous dose. As we just shared earlier, we believe this improved editing durability could be due to the loading on to A2. Furthermore, as the graph on the right shows, in the same mice, the single oligo construct completely knocked down TTR mRNA just like the TTR alone.

Since AIMers have the ability to upregulate protein expression by stabilizing mRNA, we explored the possibility of using a single oligo construct to upregulate one target and silence the other. As you may appreciate, simultaneously silencing PCSK9 and upregulating LDLR offers an attractive therapeutic approach to treat hypercholesterolemia. Using our single construct oligo, we were able to achieve exactly that. As shown on the left, using a single oligo construct, we achieved the same twofold LDLR protein upregulation as an LDLR AIMR alone. the same experiment, the single construct oligo also silences PCSK9 to the same extent as PCSK9 siRNA alone. This shows how our approach can be used to upregulate and silence distinct targets using a single oligo. Beyond the examples I have shared with you today, we continue to push the boundaries of what is possible in the field of RNA medicines to unlock new targets and modalities with the ultimate goal of providing innovative therapies to patients in need. Now for closing remarks, I would like to turn the call back over to Paul. Paul?

Thanks, Chandra. Before turning to Q&A, I'll recap the updates you heard today throughout the presentation. WVE-006 continues to advance in the RestorAATion-2 clinical trial. And as Chris shared, the single-dose portion of the third cohort is now underway at a dose of 600 milligrams with the subsequent multi-dose portion to be dosed monthly. We're on track to deliver data from the 400-milligram dose cohort in the first quarter of 2026 and from the 600-milligram cohort, both single and multi-dose data in 2026. We've selected WVE-008 as our next RNA editing candidate for PNPLA3 liver disease, which will build on the successful clinical translation we've observed with 006.

Turning to ENLIGHT, the highly significant dose-dependent activin E reductions observed post single dose are incredibly exciting, not just for 007, but for our entire siRNA capability. The knockdown observed in the 240 and 400-milligram cohorts exceeded the levels observed in preclinical models that led to weight loss. Knockdown was incredibly durable and supports dosing of once or twice a year. Based on these data, we believe that WVE-007 has the potential to achieve fat loss on par with semaglutide by 6 months post single dose, and we are on track to report clinical data updates, including body weight composition starting this quarter.

We also continue to innovate our platform and have robust extrahepatic delivery capability for both RNAi and RNA editing and an emerging new modality that has the potential to unlock novel targets. Stepping back, our investment in RNA editing and RNAi to date has rapidly yielded multiple programs with WVE-006 and WVE-007 that have the potential to create immense value for both patients and shareholders. As you heard today, we are now expanding on the success of these programs and advancing the next wave to the clinic with PNPLA3 with more to come in both hepatic and extrahepatic.

Finally, I would like to express our sincere gratitude to all the participants, study staff and their families. They continue to inspire the work we do each day. And so from our entire team here at Wave, thank you. And with that, I'll turn the call over to the operator for Q&A.

[Operator Instructions] the first question is from Joon Lee MD PhD from Truist Securities.

Thanks for that impressive presentation. Your activin E target engagement, dose dependence, exceeding the DIO mouse model, very impressive. How much more than 75% knockdown of active E and DIO model did you need to achieve the semaglutide like weight loss? And does the increase in fat burning through in drive increase in hunger drive due to chloric burning? And are you measuring potential increase in chloric intake of these patients? And what are you doing to control for that? And I have a follow-up on the platforms platform.

Yes. And thank you, Joe. I think it is important to note, hence, the box shaded in green, as Chris shared, is that we are in the range from those DIO mouse studies. And so I think it's highly encouraging as we think, again, the 240 and 400 gives us a range to continue to suppress within there. So I think it's highly, again, encouraging that we have the levels of active E reduction clinically that we need to see to set the clock. And I think just on that concept, and I'll turn it over to my colleagues. I think that's the most important take home from today is that we've essentially set the clock. The essential durability that we've seen off of the subtherapeutic dose of 75 milligrams, where we see sustained knockdown out past 6 months. And as you saw on those slides, we continue to see that slope of reduction continue and the fact that we can push that durability out even longer is highly encouraging.

So in a lot of ways, the clock is set, and we expect this degree of knockdown to be sustained for a very long period of time and therefore, to be able to track together the level of weight loss that we can see relative to active reductions. I'll turn to Eric on the [indiscernible].

Yes. So we have tracked caloric intake in the mouse models, and we don't see a shift between siRNA or the controls. What we -- what I did present today is that we actually do see some changes in some of the pathways in the fat directly, which indicates kind of an improvement of insulin sensitivity, fatty acid utilization and of fat. So there are changes to the metabolism, but we don't see anything in terms of caloric intake.

Got it. I mean I think that was actually going back to you, that was, I think, one of the most impressive features of what I call kind of parity of caloric intake is if we thought about that rebound weight gain. And I think that's an incredible opportunity as looking at IPE silencing as an off-ramp to GLP-1s, is that when we did the withdraw study, actually the color consumption was mirrored in both mice. They both increased their color consumption on when removal of the downward pressure from the GLP-1 to actually go back and resume that hedonic eating, as many of you probably heard us refer to, that hedonic eating occurred across the control and the treating. So even despite that pressure, we saw that we could again take the break off of glycolysis and not store fat post the cessation. So again, highly encouraging as we think about a different profile for obesity treatments.

Yes. And really appreciate that the weight loss is a little more gradual and takes a little longer than semaglutide. In mouse, it takes maybe 30 days longer. Extrapolating that to humans, I mean, any idea as to how long we would need to wait to see that kind of weight loss in humans? And sorry to keep going, but I have a quick follow-up after that.

Sure. I'm sure this is a question that's going to come up in the queue. So -- and I think it's an important one. Again, we're on this journey together to understand INHBE kinetics. I think we can feel highly confident based on the preclinical models that have translated with a positive control in the GLP-1s that these models do translate in the clinic. And so the effect of INHBE reduction, active reduction and weight loss in these models demonstrate that we do achieve those kinetic curves. And as you said, in preclinical models, it looks to be that there is a different slope or trajectory of that rate of decline. But we have a high degree of conviction that as you think about the 6-month time point, they do converge. And so this ability to watch that rate, we do think will come together.

I think the question will be what rate of decrease in fat do we see between the 3 and 6 months, and we'll have the opportunity to see that. And as I said before, I think this is a target that there's probably many people have dialed into the call that have extensive experience on the genetics, human genetics, biology and the study of this target.

I think what's incredibly compelling are three things. One, we have the potency that's required, meaning we're in the therapeutic range of reduction of activin E. Two, as Chris said and Eric, it is a combination, not just of a single time point of reduction, but this feature of overcoming the natural compensatory mechanisms of pushing the program -- the target protein up are suppressed by duration. So we have that durability. And I think the third and most important thing in any obesity therapy and really any therapy in general is safe and well tolerated. And the fact that we can continue dose escalation gives us a high degree of conviction that the clock started. Medicine are in these patients. It's durable. We'll continue to follow it. But again, highly encouraging as we think about being able to continue to make these assessments over time.

Great. And then on the Sino platform. Looking forward to your progress there. But how does it specifically for the muscle tropic oligos, how does it come to transferrin receptor-mediated delivery?

And, do you want to take that follow-up?

Yes. This is -- yes, the duration, as you can see what we showed here in the muscle, this is -- these are single small doses, which is very similar to a transferrin receptor antibody dosing too. So what we are seeing is, again, uptake, one thing you have to keep in mind is that it's good to deliver a molecule, but the molecule also needs to -- the oligo also needs to follow the mechanism. So we have an advantage here through our Sena platform by increasing not only delivering, but we're also increasing a loading, which actually substantially increases its potency and durability. So that's...

I think just a follow-up to Chandra's point and maybe, Joe, what you were thinking in the back of your mind and others do when they see muscle is like if you were to take kind of a DM1-like construct and imagine what you could see, I think the benefit to deliver muscle without having to use transferrin with the safety liabilities and the others that are associated with it, but actually not forgo the distribution, the durability and in fact, potentially longer durability based on the siRNA constructs we have, I think open up tremendous opportunity. So I think as we think about the opportunity in muscle more broadly, we don't have to sacrifice what others are showing with the conjugate to deliver to the tissue, but we can get that potent durable knockdown without that. And I think that's, again, highly encouraging as we think about the platform capability and future targets.

And maybe just to add one more point on that is that just recall that our chemistry is compatible with ligands when very useful, such as GalNAc. So -- but we don't have to -- it's not an either/or. We can use it when it makes sense. But for transparent to get to muscle, it doesn't make sense because we get there very efficiently, and we have shown that already with our DMD medicines.

The next question is from Joseph Schwartz at Leerink Partners.

Great. I have a question on 007 and maybe one on 008 as well. So I guess, given the early fat loss signals might be in a fairly low single-digit range after 3 months of dosing of 007. I was just wondering if we'll be able to see the slope of response in patients similar to what you've shown preclinically as well as on the activin biomarkers that way we might be able to appreciate how the effect could evolve with more time.

Yes. I mean I think it's about the data and as we laid out nicely and Chris laid out a number of time points over a number of doses, I think we'll be able to plot those kinetics and what that slope of that trajectory begins to look like. I think as you get early, you remember that slide at 1 month, you're in that like 1%, 1.5% range. And we all can acknowledge that in smaller studies, there's a high degree of variability at early points in time. But I think these moments in time at 3 months, 6 months and across doses will allow us to eventually.

And remember, the follow-up goes out for these therapeutic cohorts out to a year. So I think we're going to have the ability to really to track what fat loss looks like with a completely novel approach to treating obesity that drives healthy sustainable weight loss. So I think, again, highly encouraging as we think about this sign. But yes, by 3 months, we'll get a sense of where we are on that trajectory across both body composition, body weight and other biomarkers.

7

Okay. Great. And then on 008, given 148m expression is enriched and lean match patients who present later. I wanted to ask about your diagnostic and enrollment strategy to enroll these patients early enough in the sequel that 008 can help? And also, can you talk about the biomarkers, which you can track at various stages of development to gauge the degree of target engagement at different doses? And what is your hypothesis about the dose levels that make sense to study in these patients?

I'll hand it to Eric. We're not sharing yet, although we have biomarker data as one would imagine, sometimes biomarker evaluation is competitive in this field, and we've made strides to, as Eric pointed out in this discussion to derive biomarkers. But I'll let Eric talk holistically about that.

Yes. We haven't shared any details on this really, but there are good noninvasive biomarkers that we can apply early on. I think it's important one thing, Joe, to point out is that the variant per se is with increased risk across the whole spectrum. So it's from F1 all the way up to F4. It's just that it's more enriched and kind of a big segment of individuals in the later-stage MASH and especially lean MASH that don't really have any treatment options. But for proof of concept, it's also possible to go to a more all weights -- all ranges of BMI or early stages or late stage. And we haven't really shared exactly where we're going right now.

Just to be clear on that. So it could treat all patients that have the mutation. And again, we're talking about MASH in this context. But as Eric also pointed out, there's a range of liver diseases associated with. And so thinking about it more broadly gives the opportunity for expansion to other indications in the future as well.

[Operator Instructions] The next question is from Steve Seedhouse at Cantor Fitzgerald.

Maybe just wanted to cover at the end there, that bifunctional RNAi, RNA editing approach, you kind of slipped in at the end there, but it looks awesome. The PCSK9 LDLR application, in particular, that feels like not just a proof-of-concept experiment, but actually something that like I would want to see in the clinic. now a pretty promising approach. So how close is that, in fact, to the clinic?

Well, we're not guiding yet today in the clinic. But as you point out, I think we have two independently really well-validated targets that should be developed. Obviously, PCSK9 extraordinarily well validated. And I think in the introduction and hearing lots of feedback and people are excited about what we could do with LDL-R, there's always this discussion that goes, what about PCSK9 and how -- and I think to the point that the team takes on is there's a lot we can learn about a platform. And I think if you take anything from today's call on a research day, that the research day is incredibly translational.

When we spend time thinking about something that could be a new platform in the case of these dual conjugates, it's not isoteric. It's not thinking about what can do, but actually, as you point out, how do we apply it to high-impact, high-value programs and medicines where hopefully, the outcome is how quickly can we move this forward. So a lot of work is happening to accelerate those programs. We see lots of translation from research data going forward. And there's lots of good things behind this, as Chandra shared in the kidney as well. But yes, these are two highly compelling targets and you put them together, you get a very highly compelling program in cardiovascular disease. So we're excited to continue to make progress there.

Great. Just maybe more near-term question then. So you announced today, I guess, that you're dosing up in a couple of these studies. So AATD going to 600 milligrams. And then in the obesity study, 600 and beyond, it looks like despite already obviously really good PD data. So can you just elaborate on those decisions, and it feels like the right call in AATD to try and maximize editing efficiency, but what are you seeing in the PK/PD data that inform those decisions?

Yes. I think as Chris shared, we're modeling up to 600 because it's the last and final dose to really max out where we are on the dosing curve. We can because of safety and two, no efficacy gets left on the table. But most importantly, as you remember for the prior call, I mean, we see healthy levels of alpha-1 antitrypsin protein 2 weeks after a single dose of 200. So there's also the optimization of PK and what those dosing intervals like. Are they monthly? Are they quarterly? So to fully flush out the dosing interval. And obviously, we're collaborating on this program. I think we'll learn a lot from 600 that ultimately enables us to say that, that portion of the study is complete, so the study can move on to the subsequent portion.

As it relates to INHBE E, I mean, I think as Chris alluded to highly encouraging that we can go above 600 and still have the DSMB allow us to go higher. So I think it's highly encouraging from a safety perspective to go higher. As you saw, we're doing a phenomenal job on active and [indiscernible]. So how much more is to be gained at going higher. But again, we'll learn more about duration of activity as well as continue to establish a profile for medicine. But again, we're highly encouraging from just the 240 and 400, let alone the 600 and where we can go from there.

The next question is from Yun Zhong at Wedbush Securities.

The first one is on the obesity program. I want to confirm that you're still going to report weight loss data from the 75-milligram dose cohort this month. And based on preclinical data, so given that the knockdown efficiency is still slightly below that 75 that you talked about, is it reasonable to still expect some kind of a weight loss signal? And if that's the case, well, how much difference will maybe a higher knockdown efficiency translate into weight loss?

I think we have to be focused. 75 is modeled to be subtherapeutic as it's a Phase I study still needed to be dose low. I think to your point, highly encouraging to see durable, stable knockdown out at 6 months. So yes, actually stepping back, the answer -- short answer to your question is yes, we'll show weight loss data from the 75 milligram, and that was on Chris' slide at this Q4 time point will be 75 as well as the 240. We wouldn't be guiding this expecting to see something given the range was outside of the early reported data. But again, this is the first time INHIB E has been developed in the clinic and we'll have long-term durable knockdown. So we'll get a good sense of that. I also look, whether or not we see other biomarkers that are interrogated beyond just weight loss itself, I think, will be helpful. But again, it's a 75-milligram cohort. So it will be, if anything, level setting for where we get to with 240 as that continues.

I see. Okay. That's very helpful. Then on the 008 program, I think -- well, is it reasonable to expect that initially, you will be focused on MASH. And I think do you have any data to show whether those carriers they are showing any different response to current MASH treatment or other therapeutic in clinical development? And there are other agents, for example, working on fat synthesis modulation or fat metabolism. Do you expect your approach? I know it's a precision approach will potentially generate something different, maybe better efficacy when it narrowed down to that specific patient population?

Yes. Thanks. That's a great question. Yes, that is exactly the point of this. It's a disease-modifying correction of the causing mutation in these patients. And while you could kind of potentially have some effect of other medicines, it's going to be -- have lower efficacy than correcting the driving disease-causing variant.

The next question is from Salim Syed at Mizuho Securities.

So Paul, Chris, I just want to -- because I know a lot of people are looking at a quantitative number, and you kind of put one out today, but not really on this obesity stuff that we're getting in the 4Q here. just looking at Cohort 2, which is your therapeutic range of 240 mg where you do have 75% reduction, that's kind of the target you stated here. The sema is showing 3 months on your chart, a 2.5% fat loss. So quantitatively, is that the bogey here? And why should we not be looking at other things like amylin or even like the Nomura oral data? Why aren't those the relevant comps here?

Yes. I think we use sema because the GLP-1s have been the comp that we could use to model mouse weight loss and mouse fat loss to humans. So I think finding a harmonization of benchmarks that we can use sustainably across programs where we could look into ranges of fat loss and be able to take those ranges and extrapolate them in a forward-looking way. Again, this is healthy overweight volunteers as we move into subsequent studies, being able to try to create benchmarks on a new modality that let us look at ranges of fat loss, I think, is important. I think to your point on where we are, I think the recognition is at the 3-month time point, you have this range of what we've seen preclinically where it does look like in the early point that kinetics on lipolysis versus what happens when you have chemical starvation and lose muscle and fat look different. And so I think our view has been that we do expect to be on that curve of weight loss and particularly fat loss and then be able to see that normalize.

And so I think by the time we get to 6 months, I think we think we're over that hurdle on the normalization. But it just means where we're going to be to try to put in an exact moment of time relative to the GLP-1 and 3 months is something we're going to have to learn in running the experiment. I think in order to have the conviction to even run the experiment, you need to believe that you have active knee reductions that are within the range. And I think as Chris alluded to today, we're clearly within the range. And so I think that's going to be helpful as we look at the subsequent experiments, both at the 240 lowest therapeutic dose as well as others and continue to follow this over time.

And I think by the middle of -- as we move into 2026, as Chris shared too on the slide, we're going to have a number of patients with therapeutic ranges of active knee reduction that are highly consequential and be able to look at not just where it is at 6 months, but continue to see what that range of reduction looks like, both in terms of time and dose.

Okay. But we're getting 3 months, right? So I just want to be clear because the consensus is all over the place, like investors are all putting out different numbers. I just want to be clear to get consensus in a little bit, like people should really be thinking low single digits for this 4Q update.

Absolutely. I mean I think we were very clear on the numbers that we have put out that even if you were in a GLP-1 for fat loss, again, we have to separate for other weight loss versus what we know about the degree of fat reduction. INHBE E pathway because it is, as Eric alluded to, working across actually what actually drives healthy weight loss, meaning preserving insulin sensitivity and all of the other cardio-metabolic parameters of weight loss is by reduction of fat and that muscle. And so when we look at that degree of fat loss, I think we were very clear about the range of numbers. And as you pointed out, low single digits is what you see with fat loss within the GLP-1 space at the early guidance.

And just to add to that, like the other things that you're bringing up like amylin or any -- basically any incretin medicine or any obesity medicine in development right now, they all have an orthogonally different approach. They're all kind of acting on appetite or GI versus we are acting directly on ad. So it's a totally different approach, but the comps are always going to be like the fat loss and primarily the visceral fat, which is what increases the risk of cardiovascular disease.

The next question is from Cheng Li at Oppenheimer.

Maybe a 2-part question from me, one on 007. I'm just wondering if you can comment on the patient baseline in the Cohort 2. And just based on the patient baseline, whether the semaglutide from STAT1 is a fair benchmark? And I have a follow-up on 008.

I'll let Chris comment on that.

So the question was about the patient baseline compared to sema?

Yes.

Yes. So I mean we're looking at patients that are healthy with overweight. And so as we mentioned, we mentioned the BMI range and the A1c. They're nondiabetic and have an A1c range. I mean I have a BMI range, I think that's up to 28.

Yes. So I think the key is that they're similar in both SAD programs across both, as you're pointing out, the step 1 in this would be similar.

Okay. That's helpful. And on 008, congrats on the preclinical data. It just seems like the RNA editing efficiency you show is around 60% to 70%. So I'm just wondering is there like a ceiling for maximal RNA editing you can achieve or is there something else you can further optimize by maybe increasing the loading to the ADAR enzymes or any way to improve the RNA template design is potential learning from the siRNA modality?

The RNA editing, so there are -- if you look at it -- when you look at standard sequencing, which is the plot that we have on the left-hand side that you're talking about at 75%. But when you look at the transcript, when we did the transcriptome analysis, we see about 85% editing. So this is actually just the nature of the assay. So we are not saturated. It's very similar to what we observed with 006 as well.

I think that's something -- I mean, to Chandra's point, I mean, it's something that we learned now with human clinical data, right, from the prior study and being able to look at what occurred during an acute phase event is we learned that the drug is not substrate limited. There's plenty of drug. I mean we have editing 2 months after the last single dose, the lowest dose.

So there's plenty of drug on board, so it's not substrate limited by the stability of the construct. We also learned that when you have the acute phase event and increased transcriptional activity, the enzyme is not substrate limited. And so I think those are two highly important features as we think again about what we continue to do in optimization is realizing that we did prove that ADAR is a catalytic enzyme in there to be edited. And to Chandra's point, our medicines are highly stable and durable. And so again, it gives us a lot of work that we can continue to do in terms of driving further optimization, both in the liver and then importantly, outside the liver.

The next question is from Cha Yang at Jefferies.

This is on for Roger Song. I have two, both about your 007 program. So the first one has to do with some of the safety front. I know you said no discontinuations, but I'm hoping that you can give some color on the GI AE safety front. And then my second question just has to do with benchmarks as well to sema and tirzepatide. So I know you talked about benchmarking to visceral fat loss, but I'm wondering if you believe that the higher dose cohorts for 007 could achieve overall weight loss comparable to sema.

Yes. I mean I think if we -- and I think we have to think about fat loss weight loss. And I think we've got to stay focused on mechanistic activity, which is fat loss. But again, highly encouraging that ZIO mouse models were achieving weight loss similarities. But again, we have to look at that as a model and mechanism. So to the point on could and potential and forward-looking, particularly across doses, the models don't suggest that it's inferior too. So I think that is always a possibility. But the focus has been on optimization of fat loss relative to the fat loss that's seen with GLP-1s, and that's what we'll continue to drive and explore. But again, higher doses, time and the ability to recapitulate what we've seen in the animal models are highly encouraging. As it relates to safety?

Yes. So as we mentioned, we've been dose escalating without any issues from a safety perspective, it's been safe and well tolerated and the DMCs have been allowing us to proceed without any questions. All of the AEs that we saw were mild in terms of any pregrelated AEs. And given the mechanism, you wouldn't really expect any GI symptoms.

It is important to note when we think about the GI toxicities and they brought this up in terms of a lot of the category classes, it's not in treatment. It's not working on either suppressing appetite or slowing the GI track. And as [ Christa ] said, this is taking the brakes off of polysis. And again, highly encouraging that's a single subcu dose with long durability. So both on the preclinical studies as well as what we're seeing in the clinic, again, it's got a profile that has us encouraged for a long durable medicine. And I think the fact that DSMB could review the current data let us to go to 600, see the current 600 and enable us to go higher, again, highly encouraging.

The next question is from Catherine Novack at Jones Trading.

I have a question on 007. Can you let us know with the ENLIGHT study, what is blinded to the sponsor? Obviously, you're sharing target engagement data while the study is ongoing. So is this unblinded separately and safety and weight loss is still blinded? Or when a cohort finishes dosing, is anything unblinded at that time?

Yes. I think stepping back, it's important to realize what I said at the very beginning of this call. So the short answer to your question is yes. We're not -- we did an analysis here looking at activity. Obviously, DSMBs can look at data, both blinded data and in preparation for those and the DSMB can continue to make their decisions based on evaluation of those data sets. But no, I think it's really critical that this wasn't an unblinding of the totality of data sets, being able to even look at unblinded weight loss data, which I know some people are thinking, this was an analysis that if you remember the last update, and I'll kind of go back to the beginning of what I wanted to reiterate is a lot of the forward-looking pieces are predicated on being within a range where we've got a good model that enables us to predict where we're going to be.

And when we could model and say at the 75 subtherapeutic, we had substantial target engagement. I know there were a lot of questions of like what range of target engagement we see. How do you know that your 240 is going to be within a therapeutic range. And we have a phenomenal team that's doing a lot of modeling.

I think to see where we needed to be, to be able to be on that trajectory to deliver weight loss data, we knew we needed to be within that range. And yes, we were modeling to be in that. So this is a very specific cut at day 29 to do that assessment and assure that this 240 where we said we should be in that range, we can now switch that where it should be in the range to we are in the range where we see it.

And just to add, so we will be unblinding for 3-month readouts and for a 6-month readout with regards to weight and the entire study and other measures such as body composition and biomarkers, but not for the big 9 measures, we just were looking at biomarker target engagement.

Got it. And just one more. If you could give me any specifics about the timing of the data cut showing activin E knockdown, even though we have 24 patients in the 240 mg cohort at 1 month. Given that we know enrollment was complete before the end of July, is there a reason you don't have 1 month data for all 32 patients in that cohort? And how long after the 3-month follow-up period do you anticipate it would take to analyze once the data are unblinded?

Yes. I mean I think we haven't guided beyond where we can get to. But each one of these cuts, we were up in dosing and that's rolling forward. So as we said, day 29 are the cuts of all patients who had that data at that time. So this wasn't -- these were the patients at this time with the cut of the day 29, full 32 on 240 that pulled that data together. I can't guide other than we'll have data this quarter on the 6 -- sorry, the 3-month follow-up of those patients, which will include then also the 75.

And just recall that the study is designed so that you have a cohort of eight initially. And then if the safety and tolerability is acceptable, which has been in every case, you can expand the cohort. And all those subjects are not enrolled at the same time. So just maybe that gives you a sense of the flow of the study in terms of enrollment.

The next question is from Bill Morne PhD from Clear Street.

So just on the INHBE program, can you talk about the key remaining unknowns in the biology, given this is kind of the first foray into lowering activin E, whether there's a level of reduction that is too much or whether long term, there may be some compensatory metabolic changes that may kind of offset some of the effect.

Yes. I think part of this is relying on the human genetics, we know that on the on target, there are really no concerns about decreasing it because there are also homozygous carriers and the loss of function carriers and they're healthy actually healthier. So with regard to that, and we also do phenowise studies where we look at these carriers across every known phenotype in human, and we don't see any increases of anything. So that gives us some reassurances. And we've obviously taken this through talks, and it's all both on and off target, it's clean. So with regard to that, no really concerns about this mechanism with regard to like decreasing it. I think we can decrease that there is really no limit to how much we could potentially decrease it.

Biology on the other side of inducing it, as you were saying, we have shown on the other side, as Eric shared that we do think that we've shown across the pitch that inducing it impacts a whole bunch of features, right, beyond just fat loss, as Eric shared, when we think about other drivers of adipose inflammation and all of the features of what makes this, I think, really important, a cardio metabolic drug. I think we need to step back and think about the totality of it. Yes, it has an impact on fat loss and weight loss, and that's important. But if we think about obesity as truly a public health disease and metabolic and why fat loss and muscle sparing is crucial, it's critical. I think that's ultimately what we think is going to be the biggest driving differentiator in this program is for insulin sensitivity is saving muscle. That is important.

Yes. And I think we -- this is a largely new target since just a few years. But even today, with some of the data we've disclosed today, we're starting to put together the pieces how basically the increase in lipolysis is contributing towards the lower risk of cardio metabolic disease seen in these genetic carriers of the homozygous or heterozygous loss of function carriers. So I think the pieces we put together today with an increased insulin sensitivity, a shift from the pro-inflammatory to the anti-inflammatory state in visual fat and lower fibrosis, all of those things together contribute to the lower risk of cardiovascular disease and type 2 to Paul's point, which is ultimately really the reason for any obesity treatments.

And on PNPLA3, is that a validated enough target that you expect to be able to put forth an argument for accelerated approval? Or do you expect to have to show functional endpoints and what might those be?

I mean it's a very well established target where the biology is well known. I don't think we would guide towards regulatory interactions at this point. But to the question, it is a very well-known mechanism, I guess.

With biomarker and to Eric's point that we made, I guess, on one of the prior questions that we can have a biomarker-driven response in terms of then targeting the genetics, the biology through biomarkers and ultimately through phenotypic analysis of patients.

The next question is from Madison El-Saadi, PhD from B. Riley Securities.

I appreciate the update. Lots of things one can get excited about. Maybe first, given the NASH liver field pivot to these noninvasive tests, does this allow Wave to execute really end-to-end a Phase II or even a future Phase III in a 148 variant population just as an independent company?

I think we were excited when we saw the transition finally to looking at noninvasive imaging as endpoints. So I think to the prior question and to this one, I think it's what obviously elevated the target in our minds that we've got a highly genetic correlation. it's in commercial genetic testing. So it's a readily accessible genetic biomarker that drives disease, being able to modify that with a biomarker and noninvasive imaging is something that we can fully deliver.

5

Got it. Got it. And then secondly, Paul, has your view changed, I guess, on the future potential real-world use of 007, you've spoken about it in terms, really independent of GLP-1s as a way to lower GLP-1 dose. to improve the GI tolerability and also as an off round. Just wondering as more data came out, as you've learned more, if your view here has changed recently?

No. I mean I think on one hand, probably it's easier to have conviction with clinical data than preclinical data. So I think having seen the range of knockdown, the durability translate, you do a lot of modeling when you try to go from a DIO mouse to human. And I think the more data points you can have on actual protein reduction and durability of protein reduction, the more conviction you have. So I think it absolutely is going to be a very important cardio metabolic medicine. I think where commercially the uptake starts and whether or not people begin to use it in advance with the evolution of the GLP-1s and where they go and particularly around genericization?

I think there's easily for fat loss, muscle sparing, cardio-metabolic improvement, if the goal is to treat obesity, I think no doubt, there's no wavering from our point that it can be very much a frontline medicine. Where it gets utilized in the initial piece, which I think is a very consequential market is sustaining people on a GLP-1 where they're going to continue to learn, lose bone and muscle over time. 70% of patients can't stay on it. The ability to transition as we did on maintenance where you can move patients to a once, twice a year subcu injection and know that you're not going to get weight, you're going to sustain that benefit over time. I think is a phenomenal use case. I mean, for the U.S. where GLP-1s are used, but we have to look broader than that.

I mean there's over 1 billion patients worldwide that are in obesity. And so when we think about what those treatment paradigms look like, I know we often look at this particular market and say, well, how are we going to intersect there? But the ability in markets where people don't have access, you have large companies buying manufacturing CDMOs to try to keep up with demand and just individual marketplaces, the ability to think about how you can scale a once-a-year subcu GalNAc siRNA opens up a massive possibility of how you think about the global treatment for obesity in a way that we believe this mechanism has the potential to address.

And so highly encouraged as we go on. We actually are going -- are set to deliver, as I said, the clock started, medicines and patients, we're knocking down the target in these ranges, and we're going to be able to follow this out over time. And I think as we do that, I think that will be a huge opportunity as we think about the global obesity market. And I think that's really how we think. How do we treat the over 1 billion patients worldwide living with obesity.

And just to add, I think we are really excited about all three use cases that we have presented, and we hear a lot of that sentiment out speaking to KOLs and the community as well that there's really an opportunity in all of those a potential path forward, and we're going to be guided by data as we look forward.

I'll bring up one other point, and I think that as Eric just alluded to, I mean, we spent the time -- obviously, our heritage has been in rare diseases, and we spend a lot of time with the patient community. And as we bring patients in, I think carefully about the number of patients who tell us when they watch ads on television, advertising the weight loss potential of GLP-1s. And they truly say like even if I achieve that level of weight loss, I still wouldn't be at a healthy goal in weight reduction.

And so I think as we do think about what are the arrows in the quiver to Eric's point on talking to KOLs that can actually enable patients to achieve true healthy weight loss that's going to drive protection for patients living obesity, there very much is the need to think about a multitude of medicines that can be used together. And I think as we said, the fact that we don't work on the GI system in terms of causing nausea, vomiting and distract the fact that we don't cause anatonia because we're not actually driving appetite suppression in the CNS. The fact that we've got a very orthogonal approach to doing this and can show that we have complete synergy with the incretin.

So in this case, GLP-1s, I think does allow us to think about that middle use case, which is really about how do patients continue to be able to achieve those level of weight loss if they need it. So again, I do think that this orthogonal approach gives us a huge opportunity to think about all categories of business.

The next question is from Samantha Semenkow, PhD from Citi.

On all of the updates you've presented here today. I just have a follow-up on one of the prior questions for your RNA editors and I guess, specifically for 006, what levels of optimization would you look at to help increase the maximum editing threshold? And as you said, if that threshold is not substrate limited, is it then concentration dependent? And is that why we're seeing the editor respond when endogenous production of AAT increased in that one patient with the acute phase response?

Yes. No, thanks for the question, and we'll tag team this. I think the interesting thing on 006 independently, I think that's some of what is intriguing. I think -- and when I say this, I'll -- nothing is easy in drug development. But I think the difference between 006 and some of the other targets in editing, in some ways is 006 is one of those where you've got this other kind of variable, right? What happens during an acute phase response. So the other variability is increased transcription. That's what -- as we shared again today, that's the biological rationale and mechanism for ADV is you get this response, inflammatory response, CRP goes up, you get this increase in transcription. And so there is a different texture to how that happens.

This gets to that target differentiation. And again, it's when we have targets like PNPLA3 and others as Chandra shared, we've got other features in terms of stability of showing good stable drug activity and editing. And we do see a high degree of reproducibility across constructs, which I think, again, there's two metrics that we look for in kind of saying defining a platform is how much similarity is there to move from one construct to the other? And how do you those learnings.

The other that I use a lot is how quickly when you have a platform, does it mean moving from a target to moving to the clinic. And we use that also as a barometer of the efficiency with which there's portability. And I think we've been highly successful in that portability concept and was 18 months from our target work on the in vivo data to being in the clinic. And so I think we've been able to impart a high degree of that. And again, with PNPLA3, we see similar. others additions to that.

The only thing to add is just the way we're thinking about this acute phase response, and it's pretty well understood that you increase expression at the RNA level. So if you have more RNA, there's enough of the molecule and active enzyme to actually produce much more A we don't believe that it's an enzyme or a molecule stability question. It's really that there's lower levels of RNA and then those go up in the acute phase response and then we can convert that to and increase the overall amount of AAT. So that's how we believe it's working.

And as the prior question came up on the dose, pushing -- moving that dose to the highest third cohort as we could is also about just looking at duration, how long -- we know we've got stable construct there. So how long and frequently do we need to administer the medicine that patients can respond.

Got it. Okay. And then I guess as a follow-up to your last comment there, Paul, what is the, I guess, residual amount of Z that you think is acceptable to support commercial uptake for WAVE 006? I'm just wondering from a competitive perspective if you need to try to push Z down as low as possible and therefore, maybe you would need to do optimization in addition to improving durability there?

No, it's an interesting question because as we also know that Z has a high degree of variability, right? Because as you had success on freeing up and I also look at this as the sensitivity measurements of being able to analyze it in some moment in time. But as you push up M and then therefore, Z comes down, and we saw that dramatic, and it was nice to see kind of that corresponding, which is what you want to see in editing as your Z convert to M. There's another reservoir of Z, right, which is the aggregation over liver that's going to be various will be variable over time in patient depending on how much aggregates they have. But eventually, when you substitute M, you're going to free up Z aggregates. And so it is something that we'll have to watch for over time. So again, we would expect to see if we continue to push M higher that Z would go lower. That's the natural inverse relationship.

With the exception of the fact that as you do these measurements, if you're clearing Z aggregates from the liver, there will be periods of time until you completely flush the Z aggregates out that will confound that variable to know how low is low if you're continuing to clear aggregates. And I know that seems circuitous, but you do have to look at the two reservoirs of Z. There's the hepatic reservoir, which is aggregates and then the intracellular reservoir, which is the transcripts that are making the protein. And we'll have to follow both of those over complete time and then you fully flushed out the lower limit of Z.

But we do know that Z protein itself, and this is important, once it gets outside of the liver, has some residual function. I mean we know there were companies that were trying to -- and I think a lot of this had to do with the mechanism of doing it to try to push Z protein out of the liver to restore some degree of functionality systemically, and those were kind of the small molecule disaggregators. So it's not that Z itself has 0 biological function that's detrimental once it's freed out of the aggregates in the liver.

Maybe just add one more thing is an advantage both for 006 and 008 that we're modeling our medicines for human genetics. So in this case, just as a reminder, the MC patients, AAT patients they're more or less healthy. They have very low risk of liver disease and also lung disease. So then that means that some Z circulating is okay, right? So that's what we're trying to see. And the same with PNMP3 really that the MCP or in this case, it's a homozygous -- sorry, heterozygotes, they have 80% lower risk of dying from liver complications than the homozygotes. So that's the advantage of using [indiscernible] as our starting point for developing medicines.

The final question is from Craig McLean at Wells Fargo.

Just a quick one from us. I want to kind of go back to the safety of 007. Given the mechanism of action, how you're putting a brakes on glycolysis instead to upregulate, let's say, lipid catabolism. Can you share what you're seeing, if anything, in terms of serum glucose levels? Is this something that you've seen perhaps below a dangerous level in your patients in the study?

Just say the first taking the break off taking a break off lipolysis. So it's a lipo. So it induces lipolysis to make sure everybody else. So that's key. But as Chris pointed out, we really haven't seen anything like that. I mean, again, we've been dose escalating up to 600 milligrams and potentially beyond, and we've not really seen anything except for mild events. So nothing really to speak of from that perspective.

And I don't think that the human data with individuals that have the mutations also would support that. So there's not really no evidence of hypoglycemia or other things even in homozygous.

Or in any of the preclinical studies that we do that would ultimately push bounds in doses as we go forward. But no, it's a great question and something, obviously, you continue to follow all apps as you move into mechanism.

All right. Well, thank you, everyone, for joining us today, and we look forward to connecting with many of you in the very near future. Have a great day.

Good morning, and welcome to the Wave Life Sciences RestorAATion-2 Clinical Update Conference Call. [Operator Instructions] Also, as a reminder, this conference call is being recorded today.

I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator. This morning, we issued a press release announcing a positive update from our ongoing RestorAATion-2 trial of WVE-006 in alpha-1 antitrypsin deficiency.

Our press release can be found in the Investor Relations section of our website, www.wavelifesciences.com, and the slide presentation to accompany this call will be available on the website following the prepared remarks.

Before we begin, I'd like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements.

The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our Annual Report on Form 10-K for the year ended December 31, 2024. We undertake no obligation to update or revise any forward-looking statement for any reason.

Today, Dr. Paul Bolno, President and Chief Executive Officer, will begin with opening remarks. Next, Dr. Chris Wright, Chief Medical Officer, will present the RestorAATion-2 clinical data update. Paul will conclude the prepared remarks with next steps and anticipated milestones before turning it over to Q&A.

Dr. Erik Ingelsson, Chief Scientific Officer; and Dr. Chandra Vargeese, Chief Technology Officer, will also be available to answer questions.

I'd now like to turn the call over to Paul.

Thanks, Kate. Good morning, and thank you for joining us today. Today, we are excited to share the full results from our first 200-milligram dose cohort and 400-milligram single-dose cohort in our RestorAATion-2 clinical trial.

Our goal in RestorAATion was to recapitulate the MZ phenotype, including durable production of M protein, reduction of Z protein and the ability to produce a dynamic AAT response when needed.

Within our first 200-milligram cohort, we're pleased to share that treatment with multiple doses of WVE-006 achieved 11.9 micromolar of total AAT, 7.2 micromolar of M-AAT. Circulating M-AAT and serum reached 64% of total AAT and Z-AAT protein declined over 60% from baseline.

RNA editing effects were incredibly durable and sustained at least 2 months following last dose. Notably, we achieved yet another significant milestone in the field of editing with 006 as we observed the first-ever demonstration of therapeutic restoration of a Pi*ZZ individual's ability to increase serum AAT production of over 20 micromolar during an acute phase response.

Chris will share more detail on this momentarily.

This is a particularly meaningful achievement for individuals living with AATD, as it demonstrates that 006 can dynamically generate more healthy protein when individuals living with AATD are most susceptible to lung damage.

Initial results from our second dose cohort demonstrate that a single 400-milligram dose of WVE-006 leads to serum total AAT of approximately 13 micromolar. And based on our 200-milligram results, multi-dosing is expected to drive greater AAT production. The multi-dose 400-milligram cohort is ongoing with monthly dosing, and we expect to share data in the first quarter of next year.

There is an immense need for effective therapies for AATD, which is caused by the aggregation of mutant Z-AAT protein in the liver and lack of functional AAT in the lungs. Damage in the lungs occurs during exacerbations that induce an inflammatory acute phase response.

Healthy individuals are able to produce elevated levels of protective functional AAT protein during these events, and it protects the lung from damage. Progressive liver disease results from Z-AAT-induced proteotoxic stress.

Treatment today is limited to weekly IV augmentation therapy for lung disease, which does not allow for protective increases in AAT protein during acute phase response without additional infusions. There are no approved therapies that address AATD liver disease and the siRNA treatments in development could potentially exacerbate lung injury.

There are an estimated 200,000 homozygous Pi*ZZ individuals in the U.S. and Europe. We've heard many powerful testimonials directly from the AATD community that speak to the harsh impact of this disease, which progresses over time as a result of accumulated injury and is often misdiagnosed.

Risk for AATD is related to genotype with MM being healthy and MZ individuals having low risk for disease. ZZ individuals have high risk for both severe lung and liver diseases due to the lack of wild-type M-AAT protein and serum and misfolded Z-AAT protein trapped in the liver.

Since the approval of weekly IV augmentation therapies to treat lung disease, the field has focused on keeping serum AAT levels above a minimum threshold, in part because ZZ individuals do not produce any M-AAT and have a limited ability to increase serum AAT levels during an acute phase response for exacerbation.

Editing by RNA, at least 50% would shift ZZ individuals to an AAT biomarker profile consistent with the MZ phenotype with low risk of disease. One of the key treatment goals is to protect against lung injury by reducing the frequency and severity of exacerbations, which drive disease progression.

During these events, immune activity, proteolytic enzymes and inflammation cause damage to the lungs, because AAT protein, a key protector against these insults is missing.

On the left of Slide 8, you can see the kinetic profile for C-reactive protein or CRP, and AAT protein during an acute phase response. CRP spikes early and the peak level impacts the intensity of the immune response. AAT protein expression is upregulated proportional to the CRP elevation. This ability to upregulate AAT is severely impaired in ZZ individuals with AATD, which is shown on the right of this slide.

The best way to limit exacerbations and the associated damage that drives disease progression would be to enable ZZ individuals to respond like an MZ or a healthy individual and make protective AAT protein when it's needed. And this is exactly what we were able to observe with 006 during an acute phase response.

Designed using our proprietary chemistry, which drives potency, stability, distribution and delivery, 006 has the potential to be the first treatment for AATD that enables patients to produce protective AAT protein when needed and address the root cause of the disease with a convenient and infrequent subcutaneously dosed therapeutic.

006 corrects the Z mutation, increasing circulating levels of wild-type M-AAT protein and reducing mutant Z-AAT protein aggregation in the liver, thereby treating patients with lung manifestations, liver manifestations or both.

As Chris will share momentarily, our clinical data with 006 strongly supports a differentiated therapeutic profile as we observed restoration of dynamic physiological AAT protein production during a non-drug-related acute phase response, efficient production of M-AAT and corresponding decreases in mutant Z-AAT.

Now to review the clinical results, I'd like to turn the call over to our Chief Medical Officer, Dr. Chris Wright.

Thanks, Paul, and good morning to everybody on the call.

Today, I'm excited to share an update from multiple cohorts of our RestorAATion-2 clinical trial. Our RestorAATion program started with healthy volunteers in RestorAATion-1. This was a safety, tolerability and PK dose escalation study that proceeded through single ascending and multiple ascending dose phases, ultimately evaluating up to three 600-milligram doses of 006 administered every other week.

Data from RestorAATion-1 informed the starting dose of RestorAATion-2, our open-label dose escalation study of individuals with AATD, who have the homozygous Pi*ZZ genotype.

Each cohort was designed to enroll eight participants who began with a single dose of 006 and then continued into the multi-dose cohort. Participants in the first lowest dose cohort of RestorAATion-2 received a single 200-milligram dose of 006 and were followed for at least 12 weeks. These same participants then rolled over into the multi-dose portion where they received seven 200-milligram doses every other week for 12 weeks. They were then followed for 12 weeks after their final seventh dose.

Today's update includes data from both the single and multi-dose portions of the 200-milligram low-dose cohort as well as data from the 400-milligram single-dose cohort.

I'll quickly touch on the safety and tolerability we observed in RestorAATion-1, the healthy volunteers study. The study enrolled 29 individuals on active drug with participants receiving up to three 600-milligram doses every other week in the highest dose cohort. 006 was safe and well tolerated with the related TAE being mild in intensity.

In RestorAATion-2, we enrolled eight patients with AATD into each of the 200 and 400-milligram cohorts. Baseline characteristics were similar between the cohorts with some minor differences in gender and weight.

Participants mostly had no or mild evidence of liver or lung disease as required by protocol with one participant having moderate liver disease. All participants were required to be between 18 and 70, have a Pi*ZZ genotype and be non-smokers for at least 1 year prior to screening.

006 was safe and well tolerated across all doses and regimens tested. All drug-related adverse events were mild to moderate in intensity. There were no serious adverse events or study discontinuations. Additionally, there were no clinically meaningful treatment-related lab, ECG or vital sign changes. Overall, we're encouraged to see such a favorable safety profile for all evaluated doses.

Now turning to our biomarker results in today's update. In the single and multiple dose cohorts, we observed a mean max total AAT of 12.9 and 11.9 micromolar, respectively. These results were consistent across participants as shown in the chart on the left, except for one individual with an acute phase response, which I will cover in more detail later.

On the right side, we show the time course of RNA editing across the study periods. The bar graph shows the proportion of mutant Z-AAT in light blue and wild-type M-AAT in dark blue. Remember, individuals with the ZZ phenotype cannot make any M-AAT. So at baseline, circulating AAT protein is 100% Z-AAT.

Even with a 200-milligram single dose of 006, M-AAT protein reached nearly 50% of total AAT and editing effects persisted out to 3 months, marking the end of the follow-up period.

Looking at the multi-dose phase where participants received seven total doses, one every other week, M-AAT protein reached a higher proportion of total AAT than in the single-dose phase with a mean max at around 64%. This proportion of M-AAT is consistent over most of the observation period with a level still at approximately 50% edited protein 2 months after the last dose.

These data indicate that the proportion of circulating M-AAT increases with multiple doses and that 006's RNA editing activity is durable.

Looking at the dynamic changes in M-AAT and Z-AAT at an individual level, you can see just how consistent the effects of 006 were across participants with everybody responding to treatment.

On the top left, you see a substantial increase in M-AAT protein, which persists up to 3 months following a single dose. There's a corresponding decrease in Z-AAT on the bottom left of the slide, consistent with the presence of significant RNA editing. A similar pattern with more substantial responses was observed in the MAD portion of the study, as shown in the middle of the slide in dark blue.

Across both M-AAT and Z-AAT, there was a statistically greater effect in the MAD as compared to the SAD shown on the right, supporting exposure-related enhancements of the effects. In the MAD, the mean max M-AAT reached 7.2 micromolar from 0 at baseline. And there was a 60.3% reduction in mutant Z-AAT protein from 10.7 micromolar at baseline.

If you look at the SAD data on the left again, you'll note one participant also seen in the box plot on the upper right, had a very strong M-AAT response, followed by a decline over about 4 weeks.

In the next slide, I will focus on this response as it potentially is telling us something very unique and impactful about the effects of 006. Looking closer at this individual response, serum total AAT increased to a level exceeding 20 micromolar. There was also a moderate elevation in C-reactive protein or CRP, which is indicative of an acute phase response.

After investigating this case further, it was noted that this 200-milligram single-dose participant experienced a kidney stone, which was unrelated to study drug. This presented us with a rare opportunity to assess the impact of 006 on the dynamics of endogenous AAT protein production in the context of an acute phase response.

As you can see, there's a simultaneous and rapid increase in both total and M-AAT levels followed by a period in which AAT remains elevated. This pattern resembles a typical acute phase response.

To the right in this slide is the natural history data that you may recall from Paul's introduction, showing ZZ individuals are not expected to have increased serum AAT levels during an acute phase response. MZ and MM individuals both up-regulate AAT when CRP levels are around 20 to 50 milligrams per liter. The observed strong AAT elevation in our ZZ participant affirms that 006 enabled an MZ response. This participant illustrates that a single 200-milligram dose of 006 resulted in substantial up-regulation of AAT when it was needed in the ZZ individual.

Importantly, CRP elevations in this participant were moderate. So it's likely that 006 could result in an even greater AAT elevation with a stronger acute phase response. A long-standing goal of the AATD community has been to ensure individuals living with AATD are protected with sufficient serum AAT during exacerbations.

Restoring endogenous expression dynamics of AAT during an exacerbation when it's most needed achieve this goal. These data represent the first ever therapeutic demonstrating RestorAATion of dynamic, physiologic AAT production during an acute phase response.

Now turning to the 400-milligram cohort. The single dose achieved serum total AAT of 12.8 micromolar and M-AAT of 5.3 micromolar. Circulating serum M-AAT levels reached 47.2% of total AAT and Z-AAT decreased by 49% versus baseline. Relative to the 200-milligram single-dose cohort, greater M-AAT was produced and a larger decrease in Z-AAT was observed.

Based on the differences between dose levels in the SAD cohorts and the impact of multiple doses in the 200-milligram cohort, we expect that the 400-milligram multiple cohort may lead to even greater effects on AAT expression. The data gathered to date, along with the PK/PD modeling supports monthly or less frequent dosing and our 400-milligram MAD cohort is currently ongoing with once monthly dosing.

We look forward to sharing the complete 400-milligram data set with you in Q1 2026.

I'll now turn the call back to Paul.

Thanks, Chris. Our goal in RestorAATion-2 was to recapitulate the MZ phenotype, including durable production of M-AAT, reduction of Z-AAT and restoring the ability to produce a dynamic AAT response when needed. The results of our first cohort clearly show we have already achieved this goal.

With efficient and durable RNA editing, we are restoring a biomarker profile in individuals living with AATD that is consistent with low risk of lung and liver disease, including total AAT protein levels of 13 micromolar and over 60% circulating M-AAT and serum with no bystander edited protein.

Consistent with what we would expect to see in MZ individuals, we are also restoring physiologic AAT production and the ability for ZZ patients to respond with increased protein levels during an acute phase response to prevent lung damage.

By reducing Z-AAT levels, we have also had the potential to prevent liver damage. Importantly, we have not observed any liver enzyme adverse events nor do we use LNP delivery, which have known risk for hepatotoxicity.

With convenient subcutaneous monthly or less frequent dosing, we have potential to bring a truly transformative therapy to the AAT -- alpha-1 community, and we are incredibly encouraged by the safety profile we are observing today.

GSK was early to recognize the potential of RNA editing and our multimodal platform more broadly. Their leadership in respiratory medicine development and commercialization makes them an ideal partner for 006. We also continue to advance our GSK research collaboration programs. GSK has now selected a third program to advance the development candidate following achievement of target validation, which carries an associated milestone.

Additionally, this collaboration enables expansion of our wholly owned pipeline of genetically validated targets, including INHBE for the treatment of obesity. Across WVE-006 and these collaboration programs, we are eligible for substantial milestone payments of up to $3.3 billion and anticipated payments in 2025 and beyond, which are not included in our cash runway.

Our data with WVE-006 continue to demonstrate the clinical translation of our RNA editing capability, including safety, greater than 60% edited protein and consistency across patients and impressive durability. Beyond 006, we are building a wholly owned editing pipeline, which leverages these learnings.

Our next expected clinical program is PNPLA3, a GalNAc RNA editing program with the potential to address 9 million homozygous I148M carriers in the U.S. and Europe with liver disease. We have shown that RNA editing has the potential to be a superior approach to siRNA knockdown in liver disease patients with this genetic background due to the important role of wild-type protein. We remain on track for CTA filing in 2026 for this program.

Beyond 006 and 007, our siRNA program for obesity, we are continuing to advance a wholly owned discovery pipeline addressing hepatic as well as extrahepatic targets, and these programs utilize our proprietary chemistry to achieve best-in-class RNA editing and siRNA silencing in both rare and common diseases.

Last year, we shared preclinical data highlighting our ability to direct silencing and editing to high-priority extrahepatic tissues, including CNS, skeletal muscle, adipose, heart, pancreas and lung.

We look forward to providing a further update from our emerging pipeline at our Analyst and Investor Research Day this fall. For over a decade, we've been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health. Today's results accelerate the already strong momentum of our best-in-class pipeline and the strength and differentiation of our platform, which continues to translate in the clinic.

Building on today's results, we expect to share data in the first quarter of 2026 from our ongoing 400-milligram multi-dose cohort, which is evaluating a monthly dosing regimen.

In addition to our strong progress in AATD, our INLIGHT clinical trial in obesity is off to an excellent start. We've expanded and completed dosing in our second cohort, which evaluates a 240-milligram dose following favorable safety and tolerability as well as robust Activin E reduction observed in Cohort 1.

We remain on track to report data from the expanded Cohort 2 and data from Cohort 1 in the fourth quarter of 2025 as well as data from Cohort 3 during the first quarter of 2026.

Before turning the call over to questions, I would like to take a moment to thank all individuals participating in our RestorAATion clinical program, the clinicians involved and the study staff. The patients we serve inspire the work we do every day and from everyone at Wave, we'd like to express our sincerest gratitude.

And with that, I'll turn the call over to the operator for Q&A. Operator?

[Operator Instructions] We'll take our first question from Joseph Schwartz with Leerink Partners.

Congratulations on these groundbreaking results. I was just wondering, does it seem like there's an asymptotic set point above which it's hard to drive M-AAT, AAT protein levels when it's not needed? And why do you think that is? And how do your models predict repeat dose 400 milligrams will work? Will it push the envelope further or push on a string?

I think, it's a great question, Joe, and I appreciate the fact that we're actually going to be able to observe this over time in addition to the dynamic response rate.

So if we think about total AAT, it's a composition of Z, which obviously with editing would be expected to decline, which is what we saw. And M protein, which these patients don't have, increases. And we do see that over time, so with longer exposure, the proportion of M-AAT and serum does increase. And in fact, at higher doses, that M-AAT increases. So yes, we do think there's still a drive and more continued work that will push the M-AAT protein higher, both with time as well as increased exposure.

What that is separate from? And I think this is really the unique aspect that we demonstrated today, is the dynamic response rate. And this speaks to having more substrate to edit. So what we learned today based on being able to observe what happens during an acute phase response, is during that response, you have an increase in transcription. So there's more transcript to be edited.

It tells us that we've got ample drug inside the cell with a catalytic enzyme with which to be able to edit. And so it's not substrate bound. So if there's more substrate to be edited as in the case of the acute phase response, we can continue to drive that editing higher to meet the challenges as we saw getting up to 20 micromolars where it's required.

I'll ask Chris or Erik, if there's anything else to share.

No, I think, Paul, you summarized it very nicely. I think the only additional thing to say is that, I think we, as a field, need to kind of move away from this threshold at baseline. And I think we're up over that threshold here already with the lowest dose. But the most important part is to have a physiologically dynamic response to insult when it's needed. So it's basically when AAT is needed as an acute phase protein, it can respond and go up to very high levels.

I think, just to piggyback on Erik's last point, because I think it's an important one as we go through Q&A is, is this notion of what's the therapeutic treatment for AATD. And I do think, the field comes at it with this concept of IV protein replacement therapy, to Erik's point on baseline. And this notion that if you infuse and sustain this kind of basal level, then it's there when you need it and needs to be at this threshold to melt the response.

Again, I think the data that we demonstrated today, which demonstrates actually that you can rise to meet the occasion wherever it is to drive down and protect during exacerbations is the key therapeutic treatment for alpha-1 antitrypsin patients. I mean, that is the functional -- that's how you want to actually drive a response is being there during these acute exacerbations to meet that need and taking ZZ patients who are non-responsive to these acute phased responses and now turning them to MZ heterozygous phenotypes to mount that response is huge in terms of the treatment goals.

Our next question comes from Joon Lee with Truist.

Congrats on the data. Given competitive dynamics, including those from base editing, prime editing and gene writing and some questions around the levels of M-AAT, do you have any plans to assess clinical outcomes to potentially differentiate from a commercial standpoint? And also, as a quick clarification, in your Cohort 2, how many actually had both liver and lung manifestations or one or the other? Just wanted to understand the baseline characteristics in terms of the liver versus lung patients.

Yes. So on the last one, and I think it's an interesting question to your point on how -- ultimately, what do clinical outcome studies look like. And I think there's no better partner for a respiratory outcome study than GSK with extensive experience in diseases of acute exacerbation in respiratory diseases.

I think that is why they're excited about these data. I think this does demonstrate that ability to mount the response during acute exacerbations, which actually bode well for treating that -- those clinical outcome studies. I mean, if we think about the challenges in the field to date on IV protein replacement therapy and meeting those challenges have been -- if you have these kind of trough levels that everybody is thinking about with a protein that's immediately consumed once you have these acute phase responses, then if somebody were at the trough at a point in time where they actually had an exacerbation that would be substantial like in pneumonia.

You could see that theoretically, you'd consume all of the available protein that would be there to continue to protect the lung. When you have this opportunity, you're not rate limited. The body is making more. They're generating more protein and you continue to meet those responses, which actually bode very well for continuing to follow those clinical outcome measure.

And I think there's a great partner thinking about that development pathway and commercial differentiation down the road that understands the space very, very well in conjunction with us.

To your first question, I'll defer to Chris who can comment on the patient disposition.

Sure. So overall, our patient population had healthy or mild to moderate lung disease as well as liver disease. You can look at the baseline table, and you'll see that there were -- the majority of patients were F0, so didn't have any fibrosis. There were a couple that had F1 and one that had F2 levels. So we didn't really -- we had allowed people into the study that had some degree of liver and lung disease since we don't really see any safety issues with this particular approach. And they all performed well from a safety perspective.

I think the other piece, getting back, Joon, to your question around just in general, the commercial differentiation besides just meeting the threshold levels and saying it's dynamic and it's there. I think, as we think about an opportunity where you've got an infrequent subcutaneously administered GalNAc molecule, so you can be thinking about quarterly, potentially even less frequently based on these dose exploration studies, I think, highly differentiate the program and actually make it very amenable to patients to be able to use that and physicians to be able to monitor patients.

And just a quick follow-up. Are there plans for Cohort 3? And what does Cohort 3 look like in terms of the dose and dosing frequency?

Yes. Obviously, as part of the collaboration, we have a partner who assumes the development on the other side. And so we're working closely with them in terms of the design of that third cohort. But I think it's safe to assume. As Chris mentioned, we've got safety well to cover 600 and repeat dose, I think it would enable us to continue to build out the PK/PD curve, which could continue to support not just more AAT protein, M-AAT protein, but most importantly, derive this frequency strategy where we better understand the pharmacokinetics in terms of how infrequently do we need to administer this to mount a substantial response.

The next question comes from Salim Syed from Mizuho.

Congrats on the data. Just one for me on Cohort 3. Paul, Chris, do you guys feel -- Erik, do you guys feel like you have what you need here in terms of total AAT and AAT, just especially now given what we understand with the acute patient data? Or are you more focused on durability or still pushing the actual levels here of AAT, M-AAT?

And then just related to that, just kind of with what we understand now with this acute patient data, it seems like we're still trying to understand the biology. Is there any room in the protocol here to add an additional cohort if you feel like you need to for the -- all time?

Yes. I think great question, Salim. So stepping back, thinking about the treatment goal, at the outset, the treatment goal on MZ was could you cross the 11 micromolar threshold of total with greater than 50% M protein. So we had 12 micromolar with over 60% edited M protein. And that's still dynamically going up as we see time and the potential to increase dose.

So if we think about that and, and I think the end is very important, the dynamic response, which is actually the biology of the disease. So it's not an interesting finding between it. It's actually one of the important drivers in the disease. In fact, part of the differential diagnosis for the disease, if you see an individual patient who comes with a spike in CRP, but doesn't have a corresponding elevation in alpha-1 antitrypsin deficiency, then part of that differential diagnosis is alpha-1 antitrypsin deficiency. So these are tightly linked in the literature and as part of clinical practice.

And so, I mean, as the KOLs we talk to, have been talking about this being an opportunity for a long time for editing. I think they've been extraordinarily excited to see these data. As we think about those subsequent cohorts, they do give us the opportunity to do two things.

One, continue to explore that dynamic range of total and M-AAT protein and what happens on those dynamics. But most importantly, as you point out, allow us to continue to explore the pharmacokinetic profile. I don't think, given what we're modeling out quarterly or less frequently as we get to that third cohort, anticipate a need for any additional cohorts beyond that, because I think we'll have flushed out the dose range finding in terms of optimizing that dosing frequency across those 3 cohorts.

Our next question comes from Samantha Semenkow with Citi.

This is Benjamin Paluch on for Sam Semenkow. Recognizing that it's only a nano 1 with the patient that had the acute phase response, do you think the levels achieved with that patient could be sufficient to support approval?

It's a wonderful question. It's hard to contemplate approval. Obviously, above 11 micromolar and that's consistent there. I think it demonstrates that one can get there. I think, the key is continuing to explore the total profile. But to your point, while it's one patient, that's the one patient that actually represents the dynamics of the disease. And so being able to see what happens when you have an acute phase response, how ultimately do patients achieve and being able to not just achieve an increase, but a substantial increase. 20 micromolar is the lower limit of what you see in an MM patient is consequential.

And so that ability to continue to explore that and obviously, with our collaborators in GSK who are thinking about not just the regulatory framework, but importantly, ways of elucidating, we keep talking about pushing the dose higher to explore total. There's also this effect of what's that dynamic response and how much this -- we saw that shortly after, so a patient leaves the office, they're more or less protected from those acute exacerbations. That's what you want.

Given that, that was at the lowest single dose, and again, we're just at the beginning of the study, and able to mount a response of 20 micromolar, I think, really speaks well to editing and that editing is highly efficient. The drug is highly stable. So let's just think about the totality of the program and really exploring what do you need to have that response. And I think 20 may just be the floor. Again, this was a modest response in the kidney stone on CRP. If this were a pneumonia infection, you'd expect those CRP levels to be higher and therefore, with increase in transcription actually drive higher levels of AAT protein. So it's interesting to continue to explore.

Our next question comes from Roger Song with Jefferies.

Congrats for the data as well. Just a little bit more on the dose response from 200 to 400. So very helpful to have the spider plot for the 200 SAD and the MAD patients. As far as I can tell, so since the 200 SAD is the mean peak is driven by two patients. So just curious how consistent for the 400 SAD, because you didn't give us the plot. Just want to understand a little bit about the dose response from 200 to 400 on the SAD population and the MAD.

So I think, from the 400-milligram SAD perspective, we did see quite consistent responses. We haven't broken it down in terms of the individual responses at this time, but I mean, I think what you can appreciate is, if you remove the one outlier, which we're talking about that had the acute phase response, the SAD max comes down slightly.

So you see more of a dose response, which is probably representative of the 200 versus the 400. So I mean, the 400 is already higher from the M protein production perspective. But if you adjust the SAD from 200, as I mentioned, you see that, that's a bigger gap. So again, we didn't want to sort of pull data points out and things like that. But if you sort of look at the data and understand that outlier and sort of look at the mean without it included, you do see a bigger step-up with the M-AAT with 400. And so we anticipate when you take 400 and go into a multiple dose study, you're going to see an equivalent sort of step-up just like we saw with the 200 MAD relative to the 200 SAD.

It is interesting, as Chris pointed out. If you take the M-AAT, and that's the best way of following the protein response with both repeat doses and exposure. You do see that continued increase from the 200 SAD to the 200 MAD and then ultimately, if you rebaseline that the 400.

I think the ultimate goal of what we're seeing is that, that composition within the total protein of M continues to go up. And I think that end is really important. The dynamic response is ultimately what's going to be there to rise to meet the needs of patients when ultimately they have these acute exacerbations. So I think we have both the threshold, as Chris is saying, already, and you can expect to see more from 200 to 400, but particularly important is that acute phase response and being there to meet that need starts early.

And I have to say, and that's why it was important for us to show not just mean plots, but actually all the patient responses. As Chris said, the responses were incredibly consistent. So everybody is seeing editing. And so it does speak to the fact that our GalNAc stable AIMers are delivering to those cells, there's adequate and substantial amounts of drug in that cell to be able to engage the machinery of ADAR. And we see that in the concept of if you put more substrate in the cell, you can generate a lot more protein.

Our next question comes from Yun Zhong with Wedbush Securities.

So I just want to confirm that when comparing data from single-dose cohort versus repeat dosing cohort and the most -- well, the biggest impact is really the increase in M-ATT (sic) [ M-AAT ] protein level instead of total ATT (sic) [ AAT ] protein level. So it doesn't seems to be quite same as what you probably saw from preclinical data and because the mouse continue to show increase in total ATT (sic) [ AAT ] level as well. And is that a correct observation, please?

Yes. I mean I think if we step back and look at these data with M protein substantially increasing, Z protein substantially decreasing, that is the definition of what editing is supposed to do, right? Editing is derived to take the substrate that's inside the cell and correct it from Z to M. And so we see highly efficient, highly durable editing.

I think as we look between the mouse to humans, we have to think about some of the implications of where those models are in terms of what the substrate available for editing is and knowing that we've got a stable durable construct that in the animal model could drive that and see, as you said, we could continue to see more.

Now I think what's important here on highlighting what we can continue to see over more is we do believe that the trend in total, the trend in M should increase over time, like we saw in the model. The model in mice is obviously, I would say, mice are faster. So the time horizon is more expedient.

But what we saw in the mouse was that actually we decreased aggregates in the liver. So again, demonstrating now Z protein substantially decreasing means we should be decreasing aggregates and build up in the liver. That creates healthier hepatocytes. Those hepatocytes should be more functional in terms of producing protein. You get rid of the residual Z polymers. And so essentially, the process gets more efficient. That's what we saw in the mouse model over time.

And given that what we see now in patients, which is this decrease in Z, substantial increase in M, it's reasonable to expect that with time too, those same features take place, right? You're improving ultimately hepatic health.

Great. Would you expect a higher editing efficiency, say, with the 600 milligram?

I mean, that's exactly right. Yes. As we say, the difference between M, even between single and multi, the amount of M, that's the editing efficiency. Edited protein goes up and continues to go up over time. If we stop the study to do follow-up, and it was still trending. So if we see, again, at the 400, we have another opportunity to see with multi-dose continued trend on editing going up on M protein. And as you said, 600. I think that's the piece to follow is that editing efficiency over time with them.

Our next question comes from Catherine Novack with Jones Trading.

Can you hear me?

Yes.

Okay. Great. Just trying to think about what is the scope of this study before turning the program over to GSK? Obviously, you mentioned most of the patients were F0. But if there's a handful of patients who have some liver fibrosis, would you have the opportunity to look at improvement so that we can kind of get beyond this focus on biomarkers between RNA and base editing and really look at some clinical outcomes?

Yes. I mean, so if we think about the totality of the study, the study is designed to be that exploratory Phase I/II study that's going to give us insights into the biology. I mean obviously, today, we opened up a whole new portion of biology for actually treatment of NZ patients as it relates to response during those acute phase responses.

But as you point out, with having patients where we didn't have to exclude patients with pre-existing liver disease, gives us opportunities, new biopsies and others over the course of the study to be able to do additional work as we evaluate patients through the cohort and particularly as we get to the highest dose cohort. So we're in the middle dose now with the 400 monthly, one more higher dose to explore that, that just evaluate pharmacology and frequency, but it also just gives us an opportunity to continue to gain insights into what's happening in the liver and with editing. So I think it's set up for us to be able to explore that.

Our next question comes from Madison El-Saadi from B. Riley Securities.

I just wanted to ask, why go from 200 mg biweekly to monthly in the 400 mg arm? Just wondering what drove that decision? And should we expect monthly dosing in the higher dose cohort? Or has that decision been made yet? And then secondly, I guess maybe what's really driving the temporal change? How much of this is GalNAc pharmacodynamic related versus editing efficiency related?

Chris, I can take the first part of that question. So based on the data that we've seen to date and as I've showed earlier today, there's quite a long tail to the editing. So in the multiple dose after you stop dosing, we have great editing continues to be 50% edited out to 2 months after follow-up. And we also have our 400-milligram single-dose data.

And so using that data as well as some of the modeling, that supported moving forward with the 400-milligram dose on a monthly basis. And we -- it's possible that we could have even less frequent dosing based on the PK we're seeing. So that's part of the reason why we want to go forward with that 400 once monthly dosing, and we'll consider what to do in that third cohort as the data comes in that might help us to support less frequent dosing than once monthly.

I think the second part of your question just builds on that, which is GalNAc is efficient at drug in, right? It gives us highly efficient drug access to the cell. But it's all of the other chemistries that we've been driving as we think about PN and stability that allow us as for repeat dosing to have substantial amount of stable, durable drug inside the cell with which to continue to edit. And so that allows us to have two things.

One, that durability and that less frequent administration over time, because you're actually continuing to accumulate. I think even as we get monthly, we'll continue to see that as we saw with M protein continuing up between just the 200 SAD and MAD. I think, it's going to be interesting with more drugs sitting there.

But most importantly, and kind of getting back to this dynamics question, it's the fact that the uniqueness of the stability of the drug that's in the cell, right? Because if the drug wasn't stable, it wouldn't be there to meet the acute phase responses when they happen. But having really stable drug infrequently means that the drug is in the cell, it's poised to engage both the enzyme and a transcript in terms of editing. And so it can rise to meet that occasion wherever it comes. And so it really does get back to the chemistry beyond just GalNAc that gets you in that drives that stability, the durability and ultimately enables the dynamic response.

Our next question comes from Steve Seedhouse with Cantor Fitzgerald.

Congrats on the milestone of really successfully translating safety, efficacy and consistency, it looks like of RNA editing into the clinic. I had actually two quick questions. First, can you comment on the LC-MS assay for quantifying AAT, the rationale for implementing that, sort of when it was implemented? It looks like that's potentially new based on the LLOQ. And then also, can you clarify or confirm if the acute phase response patient was one of the first two that were treated in the 200 mg SAD cohort?

I'll take your last question, and Erik will take the first question on the assay development. But yes, the patient with the acute phase response was in the initial patient.

Yes. And on the LC-MS assays, we -- it's correct that we have -- we didn't have the C assay developed in the fall. So that's a new addition. And we have moved to M and C assays because they're highly sensitive and also highly specific.

As we presented in one of the slides, the limit of quantification is very low, below 0.1 micromolar. So they're highly sensitive. And that was a move that we made because the turbidimetry assays, that way of measuring total AAT is -- has a lot of disadvantages. It's actually not at all sensitive. It's 10 to 100-fold higher LLQ. It's also designed for healthy individuals. It's known to underestimate C levels, because it's an immune-based assay that doesn't really see the epitopes. So for all of those reasons, we went for a highly sensitive and specific M assay and C assay with MS -- LC-MS.