Denali Therapeutics Inc. Stock

Good afternoon, everyone. I'm Sean Laaman, Head of U.S. SMID-Cap Biotech Equity Research here at Morgan Stanley, and welcome to our Global Healthcare Conference. Before we begin, make you aware of some important disclosures, and for those disclosures, visit our website at www.morganstanley.com/researchdisclosures. If you do have any questions, please reach out to your Morgan Stanley sales representative.

For this session, we have the pleasure to host from Denali Therapeutics, their CEO, Ryan Watts. Thank you, and pleasure to host you.

Great. Great to be here. Yes.

A couple of macro questions to begin with, Ryan. We were just debating it then, like how's the rise of China-originated innovation changing, if at all, your competitive positioning and your R&D and BD playbook?

Yes, I mean, I think that it's a great question, and it's a relevant question, and it's a question that we ask at really 2 levels. One is a biotech community, and specifically here in the U.S., how do we view China from a competitive perspective, and then, in our case, talking about it around invention and the blood-brain barrier specifically. And I think there's varying views, and I often refrain from talking too much about my general feelings about either politics or regional considerations, but I will say that my general impression is that competition is almost always considered, in my opinion, a good thing, because it will ultimately lead to the very best medicines for patients and the more competition there is, the more invention there is in order to either stay ahead or to find the next best medicine. And that's ultimately who wins in that category are the patients.

Now, as a company, you view it a little differently. You'd love to be on an island and have a technology that no one else in the world has. And that technology is essentially needed and no one else can access it. But that's not how biotech works. We all live in this biotech world and when something shows promise, almost everyone starts pursuing it, from Big Pharma to mid-sized biotech. Even academic labs will start going into it. And that's when I look back 20 years ago, when we started working on blood-brain barrier, there was essentially very few or no one working. There were a couple of academic labs and some obscure companies that were working on blood-brain barrier technologies.

And so we picked this up 20 years ago, this is prior to the founding of Denali, and just made everything that was in the patent literature and that had been published and asked do any of these technologies get medicines into the brain. And usually what happens is if there's not a lot of people working on it, what was first published doesn't really work. And people tried the same thing. They made it, it didn't work. That's not where we are today.

So with blood-brain barrier technologies, you're now seeing the first FDA-approved medicine in AVLAYAH, which we launched earlier this year. You're seeing exciting data in Alzheimer's disease where you can take a standard antibody and put a blood-brain barrier technology on it and get 3x faster plaque reduction.

And as a reality to that, everyone's going to start pursuing it, including in China. And the question is how to stay ahead, how to continue to invent. But I think importantly, when you're pioneering a field, it's important to really lay that solid foundation with great science, but recognize, you should feel the competition, but if you don't have competition, you're probably going in the wrong direction. My expectation is that China's competition is just going to heat up, including in the blood-brain barrier space, and I think ultimately it should be great for patients.

Moving on to another macro consideration, AI adoption. So how are you adopting or implementing AI in your business? And is there an example you can give us where it's changed a decision, a cost, a POS on a program?

Yes -- so, yes. I mean, it's a timely question as AI starts to take over the world, even in an unmonitored way. We, I think like many, have started to experience the absolute value and efficiency, and in some cases accuracy, but really efficiency of AI. And I think the most important thing is to take repetitive tasks or tasks that may be prone to bias and implement AI in that context. You can do that in the preclinical setting. You can do it in the clinical setting.

I know for me personally, I use it all the time in terms of my analysis. I actually sometimes like to compare or even compete with AI to see do I have the ability to still make those independent decisions that maybe my project in Claude couldn't make. And the reality is it's extraordinary. It really accelerates the mundane. I don't know yet if it's going to accelerate the actual fundamental discovery. And part of that is because you need the data to train it, and biology's complexity is such that I don't know if we have enough data to really train to have that independent thought.

But that doesn't matter. Like in our world, especially in the world now we have a proven platform and that platform we need to apply. So application with example is a great place to use AI. So we use it in all aspects of our business. In fact, we reward it, we accelerate it, we find any way we can use it. But I think there are areas where it's more advantageous than others and I think it's really those repetitive tasks where you're looking for consistency.

Sure, and I'm asking these questions across all our companies, but this last one is probably very interesting for you, particularly because Denali just crossed that threshold from being clinical to commercial stage. So which policy variable, is it FDA, Medicare negotiation, MFN, tariffs, or global pricing matters most to your economics? And what have you changed, if anything, because of it?

Yes, I think, in some ways, I want to say that we had the foresight to do this, but maybe we did, maybe we didn't. But we decided to onshore manufacturing in the U.S. And part of it is, if you look at the cycle of invention and application across biotech, it was the case that we -- everyone externalized manufacturing. I mean, why you build your own manufacturing? It's expensive, it takes time.

And what ended up happening is what used to be inexpensive and super efficient to outsource manufacturing has become extraordinarily expensive because when those are made available, what happens, those companies are trying to really maximize their margins in the way that they interact with biotech. And so we made the decision now 4 years ago to onshore manufacturing. And I think as a result, something like tariffs really matters because you're buying raw material and you want to do -- and so you're looking for obviously a paradigm in which you can reduce costs.

And it's been great for us. I think the flexibility, the speed, and what we manufacture, which are biologics, which -- there are many CDMOs that do this. Ours are actually fusion proteins that are unique. We end up having to build our own parallel teams for process development for AVLAYAH, our first product launch. It was just much easier for us to bring that in-house, and I think we're at a point where it's an advantage to do your own manufacturing, I think, here in the U.S.

Sure, thank you. And onto Denali-specific questions, but of AVLAYAH, a year ago it was pre-commercial, now it's been launched. And what can you tell investors about, it's the first TransportVehicle therapy for neurological symptoms in Hunter, but what can you tell us about the differentiation to the standard of care and why you think there will be ultimately a displacement of the standard of care with AVLAYAH?

Yes, so I think it's important first to describe briefly Hunter syndrome and what the standard of care is. So Hunter syndrome is one of many mucopolysaccharidoses or MPS diseases. It's a monogenic disease, a loss of enzyme function and what happens is lysosomes become dysfunctional. It's a lysosomal storage disease. And now I think 30 or plus years ago, it was discovered that you can take these lysosomal enzymes, you can manufacture them, and you can inject them systemically and a fraction of what you inject gets taken up into cells. And starts to restore lysosomal function. These are the enzyme replacement therapies. And it's been decades since that was discovered.

And this was a really important class of medicines. But the challenge with all of those enzyme replacement therapies is that they cannot access the brain. So of the totality of MPS patients, 70% of them have some type of neurologic dysfunction. It's probably greater if you include hearing. It might be as high as 95% have some neurologic manifestation. And so the standard of care does not cross the blood-brain barrier. These enzymes don't get into the brain and hence there's this big unmet need.

And I'll just give one example. So in Hunter syndrome, about 70% of patients upon diagnosis have neuronopathic disease. So they have complete enzyme loss of function. And those patients on standard of care will live on average to about age 15. So they'll initially learn how to walk and talk, and then by age 5, 6, 7, 8, they'll lose the ability to walk -- or sorry, lose the ability to talk, some will be able to walk and have other dysfunction, toileting, and that's on the standard of care. And the reason is that the nervous system is degenerating.

In the case of Sanfilippo, which is another disease we're working on, that degeneration is super rapid. It's like Alzheimer's of childhood. It's a very rapid neurodegenerative disease. And there, there's actually no standard of care because basically it's a neurologic disease and the standard enzymes don't get into the brain.

And so ultimately what AVLAYAH is engineered to do, it's hitching a ride with an iron transporter. It can treat the whole body, that's important, so we replace the standard of care, but it crosses the blood-brain barrier addressing the neurologic manifestations of disease. And I think the data that supports that was published earlier this year in The New England Journal, and obviously that went into the broader context of the filing with the approval in March and now the launch of AVLAYAH.

And maybe talk about when the neurological deficits start associated with Hunter and the optimal time for intervention. And you mentioned patients living to 50 (sic) [ 15, ] but I imagine that the earlier the intervention, the better the long-term outcomes. And that data will play out over time.

Yes, so I think that's -- you nailed it, which is earlier is better. I think our data shows that. In fact, we presented data recently that shows neurofilament, which is a marker of neurodegeneration. If you intervene early, the NfL goes down more rapidly. If you intervene later, you still get normalization, but there's a delay in the time before you actually halt the neurodegeneration, probably because there's a lot of neurodegeneration that's happening.

But I think, again, without newborn screening, which is really where we got, we have to go, we have to go as a country, newborn screening for all of these diseases, especially have medicines that can really impact. If you're getting diagnosed at age 2, usually it's ear infections, there's changes in like skin features and facial features. But the newborn screening is the way to go.

And when we think about the AVLAYAH launch, you know, most of our patients right now are switching from standard of care to AVLAYAH, but there are a percentage of patients that are newly diagnosed. And even better if they come out of newborn screening and can start taking this medicine in their really early life and hopefully have a normal life.

Sure. And as the, I guess, newborn screening proliferates, do you think estimates of the epidemiology may go up, or do you think that it's a fairly well-observed disease?

I think it's well-observed, and the reason for that is that eventually patients get diagnosed. Hunter is a very severe disease, and so you'll miss it, but by age 2, 3, and sometimes even 4, and maybe in the attenuated patients a little bit later, but -- it's diagnosed. And even on standard of care, just restate that at 15 years of age is the average lifespan of someone with severe disease. So that's happening. I don't think you're going to see the numbers go up, but we hope that the prevalence goes up because this medicine will have a big impact on life and other aspects, not just neurologic, which is a big piece of that.

And so far we've seen a Q2 revenue, I think, was about $3.6 million. You've guided to Q3 at $10 million to $12 million. Of that $10 million to $12 million, you know, are you able to tell us how many patients are new starts versus reimbursement conversions, if that question makes sense? And what particular rare disease, I imagine you have a pretty good hold on how the revenue is going to look for quarter-to-quarter as you get to the end of the quarter, if that makes sense.

Yes, let me just -- I'll ask a question just to make sure I get it exactly right. So new starts, meaning also including switches from ELAPRASE versus those that convert from the Phase I/II trial.

Correct.

Yes, okay. I mean, right now, the vast majority of our patients are all new starts. Our goal is by end of year to switch patients on the Phase I/II trial to commercial. So that's going to happen over time. But really out of the gates, it's new starts. And so I don't really have a percentage on that. And we did something a little bit unusual. We guided to revenue on a quarter basis. We thought of all the different metrics that are useful. And it's a little complicated in Hunter syndrome because there's, it's weight-based dosing. Obviously we have a dose escalation.

And the simplest thing is that we just, to take away that mystery, we guided towards what we think will be revenue in Q3. We'll likely do the same in Q4, and then we'll reassess what we're going to do for 2027, but obviously this is a great starting point for us. I think really importantly here is this is not a single product story. It's really the platform that has been validated by this product, AVLAYAH, and its now application across many disease areas.

And so we think that the commercial execution is critically important, and we can build an enzyme franchise that will create a lot of value for patients, and obviously for Denali, and hopefully for shareholders. But in reality, those these numbers don't really matter today, it's can we execute? And I think for us what's been really exciting is to see that commercial team execute. It doesn't have to be a big team. It's an ultra-rare disease. And certainly with the label the way that it is, we're in, I think, a really strong place in the initial launch of this medicine.

How should we think about the shape of the launch into 2027 without drawing on specific numbers? But do you think it's going to be kind of a rapid conversion of a prevalent pool or a sort of slower ramp over sort of 4 to 6 quarters?

Yes, we don't -- it's actually early innings, so we don't know how that's going to look. I'll tell you what our dream is. Our dream is to try to hit a plateau as fast as possible.

Sure.

We want to get as many patients in the U.S. on the medicine. We then want to work on the next 1/3 of patients outside the U.S. that can benefit from, I think, this transformative medicine. The final 1/3 is probably going to be unlocked with our COMPASS trial as we think about Europe in particular, and I think there that's as much about reimbursement as anything. And so our goal, the S-shaped launch in part is not the patient starts as much as it is dose escalation and growth and as you see a broader range of weights on drug.

And maybe thinking about some of the prescribing dynamics behind AVLAYAH, and I think there's more than 50% of commercial lives and 14 state Medicaid programs now have coverage. What's the typical time frame for from treatment to first infusion? And where does the access still break down, if at all?

Yes, so the short answer is it's variable, obviously from state to state and from clinic to clinic. And I think the 2 most -- I mean there's really 3 components. One is everything we can do to assess, but there's a limit to that. It's really the physician and the families that drive. And that's been probably the most inspiring thing to see in this community, is the drive to get these young patients, these young boys on medicine, driven by their families and the physicians. And so we don't like -- again, early innings, we don't have, and I don't even know if it's relevant, the revenue is ultimately what we calculate, but it's been exciting and inspiring to see that level of motivation to get access to medicine.

Sure. And I think you've mentioned 375 eligible U.S. pediatric patients, out of a potential of 500. So where's that other 25%? And what's the realistic addressability of the market?

I mean, the other 25% is essentially adult. And if you think about the prevalence of the 500 patients, the long-term, you start to see that shift from 70% neuronopathic to 30% attenuated to then about 50-50 because the attenuated patients live much longer. So that's where the other portion of patients and they're obviously -- they're not covered by label, a lot of interest from that community and there we hope to unlock that with the COMPASS trial data.

Sure, and maybe talk us through the conversion from ELAPRASE. How does that dialogue go?

Yes, so I think the conversion from ELAPRASE, I mean, number one, you go back into the clinic. That's the process as you go through the dose escalation process. The 47 patients that were on the Phase I/II trial, those patients eventually are now at home infused, and that's the goal, so you go back to the clinic. And that, we had assumed, would probably be a barrier, but the motivation, again, from families and physicians to see the benefit that AVLAYAH can offer, treating the neurologic manifestations.

And part of that is just making sure we get to the optimal dose. And we just haven't seen that as a big barrier. Now, there are probably going to be some patients that are less severe or families are not as motivated as they've kind of hit a comfortable position of where they are. And that's, I think, where there'll be work to be done.

Okay. And still thinking about some of the launch dynamics. How concentrated is the prescriber base, Ryan, and how many treatment centers are needed to reach most eligible patients?

It's pretty concentrated in sort of what we call centers of excellence in different parts of the United States. In fact, often families will relocate to be adjacent to those centers and, and so that's critical. Many of them were involved in the Phase I/II trial, have a lot of experience with AVLAYAH now. And then there are other areas where it's less so, and that's where work also needs to be done. It also comes down to how connected the families are with the MPS community. But I think we've estimated like 80 to 100 centers of excellence, of which we know many of them and engage with many of them. That includes also worldwide, but it's pretty concentrated.

Sure, and on worldwide, I think you've estimated 2,000 patients.

Right.

And what's the ex-U.S. filing sequence? And does COMPASS gate those assumptions?

Right. So again, if I look at the entire Hunter market, I think of the U.S., I think of Europe proper and then rest of world. And you can access most of rest of world now, and we're in that process of doing that with the data from the Phase I/II trial, with the accelerated approval, and with Europe it's going to be unlocked ultimately with COMPASS. And so really like 1/3, 1/3, 1/3. And why do we have that type of visibility? It's because there's a standard of care for the last 20 years, and we have an idea where that medicine is prescribed and where it's used.

Sure, I do have some AVLAYAH, more AVLAYAH questions, but I want to skip forward, giving said validation of the platform, I want to make sure we get to some of these other programs, given we've got 13 minutes. So on DNL126 in Sanfilippo. So TransportVehicle platform, you know, has its first validation. So how should investors view Denali now? Is this a single asset launch story or biologics delivery platform for new medicines with scale?

Yes, so this is zafinofusp alfa, or as what we call zafi, so we have its generic name. Simple, we have tivi, now we have zafi, tivi is now AVLAYAH in terms of its commercial name. So zafi is, you know, we've presented 8 patients worth of data at WORLD this year. Those 8 patients were really dose finding and it was really insightful because unlike Hunter, there's no standard of care. So this is the first time that we're really exploring and we can't really use a standard looking at what's out there.

We explored every-other-week dosing, frankly, to be optimized for patient families. And what we discovered is that actually weekly dosing is much better tolerated than every-other-week dosing, and that's because it's an enzyme, and these patients have no enzyme, and enzyme replacement therapies, you have to build tolerance, so you need drug on board. That was point #1. You can look at, like, the study design, the way that we presented it at WORLD, and this is some detail that wasn't really expressed at WORLD, but I think it's really interesting.

In addition to that, we can drive a better dose with that weekly dosing. What we're able to achieve is greater than 80% reduction in CSF heparan sulfate. Patients can achieve normalization. Those that don't have, like you see with most enzyme replacement therapies, anti-drug antibodies, and so modulating that is, I think, a key aspect. We also see that 6 out of 7 patients had normalized GM3, which is a downstream biomarker.

And so those are the 8 patients that allow us to really think about the dosing regimen and the dose. We then expanded to an additional 12 patients. Those patients are completing the 49-week now. And then we go through the -- and that was all pre-specified with the FDA, as we thought about how heparan sulfate as the biomarker to drive accelerated approval. So this program was selected for the START program. We engaged with the FDA quarterly in defining the path for approval for this medicine. And now we're in the process of like officially locking the database, going through that process, preparing for the BLA filing. And we look forward to sharing new data at WORLD next year, which is basically the additional patients on that trial.

We then also plan to launch this medicine from our own commercial manufacturing in Salt Lake City, so this is part of what we were talking about before, one of the biggest factors for us building our own commercial -- our own manufacturing, that will be the rate limiting step for the BLA filing, but we're looking forward to 2027 and filing on zafi.

Right, I think you've just answered my next question, but I'm going to ask it anyway just to make sure I got it. Produced an 80% -- on 126, produced an 80% reduction in HS in the CSF, but does AVLAYAH materially de-risk the accelerated approval process in Sanfilippo A, or must the FDA independently validate the surrogate in the disease?

Yes, so I think for the surrogate itself, heparan sulfate, and the belief that it's reasonably likely to predict clinical benefit, that's really solid. I think what the FDA does is it reviews every application independently, right? And so the precedent is very important. I think it substantially increases probability of success is using this biomarker, including in Sanfilippo. And the FDA got that. I mean, you can see what's happened over the last 1.5 years.

I mean, I love sitting on this stage today versus last year and all the uncertainty as we're thinking about the path to approval. But our review division has been fantastic. They're rigorous. We spent probably 3 years arguing why heparan sulfate and CSF actually would be reasonably likely to predict clinical benefit. And it was, frankly, the community that came around, and the community being the treating physicians, families and gathering with the FDA to say this is why heparan sulfate is the biomarker to predict clinical benefit.

So that foundation is laid. And so I think the future for zafi is just defining the clinical, the to-be-marketed dose, getting the data, showing that, and then designing it. Importantly, and now very soon beginning our Phase III trial to confirm efficacy. So that's going to be key. I think that's the bar that the FDA holds, and we understand why that's the case.

Sure. And just a question on the competitive positioning. So UX111 could establish a one-time gene therapy ahead of a potential launch of zafi. So how do you think about the competitive positioning of zafi?

Yes, so just to restate, there are gene therapy competitors in Hunter and in Sanfilippo. What's unique about this particular gene therapy is it's delivered systemically, not to the brain. And we just feel like there's going to be unmet need even on gene therapy, so there's probably room for multiple, and that's how we thought about it with Hunter as well. Part of it is heterogeneity, but also we have biomarkers, and the biomarkers can tell us are you really driving robust CSF reduction. And if you are, great, but if you're not, we have this medicine that can really drive that with zafi.

Okay. Great, thank you. Moving on to OTV:MAPT and ATV:Abeta programs, which are super exciting. But AVLAYAH validated the TfR-mediated transport for enzyme in a lysosomal disease? What does that generally de-risk for oligonucleotides and antibodies in neurodegeneration? And what remains target or modality specific?

Yes, so I think that the blood-brain barrier -- if you look at the history of blood-brain barrier discovery, it was 1989 when the first paper was published using a transferrin receptor technology to get a medicine in the brain. And now fast forward to 2026 to the FDA approval. I mean, it's -- I don't want to say it's embarrassing. I don't even know what I was doing in 1989, but that's not unusual for drug discovery and drug development. It's a long road where you're really defining the right properties to drive this.

And so I think in many ways, that FDA approval is, it very much just unlocks the field of BBB, back to our original question around competition. Everyone's going to start going after it. We already see that, we already know that. But specifically for the TransportVehicle, it's very important to now go after other targets. And we're, I mean, we have an endless number of exciting targets to use the TransportVehicle for. First, it's in enzymes, now it's in Alzheimer's, and there are many others that there's interest in, and we can do that in different ways. We can do it through partnerships, we can do it through small efforts within Denali. There are academic partnerships, and you'll see some of that, and you're seeing that really blossom throughout the field.

But in Alzheimer's disease in particular, we now have a validated approach and we can put it on the antibody. We can put it on oligonucleotide. So antibodies we already know, we've done 1 antibody already, we worked on TREM2 way back when. We saw fantastic biomarker data, like really robust activation at about 1/60th naked antibodies approach. So we know it's going to get in brain. We also know that from some of the Roche data. The oligonucleotides is just the untapped potential. Also highly competitive, because now we know transferrin receptor works and getting these oligonucleotides in the brain will be really exciting. So instead of having to do intrathecal delivery, which has its limitations with bio-distribution and everything that comes along with having to inject in the spinal cord, you can give systemically.

So these are the 2 approaches in Alzheimer's targeting A-beta. People have known about this target. I think 1991 was when APP was first sort of discovered as a gene in Alzheimer's disease. And tau, the other like histological hallmark of Alzheimer's, and those are the 2 targets that we're going after.

Sure, and on those programs, which would you have the high conviction of? And I do believe that we're going to see data for both programs next year.

That's right.

And what data would you be looking for to justify broader development? Development of either?

Yes, so these, the data next year is around dose. It's like what's the right dose to engage the target. So in one case we want to remove amyloid plaque, in the other case we want to reduce tau expression. And I mean, I think no one would argue with me that right now the clinical data points really strongly towards amyloid as being a positive target. Now, there are some people that still question. I think prevention is going to be key, early intervention, removing amyloid before you have cognitive decline is going to be key.

But the way that the data plays out right now is that it appears that plaque forms 20 years before we have cognitive decline. And then you start to see tau pathology rise and it rises several years and then its pathology correlates with cognitive decline. So it seems that A-beta is upstream and it in many ways accelerates tau spreading histologically.

And so they're both, I think, very promising targets. And I think much like a lot of disease areas that are complex, like cancer and otherwise, going after multiple targets. And the way I describe it is that A-beta is the trigger and tau is the executioner. And they both will be important targets. You need to get rid of the trigger. You need to get rid of the executioner. Then you have a set of accelerators or contributors, many of which are like immune modulators, but those are the 2 real hallmark targets.

Sure, wonderful. And moving on to FTD-GRN, which you're calling DNL593, data. Let's move to the first half of 2027 to allow for longer neurofilament follow-up. What would constitute a convincing package, progranulin restoration alone, or do you need NfL movement?

Yes, so we, I mean, I think in this particular program, I'd put in the category of high risk, but really high reward. And part of it is, it's a neurodegenerative disease, but it acts like a lysosomal storage disease from a biological perspective. It's very similar to what we're seeing with Hunter and Sanfilippo in the sense that the biology is a lysosomal biology. There's a set of lysosomal biomarkers. This is a hemizygous haploinsufficiency of loss of 1 copy of granulin, which codes for progranulin, a protein that produces like 7.5 granulins. And the idea is just like Hunter and Sanfilippo, we're restoring progranulin with a protein replacement. And it acts -- frankly, it acts a lot like an enzyme in terms of its lysosomal function.

So there I think the data and the science is pretty clear. The challenge is that it's frontotemporal dementia, which is not Hunter or Sanfilippo. They're a little bit more challenging to diagnose these patients, to say the least. And then it's a genetic subpopulation of FTD. And when we look at the biomarkers, we realize that unlike heparan sulfate that's 10-fold or 20-fold elevated in Hunter and Sanfilippo respectively, the biomarkers in a haploinsufficient disease are much more modest, so like 10%, 15%.

They're not big differences, but NfL is about 4-fold elevated. So this is a real biomarker of neurodegenerative disease. And then our experience with NfL is that it can take time. So you can restore the lysosome, but in 6 months, you're asking a lot to see NfL decline and so we just said, you know what, before we see any of the data, let's focus on a big signal to noise, a high-risk benefit sort of a paradigm. And we can do that. We wholly own the program now. Gives us the ability to make the decision and now we're focusing on NfL as the endpoint for that.

Awesome. So two Alzheimer's programs, one on FTD. What's your thoughts around ongoing internal development of those programs versus partnering with Big Pharma given that particularly Alzheimer's would be big studies?

Yes, and the other program that equally excited about, which we haven't mentioned yet, which is Pompe disease, right? I bring that up just because there is a set of enzymes that we can develop on our own. We now have a commercial team. We can hopefully launch multiple enzymes. I think with these Alzheimer's programs, they're definitely the programs that we've had the most incoming interest, not surprising. These are huge indications. A lot of rationale, a lot of competition, a lot of other cool approaches being taken around, like, you know, blood-brain barrier technologies, and that interest remains high.

I mean, I'd love a world where we're able to launch our enzymes, generate enough revenue, develop an Alzheimer's portfolio, launch in Alzheimer's, that would be brilliant. That would be brilliant for Denali, but I think realistically we will continue to be opportunistic about the right partner. And that partner would have to be someone who shares our vision for the right risk taking and has a set of resources that we don't have. Certainly global is one consideration.

Now, I do have time to circle back to this AVLAYAH question. You may have already answered it. But how does COMPASS support the adult label expansion? And would the current prior to advanced neurological impairment language apply to adults?

Yes, okay. Two separate questions very quickly. So COMPASS has cohort A and cohort B. Cohort A is ages 2 to 6, and it's really focused on the neurologic manifestations. The other cohort is up to age 26, and that's looking for comparability with ELAPRASE. What's certainly the case is that even adult patients that are attenuated have neurologic manifestations.

Hearing, absolutely. And that's some of the most robust data we've generated is looking at hearing benefit. But in addition to that, cognitive decline in those aspects, it's really an area of unmet need. And we're excited to see the data and move AVLAYAH forward.

Well, we're right at time. Is there anything I didn't ask that I should have, Ryan, or a message that you would like to leave the audience with?

Yes, I think I'll just end. For us, the story is our first product, which validates our platform, which drives our pipeline. And that platform is the TransportVehicle. We're very excited to be in this very competitive field and seeing a number of companies explore biologics for the brain, something that was started in the late 1980s, and now we can bring it forward.

Wonderful. Well, thanks for your time today, Ryan, and thanks, everyone, for listening. Thank you.

Thank you. Good day and thank you for standing by. Welcome to the second quarter 2026 financial results and business highlights. At this time all participants are in a listen only mode. After the speaker's presentation there will be a question and answer session. a question during this session you will need to press star 1 1 on your telephone you will then hear an automated message advising your hand is raised to withdraw your question please press star 1 1 again Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Laura Hansen. Please go ahead.

Good afternoon, everyone, and thank you for joining us today to discuss Denali Therapeutics second quarter 2026 financial results and business highlights. Earlier today we issued our earnings press release and filed our quarterly report. The press release, financial tables, and today's presentation are available in the investor relations section of our website. Before we begin, I would like to remind everyone that today's discussion will include forward-looking statements. These statements are based on our current expectations and are subject to risks and uncertainties that could cause actual results to differ materially. Please refer to our SEC filings and the questionnaire language in today's press release and presentation for discussion of these rules. Finale undertakes no obligation to update these forward-listing statements, except as required by law.

Joining me today are Ryan Watts, our Chief Executive Officer, Katie Pang, our Chief Commercial Officer, Alexander Shuth, our Chief Operating and Financial Officer, and Peter Chin, our Chief Medical Officer in Health Development. Ryan will begin with opening remarks. Katie will then provide an update on the U.S. launch of Ablea. Ryan will return to discuss pipeline highlights, and Alex will review our financial results. Peter will join the team for the question and answer session.

Thanks, Laura, and thank you, everyone, for joining us today. We will begin on slide five. This was a transformative quarter for Denali. We completed the first full quarter of the Avalaya launch, advanced to transport vehicle enabled Alzheimer's disease programs into clinical development and further strengthened our financial position. Before I discuss those highlights, I want to begin with why we are here. At Denali, our purpose is to transform life for for people living with serious diseases. That includes children and adults with rare genetic diseases such as Hunter syndrome, San Felipe syndrome, FTD granulone, and Pompe disease, as well as the millions of people living with common neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

Across both groups, our mission is the same, to bring the power of biologic medicine to the brain. Slide six, the common challenge across many of these diseases is the blood-brain barrier. For over a decade, we have built the transport vehicle platform to address that challenge by engineering biologic medicines to cross the blurring barrier through receptor media transport. Earlier this year, that work reached an important milestone. With FDA approval of Avalaya, Denali became a commercial company and began delivering our first medicine to patients. In the Hunter Syndrome community, Avalaya is the first new FDA approved therapy in nearly 20 years and a new treatment option designed to reach both the body and the brain. Importantly, Avalaya became the first approved medicine developed using our transport vehicle platform and the first FDA approved biologics specifically designed to cross the blood-brain barrier.

For Denali, Ablea is much more than a product. It is the first proof that our platform can progress from scientific concept to an approved medicine for patients. Slide eight. We believe Denali today represents a powerful and differentiated combination to create significant value for patients. system and investors in the near and long term. We have a commercial product in Avalaya and an encouraging early launch. We have a broad clinical pipeline spanning rare genetic diseases and common neurodegenerative diseases, each with substantial market potential. We have a validated and scalable transport vehicle platform and scientific leadership in the field of BBB transport. We have the operational capabilities and financial strength to execute from discovery through development, manufacturing, and commercialization.

Together, these attributes positions in OLLI to create near-term growth and sustainable long-term value. Slide nine, turning to the quarter Avalaya generated 3.6 million in net product revenue in its first full commercial quarter. The positive response from the Hunter Syndrome community and the physicians caring for these individuals reflects years of partnership with patients, families, advocacy organizations, and clinicians. We could not have achieved this milestone without their unwavering commitment to advancing new treatment options. I also want to recognize the outstanding execution by our commercial team in the early stages of this launch. In the pipeline, BNL628 targeting Tau and BNL921 targeting A-beta both advanced into clinical development for Alzheimer's disease, with initial clinical data expected in 2027. And following the sale of our priority review voucher in July, our pro forma cash, cash equivalents, and marketable securities exceeded 1.15.

Slide 10. A key focus of today's call will be the Avalaya launch. Katie will walk through the early commercial indicators, what we are learning, and how we are building the foundation for continued growth.

Thank you, Ryan. On slide 12, I'd like to start by reinforcing why we believe Avalaya is setting a new bar for the treatment of MPS II. For the first time, a therapy is designed to reach the whole body, including the brain, and can normalize key disease biomarkers, both in the CNS and peripherally. These data continue to reinforce physician confidence and resonance. with families, supporting the strong momentum we are seeing in the launch. Slide 12. Hunter syndrome represents one of the more prevalent mucopolysaccharide doses and affects a meaningful patient population within the rare disease community. The U.S. opportunity is highly concentrated with most eligible patients already identified and receiving conventional IDS enzyme replacement therapy at a relatively small number of specialized treatment centers. These are pediatric patients with pre-symptomatic or symptomatic neurologic manifestations who have not progressed to advanced neurologic impairment. We estimate that there are approximately 2,000 patients worldwide in the addressable market, including approximately 500 prevalent patients with Hunter syndrome in the United States.

Based on the FDA approved indication, approximately 75% of the US prevalent population, or roughly 375 patients, are currently eligible for Ablea. In addition, about 30 children are born each year with Hunter syndrome, providing an ongoing opportunity to initiate treatment early. Our ongoing face-free COMPASS study is an important next step in advancing Ablea, with the goal of supporting full approval and expansion of the label to include adults. Ultimately, our goal is to reach all eligible patients worldwide. Slide 13. Our launch is being executed against four core strategies. First, partnering closely with the Hunter Syndrome community through a high-touch, community-centered approach. In rare diseases, families often learn from and support one another.

We believe that positive experience with both Ablea and the Denali team helps build trust, increase awareness, and encourage additional families to seek treatment. Second, helping physicians evaluate Ablea and supporting treatment centers as they prepare to initiate therapy. strong clinical conviction is creating urgency amongst physicians to switch eligible patients and engage payers to accelerate access. Third, helping each patient and family navigate the steps from prescription through their first infusion. And fourth, driving fast label-aligned coverage decisions that help remove payer roadblocks. After our first full quarter of launch, what has been particularly encouraging is how these four strategies have reinforced one another. strong clinical conviction has driven physicians and patient demand. That demand has accelerated payer coverage, and together, these dynamics are enabling more patients to begin therapy. Slide 14. Beginning with physicians, we entered the launch with a strong foundation.

For approval, more than 80% of physicians surveyed were already aware of Ablea. 90% viewed the biomarker and clinical data as motivating to prescribe. Since approval, we have reached approximately 80% of targeted healthcare organizations with Ablea's launch information through our field engagements, scientific exchange, educational webinars and treatment center support. These activities have been highly impactful and are driving strong engagement across a significant number of treating physicians. Physicians constantly tell us that the ability to address neurologic manifestations is highly meaningful and that most patients experience neurologic symptoms at some point during the course of their disease. That belief is translating into action, as many treatment centers with eligible patients are working with families to navigate reimbursement and transition patients to Ablea. Slide 15. We have seen equally strong engagement from patients and caregivers. Through our launch webinars focused on clinical data and access, as well as with Denali Patient Services, we reached more than 100 families.

That represents greater than one quarter of the eligible U.S. patients. This high level of engagement reflects the impact of the reflects both unmet need in Hunter syndrome and the extent to which families have followed the development of Ablea. We are also seeing families share their experiences through advocacy networks and local media, helping other members of the community learn about the availability of a new treatment option. Slide 16. One of the most powerful aspects of LAUNCH has been hearing directly from families and advocates about their experience with Ablea and Denali. They have described the opportunity to begin Ablea as a source of hope and in some cases as the possibility of gaining more meaningful time with their children. They are careful not to draw clinical conclusions from individual experiences. However, these stories illustrate how much the approval of Avalaya means to this community and that has waited many years for a therapy designed to reach both the brain and the body.

We are also hearing very positive feedback about the way the Denali team is supporting families and healthcare organizations. For many patients, initiating a new therapy involves coordinating physicians, infusion centers, insurers, specialty distributors, and patient services. Our team works closely with each family and treatment center to help them navigate those steps. The feedback from families and advocacy organizations have consistently highlighted the responsiveness, compassion, and partnership of the Denali team. That experience matters. confidence in treatment, helps patients move through the access process, and supports continuity once treatment begins. Slide 17. Now turning to payer access. We have made exceptional progress during the first quarter of launch.

Commercial policies covering more than 50% of lives have already been established. As with many rare diseases, a significant portion of MPS II patients is covered by Medicaid. Recognizing that not every state will publish a product-specific specific policy, 14 state Medicaid programs publicly listed Ablea as covered. we are also seeing managed Medicaid policy align their coverage with commercial plans. These results compare favorably with early coverage achieved by analogous rare disease launches. Importantly, the absence of published policy does not mean a patient cannot obtain access. To date, physicians and families have successfully used prior authorizations, appeals, and medical exceptions while formal policies are being developed. The willingness of physicians to initiate these requests reflects their conviction in Ablea and our payer and patient access teams are working closely with them to move eligible patients towards treatment.

Slide 18. We are extremely pleased with the trajectory of the U.S. launch. In our first full commercial quarter, we generated $3.6 million in net product revenue and secured commercial coverage for more than 50% of covered lives. Before discussing the outlook, I want to briefly address our approach to communicating launch dynamics and metrics. We understand that visibility is important to our investors and we are committed to maintaining an open dialogue. There are many factors that influence the trajectory of Avalaya adoption, and every patient journey is unique, from the initial expression of interest through reimbursement approval and ultimately dosing. In addition, because Avalaya is weight-based, the number of vials used can vary meaningfully between a newly-diagnosed infant and a 16-year-old adult. adolescent. For the first two quarters of launch, we therefore plan to provide guidance on expected net product revenue for the following quarter.

We believe that this approach together with the prior quarters reported net product revenue will provide the clearest view of the launch trajectory during this early period. Before launch, we described an adoption curve that would build over time. We expected the earliest patients to be highly engaged families who are waiting for Ablea and were prepared to move quickly through the medical exceptions process. That initial demand has been stronger than we anticipated, reflecting both the high awareness of Ablea and the significant unmet need in the Hunter Syndrome community. While many patients have already started therapies, others continue to move through the reimbursement and treatment journey. As payer coverage expands and treatment centers gain experience with Ablea, we expect the patient journey from prescription to infusion to become increasingly efficient, enabling more eligible patients to begin treatment. Given the pace of adoption, expanding access, and continued strong execution, we expect Q3 net product revenue to be in the range of $10 to $12 million.

Most importantly, families continue to tell us that Ablea and the support they receive from the Denali team is making a meaningful difference in their lives. Slide 19. The Ablea launch also has significance beyond a single product. It establishes the first commercial foundation for our enzyme transport vehicle franchise across lysosomal storage disorders. The ETV platform is designed to reach the whole body, including the brain, and it provides opportunities across Hunter syndrome, San Felipe syndrome, FDL-1, PPD granulon, Pompe's disease, Gaucher's disease, and Hurla syndrome. The ERT market alone represents more than a $9 billion opportunity. Across these diseases, we expect to benefit from shared scientific expertise, establish relationships with treatment centers and advocacy organizations, and commercial capabilities that could be leveraged across future launches. Each patient we support and each treatment center we activate strengthens the infrastructure that can serve the broader ETV franchise.

Ablea is therefore both an important medicine for Hunter Syndrome community and an early demonstration of our ability to discover, develop, manufacture, and develop. and commercialize innovative therapies efficiently and successfully. We are proud of the start while recognizing that this is still the beginning of the launch. Our priorities remain expanding access, supporting a positive treatment experience, reaching additional eligible patients, and preparing for the international expansion. With that, I'll turn it back to you, Ryan, to discuss the broader pipeline.

Thanks, Katie. Slide 21. Earlier I described Avalaya as the commercial foundation for Denali and the first proof that the transport vehicle platform can enable medicines for patients. I would now like to provide an update on the broader pipeline and then spend most of my time on our Alzheimer's disease programs. strategy remains unchanged, deliver, develop, and discover. Over the 2026 to 2028 period, our goals are to build two growing commercial brands, generate five clinical proofs of concept, and advance four to six additional programs into the clinic through continued leadership and invention in blood-brain barrier technologies. Slide 22. Next, I would like to briefly update you on DNL593. DNL593 is a direct progranulin replacement therapy designed to deliver progranulin across the blood-brain barrier and restore the missing protein to key cell types in the brain, including the lysosome, where progranulin normally functions. Earlier this year, we regained full ownership and control of the program from Takeda. That provides us with greater flexibility over the development strategy and timing of the data analysis.

We have decided to allow for a longer period of observation in the open label extension portion of the ongoing phase one two study. We now expect data in first half 2027 updated from our prior expectation results by the end of the year. The additional follow-up will allow us to better characterize treatment effects across multiple biomarkers, including neurofilament light chain, or NFL, which may change gradually following treatment. Pending the totality of the data, we also plan to explore whether a biomarker-driven accelerated approval path may be appropriate. NFL has regulatory precedent in the related neurodegenerative disease, ALS, although any potential path for DL593 would require discussion and alignment with regulators. We are excited about DL593. because it directly addresses the genetic cause of FTD granuline by replacing progranuline. This week, the FDA granted orphan drug designation to DNL593 for FTD granuline, underscoring the significant unmet need facing individuals affected by this disease and the potentially promising rationale of our approach with PTV progranuline.

Progranulin. Earlier, healthy volunteer data demonstrated dose-dependent increases in cerebrospinal fluid progranulin following intravenous administration. providing evidence of brain delivery and further validation of the transport vehicle platform. I will now turn to what we believe is one of the most exciting areas of our pipeline, Alzheimer's disease. A few weeks ago, I had the privilege of delivering a plenary presentation at the Alzheimer's Association International Conference in London. After working in Alzheimer's disease for more than 20 years, I believe the field has entered a transformative period because of extraordinary progress in three historically challenging areas, biology, biomarkers, and the blood-brain barrier. in genetics and pharmacology are sharpening our understanding of the multifaceted biology of disease. Biogene and blood-based biomarkers are enabling earlier diagnosis and increasingly precise measurements of disease progression and treatment response. And brain transport technologies are creating the potential to deliver biologic medicines broadly throughout the brain. Together, these advances create new opportunities for the next generation of Alzheimer's therapies.

Slide 24. We believe the next advances in Alzheimer's disease may depend on delivering therapies more effectively throughout the brain. Amyloid plaque clearance is now clinically validated, but currently available antibodies are limited by modest efficacy and the risk of amyloid-related imaging abnormalities or RAF. Cout reduction has also shown encouraging clinical signals, but current antisense approaches rely on intrathecal administration and may not achieve uniform distribution throughout the brain and have other limitations. Our two clinical programs are designed to address these limitations through better brain delivery. DL921 is a potential best-in-class BBB-crossing anti-amyloid antibody designed to improve plaque engagement while reducing ARIA potential and peripheral immune activation. DL628 is a potential first-in-class BBB-crossing anti-amyloid antibody designed to improve plaque engagement while reducing aria potential and peripheral immune activation. crossing tau antisense oligonucleotide designed for intravenous administration and broad uniform distribution throughout the capillary network. Slide 25. Starting with DNL921, one of the important features of transport vehicle-enabled delivery is the route of entry into the brain.

When conventional anti-amyloid antibodies enter the brain, they concentrate around larger arteries and arterioles where a vascular amyloid is present. We believe that localization contributes to ARIA risk. By engaging the transfer receptor, antibody transfer vehicle enabled antibodies enter the brain through the extensive capillary network and distribute more evenly throughout the brain. In preclinical models, this route of entry was associated with substantially fewer MRI lesions than a conventional anti-amyloid antibody, including at dose levels that achieved strong target engagement. These data support our hypothesis that improved brain delivery and biodistribution may enhance plaque engagement while reducing ARIA potential. Slide 26. We've also engineered DL921 to address the broader attributes required for successful medicine. Unlike fusion approaches that append a transparent receptor binding arm to an antibody, our transport vehicle binding is embedded directly into the FC.

DL921 is designed to achieve robust brain concentrations while remaining intact and minimizing effects on immature reticulocytes. With the goal of preserving activity at amyloid plaques while reducing peripheral immune activation, DL921 incorporates conditional effector function through our CISLALA design. Turning to DLN 628, the central opportunity is to improve both distribution and convenience for antisense therapy. Intrathecally administered antisense oligonucleotides distribute from cerebral spinal fluid and can produce uneven exposure across brain regions with greater treatment burden for patients. By contrast, intravenous oligonucleotide transport vehicle, OTV delivery, uses the capillary network to distribute the antisense oligo broadly across the brain and spinal cord. This distribution includes key cell types involved in neurodegeneration, including neurons, astrocytes, and microglia. Slide 28. expressing human tau and the human transfer receptor, DNL628 produced robust reductions in MAP-T RNA and tau protein.

Importantly, tau protein reduction persisted for more than 12 weeks after dosing, supporting the potential for a practical dosing interval. These data support the design of the ongoing Phase 1B study where we are evaluating safety dose selection effects on tau levels and imaging measures in people with biomarker-confirmed early Alzheimer's disease. Slide 29. Both Alzheimer's disease programs are now in clinical development. DNO 628 Phase 1B study is ongoing and we expect initial clinical biomarker data in the first half of 2027. BNL921, the clinical trial application was submitted in the first half of this year, and we expect initial safety and clinical proof of concept data in 2027. These readouts will be important not only for individual programs, but also for the broad validation of our oligonucleotide and antibody transport vehicle platforms in common neurodegenerative disease. Taken together, our progress this quarter demonstrates the breadth of Denali, a growing commercial business, broad clinical pipeline, and a repeatable platform capable of supporting multiple therapeutic modalities. all focused on delivering meaningful medicines to patients and families.

Slide 30. With that, I will turn the call over to Alex to review our financial results.

Thank you, Ryan. Slide 31. I will close our prepared remarks today with a look at our portfolio, capital allocation priorities and second quarter financial results. We have built a broad portfolio based on the transport vehicle platform, which is now clinically and commercially validated through Avlea. This portfolio has the potential to create significant value in the near and long term with each program designed to offer first or best in class potential in its respective indication. And we are well capitalized to execute against it. Our portfolio has two key components. First, we have a pipeline of next generation enzyme and protein replacement therapies designed to treat the whole body, including the brain. Across these programs, we can apply the clinical and regulatory learnings from Eblea and leverage our existing capabilities in development, manufacturing, and commercialization.

We estimate that each program represents a potential market opportunity ranging from approximately 500 million to more than 1 billion, creating a multibillion dollar opportunity across the franchise. These programs benefit from a well established therapeutic modality, measurable biomarkers, and in certain diseases, the potential for biomarkers In addition, and shown on the right, is our portfolio targeting common neurodegenerative diseases. This includes two clinical stage blood-brain barrier-enabled molecules targeting tau and amyloid beta for Alzheimer's disease with first and or best-in-class potential. If successful, these programs could reach millions. of patients and represent substantial multi-billion dollar market opportunities. Slide 32, turning to the financials and capital allocation. We ended the second quarter with approximately $940 million in cash, cash equivalents and marketable securities. In July, we received $195 million in proceeds from the sale of the rare pediatric disease priority review voucher awarded following the approval of Ablea.

Together, this brings our pro forma cash, cash equivalents, and marketable security to more than $1.1 billion. gives us flexibility to pursue three priorities with discipline. First, it allows us to invest in the execution of our portfolio, including the commercial activities for AvLeia as outlined by Katie, preparations for the potential launch of DL-126 or Safinofasp Alpha in 2027, and clinical programs. Second, we can continue to build capabilities and infrastructure for efficiency. In particular, our internal manufacturing facility in Salt Lake City provides opportunities for speed and development and attractive COGS as we bring additional products forward. Third, our balance sheet provides strategic flexibility with respect to potential future partnerships diversified sources of capital. Slide 33. The complete details of our financial results are included in today's press release in Form 10Q, so I will focus only on the key items. Avleya generated 3.6 million in net product revenues during the first full quarter of commercial availability.

Research and development expenses were 97 million compared compared with 102.7 million for the same period in 2025. The decrease primarily reflected the timing of Adelaide commercial supply manufacturing in the prior year period and lower external spending on small molecule programs. Selling general and administrative expenses were $36.3 million compared to $32.3 million in the second quarter 2025. The increase primarily reflected investments to support the Ad Layer commercial launch. As noted, we ended the quarter with approximately 940 million in cash, cash equivalents and marketable securities before receipt of the 195 million in PRV proceeds in July. In closing, we believe Denali is entering this exciting next phase from a position of strength, with a commercial product, a broad pipeline, a validated platform, and the capabilities and capital to deliver value for patients and investors. With that, I will turn the call back to the operator to begin the Q&A session.

Thank you.

Thank you. We will now begin the question and answer session. If you wish to ask a question, you will need to press star 1 1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1 1 again. We will take our first question and the question comes from the line of Jessica Fry from J.P. Morgan. Please go ahead, your line is open.

Hello, this is Adam on for Jess. Thanks for taking our question. I just was curious, what in the launch so far has helped you come up with the next quarter's guidance? Can we assume that growth trajectory to continue through the end of the year? And could we see maybe op-eds guidance in the future? Thank you.

Thanks, Adam. Thanks for your question. So, what's giving us confidence is all of the leading indicators are moving in a very positive direction. As you saw from the presentation, physician awareness is extremely high of the Ablea data, and they're highly motivated to switch patients. In addition, we've seen tremendous disengagement from families as well. And we've also had great success moving patients through reimbursement with the medical exceptions process. And as you can see, also we've had success with payer access and we have now greater than 50% of commercial lives covered as of the end of Q2. So given all the dynamics are moving in the right direction, we feel very confident that the momentum will continue.

I can take the second part of this, Alex. I can take the second part on OpEx. So capital efficiency is very important to us, and we are pleased that we're able to keep OpEx flat in Q2 of 26 versus Q2 of 25 and actually slightly lower on a six-month basis, while at the same time preparing for the launch and advancing important new programs into the cloud. with respect to an outlook we generally provide an outlook for the full year at the beginning of the year so please stay tuned for that.

Thank you. Thank you. We will take our next question. and the question comes from salveen richler from goldman sachs please go ahead your line is open.

GOOD AFTERNOON. THIS IS LYDIA ON FOR SALVEEN. CONGRATS ON THE PROGRESS AND ON YOUR FIRST EARNINGS CALL. just speak to the patient profile of the initial patients on therapy and kind of the breakdown between the newly diagnosed versus switched patients? Thanks so much.

Great, thanks for that question, Lydia. So as you know, with this patient population, majority of the patients are already treated on Idar cell phase. So we expect 90% of patients, prevalent patients would be then switching. So the majority of that, Of course, we are seeing as well newly diagnosed patients being put on Avalaya, but the majority will come from patients that are switching. In terms of patient profiles, we initially believe that patients may skew to the younger population because those are the families that were most engaged and have been following the development of Ablea. But we've been really pleased to see that what we can do what we can gather today is that it's very broad. In fact, patients across the different age groups within the pediatric population have demonstrated interest in being prescribed Avlea.

Thanks so much. Thank you. We will take our next question. And a question comes from Andrew Sy from Jefferies. Please go ahead. Your line is open.

hey good afternoon thanks for sharing all these positive updates so maybe one more on hunter you know your They're guiding to a strong sales number for Q3. And then I think in your prepared remarks, the original guidance for an S-shaped curve still seems to hold. So, to me, that would mean that come next year, could we be talking about a quarterly revenue number that's significantly larger than 10 million? Is that the right way to think about it? And then secondly, and Biogen just shared their phase two tau data set. So I'd be curious to gauge your thoughts on the degree of efficacy they're seeing. How much do you think that is attributed to too much tau lowering, or is it the mode of administration or something else nice to gauge your views on these possibilities or variables around efficacy thank you.

Thanks, Andrew. I'll start with the first part of your question. And yes, we still believe that this year is a foundational year. We talked about getting as many patients on therapy as possible. And we are definitely at the beginning stages of that S-curve. But of course, our goal is to tighten that S-shaped curve and bring in the inflection point as soon as possible. And that's why our focus on driving awareness, making sure the experience on Avalaya is very positive so that the community can further share that and drive the momentum. that will drive, as well as with payer access, that will drive that inflection point.

I'm happy to take the second question, Andrew. As you know, we spoke before the data was shared at AIC in London, and then, of course, a lot came out after the data presentation, and I think our response is that, in general, it's the first data set to show that tau lowering may lead to a clinical benefit. And I think what's probably the most compelling is you look across not just ADAS-COG, or sorry, CDR sum of boxes, but also ADAS-COG and MMSC, and you're seeing consistency in potential clinical benefit. I think the challenge is, as you have highlighted, is a question around why was there not a dose response? Why did the higher doses not lead to more efficacy? And I think just a couple of points without going into too much detail. You know, obviously there were more discontinuation and adverse events in the higher doses. I think it's well understood with intrathecal administration that this is not uncommonly seen, including transient confusion. So I think we, like others, look forward to seeing more details and the differences between the doses and that may this actually be masking some of the efficacy.

But in general, first data set showing power lowering and potential.

clinical benefit. Thank you. Thank you. We will take our next question, and the question comes from Tazim Ahmed from Bank of America. Please go ahead. Your line is open.

Hi, guys. Thanks so much for taking my questions. I wanted to just focus on 593 for a second. I'm sorry if I missed this in your prepared remarks, but can you share any color on what level of data you plan to share when you release it? And what, in your view, would be good data? And then can you just clarify why you want to wait for NFL data? I think in the past you mentioned the focus was going to be on lysosomal function.

Thanks. Yes, thanks, Zuzana. I'm happy to take that. I think the most important point here is that, you know, as we've regained full rights to this program, we're now in a position where we can essentially drive the strategy on this program. And I think in our experience, I think point number one is that longer-term data is often needed when looking at biomarkers like NFL. And I think what's unique about FTD granulon from, let's say, some of our other lysosomal storage disease programs, that this is a haploid insufficiency in terms of the underlying disease. And as a result, you know, as we look at some of the lysosomal biomarkers historically, there's elevation, but it's modest, not like what you see with heparin sulfate in Hunter syndrome. So what we've decided to do is we're trying to find an accelerated path. As you may have also noted, we received orphan disease designation for this program just recently as well.

And so we think we have the best chance of seeing robust data specifically on the distal biomarkers such as NFL and more broadly. just looking at the entire biomarker set, including lysosomal biomarkers as well. So I think the key here is just giving this program the best chance of a potential accelerated path. Obviously, with data in hand, then we'd have to address that with regulators.

Thank you. We will take our next question and the question comes from Michael Yee from UBS. Please go ahead, your line is open.

Hi, this is on from Michael. I just wanted to ask a couple more on the lunch. a strong number right out of the boat. Just wondering... Given your comments around stronger than expected early demand and the fact that we sort of there. Do we expect a sort of bolus effect in the US of these patients who are covered on the label now coming on? And then for these patients that are having to go through sort of medical exceptions and fire off, do you have any sense of what the time is from like getting the scripts to actually getting infused?.

Thank you for that question. So, in terms of what we expected, we definitely expected that pool of patients who've been following Ablaa's development very closely. And that pool of highly interested families is bigger than we initially had expected. But we are working through, with the early experience, with these early families, though, we are seeing expansion into the broader patient population, as I described earlier. And so we're very excited about the fact that it's going beyond just those early families, and we're going to expect to see continued growth. into the broader population. And as you stated, the total eligible population is around 375 that are considered pediatric patients in the U.S. In terms of, I think your question was starting the interest to infusion and what's the timeline for that. As you know with or this early in launch and without payer coverage initially of though of course that's expanding now there is huge variability in the time between patients expressing interest to when they actually get infused so it's really hard to comment on that this early in in in launch however with payer coverage improving over time, that timeline should get more straightforward, more efficient.

Thank you. We will take our next question. And the question comes from Sean Laman from Morgan Stanley. Please go ahead. Your line is open.

Hi, this is Mike Riad on for Sean. Thank you for taking our questions and congratulations on the strong start. Can you remind us how is progress going on for the adult confirmatory study? And given what you've learned so far, acknowledging it's only one quarter into the launch, is there anything that has changed your excitement or views as to how that adult study could influence launch trajectory or pricing?.

So, what we're hearing today, certainly there are adult patients that are very much interested in getting treated with Ablea. I think that's your question. I don't think launch price will change since we've already gone into market, even when we hopefully will get the label expansion. And I'll let Peter comment on the study. Yes, and in terms of the Compass Phase 2-3 study, we're excited about reading out the study, which is set to end.

the end of next year. It is going to be the basis for expanding the label both in the U.S. as a confirmatory study and for global, potential global launches.

Thank you. That's very helpful. And then just thinking about the 2Q to 3Q revenue guidance and RAMP, can you walk us through any key drivers of that acceleration? How much of it is coming from new patient starts versus patients converting to reimbursement?.

So I think it's a combination of all those factors. So we're seeing, as I stated earlier, all of the leading indicators, the high level of engagement from physicians and families, the conviction that physicians have in going for a medical exceptions process, and then the fact that our payer coverage is getting better every day. I think all of those things are going to be contributing to the growth over the next quarter.

Thank you. Bring out the gun. Thank you. We will take our next question. And a question comes from the line of Paul Matisse from Stifel. Please go ahead. Your line is open.

Great, thanks very much and congrats on the early launch progress. I guess taking a step back, given everything you kind of understand around this patient population, the degree to which families are plugged in and we're waiting for Avalaya, do you think you're seeing a bolus right now? And might we see some attenuation in the ad rate later this year? or do you feel like this is actually potentially sustainable? And then as it relates to tau and the upcoming data next year, Ryan, I think you've talked about CSF tau data being an interesting early biomarker, given that pet changes can take some time. I'm wondering, though, that do you think your CSF tau data for the shuttle will be comparable to the CSF tau data for an intrathecal drug, given that IT-administered drugs can maybe bias CSF biomarkers, given sort of the site of administration. Thanks so much.

Thanks. I will take the bolus question first. And certainly you're correct that we expected this bolus. The bolus is bigger than we expected. But I think the key thing that we're seeing is that this early experience from this initial patient population is translating to the broader population. And over time, especially as physicians gain more experience and the stories are shared more broadly through the patient community, we expect the growth to continue into the full eligible population.

Thanks, Katie. Paul, fantastic question. Obviously very mechanistic. You know, obviously my kind of question. I think you're exactly right. It's really difficult to compare CSF tau in an intrathecally delivered molecule versus one that's delivered through, you know, capillaries through transplants. the transport vehicle through transfer receptor. And the experience we have related to this is actually with, you know, early days of ETVIDS now Avalaya and its comparison with intrathecal delivery of Idaronate 2 sulfatase where you know there's a regional very high concentrations of enzyme in this case it would be high concentration of the antisense oligo and so I think it's really apples to oranges in terms of like percent reduction and what we would correlate ultimately with clinical benefit. But what we can say is that our biodistribution is even and robust. So when we look at different cell types throughout the brain and brain regions, we get basically roughly the same knockdown of gene expression across these various cell types. So when we measure... CSF levels of tau, we're confident that that's the level of knockdown we're getting throughout the brain.

And I think if you then relate that to maybe some disappointment in the maximal efficacy seen with intrathecal delivery, that may be simply because you're not penetrating deeper brain regions that may be impacted by TAS. Tau and Tau pathology. And then to the sort of first half of your question around CSF Tau and Tau PET, I think what's really remarkable, and I just, you know, we mentioned this at AAIC. intrathecal data has essentially proven that tau PET can be reversed. That was actually a fundamental question, and many mouse models actually had never really necessarily shown that. So in other words, if you reduce the expression of MAPT, which codes for tau, and then you reduce the expression of tau proteins. over time you start to see a reduction in the tau PET signal. And if you look at the totality of the data, including the new data that's been presented, it seems like the shortest window is about a year from when they see tau PET reduction. The early data set didn't really show much reduction at six months, and then they looked later. It was either 18 months or two months. two years, this data set shows that a year they're seeing, albeit variable from patient to patient.

And actually, if you look at the data sets carefully, they've been published. Some patients get no tau reduction by PET and others get robust. We think this is actually heterogeneity in intrathecal delivery. And so the take home is, you know, biodegradable. distribution is going to be, you know, critically important and different with the transport vehicle technology. And CSF Tau will still be very informative, just like heparin sulfate. CSF was informative for our Hunter program. But we're not comparing percent reductions because of exactly the point you made.

These are fundamentally different. different delivery approaches. Great. Thanks, Ryan. Thank you.

We will take our next question and the question comes from the line of Mayank Mamthani from B Riley Securities. Please go ahead, your line is open.

Good afternoon. Thanks for taking my questions and congrats on a strong launch. Maybe right on the prior point on the OTD map key, strategy, are there any genetic type of things you could potentially look at and just taking the logic that you're applying to the DRM program, you know, So there are FTD map things also that could be looked at. And then maybe just a higher level question, there's a lot still we need to see from a biomarker standpoint in the CREA study. But there are sort of the right things to kind of look out for as you obviously think about the biomarkers you want to look at in your six to eight cohort reading.

Thanks, Neil. Thanks, Neil. Again, great questions. You know, my... My take is I think with MAP-T, The key point here is really focusing on tau reduction, showing that the OTV works, that you can deliver medicine systemically and get tau reduction. We're definitely interested in these genetic cell populations, but our experience actually with FTD granulone is that initially it was very, very difficult to enroll these more rare cases. And the telepathies are not unlike FTD. And in fact, there are FTD sort of telepathies. So sort of rare, hard to diagnose initially, and then you have to genetically diagnose them. So we're interested in that. I just don't think that it's the fastest path. to really proving the platform and then subsequently driving for the first approval.

In terms of what to look for, we're essentially looking for tau reduction in CSF, not really hitting a target. The genetic data in mice suggests that the haploinsufficiency loss of one copy of tau is highly protective. in the Alzheimer's models. And so, you know, you could imagine somewhere between 25 and, you know, 70% reduction. But I think that fundamentally, what's actually very interesting about the data set that has recently been presented is that there was a non-dose proportional reduction in tau. So as you go up 2X in dose and 4X in dose, there's only really about a 20% difference in overall tau reduction in that range. And yet there is sort of a different, obviously, AE profile for those higher doses. And so we feel like the CSF data for intrathecal is apples to oranges, but we look at our own data and our own preclinical data and what's sort of been published to set the tone that, you know, we really need to see CSF tau reduction as really a proof of the platform.

I don't know, Peter, if you want to add anything there. No, I think you covered it well. I think we're really focused on executing the program, generating the data that Ryan alluded to, and I think other potential indications is something that we can consider in the future.

Thank you. Thank you. We will take our next question. The question comes from the line of Ananda Ghosh from H.C. Wayne Writing Co. Please go ahead, your line is open.

Hi, thanks guys and comrades on the great quarter. I have actually two questions. In 2025 CTAD, Biogen presented some data using this zirconium dye where they tried to show their intrathecal, the tau modality, how well they distribute throughout the CNS. And you would see that it's a very poor distribution. Now, the question is that despite such a poor distribution, they do see, as you rightly mentioned, that they can move the clinical endpoints at least in a trend way. Thank you. And so just wanted to get your thoughts on that aspect of it, that how did, even with such a poor distribution, how can they see some efficacy with respect to both as a biomarker as well as from clinical endpoints? The second question is, there are also these ideas that, and especially from the Donanemab trial that, in patients where you have low tau, there you can see those patients are much more amenable to either both anti-abeta therapy or anti-tau therapy. So as you are thinking about your phase 1b, is there a way.

to enrich patients with low tau in your phase 1, the trial population? Thanks. Yes, good questions. I'll try to be brief because we have a number of other questions. I think let's look at additional data that hopefully will be presented on BID-80 to really understand that dynamic. But you're right. There's enormous heterogeneity. There is. And we've published this already in Monkey. And so I think that the positive clinical signal across three different endpoints, ADAS, COG, CDR, sum of boxes, and MMSC is really encouraging. And there are some patients that get really decent biodistribution in the pancreatic. particular study that you're referencing.

And so I think that, you know, that's I think the the main point.

Great, thanks. Thank you. We will take our next question and the question comes from Joseph Thorne from TD Co. And please go ahead, your line is open.

Hi, this is Jacob on the line for Joe. Thanks for taking our question. Kind of going along with, you know, patient enrichment or kind of patient selection, I was curious how you're thinking about some of these co-pathologies that often come along with AD, like alpha-synuclein and TDP-43 and how those could be used to help with patient selection. play a role in patient selection or kind of pre-specified subgroup analyses. And then just additionally, looking farther ahead, how you're thinking about, you know, what a bar might look like given some of the currently approved amyloid beta therapies on things like CD-RSB. Thanks.

So I'll address the first one on the co-pathologies. And then, Peter, why don't you address the bar on – I'm assuming what you're asking is the bar for approval or for, like, clear differentiation with the anti-amyloids. Yes. Yes. So I think with copathologies, the two, obviously the most common copathology, which is actually in some ways defines Alzheimer's is A-beta plaque or amyloid plaque and tau neuroflag rate tangles. I think what you're referencing is also, it's been shown like, you see Lewy bodies and other sort of vascular pathologies. challenge with those type of co-pathologies there aren't imaging biomarkers yet that allow you to look at the level of let's say Lewy bodies that can also be observed with amyloid plaque or tau and so at this point our focus is on the two most common and prevalent. I'll add that there's by the way a fourth one TDP43 pathology, which I think represents roughly 30% of Alzheimer's. All of this being said, amyloid appears to be at the top of the cascade. So amyloid eventually drives the formation of tau pathology and then tau pathology correlates with cognitive decline.

And so we're keen on targeting both amyloid and tau. And I think as biomarkers improve, you'll be able to see hopefully we'll be able to identify patients that have other pathologies, which in some ways is probably complicating the clinical picture. With that in mind, I'll hand it to Peter to talk about what the bar might be for anti-amyloid approvals.

Yes, thank you, Ryan, and thanks for the question. I mean, I think I'll start by saying this is a very exciting time for Alzheimer's, and coming off the vast amount of data that was presented at AAIC, there's a lot that's being learned about Alzheimer's. different aspects of the patient populations. I think it's premature to say exactly where we're headed, but I do think that with all the data that's being generated and understanding both progression rates and response to different types of therapies, this is something that we'll definitely pay attention to both with targeting tau as well as with amyloid. I think from an analog perspective, we're very excited about the differentiating potential of DNL921. I think our goal is really to generate proof of concept with that first. Great. Thank you.

Thank you. We will take our next question. The question comes from the line of Laura Chico from Wedbush. Please go ahead. Your line is open.

Hey, thanks very much for taking the question. Congrats guys in the quarter. Maybe one for Katie. I'm wondering if you could expand a little bit further, what capacity do the centers have for switch patients? Just wondering if there's any additional considerations that the physicians need to work through for a switch patient versus perhaps somebody that's new to treatment. you indicated in the webinars that you encompassed or encountered over 100 families or about greater than 25% of the eligible patient pool. So I guess I'm just trying to understand if there's any capacity considerations that we should be making as you're progressing here. Thanks very much.

Thank you, Laura. That's a great question, and you're exactly right. There are definitely dynamics, both for the newly diagnosed patients and for the switchers. As you remember, the majority of the idesophores patients are treated at home. And so these are patients coming back to the clinic. And definitely infusion scheduling is one of the steps that families have to work through. And so with all the families coming back, there is a sequencing depending on the center, depending on if you're at a center that has specialized centers of care, they are going to have a little bit more capacity than other centers. So that is the dynamic that has significant variability that we're going to be working through.

But what we've seen is the sense of urgency and the motivation from families have been very strong.

Thanks very much. Thank you. We will take our next question. And the question comes from Mark Goodman from Near Ink Partners. Please go ahead. Your line is open.

Hi, good evening everyone. This is Alyssa on for Mark. Thank you for taking our question. I was wondering if you could help us think about the average price per patient for Avlyia given the weight based dosing and titration schedule. Since many patients will initially be up titrating over the course of the first few months, when should we expect pricing to reach a steady state? Okay. run rate and then secondly on the manufacturing facility in Salt Lake City, do you have any plans to use that facility to manufacture commercial batches of Avleya or will that be used only for clinical manufacturing? Thank you.

Great, thanks. I'll address the pricing question. So at maintenance for a 10-kilogram patient, it's roughly around $270,000 per year and up to a 30-kg patient, which is about $800,000 per year. And as you described, there is a dose escalation described in our label. And what's been provided to physicians, and this is ultimately a physician's decision on how quickly to do the escalation, is that we expected the escalation to be about four weeks at each step before they get to maintenance dose. And there may be variability as patients' dose escalate, depending, and it'll be very individualized and physician-cited.

And then I'll answer the second question. We do not have plans to manufacture in Salt Lake City for Avalaya. In fact, our plans are to go to larger scale. with Lonza and onshore to Portsmouth to go to 6,000 liter.

Okay, thank you very much. Thank you. We will take our next question. The question comes from Michael Dufour from Evercore ISI. Please go ahead. Your line is open.

Hi, guys. Thanks so much for taking my question and congrats on the so far to for me now that you have a full commercial quarter under your belt at this juncture could you give us the number of patients on drug as well as the number of cumulative start forms and if not when might you be able to share this information and the second question is as patients switch off of Ella praise have you seen any competitive response response from Takeda, either on contracting pricing or account level pushback for that matter.

Okay, let me see if I can address all the questions. So your first question was on start forms and patient numbers. So at this stage, we intentionally focused on communicating the overall trajectory rather than providing individual operational metrics. So I shared earlier why we have confidence is we're seeing all of the progress with the various stakeholders within the ecosystems with physicians being highly aware. and engage families highly engaged and driving towards switching, as well as centers working through reimbursement and payer access. With regard to start forms, we also feel that at this point, start forms are not predictive of revenue, and it's because Each individual patient journey is very unique. And the time, depending on what their insurance plan is, which centers they're getting treatment at, that is highly variable at this point. And we haven't provided guidance as to when in the future we may provide patient or start form information.

For now, we really want our investor to rely on the revenue guidance because we feel like it's the most clear quantitative indicator of how our launch is progressing.

I think those were, oh, did you have one more question? Yes, I did. Just regarding the switch off from LRAs. Any competitive response from Takeda that you've seen?.

Yes, so in terms of competitive response, you know, we've been very much focused on making sure that the clinical value and the biomarker data is well recognized. So I think we haven't seen a ton of pushback because it's very well recognized that L-apran does not address neurologic manifestations. And we haven't seen the other activities that you've described, which is contracting, and I think you've described another one, but we haven't seen any activity related to that.

Thank you. We will take our next question. The next question comes from Miles Minter from William Blair. Please go ahead. Your line is open.

Hey, team, this is John. I'm from IELTS. Congrats on a strong first launch quarter and thanks so much for taking our question. So for Avleya, wondering if any of your commercial patients have previously been clinical trial participants and wondering if you can give us any color on the cadence you expect for clinical trial participants to transition.

over to commercial therapy? Yes, so the majority of patients that have started today are not actually our clinical trial patients. We expect all of our clinical trial patients to be able to convert to commercial patients by the end of this year.

Thank you. We will take our next question. And the question comes from David Hong from Deutsche Bank. Please go ahead. Your line is open.

Hi, this is Rosemary on for David. Thank you so much for taking my question and congrats on the quarter I was just wondering how you might be thinking about the competitive landscape evolution for Avleya as There's some competitor resubmission happening this year and KCR farmers is cargo. Maybe having a global phase three readout next year. Thank you.

Yes, thanks for that question. Of course, we're always very encouraged to see continued innovation in Hunter syndrome, but we are very confident in our biomarker and clinical evidence. As you know, we've shown normalization for the first time in this disease area for key disease biomarkers, and our focus is on executing on our launch and driving the momentum that we're seeing today.

Thank you. Apologies for the delay. We will take our next question. Your next question comes from the line of Charles Moore from Baird. Please go ahead. Your line is open.

Hey guys, thanks for taking the question and congrats on the great quarter. Just kind of following up on the last question, I recall your analogous trial for Avleya included patients who had been treated with gene therapy. So looking toward the DNL126 trial, are there any patients there who have been treated with the gene therapy, previously, considering that there's the possibility for a Sanfilippo gene therapy to be approved ahead of DNL-126. Thank you.

Peter, maybe I'll have you take that. I'll just make one comment. We haven't gone into great detail on the 126 patient population, but, you know, obviously presented new data earlier this year at World and very excited about that program, but great question around the competitive landscape.

Peter, do you want to add anything to that? I just don't think we've gone into much detail on the nature of those patients. Yes, thanks, Ryan. Yes, I would just say we haven't presented the baseline characteristics of the full cohort yet, but we do intend to present the data early next year at the World Symposium.

And I'll just add, you know, great memory. We did have both gene therapy and cell therapy patients in the Hunter data set and where we saw, you know, robust normalization in those patients' data in terms of CSF heparin sulfate. But I think the key here is really focused on the sustained biomarker response. across our ETV franchise. Thanks for the question. Got it.

Thank you very much. Thank you. This concludes today's question and answer session. I'll now hand the call back to Ryan Watts for closing remarks.

We thank everyone for joining the call today. We're very excited about where we are and look forward to continued momentum. Thanks, everyone.

This concludes today's conference call. Thank you for participating. You may now disconnect.

This live transcript is auto-generated without human intervention or review.

[Call has ended.]

Great. Good morning, everyone. Thank you so much for joining us. It's a pleasure to have the Denali team here with us. We have Ryan Watts, CEO; and Alex Schuth, CFO.

To start here, the recent approval of AVLAYAH in Hunter syndrome serves as Denali's first commercial launch and the first from the transport vehicle platform. In this context, can you frame the outlook for your vertical specifically, the blood-brain barrier vertical, your key priorities and the catalyst outlook as we look to the next 12 to 18 months?

Yes. Maybe before I talk about the future, I'll just have a comment or two about the past. We've been working on blood-brain barrier technologies for almost exactly 20 years. And in fact, it was 20 years ago that the first medicine was approved for Hunter syndrome idursulfase and so for us, it's been a journey of inventing a platform, I think, really pioneering this space for over 2 decades. And the last 2 or 3 months have been extraordinary for us. It's really exciting to be able to launch our first medicine, have the first FDA-approved blood-brain barrier enabled technology with AVLAYAH, and it's been an exciting time.

And I think just -- I think an important point is this now becomes a new area of biotherapeutics where the competition is rising, which is great news. In biotech, whenever anything works, everyone jumps in. And so we're happy to be leading the way with transferrin receptor and with the TransportVehicle technology. Of course, this is just the beginning as well. And so talking about the next really 6 to 12 months, in addition to everything related to the launch, which is, of course, our focus of the commercial team, we also have the next enzyme replacement therapy, which is for Sanfilippo, where we'll complete the 49-week portion of that study in September, basically get the data ready, ideally present at world and then submit the BLA in 2027.

What's exciting about that product is we're actually going to do the commercial manufacturing ourselves. Our original with AVLAYAH, we've worked with CDMOs. Now we're going to be manufacturing for Sanfilippo, and we think this is the beginning of many enzyme replacement therapies. The next will be in Pompe, where we're enrolling that study now, also looking at data in 2027. And then at the end of this year, we have -- we've sort of categorically put our progranulin program into the enzyme replacement therapy because it's very similar to enzyme replacement therapies, but we'll have our first look at the Cohort B3, that's sort of the highest dose for that study. That's coming up soon.

Now I think what's happened for us is that we often get asked the question, why not just be an enzyme replacement therapy company. You know the technology works. You have your first launch, a lot of enthusiasm around that and in the community to bring forward other programs. But actually, we founded the company to ideally treat neurodegenerative diseases as well like Alzheimer's and Parkinson's. So we'll have our first 2 data readouts in Alzheimer's disease also in the next 12 to 18 months. One is an oligonucleotide that knocks down the gene that codes for tau and the other is an Abeta antibody, which we published last year in August 2025 in Science around our mechanism of basically removing amyloid plaque, which we hope safer and ideally subcu dosing. And so that's also what's on the horizon. And I know we'll go into each of those aspects, but a very exciting time at Denali.

Definitely. Perhaps we can just start on the Hunter syndrome program here. So given the first commercial patients have been treated and -- could you just speak to early launch dynamics to date, including the conversion rate from start forms to active patients and how the medical exemption process and reimbursement has evolved since approval?

I have to remind myself that it's been about 10 weeks or so since approval. And I think what happened first is let's get the drug in the channel. We were able to do that within 2 weeks, obviously, with the label. And then in 3.5 weeks, our first patient was dosed in the commercial setting. And this is not a patient that's switching over from trials. So it's really exciting. It actually wasn't at one of our trial sites.

And now we have multiple patients who have been dosed in the commercial product. And so it's very early days to understand the dynamic of conversion from start forms to approval and getting the first dose, first infusion. But what we can say is that it's exceeded our expectations in terms of the enthusiasm from the field, and we're seeing really positive trends on time from start form to infusion.

And what is the mix of treatment-naive to newly diagnosed patients and those on prior standard of care? And has there been any pushback on patients or physicians on the need to return to clinic to initiate treatment though?

The vast majority of patients, especially early on, are going to be switched. If you think about it, there's 500 patients in the U.S. I think almost all patients are on idursulfase or the vast majority unless it's sort of like end of life. And so that dynamic, what's happened in the field is there's just real enthusiasm about the possibility of treating neurologic manifestations in addition to the fundamental treatment of the disease.

We also saw our peripheral biomarkers were better than what has been shown for standard of care. And so we haven't seen really barriers to that. I think, again, the field is driving that enthusiasm. So most of the patients that are on drug now, our commercial patients have switched from idursulfase. A handful will be newly diagnosed, and that will just happen over time.

And the drug is priced at a premium to previous standard of care Elaprase. And so as you engage with payers, what has feedback been around pricing and weight-based dose -- the weight-based dose model?

I'll hand that to Alex.

Yes. I'll take that one. So the pricing does reflect the clinical profile. So what we've shown in the clinical studies is that we are able to normalize the key biomarkers, heparan sulfate and also neurofilament. And it is the one, the first and the only drug that treats the whole body, including the brain, and that is appreciated by payers. So we have not encountered pushback on the price by payers. It has not been a barrier to access at this point. The weight -- it is priced by weight. The weight-based model is very well understood. It's a very standard in enzyme replacement therapy, so we feel very good about the price.

And have your expectations for modest revenue this year changed as the payers come online and as you kind of watch the trends that are playing out, just given -- I think you've guided to kind of the whole year needed in order to get that payer dynamic settled before you see that inflection in revenue more in '27?

Yes. So this is -- as Ryan said, we're very pleased about how the launch is going. We're very pleased about the interest, about the engagements, about the enthusiasm in this product and also what's coming in the pipeline. What is expected in a rare disease launch, especially in a buy-and-bill setting, is that prescription activity will outpace revenues in the early stages of launch. And that's exactly what we're seeing right here. 2026 is the setup year.

This is why we guide towards the modest revenue, and this is why we use the illustration of the S-shaped curve, right? We think '26 is the setup year, '27 will be the inflection year. We think in '27, once patients are on drug for a number -- for a period of time, but especially once all the payer engagement, once the payer policies are in place. We have guided that -- or we have stated that it's about 50-50 with respect to the payer mix. And it will take about 6 months or so for commercial insurance, 9 to 12 months for Medicaid. So that's when we then expect that in '27.

And what is the status of the European filing?

Yes, I'll go on -- I mean, European filing, but also really international. So the international market is very important. About 2/3 of overall Hunter market is internationally. And ultimately, our goal is to capture that full market and make sure that every patient that can benefit from AVLAYAH will have the opportunity to do so. So we're very actively engaged internationally.

In some instances, we can work with accelerated or conditional approval settings. We can work with pharmaceutical product certification, which will allow us to capture part of the international market before COMPASS reads out, so that's with the current data set in hand. Now specifically with respect to Europe, we will need to wait until COMPASS reads out. So COMPASS was fully enrolled by the end of last year at a 2-year endpoint. So we expect it by then and then file in Europe.

On the confirmatory study, which includes patients up to 26 years of age, what is your current target for filing a supplemental BLA here to expand the label to include the adult Hunter syndrome patients?

I think there was two reactions to the approval of AVLAYAH. The first was enormous enthusiasm that there's finally a medicine that can treat the central nervous system, but the other was disappointment that the drug wasn't immediately made available to adults. And so obviously, that's one of the important focus for us. What's interesting is once you're on drug, you stay on drug. So it's not like as you transition to adult, you then come off AVLAYAH and go on idursulfase. And so that's important to note and clearly articulated in the label.

The COMPASS study is a little bit more than 60 patients split into 2 cohorts, Cohort A, which focuses mainly on neurologic manifestations and then Cohort B, which has a broader age range, including adult. And so the key there, that's more peripheral, and we're looking for equivalency and frankly, ultimately, we should see data that's superior to standard of care, but it's powered to show sort of equivalency on biomarkers, things like liver and spleen volume and 6-minute walk.

And so the goal is that totality of that data will put us in a position to go to Europe, which is the main focus of COMPASS, at least Germany, France, some of the countries that won't really recognize an accelerated path, but also to really focus on expanding the label.

Just maybe broadening out on the TransportVehicle platform here following the preliminary Phase I/II data that was presented from DNL126 in Sanfilippo syndrome at the WORLD Symposium. How is your dialogue with the FDA evolved here regarding the use of heparan sulfate as a surrogate endpoint for the BLA filing? And does the 2027 filing remain on track at this point?

I thought this might be the first fireside chat where we don't get a question about the FDA. It's been an incredible journey for the last 2 or 3 years. You'll recall 2 or 3 years ago, we were talking about the inconsistency between CBER and CDER. With CBER, I think, being much more aggressive on biomarkers as a potential path to accelerate approval. And then in some ways, obviously, that switched as everything panned out over the last 9 to 12 months.

And I think what's really been important for us is that the review team has been the same over that 3 years. And so the evolution of thinking about biomarkers has been with the same people who have seen, for example, the Reagan-Udall Foundation presentation now over 2 years or so ago that articulated why CSF heparan sulfate should be a surrogate endpoint reasonably likely to predict clinical benefit. And that was the foundation of that mindset shift. Those are all the same individuals.

So those that were briefly concerned about it were the ones who then understood, agreed and then understood that the approval of AVLAYAH is setting and so our engagement with the FDA on DNL126 has remained consistent, obviously, setting a high bar. We saw, on average, 80% reduction of CSF heparan sulfate in Sanfilippo with the ability to normalize. What's different about Sanfilippo is that all patients are treatment naive. And so basically, you have to build tolerance and when you do, you're able to see this robust reduction in heparan sulfate.

And the other thing that's like this very distinct about Sanfilippo over Hunter is it is a very aggressive degenerative disease. Patients will often have pretty significant volumetric loss even before we begin dosing. And so early is going to be really important. But our engagement with the FDA remains consistent. We've always, sort of, I would say the way we've approached it is around the review team. The review division is the most important relationship and interactions that we have for our medicine.

And given there's no standard of care therapy on the market for Sanfilippo here, how do you think the launch trajectory will pay out versus Hunters?

Yes. I think that's -- as I pointed out, no standard of care. It's not a switch dynamic. I think the other point is you need to find these patients and diagnose them. They often are diagnosed in the same center. So from a positive point of view, we -- it's the same physicians. We'll have the same commercial team. All the interactions are similar. The MPS society has been very involved with both Hunter, Sanfilippo, Hurler-Scheie. That part, I think that dynamic is going to be fantastic because we're -- you see the momentum of AVLAYAH, which will then feed into 126.

But there is no standard of care. So I think it's important to continue to push for newborn screening. As I mentioned before, because of the rapidity of how quickly this disease degenerates, finding patients really early is ultimately going to be key to have the most robust clinical benefit. So with similar patient numbers ultimately. So we see the combination of AVLAYAH and 126 is probably $1 billion-plus opportunity worldwide with just those two products. And that's just the beginning of the enzyme TransportVehicle franchise.

Can you just remind us what the rationale was for Takeda's decision to end the collaboration on 593 in the frontotemporal dementia program?

Yes, I'll take that one. So Takeda made a strategic portfolio prioritization decision in the broader context of their restructuring of the rare disease and neurology portfolio. Takeda has been a great partner for 9 years since we started the partnership, but now we take the program forward ourselves. It's very strong biology. It's a very direct mechanism substituting progranulin, which is missing or lacking in these patients with that form of frontotemporal dementia. The study is ongoing. It's fully enrolled now, and we expect the data by the end.

And what specific biomarker thresholds are we looking for with that data read?

Yes. So I think as Alex mentioned, this form of FTD is a mutation in granulin, these are heterozygous carriers so they have one copy loss of function. We published a paper in 2021 in Cell categorizing a set of biomarkers that we think may be relevant that are downstream of this loss of function. And so there are lysosomal-related biomarkers like glucosylsphingosine and a number of like BMP and other biomarkers.

Those are the proximal biomarkers. The distal biomarkers are the traditional degenerative biomarkers like NfL and GFAP. And so for us, we're interested in both proximal and distal. And our experience in Hunter syndrome and Sanfilippo is that you hit the proximal first, you establish dose and then over time, assuming that this is disease-modifying, you should expect the ability to reduce the distal biomarkers like NfL. And so that's what we're looking for early on here is early data trying to understand the proximal biomarker and dose that will then drive ultimately that what we believe will be the clinical benefit, which is then obviously looking at biomarkers like NfL.

I think one challenge you have here is because it's a single copy loss of function, the signal to noise in your biomarkers is not the same as what you see in Hunter and Sanfilippo, where those are complete loss of function. Heparan sulfate is elevated tenfold, where like glucosylsphingosine is elevated 25%, 30%, not even twofold.

And so that's a dynamic that we're -- we'll have to be prepared for and especially as we sort of select dose. And I think the ultimate goal would be to pin a decision on the distal biomarkers like NfL with longer-term data. And that's the other thing we've learned quite a bit from Hunter is that they have a fantastic medicine, but it took time to basically normalize NfL.

Following Biogen's recent data from its tau-targeted ASO in Alzheimer's, where we're going to see the full data, I guess, or whatever data we can midyear at the Alzheimer's conference in London. But they commented on demonstrating a slowing clinical decline in tau reductions, but they did not show a clear dose response. Maybe help us understand what you believe is the read-through to your own programs here.

I mean taken at face value, this could be historic. Why? There's really only one drug target in Alzheimer's that have shown clinical benefit, which is Abeta. This would be the second. So -- and if you look at the totality of the data, at least as articulated in the press release, what it tells you is reducing tau and slow cognitive decline. And that would then represent the second Alzheimer's target that has clinical validation.

I think it's, as usual, complicated to read into dose response. I think added complexity with their particular program is that intrathecal delivery introduces a significant amount of heterogeneity in brain biodistribution. And so it will be very interesting to look at the data and understand how many patients were in each of the dose cohorts. If I understood correctly, there are 3 dose cohorts. But it's possible, for example, that the lower dose had fewer patients and then maybe more subject to heterogeneity.

But I think the take-home message is reducing tau appears to result in a clinical benefit and a cognitive benefit. And I think that's historic actually because now it's like how do we improve Abeta, how do we improve tau. We have a real opportunity and I think then enter our approach, which is the transport vehicle that allows you to have much more consistency from patient to patient in terms of biodistribution.

We saw this in our nonhuman primate studies with an intrathecal delivery and compared it to the oligo TransportVehicle. And with intrathecal, our monkeys, some had decent brain exposure and some had very little. So you had always had great spinal cord exposure because these are lumbar delivery, but you had very significant heterogeneity and how much gets into the brain. With the oligo TransportVehicle where you're delivering across capillaries, you have an even distribution, and it was consistent from monkey to monkey.

And so I think that's just part of the dynamic. And I think we've seen it in the Abeta field as well is that as these new technologies, these brain shuttles and in our case, specifically the TransportVehicle they enter, you have now this ability to very rapidly reduce amyloid about 3x faster at maybe 1/5 the dose. And so I think it's very exciting. It's very exciting to see another target that may be clinically validated in Alzheimer's.

And remind us on the time lines for your program here?

Yes. So we're targeting 2027 for the first biomarker data. We're enrolling now rapidly the Alzheimer's patient study. It's a multiple dose out of the gates for OTV:MAPT. The key here is obviously to see tau reduction and understand the dose that drives tau reduction. And I think everything will follow the tau imaging PET and then ultimately running the study large enough to look at clinical benefit.

Again, timing of intervention matters, and we'll also be at AAIC, very excited to be there. We'll be presenting there. I think the thesis that I like to articulate is that amyloid is a trigger, tau is an executioner. And then you have all these other contributors to disease that are these microglial targets. They probably contribute the inability to remove amyloid. But if you look at the data, it's pretty consistent that amyloid is at the top of the cascade, but tau, I mean, I think ultimately is driving neuronal loss. And so I think they're both obviously very interesting targets.

You also have the beta-amyloid program that's moving forward. Can you just walk us through the learnings that have played out with the programs that are approved also in the clinic and how that translates to your program?

So both OTV:MAPT, which is our tau reducer and then ATV:Abeta as the rest of our portfolio uses the TransportVehicle, so it's transferrin receptor to get across the blood-brain barrier. And what we've learned about Abeta in particular, there's room for improvement. I mean, one, it used to be thought very simply, you remove amyloid, you cause vasogenic edema or what is now termed ARIA. But now that's disconnected. You can remove amyloid much more rapidly and have less ARIA. And it's probably around the biodistribution, similar to what we were just discussing with intrathecal for oligonucleotides.

In the case of antibodies for Abeta, when you deliver using the TransportVehicle technology, you don't have extraordinarily high concentrations in these perivascular spaces that cause breakdown the blood-brain barrier and vasogenic edema. Instead, you get this even distribution throughout brain. And we show that in our science publication in August of last year, how that is differentiated. The other important point is we can preserve the effector function. We can preserve the immunological function of the antibody when bound to amyloid plaque. But when bound to transferrin receptor, we can silence it. And that is through a unique engineering insight where we create a mutation on the Fc that makes it silent when bound to transferrin receptor. That is distinct and I think is unique to the architecture of the transport vehicle.

And so our expectation is a safer profile, the binding to transferrin receptor is integrated to less immunogenicity than what I think is being seen for other brain shuttles and then ultimately, subcu dosing where you have rapid plaque reduction and less ARIA.

And what are the key metrics from the initial Phase I trial in Pompe disease that we should look to understand how that's working out specifically as we look to understand the impact on muscle and bone.

Yes. So shifting gears now back to the enzyme TransportVehicle. Here, we're delivering GAA. There's a series of medicines in Pompe that are enzyme replacement therapies for Pompe. What we're seeing is that there's not fantastic delivery in particular to skeletal muscle. So even with standard of care, there's still a significant unmet need. I think major advances in cardiac, obviously, overall survival is better for IOPD, but a real unmet need. And the question is why. As we engage with -- by the way, the same investigators in Hunter and Sanfilippo are also made of these investigators seeing Pompe patients.

And the general thesis is that standard enzyme replacement therapy for Pompe relies on this mannose-6-phosphate receptor in muscle, which apparently is not highly expressed. And so there's not great distribution of muscle. And so what we see is a very substantial differentiation with any of the standard of care in Pompe when you use the TransportVehicle. This is now enhanced delivery to muscle. Obviously, we'll have delivery to the CNS, which standard enzymes don't have. So that's going to be important. That would be more in IOPD.

But what we're looking at in these early studies, so Pompe is enrolling now, 2027 data as well. And the goal there are these glycogen products to show that we've got the right dose target engagement and then rely on the biology where we have improvement in muscle delivery, which should ultimately lead to clinical differentiation.

Great. And just on the small molecule pipeline here. So following the announcement that the Phase IIb study in idiopathic Parkinson's did not meet its primary endpoint, were there any analyzable trends that you can talk to that played out in these LRRK2 patients?

Yes. I'll take LRRK2. And as you mentioned, the LRRK2 inhibitor was part of our legacy portfolio of small molecules, so completely separate from the TransportVehicle. As you mentioned [Technical Difficulty] which was time to confirm worsening [Technical Difficulty] Part 2 and 3 and importantly, in the idiopathic Parkinson's population. So essentially the all-comers Parkinson's population. The study was well designed. It was well executed. The molecule performed as expected. We saw very strong target engagement and acceptable safety. But I think we have to conclude that LRRK2 inhibition is not the path at least in idiopathic Parkinson's [Technical Difficulty].

Now importantly, we have another study ongoing in parallel of the BEACON study, which is purely focused on LRRK2 carriers. So that is 50 LRRK2 carriers, biomarker study, we expect to see those data by the end of the year. In LUMA, the number of LRRK2 carriers was too small to really look for a signal in the subset. There were only about 10 LRRK2 carriers out of the 650 patients. So that really does not give us any [Technical Difficulty].

Alex, another question for you here. You've been busy in terms all along since the genesis of this company with partnering and business development strategy. Maybe talk to the types of deals that make sense for you from here?

Yes, absolutely. Thank you for that question. I mean partnering business development is a key part of our strategy. We have a track record. We set up collaborations early in the phase of Denali until about half of our portfolio was partnered. Then there was a period when we prioritized wholly-owned programs and advancing those. And now we're at the stage where essentially our portfolio is almost entirely wholly-owned. So that opens up a lot of new partnering opportunity.

The blood-brain barrier field has been very active in the last 2 years. 10 years ago, we were essentially the only ones, but now we see a lot of activity. There's a lot of interest from large pharma. There are a number of smaller companies as well. We've been engaged in many of those conversations. But right now, we're very well financed. We ended Q1 with just over $1 billion in cash. So we have the ability to really advance the program to the right moment in time of when we would do a deal.

I think really to highlight, we are one of the few companies to have a wholly-owned Alzheimer's portfolio as we just discussed, right? There is Abeta, there is tau. There's a lot of preclinical expertise on additional mechanisms, which, at some point, will be a very obvious partnering opportunity. We can definitely generate clinical proof of concept, high-quality clinical proof of concept in patients, and that's probably the time when we would look for the partner.

Follow-on one of the points you made. The space has been really busy around blood-brain barriers and you have some of these larger companies working on their own programs. How do you think about yours, just given the validity here through the commercial assets that are coming out and the defensibility of kind of -- and differentiation of it versus what's playing out in the competitive landscape?

The idea of crossing the blood-brain barrier using transferrin receptor was first proposed in the late 1980s, so this is like the typical story of biotech and discovery and iteration, the industrialization from that academic proposal has been a journey. We started on that journey, as I mentioned, 20 years ago in 2006, that was prior to founding Denali. And what we did is we just made every existing platform that was out there to say, do any of these cross the blood-brain barrier in therapeutic concentrations. And 20 years ago, the answer to that was actually no. There was no existing platform that we had actually tried that was working. And so began the process of the industrialization. The question is what was wrong?

And I think the first challenge was that most of them -- most of the technologies were getting trapped in the blood vessel. You were not getting therapeutic concentrations across the BBB. So now I think of the 20-plus competitors that we count, there's probably 30 that have bonafide blood-brain barrier platforms. 97% of them, 95% of them or 90% of them are all using the original sort of conventional Fab approach. So it's an antibody approach. It's a Fab fusion. And when we founded Denali 11 years ago, we wanted to build a platform that was highly modular, that didn't give up an arm of the antibody or didn't have to, in an unnatural way, attach an arm of the antibody, but integrate the binding into the Fc similar to the FcRn or Fc gamma, and that began the engineering quest to build that in.

And we knew that because we'd already seen the first-generation brain shuttles that were out there. We had already 5, 10 years of experience, and we knew the limitations, which was stability, immunogenicity. That's the challenge with a lot of these Fab fusion, and that was actually in the original publications. And so we built the TransportVehicle in a way that we integrated the binding into the Fc. And it is now and still the only molecule that does that very distinct from all the conventional Fabs. And as you point out, it's now the only molecule that has -- is FDA approved. We will have commercial validation as well, and that allows us now to create an entire portfolio.

Now we had a decision 10 years ago, and as Alex mentioned the partnering strategy, our decision was not to create a technology to enable the world, but to create a technology to enable our medicines and then find a way to collaborate on medicines, not on the platform. But there are other BBB technologies and strategies where the strategy is to out-license the platform. But those, again, are the conventional Fab approaches. And so the transport vehicle is definitely distinct in the way that we engineered it, also have the advantage of a decade worth of experience before building it.

Great. Well with that, Ryan and Alex, thank you so much. We appreciate your time today.

Thank you.

We're going to get started on our next session. I'm Andrew Tsai, senior biotech analyst at Jefferies. Thanks for joining me. And it's my pleasure to have Ryan Watts, CEO of Denali, joining me today.

Welcome, Ryan.

Yes. Great to be here, Andrew.

Of course. So for those in the audience less familiar with the story or revisiting the story, can you maybe help us level set where Denali is, what programs you might be -- there's a lot, but what programs you're working on and the milestones over the next 12 to 18 months could be very helpful.

Yes. Thanks, Andrew. It's great to be here and definitely a lot has happened at Denali in the last year, in particular, especially with our recent approval of AVLAYAH a little more than 2 months ago. And so just as a little bit of a background, we set out to solve, I think, one of the bigger challenges in drug development, which is the blood-brain barrier, inventing medicines that readily cross the blood-brain barrier, especially biologic medicines. It's an area where 11 years ago in the founding of Denali, not many companies were working. And in fact, I think it was in the late 1980s when the first idea of engineering a molecule to cross the blood-brain barrier using some type of natural transporter was proposed, but it's taken from that point till now to actually get the first FDA-approved medicine.

So over the last 11 years, we've invented a platform, which we call the TransportVehicle platform. It's one of these broader categorically brain shuttle technologies using a natural transporter known as transferrin receptor to cross the blood-brain barrier. And looking back now just 11 years ago in the founding of Denali and 20 years ago when we first started working on blood-brain barrier technologies, it's amazing to see how this space has so rapidly evolved and is quickly becoming, I think, the next really hot area in biotherapeutics.

For us, the proof of concept was in enzyme replacement therapy. And I think the reason we chose that as the first place is that enzymes have had a very high success rate. There are a number of enzymes that have been approved, I think, about 85% success rate in developing enzymes for enzyme replacement therapy, but those enzymes do not treat the neurologic manifestation of disease. And Hunter syndrome was the first of now a number of areas that we're going to test this hypothesis that we can take an existing enzyme, engineer it to cross the blood-brain barrier and effectively treat neurologic manifestations, but also whole body. And that's going to be important as we talk about AVLAYAH and its differentiation from potential standard of care.

And so we set out to do that 11 years ago. And for me, it's been a 20-year journey working on blood-brain barrier technologies. And so the approval on March 24 was, I think, a really key step for us. But that approval is just the beginning, obviously, especially for the patient community. But within 2 weeks, we had filled the channel as we call it. And within 3.5 weeks, the first patient was dosed in the commercial setting. And so we are ready to go and have been very excited about the launch of AVLAYAH. I think the reaction from the patient community has been twofold. The first is great enthusiasm. It's the first medicine in 20 years. It's ironic. 20 years ago, we started working on blood-brain barrier. And then it took 20 years to get the first approved medicine that treats neurologic manifestations and the whole body. But also a little bit of disappointment because there is an adult segment in which the label does not cover.

And so a lot of enthusiasm broadly throughout the patient community. So what we've seen is a pretty significant engagement from prescribers and obviously, key opinion leaders and families, and it's been a really exciting time at Denali. So that's where we are today. So the question is what's next? And I think the next 6 to 12 months is also very data rich. We have -- we'll have our second BLA filing for Sanfilippo. We also have begun studies in Pompe disease. So this is another enzyme replacement therapy. And then we have a progranulin replacement therapy. So very similar to enzyme replacement therapy. So a number of medicines. Those are moving forward.

I'll put those categorically in the enzyme franchise. But also what we have to think about is the next big wave. And for us, it's Alzheimer's disease. We're now dosing patients with a MAPT oligonucleotide, which suppresses the expression of MAPT, which leads to reduction in tau protein expression. And we'll soon begin testing in the clinic our own Abeta antibody using the TransportVehicle technology.

And so if you think about the next 6 to 12 months, you're going to be seeing data across the enzyme platform, but also now in the broader neurodegenerative diseases and specifically Alzheimer's disease. And it's just -- worth mentioning that, that is the ultimate goal, I think, of Denali is to defeat degeneration to focus on the neurodegenerative diseases ultimately, but we also believe the enzyme franchise is a great foundation to begin building our commercial footprint.

Great. So again, congratulations on the approval. It's a huge milestone. And so you mentioned you're differentiated because you can cross the brain, BBB benefit clinical manifestation. So as we think about the standard of care starting with Hunter with this launch, ELAPRASE, I think they're doing $700 million worldwide sales. So how are you superior long story short to that product?

So we obviously have a head-to-head study ongoing now. That's the COMPASS study, which is the Phase III confirmatory study for accelerated approval. But I think it's worth noting, and this data was published in the New England Journal at the beginning of the year. The vast majority of patients in that Phase I/II study switched from ELAPRASE to AVLAYAH or tividenofusp alfa at the time. And basically, what we see is, obviously, the most striking is the normalization of cerebrospinal fluid heparan sulfate. That's evidence of crossing the blood-brain barrier. We subsequently see the normalization of neurofilament, which is a marker of neurodegeneration. So that's highly differentiated.

And so recall that most of these patients are on standard of care, but they have elevated heparan sulfate in CSF and in brain. But what's also striking to us is that we can also see a robust reduction in peripheral heparan sulfate. So I think that basically tells you that we're -- based on our dose and also biodistribution that the biomarkers of both the central nervous system, but also the periphery are enhanced with the medicine. And so this is important. And I think we had an important decision to make early on with AVLAYAH, which was around dose.

And part of it was, I think, most enzyme replacement therapies experience what are called antidrug antibodies that recognizes foreign -- this is well known. Infusion-related reactions are the most common adverse effect for all of these medicines and often, I think, are limiting for dose, but we made the decision, especially because of our architecture, which is an Fc fusion to really push dose. And the goal here was to get not just superior brain exposure, but also ideally superior reduction in peripheral biomarkers as well, which we believe will ultimately lead to a broader clinical benefit.

Great. And so you've launched dose the first patient in April, we're in June. I must ask how many -- to the extent you can share how many patients have you dosed, I guess, with AVLAYAH? And are they coming from ELAPRASE? Or are they naive patients?

Yes. So I was thinking about this particular question, which we get often. I mean, it's so early in the launch. It's like 9 weeks since approval, although it feels like a year ago now, immediately becoming a commercial company. What we can say is that we -- the interest has exceeded our expectations. So maybe that shouldn't be surprising. We are debating what are the right metrics to share at the right time to basically provide meaningful data to be able to predict the future of this medicine. I think for now, what we've seen is just great enthusiasm across all patient segments.

So there are those who are newly diagnosed, which come in, as you know, there are about 500 patients in the U.S. and 2,000 worldwide, but especially switch. So in many ways, this is a switch market. And all patients are, generally speaking, known, at least by age 3 or 4. And what we're seeing is a pretty significant interest in switching to AVLAYAH. But I'd say stay tuned on exact numbers. I think we're just -- we're gathering the information now and looking forward to hopefully a very successful launch.

Great. And you mentioned earlier in the community, there's a slight disappointment that the label does not cover all 500 patients in the U.S. So what does your -- what proportion of those 500 U.S. patients does your label cover?

Yes. So it covers 70% to 75% of the population today. So it's the pediatric population. And if you think about actually Hunter syndrome, it's about 70-plus percent that have severe mutations that invariably lead to severe neurologic impairment. But what's been interesting and I think very striking is that neurologic manifestations is seen throughout the entire spectrum of disease, even in what we call attenuated patients. A good example of that is hearing loss. And that's one of our most striking, I think, data points that was published in the New England Journal was improvement in hearing.

And so what the community is generally understands is that this in the label where it states neurologic manifestations, which is linked to the CSF heparan sulfate as the biomarker for accelerated approval that, that basically represents essentially all patients at some point in disease will have a neurologic manifestation if it's behavioral, sleep disturbances, hearing. And so -- but the label itself covers roughly 70% -- 75% of the existing population, so very significant.

And in the meantime, like you said, you're running a confirmatory study called COMPASS. I think the data reads out second half 2027. That's a head-to-head study versus ELAPRASE. That should also -- not only can you prove superiority, but I think -- can you confirm it opens the door to all 100% of the U.S. population.

That is the goal of COMPASS ultimately. And there really -- there are 2 cohorts. There are those that are sort of, I would say, categorically severe neurologic and then those that are -- have been categorized as attenuated, again, all of which experiencing neurologic manifestations. The attenuated patients are generally adult patients.

So in the Phase I/II, we did not enroll any adult patients, although now there are patients who are, by definition, adult that are on AVLAYAH because they began treatment at, let's say, age 14 or 15 and now they're 17 or beyond. So that is the goal of -- ultimately of COMPASS. But I think really where COMPASS has its greatest value is likely ex U.S. is in Europe and unlocking Europe, where it's not just biomarkers that drive approval, but also the correlated clinical benefit that's observed.

Right. And totally understood your sales reps cannot market superiority, but this -- any NEJM article is quite compelling. Is there any way some personnel on your team can flag that to people to convince physicians, patients that you have a differentiated product. I don't know how it works.

Yes. So I think the most important thing for us is when you look at the label is the fact that 9 out of 10 patients have normalized CSF heparan sulfate. I always worry about the tenth patient. In this case, they also have like 85% reduced CSF heparan sulfate. So it's just near normalization. That's a really important piece is that there's no other medicine that has shown that level of heparan sulfate reduction and clearly normalization in cerebrospinal fluid. And that also points to the broader validation of the TransportVehicle technology. So for us, we can just focus on really the data that we have, and it's a very distinct profile from standard of care.

And in terms of -- so there's one volume and then there's price as it relates to sales. So on the pricing side, can you give us a sense of just based on the average patient -- this is weight-based dosing. So the average patient on AVLAYAH, how much it could cost per year and how that would compare to the average price per year for ELAPRASE?

Yes. So the wholesale acquisition cost is $5,200 per 150 mg vial. So this is the vial. Most patients will need 2 to 3 vials per infusion depending on weight. So if you do the math, a 10-kilogram patient will be about $270,000 per year and a 30-kilogram patient will be roughly $800,000 per year. So that's -- obviously, that's the exact pricing dynamic. The medicine is priced at a premium, recognizing the invention and the fact that we're treating not just whole body, but also the brain, which is, I think, a key step here. It's also priced in line with more recent enzyme replacement therapies that have launched. And just if you're doing the math, the roughly 30-kilogram price for ELAPRASE is about $500,000 per year.

Okay. Very clear. And so -- gross to net, any color around that inventory build for Q2? Any color around that?

Yes. So again, I think we -- it's very early days. It depends on the payer, obviously, Medicaid versus private payers. We've -- we're just -- policies are being put in place now. Just reminding myself that we got approval 9 weeks or so ago. And so just stay tuned. But the math is the math. If you know the 340B institutions and the discount that's required, you can do that math. It depends on if it's pediatric only or adult, but you can start -- I mean that will make sense over time, definitely as we launch and you see more data. I would not over-index on 2026. This is a foundation building year for the launch. We're excited and we're enthusiastic certainly by the interest in the community, but it's going to take time, especially as you get payer policies in place.

Okay. Well, things seem to be in the right direction. So congratulations. So then shifting to Sanfilippo then the next leading program that you have, you're filing next year, that's contingent upon full 20 patient worth of data. And my understanding is all those patients should complete around September of this year. When would the data be released though?

Yes. So the data cut is not too dissimilar from when we had the data cut for the filing for AVLAYAH in the sense that we got data sometime in September, October. Obviously go through the database lock cut evaluation. We're aiming towards a WORLD presentation would be February of next year and then filing next year. Right now, the rate-limiting step for us is manufacturing. We made the decision to onshore this manufacturing. So AVLAYAH is manufactured by Lonza and DNL126 for Sanfilippo, we will manufacture ourselves, even commercial product here in the U.S., which we're very excited about. That's the key there.

The -- as we've reported previously, and we'll probably get into some detail, on average, we see about 80% reduction of heparan sulfate. We also can achieve normalization both in heparan sulfate, but also downstream biomarkers of lysosomal dysfunction. What's distinct about Sanfilippo is that it is largely a CNS disease more than Hunter syndrome. So there is components of peripheral disease, but it's mainly CNS. And it is a very rapidly and aggressive degenerative disease, especially with the complete loss of function mutations.

And so even like at the volumetric level, when you look at MRI, you already see patients before you begin dosing have pretty significant volumetric loss. And so I think with Sanfilippo, it's going to -- we need to get a drug approved and then it's going to be about newborn screening to just get there as early as possible to see a huge benefit in these patients. Hunter is -- doesn't have the same volumetric loss. The reason I just state that is that in addition, heparan sulfate is actually 2x higher in Sanfilippo in brain than it is in Hunter syndrome and probably is just where SGSH is expressed versus idursulfase. Interestingly, they're both -- we're both looking at heparan sulfate as this class of MPS diseases.

And so we're really enthusiastic about the initial data. The 20 patients will complete the 49-week point in September, and then we'll begin looking at that data and preparing for filing and presentation in 2027.

Okay. And we've discussed before the next batch of -- technically, the remaining 12 patients to be presented at WORLD are dosed at a higher dose, we should get better efficacy. So to me, the likelihood of success is very high to support an accelerated approval.

And I think just a point related to that, if you look at our presentation from this year, it's what we did with the first 8 patients, it was all about dose finding. It was dose frequency, dose finding, dose levels. And so we started with every other week dosing.

And I think what's really striking is that with enzyme replacement therapies, specifically with SGSH, the drug is better tolerated with weekly dosing. It tells you something about building tolerance. And so having more frequent dosing and having drug on board was an essential learning from that initial study. We then kind of went to what we thought would be the optimal dose to weekly dosing, but many of the patients weren't really at that dose when we took the data cut it and presented it. So at this point, obviously, with the 12 additional patients, we'll be using that optimized dose regimen.

Great. And help us frame the patient sample size in the U.S., the peak sales opportunity relative to Hunter?

Yes. I think it's similar to Hunter. The difference is there is no standard of care. And as a result, not all patients are identified like you have with Hunter syndrome. And so there's no existing enzyme replacement therapy in part because it's a largely neurologic disease. And so standard ERTs are not treating the sort of very rapidly progressing degeneration that is observed in Sanfilippo. But we think the numbers will be roughly similar, maybe a bit smaller. It depends on whose epidemiology you're reading, but obviously, having an approved medicine will be really important in this disease area.

And so because there's no approved medicine as we think about the confirmatory study that I believe you said you're going to start later this year. Is that still the plan?

That's right. So we're in start-up mode right now. We've been used -- using the word start, we were selected as -- for the START program by the FDA, which is quarterly engagement with the FDA around designing the Phase III. We think that's very important. Obviously, again, with no standard of care, the dynamic is different than what we've designed for COMPASS. And so I'd just say with that, stay tuned. We continue to engage with the FDA, but we're definitely in study start-up mode for the Phase III for Sanfilippo.

Yes. And so because of no standard of care, there is this potential maybe to be an open label rather than a placebo controlled, which maybe means you can enroll pretty fast and generate the data pretty fast. Is that the guide?

I think what's implied in that question is that patients are excited to join trials where they know they're going to get active drug. And that's generally true. And certainly, that's been the case with the Phase I/IIs for both of these studies for both of these medicines for both AVLAYAH and for 126.

Okay. Very good. And so I guess, later this year, you'll have a progranulin readout shifting gears in FTD dementia. And it's -- I would just like to know what exactly are you seeing with -- what do you want to see to move forward basically in the study?

So our sort of hypothesis with FTD granulin is that it's a progranulin replacement therapy. So take what we've just talked about with Hunter and Sanfilippo and now apply that to FTD where you have a loss of function, although it's a single copy loss of function. And so we published a paper in 2021 in cell describing the mechanism of progranulin in the lysosome and associated lysosomal biomarkers. And so here, we'll be looking at a panel of biomarkers around lysosomal function, both those are what I call the proximal biomarkers and then also distal biomarkers like NfL.

Our experience with NfL, you can see it in the New England Journal paper is that at least -- and actually for most likely lysosomal storage disease, it takes some time. So at 6 months, we didn't see a reduction, but by 12 months, we are clearly seeing a reduction. And then by 18 months, we're starting to see patients that normalize. So those are the distal biomarkers, both of which are going to be important also in FTD granulin. I think one -- if you look at that paper, the only cautionary note is that the signal to noise for biomarkers with a single loss of -- single copy loss of function is not as great as with the enzyme replacement therapies in some of these MPS diseases.

And so we don't have huge patient numbers, but we do have more than, let's say, like 8 patients or so, which we had in the original LSD studies. And so anyway, so that's -- those are the biomarkers that's what we'll be looking at end of year in Cohort B3.

Okay. Great. And so I do want to spend some time on tau. But before that, you recently had a LRRK2 update for Parkinson's oral LRRK2. Unfortunately, it failed to many people, maybe not too surprising because it did evaluate a broad Parkinson's population, not necessarily just LRRK2 specific. By chance, did you happen to see a signal though in that LRRK2 specific population? Or else, why continue on this other study that you have BEACON to completion, which is evaluating LRRK2 specifically?

So it's interesting. We talked about the last 20 years working on blood-brain barrier. We also in parallel for 20 years, have been working on LRRK2. It was first described in 2004, so I guess, 22 years ago. This is the first medicine to test LRRK2 in idiopathic Parkinson's disease. This is the like, let's call it, the home run study. What we saw is robust inhibition in periphery and brain. And I think it's important to look at the biomarkers that we use to assess that. So one is phospho-serine-1292 or, I guess, it's 935 or something.

We -- that particular biomarker, we saw greater than 90% inhibition in the periphery. In brain, we use phospho-RAB and the reason we use phospho-RAB is the same biomarkers you can't actually measure in CSF. And in a LRRK2 knockout, phospho-RAB is reduced 40%. So 100% inhibition of phospho-RAB is roughly a 40% inhibition. So we're achieving greater than 30% inhibition of phospho-RAB. So again, probably about 90% inhibition. So we think it's a good test of the LRRK2 hypothesis in idiopathic Parkinson's. The study itself only enrolled 11 LRRK2 carriers. So it's too few. In fact, really only 10 that have full data sets. One was from the original LIGHTHOUSE study.

And so we don't have enough data to be able to determine if there's a signal or not in LRRK2. So that's a very specific answer to your question. I think 5 placebo, 5 treated with data. The BEACON study is only LRRK2 carriers, 50 patients enrolled. But I think importantly there, it's focused on LRRK2 specific biomarkers. And so we want to read -- that data will read out by the end of the year, and we'll understand where we're at from really the target engagement perspective with the medicine. It is not designed to look at UPDRS, unlike this 650-patient study, the LUMA study, which was powered for clinical efficacy.

I see. And then finally, then shifting gears to your Alzheimer's portfolio of tau and Abeta like you said, starting with the tau, it's pretty interesting. Biogen just shared their own tau intrathecal, given intrathecally. I think you have an IV version. And so what is going to be the exact dosing frequency of your IV? And is there a possibility to even go to subcu over time with...

I mean we could have started here. There's so much to talk about in Alzheimer's disease. And certainly, if you look at our portfolio, the most competitive area is tau and Abeta not surprisingly using the transport vehicle technology. So DNL628 is what we call OTV MAPT, and OTV is Oligo Transport Vehicle. It's delivering an antisense oligo to MAPT, delivered IV and/or subcu. The ultimate goal will be subcu delivery for these medicines. We're obviously, again, optimizing dose. Therefore, IV is the best place to start. And our goal there is to see tau reduction with a systemic delivery of an oligonucleotide. And I think the recent data from Biogen is very encouraging.

I think it's like early days Abeta, where you're looking for a correlation between reduction in some pathological marker. In this case, it would be tau or tau imaging, leading to some correlation with clinical benefit. I think the numbers are small, so probably looking at all treated patients pooled. The biggest difference between the intrathecal delivery and the systemic delivery is the difference in biodistribution. So with intrathecal, this is our own data, but also data presented by Biogen and others, you have basically pretty significant heterogeneity from patient to patient, but also within the brain. So a lot of intrathecal delivery, you get great delivery around areas that are adjacent to cerebrospinal fluid, but not into deeper brain regions. When you deliver with TransportVehicle technologies, you can actually cross capillary beds, and we've shown this even distribution and even knockdown of expression.

So we think that will dramatically reduce the heterogeneity. And also, we don't -- like when we look at monkeys that are treated with OTV, we have even from monkey to monkey, the same distribution in the brain, whereas when we do intrathecal, some monkeys will get good brain distribution, some will get less, some will get none. And even when you're injecting it intrathecally, there's pretty significant variability.

I see. So aside from the dosing convenience, you saturate the brain better, I guess that could lead to better efficacy overall, more patients response...

Yes. When you think of where tau pathology exists in entorhinal cortex, hippocampus, ultimately cortex, there is an unevenness about the adjacency to cerebrospinal fluid. And so it's better to have a technology that gives you that even distribution.

Yes. I guess there's a debate in the community, does -- is it your view stronger tau reduction leads to greater cognitive benefit? Is there too much tau...

Well, I mean, if anything, what you saw from the Biogen data is that, again, taking it at face value, the lowest dose had the greatest benefit. That's probably because the lowest dose had the fewest number of patients and subject to the most heterogeneity would be kind of my explanation, but let's wait until we see the totality of the data. But the reality is that there doesn't seem to be a dose response. So if the higher dose is giving you more tau reduction, it's not necessarily leading to better cognitive benefit. So I just think it's too early.

We'll just wait for the data in July...

Yes and probably need more data to...

And so then Abeta also starting Phase I, this is interesting. So the tau, I think you're starting -- you're doing Phase I in actual patients. And then the Abeta, I think you're starting SAD doses in healthy volunteers first, then MAD dosing in actual patients. Data -- all the data is in 2027. But in healthy, what exactly do you want to see? Why is that important?

Yes. So I think we published a paper in science last year in August that describes our approach to Abeta. And there are 2 major differentiators. One is, again, the biodistribution that leads to even plaque reduction and less ARIA-like effects in mice and hopefully in humans, so less vasogenic edema, which is one of the limiting factors, right? The other is we engineered the molecule to be immune silent when bound to transferrin receptor.

And as a result, it preserves any reticulocytes that express very high levels of transferrin receptor. So the advantage of doing a healthy volunteer study is we can very rapidly test that first hypothesis or the second hypothesis around [ RTIX ] in particular, in hematology, and then we can rapidly move to patient studies and look at plaque reduction. So the ultimate goal for differentiation is a safer, ultimately subcu delivery with robust plaque reduction. That's what we're trying to achieve with ATV-Abeta DNL921.

Right. Okay. I think that's all the time we have, but I look forward to connecting with you in a few months, and then we'll talk again. But thank you, everyone, for listening.

My pleasure to have our next presenting company, Denali Therapeutics. Sitting up here on stage with me is Alex Schuth, who is, of course, Chief Operating Officer as well as CFO, double duty. Alex, thank you for making the, hopefully, short trip over to see us in the desert today.

All right. Well, again, thank you, Tazeen, for inviting us for a fantastic conference. But really also thank you for following us for many years now and the always very thoughtful commentary. So much appreciated. So great to be here today. It's a special time for us at Denali.

As you know, we just had our first drug approved in March, big transition for us. Big moment for Denali, but also a big moment for the Hunter syndrome community. And I think importantly, also a really big moment for the whole field of blood-brain barrier transport. So looking forward to the conversation and going deeper on all of those topics.

Yes. So maybe let's start off with your first commercial launch. How is that going so far? And I've been asking everybody to pronounce the name of their drug so that we're saying it correctly.

So this one here, if you think about Star Wars, it's [ Avlaya]. So once you think about Star Wars, you can get -- you also think about the Himalayas and then you can also remember. So the drug's name is AVLAYAH. And it is, of course, indicated for the treatment of Hunter syndrome, a rare pediatric disease, which has a severe neurodegenerative component. And our technology, as you know, is designed to treat the whole body, including the brain. So a major unmet medical need in all of lysosomal storage disease, and especially in Hunter, is that traditional enzyme replacement therapy, doesn't cross through the blood-brain barrier.

So we have shown in our clinical trials that we can very effectively deliver the drug to the brain, normalized all biomarkers, showed stabilization and improvement in measures of function. So with that, we achieved accelerated approval. So the drug was approved on March 24. We're very excited about the early days of that launch.

Yes. So can you share a little bit about how that's looking?

Yes, very much so. So we're excited about the level of engagement. We're excited about the level of interest and importantly, across all patient segments. So while at some point, we thought the first patients to be engaged might be the ones that are on the earlier diagnosis or younger, but in fact, we see that across all age groups and across all levels of severity.

So we have indicated at our quarterly report that we now have the first patients that are actually on drug in the commercial setting. These are not patients that came up from our clinical studies, but that actually were not associated with that. In one case, it was a very quick transition. It took 3.5 weeks after approval to go through the medical exception process.

We're also quite encouraged with respect to the number of start forms that we're seeing. We're not sharing that number yet. I know you may ask. But the reason why we don't share this, we want to have more confidence in what the start forms actually mean. We want to have 1 quarter of experience, how long does it take us to get in this sort of buy-and-build setting to get through the multistep process to actually turn start forms into revenues. But from an engagement and an interest perspective, I think we're safe to say that we're ahead of expectations.

Okay. So it's exciting in that you have your first opportunity for a commercial launch. But to level set expectations, this is still an ultra-rare disease. So what is your expectation for patient finding efforts? And what clip of uptake would be a good launch in your definition?

Yes, great question. So first, with respect to the patient, so it is ultra-rare, but it's unique because there has been a standard of care on the market for 20 years. And essentially, every patient with Hunter syndrome is identified. So this is not as much of a finding and identifying the patient setting, but about a switch setting, right? And switching very much depends on the level of enthusiasm in the patient community and in the physician community. So from that level, from that perspective, we're very encouraged about the early indications that we see.

With respect to the market opportunity, it is ultra-rare, but ELAPRASE is a good -- is the standard of care. It is a good guidepost. It sells about $700 million a year. We believe that we have a drug that shows definitely some aspect that ELAPRASE cannot do. It can get into the brain. It can treat the whole body.

With respect to pricing, right, there is a premium that was justified based on the clinical profile. So we see that this can be a very substantial market opportunity. What we guide to is typically, we look at our first 2 enzymes together. So that's AVLAYAH and then DNL126 for Sanfilippo, that those together are a $1 billion market opportunity, but it's -- I would say that that's on quite conservative assumptions.

Okay. So what do you think is going to be the criteria for patients who want to switch?

We actually see -- I mean, from the early interactions, we see a lot of interest in switching. And as I mentioned, across the patient segments, right? The way the label is written right now, it is indicated for the treatment of neurologic manifestations in pediatric patients, and also has a subset about -- in symptomatic and presymptomatic but symptomatic and presymptomatic is essentially everyone, right? So it's in pediatric patients, which is about 70% of the patient population. And our commercial efforts are focused on that entire segment. So that's what we look at.

Okay. I think some have thought that the label was a little bit more limited than was expected when it first came out. Like, is that a right interpretation?

Yes, we don't see it that way. I mean, I will give you -- it does read a bit clunky at first when you read it. But at the same time, that gives our field team a really good opportunity to educate physicians on it. If you really look at it, it is really all pediatric patients and again, with -- for the treatment of neurologic manifestations. But it is pretty well established that in Hunter syndrome, essentially all patients either have or will develop neurologic manifestations.

So if you really talk about it, the treatment of neurologic manifestations is not a limitation. In fact, it actually highlights the key attribute of our drug that it actually gets into the brain what the standard of care is not able to do. There is also a limitation on less -- not less than 5 kilograms, which is essentially a 3-month old child, which was linked to -- that this was the patient population that we studied and it was important to the FDA to mirror the label as closely to the study population as possible.

Okay. Do you foresee that label changing over time?

We do. We do expect that with the readout of the confirmatory study, that's the Phase II/III COMPASS study, which we expect data by the end of next year, so a little over 1.5 years [ ago ], that the label would be expanded. In the COMPASS study, we have adult patients. We have patients up to 26 years of age. So we would expect that the limitation to pediatrics would be lifted.

What would you say is the level of undermet need for the adult population, relative to the pediatric population?

Yes. There is a very strong understanding that the current standard of care is not optimal. And when you speak with even older patients that are designated as non-neuronopathic -- and by the way, that old distinction between neuronopathic and non-neuronopathic is really sort of fading away in clinical practice, and it's much an understanding that it's more of a continuum. And essentially, all patients have neurologic manifestations.

So if you speak, for example, with some of the older patients, they will talk about hearing loss, that they have reduced hearing. We have shown very definitively an improvement in hearing. We have anecdotal evidence that some of our children don't need hearing aids anymore. Older patients will talk about brain fog. They will talk about even irritability, right? Those are neurocognitive and behavioral symptoms that a drug that can actually cross through the blood-brain barrier can address.

Okay. So what are you hearing on feedback about the dose escalation aspect of the drug? How are doctors adjusting to that?

Yes. It's going very smooth, right? So the context here is that we instituted a 3-step dose escalation or a 2-step until you get to the final dose. And the context here was really with respect to the patient experience, right? Enzyme replacement therapy -- all enzyme replacement therapy is associated with infusion-related reactions. And we want to make sure that the early dosing happens in a medical setting where infusion-related reactions can be managed.

So what that does require is that patients for the first, about, 12 doses or so for the first 3 to 4 months come back into the hospital setting. But -- I mean it's early into the launch, but we do not see that as a barrier.

Okay. In terms of the ex U.S. rollout, how should we be thinking about that?

Yes. So our focus right now is definitely on the U.S., but much of the market opportunity is global. So what we have set in place is distribution agreements covering actually most parts of the world, so in LatAm, in the Middle East, in Asia Pacific, actually a separate one in Israel. We have many connections through the clinical trial in Europe as well, where we're working on a named patient sale.

So we are establishing those relationships with the physicians and with the families. And we do work, wherever possible and however possible, to bring those patients on to commercial drug. But with respect to our guidance, our focus, it's very much a U.S. launch at this point.

Okay. Great. So as you think about how this launch is going to mature, how do we set expectation? Because investors always want to get a sense of what the peak sales opportunity is going to be and how long is it going to take to get there, and how strong is your pricing power, so maybe if we wanted to think about it in totality, what advice would you give us?

I mean, again, there's ELAPRASE, $700 million. We have a drug that is superior to ELAPRASE. We have a significant premium on the price to ELAPRASE. Also remember, it is weight-based dosing, right? So what we see in our trials or what we would expect is that as children live longer, as they grow older, as they grow heavier, right, the price per patient would also increase. So $700 million is, I think, a conservative guidepost of what we can achieve.

Now what the slope looks like, right? I think we will have to wait for some time as we really understand what does it take between the start form, how -- what does it take to actually turn that into revenues. We're gathering experience right now on that. What does it take -- as the reimbursement policies are not in place yet, neither with the commercial insurers nor with Medicaid, of course, we're gathering that experience.

We are getting the question, when do you show more metrics, right? And you may ask it as well. And just to preempt that, we will show metrics. We just want to make sure that we have confidence in those -- what those metrics actually mean, right? And that's why we don't want to speak about start forms too soon without really, with confidence, being able to say, once we have a start form on average, it takes us this long to translate that person into a commercial person, but we'll get there.

Is there any reason to think that some doctors might wait until you get a full approval before embracing this drug?

We have not heard that, right? We have not heard that at all. It was -- we -- and I think part of that is the very close engagement of the physician community in the clinical trial. It was a relatively large clinical trial program, 110 patients, right, between the Phase I/II and the Phase II/III out of a -- in an ultra-rare disease. It is -- almost all centers of excellence, in one way or another are, if not direct, right, at least in one separation, involved in this trial.

So if you had to find all the Hunter's patients in the U.S., how long do you think it would take you to do that, just given what you had said a few minutes ago about this being a rare disease, but a treatment already being available before?

Yes. So we actually know all of the patients in the U.S. already. I mean you can through prescription data, right? This is very well documented. So we know where they are treated. And our field team has already been in touch with every single treating physician. So the identification of the patients will not be an obstacle.

Right. So would you say that insurance coverage is going to be the main rate limiting factor here?

So we don't think so. So we have engaged with all major payer systems, the national ones, the regional ones. We have a very strong payer team in-house that is working on that. Many of the -- or the patients that came early on, the prior authorization process, the medical acceptance process has gone smooth. We have had some denials, but that is also as expected. Some of these denials are just the normal routine if the reimbursement policy is not established. So we're quite encouraged about the reimbursement.

Okay. Maybe let's talk about Sanfilippo now. Just remind us where you are with that indication, and sizing-wise, how it would compare to Hunter.

Yes. So -- and thanks for asking this because we are very excited about AVLAYAH, but what we're also tremendously excited about is, of course, the proof of concept for blood-brain barrier transport more broadly, right? And we have a broad portfolio enabled by the TransportVehicle. On one hand, a whole what we call the franchise of enzyme replacement therapy, and then beyond that is other neurodegenerative diseases, right? We have the tau program and the Abeta program. The enzymes we feel is the commercial foundation of the company. And then neurodegeneration is sort of the upside potential.

Now the first back -- the first next on deck on the enzyme replacement therapy franchise is DNL126 for Sanfilippo. So here, that's MPS IIIA. At the WORLD conference in San Diego in February, we showed very encouraging data from the first -- from the Phase I/II study, where we have a mean 80% reduction of heparan sulfate.

Heparan sulfate is the biomarker -- measured in CSF is the biomarker that is qualified by the FDA as being reasonably likely to predict clinical benefit and therefore, the basis of accelerated approval. So 80% mean reduction in heparan sulfate normalization in some patients. So that gives us confidence that we have the data package to submit the BLA next year and potentially achieve approval by the end of next year.

What do you think of FDA's actual interpretation of HS because there's been some controversy around that?

In our conversations, the FDA -- so there was -- 2 years ago, there was the Reagan-Udall Foundation meeting, which brought together regulators, academics, industry and patient groups and the role of heparan sulfate was discussed and that marker was qualified. I think some discussion was around the extent of reduction of heparan sulfate. I mean we don't know where the FDA's bar is, but we normalize heparan sulfate for Hunter syndrome. And in Sanfilippo, we have 80% with some patients already normalizing, right? So we feel very good about the extent of that.

I didn't answer your question on the size of Sanfilippo. Generally, we think Sanfilippo is about the same market size as Hunter syndrome. Epidemiology is not as well understood because there is no standard of care. But we feel that they -- it's maybe a tad bit smaller, but it's about the same.

And are the doctors who treat Sanfilippo the same as those who treat Hunter?

There is almost perfect overlap between the 2 of them, very similar treatment centers, treating physicians. The communities are often together as well. So you'd have -- we were just in Napa on a community event, you have the MPS Society and then you will have patients with MPS II and patients with MPS IIIA. They have a lot of cross interactions as well. So a lot of synergy there.

Okay. And then I'm sorry if you mentioned it, but when is the plan for the BLA filing here?

BLA filing in 2027 and potentially approval, depending on when the BLA filing happens, also in '27.

Okay. So that could be next year, which is right about [ Hunter ]?

That's right.

And in terms of the infrastructure that you've built, would you just be able to leverage that for this [indiscernible] trial?

Almost perfect synergy on the infrastructure. We do not expect to expand the team. Obviously, some marketing material has to be made, et cetera. But other than that, it's -- we can slot the next program right in, which is also true for several of the other enzymes that we have, right?

So the next one then is for Pompe disease, where we're about to start our first clinical study. That is for the first time then testing the benefit of transferrin receptor in the periphery, right? So more improved muscle distribution, bone distribution. So that will be an exciting expansion of our ETV portfolio.

And Pompe is, relatively speaking, crowded, right? Because you do have Amicus and Sanofi there already, so what would you say is the added advantage?

It is -- so if you speak with KOLs and with families, patients are weak. They don't do really well. And mostly, that is about the imperfect muscle distribution. So standard enzyme replacement therapy relies on mannose-6 phosphate receptor. Mannose-6 phosphate receptor is not very highly expressed on the muscle, but what is highly expressed is transferrin receptor because muscle need lots of iron.

So if you want to drive something into muscle and bone, transferrin receptor is the way to go. So what we expect, and we see this preclinically -- but we expect that we could probably really have a significant impact on the musculoskeletal system.

Okay. I should actually say not Amicus, but BioMarin. That switch rate from Sanofi to the now BioMarin asset was a little bit slower than what people anticipated. Do you think that it's because those are not particularly differentiated assets from each other and your focus on transferrin could be much more notable and thus be potentially much more appealing?

That's our hypothesis, right, that just like with Hunter syndrome, it's not -- AVLAYAH is not an incremental but a stepwise benefit over the standard of care, and we would expect the same, hopefully, with Pompe.

Okay. All right. So let's move on to Parkinson's as we move up away from enzyme replacement type diseases, more into neurodegenerative diseases. So you've got this 151 BIIB122 partnership. So can you talk to us about what's going to be presented? And what would be the data?

Yes. Happy to do that. So for context, this is our last remaining product, which is a small molecule. So when we started Denali 10 years ago, we had large molecules and small molecules. Once we had confidence in the TransportVehicle, we spun out all of our preclinical small molecules as a separate company right now. The one remaining is the LRRK2 inhibitor in collaboration with Biogen for Parkinson's.

So this is very compelling biology, right? So mutations in LRRK2 are one of the strongest genetic risk factors for Parkinson's disease. LRRK2 is a kinase. The mutations are gain-of-function mutations. And when this kinase is overactive, the lysosome coalesces. And then when the lysosome coalesces, it doesn't process protein very well. Most of the neurodegenerative diseases are protein misfolding, protein accumulation diseases.

So the effect here would be inhibit LRRK2, improve lysosomal function, therefore, improve neuronal health and improve outcome in Parkinson's, right? So that's the biology, very compelling biology. We also know that we have a good compound. We tested it in a large Phase I, Phase Ib study, where we showed a dose-dependent improvement in lysosomal function.

The study that will read out, which is led by Biogen, so also the timing is determined by Biogen, is a 650-patient study with a clinical endpoint. It's UPDRS, the Unified Parkinson's Disease Rating Scale, Part 2 and 3. And it's a study that measures the rate of the progression of decline. So what we look for is for a clinically meaningful slowing in the rate of the progression of decline.

And would this be designed to be used instead of levodopa or with?

So it is a disease-modifying -- is actually the -- it would be the only and the first disease-modifying treatment in Parkinson's disease, while levodopa is a symptomatic. And ultimately, you would probably expect a -- those are 2 very different approaches that would be used in combination there. The study, by the way, includes both treatment-naive patients and patients on levodopa.

Okay. But do you have a sense of where it would work better?

I think we have to wait for it. I think we have to wait for the data. Yes.

So LRRK2 -- a few companies are looking at LRRK2 as a target. So on the one hand, it's good because several people want to pursue it. But how do you think about differentiation if that's the case?

Yes. So we have a very direct mechanism, right? It's a kinase. We have a kinase inhibitor. We know that overactive LRRK2 leads to dysfunctional lysosomes. We have shown that we can improve lysosomal function. Other approaches are a bit more indirect, either as protein degraders or other approaches. But honestly, we can hypothesize preclinically, but we would have to -- I think, here, the right thing to do is wait for the clinical data, wait for it to read out and then take it from there.

The one point that I do want to make on this program is that there are 2 studies ongoing right now, right? There is one that is -- that we just talked about, which is reading out with Biogen, which is in idiopathic Parkinson's disease. And there is a second study called BEACON, which is only in LRRK2 carriers. The strongest biologic rationale is in LRRK2 carriers. So the real decision about the future of this program would have to be made in the context of the readout of both of those studies, which would be by the end of this year.

And what percent, just remind us, of Parkinson's patients are LRRK2 carriers?

Yes. It's about 2% to 3% of Parkinson's. So there are about 1 million Parkinson's patients, so there's about 20,000 to 30,000 patients in the U.S.

Okay. In the few minutes we have, I did want to talk about Biogen's read-through for their tau program to yours. So is there a scenario where their readout does not bode well for Denali?

It's a good question. I mean we think the readouts are skewed in our favor, right? So Biogen is testing the tau hypothesis, but with a severe limitation on biodistribution, right? So Biogen's ASO in collaboration with Ionis is intrathecally administered. which has liabilities in itself, but the real limitation is that you do not have perfect distribution throughout the CNS, while the big advantage of going through the bloodstream with transferrin receptor, 300 miles of blood vessels in the brain, every neuron has its adjacent capillary, we have like perfect access to that.

So if Biogen sees some link between tau reduction and cognition and improvement in cognition, that's fantastic, right? If they don't see anything, it might be the issue on just imperfect biodistribution. I'll give you an example. An analogy is, back to Hunter syndrome, Takeda, a long time ago, ran an intrathecal ELAPRASE trial, and it didn't work, right? Intrathecal administration does not distribute the brain -- does not distribute drug very well in the brain.

Okay. And so basically, what you're saying is unless it doesn't show anything at all, it's good for Denali.

I think there is an outsized scenario where patients might actually get worse, but it's probably unlikely, and that would not be good for the whole field.

How should we be thinking about differences in the safety profile between a brain shuttler like Denali's versus the approach that Biogen is using?

Yes. I mean it is the safety profile. Again, we've -- this is the great -- one of the great things about having a drug approved with Hunter syndrome, AVLAYAH, this very strong support for the safety profile. We have patients on drug for over 5 years now dosed weekly, 15 milligrams per kilogram, a high dose. So we know it is safe.

Intrathecal administration is not perfect. It's not ideal at all, right, in -- the number of puncture with all the associated liability. So there is definitely a safety and convenience improvement, but really what we hope for is an efficacy benefit.

Okay. And then maybe last question is going to be on your 593 asset for FTD. Just talk to us about where you are in development there and when we should expect to see the next data set.

Yes. So 593 is what we call PTV, protein transport vehicle-enabled progranulin. So this is in FTD, frontotemporal dementia. A subset of those patients lacks progranulin. Progranulin again, is a lysosomal protein. It is important for lysosomal function. We substitute progranulin. So it's a very direct mechanism. You can almost think about enzyme replacement therapy. This is like protein replacement therapy.

So it is a mechanism that very directly addresses the lack of protein in these patients. We have shown in a Phase I that we can deliver safely large quantities of progranulin up to 27-fold the physiological levels. Now in this Phase Ib, what we look at in 40 patients with frontotemporal dementia granulin, if we can actually improve lysosomal function.

So by the end of this year, the study will read out, and we will look at proximal and distal markers of lysosomal function and then neuronal health. So markers of lysosomal function, GM2, GM3, Glucosylsphingosine, is what we primarily look for. There is an outsized scenario where we also look at neurofilament, right? So neurofilament would be the ultimate determinant that we can actually improve neuronal health. But remember, it's only a 6-month study. So in that short period of time, there is -- it's not impossible, but really what we focus on here is improvement in lysosomal markers.

And what about the view that for neurofilament, you need at least a year's worth of data because it seems like, with other programs from other companies, it's been kind of a noisy results?

That's probably right. We saw in Hunter syndrome, it took 2 years to normalize. On the other hand, you have, in some genetic forms of ALS, it took only 6 months. Tofersen was 6 months to really reduce. So there is a lot of variability on neurofilament.

Yes. So what would you, longer term, want to see to feel confident in this program then?

Well, early on, improvement in lysosomal markers, longer-term reduction in neurofilament, and that will give us the confidence to then actually go into an efficacy study next.

Okay. Perfect. With that, we are out of time. So thank you, Alex, for [ staying ] with me for the last 30 minutes, and thanks, everybody, for joining us.

Thank you.

Thank you for standing by, and welcome to the AVLAYAH FDA Approval Call. [Operator Instructions] As a reminder, today's program is being recorded. And now I'd like to introduce your host for today's program, Laura Hansen, Vice President of Investor Relations. Please go ahead.

Thank you Jonathan, and good day, everyone. Thank you for joining us today for our AVLAYAH FDA approval conference call. I'm Laura Hansen, Vice President of Investor Relations at Denali Therapeutics. Joining me on the call today are Ryan Watts, Chief Executive Officer; Alexander Schuth, Chief Financial and Operating Officer; Peter Chin, Chief Medical Officer; and Katie Peng, Chief Commercial Officer. Earlier today, we issued a press release announcing the FDA approval of AVLAYAH. The press release and the slide presentation to accompany today's call are available in the Investor Relations section of our website at denalitherapeutics.com.

Before we begin, I'd like to remind you that today's call will contain forward-looking statements within the meaning of the federal securities laws, including statements related to the approval, commercial launch and potential therapeutic impact of AVLAYAH tividenofusp alfa-eknm, our expectations regarding patient access and uptake, the potential addressable patient population and our plans and objectives for commercialization and future operations. These statements are based on information available to us as of today and are subject to risks and uncertainties that could cause actual results to differ materially. We undertake no obligation to update these statements, except as required by law.

For a discussion of factors that could affect our results, please refer to our recent SEC filings, including our annual report on Form 10-K and its risk factor discussion. On today's call, we will discuss the U.S. Food and Drug Administration's approval of AVLAYAH, the first enzyme replacement therapy designed to cross the blood-brain barrier using our transport vehicle platform for the treatment of Hunter syndrome, and we will outline plans for commercial launch. Following our prepared remarks, we will open the call for your questions.

And with that, I will turn the call over to Ryan.

Thank you, Laura, and thank you all for joining us on short notice. Many of you have followed our progress over the years, and this is a significant moment for Denali. We're excited to share what this approval represents. To begin, I want to recognize the Hunter syndrome or MPS II community that made this milestone possible.

As shown on Slide 4, each of these photos represents just a few of the individuals and families who have been so instrumental in reaching this moment. We are deeply grateful to this community for their partnership, their courage and for continually challenging all of us to move faster and do better. At the same time, this approval reflects the collective efforts of many, including clinicians, researchers, advocacy partners and especially the entire Denali team, all working with a shared sense of urgency to address a devastating rare disease. We also want to recognize the FDA for a rigorous, thoughtful and highly constructive review process. This approval under the accelerated approval pathway based on a surrogate biomarker represents an important scientific and regulatory advancement. It underscores both the strength of the data and the shared commitment to bringing meaningful therapies to patients as efficiently as possible while continuing to build the evidence base.

Hunter syndrome is a progressive life-limiting condition that affects children from a very young age. While some aspects of the disease have been managed historically, the neurological manifestations have remained largely out of reach. What has always stood out to us is the clarity of what this community has been asking for, therapies that reach the brain. That input has shaped how we think, how we design our studies and how we move with urgency and purpose. We view this moment as a shared achievement and also as a responsibility to continue delivering for this community. And importantly, we believe this regulatory path may help open the door for future programs targeting similar diseases.

With that foundation, let me highlight why this approval represents such an important inflection point, both for the MPS II community and for Denali on Slide 5. First, this is a historic FDA approval. AVLAYAH is the first and only therapy for Hunter syndrome designed to address the whole body, including the brain, directly targeting one of the most critical unmet needs in this disease. Second, this marks the first meaningful therapeutic advance for MPS II community in nearly 2 decades. Importantly, AVLAYAH demonstrated significant reduction and normalization of cerebrospinal fluid heparan sulfate, a key disease biomarker, supporting activity in the central nervous system and forming the basis for this accelerated approval. Third, this approval validates our transport vehicle platform. This is the first FDA-approved biologic and a new class of medicines engineered to cross the blood-brain barrier, one of the most persistent challenges in medicine. Fourth, this milestone has broader implications beyond MPS II. It provides a regulatory and scientific framework that may inform the development of other programs, including DNL126 for Sanfilippo syndrome and additional lysosomal storage disorders. Finally, this establishes the foundation for Denali's lysosomal storage disease franchise. We are entering commercialization prepared. And we see this as the beginning of a broader opportunity to address diseases across the MPS spectrum.

Stepping back, as we noted in our announcement, this milestone validates our platform and its potential to overcome the long-standing challenge of delivering biologic medicines across the blood-brain barrier with the aim of transforming treatment for a wide range of serious diseases. Taken together, this is not just a single product approval, it represents a meaningful step forward for patients and an important advancement in how therapies can be developed and approved and a defining moment for Denali.

So building on what I just outlined, both the significance of this approval for MPS II community and what it represents for Denali, let me walk you through how we will spend our time today on Slide 6. I've just framed the key messages coming out of this approval and what we believe matters most from a clinical, scientific and strategic perspective. Next, Peter Chin will take you deeper into Hunter syndrome, the disease burden, the long-standing unmet need and why reaching the brain has been such a critical challenge for this community. Peter will also review the clinical data and the FDA label for AVLAYAH, including the biomarker evidence supporting approval and how we're continuing to build the data set through our ongoing COMPASS study. Katie Peng will then present our launch readiness and commercialization strategy, including how we're working closely with the community to enable access. I'll come back at the end to connect this approval to the broader Denali story. particularly how it advances our transport vehicle platform and expands the opportunity across our pipeline. And then we'll open it up for questions.

I will now turn the call over to Peter.

Thank you, Ryan. Turning to Slide 8. Mucopolysaccharidosis type 2 or Hunter syndrome is a rare inherited lysosomal storage disorder caused by deficiency of the iduronate 2-sulfatase or IDS enzyme. IDS deficiency leads to accumulation of glycosaminoglycans or GAGs throughout the body. The disease course can vary across patients, but progression begins early in childhood and life expectancy in severe forms often extends only into the teenage years. Cardiac and respiratory failure are the leading cause of premature mortality.

On Slide 9, MPS II is a multisystem disorder with manifestations that can affect nearly every organ system as depicted on the figure on the left. The most prominent neurologic manifestations are progressive cognitive decline and behavioral changes, but can also include motor impairment and hearing loss. At the same time, patients develop significant peripheral disease burden, including cardiac, respiratory, skeletal and gastrointestinal complications. Because of this, it is important to address both the peripheral manifestations and the disease in the brain with a whole body treatment approach.

Turning to Slide 10. The current standard of care for MPS II is intravenous enzyme replacement therapy, which does not cross the blood-brain barrier. There remains a significant unmet need for therapies that can address the neurologic manifestations and better address full body disease. As a result, neurologic manifestations, including cognitive decline, behavioral symptoms and hearing loss remain inadequately addressed. Moreover, patients may continue to experience peripheral symptoms and show abnormal urine GAG levels even after treatment with IV ERT, and cardiac, skeletal and other manifestations may persist or progress despite treatment. Thus, new therapies in MPS II should aim to address both the neurologic and peripheral manifestations of disease. This is exactly the challenge AVLAYAH was designed to address. With today's approval, we now have a therapy engineered to reach both the periphery and the brain, enabled by our transport vehicle platform.

Let's go to Slide 12 to discuss further how that works. AVLAYAH uses Denali's transport vehicle technology, which is designed to optimize delivery of biotherapeutics across the blood-brain barrier. The approach leverages the transferrin receptor, which is naturally expressed on cells of the blood-brain barrier and throughout other tissues. AVLAYAH is designed to deliver IDS to both the brain and the body.

On Slide 13, the clinical data supporting AVLAYAH were recently published in the New England Journal of Medicine, describing results from the Phase I/II study of tividenofusp alfa in pediatric patients with Hunter syndrome. Treatment with tividenofusp alfa produced large and sustained reductions in biomarkers of disease activity in both the CNS and the periphery. CSF heparan sulfate, a biomarker of primary substrate accumulation in the CNS and the basis of this accelerated approval was substantially reduced to levels seen in unaffected children. Neurofilament light, an established marker of neuronal injury was also reduced to normal levels. urine heparan sulfate normalized to levels in unaffected children, reflecting clearance of peripheral substrate in both previously treated and ERT-naive participants.

On Slide 14, overall mean change in Vineland adaptive behavioral raw score functional composite demonstrated continued skill gains over time. Bayley Scales cognitive raw scores similarly demonstrated improvement with continued cognitive skill gains. Improvements in hearing threshold as assessed by pure tone average were maintained throughout the period of follow-up. These data show the potential for treated patients to improve or stabilize meaningfully.

On Slide 15, with respect to safety, infusion-related reactions, a known risk of ERTs were the most common adverse event, decreasing in incidence and severity over time. Hemoglobin levels remain generally stable during treatment following an initial decrease. Overall, the safety results were consistent with ERTs and manageable for chronic therapy. Taken together, these data represent the culmination of years of work to address the full spectrum of peripheral and neurologic manifestations of Hunter syndrome, applying our understanding of the disease and leveraging the transport vehicle platform to deliver therapy to the whole body, including the brain. Importantly, this body of evidence has now translated into regulatory recognition in the United States, marking a meaningful step forward for patients.

With that context, I'll turn to Slide 16 to highlight key elements of the AVLAYAH U.S. prescribing information. Here are select highlights of the U.S. label. AVLAYAH is now approved under U.S. accelerated approval for the treatment of MPS II based on CSF heparan sulfate as a surrogate biomarker reasonably likely to predict clinical benefit. AVLAYAH is indicated for the treatment of neurologic manifestations in patients with Hunter syndrome when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kilograms prior to advanced neurologic impairment. AVLAYAH is not recommended for use in combination with other enzyme replacement therapies. The recommended AVLAYAH maintenance dosage is 15 milligrams per kilogram administered once weekly as an intravenous infusion over approximately 4 hours. Treatment should be initiated with a dose escalation regimen. The prescribing information reflects the robust effects on the primary substrate of IDS in both CNS and periphery.

With respect to CSF heparan sulfate, treatment with AVLAYAH resulted in a significant 91% mean reduction of CSF HS from baseline with 93% of patients having CSF HS levels below the upper limit of normal at week 24. For urine GAG at baseline, 4% of patients had total urine GAG levels below the upper limit of normal. After treatment with AVLAYAH, 68% of patients had total urine GAG levels below the upper limit of normal at week 24. With respect to safety, the prescribing information includes the following: a box warning regarding hypersensitivity, including anaphylaxis consistent with other approved ERTs guidance on management of infusion-associated reactions, anemia typically occurring early with guidance to assess hemoglobin prior to treatment initiation 3 months after initiation and as clinically indicated thereafter. and membranous nephropathy related to immune complex deposition in reported case. General guidance is to monitor serum creatinine and urine protein to creatinine ratio at a frequency to be determined by the prescriber.

On Slide 17, AVLAYAH's clinical development continues with a clear path from U.S. accelerated approval to full approval. The Phase I/II study with 47 participants supported U.S. accelerated approval and will continue to support select country approvals. The COMPASS Phase II/III confirmatory study in approximately 63 participants is ongoing. The design is a head-to-head randomized controlled trial versus standard of care ERT across disease phenotypes and a broad age range. This study is designed to evaluate both neurologic and somatic clinical outcomes. COMPASS includes adults living with Hunter syndrome and represents an important evidence package to potentially broaden future access in the United States and internationally.

And now I'll turn it over to Katie Peng.

Thank you, Peter. Good afternoon, and thank you for joining us on this milestone day for Denali and the MPS II community. Today, I'll briefly cover what this approval means and how we are positioned to execute on a successful launch.

On Slide 19, as Peter outlined, MPS II is a progressive and multisystem condition. What is most compelling to physicians about the AVLAYAH data is that patients achieved normalization of CSF HS in 9 of 10 patients as early as 6 months with sustained normalization at 12 months. None of the patients in the study had normal CSF HS at base line. AVLAYAH also achieved normalization of urine GAG, a key biomarker of disease progression in 9 of 10 patients by 12 months. Only 2 patients had normal urine GAG at base. Importantly, a majority of patients in this study were previously receiving standard of care enzyme replacement therapy, reflecting a real-world transition as more than 90% of patients today are on treatment. No other therapies to date have demonstrated this level of normalization across key disease biomarkers. This is setting a new bar. For the first time, we are seeing data that support addressing both systemic and neurologic disease burden in a single therapy.

Slide 20. Now let's step back and take a look at the broader landscape. In the United States, approximately 30 new patients are diagnosed each year. There are roughly 500 patients living with MPS II in the U.S. and 2,000 worldwide. With this approval, the opportunity is to capture approximately 75% of the treated U.S. prevalent population. With a positive COMPASS study, we should be able to address the entire MPS II population. Today's prevalent population reflects the reality that individuals born with severe disease often experience shortened lifespan. With AVLAYAH, we believe there is the potential to alter that trajectory over time. Early treatment may improve neurologic outcomes and longer survival could gradually expand the prevalent population. While this evolution will occur over time, it represents the potential for meaningful long-term impact for families and a durable opportunity for Denali to continue advancing therapies in rare disease.

Slide 21. Our commercial confidence is grounded in stakeholder insights gathered prelaunch. 90% of physicians view AVLAYAH's data as highly motivating to prescribe. 80% are aware of new treatments in development and are excited to try AVLAYAH. We have also engaged with payers that cover approximately 90% of commercial lives. The feedback has been constructive. Payers recognize the unmet need and have indicated that they will likely manage to the FDA-approved label. We have seen similar excitement from the patient and advocacy community and have been engaging with them frequently as they were critical in helping to shape our launch. This is not a market where awareness needs to be created from scratch. It is a community that is informed, organized and ready for change.

On Slide 22, the structure of the MPS market is an advantage for our launch. Of the 500 U.S. patients currently treated with enzyme replacement therapy, the majority are managed by clinical genetics in about 100 centers of excellence. The concentration enables a small and focused field team. We have already established relationships with all major MPS II centers. Our sales team have profiled and segmented all accounts with MPS II patients to optimize execution from day 1.

Slide 23. I could not be more excited or confident in the team we have in place. Our leadership team brings experience across product strategy, U.S. and global marketing, market access, analytics and medical affairs. We have marketed oral products, injectables and IV-infused products. Collectively, the team has launched 19 products or indications, including global blockbusters and rare disease therapy. Across our field organization in the U.S., 96% of our teams have lysosomal storage or rare disease experience. The depth of that experience is on average 12 years.

Slide 24. As the first TfR-enabled enzyme replacement therapy designed to cross the blood-brain barrier, AVLAYAH addresses progressive neurologic decline in MPS II, a critical unmet need not targeted by existing therapies. The innovation meaningfully differentiates AVLAYAH within the current MPS II treatment paradigm. The degree of biomarker normalization and CNS engagement is unprecedented and reflects the differentiated value of the therapy. AVLAYAH's pricing balances our 4 core principles: access, affordability, sustained R&D investment and the therapeutic innovation of our medicines. Our wholesale acquisition price is $5,200 per 150-milligram single-use vial. AVLAYAH is dosed weekly at 15 milligrams per kilogram. Most pediatric patients will require 2 to 3 vials per week depending on weight. The annual cost of maintenance dosing for a 10-kilogram infant is about $270,000. The annual cost of maintenance dosing a 30-kilogram child is about $811,000. We are deeply committed to broad and equitable access for eligible patients. Our teams have engaged with payers prelaunch and we will continue those discussions to support coverage for eligible patients at launch and beyond. Importantly, this launch establishes a sustainable revenue stream that supports expansion of our TfR-enabled platform across additional neurodegenerative diseases. We believe AVLAYAH is well positioned for long-term success, driven by the significant unmet need it addresses and the strength of our commercial execution. We are confident in this price supports a successful launch while balancing innovation, access and sustainable value creation.

Slide 25. Market access execution is critical in rare disease, so we invested heavily here. Through our Denali Care Program, we will provide personalized support throughout the treatment journey. Our comprehensive patient support services include benefit investigation, prior authorization and assistance navigating insurance coverage. In addition, the team will support treatment coordination, provide information and educational resources and financial assistance support where appropriate. Our objective is simple: reduce the time from prescription to first infusion and minimize friction for families.

Slide 26. Looking ahead, our road map is structured across stakeholders. For physicians, we are supporting in-service education, infusion training and robust scientific exchange to instill confidence in clinical use. For payers, we are securing commercial coverage policies, advancing Medicaid access and operationalizing prior authorizations and acceptance processes. For patients and caregivers, we are activating with the advocacy community, driving awareness and consideration and focusing on reducing the time to therapy initiation. AVLAYAH is expected to be available in the United States 2 weeks from tomorrow. We are prepared operationally for that time line. Rare disease launches follow a predictable uptake curve. In 2026, the focus is activation and access. In 2027, we expect adoption acceleration when we will see coverage policies in place and revenue inflection as workflows stabilize and confidence in AVLAYAH matures.

Slide 27. Let me briefly walk you through how we think about global access following our U.S. approval. The U.S. decision really serves as the anchor for our ex-U.S. regulatory strategy. In many markets, we can leverage that approval through a mechanism like the Certificate of Pharmaceutical Product, or CPP, and other conditional approval pathways to begin the registration process. Of course, registration is just the first step. After approval in each country, we will still need to go through local reimbursement processes to ensure patients can access the therapy. We expect global access to occur in phases. Roughly 1/3 of the market could become available in the near term with additional markets opening in the mid and longer term as both regulatory and reimbursement processes are completed. To support that expansion, we have already established distributor partnerships across select markets in Lat Am and MENA regions.

Slide 28. Let me leave you with a few key takeaways. AVLAYAH represents the first meaningful advancement in MPS II treatment in 20 years. Second, we have built a fully staffed and experienced rare disease commercial organization. Third, the competitive landscape is favorable and no direct CNS penetrant therapies are currently approved. And fourth, the community is ready and waiting. Our priorities are super clear: drive patient starts, ensure smooth reimbursement, deliver a consistent high-quality patient experience and build a durable franchise starting with MPS II. We look forward to updating you as we move through the first phases of launch.

Now I'll turn it back to Ryan.

Thank you, Katie. Slide 30. Established by today's approval of AVLAYAH, I'd like to discuss the broader strategic context, which is the ETV franchise we are building in lysosomal storage disorders. What this slide shows is that we are not pursuing a single indication, but a platform-driven opportunity across multiple diseases with meaningful patient populations, including MPS II, MPS IIIA, Pompe, Gaucher and others. Collectively, this represents a substantial addressable market. What differentiates our approach is that the ETV platform is designed to address both systemic and neurologic disease.

Historically, enzyme replacement therapies have been limited to peripheral tissues, leaving the brain untreated. We believe AVLAYAH demonstrates that this paradigm can change. From a commercial standpoint, this is also a highly leverageable model. We can build on existing infrastructure, apply a consistent development and launch approach across indications and drive efficiencies as we scale. Importantly, we are entering a large, well-established ERT market with significant precedent for adoption, reimbursement and long-term value creation. So when we talk about AVLAYAH, we see it not just as a product but as the foundation of a durable multi-program franchise in lysosomal storage disorders.

Slide 31. Let me close by putting this moment into perspective. With AVLAYAH, we believe we have reached an important first summit, one that reflects years of scientific invention, disciplined execution and deep partnership with patient community. First, this is proof. AVLAYAH is the first FDA-approved biologic design to cross the blood-brain barrier, demonstrating that we can deliver medicines to the brain in a meaningful way. Second, this validates our platform. The transport vehicle is now proven in humans, opening the door to an entirely new class of biologic medicines. Third, this fuels our pipeline. What we've established here creates a clear path to expand into additional lysosomal storage disorders, including DNL126 for Sanfilippo syndrome, which we plan to advance towards launch next year as well as into broader neurodegenerative diseases such as Alzheimer's disease. where we expect to have 2 programs in clinical development this year. And most importantly, this is about our patients. While we are starting in rare diseases, our ambition is much larger to transform treatment for millions of people affected by serious diseases. So while today marks a major milestone, we see it as the beginning of what this platform can deliver. We remain steadfast in our purpose to transform life for patients. We look forward to continuing this journey with all of you. And now we will take your questions.

Operator, could you please open the lines for questions?

[Operator Instructions] And our first question for today comes from the line of Andrew Tsai from Jefferies.

Congratulations on approval. It's exciting. I know you guys have mentioned to think about an S-type trajectory acceleration later in 2027. Is there a low-hanging fruit though right now, maybe within naive or switch patients? And maybe asked another way, what exactly would it take for this S curve to look more linear or parabolic instead?

Thank you, Andrew. I'll hand back to Katie to answer that question.

Thanks for the question. Yes, I mean, certainly, the patient population is very excited. We've already gotten a lot of outreach since the announcement from the community, excited to start. And I think as we've spoken before, a lot of it has to do with the mechanics of getting reimbursement, and it will take time for, of course, the product to get into the channel, which will take about 2 weeks. and then for the reimbursement process to start. And that's why we're guiding to an SJ curve more because of the mechanics of launch and not for the lack of excitement from the community.

Makes sense. And as you guys mentioned, you clearly have data showing clear benefits on functional outcomes violin Bayley. The label technically doesn't have that right now. So can your sales reps technically go out and message the functional data you're seeing? It was published in the NEJM paper or do we have to technically wait for COMPASS data in order for you to promote that?

That's a great question. Our sales team will focus on promoting what is within the label and consistent with label. In terms of the clinical data that's available through the NEJM article, our medical affairs team will be able to speak to that in engaging on scientific exchange with the physicians. So it's a dual approach essentially with our field team very much focused on the biomarkers and the safety data that's in the label, but med affairs will certainly be able to talk to the data set that is in New England Journal of Medicine.

And our next question comes from the line of Salveen Richter from Goldman Sachs.

This is Lydia on for Salveen. Congrats on the approval. I guess just given the language in the label, do you anticipate any payer pushback for the non-neuronopathic or attenuated patients? And then if you could just talk about your plans to monetize the PRV.

Great. Thank you, Lydia. Great to hear from you. Katie will answer your first question around payers and the details on label, and then Alex will answer your second question on the PRB.

Yes. So that's a great question. No, we don't expect there will be any limitations from the payers because the label indicates that it's for presymptomatic and symptomatic patients. So attenuated less severe patients also have neurologic manifestations. So our expectation is that the payers would cover to the label indication.

Yes, Lydia, we are, of course, pleased that the FDA has granted the rare pediatric disease priority review voucher, the PRB for the approval of AVLAYAH. As you know, this PRV can be transferred or sold, and we intend to do so in support of our operating expense in support of our long-term goal. So stay tuned on that.

And our next question comes from the line of Michael Yee from UBS.

Congrats on the approval. Two questions. I guess just thinking about the ramp, how do you technically determine if someone is neuropathic or has neurological disease? Is there a specific or requirement to determine the eligibility for that? And then secondly, how does this approval and your regulatory discussions you just went through read through to Sanfilippo and the process there and how that's going?

Thanks, Mike. I'll have maybe both Katie and Peter comment on neurologic manifestations. And as you sort of define that, maybe we'll start with Katie. And then the read-through on this for Sanfilippo will have Peter comment on that.

Thanks, Mike, for that question. In terms of how you think about the treatment landscape, the disease is really a spectrum disease. So in practice, we don't really think about neuronopathic versus non-neuronopathic. And if you look at the label today, it's really covering all of the pediatric patients, they should be able to gain access and specifically address in thinking about neurologic manifestations, which is different than neuronopathic. If you look at the literature as well as our claims data, about 90-plus percent of patients actually have neurologic manifestations. So that is not necessarily only relegated to neuronopathic patients. So that's why we're thinking in terms of the opportunity, it is really the pediatric population in the prevalent population in the U.S. So hopefully, that addresses your question.

And maybe I can add to what Katie has just shared. I do think it's important to note the distinction in the labeling language between neurologic manifestations versus neuronopathic. There's no mention of neuronopathic or non-neuronopathic or attenuated phenotypes. And really, the focus is on neurologic manifestations, recognizing that CSF HS is the basis of approval as a surrogate marker.

On the question of Sanfilippo, I think what this precedent sets is that CSF HS is an approvable surrogate marker for -- as a reasonably likely to predict clinical benefit. And in our discussions with the agency through the START program, we have frequent interactions and anticipate and have already had discussions that CSF HS could lead to an approvable path. Each disease is different. I think that's an important thing to consider as well. And I also note that at this time, Sanfilippo has no standard of care. And so we'll have specific discussions in that disease state.

And our next question comes from the line of Sean Laaman from Morgan Stanley.

This is Mike Riad on for Sean. Congratulations on AVLAYAH's approval. Could you just maybe comment more generally on like neurological manifestations? Is this like restrictive or advantageous in terms of the positioning versus Elaprase? Like how does that influence early age uptake and commercial positioning over the long run?

I'll hand that to Katie to comment.

Yes. So in terms of commercial positioning, it really doesn't change. The only difference compared to the current standard of care has to do with the separation between pediatric and adults. But we feel with the current label, it is holistically being able to treat all different manifestations of the disease, whether it's symptomatic or presymptomatic. So if a physician deems that a patient even presymptomatic has the likelihood to show neurologic manifestations, they are able to treat. So I feel like this label is very holistic and able to help us address the pediatric population with MPS II.

Perfect. And just a quick follow-up. So you noted that like with the expansion of a prevalent patient population with disease burden reduction over time that, that would grow the patient population. Is this more of a result of just early intervention? Or like post COMPASS, would there be additional label expansions to help grow the addressable population?

Yes. So I think it's threefold. Newborn screening is now increasing in the United States. So we'll be able to identify patients earlier on. And certainly, with this disease, earlier treatment will result in better benefit. And as you know, with the severe population today, lifespan is shortened, right? It's late teens. And so we believe with early treatment, newborn screening, we will be able to address the disease more holistically. And over time, we expect with the COMPASS data set, we would then be able to unlock adult patients as well. So given these 3 things over time, we believe the prevalent population should grow with MPS II.

And maybe just 2 comments. One is I want our resident neurologist, our lead neurologist, Peter, to make a comment on neurologic manifestations and just to restate what we stated before about the breadth. The second is that this is -- I think it's important to understand that on initiation of treatment, it's in the pediatric time period, but patients will stay on drug throughout life. So they will continue as adults on AVLAYAH. Maybe a comment on neurologic manifestations.

Yes. Thanks, Ryan. I think echoing what Katie has said, neurologic manifestations are prevalent across the spectrum of MPS II. Importantly, the indication includes presymptomatic and symptomatic stages of the disease prior to advanced neurologic impairment. And I think that's important from a clinical perspective because it allows the patients and the families to make the assessment of the most appropriate treatment. And so even in the presymptomatic stage, one can anticipate that patients will develop or may develop neurologic symptoms.

Congratulations on AE approval.

And our next question comes from the line of Tazeen Ahmad from Bank of America.

This is Daniel on for Tazeen. Congratulations on the approval. Just 2 on our side. We're just wondering what kind of metrics you plan to provide to help us track the launch once you get this product on the market? And then in terms of coverage, do you expect there to be differences between patients switching versus newly diagnosed patients? Do you expect any sort of step edit requirements before patients can start on AVLAYAH?

I'll hand that to Katie.

Okay. I'll answer your second question first, which is, no, we do not expect there would be any differences in how payer would handle naive patients versus switch patients given the strong label that we have. In terms of updates on the progression of the launch, I think for the first year, we're not going to be providing a lot of details other than to give qualitative updates on the mechanics of what with the launch. And as the data and our launch evolves, we will then share additional information.

And our next question comes from the line of Paul Matteis from Stifel.

Let us offer our congratulations. This is Julian on for Paul. I guess I think a lot of people are wondering whether you guys think there's a bolus of patients that may be lined up waiting to switch from Elaprase. Anything that you could say about that? And I guess, just thinking about what types of patients you think may be interested, again, that are in line with the label.

And then one other follow-up question is FDA mentioned in its press release that you're 95% enrolled for the confirmatory Phase III. Just wanted to get your thoughts on how far along you think you need to be enrolled for the Sanfilippo study in order to file a BLA there? And if any specific considerations for that indication we should think about with respect to regulatory?

I'll hand it to Katie on the first one and then myself and Peter will comment on the Sanfilippo enrollment.

Great. In terms of bolus, I would not think of it as a bolus. Usually, you think about that when there's no treatment available in a current disease area. What I will say is the bottleneck will be access and reimbursement, right? We won't have coverage from payers from day 1. And so there will be a medical acceptance process in order to get reimbursement for patients. And as you know, with rare disease being expensive, patients will not have access until reimbursement can be assessed for each of the patients.

In addition, there is logistics of getting back into the clinic for infusion. So those are the sort of mechanistic bottlenecks. In terms of patients that are excited and waiting, certainly, the newly diagnosed patients, the younger patients that have been identified as having more severe disease. We have already heard a lot of excitement from the community on getting these patients on treatment as soon as possible. And we always think about time is neurons, so we need to get these patients on. But it's more about logistical hurdles that we'll have to work through and launch and not about excitement. There's not a lack of that in the community.

I'll add a couple of points to the second question around Sanippolics maybe just make a general comment the standard of care. But obviously, getting the Phase III off the ground is a priority as we will file for accelerated approval next year. Any other thoughts on that, Peter?

Yes. Just one additional thought. I think that it's important to note that the COMPASS study started years ago with the intent for a robust Phase II/III design to enable global approval, not just confirmation for the accelerated approval today. So while the FDA noted the 95% enrollment, I don't think that is a regulatory expectation per se. It's that the confirmatory study is underway.

And our next question comes from the line of Mayank Mamtani from B. Riley Securities.

Huge congrats on getting the brain shuttle field its first FDA approved product. Sorry if I missed this. As you mentioned, the initial focus is on the early symptom pediatric subjects. And there's some dose escalation monitoring period up to, I think, 8 weeks for a variety of things, infusion reactions, anemia, et cetera. Could you sharpen the split between the Elaprase naive newly diagnosed versus the switch patients that you intend to get on drug in sort of the next 2, 3 quarters? And also, I wonder in your physician research, how important some of the attributes that you have in your data like hearing improvement and even NfL improvement how does that kind of weigh in versus some of the other things that may come later like the 6-minute walk test or other neurological endpoints, which are obviously not in the label. If you could maybe give some more color there, that would be great.

Okay. I'll hand it to Katie and Peter will sort of tag team on this question.

I'll start with that. So in terms of the dose escalation, so 2 things. The patients -- the switch patients as well as the new patients, naive patients will need to come into the centers of excellence to get their infusion. And the dose escalation schedule is 3, 7 and 15. And so there are some logistics around getting patients set up for infusion. This is why we have guided to the S shape uptake curve because of the -- getting the patients back into the clinic. That is very common for new ERTs approved. With a new safety profile, physicians will need to gain experience infusing the product in the clinic before patients can be sent home. But we do very much expect all patients to be able to go home for home infusion for those that would like to get their infusions at home.

And maybe just to add, the dose escalation was scheduled to support positive patient experience by reducing infusion-related reactions early on. Remember that the data suggests that the incidence was highest early upon initiating treatment. And so the dose escalation really is designed to support a positive patient experience. We want patients to get to the maintenance dose as rapidly and as predictably as possible.

I think the second part of the question had to do with NfL and other outcomes. The label -- I want to emphasize the label is based on the Phase I/II study design, and that design had a primary study period of 24 weeks. And so the label outcomes are based on that primary study period. Now that said, as we've talked about before, we're highly encouraged by the NfL results and the large proportion of participants who normalized on NfL. And we think that also is highly meaningful. COMPASS is our confirmatory trial, and we will be analyzing a large number of outcomes, both peripheral and CNS across a very broad population from age 6 to 26. So that will -- that is intended to provide a very definitive and comprehensive efficacy.

I think I'll just add one other point, which I think you asked about hearing and some of these other endpoints. I think very much meaningful. within the community. And I think the great thing we have here is we have a rigorous FDA that based a label on the 24-week endpoint from the Phase I/II. And then we have the New England Journal publication that shows really longer-term data and what this medicine can actually do. I think it's a great combination. And then, of course, what Peter already mentioned, which is the COMPASS study as follow-up, but definitely viewed as meaningful, obviously, behavior cognition, and I think we hear a lot about hearing in particular.

And our next question comes from the line of Ananda Ghosh from H.C. Wainwright & Company.

On the data and of course, on this very fulfilling journey since inception. I have 2 questions. The first one, given the concentrated prescriber base, what does your survey work kind of tell about the percentage of docs willing to prescribe now versus those willing to see or wishing to see results from the head-to-head ERT study -- the study in the ERT?

Go ahead, Katie.

So our market research suggests that once they see and understand our biomarker data, they do see it as unprecedented given that no one has shown normalization in this treatment paradigm. Of course, with all launches, there will be a segment of physicians who have the wait-and-see approach, but there are much fewer of those because as I stated earlier, 100 -- 100 centers of excellence are managing these patients, and they have the level of depth and understanding of what is not being addressed with the current standard of care. And given that this is a progressive disease, we do see the level of excitement and willingness to prescribe. And I would say there may be a segment of physicians that's not as familiar with our data today that, of course, we're going to need to get to as part of this.

And maybe...

I just -- you have a second question, A. Go ahead.

Yes. So the second question is, I think, extension of what others have already asked, and that is based on some of the regulatory interactions you had over the past several months now, what are some of the -- what's the regulatory ramification with respect to some of the other assets in the platform beyond Sanfilippo? So what have you learned from this process? And how do you see a path forward for other programs?

Yes. I'll comment on that. Just to restate what we've stated before. I think it's obviously positive read-through, especially for Sanfilippo, which is a very aggressive neurologic disease where there is no standard of care, patients advance very rapidly. And I think importantly, it's precedent setting that heparan sulfate is used as a surrogate biomarker reasonably likely to predict clinical benefit.

Now we think about the broader pipeline. So that's, I think, clear for Sanfilippo, but our broader pipeline, each one of our medicines and each one of our desired therapeutic areas will have its own nuances. Pompe, for example, Gaucher, Alzheimer's. But I think most importantly, these data and this approval validates that the transport vehicle works. We can get biologics into the brain, but we'll approach each of those separately. We, of course, are looking for indications where biomarkers can allow for an accelerated approval. That's obviously advantageous.

And our next question comes from the line of Laura Chico from Wedbush.

Just a couple of follow-ups on my side here. Great color from Katie on the launch setup. Just wondering if you could expand a little bit more on the expectations around the payer mix within the U.S. And then this is more of a logistical clarification. Will there be patients converting from the trial to paid status? I know you're not looking for a bolus of switches or anything like that coming through. But just trying to understand if there's a conversion that has to happen here for AVLAYAH patients already on drug.

I'll hand back to Katie for those questions.

Thanks, Laura, for your question. In terms of the payer mix, our expectation is that 50% will be -- roughly 50% are commercial payers who have MPS II today and then the other 50% is likely Medicaid with very little Medicare. And maybe I'll address maybe part of your question, Peter can add in terms of the study. Now of course, with the U.S. approval, patients could drop out of study to get on to commercial therapy. But we haven't made any decisions or announcements in terms of our E2 program. So there will be more to come on that.

Yes. I'll just add that the study remains ongoing at this time.

And our next question comes from the line of Peyton Bonsek from TD Cowen.

This is [indiscernible] on for Peyton. I guess the first one is, when you look at the label and you finish the confirmatory trial, do you think that you could broaden it and get rid of the manifestations as part of the label? And the second thing is if you have any dose interruptions, do you imagine that you will have to go through a reauthorization step?

Okay. We'll have Peter talk about broadening the label, and then Katie will talk about if there needs to be reauthorization. Go ahead, Peter.

Yes. So thank you for the question. The question about the neurologic manifestations, that is a reflection of the accelerated approval based on the CSF surrogate. I think with the confirmatory study and the way that we have designed this with Cohort A with neurologic manifestations and Cohort B, which is an attenuated population and the totality of endpoints that we anticipate showing efficacy on we should be able to remove the neurologic manifestations because the study -- the confirmatory study is designed to assess comprehensive efficacy across a broad population.

In terms of reauthorization, what we understand from the standard of care today is that the reauthorizations and payers are usually at 6 months or at 1 year. And that's our assumptions to date.

I'm just going to add one other point around neurologic manifestations that Peter made earlier in the call. Again, linking it to CSF heparan sulfate is key, and that was, I think, a key for the FDA. But importantly, the majority -- the vast majority of patients experienced neurologic manifestations, both neuronopathic and attenuated. So I think what we think more about is would we initiate treatment in adult, which of course is a smaller fraction of the overall patient as we think about the expansion of the label. But we're very happy with the label. We think it does reflect the Phase I/II data, and it's a great place for us to start.

And our next question comes from the line of Myles Minter from William Blair.

This is John on for Myles. Congrats on the approval. So maybe just one final one on the neurological manifestations. Can you just talk a little bit more about how clinicians are defining these? And then maybe could you just provide us some clarity on what percentage of the attenuated population would not have those manifestations and therefore, would not be eligible as indicated?

Yes. Okay. We'll start with Peter on defining neurologic manifestations and then we'll hand it to Katie around the percentages.

Yes. Thank you. Thank you for the question. I think the first thing to reiterate from my perspective is the indication is for neurologic manifestations in the presymptomatic and symptomatic stages. And remember that approximately 2/3 to 70% of MPS II patients are -- have a more severe phenotype with neurological involvement. And as Katie noted earlier, a large proportion of patients who are attenuated or classified as attenuated will also develop neurologic manifestations. So it's hard to put a specific number to it, but it's the majority of patients are expected to have neurologic manifestations.

The other thing I would say is important in the indication statement, there is a note that AVLAYAH is not recommended for use in combination with other therapies. And that is an implicit acknowledgment that AVLAYAH does address peripheral manifestations as well. And the urinary GAG normalization is also labeled in the pharmacodynamic results.

And maybe I'll just add a little bit of color because what the data that we have, there is a paper published that shows that actually before the age of 10, attenuated patients will develop neurologic manifestations. And based on our claims data set, when we looked at the list of what is considered neurologic manifestations, about 94% of patients have codes that cope to neurologic manifestations. So that's why we believe it is the majority of the population of the pediatric population.

I think we have time for at least one more question. I know we're at time, but we want to be able to get more questions. I think as we start repeating some questions, we realize we've kind of hit that limit. So let's take another question.

Our next question comes from the line of Jay Olson from Oppenheimer.

Congratulations on this landmark approval. We have a few questions. Can you talk about any educational support that you'll provide for patients to transition from Elaprase to AVLAYAH in clinical practice? And then second, can you share any color on the potential launch timing and strategy for countries outside the U.S. that also might provide approval based on your Phase I/II study results? And then finally, can you talk about whether there could be a platform technology designation granted by the FDA along with this AVLAYAH approval? And if so, how important would that be for future programs?

I'll hand it to Katie.

Great. Thanks, Dave, for your question. So our Denali CRE program or the care team, they will absolutely be supporting every patient and family with educational resources on how to transition from the current standard of care to AVLAYAH. And so our team is ready and waiting to be able to do that.

In terms of the global expansion, yes, and Peter mentioned this as well, we will be seeking regulatory approval with the U.S. approval now in hand, we can leverage the CPP or CMA process to be able to access other markets. But as you know, other markets will also require reimbursement unlike the U.S. market where we can go on day 1. So we'll have to be able to obtain reimbursement in those countries. And it will be local country by country as we go forward with registration in these various countries.

Yes, I'll end and we'll end the call after this comment. So great question around the platform designation. It's something that we've contemplated multiple times. And as you know, we have 3 different platform franchises, the enzyme transport vehicle, the oligonucleotide transport vehicle and the antibody transport vehicle. In our assessment, of the 3, the one probably most likely to qualify for platform designation may actually be the oligo transport vehicle because the core can be similar across medicines. With the enzyme, each enzyme actually behaves pretty differently. For example, SGSH and IDS behave differently. That being said, it's something that we're -- we would pursue that path if we believe it would be the fastest way to get more medicines to patients. And I think with that, we'll close questions. Those that we didn't get to, we apologize, we'll be following up with you directly.

Thank you. And thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.

Great. Thanks, everybody, for continuing on here. It's my pleasure to be moderating a chat with Ryan Watts, Founder and CEO of Denali. I'm sure most folks know the story decently well. But maybe, Ryan, you can just give us a couple of minutes to sort of set the stage on 2026 is a big year for Denali with Hunter and the pipeline, and then we'll do Q&A. So thanks again.

Sounds great, Paul. Great to be here again. I was trying to count how many CNS days this is for me, but probably...

6 or 7. Do you know the first one was not on video. Well, no, I've done 7. The first one for you was probably 6 years ago, audio-only 5 days into COVID.

Yes. I remember that.

Crazy. So thank you. Appreciate it.

It's good to be back. And I think that might have even been a panel, if I recall, back...

Yes, that was interesting. We can talk about that another time. That was interesting.

I mean, 2026 is set up to be a very important year for Denali. I mean, obviously, we're at the very final stages of our first approval for tividenofusp alfa in Hunter syndrome. I think not only does this program have its own opportunity in a very significant area where there hasn't been an approved medicine for 20 years. And of course, in our case, engineering brain delivery has allowed us to take the next step and treat the brain for these patients.

But also, we kicked off the year with new data on our Sanfilippo program, very similar to the Hunter program. We'll have new data on our PTV: Progranulin program, which is another transport vehicle-enabled medicine. We're going to read out our LRRK2 program. And then we've started three new clinical trials. Well, two are starting and one we're just about to file. So one in Alzheimer's, another in Pompe and then another in Alzheimer's. So obviously, a very exciting year.

I think last year, I think as we shared in the last time we spoke a month or so ago, was the year of harvesting a lot of science for Denali. We had a couple of basic biology papers on Alzheimer's. We had a science paper on our ATV:Abeta approach, but we ended the year and began this year with our New England Journal publication on the Tivi program, on the Hunter program. And so what we've seen is a shift at Denali. Starting 2 years ago, we've harvested the fruits of our scientific efforts, but now we're applying the transport vehicle to many other programs. The goal is to accelerate and to expand the portfolio using the transport vehicle also at a time where TfR-enabled programs are highly competitive. So it's an exciting time in the field for sure and looking forward to diving into details, Paul.

Yes. Awesome. Well, I think just to start, I mean, everyone wants to know how you feel ahead of the PDUFA, right? We're in probably one of the weirdest years for the FDA that I can remember. And you're right in the center of rare disease, an area where I think people are debating to what degree have some of these negative decisions been product-specific versus a changing of the goalpost. You've expressed confidence, talked about being in labeling discussions. Like anything else you can kind of convey to us here about the 310 PDUFA?

Yes. I agree that the last year has been unusual, especially in rare disease, accelerated approval, biomarkers that are reasonably likely to predict clinical benefit. And I think we're confident. We have had a fantastic engagement with the FDA over the last 9 months or so. And I think our confidence comes from the robustness of our data, our clinical data, our biomarker data that we believe it will translate and is translating to clinical benefit for patients. And so I think having a rigorous bar has been important. Obviously, it's -- and we're going to get into, I'm sure, more details, it's definitely a complicated time with the FDA.

Yes. Yes. Okay. I mean I think you said in November, you were in labeling discussions, which was a while ago. I hear labeling discussions, and I think that's super bullish, but it's also been quite a long time. Like how should I make sense of that from the outside looking in?

I think it's important to set the context of our review cycle. So basically, what happened for us is that our original PDUFA date was January 5, as you know. And leading into this sort of late cycle meeting, we were made aware and engaged with the FDA on a miscalculation of a molecular weight of Tivi, which is so unusual, solved it very quickly. But I think by statute alone, it resulted in a major amendment and a shift of the PDUFA date to April 5. So I think what the FDA did is they did their best to stay on track to the January 5. But inevitably, there isn't the time pressure that you have of January 5. And so I think we've been really in serious label discussions in the last month. Those early days, we basically took a bit longer for the CMC review, which is now completed. And basically, the right timeline kind of moved into 2026 is the best way to describe it. Maybe not as quick a turnaround on the back and forth, but we're -- now it's -- like you said, we're here. We're at the final stage.

Right. So I mean, the value proposition of this drug, as I see it, is, hey, you can maintain the same peripheral disease control you have in Elaprase, but treat the neurological part of the disease. Do you envision a label where it sort of indicates this for all Hunter as an Elaprase alternative? Or is it going to be like more neuro-centric?

Yes, it's a good question. I think we're too close to the finish line to go into detail on anything related to the label. And I think your -- the way you articulate it is right that what this medicine does is it does essentially what Elaprase or standard of care has done historically, but crosses the blood-brain barrier. And one of the things that we've done is we've really pushed dose. We want to maximize efficacy. We want to maximize efficacy in the periphery and in the brain. And I think inevitably, these patients, even if they're like attenuated, which at sort of diagnosis represents maybe 30% of the patients, they eventually develop neurological disease like hearing deficits and other challenges. So obviously, our ultimate goal is to treat all patients, but let's stay tuned. We're at the end here. I should say we're at the beginning, hopefully.

Okay. Yes, yes. Okay. All right. And then assuming you do get approval, like how are you setting expectations and what a good outcome would be for the first year of the launch?

I think that realistically, this is a switch market. Obviously, newly diagnosed patients is going to be key. The challenge is, in general, as you know, is reimbursement in the rare disease. So the way that we're setting expectation is sort of the S-shaped curve. We expect minimal revenue this year, but our focus isn't on that. Our focus is really patient starts, like how many patients can we get on drug out of the gates. That's going to be key.

Any thoughts on pricing and premium pricing potentially to Elaprase?

Right. I mean, again, it's too close to the beginning to discuss pricing in detail. But I think in general, we see this as not just an incremental leap from Elaprase, but a very significant leap of being able to cross the blood-brain barrier and access the central nervous system while not only adequately but maybe really robustly treating the periphery.

When you talk to clinicians in this space, do they think all patients have some element of neurological disease, whether it's a lot or even just a little? Or is it really a view that this is two different diseases peripheral-only in peripheral-plus-CNS.

Yes. I think that there's a spectrum of the disease, and there's a spectrum of how physicians view this. But in general, I think no one will argue with you that even like really attenuated patients will develop, for example, hearing loss and hearing deficiency, which is neurological, I think, by definition, there's both peripheral and central roles in hearing, but in general, believed to be behind the blood-brain-barrier. And so I think it's just a matter of time. So when I say spectrum, those individuals that carry severe mutations will experience neurological symptoms early on, age 2, 3, 4. Again, that represents 70% of patients. What's interesting, if you look at those that are on drug, attenuate patients obviously live much longer, but they eventually develop some type of neurological disease.

Yes. Okay. Okay. So I guess, does that argue for switching that is like a little bit slower?

Yes, it's a good question. I mean I think there -- obviously, the patients that are eagerly awaiting are those with neurologic disease. There's no question about that. And I think beyond that, it's really educating the community and asking what else is there, what represents some type of deficit that could benefit from Tivi.

Yes. Okay. So if Tivi gets accelerated approval, how fast can you then run with Sanfilippo?

Yes. So Sanfilippo for us, we just presented data for the first 8 patients. I think what's most interesting about the Sanfilippo data is that those 8 patients, we really explored the dosing regimen, both dose level and dose frequency. And I think actually, the last time you and I met, we were a day or 2 away from presenting that data at World. But now that it's presented, I can go into some detail. And I think it's actually -- was really, really insightful.

So I think one of the things we learned is that weekly dosing is much better tolerated than every-other-week dosing. And part of that is infusion-related reactions are all related to tolerance, right? And invariably, essentially almost every patient developed antidrug, antibodies to enzyme replacement therapies, some higher than others. But in general, these proteins are viewed as foreign.

And what we learned in that particular study is that as we shifted even at the high dose from every other week back to weekly, weekly was much better tolerated. And so we had a dose escalation. And now we've nailed down the -- what we call key efficacy cohorts, which are fully enrolled. That data will -- that data cut will be September of this year. And the planned BLA filing will be 2027 with approval in 2027.

Actually, the rate-limiting step for filing that medicine, part of it will be the data, but the real rate-limiting step is that we plan to manufacture that ourselves in our own facility. And I think as a result, we got to nail that down. We hope to be part of the FDA precheck effort where we can really engage with the FDA on the facility as it's a new facility, that could help us accelerate. But I think the timing will be driven largely by manufacturing for that medicine.

Okay. But I guess the thought is you file early in '27 then, just given the timelines you outlined?

Yes. I think probably the safest thing to say is first half of '27, second half approval, something along those lines.

I see. Okay. And we'll move on to the pipeline in a second. But with Hunter, I mean, I think it's pretty easy to size the global market just given the maturity of Elaprase. With Sanfilippo, like maybe talk about what the thought is on the likely prevalence and subsequently, the likely diagnosis rate or pool of diagnosed patients right now?

I think as you appreciate with Sanfilippo, there's no standard of care. So you're exactly right. It's much easier to size the market, understand the regionality of Hunter, where the primary cells, 1/3 in the U.S., 1/3 in Europe and 1/3 elsewhere. With Sanfilippo, there's less known. We think it's similar in size with similar distribution is probably the best way to look at it, but obviously, no standard of care.

Yes. Okay. And then you're doing Pompe, right? So what are sort of the similarities and differences between these programs in Pompe, like I guess you're targeting muscle there, so that is different. Like to what degree does your work here derisk that? To what degree is that kind of testing a new avenue for this technology?

That's a great -- that's a fantastic question. So Pompe also similar to Hunter and many of these genetic diseases comes in multiple forms based on the genetic -- the underlying genetic lesion or the mutation. In Pompe, you have IOPD and LOPD. Our ultimate goal is to compete in LOPD. And as you point out, the transferrin receptor has -- can enhance delivery to muscle just like it can to brain. What's unique about GAA in Pompe is that you're using this mannose-6-phosphate receptor for biodistribution. That appears to be limited in skeletal muscles. But by using transferrin receptor, we can pretty significantly enhance that delivery.

So the ultimate goal is really head-to-head. So it's a different dynamic here with LOPD. But I'd say sort of the other consideration is IOPD, which has a central nervous system component to it, which is not treated by any of the standard of care. And so we'll pursue those, obviously, in parallel. And so it's unique. I think the way to like summarize Hunter, cross the blood-brain barrier, almost everyone has some form of neurological disease. Obviously, there are those who are eagerly awaiting. Sanfilippo is largely a neurodegeneration in fact. It does have -- we saw normalization in liver volume, which was interesting. You never think about the peripheral effects of Sanfilippo. And then Pompe, largely muscle. So it is that new dynamic of what the transferrin receptor can do, but there's still the CNS component in the more severe cases.

Yes. Okay. Great. And Pompe, first proof-of-concept timing?

Yes. So I think if we look at the three programs that we're starting clinical studies this year, the Pompe and two Alzheimer's programs, just in general, we're stating 2027. We have a lot on our plate in 2026 with the potential launch, obviously, the new data in Sanfilippo, progranulin and LRRK2. But in general, we're stating 2027 for these three programs. That being said, we got to move as quickly as we can on all three. And they all have some type of biomarker data, if it's some type of glucose metabolite, if it's Hex3 or muscle-specific biomarker, that's what we look at in Pompe. For Alzheimer's disease, if it's an Abeta molecule, it's targeting plaque. If it's tau, it's targeting tau protein and tau PET. And so in general, I'd just state that those programs are 2027 readouts, and that represents the real expansion for vehicle platform.

Yes. Yes, makes sense. Maybe for the Abeta brain shuttle, we've got the data from trontinemab that looks great. What do you see as the one to two key points of differentiation for what you're doing?

Yes. I think you're right that -- if you look at all of transferrin receptor-enabled programs, you have those that are categorically muscle and then you have those that are CNS. And the two data sets that convince me that this is going to be a new class of medicines are our Hunter data, obviously, recently published and waiting for the first approval with a transferrin receptor molecule in accessing the brain and the trontinemab data.

And what you see with trontinemab, which is really fascinating is basically about 1/5 the dose, you have 3x faster plaque reduction. and it's obviously very robust. Now we don't know if speed of plaque reduction will correlate to enhanced clinical benefit. Probably the strongest driver of clinical benefit for Alzheimer's, in my opinion, is timing of intervention. So getting there as early as possible because you have two decades of plaque that cause synaptic loss and cell loss.

So I don't know. I mean that's obviously one thing that the brain shuttle and trontinemab has enabled is a faster plaque progression. And number two, significantly lower ARIA rates. That being said, there is definitely room for improvement. I think tolerability, I think one of the challenges that is obviously monitorable and reversible is any hematological findings. That was part of our engineering with the -- what we call the cisLALA mutation that allows us to engage transferrin receptor, get across the blood-brain barrier, but not engage transferrin receptor and the immune system on, let's say, reticulocytes.

And then I think the other component is that if you look at all of these brain shuttles, they're fusion proteins. They're essentially fusing Fabs or single chain Fvs to these full-length IgGs, and they struggle with stability. So if you look at 24 hours or 48 hours after dosing, you don't maintain the brain uptake, but also we think that also results in some risk around immunogenicity. And that's where we think the room for improvement is, is really tolerability around immunogenicity and potentially hematological outcomes.

Yes. Okay. How are you thinking about the right amyloid subtype or subtypes to target to maximize efficacy?

Yes. I think for us, we'd rather not reinvent what's already been discovered clinically. We're already inventing with the transport vehicle. So the goal is to look at all the profiles of successes and failures. And I think what you can determine is that those molecules that bound monomeric Abeta and did not bind aggregated Abeta failed in clinical studies, but those that found aggregated Abeta. And what I mean by aggregated, I mean plaque. I mean oligomers. I mean, basically, the challenge you have is if you're picking a single aggregate or single form of oligomer and you're not eliminating plaque, you're basically at very high risk because only correlation today that is plaque reduction and clinical benefit. So our Abeta arms target aggregated Abeta, both plaque and oligomeric and are less preferring to monomeric Abeta.

Yes. Okay. Okay. Makes a lot of sense. And the first study there from a proof-of-concept perspective, like you'll be able to answer some of the questions on amyloid anemia and ARIA, you think all in that first readout?

Well, it's a great question because if you think of the, let's call them like the 7th generation Abeta molecules, it's taken a long time for naked Abeta molecules to show some clinical readouts, right? And part of that is just the time it takes to see plaque reduction with standard antibodies. Now with trontinemab, that happens more rapidly. And so we hope to be able to get a quicker signal. But I think the order of assessment is essentially hematological plaque reduction and then you need larger patient numbers to look at rates of ARIA. I mean the ARIA, it's about statistics, right? It's about how many patients you treat that are APOE4 positive, which have higher risk of ARIA. And so these data will come in sort of in tranches as we first test the hypothesis around the cisLALA on tolerability and then go into plaque and then ultimately to ARIA.

Yes. Okay. You're also doing a tau conjugate as well. From a technical like feasibility perspective, I guess we haven't seen someone use transferrin to deliver an oligo into neurons yet, but we've seen it in muscle. Does the muscle space kind of derisk this along with your preclinical data? Or like how would you characterize the risk profile of this program translating from like preclinical animals to humans?

Yes. I mean this was -- to me, it was one of the most interesting technologies and surprising in the last decade is the ability to get oligonucleotides across the blood-brain barrier. Because think of your -- the path to a neuron or an astrocyte or microglia for an oligonucleotide, not only does that have to get across the blood vessel, but it's then got to get into those cells and knock down gene expression. So our preclinical data, we have a humanized mouse model that has a humanized apical domain of transferrin receptor has been pretty accurate at predicting clinical dose and clinical efficacy for the enzymes and for the antibodies. We expect the same for the oligonucleotides. I wouldn't say that the muscle delivery derisks it in any way because a lot of the muscle delivery technologies are using either bivalent or high affinity Fabs. So you obviously are testing this idea of getting the oligonucleotide into the brain, but the animal data are very convincing that this is doable.

Okay. Makes sense. Do you have a view on the BIIB080 study coming up and the probability of success of that trial?

So I think the most interesting thing about BIIB080 is it taught us that not only can you remove, you can lower tau in cerebrospinal fluid, but you also by tau PET, can see a reduction in the PET signal. What that actually means is that neurofibrillary tangles are in some equilibrium, which is not a known factor. I mean the plaque, we get it that microglia will engulf the plaque, but what we don't really know is can you remove existing neuropathology in this case, neurofibrillary tangles. And that's what the original data showed. This new data set, you -- I would read your note on what your opinion is, but 416 patients, I think it is actually 4 arms, 1 placebo and 3 dose arms. The lowest dose, I think, has enrolled fewer patients than the 2 higher doses. And I'm guessing they're going to do some type of pooled analysis. The great outcome would be directionally positive clinical benefit, some type of cognitive benefit. I think my only cautionary note is that those are not huge numbers when you're looking at things like CDR sum of boxes, and we just have to make sure that we take that with a grain of salt.

Yes. Yes. Okay. Okay. Makes sense. Maybe in the last couple of minutes here, I don't know if the stat is true, Ryan, but someone from another company told me that there are 16 brain shuttles in development in biotech. That obviously includes a lot that are probably named preclinical, early preclinical. But on the one hand, that's extraordinarily validating to what you're doing. On the other hand, right, there kind of becomes this whole question of like, is this technology going to become commoditized? Is it going to become like GalNAc in the liver? Like what would you say to that? Like why does a company like Denali deserve like a real premium for its transferrin technology over everybody else?

No, I agree that it's gratifying. I remember running the first experiments on transferrin receptor prior to founding Denali. But the idea of using transferrin receptor to get medicines in the brain was proposed in the 1980s. It's just taken a long time to industrialize it. And the question is why? Why did it take like multiple decades to get the first clinical data in Hunter syndrome or in Alzheimer's disease? And what -- and the reason for that is it's not just intuitive. It's not like you just take an antibody and it works or you take a Fab and it works. And so I think the winner will come down to those that really understand the engineering and how that engineering translates to the best outcome.

I'll just give an example. I think most enzymes, you cannot deliver with just a Fab fusion. The Fc is a huge differentiator relative to a Fab for iduronate-2-sulfatase or SGSH or GAA, and it brings a whole another area of benefit in biology and around building tolerance and PK. And so that's ultimately what's going to win. I don't know if there are 60 companies. I have no doubt that there are 60 medicines using transferrin receptor, but that's what happens. In biotech, it's really simple. If something works, everyone starts doing it. And then the question is, can you get there first? Or can you be the best?

Yes. Okay. Great. Anything else you'd like to highlight in the last couple of minutes here?

I think it's -- again, it's an exciting year. We obviously are waiting for our first approval. Waiting is probably -- that's a passive term, but we're very actively and constructive with the FDA and fully prepared to launch. We have the teams hired and ready to go. Looking forward to filing the next molecule. And then we want to lead the area of blood-brain barrier engineering. And I think it's a very exciting time, and it is gratifying to see everyone latching on to these transferrin receptor approaches.

Right. Okay. And the new PDUFA is what date? The 5th?

April 5.

April 5. Okay. That's Easter.

I know it's Easter Sunday.

And Good Friday is the Friday before. Okay. We'll see when you get the notice. Okay. Best of luck. Thank you, Ryan. Appreciate it.

Okay. Thanks for joining us, everybody. I'm Marc Goodman, one of the biopharma analysts at Leerink Partners, and we are lucky to have Denali Therapeutics. We have Ryan Watts, who's the CEO of the company; and we have Katie Peng, who is the Chief Commercial Officer, who I was just joking around with her, but I'm very serious as we all are, we need her to be very busy with an approved drug very, very soon.

And we probably should start right there and just give us a sense of -- I don't even know where to start, Ryan, just what's going on with the back and the forth and this and that and where are we?

Thanks for having us here. Great to be in Miami. It's an extraordinarily exciting time for us at Denali. We have a PDUFA date coming up April 5. Obviously, it's been something we've been looking forward to since the founding of the company over a decade ago with the goal of obviously delivering medicines to the brain using these novel technologies, using the transferrin receptor-enabled technologies, in this case, of transport vehicle. So the question you're really asking is on tividenofusp alfa, which is our lead program for Hunter syndrome. A little bit of back story behind tivi.

We started developing tivi in 2020. And really the first 5 patients of data, we saw that 4 out of those 5 patients had normalized heparan sulfate. This is just after 4 doses. And that was sort of unprecedented in the field and heparan sulfate is a biomarker of the enzyme, and we're measuring it in brain through, I guess, through a surrogate through cerebrospinal fluid. And at the time, we were, of course, that data told us that our platform is working in 2020. And now the question is, how could we expand that platform and at the same time, accelerate the Hunter program to some form of approval.

And I think as people appreciate, it's been a long story of imagining a surrogate endpoint of a biomarker that's reasonably likely to predict clinical benefit as the category in these monogenic diseases where the FDA has given us single enzyme guidance on sort of the simplicity of this. That being said, in MPS diseases, there is no precedent yet of using a biomarker as a surrogate endpoint. And so we began this long journey. Obviously, there are others on this journey as well in gene therapy and in our case, it's an enzyme replacement therapy, as I mentioned, engineered to cross the blood-brain barrier.

We submitted our BLA last year and have had, frankly, the way you describe it is really constructive, very engaging interaction with the FDA. As anyone who has gone through this process, a lot of back and forth, a lot of back and forth on the CMC as we sort of nail down this biologic [indiscernible], it's the first medicine using transferrin receptor as a mechanism for delivery to be reviewed at the FDA. So setting the precedent there as well. And at this point, we're weeks away from a decision, but moving in a positive direction.

So it was delayed by a short amount of time...

Right.

Do we have any idea what that delay was?

Yes, we know exactly what that delay was about. As we were nearing the late cycle review, it was identified that there was a miscalculation on a molecular weight from a public database that actually someone, a third party used to calculate our population PK. That was corrected in like 4 days. And the FDA, in general, sort of stayed on track with the review. And as I mentioned, like that longer period of time, probably going mainly through CMC.

But now let's put all of this in the context of the complexity of the regulatory environment right now. And I think a lot of has been said about accelerated approval in rare disease and providing medicines in these patients, especially in patients where you have these neurological deficits. And what I would say is that our experience with our review division has been generally positive and constructive. So that was completed. There's been actually no more questions around that particular piece. And now it's just the final stages, label discussions, post-marketing commitments, everything you'd expect at this timing of the review.

But you've been in labeling discussions, right, for a while? Or is that not a fair statement?

I think we have -- I would say that in the last month or 2, we're like really in it.

Okay.

Right. So it's like we began that process. We had a late cycle meeting towards the end of last year, but now this is -- we're really in the thick of it now.

Right. And then ReGenX gets a CRL. And I think everybody says, did something change here for Denali as well. So I guess I'll let you kind of answer that question.

I think the best way for me to answer that is rather than comment on [ ReGenX ] and their data set, specifically, what I can tell you is sort of the totality of our data set, right? So 47 patients worth of data. Patients have now been treated up to 4 to 5 years. We have a confirmatory trial, the COMPASS trial that has a significant number of patients as well, both neuronopathic as well as attenuated. And what we see is a normalization of heparan sulfate, and we'll just call it total heparan sulfate. So the 4 major dextrans as measured.

So no specific -- not measuring just one specific dextran and looking at effect, but there, we're seeing normalization. I think importantly, we also see NfL normalization, which is a biomarker of neurodegeneration. And so I think we, obviously, like others, have looked very carefully at what the FDA has said in that CRL. We feel like we're in a strong position with our data and our engagement with the FDA.

Not to keep harping on this, but they didn't have 4 major dextrans, right, in their data...

That's right.

They were kind of focused on.

Yes. I think historically, they did, but then they focused in on a single dextrans.

Do you think that's a potential reason?

Well, I think the issue you have and sort of cited in the CRL, again, without going into too much detail, is the great debate with biomarkers, and you've seen this in the last month or 2 is what level of biomarker correction is needed to drive a clinical benefit, right? And until you know what that level is, the best case scenario is you normalize, and therefore, it puts you in the highest probability of confirming that, that biomarker is leading to clinical benefit. And I think this is where the FDA is in my -- the way I would state it is holding a high bar. It's holding a high bar. And obviously, we were behind our competitors, both ReGenX and JCR, and our goal has been to develop a platform broadly to prove it with Hunter syndrome, but to hold ourselves also to a high bar in terms of the quality of the data we generate and the path towards approval.

So let's talk about what is the standard of care for Hunter today? And is there any way to make a comparison of your product versus that product?

Yes. So I'll answer that. And then as we get into more, Katie will add to it. But the standard of care today is it's now been almost 20 years since idursulfase was approved, which is an enzyme replacement therapy, and it's delivered systemically. And what I can just say generally is that if you look at our data, specifically looking at like peripheral urine heparan sulfate, we see even normalization in that as well when patients switch from standard of care to tivi. And part of that is probably around dose, the dose that we selected.

But in reality, that particular medicine is not engineered to cross the blood-brain barrier. 70% of patients on diagnosis are determined to be neuronopathic will have severe neurological deficits. And the idea is that those patients, in particular, will greatly benefit from a medicine that can also cross the blood-brain barrier. But we replace standard of care. So we -- we're not dosed on top of any other medicine, but we're dosed to treat both the entire body and the brain.

Right, right, right. So Katie, why don't you talk about commercial now? What's the plan?

Yes. So we're very excited to be here at this stage. And we've actually built our field team at the end of last year, getting ready originally for a January approval. So our payer field team, our sales team, our medical science liaison team are all out now. We've had great engagements with payers so far to share our data and to get an understanding of how they see pricing and coverage for patients. In addition, we've also engaged with all of the centers of excellence because our MSL team is very familiar with the investigators, but also we've been sharing our data along the way for a few years now.

There's tremendous excitement in the community. There's high awareness of the tivi data, but not just with physicians, but with the patient community as well. So there's general excitement. In addition, this year, now we finished setting up our distribution model as well as our patient services because we know that's really important to get patients reimbursed and supported as we launch this medicine. So we expect to see a very strong uptake in the patients who are just recently diagnosed and also patients that are diagnosed with the severe neurologic manifestations.

Do you think patients will switch?

Yes. So today, about 95% of patients are on Elaprase. So it is absolutely a switch strategy. And as Ryan mentioned earlier on the data, our Phase I/II data showed, right, patients who were on Elaprase switching to tivi and doing much better on all the biomarkers. So it is actually the most compelling point because physicians monitor patient progression today using urinary GAGs, and we see that tivi does much, much better. And so for all the market research we've done and the advisory boards we've done, this data is what's going to compel physicians to make the switch.

And the doctors are saying, even though the patient -- it seems to be working, this works even better, so we should switch.

Yes. One interesting fact that we've learned is that because there's been no innovation for 20 years, there was nothing to switch to. But as we get into these deeper conversations, almost all patients are still progressing on the standard of care. So it could be neurologically, it could be in the periphery. So what we have learned is that standard of care, even in the periphery, I think there's still unmet need.

Yes. What about genetic testing? How does that fit in?

Yes. So in order to get an official Hunter syndrome or MPS II diagnosis, patients do have to be genetically tested. And so once they get tested, then they confirm they have an ICD9 code and they can start billing for having Hunter syndrome. Are you asking maybe about newborn screening?

Yes, I was about ask, that's where I was...

Yes. So in the U.S. now, about 13 states have adopted newborn screening, which is great because we know in this disease, the earlier you can impact the treatment and treat the disease, the better it will be for patients. And so 13 states have now adopted it. But as you can imagine, with medicines now being approved in this space, there will be more incentive to push newborn screening more holistically across the U.S.

Yes. Interesting. And lastly, just on the subject, the Royalty Pharma deal, what was the purpose of that?

Yes. So I think for us, if we step back a little bit and look at the entire portfolio, our goal, which we've set now a while back was to commercialize our own medicines, specifically in the enzyme replacement therapies, right? And so we set out to figure out how would we do that as really leaving it ourselves. And the Royalty Pharma deal puts us in a very strong position. That with also an equity financing brings in another year of capital, really takes us to the end of 2028.

But I think also is reflective of the deep diligence on the platform in order to say, okay, there's real promise here. And there's real promise in Hunter as a commercial opportunity, right? We wanted to be able to finance ourselves through our 3-year goals. And we've laid those out at the end of last year, which was to have 2 growing brands, one with tivi in Hunter syndrome, another with DNL126 in Sanfilippo, 5 clinical proof of concepts and bringing an additional 5 medicines into the clinic using the transport vehicle. At this point, we have 5 [ tivi-enabled ] programs. So the royalty financing with the equity financing at the end of last year lays that foundation for the next 3 years.

Yes. Interesting. So let's flip gears to Sanfilippo 126. So where are we with that program? And what do we have to show? Because there seems to be some derisking that's already occurred, I would think.

Yes. I'll start on where we are with the program and then Katie, you can add to that. So we just presented data at WORLD. This is the first data, the most robust data set, I think, yet presented in Sanfilippo. We have a robust reduction in CSF heparan sulfate, again, our familiar biomarker as well as GM2 and other lysosomal biomarkers. We also see reduction in urine heparan sulfate, normalization of liver volume. And basically, we're in a strong position.

What's interesting about that data set is that it was essentially 2 cohorts that were dose finding, and we really need to figure out the dose frequency and the dose levels. And if you look closely at the data, you can see how that plays out in the biomarker over time as well, especially the urinary GAGs. You can really see that as we shifted to weekly dosing at the high dose, we drove a really robust effect. And we also improved tolerance going to weekly from every other week dosing. And part of that is in these enzyme replacement therapies, having drug on board allows you to build tolerance. So a lot of really important insight in that data set.

We now have what we call the key efficacy cohorts, which are fully enrolled. We'll complete -- we'll have a data cut in September, and that will be the data that goes into our BLA filing for accelerated approval, again, using CSF heparan sulfate as a surrogate biomarker reasonably likely to predict clinical benefit. So a lot of similarities with Hunter, but also some significant differences. There's no standard of care in this disease. It is a very aggressive neurodegenerative disease. I'd say even more so than Hunter. Hunter is, of course, whole body and brain. Sanfilippo tends to really impact the central nervous system. Even the heparan sulfate is elevated about twofold above what you see in Hunter. And so I think timing of intervention is really going to matter with Sanfilippo and more so than some of these other diseases.

So in terms of the commercial opportunity, it is exciting because the infrastructure today that we're building for tivi is going to be the same infrastructure that we'll be launching DNL126 as well. So we will not have to add additional headcount. Same call point, same customers. And so you can imagine that with our ETB portfolio, we can get very, very high brand margins because our spend will be limited.

Interesting. And just lastly, before we move on, the number of patients in each one of these populations.?

Yes. So we're -- it's hard to because there's no treatment, getting the right epi is hard, but we're roughly estimating that it's about 75% of the MPS II market, so around 1,500 patients worldwide versus for MPS -- sorry, MPS II. MPS IIIA is 1,500, MPS II is 2,000 worldwide.

Yes. Okay. Terrific. I want to step back just for a second. One of the -- well, actually, before we do that, let's talk about any other lysosomal storage disorder pipeline products that we can talk about...

Yes. We just received clearance, and we'll soon begin dosing with our Pompe program using the transport vehicle technology. This is ETV:GAA. What we've shown there, which is a little unique from Hunter and Sanfilippo is the ability for transferrin receptor-enabled technology to improve muscle biodistribution. So that's well known. There are other companies that are using TFR platforms to deliver, for example, oligonucleotides to muscle. And what we've seen compared to the standard of care is more robust benefit in muscle endpoints in Pompe. So LOPD obviously, is the primary goal here.

Now fortunately, there's also a rare population that has more severe mutations, IOPD, where we also believe ETV:GAA can be differentiated because we can deliver across the blood-brain barrier. So improve muscle delivery, improve brain delivery. That program will begin dosing and really expecting data for this next set of transport vehicles that includes GA MAPT for Alzheimer's, Abeta for Alzheimer's in 2027, but it all comes down to our ability to enroll and dose escalate in each of these studies. So a very exciting time expanding the portfolio at the same time that Katie and her team are preparing for our first commercial launch.

So 5, 6 years ago, I feel like you were the blood-based barrier buster, right? I mean you were the one. And now it feels like I don't know everybody seems to want to have one. How is yours different? Like as you hear about each one of these, I'm sure you get questions like what do you think of this? What do you think -- how do you differentiate?

I mean it's very good news that everyone else is wanting to do it. If you're in a field and you're the only one doing it, it probably means that what you're doing is not working. And I think in biotech, like once something starts to work, everyone jumps on board with a variation. And frankly, that's actually what's best for patients because then they'll have many options and people will use their deep expertise to invent in whatever part of this technology, if it's the protein engineering, if it's the cargo that you're delivering. And so obviously, you're right, we probably had a decade head start in this area. It's something that I've worked on now for 20 years and started working on blood-brain barrier in actually 2006.

And I remember first working on this is prior to founding of Denali, we looked at everything that existed in the patent literature and everything that existed in the publication literature and just made them and said, is there something that already works and that's where we started to invent and really understand the dynamics of trafficking at the blood-brain barrier, first with transferrin receptor, then with CD98 and then we've now combined them. And what we learned when we founded Denali now over a decade ago is that we wanted really something that was modular that allowed us to make fusion proteins that allowed us to make antibodies.

And then eventually, we were the first to show that you could actually get an oligonucleotide into the brain. That had never been shown. And frankly, I didn't think it was possible because think of what has to happen. You deliver this thing either subcu or IV. It has to cross the blood-brain barrier, get into a cell, release the oligonucleotide and then modulate gene expression in the neuron. I mean that's a journey. That's multiple cells that you're crossing to this -- to get to this spot.

So when we saw that for the first time, and we actually published that in 2024, but saw it for the first time in 2021, we thought this is really like this can really change things. And I actually feel like that presentation of that data in '21 and [indiscernible] that's become one of the most competitive areas in blood-brain barrier is delivery of oligonucleotides because now you can regulate gene expression in the brain. And so of course, we want to win. We're competitive. That's great. But also, if it's working, you should expect a lot of people to do it, which was my original point.

Now to answer the question, what is differentiated. And I think the fact that we built receptor binding into the Fc is unique. We haven't seen that with any other competitors. Part of that is we have a very strong IP landscape. The fab approach is what most people are taking. There's some variation of fab and they make fab fusions, fusions with oligos, fusions with antibodies. I think stability can be a challenge there. And we've done a lot of work on differentiation. In some cases, directly against the exact architecture of a competitor in other cases, like theoretical differences. Some of that has been published. Others we presented at the end of last year in an extensive R&D Day.

So I think that those areas of differentiation are important. But all of them may work to some extent. The question is who will get there first and who will ultimately be better and let's see how -- I mean, I would love to look back 10 years from now and have like 20 or 30 approved transferrin receptor programs. Now great if a lot of them are ours, but also okay if the field is now really growing and can actually deliver medicines that way.

Yes. You mentioned the MAPT and the Abeta. Talk about those products a little bit. Obviously, there's 2 drugs for Alzheimer's on the market. Obviously, Roche is working very hard with tronti to kind of get there as well. Where do these fit in?

Yes. We're on the -- as we're on the eve of our first approval, I think it's important to step back and say a decade ago, we founded Denali because we wanted to defeat degeneration. Our goal was to make medicines for Alzheimer's and Parkinson's. But as almost always the case in biotech, you follow the science, and it was actually much more compelling for us to start with Hunter and Sanfilippo, where it's a monogenic disease. There's approved enzymes, they don't get in the brain. So there's a linearity, like you know there's a high probability of success.

What's changed for us is that I didn't never imagine working on childhood diseases. It's profoundly impactful, like beyond measure as you engage with these families and you engage with the community, and that ended up being very foundational for Denali is working in the enzyme replacement therapies. But we never forgot that we wanted to solve, at least be part of solving Alzheimer's and Parkinson's and these other areas. And so it's very exciting that our first real oligonucleotide program, MAPT, is now entering the clinic it's going to silence the expression of the gene MAPT that codes for tau.

And the idea is right now, there's intrathecal delivery, but can we replace that with IV delivery and subcu delivery and knockdown expression of tau. And in addition to that, there's now a class of molecules. I mean, let's all face it, everyone either believed in Abeta or tau, and now you can hopefully believe in both. I mean we're still waiting to see if tau knockdown will lead to clinical benefit. But there are now -- like now we need a best-in-class Abeta molecule, and that's where our ATV:Abeta program comes. And so that's -- I think it's an exciting time to go back to our origin and make neurodegeneration medicines using the transport vehicle technology to create this best-in-class, certainly in the Abeta field.

So just to be clear, the Abeta, this is your own Abeta...

Yes. So -- what we've done, and I think it's probably best described in a paper we published in science last year in August is we've engineered this antibody to be immune silent when bound to transferrin receptor. But when bound to amyloid plaque, we can remove amyloid plaque through the Fc gamma receptor interaction. It's called a cisLALA mutation. I think it's very clever. Our engineers proposed this idea and then determined it sort of empirically.

And so the goal is to have the robustness of plaque removal that you have with any standard full effector function antibody, but have that molecule be silent when bound to transferrin receptor. Then in terms of the Abeta arms, we're selecting arms that bind aggregated Abeta preferentially, not monomeric, and that's essentially the approach we're taking with that program.

Interesting. And where is that program?

We'll be filing it very soon. So we'll be starting clinical studies this year. I think with both MAPT, Abeta and our GAA program for Pompe, we're just generally seeing data in 2027, but full speed ahead. The faster we can go, the better with any of those 3 programs. Obviously, the Pompe program expands the ETV franchise to a larger market, including muscle, but let's face it like tau and Abeta are really important targets, one of which has at least been clinically validated.

So we're all watching Biogen, I guess, is probably the next tau oligo, right? So we'll know what if it doesn't work? What if it does work? What does it mean?

So I think what we can say already and probably the most interesting thing we can say is that with the Biogen ASO program, they were able to reduce tau, but they're also able to reduce tau pathology by PET. And that actually is not intuitive. Now we think of amyloid plaque, you have these microglial cells. They're the -- since we're here in Miami Beach, they're the beach comers of the brain. So microglia goes around and cleans everything up. You have antibody tag the amyloid plaque and basically engulf the amyloid plaque. That's what the Abeta antibodies do.

With tau, those neurofibrillary tangles are inside a cell. And it's uncertain that reducing tau protein alone would actually reverse tau pathology, but that's what the initial data has already taught us from Biogen. So now there's one really important question, which is, does reducing tau pathology lead to a clinical benefit. The distinction of the OTV, which is an oligo transport vehicle and the way that Biogen approach it, which is an intrathecal delivery of an ASO, so injecting the spinal cord is it's a very different biodistribution profile. Our medicine will cross capillaries and give you even distribution throughout the brain, where intrathecal delivered medicines don't penetrate deeper brain regions. We've shown this in nonhuman primates. And of course, humans are -- at least our brain or central nervous system is about 18x larger than a nonhuman primate. And there, you're just relying on browny and motion for these ASOs to diffuse.

So I think there's a real chance for differentiation in biodistribution. Now does the traditional intrathecal approach, is it going to actually test the tau hypothesis? I guess it remains -- this is a type 2 experiment. In other words, if there's clinical data looks great, then we know and then we can replace that with either a subcu or an IV injection. If it doesn't look great, it could be around biodistribution, right? So there's really one outcome that's informative, which would be a clinical benefit. If not, there are multiple reasons why it may have failed.

Yes. Interesting, very interesting. Another data readout this year is LRRK2, right? So give us a quick update on LRRK2.

Yes. This is an exciting year, waiting for an approval. We just had our first data on Sanfilippo, we'll complete that. We have a LRRK2 readout midyear. That's being run by Biogen. LRRK2 is a kinase that when mutated is hyperactive and is one of the 2 major genetic risk factors in Parkinson's. GBA is the other. We're approaching that with a GCase enzyme replacement therapy. But in the case of LRRK2, it's really compelling genetics, and we've developed a LRRK2 inhibitor. This is one of few medicines that aren't using the transport vehicle in our portfolio. This is one of our very first programs way back 11 years ago that we started engineering small molecules that were blood-brain barrier penetrant. This will be a really big test of the LRRK2 hypothesis because it's 650 patients, UPDRS, real clinical endpoint.

This is a registrational sized study being run by Biogen. But I think the reason to believe is that the genetics is very compelling. The question in neurodegeneration is always timing of intervention. right? You can have a genetic cause, but even Abeta, it took time for us to understand selecting the right patients, intervening at the right time to provide a clinical benefit. So we hope we've learned from that. And in the case of LRRK2, we're actually testing idiopathic, but we also have a separate study with just LRRK2 carriers where we're looking at biomarkers. So I think it's obviously an exciting target.

Were we able to find those patients? I know it was...

We -- actually, we are. And the difference between LIGHTHOUSE, which was a 400-patient study and BEACON, which is a 50-patient study, is that we actually focus more on the biomarker aspects of BEACON and therefore, changed the enrollment criteria to allow us to quickly find those patients. And that study, we're nearing completion and enrollment in that study, much faster than we had for LIGHTHOUSE.

Yes. And then just lastly, in the last few seconds, the other program that you were mentioning...

Yes. So progranulin, this is the -- so progranulin is PTV progranulin. And the idea here is a protein replacement therapy, enzyme replacement therapy for progranulin. And here, this year, we're looking at the proximal biomarkers, the biomarkers of lysosomal function in FTD granulin.

Excellent. There's a lot going on.

It's exciting time.

Hopefully, you'll be very busy.

Yes.

Thank you very much for joining us.

Thank you.

Thank you.

Hi, everyone. Thank you for joining us in the room and online for the third day of TD Cowen's 46th Annual Healthcare Conference. I'm Joe Thome, one of the Senior Biotech Analysts here on the team at TD Cowen. And it's my pleasure to have with me today Denali Therapeutics. And up here with me, we have Co-Founder, CFO and COO, Alex Schuth. So thank you very much for being here.

Maybe before we dive into the individual programs, if you want to just give a brief kind of high-level overview of kind of where the company is at and what we should expect for the rest of 2026.

Absolutely. I mean, first of all, Joe, thanks so much for the invitation to the conference and for the great coverage, always. I do want to highlight the title of your last note, which I really enjoyed, must-see TV ready for prime time. So thanks for that.

So 2026, we're very excited. It's a big year for us. It's actually -- we founded the company back in 2015 with the premise with the idea that the blood-brain barrier is breaking open, that we can pioneer a technology that can deliver large molecules through the blood-brain barrier and open up the brain for treatments that were not possible before. So 2026, first and foremost, eagerly awaiting our PDUFA date for our first drug for Tividenofusp alfa for Hunter syndrome. That is April 5. We feel very good about the ongoing dialogue with the FDA, and I'm sure we can talk more about that.

On the heels of 310, there is DNL126, which is Sanfilippo syndrome, which is also enzyme replacement therapy, follows a very similar trajectory as 310 does. Here, we just presented data at the WORLD meeting in San Diego, and we feel that those data support the accelerated approval path, and we plan to file early next year and then launch next year. So together, these two programs has about a $1 billion market opportunity and will be the foundation for the company, the commercial foundation for the company.

Beyond those two, there are two key clinical data readouts. First, there is the LRRK2 inhibitor study, which is in Parkinson's disease, that's midyear. And then there is the progranulin program in FTD later in the year. And then we'll start 3 more clinical studies, first-in-human studies, expanding the transport vehicle into more common neurodegenerative diseases with two Alzheimer's programs, targeting Abeta, one targeting tau. And then there is another enzyme program for Pompe, which is our first entry into peripheral muscle disease, where also transferrin receptor enables higher uptake into muscle, and we're excited about that.

So big year ahead. We did raise capital at the end of last year. So we're well financed with just under $1 billion at the end of the year. And with approval, there would be another $200 million coming in from the Royalty Pharma deal that we entered into in December. So yes, big year ahead.

Great. Maybe we'll start with Tivi. Can you, yes, just highlight a little bit where you're at with the FDA now, maybe your confidence in a positive decision? And maybe what led to the 3-month delay and your confidence that you've addressed that?

Yes. So as I said, we do feel very good about the ongoing dialogue with the FDA. It's productive. It's collaborative. We're in frequent conversations. We have stated before that we're in label discussions. We're discussing the post-marketing commitments.

In our conversations, the FDA has actually always been very consistent. Since that meeting 2 years ago, the Reagan-Udall meeting where the FDA essentially validated heparan sulfate -- CSF heparan sulfate as the surrogate biomarker that is reasonably likely to predict clinical outcome. Since then, we've had a very straightforward conversation with the FDA.

We did have the hiccup with a 3-month delay, which was caused by an error in the chemical structure in the public database, which then led to a miscalculation on the molecular weight by one of our collaborators.

And we caught that. We fixed that. It had no impact on efficacy or safety. But molecular weight is an important calculation and everything from dose to exposure. So it had to be fixed and that led to the major amendment, which led to the 3-month delay, which was frustrating, but we're beyond that, and now we look at April 5.

Awesome. And a competitor in the field did recently receive a CRL for the same indication, and we have been receiving some questions on it, and I know you're differentiated here. But I think it would be helpful to kind of point out what are the considerations that investors should be thinking about before trying to kind of cross examine that experience? How is your profile maybe different than the ReGenX program?

Yes. So obviously, it's the same indication, Hunter syndrome, but it almost -- that's almost where it ends. It's obviously a different modality. One is gene therapy, where, in a way, traditional enzyme replacement therapy enabled by our transport vehicle. It's also different divisions, CBER versus CDER. But I think more importantly, it's really the data package, right?

So it's the extent, it's the robustness of our data package. We have 47 patients followed now for up to 4 years. We have rapid and durable normalization of the key biomarker, heparan sulfate, total heparan sulfate, not just D2S6, a subtype. That reduction is also accompanied by improvement or stabilization in patients in neurocognitive outcomes. We see neurofilament normalization. We see improvement in hearing. We see normalization in liver function. So kind of like more longer and better data.

Maybe just on -- because we all -- now that the FDA, it is -- we actually think it's very helpful that the FDA has the transparency of making CRLs public because we can all learn from that. Really, the importance of total heparan sulfate, which is the aggregate of at least four subtypes of which D2S6 is one. And back to the Reagan-Udall Foundation meeting, it was total heparan sulfate, which was validated. So that's one.

And the other point that was highlighted was around the genetic classification of patients. And here, we have a very robust mechanism. We have an independent genetic evaluation committee which consists of three geneticists and a neuropsychologist and a medical geneticist, so five people. And they have -- and there is an algorithm they have to really align on is this mutation one that indicates that this patient may develop a neuropathic disease. So there's lots of differences. And as I said, we continue to feel good about the strength of our data.

And maybe can you talk about your initial launch preparation? Kind of what are you doing now to make sure that once approval is hopefully in hand, you can have sort of an effective launch? Any commentary on how discussion with the payer community is going? Anything helpful there?

Yes. So we've been preparing for upcoming approval, the hopeful potential approval for a while. Katie Peng, our Chief Commercial Officer, joined us actually 4 years ago and has been -- and has since then essentially been in launch preparation.

Now those accelerated mid last year once we filed the BLA. We now at our Q, we declared what we call commercial readiness. So all of the preparations are done. The team is in place and all the infrastructure prework has happened. So on the team side, it is both the field sales team, which is a small and focused and very experienced team.

Remember, in Hunter syndrome, 95% of patients are currently treated. So it's also known where they are and what centers they are. So that helps us with the targeted force. So the field team is in place. The MSL team actually has been in place for a number of years now in connection with the scientific community. And then on the infrastructure, everything from distribution to supply chain to the patient support hub to the payer engagement.

To your question on payer engagement, we have engaged with essentially all the payers in the U.S. Payers understand the unmet need. It's very straightforward. Traditional enzyme replacement therapy doesn't get into the brain. Ours gets into the brain. So it's -- they understand the unmet need. They also understand the robustness of our data package. So the initial conversations have been very productive with payers. Obviously, the price will depend on the label, and we'll have to have that conversation at that point. But so far, we feel good about it.

And if you do go for a premium pricing strategy, which is something that the company has suggested before, I guess, do you think patients would need to demonstrate any sort of progression on CNS manifestations of the disease or anything that would kind of clearly outlay that a CNS penetrant therapy over Elaprase would be recommended? Or how do we think about that?

Yes. I think both physicians, definitely families, but also payers understand that Hunter syndrome is really a whole body disease and that the delineation between a neuronopathic and non-neuronopathic disease is somewhat arbitrary.

The consensus and the more and more growing consensus is that essentially all patients develop neuronopathic symptoms at some point. Also remember, neuronal symptoms are not just in the CNS. There are peripheral neuronal symptoms like carpal tunnel syndrome and others. So there is -- there are definitely more severe and less severe forms of the disease. That's probably the better way to delineate rather than around a certain set of symptoms.

And can you talk a little bit about the rate of switching that you anticipate maybe based on the KOL conversations that you've had? How frequently do these patients come into the doctor to even get that initial touch point? And then what proportion do you think would switch pretty readily versus maybe some that may kind of wait a little bit of time?

Yes. So ultimately, we -- the goal is to become the standard of care and that at some point in the future, all patients with Hunter syndrome are -- have access to and are treated with Tivi.

With respect to the switching or the adoption will probably first be newborn patients. And now newborn screening, by the way, is in 50% of newborns in the U.S. are actually now have access to newborn screening.

So newborn patients, probably more severe patients, probably early on, patients with more overt neuronal symptoms, those will start first. Other parts of the patient segment will probably take some time. To your question around how often they come in, it varies. It's a very good question and obviously, that we ask as well. Some come in as frequently as quarterly, others come in once a year, depending on how well the patient and the family feels that their patients are treated. So that will take time. The switching logistics, also remember that many patients right now receive home infusions.

When they switch to Tivi, they would most likely do the first few number of infusions in a clinical setting to deal with potential infusion-related reactions. So there are some mechanics that we -- what we guide to, what we believe in what we guide to is that it's an S-shaped adoption curve. So we think very modest probably to minimal revenues in 2026. It's really about bringing patients on board. And then 2027 will be the inflection year when we feel we see actually the uptick in revenues.

And maybe can you talk about potential opportunities ex U.S. Kind of what's the strategy there? Is the treatment kind of paradigm and similarities exist in the U.S. and ex U.S. and kind of your appetite in other geographies?

Yes. So a very important point about -- if you look at Elaprase, the standard of care, been on the market since 2006 as a benchmark, about 2/3 of the revenues are ex U.S. revenues, right? It's a dynamic that you often see in rare diseases. So the ex U.S. market is very -- or the international market, as we call it, is very important to us.

We do believe that -- and roughly the revenues is about 1/3 U.S., 1/3 Europe and 1/3 rest of the world. We do believe that with the accelerated approval in the U.S. we probably have access to about 60% of global patients before the confirmatory Phase III study, the COMPASS trial will read out. So those are some countries that directly follow U.S. regulation. And then there are some other countries where some -- with additional regulatory documentation, we feel we can have access.

So with accelerated approval, 1/3 of the patient population accessible in the U.S. and then about up to 60% with approval. And then the rest of the world, we would have to look at the COMPASS data.

So the COMPASS trial, that's the Phase II/III confirmatory trial, fully enrolled the cohort A, that's the neuronopathic cohort and which has a 2-year treatment duration. So that fully enrolled at the end of '25. So end of '27, we'll have the data, and then we'll look to file that in '28.

Great. And then maybe we'll jump over to 126 for MPS IIIA. Recently presented some data at World. I guess, what about the profile do you think rings kind of most heavily with physicians there? And how much can we extrapolate from the experience in Hunter directly kind of to the experience in IIIA?

Yes. So MPS IIIA, Sanfilippo Syndrome, a very closely related to MPS II. So both from a patient perspective and from a treating physician perspective. So it's almost exactly the same treating physicians.

But there are two key differences. One, MPS IIIA is a more aggressive disease. It is a more predominantly neurocognitive disease. But also there is no standard of care. right? So there hasn't -- and there's never been an attempt to develop a standard of care with traditional -- or attempt to develop a care with traditional enzyme replacement therapy because it wouldn't cross through the blood-brain barrier. So there was really no hope to have an effective medicine.

So the data we presented at WORLD, we are very excited about this. This was from our dose escalation cohorts from our dose-finding cohorts. And we showed a mean reduction in heparan sulfate about 80%, including normalization in some patients.

We have had ongoing conversations with the FDA about this program for a while. As you'll remember, we were selected in what's called the START program, which was a program instituted about 2 years ago, which enables more frequent interactions with the FDA. Through that program, we have alignment on the accelerated approval path. And we feel that this data set will support that filing in 2027 and -- early in '27 and then hopefully approval in late '27.

And you mentioned that the data that you presented were from the sort of dose finding work. I guess, the optimized dosing strategy then, I guess, do you think there's areas to kind of improve on what you showed historically? Or kind of how do you think about what was left on the table kind of in the dose-ranging part that you can kind of optimize?

Yes. So we do believe that the optimized dose data should be at least as good as what we see right now in the dose ranging. Dose ranging, we did dose escalate. That was one. But we also experimented with dosing frequency. We got so excited about the preclinical data that we had seen that we thought maybe we can enable more convenience to patients by having every other week dosing and sparing them a trip to the hospital, for the families, which can be very, very taxing over time.

We did, however, see an increase in infusion-related reactions with less frequent dosing, which from a biologic perspective, makes sense as you develop tolerance, it's actually better, more frequent dosing is better. So we went back to weekly dosing, which is the standard of really almost all enzyme replacement therapies are dosed weekly. So those are two elements where there is reason to believe that the final data would be at least as good as what we've seen in dose ranging.

And when we think about the commercial opportunity between Sanfilippo and Hunter, I guess, how do you see those kind of separate between those two opportunities? Obviously, the different dynamics with kind of the currently available standard of care and one. So how do you see those kind of panning out?

Yes. We look at them almost as a pair of programs sort of as the commercial foundation. Again, we hope to have two programs. By the end of next year, we hope to have two programs on the clinic, which share a lot of the -- back to the synergy and the similarity in the treating physician population. So what we look at is that these programs together have about $1 billion-plus market opportunity. And that's -- they -- from an epidemiological perspective, they're about the same size.

So Hunter syndrome is about 2,000 patients worldwide. Sanfilippo, the epidemiology is not as good as Hunter because there is no treatment. But generally, it's believed to be about the same size, maybe a tad bit smaller. Some say it's larger, but we think it's probably the same. Hunter syndrome has Elaprase as a benchmark. Elaprase sells about $650 million a year. Sanfilippo doesn't have a standard of care. So if you take those, it will take a little longer maybe with Hunter than it might with Sanfilippo. So together, $1 billion plus.

Great. And maybe we'll jump on to some of the other programs. As you mentioned, there's 2 kind of shots on goal with Alzheimer's and different targets. I guess, why -- I guess, can you kind of walk us through the differences in targets and obviously, different aspects of the platform that are going after these? And how will you analyze kind of what's the right target? What do you want to see?

Yes. So back to sort of our core technology, we call the transport vehicle, so to deliver biologics through the blood-brain barrier into the brain. Also when we started the company 10 years ago, [ defeating neuro-degeneration ] was our core purpose. We think that, that is the ultimate -- probably the biggest unmet medical need in at least our part of the world at this point is dementia and is probably Alzheimer's disease. Antibodies couldn't really treat -- couldn't really be developed because they don't get into the brain themselves, but now is a different time, right?

So Alzheimer's, Abeta antibodies have shown some -- they have shown ability to clear plaque and that has translated to some extent into efficacy on slowing the rate of progression of decline. Roche has shown quite impressive data with trontinemab, which is also a blood-brain barrier enabled Abeta antibody that showed that not only can plaque be cleared faster than a standard antibody, but also really importantly, the safety profile is superior because it can avoid what's called ARIA, the Amyloid-Related Imaging abnormalities, which are a key safety concern.

So our technology, the transport vehicle is clearly differentiated from the brain shuttle. It's really the architecture about how we enable transferrin receptor binding. We're the only ones, and that was intentional to use the Fc of an antibody and not to have appended sequences, which helps with stability, infusion-related reaction, immunogenicity and everything. So we believe that there is a key differentiation on Abeta. Tau, so that's -- so Abeta and tau, the two hallmark pathologies of Alzheimer's, and we go after both of them.

Differentiation on Abeta. Tau, here, it's really the differentiation against or from intrathecally administered ASOs. Biogen has a program together with Ionis, intrathecally administered ASO. It will read out in the middle of the year. Early data, Phase I data was quite encouraging with respect to tau reduction. Our differentiation here is that it's IV administered, which is not only more convenient for the patient and safer for the patient than intrathecal in the lumbar tract, but also has better distribution in the brain.

Because intrathecal administration, you will have a high gradient of drug. You'll have lots of drug in the spinal tract, but actually very little drug in the actual brain, especially in the deeper regions. If you go through the bloodstream, the brain with 300 miles of blood vessels and every neuron with its adjacent capillary, you have the perfect delivery mechanism to deliver drug to each cell. So that's why we're excited about those two Alzheimer's programs.

Great. And obviously, with the Hunter and Sanfilippo and similar size opportunities, it's very straightforward maybe for the company to commercialize those opportunities. I guess what's the appetite if you see a signal in Alzheimer's for Denali to run sort of the larger programs here versus when is the right time to maybe bring in a partner after signal finding? How do you think about your options there?

Yes. So partnering has always been a key part of our strategy. And early on, we entered into three relatively sizable partnerships with Biogen, Sanofi and Takeda. And those partnerships were also for the large neurodegenerative diseases. So overall, our plan is that in the rare diseases, just as you say, we will probably go alone on those and build the infrastructure, sizable. There's lots of synergies. We can do that.

For the large indications, we will most likely team up with a partner that has the global development capabilities, the global commercial capabilities. There has been tremendous interest to this point. We feel that we can generate clinical proof of concept or we should generate clinical proof of concept ourselves. Thereafter, we have flexibility to go forward, but I think the base case would be that we team up with a partner at that point.

And speaking of partnerships, obviously, you mentioned that the LRRK2 data are coming up. I guess what would you want to see in that data set that would give you and Biogen confidence to, you think, move forward in the indication?

Yes. So this is the LRRK2 inhibitor program, which is a bit of a legacy program because it's a small molecule. It's our only program that we participate in clinical development that is not enabled by the transport vehicle. Here -- so LRRK2, very exciting biology. LRRK2 is one of the strongest genetic risk factors for Parkinson's disease. And LRRK2 as it's a kinase and it regulates lysosomal function. If LRRK2 is overactive, lysosomal function is impaired and impaired lysosomal function is a hallmark feature of Parkinson's disease. You can even think about sort of GBA. GBA in the homozygous form causes Gaucher, a lysosomal storage disease and the heterozygous form is a risk factor for Parkinson's.

So the therapeutic hypothesis here is that inhibiting LRRK2 will boost lysosomal function and boosting lysosomal function will improve signs and symptoms of Parkinson's disease. This clinical study will always -- will be the almost definitive test of that hypothesis. 650 patients, a very well designed, very well run global clinical study with UPDRS, so a clinical endpoint. We're looking at the time to worsening in that endpoint. Biogen is controlling -- is running the study. We participate financially. It's a 50-50 deal. Biogen guided towards data in the middle of the year. So we're eagerly waiting in anticipation of those data.

And I guess when you think about moving forward, I guess, will you need both data from LUMA and BEACON to make that decision? And then maybe relatedly, obviously, there's been a lot of talk about changes at the FDA and sort of single study approvals and potential there. I guess, do you think any language coming out of that could benefit this PD program at all?

Yes, thanks for asking. That's a good nuance here. So the LUMA study that Biogen is running is essentially an all-comers Parkinson's study within 2 years of diagnosis. So it's early Parkinson's.

In parallel, what we are running is a study specifically in LRRK2 carriers. So about 2% to 3% of Parkinson's patients have a LRRK2 mutation. So that's about 30,000 patients in the U.S. So it's rare, but it's not super rare. And we have a separate study only in those. That study will read out later in the year. So by the end of the year, we and Biogen will have the benefit of having both data sets.

Now with respect to LUMA, it was intentionally and prospectively designed to be potentially registrational. The base case is that it would be one of the two registrational studies. So if positive, we would run another study with the hope that with a positive study, the second study would enroll really quickly and we could move.

Now we also follow and read the FDA's interest in accelerating development, and we'll have to see what the data look like. But the study design was very robust, and we'll see what the readout is.

Great. And maybe the last program we'll touch on is the FTD GRN program that you have. We're going to have some interim data later this year. Maybe what are the key points that differentiate this program from maybe others in the space? And I guess, will we -- will these patients be followed enough to see a true treatment effect at this point? Or how do you think about what you'll be able to see in this update?

Yes. So Frontotemporal Dementia, especially patients in Frontotemporal Dementia, especially those with a progranulin mutation have a deficiency in progranulin. Progranulin is a lysosomal protein. So the way you can think about this, it is a protein deficiency situation akin to a Lysosomal Storage disease.

Our approach is very direct. So we substitute the protein that is missing. That's very different from other approaches, approaches that target sortilin receptor, which were intended to block sortilin receptor and thereby to increase extracellular progranulin. Progranulin is an intracellular protein. It's a lysosomal protein we substitute it. So it's -- the mechanism is ours is very direct, others was indirect. It's almost as if in a Lysosomal Storage disease, you would hope to have a treatment effect by blocking the internalization of the enzyme from the extracellular space. That's not going to work.

With respect to the study, it is a biomarker study, right? So what we will look at here is obviously PK/PD and safety. We will look for markers of lysosomal function. We also will look for markers of neuronal damage. It is the -- we have data points at 6 months and at 12 months. So we will need to look at the totality of the data, but it is, first and foremost, a biomarker study.

And maybe on that point, what does the overall development path look like in this indication? What would be sort of the next step after that point, assuming you do see signals in the biomarkers?

Yes I think the base case would be a broader study with a clinical endpoint. Now if the biomarker data are striking, is it impossible that there is an accelerated approval pathway? Maybe not, but the base case is definitely a broader clinical study.

Awesome. Great. With that, we're out of time. So thank you very much.

Good day, and thank you for standing by. Welcome to Denali Analyst Call 2026 WORLDSymposium. [Operator Instructions]

I will now hand the call over to Mr. Ryan Watts, Chief Executive Officer. Please go ahead, sir.

Great. Thank you. We're looking forward to previewing our enzyme transport vehicle highlights from the WORLDSymposium, which we're here attending in San Diego.

Slide 2 is our forward-looking statements. On to Slide 4, just a reminder that Denali was founded to deliver the power of biotherapies to the whole body, including the brain, trend lives for people living with serious diseases. On Slide 5, an introduction into the transport vehicle. I know many of who are attending this call today are familiar with our technology, with engineered [indiscernible] of transfer receptor into an Fc giving us the ability to cross the [indiscernible] barrier and also access the whole body. On Slide 6, you can see our 3 different franchises, the enzyme transport vehicle, the all the go transport vehicle and the antibody transport vehicle. Today, we'll focus on our enzyme transport vehicle programs and the new data that's been presented here at the WORLDSymposium.

On Slide 7, you can see the totality of our enzyme transport vehicle franchise including our preclinical [indiscernible] molecules. And again, the focus today will be on [indiscernible]. On Slide 8 is a summary of the presentations that have been given here at [ oral ]. There are 7 presentations, 2 of which were oral presentations, just recently delivered, including new data for TV as well as DNL126. We'll also highlight the clinical trial design for ETV:GAA and new preclinical data. Our key messages are as follows: the continued analysis of a Phase I/II study in Hunter syndrome reinforces the potential for TV to address the full spectrum of disease. We've established launch readiness in anticipation of the April 5 PDUFA date and are looking forward to launching this medicine.

For DNL126, preliminary data from Phase I/II study was presented, showing an 80% mean reduction in [indiscernible] sulfate and substantial reduction in other biomarkers as will be highlighted today. The safety profile is generally consistent with established ERTs. And I think importantly, we're expecting to file our BLA and received accelerated approval in 2027, using these interim data as a foundation for this program. For ETV:GAA, we will describe the design of an ongoing DNL952 Phase I clinical study and also present preclinical data. We expect biomarker proof of concept data in 2027.

I'll now hand it to Peter, who will begin on Slide 11.

Thank you, Ryan. Hello. I'm Peter Chin, Acting Chief Medical Officer and Head of Development. I'm pleased to join you from WORLDSymposium today.

First, I'll briefly summarize the presentation by Dr. Joseph [indiscernible] under on the tividenofusp alfa Phase I/II study results with additional follow-up. On Slide 12, a tividenofusp alfa is designed to address both the neurologic and systemic manifestations of the Hunter syndrome by leveraging TFR mediated transport to deliver IDS to the brain and the body. On Slide 13, you'll see the study 2 study design. This is the Phase I/II tividenofusp study that was recently published in the New England Journal of Medicine. It's an open-label, first-in-human study with initial dose finding cohort followed by long-term treatment in all cohorts with weekly tividenofusp alfa at a dose of 15 milligrams per kilogram. The data in this particular presentation with extended follow-up have a clinical cutoff date of March 28, 2025. This represents when the last patient enrolled completed the week 49 visit.

On Slide 14, we see the disposition. I'll note that there's no change in disposition since the primary data cut published in the New England Journal and this updated analysis and a cumulative treatment exposure includes a median of 134 weeks and a maximum of 243 weeks. On Slide 15, the biomarker results, as previously presented, both CSF and urine heparan sulfate showed substantial reductions in normalization following treatment with tividenofusp alfa. These reductions were maintained long term through 201 weeks. On Slide 16, [indiscernible] showed substantial reduction with normalization and the majority of participants [indiscernible].

Moving to Slide 17. Here are the updated data on hearing thresholds, improvements in hearing threshold as assessed by [ Puretone ] average are maintained with the additional follow-up through week 21. This was reflected across all frequencies tested. On Slide 18, you see the updated data for liver volume, normal liver volumes were maintained through the MRI assessment at week 153. On Slide 19, these next 2 slides I'll show data and way that we haven't presented before. So note that Phase 2 slides have an animated bill. The plot in green shows the overall mean change in [indiscernible] adaptive behavior of [ Rosscor ] composite, which demonstrated continued skill gains through 213 weeks. If you advance the animation, it shows subgroups by age at time of treatment initiation, younger age groups expected in teal and the medium blue plots show continuous skill gains up to the extent of follow-up at the time of the data cutoff. The participants who were over the age of 4 at the time of treatment initiated, initiation depicted in dark blue, remains stable in their abilities through 213 weeks. And this is a meaningful outcome relative to the decline of what we expect to see over time.

On Slide 20. Once again, the green plot depicts the overall change in [indiscernible] through week 201, advancing the animation. Similar to the [indiscernible] results on the previous slide, Bayley scales [indiscernible] demonstrated improvement with continued cognitive skill gains in younger age groups up to the data cutoff. The older patients above the age 4 maintained stable cognitive scores over the course of nearly 4 years. And just a note on this, while the youngest patients appear to gain the most in terms of the rate of skill acquisition, well-treated with TV. These data show the potential for treated patients to improve or stabilize meaningfully across the broad study population as highlighted in videos from [ Dr. Muenzer ], who showed cases of neuronopathic siblings who were participating in our study at our R&D Day recently.

The next slide is the safety overview. Slide 21. With additional exposure since the primary analysis, tividenofusp alfa continued to exhibit a stable and manageable safety profile in the study participants with MPS II. On Slide 22, we once again show updated data on the infusion-related reactions. These IRRs are known risk of ERTs. They were the most common adverse event in the study. And as you can see, the decrease in incidence severity over time. On Slide 23, you see the conclusions in this updated analysis of tividenofusp alfa in the Phase I/II study with additional follow-up. We continue to see substantial reduction in normalization in the majority of participants on peripheral biomarkers, which were maintained over time and we continue to show improvement across multiple domains, including cognition, behavior and hearing. The safety with additional follow-up time remain consistent with the primary analysis.

And as noted earlier, TV was designed to treat brain in by in Hunter syndrome. And in the Phase I/II study, we continue to see positive outcomes across a broad age range and in both neuronopathic and nonneuropathic media types. If we move forward to Slide 25. I'll briefly summarize a poster that's being presented by Dr. [indiscernible] of UCSF, describing the outcomes of 2 non-neuronopathic siblings enrolled in the Phase I/II divide study. The full details of the cases will be presented in the poster itself. On Slide 26, here we present the data on the cases. And so there is a male sibling payer enrolled in the ongoing Phase I/II study. The data in this presentation of note also include standard of care observations from the clinical sites beyond the study protocol. Both siblings enrolled in Cohort D of the study, which was -- we included treatment 9 with individuals with pre-existing hepatomegaly, both initiated tividenofusp treatment in September of 2022. The younger sling notably missed his week 24 assessments due to illness, not related to the study drug.

On the right-hand side, Table 1 summarizes the baseline demographics and clinical characteristics of the sibling. They were aged 6 years and 8 months and 4 years and 3 months at the time of treatment initiation. Both had evidence of reduced IDS activity and neither had received any prior MPS II therapy. The composite cognitive D2s as noted show a normal age typical range in both siblings. But both have clinical signs of somatic involvement on clinical exam. If we move to Slide 27, you see the biomarker results. which basically shows baseline levels of CFH and DS as well as urine HS and DS being elevated above the upper limit of normal. As noted in Figure 2, all levels normalized by week 49 and the substantial reductions were maintained through week [ 14 ].

If we move to Slide 28. We'll look at the somatic manifestations and there were several. So both siblings had diagnosis of carpal tonic syndrome which resolved over time, while treated with tividenofusp alfa and this is true both clinically as well as by [indiscernible] study. Anecdotally, in the study week 24 interview, parents noted that both of the boys wanted to play video games, whereas in the past they had previously avoided this due to pain in the wrist. Joint mobility also improved, particularly in the old older sibling, who had bilateral [indiscernible] shoulder a reduction at baseline, which normalized at week 104. Both siblings achieved 6-minute walk test businesses within the typical range for 40. And of note, both siblings follow typical heightened wage trajectory is expected for their agents. With the older sibling and the 50th percentile for height and the younger sibling and the 90th percentile for height in recent measurements.

We also, as part of the poster presentation, have videos, which are accessible through the poster itself and the QR code and these demonstrate the range of motion and activity levels of the siblings following treatment. If we move to Slide 29, the cognition results in these 2 signings are also quite interesting. So the processing and cognitive abilities in both siblings improved from screening to week 29 reaching above average to what we might consider upper extreme ranges for age. The standard score games indicated cognitive development exceeding age-matched [indiscernible] score norms. And so these improvements were consistent with parent reported academic and functional gains supporting meaningful cognitive change while on treatment.

On Slide 30. As a brief summary, while treated with tividenofusp alfa in the Phase I/II study, these 2 non-neuronopathic siblings with MPS II, exhibited normalized disease biomarkers, improve their somatic manifestations and mobility demonstrated a typical growth in stature and cognitive function in an above average range. And while anecdotal, these collective outcomes appear to suggest that tividenofusp alfa is enabling these siblings to reach their physical and cognitive potential. If we move forward, next, I'll change gears and summarize the preliminary data from the DNL126 Phase I/II study, which was presented by Dr. Elizabeth [indiscernible] a short while ago. On Slide 32, a brief note about MPS IIIA, it's an autosomal recessive lysosomal storage disorder, resulting in the loss of SGSH, leading to an accumulation of heparan sulfate in brain. This drives lysosomal dysfunction, neurodegeneration, early developmental delays in childhood followed by severe neurological decline and sadly death and adolescence is typical. There are also somatic symptoms associated with the disease. There are no approved therapies for MPS IIIA, thus it represents an area of high unmet medical need.

On Slide 33, DNL126 is designed to leverage TfR-mediated transport to deliver SGSH to the brain and address the relentless neurological manifestations of the disease, while also delivering ERT to the body. On Slide 34, we'll look at the study design. DNL126 is being evaluated in a Phase I/II open-label study in children with MPS IIIA. Enrollment is complete with 20 participants. This update in this presentation includes preliminary data from 14 participants with a data cutoff of June 4, 2025. The safety data in the presentation are shown for all 14 participants. The preliminary biomarker efficacy data are shown for 8 patients in the dose-finding cohorts who had available data [indiscernible. The dose-finding cohorts involve weekly and every other week fusions with intra participant dose escalation in 3 dose levels, which inform the optimized dose regimen for the efficacy cohorts that you see in the bottom portion of the figure.

The 8 cohorts recruited participants across a broad pediatric range, including severe and allowance for slower progressing phenotypes. Cohort B1 recruited participants less 28 months of agent enrollment. Cohort B2 was proposed for siblings of participants in [indiscernible], but no siblings were enrolled in P2. The primary endpoint is percent change from baseline and CSF on sulfate at week 9. If we go to Slide 35. Data from 13 out of 14 participants were available through week 25 and from 8 participants in the dose finding cohorts data were available through week 49. The median age of enrollment was approximately 4 years, with the youngest participants aged 27 months at the time of treatment. The 8 participants in the 2 dose finding cohorts had an age range of 36 to 78 months, 6 were female and 2 were [indiscernible] for a slower progressing variant.

If we go to Slide 36. Preliminary biomarker results and the dose-finding cohorts were robust with substantial reductions in CNS biomarker after 49 weeks of treatment with DNL126 on the left-hand side, [indiscernible] reductions were observed by week 13, and they showed a mean reduction of 80% at week 49 with some participants achieving normalization. On the right, you see CSF [ TM3 ], mark our secondary license storage pathology was reduced by approximately 60% with most participants in the normal range, suggesting improved lysosomal function following treatment. On Slide 37, we show the peripheral effects of DNO 126. Treatment resulted in a rapid reduction in urine HS by week 3 and showed a mean reduction of 83% in week 49. Variability beyond week 3 is consistent with interim participant differences in dose escalation and dose frequency as described on the study design fly. The liver volume normalized in all participants by week 49. These findings support systemic activity of DNL126 in addition to enzyme replacement in the CNS.

Slide 38. The preliminary safety profile of DNL126 is generally consistent with established enzyme replacement therapies. Adverse events were primarily mild or moderate in severity, and there were no treatment-related serious AEs. There were no study discontinuations or treatment discontinuations due to adverse events. The infusion-related reactions were the most common AE as expected for ERTs. On Slide 39. You'll see additional information on infusion-related reactions. These were mild or moderate in severity and the frequency and severity of IRRs decreased over time as noted by the figure, which depicts IRRs by [indiscernible]. Reactions were manageable with premedication and infusion rate adjustments and dose escalation. Notably, treatment with the optimized dosing and the later cohorts appear to show improved tolerability with the use of gradual dose escalation as noted earlier.

On Slide 40. You see the conclusions and takeaways in this preliminary analysis, DNL126 treatment resulted in CSF reductions of 8% with normalization in 3 out of 7 participants. This appears to be the largest magnitude of CSF HS reduction reported in this very difficult to treat disease. Treatment also led to substantial reductions in other disease-relevant biomarkers, including GM3 and heparan sulfate in urine as well as normalization of liver volume. The preliminary safety was consistent with enzyme replacement therapy with IRRs being the most common [indiscernible] these decrease in frequency and severity over time in our clinical manager. These preliminary data support continued evaluation of DNL126 and the ongoing efficacy cohorts. And [indiscernible] remains on track for a potential accelerated approval in 2027 based on CSF heparan sulfate as a surrogate marker, reasonably likely to predict mobenefit.

And now I'll turn it over to Joe Lewcock, our Chief Scientific Officer.

Thank you, Peter. I'm Joe Lewcock, Chief Scientific Officer at Denali Therapeutics, and I will be sharing highlights from 2 posters presented at World, evaluating DNL952 to a novel investigational therapy for treating patients with Pompe's disease. And just a reminder, Pompe's disease is caused by a deficiency in the lysosomal enzyme GAA leading to glycogen accumulation in muscle cells and progressive muscle weakness despite existing enzyme replacement therapies.

In addition, glycogen buildup in the nervous system can cause severe neurological defects in infantile onset Pompe disease, IOPD and may also contribute to weakness in late onset Pompe disease or LOPD. Therefore, there is a need for therapies that enhance enzyme delivery to both muscle and the nervous system.

So if you go to Slide 43, I'll start with the first poster that was presented which is entitled enhanced correction of skeletal muscle and brain pathology in a Pompe mouse model using transferrin mediated delivery of GAA. Moving on to Slide 44, it outlines the architecture of DNL952 on the left-hand side of the slide. where recombinant GAA shown in blue is fused to Denali's transport vehicle in gray which, as you will likely recall, is an engineered Fc fragment that contains a transfer and receptor binding site illustrated in gold. On the right-hand side of the slide, it illustrates the delivery of DNL952 to the key tissues impacted in Pompe's disease, where transferrin receptor mediated delivery enables efficient delivery to muscle cells, as well as neurons via transport across the blood-brain barrier.

In addition to trafficking to the relevant tissue types, TfR also enables the cellular uptake in intracellular trafficking through the endosomal path -- endolysosomal pathway, and therefore, through engaging transferrin receptor, DNL952 is designed to buy or distribute properly and enhance delivery and lysosomal targeting in affected tissues.

So if we move on to Slide 45, you can see some of the preclinical data with this molecule. And this is looking at first at pharmacodynamic effects of DNL952 in a mouse model of Pompe's disease, in which the GAA gene has been knocked out. These mice also express a chimeric human mouse transferrin receptor to enable binding to the TV. And what you could see on this slide in GAA, no mice, which are shown in dark blue on the left-hand side of the slide, as well as on the right-hand side, you see in muscle on the left and in nervous system on the right, significant accumulation of glycogen in both of these tissues. Again, that's shown in blue compared to wild-type animals in gray. And what you could see across a dose range is really a substantial reduction of [indiscernible] accumulation after 5 every other week doses of DNL952, which at all dose levels is superior to the level of glycogen reduction using the same dosing regimen with 20 mgs per kg of the standard of care. So very encouraging pharmacodynamic activity with this molecule.

And if we move on to Slide 46, now we can look at the pathologic hallmarks of Pompe disease in muscle downstream of glycogen accumulation. And what you're looking at here is LAMP2 and P62 which are 2 markers of autophagic morphology in these tissues, which is abnormal in the mice that lack GAA enzyme activity. And that can be seen in the pictures on the top panels of the slide. If you then look down at the bottom panel of the slide for quantification of both LAMP2 on the left-hand side and P62 on the right-hand side, you could see that increased staining in muscles of mice that lack GA enzyme activity and a dose-dependent reduction of these pathologies after treatment with DNA in the same dosing regimen shown on the previous slide. By contrast, 20 mg per kg of the standard of care is unable to effectively impact these disease pathologies, showing clear differentiation of AR TfR-enabled DNL952 molecule.

If we then move on to Slide 7, here provides a QR code, where if you're interested, you can go and take a look at all of the details of this data, the preclinical package with the conclusions of this work being that the biomarker evidence we've established from these animals provides proof of concept for DNL952 and supports advancement into clinical studies.

We then move on to Slide 48, good. I'll go over the second poster presented here at World. A Phase I multicenter open-label study designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of DNL952 in adult participants with late onset Parkinson's -- or Pompe disease, pardon me. So to go -- we'll go over the study design on Slide 49. And this study, DNLI-J-0001 is the first-in-human Phase I study of 952. It is an open-label study and adult participants with late onset Pompe disease. The primary and secondary objectives of this study are to characterize the safety, tolerability, pharmacokinetics and immunogenicity of DNL952 exploratory pharmacodynamic markers, including urine [indiscernible], serum creatine kinase and other markers will be measured as part of this study. This study will also include exploratory clinical measures of motor and respiratory function.

As shown on the graphic of the right -- on the right-hand side of the slide, enrolled participants will receive DNL952 during a 24-week core period and a 24-week extension period. Initial dose exploration will be conducted in 2 planned cohorts enrolling ERT experienced participants with optional additional cohorts to evaluate alternative doses or dose frequencies. Following initial dose exploration, selected dose regimens may also be evaluated in optional ERT-naive cohorts shown on the bottom right-hand side of the slide. So if we move on to Slide 50 is just the conclusions of this poster as well, which was meant to outline the design of the DNLI-J-0001 study and the goals of this study. For more information, you can visit clinicaltrials.gov or scan the QR code on the right-hand side of the slide for additional information.

So now I'll turn it over to our CEO, Ryan Watts, to provide conclusions for the presentation.

Thank you, Joe, and thank you, Peter. This ends the formal presentation portion of today's call. We'll now turn to the Q&A.

[Operator Instructions] Our first question coming from the line of Andrew Tsai with Jefferies.

Thanks for sharing a nice set of data sets. So for Sanfilippo, as we think about the next steps, is it fair to assume that the full 20 patients worth of data could look even better than what you're seeing right now since these next batch of patients are being dosed at the QE efficacy cohorts? And then secondly, with this nice data set you're seeing so far, especially on heparan sulfate, does it make sense to file for a breakthrough designation?

Great questions. Thank you, Andrew. I'm going to hand it to Peter and maybe we'll add a little bit as well, Peter.

Yes. Thank you. It's a great question about what we could expect to see with the efficacy cohorts. As you pointed out, we've A1 and A2 dose finding cohorts had various doses and every other week dosing for a substantial period of time, as we noted on the slide design. And so it's a slide with the study design. And so the efficacy cohorts will have an optimized slow dose escalation and weekly dosing, getting to the high dose weekly dosing at a faster rate. We hypothesized that it should be at least as good as the -- what we've seen in the dose finding cohorts, but we have to actually gather the data and show that in the future.

I think I'll just -- I'll add to that, that the -- we're very enthusiastic about the 80% reduction, the ability to normalize. I think one thing we've learned in Sanfilippo is this is a very difficult to treat disease. And this is, I think, clearly the best-in-class that's been shown to date on the ability to impact heparan sulfate. Now obviously, this is -- we've had a lot of experience with the transport vehicle. But of note, you'll see even when we look at urine heparan sulfate and then ultimately, that -- those first 2 cohorts were really important in optimizing. And so we think that this is -- I think a fantastic data really set us up for accelerated approval.

And Andrew, I think you may have had a separate second question, I don't know if we answered both questions and answering that.

Only to the extent you can share, would it make sense to follow for a breakthrough designation.

Yes, we will -- I mean my guess is we'd be moving in that direction as we did with TV.

Our next question coming from the line of Salveen Richter with Goldman Sachs.

Congrats here on the data. I was wondering if you could just speak in the context of TV here showing about a 62% of patients being previously on standard of care, how you think about outcomes or what you're seeing with regard to outcomes amongst previously treated patients versus treatment-naive patients?

That's a good question. I'll hand it to Peter and again may add a bit as well.

Yes, it's a great question. The first thing I'd say is there's heterogeneity across the population. The second thing I would say is that as an overall group, as you've seen, there is improvement, particularly in the younger population. And so I think those are the individuals that stand the greatest opportunity for benefit. The earlier we treat, the more likely they are to be treatment naive. But I think the other thing we want to say is the stabilization is highly important. And whether it's a very young patient or an older pediatric patient as we had in the study, I think the data are really important in maintaining skills over the course up to 4 years in the latest date of [indiscernible].

And I'll just add and maybe Salveen, what you're trying to get at is the switching dynamics, the fact that a large number of these patients were previously on standard of care and then switch to TV. And do we see any differences in clinical outcome with treatment naive versus switching. Notably, our COMPASS trial is designed so that patients initially start on standard of care and then switch. So most of our data, including, by the way, looking at urine heparan sulfate obviously, heparan sulfate are on standard of care. So we're seeing a robust effect even on patients that are switching from either [indiscernible] so Phase II to TV. I hope that answers your question.

And our next question coming from the line of Paul Matteis with Stifel.

This is Matthew on for Paul. I guess the questions on the urine heparan sulfate for Sanfilippo. You mentioned there was some variability in response due to the dosing titration schedule. Does that -- can we infer from that, that there is dose dependence all the way up to the high dose? And perhaps why are we only seeing it in the urine heparan sulfate and the other CSF markers?

Yes, thank you for that question. I'll answer it first and then Peter still feel free to add to it. What's been interesting for us is the sensitivity of urine seems to be greater than CSF. In other words, it returns to baseline more [indiscernible] than CSF, the duration of response seems to be longer in [indiscernible] fluid. So I think that allows us to, let's say, a more acute measure of activity. And I think what's interesting is if you line up the dose finding portion of A1 and A2 with that urine, you can see when we essentially switched everyone to weekly dosing at the high cost.

So I think that's probably the best way to look at it. Yes. I'll end there, do you want to add anything else, Peter?

I think you summarized it well. The only other thing I'd add is the A2 cohort was treated with every other week low dose for approximately 20 weeks. And so that, as Ryan said, urine tends to be more extensive. And that makes some of that variability. But as the patients in the dose-finding cohorts escalated to the higher dose, you see that we achieved an 83% reduction at week 49, which we consider quite [ less ].

I'll just add one other point, which is worth noting. I think when you think of samples you think of the severe and rapid neurological decline, which is certainly the case, but it's actually interesting in this data set to see elevated urine happen so and increased liver volume, which we can normalize. So this is clearly a whole lot [indiscernible] disease as well. And I don't think others have really shown data around that, at least to this extent. But I just an important point to highlight.

Our next question in queue coming from the line Mayank Mamtani with B. Riley Securities.

Appreciate the comprehensive presentation. So on DNL126, Ryan, if you are able to contextualize the depth and durability of [indiscernible] that we're seeing here say, relative to a gene therapy approach. And also, if you looked at any clinical measures yet, and is your expectation to have younger age groups do better like you have in TV. And in terms of next steps, are you going to assess any differences on the clinical measures relative to, say, an absolute history comparison that we've seen some of that being done. Obviously, unlike TV and Hunters, there's nothing out there here to compare against? And then I have a follow-up.

Okay. So the first question is the depth of response for CSF heparan sulfate. Let's start with that one. So maybe, Peter, you can comment on that.

Yes. I think we again, in these dose finding cohorts, we've shown an 80% mean reduction to our knowledge, is the most robust effect that has been seen. I'll also reiterate that pretty rapidly with effects shown by week 13 and an 80% reduction at week 25 as well as at week 49. So we find these data to be highly compelling even if they're preliminary.

And then the second question, or at least part of that is what is our plan to show cognitive benefit? And then the third question is are we planning to enroll younger patients. So let's talk about the [indiscernible] benefit as we go forward on this program.

Yes. As you know, these cognitive elements are more interpretable over time. And so this is a very preliminary analysis with limited follow-up. Of course, we are measuring those data over time. And this is -- there's a open label that follows the week 49 period. And so we will be assessing those. In terms of natural history, we don't have a direct natural history comparator, but that will serve as an important reference in the future as we accumulate longer-term data.

Yes. I think there is some in our experience, there is some challenge in who you select to compare in natural history. I think you asked one other -- I'll just have one other put around the heparan sulfate. Once again, people choose to measure heparan sulfate in different ways. It's either an absolute number, percentage AUC, in our case, we see this as really the best-in-class example and similar to what we've shown previously in other diseases.

Great. And a follow-up on TV world, have you broken down -- I'm sorry if I missed the biomarker and our clinical data by severed, I think you did [indiscernible], have you broken that down and what does that look like?

Sorry, Mayank, can you restate -- did you get that? Can you restate broken down the biomarkers, say that again?

For TV, have you broken down your biomarker and/or clinical data by severe and attenuated phenotypes, have you shown that?

Yes. So the on -- sorry, the 2 study, the Phase I/II study that we just presented on, 44 out of the 47 participants were neuronopathic. And so we don't typically do because it's such a small nonneuropathic formal analysis by subgroup. As we showed in the 2 siblings, both CSF and urine HS and DS were elevated even in the so-called attenuated patients, and we showed an ability to normalize all those markers rapidly. So the show long way of saying the biomarker effects that we've seen with tividenofusp cover both in neuronabathic and the non-neuronopathic patients in the ability to normalize.

I think from a clinical outcome standpoint, as we presented in the case studies, these are individuals who are already performing at an average level cognitively at baseline, and they actually continue to gain skills at quite a rapid rate. So the standard scores in the poster suggest that they're actually performing at an above-average level currently. And then finally, the somatic manifestations, I think this poster illustrates very nicely. The improvement on both pre-existing somatic manifestations such as the joint mobility as well as the resolution of carpal tunnel syndrome and some of the other highlights that are noted in poster as noted, TV was designed to treat brain and body and I think in both neuronopathic and non neuropathic patients that are available in the study, we've been able to demonstrate that [ rarely ] convincing.

Our next question coming from the line of Sean Laaman with Morgan Stanley. My question is around sort of potential clinical differentiation to elsewhere, but think about 126 and the HS reduction in the CSF of about 80%, how can you correlate that or how clinically meaningfully different might that be to something that sort of reduced HS by 65% or 50%? Or do we not know that yet is the sort of first part of the question. And the second part, still on clinical differentiation, the 61% reduction in CSF [indiscernible] is that meaningful in trying to demonstrate clinical differentiation to elsewhere?

Yes, it's a great question. And I think this is a question for all of the MPSs, what level of reduction leads to benefit. And clearly, there's -- we see substantially greater reduction than others have reported. I think ultimately, what's going to lay out is the subsequent biomarkers like GM3. I'm glad you pointed that out where 6 of 7 participants had normalized. So remember that [ perception ] is relative to the amount of increase for the particular biomarker. So when you achieve that level of we're actually normalizing the function of GM3 and rankly, what we believe is normalizing license function. But there is probably a cut at some point where you're not reducing it enough. And we don't know if that is what our goal is to maximize heparan sulfate reduction.

Our next question coming from the line of Tazeen Ahmad with Bank of America.

For 126, I just wanted to clarify, what are you expecting the go-forward dosing regimens to look like? And then secondly, what are you thinking about the trial design for Phase III [indiscernible] when could that start? And how many patients do you think roughly you need in order to enroll? And then lastly, can I ask a quick question on your interactions with FDA on Citi's review? Do you think you can get approved ahead of your PDUFA?

Great. So we'll answer those 3 questions. We'll start first with dosing.

Yes. So great question. What I refer you back to is the study design in the efficacy cohorts where we have -- this is Slide 34, where we show the dose escalation scheme, starting with a low dose for approximately 6 weeks going to a mid-dose and then going to high dose [ 2-week ] peak with weekly infusions. And so this is based on the preliminary data, what we believe to be the optimized dosing regimen.

And I'll just add very briefly, I know we have many questions to answer here. The -- we try -- I mean, as you can see in the stage of design we compare every other week versus we [indiscernible]. And this has been something that has been explored off in the enzyme replacement build. For us, the great thing about heparan sulfate is responsiveness and our ability to change the dose. But we now have the optimized dose that will be the same dose we're selecting for the Phase III.

And to answer your Phase III question, we will be sharing more. That's been a big topic with the FDA is the design and the finalization of that Phase III, which [indiscernible] that now it will not be a placebo-controlled pages, but it will actually be a comparator to baseline, which will be fantastic, and we'll share more on the number of patients. It's not going to be a very large study. Our goal 126 is to move about half as much as we did on 310 and new [indiscernible] as fast. So that's the ultimate plan. And your last question was on TV and where do we stand with the FDA. So right now, it's all about defining the post-marketing commitments and the ongoing label discussions. I can't comment if we imagine an early approval, that would be fantastic. Right now, the basis case is April 1 as a PDUFA date.

Our next question comes from the line of Michael Yee with UBS.

On the pivotal Hunter study that is ongoing. A couple of questions. One is have you guided to exactly when you would complete Cohort B? What is the general purpose of the Cohort B because I understand that obviously, that's non-neuronopathic. And so what is your confidence that would actually hit on a 6-minute walk or other endpoint? And is that for safety? Or do you actually think that would -- that population would be in the label?

Yes. Great question, Mike. In fact, I think there might have been a miss in the presentation by Dr. [indiscernible], maybe I misheard it, but Cohort B is not the rate-limiting step in completing the COMPASS trial. It's a 1-year end point as opposed to the 2-year endpoint for Cohort A. So Cohort A is fully enrolled. I think Dr. [indiscernible] mentioned, we're in search of several more patients for Cohort B, it's not rate limiting. And the purpose of that is to show comparability really to elevate 6-minute walk, but also maintaining reduction in liver and [indiscernible] and heparan sulfate. So at least that's the way that [ Scott ] was designed as we've engaged with the FDA now several years ago to show that we basically are comparable to [indiscernible]. The ultimate goal for us, obviously, is to have a broad table as possible.

The next question coming from Myles Minter with William Blair.

Congrats on all the data on the presentations here at WORLD. My question is actually about Dr. [indiscernible] said the 1 patient, I think, required a second bag infusion because of infusion-related sort of reactions. Do you know what dose that was at in the Sanfilippo program and if it was at the high dose, like what's your confidence that this will remain a single bag infusion as opposed to 2-bag infusion, which seems quite a lumpy process.

I'll hand it to Peter for that.

Yes. I would have to get back to you on the exact dose. I think what I would say is there are occasional idiosyncratic reactions that patients receiving ERT have. And this is an individual who had IRRs as we noted in the presentation, can be managed with reduction in bag concentration and slowing the rate and then slowly re-escalating at some point. And so this is an individual who continues to dose in the study. And we don't think that, that has broader implications on the tolerability of the drug.

Okay. Cool. And then just a quick one. Thanks for breaking down all [indiscernible] scores in the Hunter program as well based on age. It seems like younger than 2 years is where you get the most benefit, but I agree there's clear benefiting stabilization for those older patients. What are you going to do with the younger age group here? What's your plans there? Because I don't believe they are included in COMPASS. I don't think any patients below 2 years of age are included in that trial. So what is your plans there for that population?

Yes. So that's -- it's a great question. The way we think about the development program being a rare disease was to have complementary data coming from the E2 study, which did study patients as young as 3 months of age and all the way to adults in the COMPASS Phase II/III study that we've been discussing. And so we view the totality of the data as being important for both confirmed confirmation of an accelerated approval in the U.S. as well as global approval. So the data that we have in E2 are going to be very important, showing longer-term outcomes for the most patients.

Our next question coming from the line of Ananda Ghosh with H.C. Wainwright.

Congrats on the data. I have 2 questions. On the first one with respect to the Hunter syndrome where you show very nice adaptive and cognitive behavior. I was wondering how does it compare with Elaprase only patient, if you have, is there any data on that? That's the first question. I have a follow-up question.

Yes. I'll hand it to Peter. I think the question is natural history, but in reality, natural history is on standard of care. So how would this -- what would you expect on standard of care in these patients.

Yes. Thanks for the question. I mean our expectation is that these patients would decline over time, knowing that Elaprase is a cross the blood brain generator and address the neurological manifestations. There's limited long-term data that's interrogated targets [ award ], that's the word, for doing an actual comparison. But based on the data that are available, we end with additional follow-up. We anticipate that these patients will continue to stabilize on tividenofusp group and DDA from the natural history.

All right. And my next question, like if you look across the programs like Sanfilippo and the GM3 biomarker and then the preclinical data from the [indiscernible]. What does it -- I mean, what does like -- obviously, you are reaching [indiscernible] targeting the lysosomes. Does that open up other hard-to-treat lysosomal diseases like [indiscernible] or how are you integrating those data with respect to the future pipeline development?

The short answer is absolutely. I think what this data -- the data in Hunter and in Sanfilippo, including liver volume, urine heparan sulfate, but also all the central nerve system, we had very much opened our minds to other targets that we can go after in muscle and bone and including the central nervous system. But in your case, it's like [indiscernible] is really going after the lysosome. So the short answer is absolutely we have we have 6 minutes left. We're going to go in a rapid fire for the next 6 minutes. So apologies if they're shorter answer. So we'll do our best, really love to answer everyone's questions.

Our next question coming from the line of Laura Chico with Wedbush.

This is [ Thomas ] asking a couple of questions for Laura. So first, I wonder if you can help us understand the primary data points in the TV data package that you believe will be most you spoke to encouraging switching treatments? And what do you believe will relate most with bottlers?

I'll hand it to Peter for a brief answer.

Yes. I think, first and foremost, the urinary GAG data is showing normalization, including in those patients in the E2 study who were already treated with Elaprase with no washout I think those are highly compelling data. And then the other peripheral data that we have includes the normalization of liver volume and maintenance of normal liver volume in those who were at baseline. We're continuing to gather clinical outcomes over time. But I think the booker evidence strongly suggest that there is an advantage to switching.

Our next question coming from the line of Joseph Thome with TD Cowen.

Maybe on Sanfilippo, just based on your conversations at WORLD. If we assume that a gene therapy approach and 126 are commercially available, based on the doctor conversations, is there a subset of patients that they think might be more applicable for one versus the other? And could you combine these approaches assuming it'd be able to get reimbursed?

Yes. I mean I think the last point you made is probably been the most relevant point, which is a combination certainly the case in Hunter or gene therapy is delivered directly to the brain. I haven't seen the peripheral data in detail on the systemically delivered gene therapy, but we imagine that there will be room for both and likely in each patient as gene therapy make way.

Our next question coming from the line Marc Goodman with Leerink Partners.

This is [indiscernible] on for Mark. We just would like to clarify why whether you need to have a titration for the 126 in the Sanfilippo program because when we compare with the Hunter program, we noticed that you were able to the therapeutic dose in the efficacy cohort with that titration? And would that mainly to mitigate the side effect profile or what other reason for?

So the brief answer is to mitigate IRRs. And I think we've really know that, as you can see, with the IRRs over time with the different dosing regimens in the different cohorts, you see actually substantially less IRR. So that dose escalation allows you to do that. That will be common across most enzyme replacement therapies.

Our next question coming from the line of Jay Olson with Oppenheimer.

Congrats on these results. We had a question about the DNL126 biomarker data. What do you think is more important for driving clinical benefits, GM3 normalization or HS normalization? And then separately, can you provide any color on antidrug antibodies or neutralizing antibodies that you observed with DNL126 and whether or not the presence of ADAs or neutralizing anybody to have any impact on the efficacy of 126?

Yes. So I'll start and Peter can add up, now that we're running out of time. So I think what the GM3 data shows is that the amount of heparan sulfate reduction we achieved was sufficient to basically normalize lysosomal function as it relates to GM3, which is a separate marker. So I guess, back to, I think, one of the previous questions around the percent reduction you need to achieve ultimately, there's going to be downstream biomarkers that will also be very informative that may move later in disease, for example, like [indiscernible]. I think that answers the first question. Remind me again on the second question.

ADAs or neutralizing [indiscernible].

So ADAs are common in all ERTs and they're present obviously in our other programs, and we most certainly see antidrug antibodies with 126. I think your question is, does it seem to affect CapEx that actually remains to be seen. And I think part of these dose escalation protocol and then optimizing dose is really to optimize dosing over ADA. And that's what we learned with TV is that we pushed the dose here on questions on the dose level, but our goal there was to try to create all Hunter patients, including those that have high antidrug antibodies to enzyme, which is commonly observed. We don't have enough data yet to really define that for 126, but I think it's likely optimizing the dose is related to ADAs.

Our next question coming from the line of Michael DiFiore with Evercore ISI.

Two quick ones from me. I just want to revisit perhaps the first question that was asked around what we could expect in the efficacy cohort since these patients are dosed at the full dose or at the target dose. Could we possibly see a 90% reduction in CSF HS here? Is there a reason not to expect a greater dose response? And then separately, regarding NFL biomarker data, I know it's way too early to tell now. But could we expect 126 to exhibit similar kinetics on NFL reduction to what was seen in Hunter, where most of the reduction happened after 1 year of therapy?

Yes. So I'll answer that question. Peter gave a great answer to the first go around, we can read the transcript, and I'll add to that. So we believe 80% reduction is very robust. And we believe will be sufficient not only for the accelerated approval, but to drive clinical efficacy. I think the questions around ADAs and heterogeneity, that will play out over time now that we've optimized the dose I don't necessarily think you have to achieve any specific percent reduction as long as you get the downstream biomarkers corrected, like GM3 and ultimately, NFL.

So I think your question is a fantastic question thinking about, okay, what is needed then to drive the whole team of neurodegeneration. But we see this as a robust data set as we now optimize the dose moving forward.

Our next question coming from the line of David Hoang with Deutsche Bank.

So maybe just quickly in terms of commercialization of it, what's your level of confidence to get broad coverage and effect switches from Elaprase with an accelerated approval? Is it possible that any insurers may be looking for the COMPASS data and a full approval? And then on Pompe, are you thinking accelerated approval path there? Or would that may be a more full traditional path?

Both good questions. And obviously, that's a huge focus of us to imagine how to get coverage on TV, and that will play out over time. I don't think we have anything new beyond the data that we presented today. And then related to Pompe, I think our base case is actually head-to-head LOPD. We want to capture the broader market. We are thinking of other accretive ways, but I would just say for that, stay tuned. And for now, we're looking at some of the best-in-class again these, I guess competitors [ route ].

Our next question coming from the line of Charles Moore with Baird.

So just quickly, I wanted to know if there's any correlation between baseline cognition and improvement that you've seen with TV as well as checking in on how the post gene therapy or stem cell transplant patients are performing. And then I was just also quickly curious if you anticipate exploring infant onset Pompe as well with your asset after establishing proof of concept?

Yes. I think was with respect to the correlations, there's a lot of head originating in the clinical trial. I think we did present some correlations at Congress last year at ICA. So there are some baseline correlations, but it's difficult to have strong correlations that predict all the very outcomes that we showed earlier across the different groups.

With respect to IOPD, I think that remains to be determined. Definitely, IOPD has involvement to the brand, and that's something that we'll have to consider.

Our last question will come from the line of Tom Shrader with BTIG.

All IRR questions. The 310 patients that still have IRRs of 200 weeks, do they get normal benefit? Are the IRRs worse for 126? And do they explain any of the variability? And any read on Pompe, I think that's an extremely immunogenic payload.

Yes. I like the questions, Tom. And I think each of these diseases have a different immunogenic profile. I think we -- what we've learned from TV is that if you're seeing IRRs a lot after they've been on dose for a long time, it's usually because they've missed multiple doses. It's very often, its not always, but often in the case that these patients have missed multiple doses and then on vacation or whatever, and there's a higher rate of IRRs. I think we have enough data with 126 to say that there's more or less risk around IRRs or where Sanfilippo falls relative to Pompe versus Hunter, but there's certainly different immunogenicity profiles with these diseases.

And there are no further questions. I will now turn the call back over to Ryan Watts for any closing remarks.

Yes. Thank you. I appreciate everyone calling in, and we move on. Thank you.

This concludes today's conference call. Thank you for your participation, and you may now disconnect.

Great. Welcome, everyone. Good afternoon. My name is Jess Fye. I'm a biotech analyst at JPMorgan, and we're continuing our 44th Annual Healthcare Conference today with Denali. First, you're going to hear a presentation from the CEO, and then we're going to go into a little Q&A. If you're in the room here, and you want to ask a question, just raise your hand and then we'll bring a microphone over. If you're listening at home, you can submit questions through the portal, and I'll read them off on stage.

But with that out of the way, let me pass it over to Denali's CEO, Ryan Watts.

Thank you, Jess. Great to be back here at JPMorgan. It's an exciting year ahead for Denali. So I'm looking forward to presenting today and telling you about our path to patients. So just a reminder that we founded Denali to really deliver biotherapeutics to the brain. And our adventure has led us to actually many regions, not just the brain, but throughout the whole body with the transport vehicle technology. And a lot of the data has really come -- has matured over the last several years, both clinical data and preclinical data telling us the power of using transferrin receptor to enable biotherapeutics to access the brain and beyond. It's also become a very exciting and competitive field. So it's great to see many colleagues and and friendly competitors here today at JPMorgan.

So let's dive in. Today's key messages. I think importantly, that we believe that the transport vehicle is one of the most validated and differentiated and clinically proven BBB platforms. And we now are seeing -- we're moving our fourth and fifth transport vehicle-enabled program into the clinic and generating a fair amount of clinical data showing the power of this technology to get medicines into the brain. We're also on the cusp of our first approval with that and in Hunter syndrome and in [indiscernible], we believe that we can capture $1 billion plus market with these rare disease launches as we continue to expand the portfolio.

Also in the past year, we filed for one of our first Alzheimer's medicines, OTV MAPT. And the beginning of this year, we'll also file for ATV beta in terms of starting clinical studies with these technologies with these medicines using transferrin receptor, and this is in the Alzheimer's space. So obviously, expanding beyond rare disease. We've also learned a lot. In the first 5 years of Denali, we invented the transport vehicle. And I think a novel approach to crossing the blood-brain barrier using this technology. The last 5 years, we've proven clinically that it can work. We filed our first BLA. And I think, exciting for us in the next 3 to 5 years, it's around delivering and bringing many more of these transport vehicle-enabled programs forward.

So what do we expect for this year? And we'll -- I'm sure this is where we'll end as Jess asked questions, but we're on the cusp of our first approval with [indiscernible] and Hunter will present data on ETVGSH at World. And then we have a number of clinical studies that we're initiating in MAPT, A beta as well as GAA and then obviously, our readout for LARC 2 in the first half of this year as well.

Okay. So what is the transport vehicle. So the transport vehicle is an engineered approach to getting medicines into the brain using transfer receptor as a carrier. We have 3 franchises, the enzyme franchise, the oligonucleotide and the antibody franchise. The enzyme has matured most quickly. It was also the most linear way to go after this technology to prove that technology was using enzymes, which are proven clinical modality with approximately 85% success rate in terms of development but have a challenge in terms of crossing the blood-brain barrier. And so this is where we started first with the transport vehicle technology. We recently held an R&D Day where we described the next 3 years, what happens at Denali is we've evolved from a really science-heavy organization to now development and ultimately, commercial. And these are our [indiscernible] goals.

The first is to deliver 2 growing brands in Hunter and Sanfilippo. The second in development is to have 5 clinical proof of concepts. This is over the next 3 years. And this year, we have chances of this with several readouts and then bring in additional 4 to 6 programs into the clinic as part of our discovery efforts. Our discovery team has actually evolved pretty substantially from inventing the platform, going deep in the science in the lysosome and in Alzheimer's disease now to applying this transport vehicle technology across various targets that are known to be clinically validated but actually could be enhanced using the transport vehicle technology. Here is our broad portfolio now maturing in lysosomal stores disease as well as common neurodegenerative diseases.

And so today, I'll focus the first half of my presentation on lysosomal storage diseases in the second half on the common degenerative diseases and then talk a bit about how is the transport vehicle different than other blood-brain barrier technologies that are also being developed in this exciting field. So let's talk a little bit about the transport vehicle itself. This is an Fc-engineered molecule, meaning the IgG Fc portion is engineered to bind to the transferrin receptor. What you see in this image is a butterfly shaped receptor and the apical domain is where we have the binding site, the most validated domain for at least clinically, showing that we can basically enhance brain uptake using -- targeting this particular domain. The goal here is IV and/or subcu injection depending on what medicine we're developing systemic delivery and then obviously crossing the blood-brain barrier using basically transparent receptor receptor mediatrancytosis.

So this is one of my favorite images basically comparing a standard antibody distribution throughout an animal and the brain compared to the transport vehicle. On the left-hand side is a basically a control IgG. On the right-hand side is an antibody using the transparent receptor. What I'm going to show you now is basically the comparison in the biodistribution in the brain primarily, and then we're going to talk a little bit about the body. So what you see first is that standard antibodies have very high concentration in perivascular spaces. I think this is very relevant in Alzheimer's disease and some of the safety observations around ARIA in particular.

However, a transferrin receptor-enabled molecule has this even distribution throughout the brain as it crosses capillary beds, but it also lacks the high concentration in these perivascular spaces. What's unique about this particular image is we've also look at biodistribution across the entire animal. And the first thing you can see is basically very little antibody in brain. In the bottom left-hand corner where we're looking at the entire mouse versus high concentrations in brain on the right-hand side in the tire mouse. But what you also see is biodistribution to bone and muscle and to other tissues in which transparent receptor is expressed. And this has actually become very relevant for us in diseases like Hunter syndrome, where they are somatic diseases, they not -- they don't just affect the brain but also other parts of the body, and we see enhanced biodistribution throughout the body.

So this is just a little bit more detail around the actual transport vehicle technology. And there are 4 areas that we focused on when we first invented this. First was modularity. We wanted the ability to deliver something more than just antibodies. And so we went on to show we could deliver enzymes and ultimately, oligonucleotides. And we're very excited to advance our first oligonucleotide program into the clinic using this technology which at first, we didn't think was possible to get an oligonucleotide blood-brain barrier and then also affects gene expression in various cells in the brain.

The second is to optimize brain uptake. And the key here is that most biologics will get into the brain. The question is how much and for how long. And I think most importantly, is there a therapeutically relevant concentration of drug that gets in the brain. And for most biologics, there's not enough even with like a relatively high systemic dose. A good example is enzyme replacement therapies, even if you get very high doses, they're rapidly cleared, will not readily access the brain. The third area is around safety and engineering, the Fc, allowing us to turn on or off of factor function depending on what target we're going after. And then finally, I think integrated into all of this is the actual architecture and the stability of the molecule to build binding actually in as opposed to tagging, for example, fabs to an Fc I think I've already mentioned that this -- we have the potential to have the first FDA-approved TFR enabled therapeutic as we await the decision on the BLA for [indiscernible] and Hunter syndrome.

Now 5 clinical stage programs using this technology. We've demonstrated the ability to halt neurodegeneration, basically normalize NFL in Hunter syndrome. And then a number of other, I think, interesting points, we've given over 11,000 doses of the transport vehicle across these multiple clinical programs. So let's start first with the ETV franchise or the enzyme transport vehicle franchise. And the goal here is really replacing enzyme replacement therapies, which have been around for over 30 years.

However, it's been several decades where there's been a lack of invention to really treat the unmet need of the central nervous system in these diseases. So most enzyme replacement therapies do not readily cross the brain barrier. And so we have about 30,000 people worldwide with lysosomal storage disease, 2/3 of which have neurological deficits. Using the transport vehicle technology we can now, as I've shown before, access the brain, but also enhance distribution to other organs as well. So here is our portfolio in totality.

So many enzyme replacement therapies advancing. Today, because of time, I'm going to focus on the clinical stage programs, our TV program for Sanfilippo progranulin for FTD granulin and then finally, GAA and Pompe. So let's start first with Hunter syndrome. Hunter syndrome monogenic disease affecting an enzyme, IDS. It affects mainly boys. It's an X-linked disease. Standard of care for 20 years, either sulfate delivered systemically [indiscernible] somatic disease, not crossing the blood-brain barrier. And the goal here is that Tivican solve both somatic as well as CNS disease excited to report that at the end of this year, beginning -- or the beginning of this year, we published in New England Journal of Medicine the clinical data around TV. And I'm pulling the exact data as presented in the [indiscernible] paper.

So I think importantly, just to summarize, in terms of safety first, infusion-related reactions or the most common adverse event. And as you can see in this graph, these dramatically decline over time as you build tolerance. This is just keeping up the same steady dose of 15 mg per kg. We also see a slight dip in hemoglobin, which then also returns. We believe that this may be some of the frequent blood draws. I think importantly, we've engineered these molecules to be immune silent, so not affect reticulocytes in particular.

So this is a summary of the safety data as published in the New England Journal paper. This is now the biomarker data. And by the way, these are the data that represent the data in the BLA filing for TV. And so what you can see is a robust and sustained normalization of CSF heparan sulfate, which is the primary substrate for Tivy for either sulfate. Also normalization of NFL, which is a marker of neuro generation. You can see a delay in time. So you rescue first the primary substrate and then you see this halting of neurodegeneration as measured by serum NFL.

What's also notable and actually very interesting is that we get a robust reduction in urine heparan sulfate. The reason why this is interesting is that more than 70% of patients in this study were on standard of care and then immediately switched to tivi, meaning that we have a more robust somatic effect as well using tividenofusp alfa. And then in terms of the clinical end points, these are also obviously what's most relevant to patients, improvement in behavior, improvement in cognition and also improvement in hearing. I think it's interesting because obviously, behavior and cognition are mainly neuronopathic effects, but hearing seems to affect all patients broadly. And therefore, we're seeing robust improvements on these endpoints as well.

So what's next? We're waiting -- we have a PDUFA date, April 5. We're actively engaged with the FDA on this filing. As I mentioned before, the data that I just summarized as published in New England Journal is what constitutes the BLA filing data. We also have an ongoing Phase III study, the COMPASS study, a Phase II/III study. We completed enrollment of the neuronopathic cohort at the end of last year, which we expanded last year. We added more patients last year to a cohort. And I think importantly, the field is ready. And I just want to emphasize this New England Journal editorial, where it was commented that this is a critical turning point. And specifically, TV is designed to address both systemic and neurologic findings in Hunter syndrome.

Okay. So let's move on to SGSH for Sanfilippo. Similarly engineered molecule. In this case, it's a dimer. So you have basically 2 enzymes fused to the transport vehicle. Here, we have an ongoing Phase I/II study. This program was selected for start. And I will say that it's been fantastic to be part of start, regular engagement with the FDA as we align on an accelerated approval path, but also as we align on the Phase III study design in Sanfilippo. We recently announced, I guess it was the middle of last year that after that alignment on accelerated approval, we're now moving forward, completing enrollment of the Phase I/II study, which will be a total of 20 patients with a 49 week end point here, again, looking at CSF heparan sulfate.

We will be presenting data, although we've top lined the data last year, we'll present data world in early February and looking forward to sharing these data in the coming months. Ultimately, our goal is to submit the BLA and to have an approval by 2027.

Now shifting to DNL593. This is P2B progranulin. This is progranulin engineered across the blood-brain barrier. We've seen a very significant increase in interest in this area as the competitive landscape has has shifted. And here, I just want to emphasize, similar to the enzyme replacement therapies or the ETVs, our goal is to replace progranulin in individuals that carry 1 less copy of progranulin. So this will be systemic delivery crossing the blood-brain barrier, similar to the ETVs. Also happy to report that we've completed enrollment in this Phase I/II study. We've completed the enrollment of the MAD cohort and we plan to share data, biomarker data around this program by the end of this year. And if you're interested in what biomarkers we're looking at, I would say, take a look at the literature and which we published on ETV progranulin in cell, describing the role program in the lysosome and rescuing it with [indiscernible] programming and looking at a number of both proximal and distal biomarkers.

Now shifting to GAA. This is DNL952. This recently cleared the IND and will begin dosing soon. This is a program. This is actually our first shift out of like traditional CNS, I'll call it that, even though Hunter and Sanfilippo have obviously it's a lysosomal [indiscernible] disease with broader neurological deficits. In this case, our goal is to go after all of Pompe, including muscle we've presented data in the past that delivering GAA with the transport vehicle enhances efficacy in muscle, in particular. And so here, we'll have a very similar to our other studies will enroll patients and we'll go through dose escalation, and we'll look at standard biomarkers well known in the Pompe field, and we expect to have our initial biomarker data by 2027 with this program.

So in summary, when we look at the ETV franchise, there's great opportunity looking at both MPS II and MPS IIIA but also many other programs that we can bring forward to of which 2 additional I focused on today. We believe that there is a high probability of success and also it's time for new invention to improve medicines for enzyme replacement therapies. And we believe the transport vehicle is the ideal way to do that. So let's shift gears to Alzheimer's disease and just to highlight 2 of our programs, ATV, Abeta and OTV MAPT. And I'll just highlight briefly here that we published on ATV, Abeta will share a bit of data from that publication as we've continued to advance this particular program and also on the oligonucleotide transport vehicle published in 2024.

So let's start first with ATV Abeta. So in a mouse model in which we can look at what we call MRI lesions that are similar to ARIA, what we see is using the transport vehicle technology substantially less area. And the mechanism that we propose as highlighted on the right-hand side is basically this point I made earlier on that transport vehicle gives you even distribution throughout the brain as opposed to high perivascular localization. So the graph on the left-hand side actually quantifies the amount of MRI incidents you see with the standard Abeta antibody as compared to the ATVs, although you get about 2 to threefold better plaque reduction with ATVs. So we proposed the actual mechanism for reduced ARIA in this publication in science in August of last year. So I want to talk a little bit more about optimizing the actual transport vehicle and what makes the TV different than standard brain shuttles.

And here, I'm going to show 3 pieces of data, brain concentration reticulocyte number and then actually intact molecule. I think this is really important as we see this landscape evolving rapidly. This is maybe one of the first times in which we're comparing in the exact same animal model, which is a humanized mouse model that expresses the human apical domain of transferrin receptor across these different platform types. I think point number one, we actually expected that brain concentration would be very similar.

You're using transferrin receptor, and that's actually the limiting factor for brain uptake is how much transfer receptors express and how readily does it does it transport. But what we do see is about a twofold better uptake with the transport vehicle technology. Now the reason we believe that's the case is actually on the graph on the right-hand side, so let's shift to the far right and look at this graph. And what we see is that when you tag these fab molecules, these things are readily clipped. And therefore, at 24 hours, we're not seeing stability of these fab molecules.

This has actually been previously reported in the literature, but now we're looking across different fabs with different epitopes. And then in the center, and I think really importantly, is the ability of the transport vehicle to maintain effector function, but when bound to transferrin receptor not engage the immune system. So what we see is we don't see a reduction in meticulous [indiscernible]. However, molecules that can engage the immune system and bind transferrin receptor robustly reduced reticular sites as shown in the dark blue dots in the middle graph here.

So this is -- if you're interested in more differentiation, our recent Analyst Day, we go into great depth about the various epitopes and affinities, but definitely an exciting time in the BBB field for additional invention. So let's talk about our ATV beta, the clinical approach that we're taking here. So this is DNL921 and just a little bit about the Abeta arms themselves they are preferentially binding algae and aggregated Abeta, including plaque. Our belief right now is that data that's in the clinic that has shown plaque reduction, molecules have shown plaque reductions or those that correlate best with clinical benefits. So ideally, we're driving plaque reduction, but we're also capturing all comers and less binding to monomers. We're running a single ascending dose healthy volunteer study and then into patients in this MAD study.

And our -- we expect data in 2027 using this molecule. We're actually filing the first half of this year. Now on to DNL628. The other end of the spectrum for Alzheimer's disease, I've just referenced that the first one was targeting Abeta when the hallmark pathologies in Alzheimer's. This one is targeting tau, which makes up neurofibrillary tangles. And what we see here is the ability to actually knock down tau gene expression and protein and have a very prolonged effect in reducing tau protein levels. This particular model is, again, the human transferrin receptor apical domain crossed to human MAPT transgenic, and we see this robust and sustained knockdown of tau. So we've now filed the CTA.

This is cleared. We'll begin dosing for our OTV MAPT program. And here, we're going directly to patients in a multi-ascending dose study, the endpoints here are focused on CSF biomarkers such as TAO and then ultimately, tau PET imaging, again, expecting data in 2027 for this program. So I'll end with talking about our evolving business and where we're going. I mentioned that the first decade of discovery and development has now evolved to delivery, building our commercial organization and commercial infrastructure, preparing to launch in rare disease, which is very exciting.

We've also built our own in-house manufacturing, which allows us to move much quicker and substantially cheaper across all of these various transport vehicle molecules. And I think the last point is that we continue to invest heavily in blood-brain barrier research. We have over 30 scientists that have focused in this area now for almost 15 to 20 years, but it's exciting to see how this field has evolved.

We have the capital to execute. I think importantly, and here, the key is to invest strategically across various therapeutic areas, drive for that Phase I data Obviously, efficiency is key. What we learned in the hunter program as we took a lot of risk in that initial transport vehicle, we can apply those learnings to our other programs, such as Sanfilippo and others to move faster. We're in a strong financial position to be able to execute on this portfolio in the next 3 years. And I'll just end by highlighting again our goals. Our goals are to have 2 growing brands 5 clinical proof of concepts and then bring additional molecules in the clinic as we advance this transport vehicle technology.

So I think with that, I'd like to thank everyone who's here, especially thank everyone at Denali, who has worked on these programs for over a decade. All the patients that we interact with and the patient families, especially in the Hunter and Sanfilippo community. It's been an incredible privilege to work with all of you as we advance our medicines. And it's that, I'll call our team up here to answer questions.

Great. Thanks for the presentation. And as a reminder, anyone in the room who has a question can just raise your hand and someone will bring along a microphone. Maybe just starting with tivi for Hunter syndrome. Can you elaborate on the reason behind the PDUFA extension? Has -- whatever that issue has been addressed to the FDA satisfaction at this point?

I'm happy to do that. So the PDUFA extension was based on a molecular weight miscalculation in a public database. So we gave some detail about this when we receive that extend the PDUFA date to April from January 5, that has been addressed, in fact, addressed rapidly. I think importantly, the FDA continued continue to review. It's been actually really good engagement with the FDA. We've finished the late cycle meeting and at this point, basically, we're in discussions around the label, post-marketing commitments, and we continue on path here, we hope for approval by April.

Okay. And what are the key elements of your launch strategy for that product? And how should we think about the ramp in Hunter syndrome?

Great. Thanks. So as we think about Hunter, the market is already -- a majority of the market is already using standard of care. So 95% of patients are on treatment. So for us, the launch strategy is really driving a seamless switch. And our focus here is on engaging with the centers of excellence. There's about 100 genetics that is carrying for MPS II. Our field team has already been deployed and has been engaging them, our MSL team in exchange in scientific exchange and of course, our commercial field team doing the profiling. So it will be really important for us to continue to drive the value proposition and the clinical benefit of tivi with the centers of excellence. The other area, of course, that's really important for launch is ensuring fast payer coverage so ensuring that the payer understand the value proposition. Of course, our patient services have to be executed well to ensure that patients have support on the treatment journey to get access to the medicine. And then the last piece that's really important for the MPS community is this partnership. It's a very tight small community where patients and families get most of their information from patient advocacy groups and and the broader community and where if they support us in the clinical messaging, this is where they will be highly influenced by what the community thinks of tivi. And your second question was related to ramp. So in terms of the uptake in adoption curve, we expect in a rare disease launch, we expect to see an S-shape adoption curve.

So in 2026 this year, we're going to be very much working through the mechanics of launch, which is ensuring that patients get access as quickly as possible, but knowing that coverage is not going to be immediate. So for 2026, we expect revenues to be minimal. But as coverage expands and experience continues to drive adoption, we expect to see a strong inflection point in 2027.

And I guess, considering the product's profile, how are you approaching pricing for tivi? And can you also talk about the payer mix in Hunter in the U.S.?

Yes. So at Denali, we think about pricing in 4 key dimensions. So for pricing, we want to make sure there's going to be broad access for patients. We also think about affordability, which is why our patient support services are going to be really important that they can support the patient so that they can afford the medicine. And of course, thinking about the clinical value that our product brings and the revenue that we generate must be able to support further innovation at Denali. So given these 4 dimensions, we feel pretty confident that we'll be pricing at a premium compared to the current standard of care, given what we offer.

Now what's unique about our markets, our payer dynamics is that in rare disease, it's not uncommon to have high Medicaid payer coverage for patients. In our case, it's about 50%. And 50% commercial, 50% Medicaid, almost no Medicare, which is why I talked about the S-shape curve. There's going to be some mechanics of access and reimbursement. That will take some time in the early year of launch.

Maybe switching to DNL126, the [indiscernible] product. Can you talk about how you're going to kind of leverage the experience with tivi to compress the time line for 126? And maybe related to that, how the selection for 126 and the start program kind of factors into the development strategy?

Yes. Peter answer that.

Sure. So [indiscernible], our development program has taught us a lot that allows us to gain efficiencies in the Sanfilippo program with DNA. So first and foremost, the work that we did with the FDA, along with the MPS community to establish CSF heparan sulfate as a surrogate biomarker that is reasonably likely to predict clinical efficacy that's at the stage for us to have that discussion with FDA with the DNL126 program as well. Also the data that Ryan showed earlier that was published in the New England Journal shows the validation of our ETV platform. And so we have a high degree of confidence that we're able to address in neurological manifestations of Sanfilippo based on our ability to reduce heparan sulfate with the TV as well as peripheral biomarkers. So that is an important piece that informs the design of our program and our filing strategy. We also have had a lot of learnings on designing and executing rare disease protocols and lysosomal storage disorders as well as establishing relationships with the community. And so we're leveraging those for the Sanfilippo program as well.

In a nutshell, the tividenofusp program kind of created a playbook for us to be able to execute additional and rare disease development programs with more efficiency, including more capital efficiency. So we anticipate delivering this program to market potentially 5 years earlier than the tibia approval and at half the cost. In terms of your second question with respect to the [indiscernible] program, as Ryan alluded to, this has been highly beneficial to our ability to engage with the FDA on the program. It's given us an ability to accelerate, to engage early and to focus our interactions. Now we have an ability to plan the schedule of interactions in a predictable way in addition to having ad hoc meetings. And so we've been able to engage and de-risk a lot of the concerns that the FDA may have or perspectives that the FDA may have in terms of the heterogeneity, the patient population end points that might be meaningful and study designs, both in the Phase I/II as well as the Phase III, as Ryan alluded to. So it's definitely given us an opportunity to accelerate.

Can you just take us through what data you plan to generate to support a filing for this product?

Ryan showed the high-level slide earlier. The filing for DNL126 for accelerated approval is going to be based on the Phase I/II study that is ongoing. This is an open-label study with extended follow-up. There are dose-finding cohorts as was shown earlier as well as key efficacy cohorts. And the totality of that data is a 20-patient study. all patients at the time of filing, all patients will have at least 49 weeks of follow-up with some as anticipated to go as far as 2.5 years. And so that will provide durability of response as well as evidence for chronic safety.

Great. And how big is the [indiscernible] Type A population in the U.S., Europe and elsewhere? And how does that compare to the Hunter syndrome?

I'm happy to answer that. So it's very similar. There's about 2,000 patients worldwide for Hunter, 500 of which are in the U.S. and [indiscernible] probably about the same, maybe a little less. You'll see more variability in those numbers in part because there's no standard of care. So we'll obviously get a much better sense upon approval as -- and there's a medicine available, but that's roughly the epidemiology.

Are there any patients for whom 126 wouldn't be appropriate?

Our hope and and our aim is to be able to treat all patients with MPS IIIA.

And I think if you look at the biomarker data for both Hunter and [indiscernible], but regardless of timing of intervention, you see a robust biomarker effect, right? So the 1 thing we have learned and I think as we've shared before, and we'll share again in the upcoming world even in Hunter earlier is better. right? And especially as you look at like neurofilament and halting neurogeneration, but I think that's become obvious, although we now have data to show that. But the goal would be basically all patients for both San Flipo and Hunter. One other note is that [indiscernible] -- I mean, largely a CNS disease, there are peripheral manifestations, which we'll be able to treat with a systemic enzyme replacement therapy, which I think are important and maybe become more obvious if you only treated the central nervous system, but it is believed to be mainly a neurological disease, and certainly, there's robust decline in neurologic and robust neurological symptoms in Sanfilippo.

And for the Phase III, are you going to be using natural history data for the control?

Natural history data has been very helpful in helping us to understand the progression of disease and patient heterogeneity. That said, based on the ongoing discussions with health authorities, it's likely that our Phase III core study will be based on [indiscernible]

And baseline comparator, basically.

Maybe zooming out a little bit. What's your criteria for selecting the diseases to address with the TV platform? And just how do you prioritize what to pursue first?

Yes. Alex.

Yes. I'll take that, Jess. That is a fantastic question. So we know now from the clinical data and the preclinical data that the transport vehicle is effective wherever efficacy is limited by efficient tissue distribution. So we know the transport vehicle delivers biologics into the brain, but also delivers biologics more efficiently into other tissues, specifically into bone, muscle and others. Now as we look at that set of opportunities, how we prioritize is those where the biology is well understood, where there are biomarkers readily available so that we can efficiently and fast drive to clinical proof of concept and also those opportunities where there is a significant unmet need, so off a certain size. And those are the criteria that you will see in the next wave of programs that we take forward into the clinic.

So Ryan highlighted already in the slides a significant effort at Denali for efficient execution and capital allocation, and that will influence how we think about the selection of new indications.

You guys have had a couple of programs in ALS. I'm just curious what's your stance on those and future programs in the disease?

Yes. We remain very interested in ALS. I think about 1.5 years ago, we made the decision -- well, actually 2 years ago, we made the decision to focus entirely on the transport vehicle technology. And part of that was the data we generated in Hunter -- so we spun out our efforts in small molecules, which is where our initial efforts were in ALS. We now remain very interested in ALS, but for us, it's the right target likely a genetic medicine using oligonucleotides. So we -- that's where we're keeping our eyes open on where to go next. You may recall that we had a study with RIP kinase and ALS, which failed that was led by Sanofi and EIF2B, which is -- which also failed actually multiple programs, ours and another company failed in parallel. Those were disappointments, no doubt, especially with the integrated stress response sort of implicated in ALS, but I think there's still great hope for some genetic medicines at least in subtypes of ALS. And there, we'd use your OTV to target it.

Maybe thinking about the kind of next wave of assets and heading into the data for DNL593 for FTD. What will represent incurring results when you get that initial data?

Yes, I think as I highlighted, for FTD granulin, there's really 2 parts of how we've approached it. First was to understand what granular loss of function really is. And there, we've discovered a role for granulin in lysosomes and lysosomal biology. And it's fortuitous because we have a lot of work in lysosomal storage diseases, but actually, it's many of the same biomarkers that we're seeing for other enzyme replacement therapies like glucose [indiscernible]. So success for us, the primary success is some change and correction of the proximal biomarkers. This is highlighted in the paper that I referenced. The long-term success is the distal biomarkers, GFAP and [indiscernible]. I think ultimately, as a medicine works, you'll see a correction of these distal biomarkers as we've shown in Hunter syndrome. So those are the 2 areas. The question is, how long do you need to treat. There's a really interesting study that was alluded to at CTAD that NFL has a very long half-life like 260 days. So it's maybe not surprising that for us, we can normalize substrate and then we see a shift. And then over time, we see NFL also decreasing. So we need to keep that in mind in this neurogeneration field to be patient when you correct the substrate that you may ultimately halt neurodegeneration, but it may take some time. But those are the areas that we're most interested in, in FTD granular.

Great. So looks like we're out of time. So we'll stop there

Thank you.

Our Investor Day. We've been excited to share an update. I think often, I'm sitting in a fireside chat with many of you. So it's great to see her faces here. We're going to go into some depth today about what we're doing at Denali. And I think it's a unique opportunity for us to really set the stage for what the future looks like for Denali but then dive into some questions.

We also have some really important guests with us, which I'll introduce later from the lysosomal storage disease community. So these are our forward-looking statements, and let's dive in. Let's start with the key messages. So our purpose at Denali is to deliver the power of biotherapeutics to the whole body, including the brain.

This is a little different than what we've said maybe in the last 5 or 6 years. And what we've realized from our own clinical data is that the transport vehicle technology not only crosses the blood-brain barrier, but enhances delivery to other parts of the body.including hard-to-reach tissues. And so we've really seen now an evolution in transferrin receptor-enabled biotherapeutics, and we like to believe that we help lead this revolution.

Our ultimate goal is, of course, to transform the life of people living with serious diseases. And this is also a little bit different from what we've said in the past where it was focused primarily on neuro degeneration, but we believe we can open up now muscle disease and other areas with the transport vehicle technology. There are 4 key messages for today, and these are really important.

And in fact, the presentation is broken up into these messages, and I'll share them in the introduction as well. The first is that we have a best-in-class blood-brain barrier platform or transferrin receptor-enabled technology, which we call the transport vehicle. We recognize that brain shuttles are now front and center.

And I think again, a decade ago, it was just an idea. Now there are clinical data that really prove that we can get medicines into the brain and hard REITs tissues. The second point is that we're ready to capture $1 billion plus opportunity in enzyme replacement therapies with the ETV franchise. And so for the first time, we'll lay out our commercial plans and very excited to do so and also bring the patient community here and have a discussion around the opportunity around enzymes, which, of course, has been multiple decades since new medicines have been launched in this area.

So there's a huge unmet need. We have a deep pipeline across high-value therapeutic areas. And we thought today rather than focus on everything we're doing, we're going to focus on Alzheimer's and really the second half of the Investor Day in part because we believe the transport vehicle is set to transform Alzheimer's.

So on the one hand, we have this great opportunity with enzyme replacement therapies, but also in an area that's really starting to break open is Alzheimer's disease, mainly enabled by biomarkers, but now the first approvals in this space that the transport vehicle technology is really set to enhance these medicines. And then we'll end with a discussion around efficient execution and capital allocation.

And this is important because we know the transport vehicle works, how can we now expand and bring many programs forward, but do it faster and cheaper. And I think that's a key to our approach. So here is the transport vehicle technology. I'll spend a little bit of time and then in the second half, Joe will go into some detail. I think the #1 question we get is, how is the transport vehicle different from all the other transparent receptor-enabled technologies.

And so we want to spend time in the second half articulating that. But I want to introduce, I think, the most important concept, which is we have the ability now to deliver enzymes oligonucleotides and antibodies across the blood-brain barrier and hard-to-reach tissues. And again, the focus we'll start with is on our enzyme technology.

So here is our broad portfolio. There are really 2 areas. The lysosomal storage disorders and then common neurodegenerative diseases. And I want to give a quick update, which we shared this morning in our press release and in our 8-K. Let me start with tividenofusp alfa. So very excited to announce that we signed a deal with Royalty Pharma which could be worth up to $275 million.

$200 million is unlocked by the approval of Tivi with a capped royalty. We have details in the press release. In addition to that, I want to give you an important update. So when we -- in 2019, we received rare disease pediatric designation or rare pediatric disease designation for Tivi, which we believe made us eligible for the PRV -- when we filed the BLA, we did not file the request for the PRV.

And so unfortunately, in our discussions with the FDA, the FDA has said based on this timing gap, we may not be eligible for the PRV. So we're in discussions with the FDA that's been very productive discussions. Our primary focus is basically getting the medicine approved. Our primary focus is timing more than anything else.

Separately and important update, the third update related to Tivi, so Royalty Pharma, PRB and the third update is that we've completed our late-cycle meeting with the FDA, and we're deep in label negotiations. And so although we've had a delay to the PDUFA date, we're seeing significant progress and engagement with the FDA.

And that's been actually really fantastic back and forth. And the focus now is really getting to the finish line and launching Tivi. The second important update this morning is that we received a clinical hold on our Pompe program. This is ETV GAA. And I want to really highlight what happened with this particular program. So based on hypersensitivity in mice, the FDA has suggested protocol changes through the FDA, we obviously haven't started our clinical study yet.

The team immediately turned around those protocol changes. They've been resubmitted and we believe that they will address the questions on this clinical hold. But again, this is well known for Pompe and specifically for GAA, I think part of this is really a question of timing and the time to review and make associated protocol changes. Both of those are highlighted by the way, in the 8-K. So let's talk about what the future looks like for Denali.

So I think the first is what we call the D3 strategy, discover, develop, deliver. And I think importantly, we have been fueled by discovery from the beginning. And I think pioneering the field of blood-brain barrier delivery with the transport vehicle and with transparent receptor. We spent the last 5 years validating the transport vehicle and submitting our first BLA, which, of course, we're very excited by that, and we'll expect many more to come.

And now it's about delivery. As I mentioned before, we'll focus today on our commercial launch for Tivi and broadly how we're approaching commercial for the enzyme transport vehicle. And so it's exciting to see that transition for Denali. And so it's really by 3. So let me explain what that means. So this was actually the first time we're presenting 3-year goals. And I'll start with, I think, 1 of the most important goals, which is to really build 2 brands for Tivity 126, that will lay the foundation for Denali going forward.

Now next will be 5 clinical proof of concept. And I think on the horizon, the near-term horizon is Alzheimer's disease, and proving that the transport vehicle will deliver the best-in-class molecules for A-beta and for tau and then continue to bring programs forward in an efficient way. So 4 to 6 new clinical stage programs over the next 2 to 3 years.

And I think this year is an example where we filed 2 regulatory filings, bringing 2 more programs forward with tau and GA. So ultimately, we want to deliver both near-term value by launching medicines but also create this long-term portfolio of clinical stage and ultimately, commercial products. This is what will happen in the next 3 years. So let's talk a little bit more about the transport vehicle just so we set the stage for today's discussion.

So we invented this transport vehicle about 9 years ago, and we've proven it over the last 5 years that it works for enzymes. And the way that it works is we bind to a natural receptor known as transfer receptor. Now there are many different brain shuttle receptors but the most validated receptor is transferrin receptor. And in our efforts, we've looked at all these other receptors as well.

And we believe that transparent receptor remains the most promising approach to get across the blood-brain barrier. As I highlighted before, and part of this is through our own clinical experience, and as I'll share on the next slide, it's not just about delivery to the brain, it's also enhancing delivery to other tissues.

And so here is an example, and this is -- we've shared this at least the center images before. So what you're looking at is a standard antibody compared to a transport vehicle-enabled molecule on the right-hand side. And in the center is the brain. So obviously, you can see a really big difference between a standard antibody, which is perivascular versus a transport vehicle-enabled molecule, which gives you this even distribution throughout the mouse brain.

But what I wanted to show here is whole body distribution on either the bottom left or the bottom right. And what we've noticed is that we get great distribution to bone and muscle in addition to brain. And part of this is where transparent receptor is located. So we believe this technology now opens up other therapeutic areas. And I think Pompe is a great example of that, where we can enhance delivery to muscle and hopefully either have less frequent dosing or lower doses but even at the same dose, much better distribution into muscle.

Now if we look at the clinical data, I think importantly, we've shared many, many times the heparan sulfate reduction in cerebrospinal fluid, which is representative of brain. So I think this is really robust. Obviously, normalization of heparan sulfate -- but what I think we often miss is the fact that we also get more robust reduction in urine and in plasma.

And so what we see is, again, distribution throughout the body to enhance delivery of enzymes. And this will be important as we think about the opportunity for enzyme replacement therapies even for ERTs that are not necessarily targeting the brain but rather the whole body. So what is the transport vehicle. Basically, what we've done is we've engineered the Fc portion of an and we've engineered it to bind to transfer receptor.

So there's no unnatural linkages, which is basically what we'll talk about in some depth is a competitive landscape. What have we shown? So we have the first potential FDA approval for a TFR-enabled therapeutic Five clinical stage programs. We've demonstrated the ability to correct neuro filament, which we think is a key biomarker across many diseases.

This is, of course, is in Hunter syndrome. We have more than preclinical stage programs using this TV technology, over 200 subjects dosed to date over 11,000 doses given with the TV and a number of publications and patents. I'm not going to go into a lot of detail here, but Joe later on today will talk about modularity, brain uptake, safety and architecture, including comparisons with other basically conventional fab approaches, which are shown on this slide.

So what you see, the vast majority of other companies that are approaching this technology are using fabs and making fab fusions either using leak or chemistry or other dynamics in terms of bringing this fab. And we'll show you some of the differences between an integrated binding site versus these conventional fab approaches.

I think also important is just the overall clinical experience and how much -- how many patients not only have been dosed, but how many doses have been given and the number of clinical stage programs. So the TV is now the most clinically validated BBB technology, and I've already highlighted this before, you can see here some of the competitive landscape, which we'll discuss in detail later.

So let's talk about the 2 franchises and where they stand. Let's start with the ETV franchise. So we believe that the launch in Hunter and San Filippo gives us a combined market opportunity of about $1 billion. I think most importantly, and we're going to discuss in detail is how transformative these medicines can be -- and what do we do when we're successful, we're able to reinvest and really build a broader franchise for the TVs.

There are over 30,000 individuals living with lysosomal storage disorders. Of course, these are single enzyme deficiencies. And so when we thought about the first place to go with the transport vehicle technology. We wanted to go somewhere where the biology risk was low. We know what's causing the disease and then we can basically solve that with the transport vehicle technology.

2/3 of lysosomal storage diseases patients have CNS manifestations. And I think as we mentioned, I'll just make one other really important point, which is there's about a 90% historical success rate with enzyme replacement therapies, which is very different than, let's say, even cancer or the Alzheimer's space. So we see this as a long-term foundation for Denali to build this franchise.

And as a result, we've invested not only in the ability to launch this medicine commercially, but also to manufacture these medicines. And we'll have a -- we'll be able to spend a little bit of time about talking about our manufacturing capabilities. In terms of the longer-term potential, although this is now becoming much more near term with OTV entering the clinic and very soon.

ATVA beta at the first half of next year also entering the clinic we can now take advantage of the transport vehicle to deliver genetic medicines like oligonucleotides or variations of antibodies. And this just highlights and we'll go into some detail around our ATV A beta program, but also our OTV MAPT program using these technologies. And I think it's very exciting to see the Alzheimer's field evolve and utilize these technologies.

So let's talk about today's agenda. So we'll start first with the enzyme transport vehicle. And I have the pleasure of introducing Barbara Burton, who, I guess, when I met Barbara for the first time at the family conferences, she is basically one of the most well-known physicians treating lysosomal storage disease for a number of years.

In fact, I think Barbara won the Lifetime Achievement Award at the last MPS conference in Chicago. We'll hear first from Dr. Burton. She'll set the stage on the opportunity around these diseases. And then we'll hear from Peter Chin and Katy Pang around our clinical data and our commercial approach. And then we'll end by talking about the ETV franchise.

We will also have a panel discussion with Jason Madison, who I'll introduce in a moment, and Dr. Kim Stevens, who is our major advocates and also Jason is living with Hunter syndrome.and has been -- become a close friend and colleague and our efforts around Hunter syndrome. So with that, I'm going to hand it now over to Dr. Burton.

All right. Good morning, and thank you for the introduction. So I'm going to focus for the next few minutes on clinical aspects of 3 of the lysosomal disorders of interest to Denali, of course, MPS II, but also MPS III and Pompe disease. And as you know, these are all lysosomal storage disorder part of a family of more than 50 disorders where there is a specific enzymatic deficiency that leads to substrate accumulation throughout the lysosomes of the cells really throughout the body.

That, in turn, has not only physical impacts within the cell, but also many downstream effects, impairing lysosomal function, so impairing autophagy, triggering inflammation and leading into a complex pathophysiology that really defines these disorders and differs from one to the other based on a lot of factors where that substrate is normally distributed in the body.

So we'll start with MPS II. And of course, this is one of the most common of the mucopolysaccharidosis, a subset of the lysosomal disorders. There are 8 distinct MPS disorders that share some features in common, but also our individually distinct and associated with different enzymatic deficiencies.

We know about 1 in every 25,000 babies born has some type of MPS disorder and the estimates for Hunter syndrome or MPS II are about 1,000 and 100,000. We're actually learning through newborn screening that is probably a little bit more common than that, maybe close to 170,000 and but right in that same neighborhood. This is an X-linked disorder, genes on the X chromosome.

So almost all patients are males. There are rare affected females, but -- they certainly constitute less than 1% of the population. It's very unlike Fabry disease, where the females with a single copy of the gene on the X. They're affected just like the males, although less severely not so with MPS to the women who have a single copy of the mutant gene typically are completely normal.

So in the MPS disorders, the problem is with degradation of the glycosaminoglycans, which we used to call mucopolysaccharides. That's where the name came from. Now it's glycosaminoglycans or GAGs and in MPS II is iduronate to sulfatase DS. This leads to progressive accumulation of 2 major species of GAGs, heparan sulfate and dermatan sulfate.

It's the heparan sulfate responsible for the CNS manifestations the dermatan sulfate that's primarily responsible for the somatic manifestations. And that's illustrated by MPS VI, where we just see dermatan sulfate accumulation, and they have no CNS involvement. They have severe somatic disease but no CNS. So GAGs are complicated molecules. We talk about them being complex sugars, there's basically a core protein and then a string of simple carbohydrates that are clipped off 1 by 1 with different enzymes responsible for each step.

But they have multiple functions, and they're really ubiquitously distributed. So that's why we see such complicated multi-systemic manifestations in the MPS disorders. Now MDS I, like all lysosomal disorders occurs along a spectrum of severity related to the underlying mutation and whether there's no residual activity are just a little trickle a little bit of residual activity.

So there's a spectrum of severity, but there's 2 major subtypes of the disorder that you see described the so-called neuronopathic or severe form and the milder although I hesitate to use that word, but the less severe or attenuated form. And the major differentiator is that in the severe neuronopathic form.

We have progressive neuro degeneration and cognitive decline, whereas in the patients with the attenuated form there's normal or near normal cognitive development without progressive cognitive decline and progressive neuro degeneration. But the severity of the somatic manifestations can be comparable in the 2. There are certainly patients with the attenuated form of the disease who have quite severe somatic manifestations of the disorder.

So it's not really fair to call it mild in those patients. There are some patients who kind of fall in between with some mild nonprogressive cognitive impairment, but the spectrum is heavily weighted at the 2 ends with about 70% of patients typically being classified as neuronopathic 30% attenuated.

Of course, this is a progressive disorder. The GAG accumulation is progressive. The emergence of the clinical manifestations is progressive and the severity increases over time. But some of the earliest things that we see in babies with MPS II or hernias, umbilical and inguinal hernias. Recurrent upper airway and ear infections, recurrent otitis media, enlargement of the tonsils and adenoids with GAG deposition in those tissues.

That leads to obstructive sleep apnea in many cases, coarsening of the facial features with soft tissue deposition of GAGs leading to the fuller lips, puffiness around the as broadening of the nodes and then developmental delay in some but not all patients. Obviously, if they have the attenuated form, development can progress perfectly normally.

And in all kids, it usually does for the first year to 18 months before we start to see developmental slowing in the neuronopathic patients. And then progressive stiffness of the joint and of the fingers leading to joint restrictions. There's also a progressive skeletal disease, dysystosis, multiplex and patients may need orthopedic procedures over time.

Later on, we see progressive airway involvement, airway narrowing, also cardiac valve thickening with that valve deposition and then that leads to dysfunction and sufficient and then later in some patients stenosis, cardiomyopathy, carpal tunnel syndrome, very, very common MPS disorders are the most common cause of carpal tunnel in the pediatric population.

And a significant issue for [indiscernible] as they get older is retinal degeneration with progressive visual impairment. Now in the neuronopathic patients, like I said, we typically see developmental slowing followed by progressive loss of developmental skills and progressive neuro degeneration. Death typically occurs in the teens or at the latest early 20s for the typical neuronopathic patient, whereas those with attenuated disease may live into their or beyond depending on the severity of their manifestations.

MPS II was added to the recommended uniform screening panel in the U.S. in 2017. So it's a disorder that's recommended for newborn screening to all of the states -- it is proliferating pretty rapidly. It has come on board a lot more rapidly than MPS I did. It took us 10 years to get to a universal screening for MPS I. This is moving along much more quickly. when I made this slide, we thought about 25% of newborns were being screened.

Now I think it's even higher. The big states are doing it, New York, California, Texas even. So it's coming along very rapidly. And I think it won't be too long before we'll have a situation where virtually all babies in the U.S. are screened for MPS II. Now currently, we have one approved pharmaceutical product for MPS II, that's hydrosulface or Elaprase. Most affected individuals get this from the time of clinical diagnosis.

But it's not a stand-alone therapy in the sense that we still have to monitor the patients carefully for complications of the disease and intervene symptomatically when we need to for all of the various things that I listed on the earlier slides. So these are kids who get a lot of surgery. They see a lot of different specialists hematopoietic stem cell transplantation is used in some cases.

As you probably know, it is the standard of care for the severe form of MPS I. It does not work as well in MPS-I and there may be a variety of reasons why that's the case. But it is used to some extent, even in North America, a little bit more so in some other countries. And if it's done early enough in the first year of life, it probably does provide some CNS benefit, but not as much as in the MPS I situation. And certainly, it provides thematic benefit.

It does work thematically -- so what are the limitations of our current therapy? Well, you already heard that the current enzymes don't cross the blood-brain barrier in significant amounts. So idursulfase does not arrest the progression of the neuronopathic disease in patients. We can keep the neuronopathic patients healthier.

And as a result, they do live longer have a better quality of life, but we still see progressive neurologic decline and ultimately, early death. We also see continued progression of cardiac valve and airway disease, and these are the major causes of death in our attenuated patients. They also, of course, contribute to death in the neuronopathic patients as well.

We have to figure out how much of this is due to the timing of starting therapy since we're just getting newborn screening versus we just don't penetrate all these tissues well enough, but I think it's a combination of those things. It does not prevent retinal disease and one of the most devastating things is to have a patient.

And I have this who is doing really well thematically on long-term therapy, but now starts losing is vision, and it's devastating to our patients and really impacts their quality of life. And it also doesn't prevent hearing loss. So most of our MPS II patients do require hearing aids. So the unmet need in MPS II is obvious.

We need a treatment to address that progressive neuro degeneration, stabilize the patient, allow them to live more functional and longer life. And we need better treatment for the peripheral tissues that currently are hard to reach and where we see disease progression despite our current ERT.

Okay. Moving on to MPS III, also referred to a San Filippo syndrome. And here, we're talking about MPS IIIA. There are 4 different types of San Filippo syndrome, which clinically, we call San Filippo because they all look alike. The manifestations are the same. They all store heparan sulfate, but they are 4 different enzymatic defects.

The most common of these is San Filippo Type A. That's about 70% of cases in North America and the deficiency here is in the enzyme and sulfur glucosamine sulfa hydrolase or SGSH for short. It's also referred to as sulfamidase or heparan sulfate, sulfur taste and again, primarily heparin sulfite accumulates. So this appears predominantly as a neurodegenerative disorder without the severity of the somatic manifestations that we see in MPS I and MPS II.

The overall incidence of MPS IIIA is estimated at about 1 in 25,000 births. So it's little less common than MPS II, nonetheless, more common than most of the other MPS subtypes. Now with MPS IIIA, again, as is true with MPS II, infants are typically normal at birth. But in this case, we begin to see developmental slowing at about 2 years of age with speech delays.

So in both of these disorders, they sit, they walk, they do that stuff normally, but then speech is delayed. Unfortunately, with MPS IIIA, a lot of times we diagnose it much later than MPS II because we don't have those somatic clues that I talked about, the coarsening of the facial features is less prominent there later and we may not have hepatosplenomegaly, some of the other things we see in MPS II.

So what we have as a kid who shows up with developmental and then by about the age of 3, they're starting to get some behavioral disturbances, hyperactive aggressive behavior. So they get referred to a developmental pediatrician or a neurologist, a lot of times, they're misdiagnosed having autism or just nonspecific developmental delay or ADHD.

They may get genetic testing, but usually it's the usual developmental delay stuff, micro array, Fragile X, they don't early on. Nobody thinks about GAGs because most of the time, there aren't a lot of clues there. But eventually, the developmental delay turns into developmental regression and then a light bulb goes off. So this is something worse. This is progressive and then they get whole exome sequencing or they refer to a geneticist, and they get diagnosed at that time.

So the average age of diagnosis is not really until 4 to 5 years. The average age of death is 10 to 15 years by the time the patients are diagnosed. They're typically -- they have lost quite a bit cognitively because the decline in cognitive skills is much more rapid in MPS IIIA than it is in MPS but there are some attenuated patients with MPS IIIA also.

Although it's weighted at the severe end of the spectrum, approximately 20% have a more attenuated course. Later onset of symptoms, later diagnosis, slower progression, longer survival. I have one where the girl was walking into her 20s. And she's in her late 20s now and in a wheelchair, but much slower progression. And there have been some adults with intellectual disability picked up on whole exome with this as well.

Now they can have somatic findings. I said it's predominantly neurologic. That dominates the picture. But some of the patients will have hepatomegaly or hepatosplenomegaly. Some of them will have more coursing of the facial features. These are 2 siblings I took care of both of whom are now deceased, but you can appreciate, I think they had corse facial features, and he was thought initially by the referring physician to actually have MPS II because of the way you looked.

And we can also see chronic or recurrent diarrhea. Sometimes we see that in MPS II. Also late in the course of the disease, there's very difficult prominent GI motility that makes it hard to feed them. They wind up needing G tubes because they can't. Sucks all of that, but then we even have trouble putting stuff down the G-tube because the GI motility is impaired. Cardiac valve disease does occur skeletal findings occur.

So occasionally, we'll see 1 with hip pain, hip dysplasia. But it's sort of a back burner kind of issue. We do surveillance for it, but it's not nearly the same relevance currently as it is with MPS I and II. That may change if we get the patients living longer. I think it will.

We're going to have to pay a lot more attention to the somatic manifestations. So currently, our treatment for MPS IIIA is very frustrating because we don't have any disease-modifying therapy available for them is primarily symptomatic. HSCT does not work at all in MPS IIIA. It's been done quite a few times. It does not alter the course of the disease in any way, even if you do it in a very young baby, most or many of the patients, certainly the most of the ones I take care of are receiving an anti-inflammatory drug, Anakinra, marketed as Kineret for a different disorder, off-label therapy.

But there is one trial that showed some clinical symptomatic benefit in patients with MPS III, so many patients are on it. In the past, they were on Genistein and then some of them are minglestat and all of these kinds of things. But none of that really changes the course of the disease.

You probably know there have been lots of therapeutic trials of different things in the past from intrathecal therapy to different gene therapy trials that have failed. Hopefully, the Ultragenyx gene therapy trial will come to fruition. But there have been a lot of failures, so the frustration in the patient community is extremely high and there's huge unmet need here and just waiting in the wings for something to happen.

There is no newborn screening currently for this. it is feasible, however. So I think as soon as we get an approved therapy, there's going to be a big push to get newborn screening for this one because we really need to treat the patients early and we don't find them early enough clinically in most cases unless it's a younger sibling, of course.

So really, tremendous unmet need here to slow down the relentless progression of the disease. It's a horrible thing for families to watch as their kids just slip away. And the focus is on the brain. But like I said, I really think if we treat the brain and we get these kids living longer, we're going to have to pay a lot more attention to the body and the somatic manifestation.

So therapies that just treat the brain, some of the gene therapies that we tried in the past go directly into the brain. I mean that's not going to do it for us in the long term. So we're going to need a somatic treatment as well.

Okay. And then finally, Pompe disease. Again, spectrum of severity from what we refer to as the infantile onset Pompe, where patients have no residual enzyme activity, no mutations to a later onset form of the disorder that looks a lot like limb-girdle muscular dystrophy and the major differentiator between infantile-onset and late-onset Pompe disease is the presence or absence of cardiomyopathy.

The infants have cardio all have hypertrophic cardiomyopathy. They have it at birth, although it may not present clinically for weeks or months. But when we do newborn screening, we find them, it's there. That's the cause of death for those babies untreated, whereas, like I said, the late-onset patients don't have cardiomyopathy, they present with skeletal muscle and respiratory muscle weakness.

And the term late onset is a little misleading. It's really later onset because they can present as late in the first year of life. All the way through childhood into mid adult life. So there's a wide range of age at which it's diagnosed. And survival is long generally for the late onset patients, but with a progression like limb-girdle muscular dystrophy.

The deficient enzyme is GAA or alpha-glucosidase. This leads to progressive accumulation of glycogen and the lysosomes of cells. This is also referred to as asset multi deficiency or glycogen storage disease type 2. Some of you may follow the trials and other forms of glycogen storage disease like type 1. So you know that in addition to this lysosomal pathway for glycogen breakdown, the primary pathway for glycogen synthesis and breakdown is in the cytoplasm.

And that's where the defect is in these other disorders in patients who have cytoplasmic defects have problems with hypoglycemia, lactic acidemia hyperlipidemia, all of that. We don't have any of that with Pompe disease. The cytoplasmic pathway is completely intact. But once the glycogen gets in the lysosome, it's trapped in there and can't be degraded and progressively accumulates.

This is a pretty common lysosomal disorder between 10 and 15 and 1 in 20,000 more common much more common than the MPS disorders. I already told you about the infantile patients, hypotonia depth by 12 to 18 months without treatment. Now that we have treatment, they survive longer and there is a post-treatment phenotype that includes persistent progressive muscle weakness, hearing loss and white matter changes in the brain with progressive neurologic decline in a few.

We don't really know what the natural history of these brain changes is going to be yet. There have been only a few patients. We don't have a lot surviving beyond the age of 20 yet. We had all these immunologic issues initially. But now that we have addressed those and we get longer survival, we're starting to see it. The MRI changes are very common. Most patients are still asymptomatic, but there have been a couple with progressive neuro degeneration.

How common that's going to be, we don't know at this point, but there is that in IOP. We may very well need to get enzyme into the brain to be able to address that issue occurring later in the disease. Now in late onset Pompe, I mentioned a wide range of age of symptoms, that pragmatic weakness is very prominent, intercostal muscle weakness, so a lot of the patients need things like oxygen support, CPAP, BiPAP in addition to having to deal with their mobility issues and muscle weakness, but they don't have cardiac involvement.

Every baby now is for Pompe disease. It was added to the RES in 2015. It's now on the panel in all 50 states. And we have 3 approved of enzyme replacement therapy.

Our historical drug was Lumizyme, started as my Lumizyme approved for both IOPD and LPD. Now we have next biz and pambility. Both of these have enhanced glycosylation like the other enzymes, this gets into the cell through the mano-6-phosphate receptor. So these are -- have better glycosylation and then with the pomability we use the chaperone as well, miglustat.

Patients with IOPD are treated urgently at the time of initial diagnosis. We really hit them hard fast when we get them through a newborn screening. And it makes a different weeks make a difference in outcome. Patients with LOPD now diagnosed through newborn screening, we do not treat.

We monitor but treat them at the first onset of symptoms, which can be anywhere from a year to who knows when. So how well does the current treatment work? The answer is not very well at all.

Pompe disease treatment is not very effective compared to Goshe, Fabre, any of the others, really. It helps some. mean, it's been of incremental benefit to the patients. We had the immunologic issues early on if we address those properly, which now I think we pretty much know how to do, it's very effective for the treatment of cardiomyopathy and infants. And so it's life saving.

You can reverse that completely and get normal cardiac function. But it's much less effective for skeletal most disease, either in IPD or in LPD. Most patients show some modest improvement in muscle strength, mobility and respiratory function after the onset of treatment maybe up to a year, maybe 2 years in some cases, beyond 2 years, you never see any further improvement.

You hope for a period of stability, but ultimately, most of the patients then begin to progress ultimately. We don't really have that long-term data for the 2 newer drugs that what I just said is true for sure for Lumizyme. But I can tell you that the improvement we see when we move a patient from Lumizyme to one of these others is, again, it's incremental, a little bit maybe, but we're not making the patient healthy. We're not making them well.

We're not making them strong. They're not getting up outer wheel shares. Their life is not really changing dramatically. So there's still, I think, considerable unmet need in Pompe disease. So why is it not working very well for skeletal muscle? I think the biggest reason is very sparse [indiscernible] receptors.

On skeletal muscle [indiscernible] and so forth. So no matter how much you glycosylate these things. There's only so much you can circulate get through those receptors during the time that the patient is seeing it. in the circulation. We know in the past, we used to go up on the dose, up, go up on the frequency with Lumizyme.

We'd see a little bit better, little improvement. It's the same thing here, but there's a ceiling. So dosing was probably inadequate for most patients with Lumizyme. But now I think we're probably at the ceiling. Some patients, obviously, in the past have been diagnosed late. And if the muscles replaced with that, just like any of the other diseases, if things have died, you're not going to restore it.

And the other thing is we get lysosomal rupture over time. So we get a lot of cytoplasmic glycogen and you don't target that when you're going in through the mano6-bospate receptor into the lysosome. So you can't fix that.

So a lot of unmet need. We need treatment of the brain and IOPD, most likely, although we don't know how big a problem this is going to be at this point. But we definitely need better treatment for the skeletal must in both forms of the disease. And LOPD is 80% to 85% of cases.

And prevalence wise, it's higher than that because of the fact that they live a long time. So that's it for me. Thank you for your attention. And Peter, I guess you're up next.