Ionis Pharmaceuticals, Inc. Stock

Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts, and it's my pleasure to introduce Brett Monia, CEO of Ionis Pharmaceuticals. Just a reminder, the format for today is a fireside chat. But before we start, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative.

And with that, I'll hand it over to Brett. Thanks for joining us. And maybe you can start with a couple of introductory comments before we hop in queue.

Thanks, Mike. Good morning, everybody. It's great to be here, Mike. Thanks for the invite. So as expected and not surprising with the pipeline is deep and rich as ours, we were expecting a highly eventful year for Ionis, and that's exactly where we are with a lot more to come in the remaining months of the year. We're on track this year to push 3 breakthrough medicines across the finish line through the FDA, 3 drug approvals. We already have 2 severe hypertriglyceridemia breakthrough medicine, Tryngolza, was approved few days early in June. And just last week, we had the approval of our first wholly owned neurology medicine, Zanvastro, for Alexander disease, the first disease-modifying treatment ever approved by the FDA.

And we're expecting a third FDA approval in October with our partner, GSK, for chronic HBV, a real breakthrough that's actually producing unprecedented and functional cures in this patient population. We've also had expanding our Phase III pipeline. We completed enrollment in our Phase III Angelman's trial, which is on track for data in the second half of this year. And we're pleased to see new Phase III starts from our partner, salanersen, the first follow-on to SPINRAZA for SMA that is on track for -- to produce a medicine with deeper -- even deeper efficacy than SPINRAZA based on biomarker data with once per year administration. And then Sapablursen started Phase III development with our partner, Ono this year with a profile that has the potential to be best-in-class for polycythemia vera.

Mid-stage pipeline continues to produce as well. We are thrilled with the first ever proof of concept for our tau program with Biogen, diranersen, which showed unprecedented improvements in cognition and other functional benefits as well. And then our follow-on to Tryngolza proof of concept as a once a year or twice a year administration as a follow-on to Tryngolza, ION775 in severe hypertriglyceridemia, which is in Phase II development. With a pipeline as deep and with so many events happening, there's always disappointments. We are disappointed with the negative outcome of the CARDIO-TTRansform study for eplontersen and TTR cardiomyopathy. Despite the fact that we had remarkable reductions in TTR that were as good as anything that's out there today, approximately 80% reduction with good safety and tolerability, didn't hit the composite primary endpoint.

That was a key focus at ESC a couple of weeks ago, where the conclusions were clear that the reason why we didn't hit the primary endpoint was because there was no added benefit on top of a stabilizer. However, the monotherapy group, that is patients that weren't on stabilizer at baseline were -- had a hazard ratio that's as good as anything that's out there in TTR cardiomyopathy, a hazard ratio of approximately 30% reduction. And we're working on potential next steps there.

And then last week, we were also disappointed with the outcome of the pelacarsen Phase III trial in Lp(a) cardiomyopathy. And we're looking forward to our partner, Novartis, presenting the full data set there. But on top of those disappointments, we have a really, really strong pipeline, and we're really proud of all the successes we've had and the launches that are in progress, which are going quite well.

Great. Thanks for that introduction and a lot going on and a lot to cover here. So maybe we'll start just with the SHTG launch. You're, I think, 2 months in now, still very early here. But maybe just talk about what you're seeing there in terms of trends and how that's all progressing?

We're pleased to have delivered the first real breakthrough for severe hypertriglyceridemia with an incredibly strong, positive clean label. Unprecedented reductions in acute pancreatitis. This is the outcome that patients are most fearful of, that physicians are most fearful of, a potentially fatal acute pancreatitis attack. There has been no meaningful treatments for severe hypertriglyceridemia before Tryngolza emerged and was approved by the FDA. As a reminder to everybody, this is a label expansion. Our first indication was familial chylomicronemia syndrome, FCS, a rare population of about 3,000 people in the United States. That launch was going exceptionally well right up to the label expansion, right up to the approval for severe hypertriglyceridemia.

And then we expanded the label, adjusted the price from a rare disease price to a price that's more suitable for a highly prevalent disease, prevalence of more than 3 million people in the United States. So this has the -- this is positioned to be a blockbuster, and we're on track to achieve our goal of $3 billion plus peak product sales in the United States. The launch is going well. We're liking what we're seeing on all aspects of the launch to date, the metrics that we're assessing.

First of all, we're thrilled with the excitement by the HCP community. I'm sure you've done your research, you've talked to your docs. They're all saying how excited they are about Tryngolza and their enthusiasm to want to treat and write scripts and get their patients on this drug, particularly those patients that are at high risk for acute pancreatitis. The launch is going well. We're excited about the enthusiasm. We're excited about the scripts that are coming in. July and August were very good months. And we're excited about what we're seeing from the payer community, the coverage that we're getting for Tryngolza.

Although, of course, at this stage of the launch, most coverage is going through a medical exception process with prior authorizations. But we are getting policies in place. And based on those policies as well as all the other conversations we're having with payers, we're getting coverage to label, right, not just acute -- not just the high-risk patient population, but the label that is anyone that is -- has triglycerides above 500. We have -- we expected the patients that were going to be prioritized in this study would be those high-risk patients by physicians, endocrinologists, cardiologists, lipid specialists. And that's what we're seeing. These are the patients that have triglycerides through the roof above 880 milligrams per deciliter at high risk for acute pancreatitis attack with debilitating effects on the pancreas, of course, long term.

And those that have had a history of acute pancreatitis, around about 700,000, 800,000, 900,000 patients that are at high risk. Those are the ones that we're seeing the scripts written for first, not surprisingly. I could also tell you though, we are seeing some scripts coming in that are in the non-high-risk category, patients that are in the 500 to 800 range without a history of acute pancreatitis. So that's getting out there, too. But the priority for us and the priority with HCPs is the high-risk patient population. I could also say that we're excited or we're really pleased how well the dosing is resonating with the HCP community. We are the only medicine that offers dosing flexibility of 50 milligrams or 80 milligrams per month, self administered using a simple auto-injector. That dosing flexibility, as I said, has resonated really well.

We're seeing scripts come in with the 50-milligram dose and physicians are looking at the response to 50 milligrams and seeing if their patients are at goal that is below 500 milligrams per deciliter, they're fine. We're also seeing scripts come in at 80 milligrams right out of the gate. Remember, the 80-milligram dose is what's approved in FCS. We have a lot of docs that are managing FCS patients and are really pleased with the performance of Tryngolza in FCS, and they're saying, why start at 50 milligrams in my SHTG patients? Just roll it right through and bring on the -- and get those patients to the max dose.

We're also pleased how the response by the community, the physicians, and the patients because we require no monitoring in the study. It's a simple administration, really no significant step edits. Your patients will need to be on a triglyceride drug, like a Fibrate or a fish oil or something like that before going on to Tryngolza. But all these high-risk patients are already on these drugs, right? They are still not at goal. So it's not really a step edit. It's just getting those patients identified and bringing them on to Tryngolza.

So this is a new category. We're developing a new category. We're going to build this market. It's going to take a little bit of time, but we're pleased with the way the enthusiasm for the drug, and we're pleased with everything we're seeing with the launch today. And we're looking forward to providing a more detailed update at our end of our Q3 earnings in a few weeks.

Great. It sounds like things are on track there, but maybe you could talk about keys to driving the continued success of the launch kind of near term and then longer term.

The keys are disease awareness and drug awareness, making the physicians aware of the remarkable profile that Tryngolza offers. Efficacy, convenience, tolerability and the dosing flexibility that I highlighted with no monitoring in the study or for the drug. That has resonated really well. Launching off of FCS. All the docs that manage FCS patients also manage SHTG patients. And that experience has been so positive that we've really been able to build off of that leverage. Focusing in addition to physician HCP awareness and education is patient awareness. Know your triglycerides, get them measured, omnichannel, direct-to-consumer dissemination of information, the risks of high triglycerides. So we're going from the top, pushing down. We're going from the bottom, pushing up patients. And as I mentioned already, focusing on payer coverage and ensuring that we have a strong HCP and patient support program.

We are emphasizing and prioritizing, making the scripts that docs want to write bringing that all the way through the process in the most seamless, easiest way possible. It's really important to us, and our patient support program is a top priority, and it served us very well in FCS and off to a good start in SHTG, and we think it will serve us very well in the SHTG launch today. I want to emphasize, we remain very confident in our peak product sales of $3 billion plus in the U.S. It's going to take a little time to get there, but we're confident we're going to get there, and we're really looking forward to a big, big 2027.

Great. I also wanted to just ask your view on sort of these third-party scripts. A lot of people are taking a look at them. What's your sort of sense there?

Yes. We don't believe that like the Symphony scripts and IQVIA are a good measuring stick for what's happening in the launch. Like most companies do, we block our data. And we have several specialty pharmacies now that we're utilizing, not just one that we use for FCS. So you really can't compare the FCS data with the SHTG data and extrapolate. It's dangerous. It's unreliable. We really caution against that. Instead, I'd point you to the color we're looking forward to providing at our end of Q3 earnings and then next year at our end of our full year earnings, I think, in February of next year. So we're very cautious of that. We don't believe the data is reliable.

Yes. Understood. Can you maybe talk about the reaction to the safety profile of Tryngolza that you're seeing? And I guess, liver fat has been one area. Is that an issue, not an issue? What are you hearing?

We're hearing everything is positive about the safety profile for Tryngolza. Again, I said it twice now, I'll say it again, there's no monitoring for anything, LFTs. We have a very clean profile. Liver enzymes are clean. Everything is clean. We're really pleased with the adherence. Patients are getting on to drug. They're seeing their triglycerides plummet, get to normal and in most cases -- in many cases, and the adherence is excellent.

The HCPs are enthused about it. Liver fat is small. It's on target, and it wanes with continued treatment while triglycerides are being maintained and highly controlled and AP is being -- continued to be controlled. It's an on-target effect. We know how APOC3 works. By inhibiting APOC3 , we're substantially and very rapidly lowering triglycerides in these patients. And one of the pathways that were lowering triglycerides through the liver and the clearance. We see a small increase in liver fat. It's not even statistically significant at 50 milligrams in many patients. Most patients get to meet their goal at 50 milligrams. And at 80 milligrams, we saw a slight increase that was statistically significant at the end of the Phase III study. But then with continued dosing, it wanes and comes back to baseline.

The liver is adapting to this. We have a competitor program. There's a competitor that is following us. They're behind us by almost about a year or so. We expect to come out on SHTG and get approval. Although they didn't evaluate nearly the number of patients that we did, we evaluated because we really wanted to flesh out the full profile, like what do we need to know for Tryngolza. We evaluated 250 patients by MRI. They evaluated a few dozen.

But even with a few dozen at ESC, it was clear that you saw a numerical increase in hepatic fat. So it's an on-target effect, it's completely manageable. Most importantly, by the HCP community, it's a nonissue. It really never was an issue. And now the fact that it's coming -- they see it come back down to baseline with continued treatment, it's even less of an issue.

Yes. Makes sense. You mentioned the competitor. I don't know if you can maybe talk a little bit more about key points of differentiation. And since they might get to the market next year, kind of what impact could that have on your sort of launch?

Yes. So we're first to market by about a year, like I said. And we actually believe that having 2 players like a duopoly is very few in this massive market opportunity, more than 3 million people that are inadequately or not adequately being addressed with current treatments. We actually think that, that's going to provide an opportunity to grow the market, share of voice, better disease awareness by having 2 players actually expand the market with all of that. But we're going to take advantage of our first-to-market strategy. Our strategy is to build those contracts with payers, build first-mover advantage to get to those high-risk patients first, bring them on to Tryngolza.

We're confident once they come on to Tryngolza, they're going to be really pleased with the experience that they have, the HCPs as well as the patients. As far as differentiation, the 2 drugs look very similar. Efficacy, very, very highly efficacious. AP reductions, we think that -- we like our data a lot. We are looking forward to more details of our competitors' data. We saw what was presented at ESC, but we really do want to see the publication. It's really important to really get into the details and that kind of thing. So it's hard to say.

But overall, there's no surprises, the 2 drugs should work similarly. We're getting identical reductions of target APOC3. They should translate to similar efficacy. And we welcome 2 players in this really large market opportunity.

Yes. Makes sense. Also in your prepared remarks, you mentioned 775, your sort of next-gen program. Maybe talk a little bit more about that in terms of the data you've seen and time lines and path forward, if you can.

Yes. So when I became the CEO, I guess this is my 7th year now, not only did I commit to fully integrating the company and building our wholly-owned pipeline, delivering our medicines, I also committed to expanding and diversifying our technology. ASO, the newest chemistries, like I mentioned, salanersen, that's an Ionis chemistry that is supporting once per year dosing for SMA. We have more coming. Our Dravet program is using that same chemistry. We've expanded into siRNA. siRNA is more durable in the liver. We know that. But we've been able to take it to the next level with Ionis experience, capabilities, chemistries and so on.

And we've applied that to a follow-on to Tryngolza, recognizing that a once per year dosing or maybe twice a year dosing at a minimum, we can easily achieve that, but maybe push it to once per year dosing could really matter from a convenience standpoint for HCPs and patients. And we think our Phase I data supports that. We tested 775, and Ionis discovered using our chemistry SI, that showed incredibly durable reductions of target, APOC3, triglycerides, all good safety and tolerability, dose dependent. And we've already -- and that was a normal volunteer study in patients with mildly elevated triglycerides. That was presented at ESC, published now as well. Kind of old news, though.

We have already launched into Phase II development in SHTG, and we're enrolling quickly. Our goal is to protect Tryngolza. It's a blockbuster. We're the ones that innovated. We're the ones that came up with this program. We're the ones that came up with this target for this disease. And we want to make sure that we have waves -- next waves of approaches for this market opportunity. It's an open-label study purposely so that we can look at the data daily and look at target reduction, safety and triglyceride reduction and so that we can select the dose and dose interval and get into Phase III development as rapidly as possible, potentially next year.

Great. And what's your thought on the strategy there? Is it a replacement for Tryngolza? Is it for a different patient population? What's the early thinking?

To be determined. We'll see what the profile looks like. And we have to do -- our team is going to be doing the market research. Could it be complementary to Tryngolza? Or would it be the next best-in-class molecule for SHTG overall, and it could take everything over? We'll see about that. I suspect it will be complementary to Tryngolza, and we may be able to position it in different ways so that it offers something that Tryngolza doesn't offer and Tryngolza could offer something that 775 doesn't offer to be determined. We need to get into Phase III and move it quickly. We're working on the Phase III design now. I expect it won't look that different than our Phase III program for Tryngolza, just FDA has requirements. But we think we'll be able to trim those time lines down and move faster -- even faster than what we did for the Phase III program for Tryngolza.

Yes. Understood. You mentioned in your starting comments here about CARDIO-TTRansform and the data was a little bit disappointing. Maybe you can expand on that and what you think happened there, and then also what's the latest thinking on next steps. Is that evolving at all or where is that currently?

Yes. As I mentioned in my opening comments, we were disappointed that we didn't hit the positive -- we didn't have a positive outcome against the primary endpoint in the CARDIO-TTRansform study, eplontersen for TTR cardiomyopathy. We had 80% reductions in TTR, which was pretty much best you can do in this population, at least for current drugs that are out there that are addressing this disease, good safety, good tolerability, but we didn't hit the primary endpoint. We all had hoped that -- we all expected that the stabilizer that was primarily used in this study, we had 56% of patients on Tafamidis at baseline. Tafamidis is the standard of care. That was the only way to really run the study today.

And as Tafamidis is standard of care in the U.S. and as the markets grew outside the U.S., we saw lots of drop-ins, too. But the belief was that Tafamidis, there was a lot of room for improvement, right? Based on studies that were done 10 years ago, the ATTR-ACT study. But those patients were very sick and patients are being diagnosed much earlier in their disease today and Tafamidis did better than what most people had expected because patients are being treated earlier in their disease. That was our control group. That would have been okay had the combination of silencer plus a stabilizer showed added benefit compared to the control, but it didn't. We didn't see any added benefit of combination. That was the conclusion of an independent academic group's meta-analysis at ESC last year.

There's no evidence that the combination from any study shows added benefit, nothing deleterious, but nothing beneficial. That was the Achilles heel in the study. That's the study that needed to be done. Tafamidis is the standard of care, and we need to see if we can improve efficacy. Retrospect, maybe it wasn't surprising. We're targeting the same pathway. Stabilizer is stabilizing TTR, we're blocking the production of the TTR. So maybe we've maxed out on efficacy. Silencers work great on their own. Stabilizers appear to work very well as well on their own. And we think ultimately, it will come down to patient and physician preference, which ones they choose, but we don't think there's a path forward for combination for silencers and stabilizers.

With that said, in the group that wasn't on stabilizers at baseline, the efficacy was remarkable. We saw nearly a 30% relative risk reduction in the patients that we call the monotherapy group that weren't on stabilizers at baseline. There was a lot of drop-ins, but still they weren't on stabilizers at baseline. And that was comparable to the other silencer that was approved for TTR cardiomyopathy. So the monotherapy data looks great. Our partner and us, AstraZeneca and we are weighing next steps, and you'll probably have more clarity on that by the end of this year on whether or not we will pursue the monotherapy indication or not. So just stay tuned for that.

Okay. And if we just stick with the pipeline, I wanted to get your sort of thoughts on the Angelman program, maybe just give us a brief background there. And obviously, a competitor shared some data and read through.

Yes. It was very disappointing when we learned about the failed Phase III study with the lead program, the program that was in advance, utilizing the same mechanism that we're utilizing. This is a mechanism that we created. We were first to publish on it. We're basically targeting -- using an antisense strategy to upregulate the paternal UBE3A gene to basically replace a loss of function disease with the missing protein, UBE3A protein. It's a really elegant mechanism. And they're using the same mechanism. They saw what we published and they licensed in a drug. They licensed in a drug from an academic group that did some screening and found a molecule. I'm going to really highlight the fact that it's not routine to find an optimal molecule to do these kinds of things. It takes us years to optimize potency, durability and minimize off-target effects to reduce toxicities.

But they in-licensed the molecule and unfortunately, it caused issues on the safety side that caused them to be capped. Their dose was capped. So they couldn't go above 14 milligrams. Our Phase III study program ongoing is 80 milligrams. The 2 drugs are equally potent. So the potencies are the same. So you can imagine that maybe they underdosed. That's what we believe. And in fact, when we did our Phase II study called HALOS, we evaluated 20 milligrams quarterly, which is kind of in that range of 14 milligrams that they looked at in their Phase III program, 40 milligrams and 80 milligrams quarterly. At 20 milligrams, we kind of saw some hints of activity, but we weren't convinced.

When we went to 40 milligrams quarterly, we were convinced that we were seeing clear evidence of benefit. And when we got to 80 milligrams, our Phase III dose, we got a little bit better, but it looked like we were maxing out on efficacy. Unfortunately, we think that they underdosed in the study. It's devastating for the community. We've been ensuring the community that's been in such a desperate need for a disease-modifying treatment for this large patient population, the Angelman syndrome population.

But we will be the first to test the hypothesis because we believe that we're in the therapeutic range, the doses that are needed. And we believe that our Phase II data HALOS study strongly supports that. I also mentioned that our long-term extension data that we're now 18 months, we've got data cuts 18 months and beyond from the Phase II HALOS study and the efficacy is holding. We continue to be convinced that we're seeing strong evidence of benefit, and it continues to support Phase III development.

And we're going to publish that data soon, the long-term extension data for Angelman's. But we think we've got the right drug, and this is the right mechanism, and this will be the first test of this mechanism to address Angelman syndrome.

Great. And if we stick with the wholly owned pipeline and Alexander's disease, you mentioned that earlier, recently approved ahead of schedule. Maybe talk a little bit about that program and sort of what it means more broadly for your CNS pipeline.

Yes. We believe that, I think the evidence is clear, that we have led the way. We continue to lead the way in developing oligonucleotide therapeutics, ASO and now siRNA, we're doing a lot of work there, too, for CNS diseases. I mean, it's proven. We have 3 approved medicines now. You mentioned Zanvastro for Alexander disease. Preceding those were, of course SPINRAZA, the first ever treatment for SMA and then QALSODY, the first disease-modifying treatment for cause of ALS and now ZANVASTRO.

And we have a rich wholly-owned and partnered pipeline of CNS drugs following this. And we're expecting quite a number of readouts next year in addition to the Angelman's Phase III program, our mid-stage neuro program, we'll have several readouts next year, too. We're very proud of having delivered the first ever disease-modifying treatment for this devastating neurodegenerative disease, Alexander disease. It's caused by the overproduction of a protein called GFAP. We're normalizing GFAP. We're lowering GFAP. We've shown that, and we're having a disease-modifying impact on clinical outcomes in this study. This is an ultra-rare indication. It's estimated to be 300, 400 patients in the United States with Alexander disease. The prevalence is really not well understood.

When we unblinded our Phase III study, we saw the efficacy. We opened up an expanded access program immediately. And that expanded access program has actually enrolled pretty -- we were surprised how many patients actually enrolled in that expanded access program. Our focus is to convert our clinical trial patients and our expanded access patients over to commercial as quickly as possible. We're in the process of doing that. We're launched.

And of course, patient identification. It's a difficult disease to identify. It's a long patient journey. Every day, these patients aren't on a treatment like Zanvastro. They're one day closer usually to death. So patient identification, disease awareness is a big focus for us, and it's going well. Strategically, this is very important for Ionis because we're leaders in CNS diseases. We have a rich wholly-owned pipeline that's growing in addition to our partner pipeline. And this is strategic because it's our first wholly-owned launch in neurology.

And we have so many more neurology drugs, Angelman's, we talked about. And then many other programs that are reading out next year that can go to Phase III if they're successful. So strategically important for the company. And we're very proud of the fact that we are first -- once again, we are first in delivering a breakthrough treatment for a patient population that is in desperate need.

Great. And maybe last few minutes here, I want to focus back on your commercial assets and DAWNZERA and HAE. You launched it last year, I think. And maybe just talk about how that launch is going. It seems like you're getting more traction more recently and things are accelerating there.

Yes. DAWNZERA is going well. I mean this is very different than any of the medicines I just talked about, right? This is a highly competitive market in the sense of their existing prophylactic treatments for HAE that were already on the market when we arrived, when we were approved last August. We're 1 year into the launch and more have been coming, right, after that. So this is our first test in commercializing our own medicines, not just being first to market, which usually are, have been, but in a competitive space.

I'm proud of the team. I really am. I'm also proud of the drug. It has a real differentiating profile compared to other treatments that are out there with respect to not only efficacy, which is as good as anything that's out there today. So that's -- we've achieved that. The tolerability and the convenience of being able to self-administer once a month or every 2 months using a simple auto-injector that -- in which the drug is stable for 6 weeks at a time, longer than that, but the label says 6 weeks.

So you could put -- you could take it with you on vacation and not be worried about having to refrigerate or to reconstitute. It's a real easy drug to work with. And that profile, along with the outstanding effort that our team has done to educate HCPs and patients on the opportunity that DAWNZERA offers, launch is going well. I mean, it's a steady growth. We're having a good year for DAWNZERA, and we expect next year for it to continue to grow.

All right. Great. Looks like we're out of time here. So why don't we wrap it up. Brett, thanks so much for your time. We really appreciate it.

Thank you, Mike. It was a pleasure.

Okay. Thanks, everyone, for being here. My name is Yanan Zhu. I'm one of the biotech analysts here at Wells Fargo. It is my great pleasure to be joined by Brett Monia, CEO of Ionis Pharmaceuticals. Thank you, Brett, for being here.

Thank you, Yanan, and good morning, everybody. It's great to be here.

I was wondering if you can start us off with the overview of the company, and then we can jump into questions.

Sure. Happy to. I'll be brief, though, because I know you have a lot of questions, Yanan, and we want to get to those. But as expected, this has been a highly eventful year for Ionis. We've had several really important positive strategic outcomes this year. And we've also had some disappointments, not surprising when you're consistently seeking to deliver breakthrough treatments in therapeutic areas -- new therapeutic areas, sometimes you have disappointments.

But I really do want to emphasize the incredible success we've had this year already. We've had 2 FDA approvals, both in areas where there is high unmet need, and we're first.

Tryngolza for severe hypertriglyceridemia, Zanvastro for Alexander disease, both wholly owned products. And we're anticipating a third FDA approval by our partner, GSK, later this year in chronic HBV. Again, another breakthrough, producing unprecedented clinical functional cure rates in patients with chronic HBV.

We've had 3 Phase III readouts this year, and we are on track for 2 more. And the pipeline, in addition, continues to deliver and go very well. We initiated a Phase III study for ION-775 in severe hypertriglyceridemia that supports twice or once a year dosing. As a follow-on to Tryngolza, we started a Phase II study in Dravet syndrome using a very important new chemistry that we've created that supports potentially once per year dosing, twice a year or once a year dosing. And I can go on, but maybe we should just open up for questions, but it truly has been a strategically successful year so far.

Right, right. It's been a very eventful year for sure. I actually wanted to start with Angelman syndrome, one that you didn't have any update, but I think a lateral update from Ultragenyx programs has caused some investors to react I don't know if you can touch on when you saw that result, were you surprised? And anything that you think investors should not read through to your program?

Yes. So sad for the Angelman's community, we really feel for them. This is a community that has been in desperate need for a treatment. They've been disappointed many times with unsuccessful clinical readouts. With that said, we see 0 read-through to our program.

Prior to the readout from the program that you just referred to, we've been signaling to the investor community and to anybody that listened to us for well over a year that although we are hopeful that the study would show signs of success, we are very -- not very optimistic that it would be successful for several reasons.

But most notably, Yanan, is the fact that despite the fact that their molecule and our molecule are using similar mechanisms of action, a mechanism of action that we actually pioneered and published on for the first time, and they have similar potencies based on a whole host of data that we've generated, they were dosing substantially lower than us. And that's because that they ran into toxicity issues in the clinic and preclinically that forced them to be capped, their dose to be capped. Substantially lower dose, and we were concerned that they were under dosing. We do believe that, that was the culprit in their study at the end of the day.

Our program, of course, rides the heels of a proven platform in CNS diseases. Let's not forget that Ionis is the only company that has delivered oligonucleotide successes that have been FDA approvals in the clinic to date, proven platform that has delivered SPINRAZA, Zanvastro, now, QALSODY and proof of concept even in Alzheimer's disease with our tau program.

So we're dosing at the maximum dose that we think -- at the maximum dose we set out to dose at. And we think that we've maxed out -- we will max out on efficacy when our study reads out next year. We have fully enrolled this year, the study, and we're looking forward to data in the second half of next year.

Got it. Got it. That's very, very helpful. Let's touch on Lp(a). So this is a very surprising result. It's a very -- it's a good target with a lot of backing from human genetics. When this data readout from Novartis, your partner, can you share your thoughts on what might be the cause for the study to not turn up a positive result? And what does this mean for the program and perhaps also for the Lp(a) field?

Yes. So this is another first for an Ionis-discovered medicine to test the Lp(a) hypothesis, if you will. That is to address an independent risk factor that's been strongly associated with cardiovascular disease. High levels of Lp(a) are strongly associated with cardiovascular disease. So we set out to determine whether or not it could be modifiable with a pharmacological intervention, pelacarsen, by lowering pelacarsen to normal levels. And that's what we did in the study.

We got substantial lowering of Lp(a) that were similar to what we reported in our Phase II study on the order of 75% to 80% reductions in Lp(a). We saw good safety in the study, and those reductions in Lp(a) really normalize a lot of patients. Unfortunately, it didn't result in a successful outcome on MACE, a 4-point MACE endpoint. And the study was -- did not achieve statistical significance in the primary endpoint. It also didn't achieve demonstrate benefit in the subgroup of patients that were at higher risk in the study.

So it's unfortunate that the drug did what it was supposed to do with respect to lowering Lp(a) with good safety, but it may implicate Lp(a) as an independent risk factor, but one that may be unmodifiable, at least in this patient population that all other risk factors are well controlled, LDL, hypertension are very well controlled.

And as a secondary prevention, maybe it's just not modifiable. We'll see. We don't see a path forward for pelacarsen. Novartis is going to be presenting the full Phase III data at a medical congress as soon as they can, so maybe later this year. So stay tuned for that. But unfortunately, we don't see a path forward for pelacarsen.

Got it. Yes. Thanks for those thoughts. Let's touch on another recent development, CARDIO-TTRansform. So I know you and I'm sure everyone in the field has hoped for the combination to produce even greater efficacy than silencer or stabilizer alone. However, the result did not point that way. So could you help us understand the results in the combo part of the study and also help us understand what the path or the next steps for the program?

Yes. So I really want to highlight that we had 3 presentations related to eplontersen and ATTR cardiomyopathy, ESC last week, all high-quality presentations in large forums at the meeting. The overall study outcome and then the subgroup -- focus on the subgroup in combination with tafamidis, if you will, or stabilizers.

The study did not hit its primary endpoint in the overall -- the composite of cardiovascular mortality and events, serious CV events in the overall population. However, in patients that were not on stabilizer at baseline, we call this the monotherapy group, we saw a remarkable efficacy. We saw efficacy that's similar to the only other silencer that's on the market today with respect to a risk reduction of nearly 30% risk reduction.

We saw TTR reductions that were as good as anything that's been out there today, around 80% TTR reductions, all good safety in the Phase III study. So the monotherapy worked very well. But unfortunately, there was no added benefit in combination with stabilizers. We had more than 50% of patients on stabilizer at baseline. And then that -- the involvement of tafamidis or stabilizer in the study grew as the study continued with lots of drop-ins as tafamidis became the standard of care, not only in the United States, but in Europe and elsewhere. That would have been fine had there been added benefit on top of the stabilizer. But unfortunately, there was none.

That was not only the conclusion of Ionis at AstraZeneca, that was the conclusion of an independent academic group that presented a meta-analysis at ESC last week when they said there's no added benefit in any studies conducted to date in combination of a silencer with a stabilizer, including this one and other ones that have come out.

Recently, that is one reason that the study didn't hit its primary endpoint. The second reason is that tafamidis actually performed pretty well in the study. Remember, patients are being diagnosed much earlier in disease today, unlike the Phase III study for tafamidis and ATTR-ACT 10 years ago, where patients were being diagnosed with late-stage disease and it was difficult to impact their disease course.

Patients are being diagnosed much earlier today. The stabilizers actually performed very well as monotherapy. And we just couldn't add to the benefit that tafamidis was achieving in our study, but the study was executed very well. The monotherapy group performed exceptionally well. And AstraZeneca is weighing their options. They haven't made any definitive decisions.

We're helping them, of course, in any preparations and discussions with path forward. But I would hold off and wait to hear from AstraZeneca later this year on whether there is a path forward as a monotherapy for eplontersen in ATTR cardiomyopathy. I do want to say that in polyneuropathy, the launch continues and the drug is very effective and patient uptake continues to be relatively strong. And it's a good drug. Unfortunately, the study design caused it not to be successful in the overall population.

Great. Great. So I was wondering, of course, it's all pending the decision-making by your partner and you on the path forward. I was wondering in that process, could you walk us through the justifications perhaps arguing for next steps for the monotherapy? And also perhaps in the -- if that path works, what is the use set and use case for monotherapy?

It's a great question. My personal opinion, I think there's significant justification to bring eplontersen to ATTR cardiomyopathy patients because patients deserve options. Today, there's 2 stabilizers and there's 1 silencer. Patients deserve other options and eplontersen offers -- it differentiates from the other silencer that's on the market in several ways. Most notably, they can be administered by the patient themselves, doesn't have to -- self-administration using a simple auto-injector doesn't rely on the administration by a health care provider.

We think that that's important for patients as a choice. But the bar is high. I mean, let's not fool ourselves here. FDA generally does not accept submissions with failed primary endpoints in studies. But you're asking in my opinion, I think patients deserve choices.

I see no reason why silencer cannot be used as first-line treatment. It's the combination that we and experts that were -- it was highlighted at ESC last week, there's probably no path forward for combination usage of a stabilizer and a silencer. Let's not lose sight of the fact that we're targeting the same pathway with a silencer and a stabilizer, right? We're targeting TTR, whether we stabilize it or we knock it down, we silence it. We maxed out.

But I see silencers as they can be used as frontline therapy, absolutely. The risk reduction was as good as stabilizer, just there was no added benefit on top or you can use a stabilizer as frontline and some physicians, it's going to be on patient preference or do they want an injection once every month or a few months or do they want to take a pill a couple of times a day. It's really going to come down to preference, I think, but there's no reason why it can't be used as frontline or second-line treatment.

I also want to add, Yanan, that this is a big market, and there is room for multiple players, first line, second line. And we don't really know what the ceiling is for ATTR cardiomyopathy. It's a big market opportunity.

Great. Great. Let's talk about Tryngolza in severe hypertriglyceridemia. You have a launch going on. This is the first quarter for this indication, only started a couple of months ago. But I hope you -- could you -- I'm wondering if you could share with us what have you been seeing regarding the launch momentum. I guess some focus could be patient demand, which patient population are being prescribed the drug currently? Any insurance hurdles? And any pushback on the liver fat finding...

Yes. Sure. As I mentioned in my opening comments, we've had several very important strategic successes at Ionis this year. The FDA approval of Tryngolza for severe hypertriglyceridemia was an enormous breakthrough in this massive patient population.

In the U.S., 3 million people plus are being treated with sHTG or have sHTG, many of whom are being treated, but the treatments are inadequate. They're fibrates or fish oils or statins, which barely lower triglycerides at all, unlike Tryngolza, which shows 70%, 80% reductions in triglycerides on top of those medicines and the FDA approval included a reduction, highly statistically significant and really powerful reduction in acute pancreatitis events, the outcome that is most significant for people with severe hypertriglyceridemia in the indication statement, even though AP, acute pancreatitis, was a secondary endpoint. And the approval was 6 days early.

So we are very pleased with this breakthrough treatment, wholly owned medicine that we launched within a few days after the approval. We're pleased with the momentum of the launch to date in the U.S. We received -- we put -- we had drug in channel within a day. We had scripts received the day of approval, and the momentum is good. We're seeing lots of -- we're seeing prescriptions coming from cardiologists, endocrinologists, lipid specialists. And not surprisingly, as we expected, they are prioritizing those patients with the highest risk.

Let me remind everybody that the label is for -- is the definition of sHTG. It's for people with severe hypertriglyceridemia as an adjunctive diet and exercise, which is defined as triglycerides 500 milligrams per deciliter and above with -- as a treatment to reduce risk of acute pancreatitis. That's the label.

But as we expected, physicians are prioritizing those patients with -- that are at the highest risk to come into Tryngolza. Those are patients with a history of acute pancreatitis. Those are patients with triglycerides that are so high, 880 or above that they're at very high risk of acute pancreatitis, whether or not they've had an event or not in the past. And that's what we're seeing come in primarily from the physicians.

Payer discussions are going quite well. We're very pleased. We did a lot of payer research prior to setting price, as we went from a rare indication, FCS to a prevalent indication, sHTG. And we've had many productive discussions with payers since then as well. And we're pleased that payers are not pushing back on covering to label, not just the high-risk patients or anything like that, it's pay to label 500 milligrams per deciliter and above.

But with that said, physicians, rightfully so, are prioritizing those high-risk patients. And we're expecting a steady launch, physicians need to be educated on the label. They need to be educated on the dose options that we have approved. They -- some of them like to bring their patient in to do a triglyceride measurement prior to prescribing or getting their patient on drug and then just the normal operations that are -- happen in a launch in a highly prevalent disease with very busy doctors. But we're pleased with the enthusiasm, the sentiment, the need that we're hearing for Tryngolza for sHTG. And we're pleased with the momentum that we've built so far.

Great. Definitely looking forward to a quarterly update for continued momentum on that launch. I was wondering how reliable are the third-party vendors that capture prescriptions. This is a specialty pharmacy situation. So it's not always reliable, but we see some increases in scripts through those third-party channels. Can we use that kind of to triangulate and trying to predict sales?

No. We advise against it. We've been advising against it because we believe that the Symphony, IQVIA data is inaccurate, and we would recommend against that. We block our data. We have several different specialty pharmacies, not just one, so several. And the data is unreliable. So we've been advising against using that data. But I want to emphasize that we're pleased with the momentum that we've created for the launch to date.

I see. You do have a full year guidance for the Tryngolza sales for the full year. Are you comfortable with the guidance?

We're very pleased -- like I said, we're very pleased with the launch. I could just only reiterate what I just said is that the launch has gone according to plan. We're on track. We're seeing tremendous enthusiasm for Tryngolza. We do have a quick start program. I want to emphasize that we are getting patients on drug quickly.

We also have patient support programs for Tryngolza to make sure patients understand how to administer Tryngolza and they understand the disease and what to expect. And we're also emphasizing the need for physicians to get those triglycerides measured fairly quickly after they go on to -- patients on to Tryngolza because what they're going to see and what they are seeing is substantial reductions in triglycerides on the order of even better in many cases than what we saw in our Phase III study with no AP events.

So we're pleased about that. And we're also confident in our peak product sales in the U.S. of $3 billion plus based on everything we're seeing in the launch and the label to date. So we're feeling very good about the launch.

Great. Great. On the competitive front, Arrowhead reported their SHASTA-3 and SHASTA-4 pivotal data at ESC. I was wondering how do you view that product's profile? And how do you think this -- that pending launch could impact your outlook for Tryngolza?

The Phase III data that was presented at ESC was -- there were no surprises at Ionis. It was as expected. We see a profile that's very similar to Tryngolza. I do want to caution folks that to compare apples-to-apples, their primary endpoint was triglycerides at 12, reductions at 12 months compared to baseline. Ours was triglyceride reductions at 6 months, placebo adjusted.

If you look at our median data at 12 months, it's basically the same as theirs. If you look at their triglycerides, placebo adjusted ours actually looks better because they had a significant -- very significant placebo effect in their study. Our acute pancreatitis data is highly competitive, a little bit better, but it's the profiles look very similar.

Our safety is clean. We have no monitoring in our study, although there's been some confusion about that. We have a very clean label. You asked about hepatic fat before, Yanan, and I didn't answer that last part of the question.

We are 100% convinced that this is a nontarget effect, where we see a small increase in hepatic fat by lowering the target APOCIII in the study. We evaluated 250 patients or so by MRI, looking at changes in hepatic fat. We saw a small increase, particularly at the high dose, not statistically significant at the 50-milligram lower dose. And with continued dosing, as we've presented several times now, continued dosing, we see a return to baseline of hepatic fat with no clinical sequelae, no issues, no concerns by the HCP community.

They saw it in their study, too. They only evaluated 30 or a few dozen patients. So it's obviously not statistically significant, wasn't powered. But you can see numerically an increase in hepatic fat. It's an on-target effect. And -- but most importantly, it's of no consequence in the eyes of HCPs, never was.

Tryngolza has a very clean profile. We're first to market, and we're taking advantage of that. And as I said, the launch is going well. We're first to market by a year or so. And we also have the advantage of offering 2 dose levels, 50 milligrams, which was highly competitive and then the 80-milligram dose, which is even more competitive. And we're seeing prescriptions coming in at 80. We're seeing prescriptions coming in at 50. And that's definitely resonating very well with the cardiology community to be able to be able to look at 2 different dose levels and see how patients do at 50 and then before bumping it up to 80 milligrams or they just start at 80 milligrams and patients are doing very well.

Great. Thanks for those color. I was also wondering about your siRNA program for sHTG. You presented data at ESC, and you also had publication. So wondering help us review that data? How does that data compare with Tryngolza, with Redemplo, for example? And how does that come into your overall sHTG strategy?

Yes. So we're now -- after investing in expanding our technological base, the chemistries and other know-how, delivery methods, new methods for delivering ASOs, siRNAs to target organs, we invested in 5, 6 years ago are now starting to reach the clinic. Our first SI, Ionis discovered SIs using Ionis know-how and chemistries are now reaching the clinic.

In the liver, SIs are more durable than standard ASOs or Ionis ASOs by a few months. And we've been able to use our know-how and chemistry to further increase that to 6, 9, 12 months once dosing in the clinic. We know this how to do this. We have selected ION-775 as a follow-on to Tryngolza. It's tough to beat the efficacy of Tryngolza. I mean that bar is very high, but maybe we can do it. Really, it's focused on convenience as a once or twice per year self-administered treatment for sHTG, just to protect the franchise that we created, the first -- we were first to market, and we want to protect that with -- by offering convenience advantages for patients if they want that.

Our Phase I data that we presented at ESC completely supports twice or once per year dosing with excellent safety and remarkable APOCIII reductions on the order of 90-plus percent was dose ranging. And triglyceride reductions that were -- just were truly remarkable.

Remember -- I shouldn't say remember, in our Phase I study, we evaluated patients with mildly elevated triglycerides. You can only lower the triglycerides so much when you're mildly elevated. We are basically normalizing all the patients. We expect even greater reductions in sHTG where the triglycerides start at a very high baseline values.

And in fact, we started our Phase II study in sHTG as an open-label study, so we're continuing to monitor triglycerides and APOCIII reductions and safety because we want to select dose and dose regimen frequency as quickly as possible to get Phase III started as quickly as possible as a follow-on to Tryngolza. We expect in 2027 towards the end of the year that we'll have all the data we need to make a decision on to go to Phase III. And if we really move quickly, maybe we'll get it started in 2027. So it's a priority.

Got it. Got it. Got it. So maybe 2 quick follow-up on that. The Phase II has studied both moderate and severe HTG maybe that's a standard procedure because you also did that for Tryngolza, but I was wondering, is there any inclination to go into moderate HTG because that's not an indication for.

No, there isn't. We designed the Phase II study to have enough sHTG patients in the study to answer all the questions we need to answer for our Phase III design. But we wanted more patients to ensure that we have all the safety in the study, but it can also contribute to our ultimate Phase III safety database to have as many patients in there as possible. It's just to move enrollment quickly.

The sHTG patients are harder to find in HTG patients. And by combining both, we'll get all the information we need in the study to select dose and dose regimen. We don't plan to go after mildly elevated triglyceride patient population, which is particularly at risk for cardiovascular disease, at least not for ION-775 at this point.

We don't think the prospects for success in a cardiovascular outcome trial are high enough. We're really focused on sHTG. This is a multibillion-dollar product opportunity, and we're first, and we want to continue to hammering away -- to continue to bring medicines forward for sHTG to ensure our continued leadership in this space.

Got it. Got it. I thought I heard you say the Phase III development for ION-775 could be hopefully this year, but -- or [next '27 ].

Maybe. Certainly, we're going to have all the information we need in 2027 to design our study. Getting a Phase III study started is not a trivial task. Operationally, it's the blocking and tackling to do that, but we'll have all the information we need for sure. That's why we designed it as an open-label study. So we're continuing to evaluate the data as we go forward.

The study is enrolling well, and we like what we see so far because it is open label. The Phase III design will probably look like our Phase III design for Tryngolza in many ways -- in most ways. With that said, if there are opportunities to trim time lines based on our experience with Tryngolza, we will do so.

We do believe that even though we have proven that lowering triglycerides through this mechanism will prevent acute pancreatitis largely from happening. We still think it's important to have that data in a label when you launch. So we're going to make sure that we also have -- do everything we can to have a label similar to Tryngolza, just more convenient once or twice a year.

Great. Yes. Yes. Great to see the first Ionis siRNA program approaching the later-stage development. Perhaps let's also touch on another commercial product, DAWNZERA for HAE. This is a very competitive therapeutic area. So based on the launch that you have seen, are you incrementally more confident or less confident about your expectation for this program?

Yes, we're very confident. We're confident in our peak product sales in the U.S. of $500 million plus. We're very -- based that based on our label, based on what we're seeing in the launch, the enthusiasm for DAWNZERA. We're seeing new patients -- newly diagnosed patients going on to DAWNZERA. We're seeing patients that were previously on on-demand treatment, try their prophylactic for the first time and DAWNZERA being one of them.

But most of the patients are coming from switches, primarily TAKHZYRO, which is the market leader in the U.S. But other -- really all prophies that are out there, we're seeing switches on today. It is a very competitive market. And there's a lot of players in this market, but we think we know DAWNZERA is doing well, and we think it will continue to do well.

What we're particularly pleased with is not only the switches we're seeing, but patients, once they get an experience with DAWNZERA, they're staying on treatment. It's very sticky. It's not true for all prophies. We're seeing switches, like I said, patients often want to switch because of lack of sufficient efficacy or poor tolerability.

DAWNZERA as a once per month or once every 2-month treatment has resonated well for convenience, simple auto-injector. And patients are -- once they get experience with DAWNZERA, they're staying on treatment.

Got it. Got it. In the remaining minute or 2, I was wondering, could you say a few words about the things that we haven't touched on, like the IgAN program, any catalyst and also the HBV program?

Yes. So bepirovirsen is now approved in Japan as a treatment for chronic HBV as Hibsago. And that approval was based not only on the lowering of HBV burden in people with chronic HBV, but the functional cure rate of treatment that is unprecedented, unprecedented cures in these patients. It's launched -- it's going to be launched in Japan next month, and we're expecting approval in the U.S. in October of this year, and that represents the third approval for Ionis this year, FDA approval, for Ionis this year.

We're also expecting Phase III data for sefaxersen in IgA nephropathy, that's partnered with Roche this year. That's -- that data will be revealed, uncovered to support an accelerated approval path for sefaxersen in IgA nephropathy. That will be coming up in the second half of this year, and then Roche will be filing soon thereafter. So the pipeline is continuing to deliver.

I'll also highlight the fact that we initiated a Phase II study in Dravet syndrome earlier this year. We're excited about that. And we're excited about the rest of our CNS pipeline, which continues to deliver proof of concept and FDA approvals. So very exciting times.

Thanks. Thanks for all the color and very helpful framing and insights. Thanks, everyone for being here.

Thank you. Thanks Yanan.

Good morning, and welcome to Ionis conference call to discuss the FDA approval of ZANVASTRO for treatment of Alexander disease. As a reminder, this call is being recorded.

At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead the call. Please begin.

Thank you, Joel, and thank you to everyone joining us today as we discuss ZANVASTRO, which is now the first and only FDA-approved disease-modifying therapy for the treatment of Alexander's disease. Please be sure to visit the Investors section of the Ionis website to see the press release Ionis has issued earlier today, along with the slides accompanying today's webcast.

Before we begin, I would like to remind you that our discussion today will contain forward-looking statements that are based on our current expectations and beliefs. Such statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail.

With me on the call today are Brett Monia, Chief Executive Officer; Holly Kordasiewicz, Chief Development Officer; and Kyle Jenne, Chief Global Product Strategy Officer. Our agenda today will be as follows: Brett will provide opening remarks, Holly will provide a brief review of the unmet need associated with Alexander disease as well as the data that support the approval and label of ZANVASTRO and Kyle will review our launch strategy for ZANVASTRO, which represents Ionis' first independent commercial launch in neurology. After Brett's brief conclusion, we will open the call for your questions.

And with that, I'll turn the call over to Brett.

Thanks, Wade. Good morning, and thanks, everybody, for joining us on today's call. Today is a landmark day for people with Alexander disease and Ionis as the FDA has approved ZANVASTRO, the first and only disease-modifying treatment for this ultra-rare progressive and often fatal neurological disorder. The FDA approved ZANVASTRO with a broad label, enabling treatment of both children and adults with Alexander disease. And with today's approval coming nearly 3 weeks early, we are positioned to bring ZANVASTRO to patients even sooner than anticipated.

ZANVASTRO was approved based on positive data from our pivotal study in children and adults with Alexander disease. The study achieved a statistically significant and clinically meaningful benefit on the primary endpoint measuring motor function. Additionally, trends favoring ZANVASTRO across key symptom domains were also observed along with a favorable safety and tolerability profile. For Ionis, this approval builds on our long history of discovering and developing first-in-class treatments for rare neurological diseases such as SPINRAZA, first therapy ever approved to treat SMA, and QALSODY, the only disease-modifying treatment approved for a genetic form of ALS.

ZANVASTRO builds on our legacy of innovation and reinforces the transformational power of our technology. And as the first independent launch from our industry-leading neurology pipeline that today includes 8 wholly owned medicines addressing similarly challenging diseases like Dravet syndrome, prion disease and Angelman syndrome, ZANVASTRO provides a strong foundation to support these potential future launches. Furthermore, as Ionis' third wholly owned commercial medicine, ZANVASTRO joins TRYNGOLZA and DAWNZERA in demonstrating our ability to successfully capitalize on the opportunities from our rich and growing pipeline.

We were pleased to receive a priority review voucher from the FDA in connection with ZANVASTRO's approval. This voucher provides an opportunity to accelerate the FDA review of a future Ionis medicine and potentially accelerate our ability to bring it to patients sooner. In addition to launching in the U.S., we are also expanding access to ZANVASTRO to people with Alexander disease outside the U.S. through our commercial partner, Recordati, which remains on track to file for approval in the EU and Japan next year with additional submissions to follow.

Before I turn the call over to Holly, I want to extend my sincere thanks to the Alexander disease community, including the patients, families, investigators, advocacy organizations and research partners who help make this approval possible. I also want to recognize the Ionis team for their innovation, dedication to patients and commitment in bringing this important medicine forward.

And with that, I'll turn the call over to Holly.

Thank you, Brett. Before I begin, I would also like to thank the Alexander disease community for their partnership and support that made the approval of ZANVASTRO possible. It is a powerful determined community, and it has been a privilege to work with them. Alexander disease is an ultra-rare progressive and severe neurological disease caused by pathogenic variants in the GFAP gene. Because it affects the brain's white matter, Alexander disease can involve multiple regions of the brain and present with complex symptomology. While symptoms often present first in infancy or childhood, onset can occur at any age with most patients experiencing progressive motor and cognitive dysfunction, loss of mobility and independence and difficulty controlling the muscles needed for swallowing, airway protection and purposeful movement. And sadly, it is almost always fatal.

Alexander disease is estimated to affect approximately 1 in 1 million to 3 million people worldwide. And until today, in the absence of any approved disease-modifying treatments, care for people with Alexander disease has largely focused on symptom management and support as the disease progresses. Given the small size of this population and the urgent need for treatment and with the support of the FDA and Alexander disease community, we took an innovative approach in designing our ZANVASTRO registrational trial. We combined first-in-human dose-finding and pivotal studies into one controlled integrated trial protocol, which provided the results that supported today's approval.

The ZANVASTRO trial enrolled 54 people ages 2 to 53, the majority of whom were under the age of 18 at enrollment, reflecting the real-world Alexander disease population. The primary objective of the study was to evaluate ZANVASTRO's impact on stabilization of gross motor function in children and adults with Alexander disease. The primary endpoint in the study measured stabilization of gait speed in participants aged 5 and up using the 10-meter walk test, a commonly used measure of gross motor function in neurological diseases. The study also measured gross motor function in younger participants as well as a number of secondary and exploratory endpoints aimed at capturing the constellation of Alexander disease symptoms.

The approved dose of ZANVASTRO is 50 milligrams and is administered quarterly by intrathecal injection, the same well-established route of administration as our other approved neurology medicines. We initially tested a lower 25-milligram quarterly intrathecal dose in a small cohort of patients, which enabled us to establish ZANVASTRO's safety and pharmacokinetic profile. Once complete, we tested the approved ZANVASTRO 50-milligram dose in a larger cohort of patients, which represented the pivotal portion of the trial.

The study met its primary endpoint, showing a statistically significant and clinically meaningful stabilization of gait on the 10-meter walk test in participants treated with ZANVASTRO 50 milligrams. This was a very exciting outcome as it represented the first time a medicine demonstrated disease-modifying benefit in this patient population.

Secondary and exploratory endpoints also consistently favored ZANVASTRO. In participants aged 2 to 4, ZANVASTRO improved gross motor function compared with control on the Gross Motor Function Measure 88 or GMFM-88, a well-established measure appropriate for this age group. ZANVASTRO also substantially reduced plasma GFAP compared with control, providing evidence that ZANVASTRO engaged the intended target and is modulating the underlying mechanism of Alexander disease in ZANVASTRO-treated patients.

ZANVASTRO also demonstrated a favorable safety and tolerability profile in the trial. Most adverse reactions observed in the trial were mild to moderate in severity and serious adverse reactions occurred less frequently with ZANVASTRO compared to control. These efficacy and safety results supported a broad label for children and adults, reflecting the real-world Alexander disease population. And importantly, we believe ZANVASTRO is well positioned to become an important new treatment option and the standard of care for people living with Alexander disease.

With that, I'll turn the call over to Kyle.

Thank you, Holly. We are thrilled to bring ZANVASTRO, the first disease-modifying treatment for Alexander disease to people in the U.S. who are living with this ultra-rare progressive neurological disorder. This represents an important new medicine for a community with significant unmet need. We are launching ZANVASTRO with a broad label, enabling children and adults diagnosed with Alexander disease to access treatment. And we are working quickly to get product into the channel so we can bring this important treatment to patients in need shortly.

With our customer-facing team already in the field, we are ready to launch ZANVASTRO. Although exact prevalence is not well understood, we estimate that approximately 300 people in the U.S. are living with Alexander disease, approximately half of whom have been identified through medical claims. And among the patients who are currently -- who currently receive supportive treatment for their disease, many do so at one of the approximately 12 leukodystrophy centers of excellence in the U.S. At launch, our team will focus on these centers to ensure identified patients can gain access to ZANVASTRO if appropriate. In parallel, we will work to reach treaters in neurology centers outside this concentrated network in an effort to identify new patients who may benefit from ZANVASTRO. We will do this strategically, leveraging omnichannel resources as needed to extend our team's reach.

We have 4 initial launch priorities. First, the team will work to transition patients currently receiving ZANVASTRO in the clinical study and expanded access program to commercial drug, while ensuring continuity of care for these patients throughout the process. Second, we will work to get patients who have already been diagnosed with Alexander disease and identified through ICD-10 codes and patient registries on treatment. Third, we will work to raise disease awareness among physicians who care for people with this rare neurological disease to drive new patient identification. Finally, we will work with payers to ensure coverage and access for ZANVASTRO.

We have also tailored our Ionis Every Step patient and HCP support program to meet the unique needs of the Alexander community. For health care providers and site staff, we have adapted our access and reimbursement support services, specifically for ZANVASTRO, which is intrathecally administered, dosed quarterly and will be reimbursed mostly under the patient's medical benefit. And for patients and families, they will have access to a comprehensive suite of education and reimbursement support services designed to help patients start and stay on treatment.

Reflecting the value of ZANVASTRO can bring to the ultra-rare Alexander disease community, we are launching with a price of $285,000 per dose. We have financial assistance and reimbursement support programs in place to help eligible patients access treatment. Out-of-pocket costs for commercially insured patients may be reduced to as little as $0 per prescription. With our focused commercial approach, and experienced customer-facing team and a high-touch patient services model, we are positioned to support timely access to ZANVASTRO for people living with Alexander disease.

More broadly, the ZANVASTRO launch represents an important step in Ionis' continued growth, expanding our commercial capabilities, establishing a foundation for future independent neurology launches and advancing our goal of delivering a steady cadence of new transformational medicines for people in need.

And with that, I'll turn the call back over to Brett.

Thanks, Kyle. Today's approval is an important milestone for the Alexander disease community and for Ionis. Over the years, we've had the privilege to hear directly from many families impacted by this disease. And today, we want to again extend our heartfelt gratitude for their insight, support and partnership in making this monumental breakthrough possible.

For Ionis, with ZANVASTRO now approved, we are expanding our commercial portfolio and laying a solid foundation for our future neurology launches. We are laser-focused on delivering launch success for ZANVASTRO and across our entire commercial portfolio, thereby driving accelerating value for patients, shareholders and all Ionis stakeholders.

And with that, we'll open the call up for questions. Given the importance of today's news, we'll keep the Q&A session focused entirely on ZANVASTRO or if you want, questions applying to our wholly owned neurology pipeline as they relate to ZANVASTRO. Operator?

[Operator Instructions] Your first question comes from Yaron Werber with TD Cowen.

This is Steven Ionov on for Yaron. And congratulations again, management on the approval. One question from us. Of the roughly 150 identified U.S. patients, of which 54 were enrolled in the study? And how many more are in the OLE or expanded access program and potentially positioned for near-term conversion? And how quickly do you expect that conversion to happen?

Let me start with the numbers, and I'll let Kyle comment on the time it will take for the conversion. So we're not providing specific numbers on the expanded access program or how many patients are continuing to be in the OLE at this time. As Kyle mentioned, they are one of the key areas of focus to convert patients over to commercial as quickly as possible. I can say that -- and Holly, please add anything you want to this, the enthusiasm and the number of patients that rolled over into the open-label extension in the Phase III study was very robust. Do you want to jump in really quick?

No, that's exactly it. So the majority of patients have rolled over the OLE and all have continued.

And they all have continued. And the EAP has gone quite well. We're really, really pleased with how enthusiastic and how efficient it's been to bring in a good number of patients in the expanded access program. Kyle, what do you think about converting these over to commercial product?

Yes. Just in terms of timing, the back half of this year, it's going to take us a little bit of time, right? These are quarterly dosed patients, number one. Number two, we don't expect a bolus here at the beginning. There are some logistical as well as reimbursement dynamics that the institutions will have to navigate through. So that's the second piece to this.

And then the other part is some of these patients that have been diagnosed might end up being referred back to local centers where they reside. So there are some dynamics there in terms of making sure that they can find and identify a treater within their local community that can get on to therapy. But we will work as quickly as we can. Product will be in channel as quickly as we can get that in. And we obviously will be supporting all of the patients that are on drug today to make sure that there's no disruption in treatment.

And I'll just add one last thing, Steven. Our partner, Recordati, is working with us very closely and aggressively to open up an EAP in Europe as well. So stay tuned for that.

Your next question comes from Gary Nachman with Canaccord Genuity.

This is Denis Reznik on for Gary. Congrats on the approval. So while I recognize these are fully different therapeutic areas and different launch strategies, but maybe talk about some of the learnings you've gotten from the successful TRYNGOLZA and DAWNZERA launches that could be applied to this launch, particularly maybe with the Ionis Every Step program. And then maybe talk a little bit more about how conversations with the payers have progressed with regards to your WAC price and what the overall path to full reimbursement and access looks like?

Yes, I'm happy to touch on that. Let me -- I'll just first start. The execution on the launches that you referenced with TRYNGOLZA and DAWNZERA have really been very, very strong. So we've got all of our back-office capabilities and operational components that are in place, and the team has done a very, very good job of making sure that we can do things like get drug in channel quickly, make sure that, that drug can obviously get to patients when the prescriptions come in, et cetera. So we've learned a lot in terms of the operational dynamics of commercialization, and that's gone extremely well.

As it relates to the Ionis Every Step program, that is really one of the differentiators and one of the things that we really take to heart here at Ionis. We map what we describe as the patient journey for every single program that we have. And we think about from the very beginning of when a patient either needs to be diagnosed or is diagnosed all the way through to when that patient ends up going on to therapy and remaining on therapy, how can we support them along the way. And what's needed from a disease state standpoint, what's needed from a product education standpoint. Obviously, access and reimbursement is important and making sure that out-of-pocket expenses and things can be managed appropriately.

But those are the types of ways that we design our patient services program, Ionis Every Step. And we've done exactly that with ZANVASTRO. And I think that's a really important piece here for us is this is going to be the first time that we're moving into a buy-and-bill model. We understand the distribution. We understand the needs from the payer standpoint. We understand the institutions and also the patient community in terms of what they're going to need in order to have support from an access and reimbursement standpoint. So that's a very strong focus for us.

As it relates to working with the payers, we took a very similar approach that we've taken with our previous programs. We go out and we speak to the HCPs that are the treaters of this disease, how do they -- how are they going to use the product and what do they need in terms of reimbursement and support. And then we go to the payers, and we have conversations about the prevalence of the disease, which, as we've talked about, is an ultra-rare condition here. And we also look at other analogs within similar disease areas as well as outside of those disease areas to make sure that we can parallel that and that we ultimately end up with a price that is in alignment with what the value recognizes for the therapy.

And so we're very pleased with the conversations we've had with payers early on. We believe this is going to be a medical exception process. The institutions are very familiar with the way that they go through that process and how they manage this. And obviously, we have the resources and capabilities to help support the institutions in that process moving forward.

Your next question comes from Salveen Richter with Goldman Sachs.

Could you speak to the overlap, the centers of excellence that you're targeting have with Angelman treaters and how you can use this launch to establish referral networks for pediatric neurology more broadly?

Yes. So there is some overlap. The focus here are going to be in the leukodystrophy centers, which there will be a little distinction there. But beyond the leukodystrophy centers, we're also going to be focused on about 25 of the key neurological centers that are out there. And in those neurology centers, that's where we see some of the overlap between what we're working on here and then the program with Angelman.

I'll also mention we have our medical affairs team that has been out working in the neurology space for several years now. A very strong team, well educated. They know the key opinion leaders in the Alexander disease space as well as in the Angelman space. And they're appropriately going out and educating on the disease and supporting those HCPs and the science and the needs that they have in order to learn and understand how to diagnose and treat these patients.

And just to remind everybody, this disease also is a disease very similar like Angelman and that affects both children and adults. So about 2/3 are children, the other 1/3 are adults, similar to the Angelman population. So we've seen those neurologists and have a lot of those same challenges with converting from doctors from the pediatric neurologists to the more standard neurologists, and those are all communities that are talking and working together because it is a unique challenge for some of these diseases.

Your next question comes from Jason Gerberry with Bank of America.

This is Chi on for Jason. Congrats on the approval. I think I want to ask the pipeline related to ZANVASTRO question. So if you may, can you remind us what ASO backbone technology is ZANVASTRO based on? What other key neuro pipeline programs of yours use the same backbone technology and how today's approval changed your confidence of the delivery mechanism for the broader neuro pipeline, given perhaps renewed focus on this topic in light of recent competitive news?

So thank you for the question. So this is a mixed backbone gapmer oligonucleotide. So it's the same chemistry as diranersen, our tau program that is partnered with Biogen. Within our wholly owned pipeline, it's the same chemistry as our Angelman syndrome program as well as our Pelizaeus-Merzbacher disease and MECP2 duplication syndrome program, all in our pediatric neurology pipeline. So it's a chemistry that we're extremely familiar with. It's a similar chemistry that was used for QALSODY, between QALSODY and now in ZANVASTRO, we had improved our screening paradigm.

So ZANVASTRO is using the latest optimized screening techniques as similarly to our Angelman syndrome program. Like our Alexander program, our Angelman program is also quarterly dosed and at a similar dose range. ZANVASTRO was dosed at 50 milligrams and our Angelman syndrome program, which is in Phase III right now, is dosed at 80 milligrams.

So just to put a fine point on that. Thanks, Holly. It's a proven platform, Chi, chemistry is absolutely critical. And it goes beyond chemistry, however. We also have what I believe is by far the most rigorous approach to selection, screening and identification of optimized molecules to maximize potency and avoid off-target effects of oligonucleotides. That, coupled with the chemistry that Holly highlighted, is also very, very important to select safe and effective molecules. And that's what we do with ZANVASTRO, that's what we do with Angelman's and the other programs that are in our wholly owned pipeline that Holly just touched on.

Your next question comes from Mike Ulz with Morgan Stanley.

It's Avi Novick on the line for Mike. Congratulations on the approval. I guess, one, can you talk about feedback you've heard from KOLs and how enthusiastic are they about prescribing ZANVASTRO to their patients? And then second, can you also maybe speak to your efforts to identify the approximately 50% of patients who are not yet diagnosed?

Yes. So I can touch on the first point. So the community is overjoyed. The flooding of e-mails and notes that we have gotten is extremely strong. The KOLs, as soon as we saw the data have been encouraged and looking forward to this day today. And you can see that also in our EAP program where we have had significant demand from the patients as well as the KOLs to participate in that and to get their patients on drug. So the enthusiasm is absolutely there from the community and the KOLs.

Yes. And in terms of patient identification, we've already launched programs to do disease awareness, disease education through our medical affairs group. We will have a very strong presence on different channels through our omnichannel capabilities and our digital nonpersonal channels to be able to do even broader education. But it will obviously take time. It's not easily done. The other thing I'll mention is there are a lot of things related to AI that are happening now to help triangulate and potentially help accelerate identifying some of these patients.

So between the claims data, our tactics and resources to educate broadly through our marketing channels and then combined with some of the AI technologies, we're going to do everything we can to try to help this community and identify as many patients as we can.

Your next question comes from Jessica Fye with JPMorgan.

This is Silvia on for Jess Fye. Just one from me. How do you see the trajectory towards peak sales? Like has that number changed? And how would that launch might differ to other rare disease launch trajectories?

Yes. Yes, great question. Peak sales is estimated right now to be greater than $100 million for this program. We've maintained that number for quite some time. It's going to take a while to get to that peak sales number purely because of the patient identification and doing what I was describing earlier in terms of figuring out where these patients are and making sure that we can get them treated as quickly as possible. But we're still confident in the greater than $100 million, and we'll do everything we can to help as many patients as we can with this disease.

Your next question comes from Eric Joseph with Citi.

Let me add my congrats on the approval. Just coming back to the patient ID effort, can you talk about the role of that newborn screening might potentially have here and the extent to which that's well established for Alexander disease. And also from a resourcing standpoint, I would just be curious to know how you size the MSO and sales force here detailing to COEs and sort of local care centers.

So Alexander disease currently is not on the newborn screening panel. That is not something that's actively being done. The way this is typically diagnosed is the symptoms begin to onset, then it's diagnosed by MRI and then genetic confirmation of testing.

And maybe, Holly, you go into a little bit why -- what the challenges are about getting it on to newborn screening, which is formidable.

Yes. So the main challenge with this is you have to have an assay that can be done easily and simply and then you have to go to each individual jurisdiction to show the evidence that this can be done reproducibly and then to get approval to do this. And so it is a long arduous process. There's also the challenge that not every mutation in Alexander disease is -- they're not all fully penetrant. And so that adds an additional challenge with doing newborn screening.

Yes. Great question on the field force sizing. There are a couple of different teams that we have. Medical affairs, I'll mention first. That team has been in the field and deployed for quite some time. They're covering the major neurology centers across the U.S. because they do more than just Alexander disease as we were talking about earlier. They also cover the Angelman program and other pipeline programs that we have for neurology. And in addition to the 25 neurology centers, there are also obviously the 12 leukodystrophy centers specific to Alexander disease that's a part of that. So that's our medical affairs team.

We are modestly sized for our sales efforts. We know based on the number of institutions that we want to get to that we can rightsize for the number of people across the United States. It's a small team at this point because we're able to support that team with our omnichannel and digital capabilities to go out and educate more broadly around this disease with some of our marketing tactics. We also have our patient education managers, which are going to be a critical component to this. This is part of our Ionis Every Step program. These are individuals that will be able to work directly with the patients and caregivers of them to make sure that they understand the process and have disease resources, product education, reimbursement support, et cetera, associated with that.

So we've got all of the right teams and the right size to be able to accommodate for the known patients today that we were talking about, clinical trial, EAP and also the ability to help support those that are already identified and just not yet on treatment. So we are right sized and it's a very efficient organization.

Your next question comes from David Lebowitz with BMO Capital Markets.

I'm curious, at this stage in the game, where do you expect patients will get their intrathecal injections? And to what extent is the ability to provide such injections as we get further from the academic centers?

Yes. The fortunate thing here is we've had SPINRAZA for a long time, right? Obviously, Biogen is running that program, but we've been very close partners with them, and we understand exactly how they've orchestrated that model where the local communities are educated and set up with the capability to be able to do intrathecal administration. So we have mapped the United States. We've got a good sense of where those capabilities are today. I expect the majority of patients will fall into one of those centers that has a capability in existence currently. And if they don't, we'll be able to work effectively with them to get them set up and help them with that process.

Yes. And just to add to that, Kyle. David, it's a really good question because this, of course, is a chronic therapy, ZANVASTRO is. And over time, we do expect patients wanting to -- families wanting to move towards their more local community settings away from those centers of excellence and leukodystrophy centers of excellence. We will support them. That will happen over time. We recognize that. And that will be one of the challenges that lies ahead for us is to make sure that they are not losing access to the drug due to administration issues and those sorts of things, working with those local communities to ensure that they're fully capitalized to administer IT.

But it will evolve over time. Right now, it's primarily the centers of excellence and leukodystrophy centers, which are well equipped and well experienced. But like Kyle said, SPINRAZA and QALSODY and other medicines that we've developed over the years has really changed the landscape on the capabilities of IT administration across the country.

Your next question comes from Yale Jen with Laidlaw & Company.

On the approval. You mentioned earlier that you will use the buy-in health model. So would that be -- should that be the case given the price of the drug? Should the identifying the patient first will be the key things before the physicians will stock the drug to their centers for the subsequent treatment administration?

Yes. Great question on the logistics here and how this works. So this will be a medical benefit product, right? So it will go through the medical benefit side of the Medicare Part B, for example, or medical benefit under the commercial plans. It will be a buy-and-bill scenario where the institution will purchase the product and then seek reimbursement on the back end, very consistent with what they do with a lot of other therapies that they're currently using.

Medical exception will be the predominant payer coverage that we believe ZANVASTRO will be covered by. So it will be a patient-by-patient request for the therapy. They will submit the request based on the diagnosis consistent with the clinical trial. And then they wouldn't purchase product until that patient has been approved through their payer so that they know that reimbursement is going to be accepted. So that's part of the process and the steps that we'll work through. But it's not uncommon for the institutions to do this. We've done a lot of research and spoken with many of the institutions that will be treating these patients already. They know how to do it. It's more of a time component in the back and forth with the payers in order to get all of that -- those steps of the process completed.

Your next question comes from Myles Minter with William Blair.

First one is just on the 25 neurology specialty centers you're targeting. Do every single one of them already have prescribers with experience in using SPINRAZA and/or QALSODY? That's the first one.

And the second one is just on the safety profile, the vomiting, the back pain, the post-lumbar puncture syndrome. Is that different between pediatrics and adults considering you're approved in both populations?

So I can answer the safety question first. No, there aren't major differences between the profile in adults and kids. It's very similar.

Yes. And on the 25 centers, I don't know that all of them do have experience with SPINRAZA and QALSODY. Many of them do, because these are the key centers and where neurology is being practiced and where a lot of these patients are being identified. But regardless if they have the experience or they don't, we've actually mapped, as I mentioned, across the United States, capabilities in all of the major cities to figure out where we are going to be able to help these patients and get them treated.

That being said, depending upon where those institutions are referring patients back to or where patients might reside today, there could be some additional work for us to set up the capability and help them make sure that they're able to administer intrathecal administrations within the institution of the group in which they work with. But we've got the resources to help them and make sure that, that happens.

Yes. And I'll just add one other thing, Myles. Obviously, pediatric neurologists are the central physician population that manages SMA. And that will be similar for ZANVASTRO. So they're well experienced with SPINRAZA and certainly well aware of SPINRAZA because they're treating kids with these rare genetic diseases.

And maybe now we have time for one last question before closing out.

Our last question comes from Moritz Reiterer with Guggenheim Securities.

This is Moritz on for Debjit. Congrats on the approval again. Could you just reiterate your plans for the priority review voucher? Are you planning on using that internally for an Ionis program? Or are you considering selling it?

Thanks, Moritz. To be determined. But right now, our focus is on our wholly owned pipeline. We have 8 medicines now in clinical development that are wholly owned in neurology that would certainly could potentially benefit from the usage of our PRV. That's the priority now. And that pipeline is going to grow. We're expecting additional neurology medicines to enter the clinic in the near future. So no commitment one way or the other right now, but certainly, we see a lot of potential to utilize our PRV for our rich and growing wholly owned neurology pipeline. So stay tuned for that.

Thanks for the question, and thanks, everybody, for joining us today for participating in our call. We're really looking forward to an exciting second half of the year and looking forward to sharing all the progress we're making at Ionis along the way. So thanks again for participating, and everybody, have a great Labor Day weekend.

Ladies and gentlemen, this concludes your conference call for today. We thank you for participating and ask that you please disconnect your lines.

Good morning, and welcome to Ionis Second Quarter 2026 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please go ahead.

Thank you, Andrea. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany today's call.

With me this morning are Brett Monia, Chief Executive Officer; Kyle Jenne, Chief Global Product Strategy Officer; Holly Kordasiewicz, Chief Development Officer; and Beth Hougen, Chief Financial Officer; Eugene Schneider, Chief Clinical Development Officer; and Eric Swayze, Executive Vice President of Research, will also join us for the Q&A portion of the call.

I would like to draw your attention to Slide 3, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail.

With that, I'll turn the call over to Brett.

Thanks, Wade. Good morning, everyone, and thank you for joining us on today's call. on the center is the second half of 2026, well positioned to achieve the strategic opportunities that lie ahead. We have the R&D engine, the pipeline, commercial capabilities and financial discipline we need to execute on and achieve our goals. We are continuing to build momentum across our commercial medicines. And in parallel, we continue to strengthen and advance our wholly owned pipeline to deliver our next wave of important medicines.

Last month, we achieved a landmark milestone with the approval of TRYNGOLZA as the first and only FDA-approved medicine to reduce triglycerides in the risk of acute pancreatitis in adults with severe hypertriglyceridemia or SHTG. Although still early days, we are highly encouraged with our launch momentum to date. In fact, we began receiving prescriptions for TRYNGOLZA on the day of approval.

We are also pleased that both the 50-milligram and 80-milligram doses were in the channel within 1 week. Based on a strong profile and the enthusiasm we are seeing in prescribing, we are confident that TRYNGOLZA is well positioned to help a large population of patients in need and become the first Ionis own multibillion-dollar medicine. DAWNZERA 0 for hereditary angioedema also continues to gain momentum, we expect Unser to continue driving growth as it becomes more established in the HAE prophylactic treatment landscape.

We also continue to advance our leadership in the development of breakthrough treatments for a wide range of neurological diseases. We remain on track for the anticipated launch of Zilganerse, coming up soon, which is positioned to be the first disease-modifying treatment for Alexander's disease and the first independent launch from our neurological disease pipeline.

Following closely behind Zilganerse by the nurse, our medicine for Angelman Syndrome, which completed enrollment in the Phase III REVEAL study last month, keeping it on track for data next year. Earlier this month, we also announced the initiation of clinical development for ION337 in Dravet syndrome, expanding our clinical stage neurology pipeline, which now includes 8 medicines that are wholly owned.

Complementing our wholly owned pipeline is our partnered pipeline, which includes medicines targeting both rare and highly prevalent diseases, providing significant additional value for Ionis. This includes Bepirovirsen, our medicine for chronic hepatitis B. With a PDUFA target action date of October 26 and additional global filings under review, Bepirovirsen is on track for a global launch this year, positioning it to be a first-in-class medicine for the millions of people around the world living with this disease.

Data from the Phase III pelacarsen LPA horizon study in patients with elevated Lp(a) and cardiovascular disease is also a key catalyst coming up in the second half of this year. We were disappointed with the outcome of the cardio transform Phase III study for eplantersen in ATTR cardiomyopathy that we reported earlier this month. Although eplontersen demonstrated substantial and durable reductions in TTR, nominally significant results in the monotherapy subgroup and favorable safety, it did not meet the primary efficacy endpoint in the overall population.

We and AstraZeneca continue to analyze the data and will present the results at ESC in August. Our strong commercial execution, continued pipeline progress and our strong second quarter financial performance underscore the many opportunities we have to continue building substantial value. We remain on track to deliver on our 2026 financial guidance and achieve our goal of cash flow breakeven in 2028.

With that, I'll now turn the call over to Kyle, who will speak to the commercial execution of TRYNGOLZA and DAWNZERA and launch preparations for zilginerson. Olli will going to discuss how we are advancing our pipeline, highlighting several important catalysts ahead and Beth will review our financial results and outlook.

And with that, I'll turn it over to Kyle.

Thank you, Brett. Our commercial momentum continues to build, positioning us to deliver even greater impact in the second half of the year and beyond. We are executing well against our commercial priorities, including strong progress on the TRYNGOLZA and DAWNZERA launches and preparation for the zolginersen launch. Beginning with TRYNGOLZA, demand continues to build in FCS driven by an increasing number of patients initiating and remaining on treatment.

As expected, second quarter product sales reflected the reduced TRYNGOLZA wholesale acquisition cost that went into effect on April 1. The -- we updated the price ahead of the anticipated SHTG approval to align with annual payer contracting cycles to accelerate access to TRYNGOLZA. Underlying demand in FCS remained strong with the second quarter delivering the highest number of patient starts since the launch began.

Together with our commercial execution in FCS and early market access efforts we've established a strong foundation for the next phase of TRYNGOLZA growth as we launch in the broader patient population. The recent approval of TRYNGOLZA for SHTG marked the defining moment for Ionis. Importantly, it expanded our opportunity to serve millions of people living with severely elevated triglycerides.

We were particularly pleased with the TRYNGOLZA label, which includes prevention of acute pancreatitis in the indication statement. The label is supported by the groundbreaking results from the Phase III CORE and CORE II studies, which further underscores the importance of preventing acute pancreatitis in people with SHTG.

Building on this strong foundation, I'm happy to share that the SHTG launch is off to an encouraging start in the first few weeks. Thanks to the exceptional execution of our commercial team -- we began receiving prescriptions on day 1, and both the 50-milligram and 80-milligram doses were in the channel within approximately 1 week. Since the approval, our team has already engaged with many of our top physician targets who care for the majority of high-risk patients.

In addition, our omnichannel launch campaign has produced strong engagement, which is further helping to rapidly build awareness of SHTG, APOC3 biology and TRYNGOLZA. There are an estimated 3 million people in the U.S. with SHTG, including approximately 1 million people with high-risk SHTG who have triglycerides above 880 milligrams per deciliter, or triglycerides above 500 in a history of acute pancreatitis or other comorbidities.

The risk of acute pancreatitis begins to increase at triglyceride levels above 500 and rises exponentially in people with triglycerides above 880. As the first-to-market therapy with a novel mechanism proven to reduce the risk of painful, costly and potentially fatal acute pancreatitis attacks TRYNGOLZA is well positioned to serve patients across both segments. The majority of high-risk SHTG patients are treated by approximately 20,000 cardiologists, endocrinologists and lipidologists across the U.S. with additional patients treated by primary care physicians.

Early in the launch, we are seeing prescriptions from all 3 specialties in addition to a meaningful contribution from primary care physicians. We've also seen physicians prescribe TRYNGOLZA to people with high-risk SHTG and those with TGs between 500 and 800 milligrams per deciliter with no history of acute pancreatitis. Physicians are prescribing both the 50- and 80-milligram doses, highlighting the importance of dosing flexibility, which enables treating physicians to tailor treatment to the individual needs of each patient.

Importantly, we are executing on our market access strategy as planned. We have made good progress obtaining coverage for the broad population in patients with triglycerides above 500 milligrams per deciliter and across both commercial and government plans. Ultimately, we expect the SHTG market to comprise approximately 60% commercial and 40% government-covered patients. We also expect payer coverage to continue expanding through the remainder of this year and into next year as payers complete their reviews.

We're also making progress in expanding access to TRYNGOLZA outside the U.S. In the EU, Sobi is continuing to advance the launch in FCS, while also actively laying the groundwork for a strong launch in the broader SHTG indication anticipated next year. With this early SCG launch momentum, TRYNGOLZA is on track to meet our full year 2026 revenue guidance and positioned to achieve our projections for more than $3 billion in peak annual revenue.

The DAWNZERA launch also continued to gain momentum. In less than 1 year on the market, DAWNZERA has already captured a meaningful share of the U.S. HAE prophylaxis market, which is largely a switch market. This growth is driven by increasing adoption across all patient segments, including patients switching from existing prophylactic therapies, patients who were previously only using on-demand treatment and treatment-naive patients.

Physicians and patients consistently provide positive feedback on DAWNZERA, highlighting DAWNZERA strong efficacy and favorable safety profile Its differentiated RNA targeted mechanism, the positive switch data, which HCPs described as "differentiating and motivating" and on Zara's patient-friendly profile that includes a self-administered auto-injector that can be stored at room temperature for up to 6 weeks.

The base of repeat prescribers continues to grow. This is a key indicator that DAWNZERA is providing substantial benefit for patients and HCPs are having a positive experience prescribing it. Given that most patients on HE prophylactic medicines are already established on existing therapies Continued penetration will take time. However, the launch fundamentals give us confidence that DAWNZERA will contribute meaningfully to our commercial revenue growth in 2026 and beyond.

Outside the U.S., our partner Otsuka is making good progress with DAWNZERA and the launch in the EU. Over time, we expect ex U.S. countries to become an important contributor to overall DAWNZERA growth.

Turning to Zilganerse. We are well prepared for the launch for the treatment of Alexander disease coming up later this year. Based on the positive Phase III results for Zilganerse, we received FDA priority review with a PDUFA date of September 22. We have an expanded access program underway, and our commercial preparations are right on track to center around 4 key priorities.

First, pending approval, we will work to transition patients who are currently receiving Zilganerse through the clinical study or the expanded access program to commercial therapy. Second, we will focus on getting patients already diagnosed with Alexander's disease in the U.S. on Zilganerse. It's estimated that about half of the approximately 300 patients in the U.S. are already identified through ICD-10 codes and patient registries.

Third, we will drive disease awareness among physicians who care for people with rare neurological diseases, prioritizing engagement with the dozen U.S. leukodystrophy centers. Following approval, we expect these centers as key referral and treatment hubs to play a central role in identifying more patients and providing them with treatment. And fourth, we are building a dedicated patient services platform, which we have designed based on feedback from stakeholders to address the specific needs of the Alexander disease community.

Additionally, our customer-facing team is now in place and prepared to rapidly reach patients upon our potential Zilganerse approval. Importantly, we expect to leverage many of the capabilities we are building for Zilganerse for our future neurology medicine launches. We also recently took an important step toward bringing Zilganerse to people with Alexander's disease outside the U.S. to our agreement with Recordati.

Recordati plans to file for regulatory approval for Zilganerse in the EU and Japan next year with additional global filings to follow. With our first broad patient population launch now underway, growing momentum across our commercial portfolio and a strong pipeline behind it, we believe Ionis is well positioned to bring more important medicines to people with serious diseases.

And with that, I'll turn the call over to Holly.

Thank you, Kyle. This quarter, we made meaningful progress across our pipeline. TRYNGOLZA approval for the treatment of SHTG is a significant milestone for Ionis and for patients. Our goals of approval was supported by the unprecedented results from the Phase III CORE and HRI study, in which TRYNGOLZA acheived rapid, substantial and clinically meaningful placebo-adjusted main reductions in triglycerides of up to 72%. -- these trigoside reductions resulted in a profound reduction in acute pancreatitis events by up to 91%.

TRYNGOLZA treatment also led to 86% of patients reaching triglyceride levels below 500 mg per deciliter, the threshold that defines SHTG. Up to 54% of patients reaching normal levels below 150 mg per deciliter and favorable safety and tolerability, which resulted were further reinforced by longer-term data from the core and core 2 open-label extension study, which we recently presented at the National Lipid Association Scientific session.

We will share additional data from the OLE at ESC in August. As Kyle mentioned, the TRYNGOLZA label includes acute pancreatitis risk reduction in the indication statement which underscores the importance of preventing these debilitating and potentially fatal attacks and further validate our unprecedented results. With this groundbreaking clinical profile, TRYNGOLZA is poised to redefine the treatment of this underserved disease.

Beyond TRYNGOLZA, we are advancing a number of promising wholly-owned cardiometabolic disease medicines, including IN-775, our next-generation medicine for the treatment of STG. We recently advanced IN775 into a Phase IIb study in patients with SHTG are moderately elevated triglycerides based on positive Phase I data in healthy volunteers with elevated triglycerides.

These results showed the potential for an optimized profile characterized by substantial durable and sustained reductions in APOC3 and triglycerides with the potential for semiannual or less frequent dosing. We look forward to presenting these data on ION775 at ESC next month. And as Brett mentioned, we will also show detailed data from the aplontersen cardiotransform study at ESC.

Turning next to our neurology franchise. We remain on track to bring Zilganerse to patients with Alexander disease later this year, assuming approval. This rare progressive and often fatal leukodystrophy profoundly affects patients and families. And today, there are no approved disease-modifying therapies. Our positive Phase III results marked the first time any therapy demonstrated a disease-modifying impact in these patients.

Our next wholly on Phase III program is open in expense for the treatment of Angelman syndrome. Angelman Syndrome is a neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairment, estimated effect more than 100,000 people globally. We recently announced that enrollment in the Phase III REVEAL study is complete which keeps us on track to report data in the second half of next year, bringing us an important step closer to potentially delivering this medicine to families in need.

We recently advanced our medicine for the treatment of Dravet syndrome, a rare, severe and lifelong neurological disorder into a Phase I/II first-in-human study. We advanced IM337 based on encouraging preclinical data, which we believe positions this program to become a best-in-class treatment for this devastating disease. IO-337 is our first wholly owned medicine that uses our proprietary NMA chemistry, designed to achieve maximal and sustained modulation of SCN1a with a long dosing interval.

Our NMA chemistry is the same breakthrough technology that enables Zilganerse to achieve substantial efficacy and favorable safety with annual dosing in a Phase I study in patients with spinal muscular atrophy. Our partner, Biogen recently advanced Zilganerse on into Phase III development based on these positive results, positioning it to meet the remaining unmet needs of people living with spinal muscular atrophy.

We were also encouraged by the Phase II Celio data, Biogen presented at AAIC for derinersen in early Alzheimer's disease. These results are the first to demonstrate the significant potential of targeting intracellular tile as a treatment for AD. Zilganerse showed significant reductions in CSF to levels, accompanied by a reversal of how pathology as measured by Tapad.

We also saw remarkable effects on cognition as shown by a 34% to 50% slow decline in MMSE versus placebo and a meaningful effect on composite endpoints that include both cognitive and functional domain. Although the Phase II study did not meet the primary endpoint, the totality of these data support Biogen's plan to initiate Phase III development.

We are also pleased with the recent initiation of the Phase III INTREPID study of sapablersen by our partner, Ono. This study is evaluating sapablarsen in people with phlebotomy-dependent policemavera a rare, but potentially lipreading hematologic disease with significant unmet need. Assuming positive data, sapablursen would represent an important value driver from our partner pipeline.

In Bepirovirsen, our medicine for the treatment of chronic hepatitis B partnered with GSK is on track for approval in the U.S. and Japan later this year with multiple additional global approvals anticipated next year. Based on positive data from the Phase IIIb well studies demonstrating unprecedented functional cure rates, Bepirovirsen is positioned to become a first-in-class treatment for chronic hepatitis B, a disease affecting millions of people around the world.

Also in the second half, we expect late-stage readouts from several partner programs, including pelacarsen for Lp(a)-driven cardiovascular disease with Novartis, ulusnersen for FUS-ALS with Otsuka and Sutaxtison for IgA nephropathy with Roche. Overall, the progress we have made across the pipeline this year reinforces both the strength of our R&D engine and our confidence in the next wave of opportunities to reach more and more patients in need and drive future growth.

And with that, I'll turn the call over to Beth.

Thank you, Holly. We delivered strong financial results in the first half of this year, supported by increased revenue from our commercial medicines and meaningful R&D revenue from our partnered programs, while we continued to invest in our long-term growth. Revenues in the second quarter and first half of this year were $268 million and $540 million, respectively, representing significant year-over-year growth of 56% and 69% compared to the same period last year.

Excluding the $280 million onetime payment we received from Ono in the first half of last year for Sapoblursen. Commercial revenue increased to $119 million in the second quarter, and $226 million in the first half, up 15% and 27%, respectively, from the same periods last year. These increases were driven primarily by DAWNZERA product sales. Shinola generated product sales of $5 million and $32 million in the second quarter and first half of this year.

The decrease in revenues in the second quarter followed the April 1 reduction in the TRYNGOLZA WAC price. -- which we implemented strategically ahead of our expansion into the broader SHTG indication. We continue to expect TRYNGOLZA to return to revenue growth in the second half of this year as the SHTG launch gains momentum. DAWNZERA generated $26 million in the second quarter and $42 million in the first half, with second quarter sales increasing by 63% compared to this year's first quarter.

Research and development revenue was $149 million in the second quarter and $288 million year-to-date, reflecting continued progress across our partnered pipeline. Operating expenses increased as expected in the second quarter and first half of this year compared to the same period last year, driven by costs associated with commercializing TRYNGOLZA and DAWNZERA preparations to launch Zigonersen later this year and advancing medicines in our rich pipeline.

We ended the second quarter with $2.1 billion in cash, cash equivalents and short-term investments. enabling us to continue investing in our commercial medicines and wholly owned pipeline.

Looking to the remainder of the year, our strong first half results keep us on track to achieve our full year 2026 financial guidance. We continue to project full year revenue in the range of $875 million to $900 million, with results weighted slightly more towards commercial revenues. We remain on track to achieve our TRYNGOLZA and DANZ product level guidance. This includes full year TRYNGOLZA product sales of $100 million to $110 million with TRYNGOLZA expected to return to revenue growth in the second half of this year as the SHTG launch gains momentum.

And full year DAWNZERA product sales of $110 million to $120 million with continued growth forecasted in the second half of this year. Additionally, we anticipate meaningful R&D revenue from existing collaborations including the potential for additional milestones tied to bepuraversen, palocarsen and other partner programs as they advance.

On the expense side, we continue to expect 2026 operating expenses to increase in the low teens percentage range compared to last year. driven primarily by sales and marketing expenses related to our ongoing and upcoming commercial launches. We project R&D expenses to remain consistent with last year as several of our late-stage studies conclude and we redeploy resources to earlier-stage programs within our wholly owned pipeline.

And as a result of our focus on improving our operating leverage, we expect a non-GAAP operating loss between $425 million and $475 million. This is similar to our 2025 operating loss after adjusting for the onetime Safalorsen license fee we are last year. And finally, we are projecting a 2026 year-end cash balance of greater than $1.6 billion.

With our strong first half financial performance and our outlook for the remainder of this year, we remain on track to achieve our full year 2026 financial guidance and cash flow breakeven in 2028, while continuing to drive substantial growth and longer-term value creation.

With that, I'll turn the call back over to Brett.

Thank you, Beth. Our outlook for the remainder of 2026 and beyond reflects Ionis' strength and the substantial opportunity for continued success that lies ahead. We are executing well on our independent launches for TRYNGOLZA and DAWNZERA and are well prepared for our next launch zilgonersen in Alexander's disease anticipated later this year.

In addition to driving value through commercial success, we also have many important near and midterm catalysts from across our development pipeline, each with the potential to further drive substantial value. We are well positioned to continue executing successfully on our commercial launches and to deliver a steady cadence of breakthrough medicines to patients.

Now before we move to Q&A, I'd like to take a moment to recognize Frank Bennett, our Chief Scientific Officer, whose planned retirement we announced earlier this morning. Frank is one of Ionis' founding scientists and has helped shape Ionis and advance the field of RNA targeted medicines. While his leadership helped create this new sector for human therapeutics, some of the greatest contributions were in the field of neurology, which led to the approval of SPINRAZA for SMA and Kaldi for SOD1 ALS, along with the establishment of a rich pipeline poised to deliver a steady stream of breakthrough treatments for neurological thesis.

On behalf of the entire Ionis team, I want to thank Frank for his many contributions, his dedication to patients and lasting impact he has had on Ionis in the field of organically type therapeutics.

And with that, we'll open the call up for questions.

[Operator Instructions] Our first question will come from Jason Gerberry of Bank of America.

Just wanted to key in a little bit on early adoption of TRYNGOLZA. How much of that is being driven by physicians with overlapping FCS patients that they were treating -- is that sort of the core early prescriber in this initial kind of 6 to 9 months? And where physicians are attempting to write prescriptions. Can you talk a little bit about the average processing time for them to go from an enrollment form to getting a script covered?

Is that through medical exceptions, I assume? So those are my questions.

Thanks, Jason. This is Kyle. Happy to cover off on those. First, I'll say that the FCS launch really was important to the launch now in SHTG. Obviously, that laid the groundwork and the foundation for the readiness to bring the drug forward to a prevalent population. Many of the early prescribers are previous treaters of FCS. They have experience using the drug, and they've had really, really positive results from doing so. But we're also seeing more physicians than just the FCS prescribers starting to use TRYNGOLZA for SHTG.

The other thing that I'll just mention here is the FCS growth in Q2 and the demand continued to accelerate significantly. Having more treaters and more patients on drug, obviously, will help us accelerate the SHTG launch as well. So the short answer to your question is yes. There are treaters of FCS that are also prescribing, but it goes well beyond that.

In terms of process time, it's really too early to discuss those details. We're just a couple of weeks into the launch. What we've seen from payers so far is very encouraging, not only in terms of the Rx to approval time so far, but also just in terms of our conversations that we're having with the payers where they are beginning to assess SHTG and assess to put coverage criteria in place so that there's a clear pathway for approval.

Here early in the launch, the majority of the coverage criteria is going to be through medical exception. That was to be anticipated. And we would expect to see continued coverage improve through the back half of this year and as we start 2027 should look much better.

Next question comes from Elie Merrill of Barclays.

Can you just elaborate a little bit more in terms of what you're seeing in terms of reimbursement? I know you mentioned that you're seeing reimbursement firing, patients with triglycerides over 500. But are you seeing any differences in how payers are treating the coverage of patients with triglycerides over 880 versus those over 500.

And then just a second question. What are your expectations for wage sales in polyneuropathy now after the cardiotransform data given much of the polyneuropathy patients are mixtape.

Yes. Thanks, Ellie. Let me -- I'll start with the Trengolza question. We are seeing coverage to label. The label is very strong here, right, greater than 500, it does not limit patients over 880. It does not limit a history of acute pancreatitis. So the conversations that we've had with payers and what we've seen from the early approvals through the medical exception process, has all reflected the actual indication statement in the label, which is what we expected based on our payer research going into the launch.

So it will take a little bit of work for the HCPs as expected at launch to do these prior authorizations to provide a letter of medical necessity potentially to justify the background therapy that the patient has been on and what their triglyceride levels are, but that's all very consistent with what we expected the policies to represent. So I think things are on track, and we're very encouraged by the early interactions and discussions that we've had with payers.

On the WAINUA side, demand continues to be strong for the hereditary polyneuropathy patient -- the challenge that we are seeing on the WAINUA side is with the mixed phenotype patient where Ambutra has an indication for both polynopathy and cardiomyopat but otherwise, physicians are having very positive experience prescribing and treating these patients, and feedback has been very strong in terms of control of TTR and knockdown, control of polyneuropathy symptoms, payer access and coverage and the ability to self-administer with an auto-injector.

So we expect sales to continue in polyneuropathy and the teams continue to do a nice job.

The next question comes from Gary Nachman of Canaccord Genuity.

So for SHTG, are you finding that most of these patients are already on SMCG lowering or lipid lowering drugs? Are they switching to TRYNGOLZA . -- we're adding TRYNGOLZA on top of their other treatments? And are there any real true naive patients that are being put on drug at this point?

And then -- just what are you hearing from physicians on TRYNGOLZA's profile as the monthly subcu -- and has there been any real concerns with the elevated liver fat holding back prescribing at all? And how are you communicating that.

Yes. Thanks, Gary. So the short answer to the first question is we're seeing a mix of patients. The majority of these patients, obviously, are high-risk SHTG patients. They're above -- the majority of these patients have been on some sort of background therapy, which is very consistent with our core and CORE II trials. I mean, almost 100% of the patients were on some sort of fibroid or omega-3 or statin in the clinical trial and that's consistent with how HCPs are using standard of care today and doing everything they can to try to get triglycerides lowered below 500 and get these patients out of the risk of acute pancreatitis but have just been unable to do so.

So the majority of these patients are on background standard of care therapy, and they are adding TRYNGOLZA to those patients in order to get the benefit of up to 72% risk -- excuse me, reduction in triglycerides and up to a 91% reduction in acute pancreatitis. So -- they're using it very consistent with the way that the clinical trial was designed and the way that HCPs have been treating these patients up to this time.

The profile is coming across very strong. First, I'll just mention the indication statement having AP represented there. It really reflects the outcome of treating high triglycerides and what that means for patients and what that means for HCPs that are trying to treat these patients and get them out of harm's wave acute pancreatitis.

The monthly auto injector is very well received. It's low dose. It's very easy to use. The patients can take it once a month. They don't have to try to figure out, is it month 1 or month 2 or month 3. And we're finding that consistent with the FCS launch, adherence and persistency in patients are starting and staying on and doing very well on the monthly administration with the auto-injector.

And for hepatic fat, I'll turn it over to Brett.

Yes. Thanks, Kyle. And Gary, thanks for the question. So -- we are -- we believe that the evidence that the effects on the liver fat -- small increases in liver that we see is an on-target effect, is very convincing. And prior to us presenting the data at National Lipid Association earlier this year, we didn't even have push back at that time from HCPs on concerns over the small increases in liver fat, especially because there was no association with any clinical sequelae. There were no clinical complications associated with the small increases in liver fat that we saw.

That was further reinforced when we presented the NLA data, the data NLA, which we showed that with continued treatment, the increase in liver fat was returning to baseline. Again, long-term treatment, no association with clinical sequel. So that was just reinforced there. And as we continue to evaluate patients in the long-term, even further long-term open-label extension. Again, we're not seeing any emerging adverse events in the study. So no concerns on the HCP community and that's been further reinforced with long-term data.

The next question comes from Moritz writer of Guggenheim Securities.

This is Marc on for Doucet. I have 2 questions. The first 1 on Cingular, How, if at all, has the recent precaseran data changed your outlook for rings -- and the second 1 on Horizon. What's your confidence in the trial? And should Horizon disappoint how are you thinking about your path to profitability?

Yes. So Marc, thank you for the question. We believe we have -- based on everything we've seen so far, we continue to believe that we have a best-in-class medicine when you look at the totality of the data for the treatment of SHTG. And when you look at the triglyceride lowering, that Holly summarized in her prepared remarks and the and the overall reduction in acute pancreatitis along with safety and tolerability and first-mover advantage.

Also, we have no we have no concerns about competition. We continue to reiterate our peak product sales in the U.S. of being $3 billion plus. So there was no surprises in any data that has emerged since we've launched.

With respect to Horizon, our confidence remains -- continues to be the same high -- we believe that Las cardiovascular risk factor, independent risk factor, the evidence is overwhelming. We have the right drug. The baseline demographics last all manuscript lays it all out on the powering assumptions in that study. and the drug has been well tolerated. And we're looking forward to the results in the -- later this year. And then -- I'm sorry, the third part of the question was.

Should anoint what's the route to profitability?

Yes. So I would say in the in the event that helecarsen Phase III were not to be positive, it would not have an impact on our 2026 financial guidance. it would put some pressure on our ability to achieve our goal of cash flow breakeven in 2028. But I want to emphasize that's a very important goal for us at Ionis -- and we will work very, very hard to achieve that goal.

The next question comes from Mike Os of Morgan Stanley.

Maybe a few just on ION 775. Just curious if you can give us a sense of what data we might expect at the upcoming ESC meeting maybe in terms of end point level of follow-up, et cetera, there? And then maybe just secondly, as we think about time lines for this program, maybe you can share how you're thinking about that in terms of path to market number of clinical studies? And is there ways to sort of shorten that just given your experience with the core programs.

This is Holly. Thank you. The IN 775 data that we'll be sharing at ESC, it's this year-long data, safety as well as our efficacy and activity data on our key biomarkers. So it should be a very interesting data set for everybody to view in terms of where we're at. So we are in the Phase IIB study right now. Of course, we are using all of our previous learnings to accelerate the program as much as we can. We haven't discussed timing externally, but we are absolutely using everything that we've learned from our previous programs and data sets to apply to this program.

Yes. And just to add to that, Mike. So you'll see the long-term data on triglycerides in the mildly elevated triglyceride population and the durability that 775 is offering, as Holly mentioned, in our prepared remarks, this is at least twice a year or even less frequent dosing opportunity. So it's a pure play on convenience.

We don't believe that we can do much better than the efficacy that TRYNGOLZA is already presenting. I mean it's best-in-class efficacy profile. It's really allowing us to get to maybe twice a year once a year dosing. I mean, that's what we're going to focus on. And the data will show APOC3 reductions that support that conclusion, triglyceride reductions that support that conclusion as well as the good tolerability.

And also just to add, the enrollment is going well for -- although it's early innings for the Phase IIb study, it's going well. And our focus is to get that study done selected dose and move to Phase III as quickly as possible, but it's still too early to put time lines on when we can get that done.

The next question comes from Lana Zao of Wells Fargo Securities.

Great. For SHTG, I was wondering, based on the first few weeks of launch, how does that early momentum track with your internal expectation? Especially in relationship to the full year guidance. Apparently, you made that guidance without any first-hand experience of the launch.

So just curious, are you do you think you're ahead of that internal expectation at this point of time or in line? And for cardio transform, I was wondering if there regulatory path for monotherapy? And could any of the data to be presented at ESC inform how you and estrogenic think about any potential range path?

Thanks, Ann. And I'll take the first -- the second question first, and then I'll hand it over to Kyle to talk about how the HCG is tracking with respect to guidance and so on. So we and AstraZeneca continue to review the data from the cardio transform studies, a lot of data. We're preparing to present at ESC. We present -- I'm referring to published. We have several public presentations at ESC, including the cardio transform study, the combination subgroup as well as a meta-analysis study that is being conducted by an independent group of academic physicians.

As far as regulatory path, AstraZeneca is weighing all their options in and they're still going through the data. There's a lot to process there. So -- there's nothing new to report with that. And the data at ESC, I think will support all the conclusions we've made already, which is very clear that in the mogroup that was on monotherapy at baseline, so not tafamidis at baseline.

The efficacy in the composite primary endpoint as well as the secondary end points are in line with the silencer class. There was no benefit in the combination group, and you'll see that data in quite detailed at the ESC meeting. Kyle?

Yes. Thanks, Jan. I'll say internally, we are absolutely meeting the expectations of the launch here, keeping in mind that we're only 4 or 5 weeks into this. So it's very early. The key priorities right out of the gate, obviously, is to get drug into channel. We did that within 1 week, both the 50- and 80-milligram doses were in channel very, very quickly allowing the prescriptions that were coming in early, if approved by the payer to be able to go out directly to patients and get patients on drug very quickly.

So a lot of this is operational at the very beginning. And based on the launches of TRYNGOLZA FCS and on DAWNZERA and HAE, we had a really good experience recently of launching drugs and making sure that we did this expeditiously and effectively. -- and it's exactly what we've done with SHTG. So I'm very pleased with the team's execution there.

The other components, things around training, for example, training to the field teams, approval of materials, deployment of content, those types of things went extremely well. Our omnichannel capabilities are operating exactly as planned. So we've been able to give notice about the approval to tens of thousands of HCPs that see patients with high triglycerides.

So building awareness and making sure that there is an understanding that there's a product now available to treat those patients. Payer engagement and patient services are the other 2 areas that I would highlight, which have both gone very well. So operationally, I'm very pleased with the team, and we're off to a very good start with the launch.

In terms of full year guidance, $100 million to $110 million, we are still confident in that based on the FCS performance that we saw earlier in the year. And based on the early signs and signals that we're seeing combined with the very strong label that we achieved for Tangos on SHTG.

The next question comes from Johan Werber of TD Cowen.

Great congrats on the progress. Maybe, Karl, 2 questions for you, commercially. On SHTG, 1 of the questions we've been getting is, do you think there's going to be sort of an initial pent-up demand or bolus or some clinics or kind of triaging patients to get treated with TRYNGOLZA now that it's approved?

And then secondly, for DAWNZERA, I mean you're seeing very nice kind of quarter-over-quarter growth -- you mentioned, obviously, it's a switch market. What sort of is the main competitor at this point? And how are you -- what are you seeing in terms of demand?

Yes. Thanks for the questions. In terms of pent-up demand, we believe this is going to be a gradual build and a moderate build over time for a couple of reasons. Number one, this is a new mechanism and a new treatment, and it takes some time to educate the HCPs.

Number two, we've got to get those patients into the clinic to see these HCPs. So we've got to drive that awareness and interest to the patient. -- so that they're motivated to get into these clinics and can be treated. And then the third component is the payer access piece that I discussed earlier, right? We've got medical exception process here early on as we're gaining the utilization management criteria with payers.

So it will take a little bit of time for that to build and grow. I expect that to happen through the back half of this year and then 2027 is where we will really see the launch begin to build and pick up. As HCPs gain more experience and more patients begin to come in. And be treated for SHTG.

On the DONZERa side, I couldn't be more pleased with how the team is performing and how we are building the momentum. Q2, we did $26 million in revenue is up 63% over Q1. This is less than 1 year in the market, and we've got a meaningful share of a market that is a switch market. We're seeing switches. We're also seeing patients that are being treated with on-demand only therapies to be started on DUNZER and also naive patients.

But as you would expect, there are multiple therapies in the class, and they have different profiles. And what we know from the switch data is that some patients have an efficacy challenge. Some have a tolerability challenge and some have an experience in duration of treatment issue, right, where they're having to take the drug too frequently. So it depends on which drug it is, but we're seeing switches from all of the prophylactic therapies out there. and HCPs are having very positive experiences prescribing and they're coming back to use the drug more and more, which we're very encouraged by.

The next question comes from Acis Tiwari of Jefferies.

Okay. This is Manoj on for Akash. Just 1 from our end. -- do you expect GTX102 demonstrate a meaningful efficacy trend and upcoming engine went trade out? And how should we think about the potential read-through from that data to expectations? So Iona,.

Can you repeat the question, please? We didn't quite get that.

for the Angelman's upcoming readout for GTX-102, -- how should we think about the rate through from data to your program?

Yes, yes. Yes. This is Holly. I'd be happy to take that. So the Ultragenyx data readout, we're expecting that later this year, that will teach us a couple of things. One of the big things that we're looking for from that is to understand the placebo effect that that patient population will have, that's not something that we know from this. So we are looking to do that.

In terms of the read-through to our program for the Ultragenyx data itself, you have to remember that those are very different molecules. So they're dosing at a much lower dose than we're dosing. So we hope that they have positive effects that are encouraging for the community. However, if they don't, it will likely be because we -- that they're dosing lower than we are for our study.

Yes. And I'll just add to that. Our research organization has done a very nice job benchmarking Obus Anderson with ION-582 with other molecules that are out there that are in development, and we don't see any potency advantages of any other molecule compared to IN582. So we have a highly potent molecule -- and as Holli said, we've been able to dose to the maximum dose that we've set out the dose to drive efficacy as an 80-milligram quarterly dose. So -- so looking forward to emerging data, and we're looking forward to reading out our study next year.

The next question comes from Salveen Richter of Goldman Sachs.

This is Tom on for Salveen and just 2 on Trina -- so in FCS, maybe some more color on the impact from switches from Arrowhead and on the capture of new starts, if you're seeing any -- and on SHTG, maybe if you could lean more into what you're seeing from the primary care side?

Yes. Thanks, Tommy. We've seen no meaningful impact from the competition in Q2 was by far our strongest demand quarter and the highest quarter that we've had for new patient starts. The profile of Trengolza is being very well received by HCP HCPs that are using Tringolza for the first time, are looking to come back to it.

And when they see the triglyceride lowering and the ability to self-administer with the auto-injector the profile is stacking up very, very strong in terms of the way that they need to treat these patients in the way that the patients feel and are doing on treatment once they get initiated. On the primary care side of things, part of the audience of the 20,000 HCPs that we have targeted that are treating these SHTG patients at high risk also are from the PCP audience. So they are seeing these patients.

And I think the predominant prescriptions we're going to get are going to be from cardiology, endocrinology and lipidology -- but I just think it's important to note that PCPs are seeing these patients and they are willing to prescribe and they're interested in trying to treat these patients on their own because they've been trying to do so with standard of care with fibrates, omega-3, statins, et cetera, and just have been unsuccessful up to this point. So we will continue the very broad awareness and disease education. to all specialties that are seeing these patients. And early on, we've got very positive indicators across the board.

The next question comes from Luca Ice of RBC.

Progress Maybe, Kyle, 1 more for you. on the launch of severe hyproducerademia, obviously clear enthusiasm here from the KOL community to prescribe the drug. However, we have heard from a docs that are the barrier is that there's no dedicated ICD-10 code specifically for over a erode -- so doc needs to use codes for related conditions like hyperchylomimia syndrome or maybe hyperglycemia -- and so that can sometimes create some barriers, some confusions to get the drug reimbursed.

Is that consistent with what you've been hearing? And if so, can you talk about how you're planning to address that. And then maybe second for Recolomyopathy, Brett, if I can circle back on the prior question, you mentioned at ESC, you will present this meta-analysis done by an independent group of physicians. Can you maybe just expand a little bit more on that? What's the purpose of that analysis? And how should we think about the implication of that analysis for the broader field?

Yes. Thanks, Luca. On the ICD-10 code side, I'll start by saying that has been on our radar for quite some time, and it's something that we are looking for opportunities to help the community come up with an ICD-10 code that they can use to explicitly reference SHTG. So that work is ongoing with the agencies, and we'll see what we can do in order to help that happen. But in terms of reimbursement, there are other things that they can use to justify the appropriate use of the drug and get reimbursement. First is the labeled indication.

Second is to support that labeled indication with the patient's medical history and reference the drugs that those patients are being treated on as well as the triglyceride levels that the patients still exhibit even though that they're on those medications. So doing a prior authorization, including a letter of medical necessity is pretty standard for a specialty product like this at launch.

And we're working with the different HCPs in order to make sure they understand what's required in order to do that and also supporting them in a compliant way so that they can do that successfully.

And Luke, I'm going to ask Holly to take the question back expanding on the meta analysis.

Yes. So the meta analysis is really focused on the silence or class and understanding the totality of data within that class, including our new cardio transform data and comparing them both as monotherapies as well as on top of the stabilizers.

That's the main presentation. It's going to be comparing those 2 studies and as single agents as well as combination.

The next question will come from Jessica of JPMorgan.

I was curious about ION 337 for Dravet. Can you help us think about when we might see the Part 1 data from the Phase II -- and just given the long lead time for zurivinersen, how might 337 differentiate.

Yes, I'm happy to take that one. So for 337, we just started dosing. So it's too early to talk about time lines, but we are -- there's a lot of enthusiasm from the community, the KOL no Ionis and NOR technology. and are -- we're excited to get that moving quickly as is the community.

In terms of differentiation, because we're using our new NMA technology, -- it's more potent than the Mo chemistry, our previous chemistry that we use for Spice modulation, you get increased potency and then allows you to spread out your dosing interval and increase your efficacy.

Thanks, Jess. I think we have time for 1 more question.

Our last question comes from Eric Joseph of Citi.

Just thinking about the upcoming core OLE data at ESC, -- maybe just a little bit of expectation setting there. What incremental endpoints in addition to the NLA presentation are interest? Or would you have a focus on there? To what extent, I guess, is an ongoing AP of that rate, something that you're tracking in the OLE portion?

And then just perhaps a clarifying question on the strategy with 775. Is the goal here predominantly to be a convenience play over Tingo in SHTG -- or is there an expansion opportunity in moderate HTG that you think is worth pursuing? And if so, what would TPP look like there?

Yes. Thanks, Eric. I'll ask Ali to talk a little bit about what we're planning to present at ESC on the long-term data on core and core 2, I'll take 775. So the goal is primarily -- we're primarily focused right now on severe hypertriglyceridemia. 775 as a follow-on molecule for this indication, and it is primarily a convenience play I think I mentioned earlier that the efficacy and tolerability safety profile of Trinco and SHTG is difficult to beat.

So we'll strive to do that, but it's really a convenience play that we think that we can dose this drug twice a year, maybe once per year based on our Phase I data. And that Phase I data will be presented at ESC and I think it will be clear how durable 75-inch.

We'll always consider other indications, but primarily -- and we haven't laid out -- we have not established our Phase III plan. Yes, we're still working through that and the speed we need more Phase II data before we can really make those decisions. But it's really primarily focused on this HTG. And Holly, what can we expect on the long-term data for CO2 ESC.

This is looking at 1 year into the OLE. So of course, we'll be looking at triglyceride levels as well as full safety data and all of the key biomarkers looking at remit cholesterol, APOC3, on HDL, all of those various markers.

Yes. It's very exciting long-term data. on the durability of efficacy as well as lack of any emerging adverse events or anything. on the safety side. So thanks for the question, Eric. Thank you, everybody, for joining us today for participating in our call. We really are looking forward to an exciting second half of the year for Ionis, and we look forward to sharing our progress along the way. Until then, thanks, everybody, and have a great day.

The conference has now concluded. Thank you for attending today's presentation, and you may now disconnect.

Good afternoon, and welcome to Ionis' conference call to discuss the FDA approval of TRYNGOLZA for sHTG. As a reminder, note that this conference call is being recorded.

At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Wade, please begin.

Thank you, Sylvie, and thank you to everyone who has joined us today as we discuss the FDA approval of TRYNGOLZA for sHTG, which is now approved in the U.S. to reduce triglycerides and the risk of acute pancreatitis in adults with severe hypertriglyceridemia. Please be sure to visit the Investors section of the Ionis website to see the press release and Ionis issued -- press release that Ionis issued earlier today, along with the slides accompanying today's webcast.

Before we begin, I would like to remind you that our discussion today will contain forward-looking statements based on our current expectations and beliefs. Such statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail.

With me on the call today are Brett Monia, Chief Executive Officer; Sam Tsimikas, SVP, Global Cardiovascular Development; and Kyle Jenne, Chief Global Product Strategy Officer.

For our agenda today, Brett will provide opening remarks. Sam will provide a brief review of the data that supported the approval and label of TRYNGOLZA. Kyle will review our strategy to achieve launch success with TRYNGOLZA now that it's approved for the larger sHTG indication. And after Brett's brief conclusion, we will open the call for your questions regarding TRYNGOLZA.

And with that, I'll turn the call over to Brett.

Thanks, Wade, and thanks to everybody for joining us today. I'm thrilled to share that TRYNGOLZA is now approved as the first and only therapy indicated to reduce triglycerides and the risk of acute pancreatitis in adults with severe hypertriglyceridemia. TRYNGOLZA's approval is a landmark milestone establishing it as the first-ever medicine approved to prevent acute pancreatitis for people living with sHTG.

This approval is also a transformational achievement for Ionis. It not only demonstrates our continued leadership in translating groundbreaking science into the delivery of breakthrough medicines, but also further demonstrates our commitment in establishing Ionis as a leading fully integrated commercial stage biopharmaceutical company. The approval of TRYNGOLZA for sHTG was supported by the unprecedented Phase III results we reported last year in which TRYNGOLZA demonstrated rapid, substantial, durable and clinically meaningful reductions in triglycerides of up to 72% on top of standard of care.

These reductions in triglycerides resulted in the reduction of acute pancreatitis events by up to 91%, making TRYNGOLZA the first and only treatment to achieve this outcome in sHTG. Importantly, 86% of treated patients reduced their mean triglyceride levels below 500 milligrams per deciliter, the threshold that defines sHTG, and up to 54% of patients achieved normal triglyceride levels.

These groundbreaking results, together with our substantial first-mover advantage, position TRYNGOLZA to fundamentally change the treatment paradigm for people with sHTG and become the new standard of care in the management of this disease. Notably, the TRYNGOLZA label includes acute pancreatitis risk reduction in the indication statement, which underscores the importance of preventing these debilitating and potentially fatal attacks and further validates the unprecedented results from our clinical trials.

We received approval for both the 50-milligram and 80-milligram doses administered once monthly, providing physicians with dosing flexibility to tailor treatment based on individual patient needs and treatment goals. This flexibility will resonate well with physicians who manage sHTG patients based on our extensive HCP research.

With the label now in hand, we are reaffirming our full year 2026 guidance of $100 million to $110 million and our peak sales guidance for TRYNGOLZA of greater than $3 billion, positioning TRYNGOLZA to become our first Ionis wholly-owned multibillion-dollar medicine.

Before I turn the call over to Sam, I want to extend my sincere thanks to the patients, families, clinical investigators, advocacy groups and research partners who made this approval possible, especially those who participated in our clinical trials. I also want to recognize the Ionis team whose dedication to patients and commitment to groundbreaking science in the TRYNGOLZA program were essential in achieving today's positive outcome.

And with that, I'll turn the call over to Sam.

Thank you, Brett. Like Brett, I'm very excited with today's approval and what it means for people living with severe hypertriglyceridemia. Severe hypertriglyceridemia, or sHTG, is characterized by markedly elevated triglyceride levels above 500 milligrams per deciliter. These patients are not able to get their triglyceride levels below 500 milligrams per deciliter, which defines the risk threshold for acute pancreatitis despite lifetime modifications and treatment with standard lipid-lowering therapies.

Very high triglyceride levels are a well-recognized cause of acute pancreatitis, a serious and potentially life-threatening condition associated with hospitalization that often need intensive care admission as well as long-term complications that include repeat pancreatitis events and the destruction of pancreatic function.

Traditional triglyceride-lowering treatments such as fibrates and omega-3 fatty acids offer only modest effectiveness and frequently fail to reduce triglycerides to below the threshold for pancreatitis risk. Moreover, none have demonstrated benefit in reducing acute pancreatitis events.

sHTG is estimated to affect more than 3 million people in the U.S., and many of these people have a history of pancreatitis or are at high risk for a first event and often have additional comorbidities such as diabetes or cardiovascular disease. Until TRYNGOLZA's approval, patients and physicians were lack of therapy that could reliably lower triglycerides below the pancreatitis risk threshold. With TRYNGOLZA now approved, we believe that treatment gap is being addressed.

sHTG is driven in large part by dysregulated triglyceride-rich lipoprotein metabolism. Apolipoprotein C-III, or apoC-III, is a key regulator of the system. Elevated apoC-III inhibits lipoprotein lipase, the enzyme that breaks down triglyceride-rich particles, and it also blocks the clearance of these particles from the circulation. We designed TRYNGOLZA to selectively reduce apoC-III production in the liver by targeting apoC-III messenger RNA. We were the first to demonstrate that lowering apoC-III results in substantial reductions in triglycerides and acute pancreatitis events in patients living with severely elevated triglycerides.

Importantly, TRYNGOLZA was also highly effective on top of existing standard of care therapies, such as statins, fibrates and omega-3 fatty acid, adding a distinct and powerful new mechanism for lowering triglycerides. The sHTG approval was based primarily on positive results from the Phase III CORE and CORE2 studies, which evaluated TRYNGOLZA in adults with severe hypertriglyceridemia on stable background therapy in the largest pivotal program ever conducted in this patient population.

Pivotal CORE and CORE2 studies demonstrated substantial and sustained reductions in triglyceride levels of up to 72% compared to placebo at 6 months with sustained reductions at 12 months. Furthermore, 86% of patients treating with TRYNGOLZA achieved triglyceride levels below 500 milligrams per deciliter, a threshold for acute pancreatitis. Notably, up to 54% of patients in this study also achieved normal triglyceride levels.

We saw a remarkable reduction in the rate of pancreatitis events of up to 91% after only 12 months of treatment. In the overall pooled analysis from CORE and CORE2, treating just 20 patients with TRYNGOLZA for 1 year is estimated to prevent 1 potentially fatal pancreatitis attack. In the highest risk group, those with triglycerides above 880 milligrams per deciliter and a history of acute pancreatitis, the number needed to treat to prevent 1 potentially fatal acute pancreatitis attack is only 4 patients after just 12 months of treatment.

Being a number to treat ranging from 4 to 20 or potentially life-threatening about like pancreatitis and achieved in just 1 year is very compelling to physicians, which we believe will provide a sense of urgency to treat patients with TRYNGOLZA. For context, statins used in primary prevention of cardiovascular disease have a number needed to treat in the range of 50 to 100, meaning 50 to 100 patients need to be treated for more than 5 years to prevent 1 cardiovascular event.

TRYNGOLZA demonstrated an overall favorable safety profile in the Phase III studies with adverse events balanced across treatment arms. The most common adverse events were generally mild to moderate and manageable. The most common treatment-emergent events were injection site reactions, which were mostly mild and typically transient. At the 50-milligram dose, there were no imbalances in liver enzyme elevations. Asymptomatic liver enzyme elevations of greater than or equal to 3x the upper limit of normal were observed in 7% of participants treated with the 80-milligram dose versus 2% treated with placebo. These events were not associated with clinical complications, generally resolved with continued treatment and no cases met Hy's Law criteria.

These unprecedented data from the TRYNGOLZA development program, beginning with FCS and now the broader severe hypertriglyceridemia population have also been presented in major cardiology and lipidology congresses and published in leading peer-reviewed medical journals. The level of external validation underscore the scientific rigor and clinical importance of targeting apoC-III in triglyceride-rich disorders. For patients and physicians who have struggled to control severe triglycerides with existing therapies, we believe TRYNGOLZA set a new standard for the management of sHTG.

I'll now turn the call over to Kyle.

Thank you, Sam. The approval of TRYNGOLZA for sHTG is a defining moment in our journey to bring a much needed new medicine to this long underserved patient population. Our team is energized and focused on delivering a successful launch and capitalizing on our first-mover advantage. We have a highly experienced field organization with deep backgrounds in lipidology and cardiometabolic diseases. They have been preparing for this approval over the past several months by providing disease state education to the highest sHTG treaters. In parallel, they have been strengthening patient identification efforts and laying the foundation for a seamless expansion from FCS into sHTG.

We expect the product to be available in the channel in the coming days, and our teams are ready to begin promoting TRYNGOLZA for sHTG. The U.S. market is both sizable and underserved with no effective treatments available until now. As represented by the pyramid shown on this slide, there are estimated to be more than 3 million people with sHTG in the U.S. Triglyceride management is concentrated among cardiologists, endocrinologists and lipidologists, which allows us to reach hundreds of thousands of eligible patients with a focused commercial footprint.

Our customer-facing team plans to initially focus on the high-risk patient population, which includes patients with triglycerides of greater than 880 milligrams per deciliter or with triglycerides of greater than 500 milligrams per deciliter and a history of acute pancreatitis or other comorbidities. With our commercial footprint, we are positioned to engage approximately 20,000 high-volume prescribers across the country. As we did for FCS, we also plan to leverage Ionis' omnichannel marketing capabilities to further reach both physicians and patients with tailored educational content and support.

Despite widespread use of statins, fibrates and omega-3s, many patients do not reach triglyceride targets and remain at high risk for pancreatitis. This treatment gap is well recognized by physicians and payers. Consistent with the label, TRYNGOLZA's compelling clinical profile and differentiated mechanism position it to play an important role alongside existing therapies to reduce the risk of acute pancreatitis.

Until today, physicians have not had an effective therapy for severe hypertriglyceridemia. TRYNGOLZA changes that. It has demonstrated robust triglyceride lowering, statistically significant reduction in acute pancreatitis events, a compelling number needed to treat to prevent acute pancreatitis. We are pleased to offer both the 50-milligram and 80-milligram doses of TRYNGOLZA for sHTG packaged in a patient-friendly auto-injector designed for real-world use. This provides important flexibility for health care providers and patients and supports a tailored approach to treatment based on individual patient needs and treatment goals.

Taken together, we believe TRYNGOLZA is a breakthrough for patients who are struggling with their disease and a meaningful advancement for physicians managing this high-risk population. Our launch strategy is designed for success and builds on our expanding commercial capabilities with 2 successful launches under our belt, including the launch of TRYNGOLZA in FCS. A key component of this strategy is our medical affairs effort with the team actively participating in major cardiology, endocrinology and lipid meetings to share data from CORE, CORE2 and related studies while also helping educate the market on apoC-III biology and the burden of sHTG.

On the market access front, our reimbursement and payer teams have proactively engaged with U.S. payers. With the updated WACC price of $40,000 effective April 1, we are launching TRYNGOLZA and sHTG at a price that reflects its substantial clinical value and the high burden of disease while recognizing the need for broad responsible access. We are committed to ensuring affordability for patients who need TRYNGOLZA. For eligible commercially insured patients, our financial assistance programs can significantly reduce out-of-pocket costs, in some cases, to as little as $0 per prescription.

Supporting patients throughout their treatment journey is central to our commercial approach. Ionis Every Step, our patient support program, will now be expanded to support the needs of sHTG patients and caregivers throughout their treatment journey. The program is designed to provide disease state and product education, meaningful caregiver support and reimbursement assistance that helps facilitate access and continuity of care. For health care providers, Ionis Every Step is intended to simplify the process of initiating therapy for appropriate patients while keeping the emphasis where it belongs on helping patients better understand their disease, navigate treatment options and access the support they need.

Before I turn the call back to Brett, I want to underscore our excitement about this approval and the opportunity it creates to meaningfully improve outcomes for people living with severe hypertriglyceridemia. While we recognize that building awareness and changing treatment paradigms by integrating a new therapy into clinical practice will take time, we are highly encouraged by the HCP feedback and the opportunity to address the significant unmet need in sHTG.

TRYNGOLZA's strong clinical profile and compelling label, including the significance of acute pancreatitis prevention in the indication statement, together with an experienced commercial organization that is launch-ready, position us to seamlessly execute. Most importantly, this helps us close an important gap in care for appropriate patients. More broadly, we believe this launch creates an important opportunity to expand the impact of TRYNGOLZA by bringing meaningful innovation to a larger population of patients with serious unmet need.

With that, I'll turn the call back over to Brett.

Thanks, Kyle. Today marks a pivotal moment for Ionis. With today's approval, we are poised to reach hundreds of thousands of people living with sHTG, and in turn, make TRYNGOLZA our first potential blockbuster medicine. Today's milestone underscores how we are delivering on our promise to bring a steady cadence of transformational medicines to people living with serious diseases.

In just the last 18 months, we have successfully launched TRYNGOLZA for FCS, our first independently launched commercial medicine. We have also successfully launched DAWNZERA in hereditary angioedema, which is gaining significant momentum. And now, we're expanding TRYNGOLZA into sHTG, our first independent launch into a broad population. We also look forward to our anticipated approval of Zilganersen for Alexander disease with a PDUFA date in September and advancing our rich, wholly-owned pipeline of potential best-in-class medicines focused primarily on cardiometabolic and neurological diseases.

The approval of TRYNGOLZA in sHTG underscores the strength of Ionis today. With 2 independent launches underway, TRYNGOLZA in sHTG expected to launch in the coming days and with more anticipated approvals and launches to come, we are well-positioned to deliver increasing value for patients and all Ionis stakeholders.

And with that, I'll now open the call up for questions. Given the importance of today's news, we will keep the Q&A session focused entirely on TRYNGOLZA.

Now, operator, please open up for questions.

[Operator Instructions] And your first question will be from Yaron Werber at TD Cowen.

This is Steven Ionov on for Yaron Werber. Congratulations on this landmark approval. One question from us. Could you give us some more color on where the conversations with payers currently stand on coverage? And specifically, are you expecting payers to try to narrow coverage to patients with an AP, acute pancreatitis, history? Or have you seen positive feedback on a more broad label across the board?

Thanks for the question, Steven. This is Kyle. I couldn't be more pleased with the interactions that we've had with payers up to this point. We've been able to share with them, obviously, information related to the CORE and CORE2 studies. They've also seen HCP demand research on where HCPs anticipate using this treatment. And the expectation is that the coverage will be broad and that anyone with triglyceride levels above 500 will have access to TRYNGOLZA.

We're working on payer discussions currently, as you would expect, to getting the approval today. We'll need to go with the final label and have ongoing discussions with them. But all of our conversations have been for the broad population being greater than 500. That also represents the pricing that we set on April 1 at $40,000 for the WACC. That price point is intended to cover all patients and not limit it or restrict it to a high-risk sHTG patient population. That's exactly where HCPs are telling us that they want to treat and use this product based on the strength of the data.

The 72% reductions in triglycerides, the 91% reduction in AP events and the ability to use this on top of standard of care today really make this a meaningful treatment to potentially change and advance the way that medicine is treated for these patients that haven't had a treatment up to this time. So broad payer access is what we expect, and those are the ongoing conversations we continue to have.

Next question will be from Yanan Zhu at Wells Fargo.

Congrats on the early approval and the great label. So maybe 2 questions from us. One is in terms of -- on the front page, the only warnings mentioned was the liver enzyme abnormalities. I think you went over it in the prepared remarks as well. I was wondering how do we think about any implication of this item in terms of the launch? Does this mean certain monitoring requirements?

And then, another observation, you mentioned 91% risk reduction for the pancreatitis attacks, that actually -- it came from the 50 mg group. So it seems like you had even a better pancreatitis reduction at the lower dose than the 80 mg higher dose. How does that impact your launch activity or promotion activity? I would note that at that dose, the safety is overall even better than 80 mg, including liver fat.

Thanks, Yanan. I'll start, and then, I'll pass over to Sam. I'd love for him to give his perspective on the recommendation to consider testing for liver enzymes prior to treating -- beginning treatment with TRYNGOLZA or escalating dose because it's very common practice in the business. But let me start with your second question first. So the 91% reduction in acute pancreatitis was called out by the FDA, the AP reductions of 91% for the 50-milligram dose, as you pointed out, Yanan, we were thrilled with the 85% reduction in the pooled analysis, of course, an AP reduction unprecedented. The 91% in the 50-milligram dose, we just want to be consistent with the label, which reflects up to 91% in there.

As for the reasons between 80 and 50 showing slightly different reductions in acute pancreatitis on a percentage basis, we don't have an explanation for that. It's remarkable data for both doses, and we do not believe that that's going to impact in any way the preference for 50 or 80 milligrams in the launch in the marketing commercialization of TRYNGOLZA for sHTG in any way. I do want to point out that the 80-milligram dose is very well tolerated. And as we highlighted in our prepared remarks, it provides dosing flexibility for physicians, which is common practice and also preference so that patients can -- or physicians can use the dose that they believe is going to provide the greatest benefit depending on the patient's needs.

Regarding the second part of your question, no monitoring. There's no monitoring in this label required for anything, let alone liver enzymes. But I'd like to send it over to Sam to provide his perspective on how this is so consistent with available treatments today for cardiovascular diseases.

Yes. I think what the label is basically saying is you just need to make sure you're a good doctor, right? If you give a chronic therapy, you need to know their baseline values of their labs, including the liver test. And if you want to change the dose, then you just check it again. So it just tells you why you should check it once before you start and if you want to change the dose, that's it, and you don't need to worry in between about checking regular labs all the time. So this is consistent with good medical care and nothing out of the ordinary in terms of checking LFTs.

And Yanan, maybe I can address a little bit on the launch implications here because all of them are favorable, everything that we're discussing here. To have AP in the indication statement, number one, is going to strengthen the position and strengthen the understanding by HCPs in terms of how and why to use this treatment for sHTG patients, any patient that's above 500. So that strengthens the argument there.

Number two, the 50- and 80-milligram doses allow for dosing flexibility, which is exactly what HCPs are telling us that they want and that they will use in this patient population. Therefore, again, strengthening the launch implications. No monitoring required strengthens the launch implications. So for us, everything is pointed towards very strong favorability in terms of what this label looks like and it represents.

Next question will be from Salveen Richter at Goldman Sachs.

With regard to liver monitoring, could you just speak to how it's done in practice, how much of an extra lift this is and whether you think doctors will actually do that? And then, just noting the label's language around liver fat, what feedback have you been getting from stakeholders on the open-label extension data? And why do you believe the 50-milligram to 80-milligram transition patients saw that kind of elevation or did not see the decreases in their HFF elevations within the follow-up?

So Salveen, as we addressed in the last question, there's no monitoring required at all for anything -- liver enzymes or anything for TRYNGOLZA. It's a very clean label. As Sam pointed out, it's common practice by physicians when they move a patient onto a new treatment for the first time to do some -- to recommend some initial testing of liver enzymes or you don't have to continue testing in any way. And prior to a dose escalation, it's recommended, not required to consider testing again before you dose escalate. Again, no monitoring, no monitoring at all in the label for TRYNGOLZA.

As far as hepatic fat fraction, as we presented at NLA last week and as predicted, the on-target small increases in liver fat that we observed in our Phase III sHTG studies are returning to baseline as we presented at NLA last week. Again, there's no clinical sequelae, no emerging AEs with long-term treatment, no -- obviously, no monitoring, as I covered. And this profile that includes the small increases of what appeared to be transient increases in liver fat are completely consistent with our $3 billion product sales -- peak sales that we've guided to. Maybe you can talk a little bit about that, Kyle, on how all this is contained within our -- with our expectation for peak product sales.

Yes, that's exactly right. I mean, we have tested after the CORE and CORE2 data came out, the exact profile from the Phase III trial, these data with HCPs. They are very supportive. They are -- they do not have concerns around hepatic fat, for example, or needing to consider testing for something like liver enzymes.

The strength of the data here, the need in the patient population, how clean overall this profile is and how strong the data are, HCPs and the demand research are very supportive of using this drug. We did the same presentation to payers, similar response, payers understand it and payers are very accepting of this. I think we are set up for tremendous success based on the label that we received today.

And Sam, maybe you want to comment on how it's common practice to have when you have 2 doses approved starting with a 50-milligram dose or the lower dose before you go to dose escalate.

Sure. Yes, we're used to using different doses for lipid-lowering therapy. So this is going to be completely consistent in practice how we use statins, right? So it's going to be very similar, almost identical to it. Before you start a statin, you need to know what the lipid levels are and what the labs are. And then, after you give it, you want to see what effect it has. So you'll check labs again, and you'll check the liver test and you'll check the lipid panel. That's basically what's going to happen here. I think clinicians will be very used to doing exactly what they do now with statin. There's not going to be any other extra burden on anybody.

Next question will be from Michael at Morgan Stanley.

Congrats on the approval as well. Maybe just a quick one around pricing, and it has to do with the addition of the 50-milligram dose in addition to the current 80-milligram dose. Just to clarify, is it going to be flat pricing across both those doses?

Yes. Thanks for the question, Mike. It will be flat pricing. So from a payer standpoint, again, all of the testing that we've done and the conversations that we've had with them around utilization management criteria, WACC pricing, et cetera, they've been very supportive of that. And I think flat pricing, 50 and 80 just helps us even more with payers and streamline access ultimately for HCPs to prescribe and patients to receive an appropriate medication.

Next question will be from Jessica Fye at JPMorgan.

This is [ Sylvia ] on for Jeff Fye. Two questions from me. First, can you talk about how the label compares to your expectations?

And my second question is, can you remind us of how you think about the size of the subgroups in the high-risk sHTG population, so those with AP history and NG without as well as any differences to how you may approach these subgroups commercially?

Yes. Kyle will address the -- how we're planning to address the various subsegments of the sHTG population commercially. With respect to label expectations, we were hopeful to have acute pancreatitis in the label based on the compelling data that we generated from our Phase III CORE and CORE2 studies. It is highly unusual to include an outcome like acute pancreatitis in the indication state when it's not a primary endpoint in the trial. It was a key secondary endpoint in our trial, but we were hopeful, and we achieved it. And that really reflects the compelling and importance of the data that we generate showing that or potentially significantly we can prevent potentially fatal acute pancreatitis attacks in sHTG patients for the first time ever for any medicine. So I think the FDA got it, and they recognized the importance of this, and they wanted it in the label because it's to the benefit of patients. And so physicians get their attention and they prescribe.

Talk a little bit about segments in the population.

Sure. Yes. The overall population, as we have been discussing, is greater than 3 million patients. The high-risk sHTG population has approximately 50,000 patients that are over 500 with a history of AP. There are approximately 550,000 patients that are over 880, and there are several hundred thousand -- 400,000-plus patients that are over 500 with comorbidities, such as ASCVD or type 2 diabetes that could potentially be well controlled, but still be above 500 with their triglyceride levels and be at high risk for acute pancreatitis. So out of the gates, that's where the focus will be. Obviously, the highest risk patients and the urgency to treat those patients.

HCPs are largely aware of who these patients are. They're trying to treat them today with omega-3s and fibrates and other triglyceride-lowering agents that just are suboptimal and not effective enough to get the patients out of harm's way. And we know from the core studies that by adding TRYNGOLZA on to those patients that you can have up to 72% reductions in addition to that in their triglyceride levels. So this fits in very nicely with a number of patients that the HCPs are seeing and treating today and need a better therapy to address them. And we believe that TRYNGOLZA is going to be that therapy to be able to step in and help them. And it's very nice to have a first-mover advantage here as well, where we're going to be able to have access to this very broad prevalent patient population with no competitor directly working against us at this point.

Next question will be from Jason Gerberry at Bank of America.

Kyle, curious, what do you think are the most important distinctions relative to the Vascepa launch in sHTG? Why couldn't TRYNGOLZA sort of have a similar sort of patient level demand in the first few quarters? Has it just come down to a simple oral versus injectable barrier to entry? Do you think it's payer related? I'm just kind of curious if you can offer some perspective there.

And then secondly, it appears like some health care providers who are intimately familiar with CORE talk about having an early bolus of patients. But these could just be a small subset perhaps of early adopters. And so I guess -- I know you guys have been asked this question before, but what would be your expectation for the proportion of doctors that have an early bolus of patients? And is really the challenge there just pulling those patients through under medical exceptions in the first few quarters?

Yes. Thanks, Jason. So a couple of things on this launch. We believe with TRYNGOLZA, this is -- I'm describing it as a moderate launch at this point. That is based on -- this is a new therapy, new class of therapy. We're going to a very broad number of HCPs, greater than 20,000 HCPs. So educating those HCPs on the label, the product, where to use, why to use, et cetera, will take a little bit of time.

Number two, these are patients that typically see their HCP 1 to 2 times per year. So they're not just coming in on a monthly basis to see their HCP. So there are a little bit of that dynamic in terms of getting these patients in to be, again, assessed and diagnosed and then receive their prescription.

And then the third thing that you mentioned is part of this as well, which is the payer dynamic. We know out of the gate based on the fact that this is a new indication for a product that payers will need to go through the P&T process and make decisions around the coverage criteria for these patients. So it will take a little bit of time for us to navigate that, and there will be medical exceptions that will be in place for a period of time. However, the work that we've done leading up to this, we believe, is going to help us streamline that process, but we still have to fit that into the process that each individual payer takes as it relates to assessing a new indication for a product. So those are the dynamics there. We're very encouraged. We'll learn more in the second half of this year. And I think 2027, you'll see obviously, acceleration as we get into the new year and more experience comes from using the product.

In terms of the bolus of patients, we're working through that right now. We know from the data where -- which HCPs are using high volumes of omega-3s and fibrates today. That kind of puts you in the general vicinity of who's treating patients with high triglycerides to begin with. But then you've got to get in there, again, and educate on the product and then talk to them about that patient population to see who is potentially still eligible to take the drug and still above 500, for example. So we are doing that currently, and the launch team is ready to execute against that now that we have the approval, and we can speak directly to the label, and we can compliantly sell for sHTG in the broad patient population. So I think a lot more to learn here over the next couple of months, but I am super excited about the label, and I know the sales team is ready to get out there and help as many patients as possible.

And I'll just add very quickly, Jason. We don't believe Vascepa is a good analog for TRYNGOLZA in any way. I mean, there's differences in administration, as you mentioned, the efficacy that we have reported that's in our label now on TG reductions and AP reductions is unprecedented. It's never been shown for that medicine. So we don't -- we just don't think it's a good analog for several different reasons.

Next question will be from Jasmine Fels at Barclays.

This is Jasmine on for Ellie Merle from Barclays. Congratulations. So first, what kind of launch metrics should we expect you to give in the initial quarters of the launch?

And then second, do you have a plan to give free drug to patients who are working to secure access but haven't yet?

Yes. Great question, Jasmine. Thank you for that. So for launch metrics, I think the most important one is going to be -- is quarterly revenues. We will share how the product is performing on a quarterly basis and what the revenues look like during our earnings calls. We will give some color probably around HCP specialties, who is prescribing and what that mix looks like, payer dynamics and how coverage is coming along, et cetera. I don't anticipate, consistent with the FCS and our HAE launch, going far beyond that in terms of how many HCPs are prescribing or how many patients are receiving prescriptions yet. It is a competitive space. And I think some of those metrics we'll probably keep in-house for our own knowledge and make decisions around that.

In terms of free product, we will offer the typical programs that you would expect for this type of treatment. So there will be a quick start program, and patients who are navigating the reimbursement process, there will be drug available for them while they're working through the prior authorizations that might be required in order to get patients started on treatment.

Next question will be from Gary Nachman at Canaccord Genuity.

My congrats as well on the early approval. With this first approval in severe high trigs, how soon can the guidelines be updated for this indication? And how much will that help you in this market, both with physicians and payers? Is that even needed here? And just remind us where you are in terms of the full sales force that's in place for the launch, the size and experience? And any more hirings that need to occur, especially given the broad label?

Thank you, Gary. Sam, what do you think about guidelines?

Yes. So guidelines, there are a lot of different guidelines, ACC/AHA, Canadian, European. So it depends on the timing when that group is meeting. So we anticipate whenever a new guideline comes out, this has to be on there. I mean, this is unprecedented data. And so I'm sure it's going to be a Class I indication as best as I can tell based on the label and the data that we got. But it will depend on the geographic flow in terms of which guidelines. So just recently, we did have the ACC/AHA guidelines just get updated, olezarsen to get a recommendation for FCS -- sorry, yes, TRYNGOLZA. So that one may be a little bit delayed when they do the next one. But sometimes they also have to give updates. When something really cool happens, they need to be able to keep up with the times. So we'll see. We anticipate this going in all the guidelines eventually, though, when they get updated.

Before handing over to you, Kyle, I do want to highlight something that you said, Sam. TRYNGOLZA is the only approved, recommended medicine in the guidelines for FCS today. That's a huge step forward for TRYNGOLZA, and we're hopeful that we're going to get a similar -- that will also be reflected for sHTG as quickly as possible.

Impact tailwinds for the launch and then on sales force?

Yes. And let me just add to what Sam said for a second. There are guidelines in place today that reflect the 500 milligram per deciliter threshold for acute pancreatitis. And we've been using those already, both cardiology and endocrinology have those guidelines. So in terms of being able to help us with HCPs and payers, I think we have very strong evidence today and very strong supporting guidelines to be able to do what we need to, to communicate the message and the story and the value that this treatment offers. And there's also a very strong understanding from HCPs of that 500 milligram per deciliter threshold, right?

If they've seen a patient that has had an AP event, they never want to see that patient have another event, and they also never want to see any of their patients above 500 have their first event. And these guidelines help that, but also the evidence and the experience of these HCPs is helping drive that understanding.

The field force size today, we did an expansion at the very beginning of this year. There are approximately 200 customer-facing field team members in place right now. That is a specialty-sized launch field force. It's exactly where we need to be to reach the audience of the highest treaters of sHTG being the endocrinologists, cardiologists and lipidologists. So right now, I think we've got the right size, the right team and the right strategy in place in order to go forward with the launch.

Next question will be from Luca Issi at RBC Capital Markets.

This is [ Cathy ] for Luca and adding our congrats on an extremely strong label. A quick follow-up on the 50 mg dose seeing 91% acute pancreatitis event reduction. Did you maybe also see more patients in the 50 mg cohort to have trig normalized?

And then separately, Kyle, in the same spirit of prior questions asked on the launch and the bolus demand, but looking more longer term, how should we draw our launch curve to look like? What you would anticipate to reach the 1 million versus 3 million patient segment? And specifically, what are some potential scenarios where you would see competition to be more intense than you expect in a year or so?

Sam, anything in the baseline demographics that could explain a slightly better AP rate in 50 milligram versus 80 milligram?

We look -- there's nothing really that we can explain this. This is, of course, pool data from both trials. There were some differences in the trials in terms of slightly different triglyceride levels, geographic location. But the drug was -- both doses were highly effective. So we're talking about differences, but in the very high range, right, in the mid-80s is on average. So no, I can't say that we found anything obvious. It could be just a play of chance. So there's nothing I think that can explain it right now that we found.

Yes. And let me talk a little bit about the patient populations. Obviously, I mentioned starting with the 1 million or so high-risk sHTG patients, which, by the way, is a very large patient population that's very underserved that has tremendous need for a treatment like this. That will give us runway for a couple of years in terms of being able to penetrate and work within that existing 1 million patient population or so.

To go from 1 million to 3 million, you start getting into patients that are largely in the 500 to 880 range. A lot of those patients are treated in a different care setting, either internal medicine or primary care. So that will take a little bit more work to educate and bring forward a novel therapy like this and educate that audience in terms of why to treat and how to treat that patient population. We'll be able to do that in parallel, as we're launching into this 1 million patient population.

I made reference to our omnichannel marketing capabilities, for example, we can do things that are very efficient and very targeted to help address some of that education and drive disease state awareness to the broader HCP treating community. So we will obviously do that.

And you mentioned competition as well. We know what's coming up behind us. And I think having more than one share of voice in this space is not a bad thing. When we're going to conferences right now, we're seeing multiple podium presentations on triglycerides, the importance of treating triglycerides, what levels should you treat, why should you be treating, et cetera. Share of voice, I think, is just going to elevate the entire market. And we do believe that we're in a great position to continue to get this launch off to a great start and make things happen.

Next question will be from Mitchell Kapoor at H.C. Wainwright.

This is [ Manav ] for Mitchell. Congrats on the approval and strong label. Just a few questions on the TRYNGOLZA. So do you expect it will be used mostly as an add-on after fibrates and omega-3s? Or could it move earlier for appropriate patients? And do you expect payers based on your conversations to require prior use or inadequate response to fibrates? And in your conversations with physicians, is TRYNGOLZA to be layered on top of legacy triglyceride-lowering therapy indefinitely? Or should physicians deescalate those agents once patients get below the 500 mg level?

Thank you for the question. I'd like to give you a medical perspective on that as well as a commercial perspective on that. It's a very important question.

Thanks. This is Sam. First, we designed our trials for this to get an add-on therapy. So the data that you're seeing is actually on top of fibrates or omega-3 fatty acids. In fact, in our trials, over 80% of patients were on statins, 70% or so were on fibrates, 33% were on omega-3 fatty acids. So the results that you're seeing are on top. Now, the patients are coming in with high triglycerides despite treatment of all those. And so this is really meant to be on top of standard of care. Now, what that standard of care may differ among some patients. Right now, we don't know how it's going to pan out in the community, but we have to have some patients have dramatic responses. So the 70% reduction is mean, but we have some patients have over 90%. So there, the physicians may need to kind of tweak their meds around a little bit and figure out where one is optimal.

So there could be some management of the medication depending on the responses. But really, our data is on top of everything that the patients still need for their care. I think that's where the initial focus will be. How that pans out later, we'll have to see. One thing to keep in mind is that physicians have not seen this kind of reduction in any lipid-lowering therapy, not just with this drug. But when you give a statin, 30%, 40%, 50%, 60% if you're lucky. Here, we're going to be getting 60%, 70%, 80%. They're going to be shocked how effective this drug is, I think. And there's going to be some recalibration about concomitant therapies. But we're not in a position right now to be able to answer your question until we get some further experience.

In other words, although our clinical trials were on top of standard of care, physicians that manage these patients today are fully aware of the marginal decreases in triglycerides that they can achieve with existing therapies. So they're going to be very enthusiastic to move to TRYNGOLZA as quickly as possible.

Absolutely.

Yes. Yes.

Once they see the results, it's going to make a bigger impact in their practice, and they'll find these patients because up to now, there wasn't anything they could even treat. They would give a drug, and they would get a triglyceride from 800 to 600, and it's very unsatisfying. Now, they're going to have a real potent therapy.

Right. And it's not a requirement in the label to be treated with anything prior to TRYNGOLZA for sHTG, but there's a commercial perspective, too.

Yes, absolutely. So on the payer dynamics, and as I said, we've been having these conversations for quite a while with payers. They typically take 2 steps. The first step is what is your indication statement, right, which this indication statement is so strong with the inclusion of all patients greater than 500 as well as having the inclusion of to reduce AP events, it's just telling us that from a payer standpoint, that's going to hopefully provide broad access as we work on those negotiations, and I would expect it to do so.

Then, there's the utilization management criteria, which is the second step. And for that step, what we would expect is the coverage to be consistent with what the clinical trial represented, which is exactly what Sam just said. So on some sort of background triglyceride-lowering therapy for a period of time, and then, they should be eligible to go directly on to TRYNGOLZA at that point.

Got it. If I can just follow up real quick on the competition question that came up earlier, as we think about the competition, is your view that the bar is now acute pancreatitis reduction on top of triglycerides lowering? And given the label and data you have shown, what would a competitor need to show to change your view of the $3 billion U.S. opportunity?

So we're not focused on competition. We're focused on TRYNGOLZA and the upcoming launch and to maximize value for patients and for all our shareholders. That's where we're focused on. Certainly, the data we presented, including acute pancreatitis is an unprecedented very high bar with respect to efficacy as it is on safety and tolerability. So we love our profile. But as Kyle mentioned before, having multiple players in this open green space where the unmet need is so large, just expands the share of voice, which can help everybody. And that's really where our view on that.

Next question is from Jay Olson at Oppenheimer.

Congrats on the early approval and solid label. How quickly do you expect TRYNGOLZA adoption in sHTG to move beyond lipid specialists into broader prescriber bases? And do you think sHTG treatment goals may eventually come down now that there's finally an effective treatment available just as we've seen with LDL cholesterol?

Why don't you take the first part of that question, Kyle?

Yes. So I think out of the gates here, the focus really is on the specialists, as I mentioned. That's where the highest volume of patients are being treated today. It's where the highest risk patients are being seen. It's where you're seeing the highest volumes of other triglyceride-lowering agents be prescribed because of the patient population that I just mentioned. So it's definitely going to start there. But I believe this is going to start to bleed out fairly quickly.

I think Sam's comment about once you start to get experience using TRYNGOLZA and you see the magnitude of effect and reductions in triglycerides, number one, those HCPs that I just referenced that are specialists will begin using it more broadly than just their high-risk patients, and we believe that will happen fairly quickly over time as they gain that experience.

And then the second thing is it will bleed out into the community. Whenever some of these patients go back to see their primary care physician or internal medicine physician and they're on TRYNGOLZA and that physician starts to see the response that these patients are getting, that will help, right? You start with the top of the pyramid and work your way down. That will help, I think, instill that broad education and awareness about the product. So it will happen over time, and we're going to do everything we can to support that through our other tactics and means that we have available to us.

Treatment goals?

Yes. Treatment goals, I don't think we're ready for something like with LDL, it has to be under 55 or 70 yet, but we're close. What I think you're going to see, as the guidelines evolve, right now, as Kyle said, they're more like check triglycerides or XYZ, pay attention to the patient. And now what they're going to say is exactly what's in the label. If somebody is over 500, your drug will be indicated as a Class I, let's say, to reduce the risk of pancreatitis. So there'll be that much more firm now, I think, level of which you should treat and what you would expect to get out of that treatment, which is pancreatitis. How low it'll go beyond that? I think at this point, under 500 is perfectly fine because that's where the pancreatitis risk is. Whether it goes lower than that, I doubt it. Based on these data, it's really pancreatitis focused. But as the field evolves, we might see some -- give some numbers that's close to target.

Next question will be from Eric Joseph at Citigroup.

Let me add my congrats on the expanded label. It seems like there are a couple of new data points in the label versus prior publications, specifically ApOB-48, and also, the month 1, fasting TG declines. Can you talk a little bit about the intent behind the inclusion and how they might resonate with clinicians?

And then just on the commercial side, I wonder if you could speak to where -- sort of the lead time to where you might achieve coverage -- the conclusion of coverage reviews for say like a milestone of greater than 80% of covered lives? And what the lead time is like for medical exemption as will be sort of has to be leveraged near term?

Before we go to you, Kyle, Sam, thoughts on ApoB-48.

Yes. So clinicians focus on the typical lipid panel, right? That includes total cholesterol, LDL, triglycerides, HDL and LDL. And so that's what they're going to be using clinically to help them. So it's going to be basically triglycerides. The ApoB-48 is important because that's where the chylomicrons are, and this is a chylomicronemic population. So as you see here, it's elevated.

By having ApoB-48 in the label, it's going to tell us basically that we're targeting the right particles that are triglyceride rich. And there's a marked reduction in ApoB-48, right, 76%. So this goes along with the drug is doing what it's supposed to, it's targeting the particles that cause pancreatitis. So that's going to resonate very well.

And the rest of the question about timing, these drugs are not giving daily, right? So there has to be some steady state to reach before you expect the full effect. And that's seen in the curves, I think, that you saw in the label. So there's nothing unusual there from that perspective in terms of what the clinician might anticipate.

Right. We have a fast onset of action, and that's highlighted in the label where triglycerides are coming down at the first time in which we've measured, which is at 1 month after starting. But we do encourage and support the label with respect to testing after 3 months when we're at steady state, where a physician can actually see the maximum efficacy that TRYNGOLZA offers on triglycerides and make decisions on whether to -- for example, whether they want to dose escalate at that point.

Kyle?

Yes. As it relates to payers and the process in terms of getting coverage and access in place, I think this is going to be very consistent with what you've seen with other products that have a new indication. The indication is there. We have first-mover advantage. There's no other treatment out there that's able to do what TRYNGOLZA is now labeled and approved to do. So we do believe that this is going to accelerate the review process with some payers, but the payers are still going to have to fit us into their P&T review processes. So I would expect the first 3 to 6 months, the payers to start to come on board.

As I mentioned in my earlier remarks, starting next year in 2027, I would expect that to accelerate even more broadly. And the expectation is that we've got coverage of all patients above 500 regardless of -- if they're high risk or not. And coverage the label, as I described earlier, in terms of consistent with the clinical trial design is exactly what we expect for payer coverage. So access will happen. We're at the mercy of the payers, but we're working very closely with them in order to open that up and make sure that HCPs can prescribe for the patients they want to treat and patients obviously can benefit from a tremendous therapy that was approved today.

Thanks, Eric. And I think we have time for one last question.

And our last question comes from Myles Minter at William Blair.

Congrats on the approval here. It's great to see. I completely get the messaging about treating patients and getting them below 500 mg per deciliter and reducing the AP risk as per label. What's your messaging to clinicians on how to sort of combat that LDL-C increase? Is that an issue at all? Do you just expect patients to up titrate on statins? Maybe you can explain to me how it's done in FCS currently and if there's any parallels that's going on with this broader population. Congrats again.

Thank you, Myles. I'm going to ask Sam to comment on the biology and from a clinical perspective and everything.

Yes. Thank you, Myles. The best way to characterize these patients, both with FCS and sHTG is that because a lot of their cholesterol is on larger particles, chylomicrons, LDL, their LDL is suppressed. So FCS, LDLs are 50 and that continued to 60. So they're kind of recalibrating back to where they would have gone if the patient didn't have a triglyceride disorder. In this case, we correct the triglyceride disorder. So you're right, there is a small increase in the LDL, but it's in the normal range essentially, and it's recalibrating. It's very easy to treat that with just adjusting their LDL medications. So it's not a clinical issue. Clinicians are not going to be concerned if somebody goes from, say, 50 to 65. That's not really a problem. And so the bottom line is it's consistent with the pathophysiology. It's easily to manage, and we don't see this as a major issue at all, even a minor issue for managing these patients.

Any commercial perspective?

Yes. I'll just mention on the FCS side, this is -- it's not been a sticking point. It's not been a major question or concern. It's been manageable as Sam just mentioned. But in the FCS space, it's not been an issue. I'll also add that we've tested this profile very broadly with CORE and CORE2 data in its totality with HCPs. HCPs are aware of the data, and that's -- it's not really coming up as something that they're concerned about. They're more concerned about being over 500 risk of AP and the strength of the data that's represented in the label.

Thanks, Myles. Appreciate the question, and thanks to everybody again for joining us on today's important news. The approval of TRYNGOLZA in sHTG is a major step forward for patients and an important milestone in Ionis' evolution as a fully integrated biotechnology company, something we're incredibly proud of. We look forward to updating you all on our launch progress and our momentum as we advance our pipeline, bring additional transformational medicines to patients around the world. So thanks again, everybody, for joining. Have a great day.

Thank you, sir. Ladies and gentlemen, this does indeed conclude your conference call for today. Once again, thank you for attending. And at this time, we do ask that you please disconnect your lines.

Great. Good morning, everyone. Thank you so much for joining us. It's my pleasure to introduce Ionis. And with us, we have Brett Monia, CEO.

Brett, thank you for being here.

Pleasure, Salveen, and great to be here.

So to start here, you've laid out a transition to a more balanced portfolio in terms of your wholly owned and partnered programs and now have independent launches as well as several wholly owned pipeline programs.

Could you just start with discussing how you've executed on the transition and your key priorities as you look to the outlook into the end of this decade?

Yes, happy to. So we are going through a transition evolution. Really, it's the product of a vision that I laid out when I moved into this role as CEO in January of 2020. Really focused on 2 key objectives. The first was to expand and diversify our technology, really advance new chemistries for antisense technology to expand into siRNA technology using Ionis know-how, even some gene editing, really genetic medicine. And that wasn't as big a lift as you might think because we have an outstanding research organization. And really what I needed to do is unleash the hounds, if you will, and we're all over. We have our first new chemistries for ASOs in the clinic, siRNAs in the clinic. We're moving forward with gene editing and so on.

The second objective was a big lift, and that was to move Ionis from an R&D organization. And when I say D, I mean like early stage development, which partnered all of our programs to a fully integrated commercial stage biotech company. That was obviously -- there was a lot to do there. We had -- all of our programs are partnered so we had to build our wholly owned pipeline. A -- In 2 therapeutic areas, cardiometabolic, [Audio Gap] 2 areas, we have a proven track record to build our medical team, build our commercial organization, and we wanted to do this to really drive value for the company to retain the value that we created in drug discovery, but also to control our own destiny, right, move at our pace and not rely on partners so much.

I'm proud to say that we've achieved this. It's still early days, but we've had a great deal of success. Last year, we launched our first 2 products, wholly owned products, TRYNGOLZA for familial chylomicronemia syndrome. That launch is off to an outstanding beginning, and it sets us up for a much larger indication, sHTG and DAWNZERA for hereditary angioedema. And we're prepared to launch independently 2 new programs this year. I already mentioned severe hypertriglyceridemia with a PDUFA date on June 30 coming up and Zilganersen, our first wholly-owned neurology drug to be launched in September for Alexander disease. So the company really has evolved. We still have a lot more coming up, but it's really the product of the vision I laid out in January of 2020.

As you think about the 12- to 18-month catalyst path here, what would you highlight as the key updates read through to these 5-year goals for the company?

Yes. So there's a lot coming up for the company for Ionis. But I would start with the PDUFA date, the approval of TRYNGOLZA for severe hypertriglyceridemia. This program represents our first launch into a multibillion-dollar product opportunity for severe hypertriglyceridemia. Millions of people in the United States today suffer from the risk of acute pancreatitis, which can be fatal or/and cardiovascular disease due to severely elevated triglycerides.

And we reported remarkable groundbreaking data at the AHA last year, Phase III data showing not only substantial productions up to 72% reductions in triglycerides on top of standard of care. Nearly -- more than 50% of patients we were able to normalize their triglycerides, but also an 85% reduction in outcome, acute pancreatitis, which is groundbreaking unprecedented. And this is this multibillion-dollar product opportunity is obviously a big, big event for the company that sets us up for a lot of success into the future.

The approval of Zilganersen by the FDA in September is a big event, too. Although it's an ultra-rare indication, it's our first launch into wholly owned launch in neurology, and we have 7 drugs in our wholly owned pipeline in neurology today, 13 total with partners, but 7, including our Angelman's program I would highlight the Angelman's program, too, where we expect to complete enrollment this year and have Phase III data next year as well. So those are big events that are coming up for the company as well as our partnered pipeline, which we could talk more about later, which we have to manage to drive continued success. But our objective is to be cash flow breakeven in 2028 with revenue growth, consistent revenue growth to follow year-over-year, quarter-over-quarter and ultimately be profitable. So those are some big events that sets us up to achieve that.

In the context of the cash breakeven in 2028, how are you thinking about longer-term margins?

Growing, growing extensively as we continue to grow. We expect continued growth as these launches take shape. Our wholly owned launches take shape, growing margins quarter-over-quarter, year-over-year and as our partnered pipeline. We have a rich -- it's a big advantage to have multiple sources of revenue for the company. Our wholly owned pipeline is our priority. However, we have a rich revenue stream from our partnered pipeline as well. SPINRAZA continues to perform exceptionally well. We have a follow-on to SPINRAZA, Salanersen, which is coming -- which provides really attractive economics to Ionis.

We have a chronic HPV drug with GSK, which we expect approval in October, where we have attractive economics, then we have 4 more Phase III readouts from our partner pipeline this year. So this really -- we refer to this as a revenue accelerator our partner pipeline on top of our wholly owned pipeline, which, of course, we own to really drive those margins -- continued growth for those margins for well into the future.

Strategically, what is the role of external business development here and other modalities for advancing your portfolio? Historically, the company was very much focused on ASOs and we're now seeing you bring in other technologies. So maybe you could speak to those as well as your work on the blood-brain barrier technology.

Yes. Our research organization is incredibly prolific. I don't see the need for us to in-license drugs at all in the near future. I mean we'll always pay attention if there's something that was really attractive to us, we'd be surprised that we couldn't do it better ourselves. But we'll pay attention to it. But in-licensing drugs is not a priority for us today. We moved 3 to 5 new drugs into development every year, particularly in CNS and cardiometabolic diseases.

Technology and licensing is something we have done in the -- over the last few years since I've moved into this role. And in particular, we've in-licensed targeted ligand targeting strategies to open up new tissues and overcome the blood-brain barrier to your point. For example, we in-licensed exclusive rights from bicycle technology, Bicycle Therapeutics, in which we're using very low molecular at peptides attached to siRNAs or attached to ASOs that are opening up skeletal muscle, therapeutic opportunities, cardiac muscle, therapeutic opportunities and also allowing us to further extend our leadership in neurology by allowing us to not only administer our drugs intrathecally twice a year, once a year.

But to now to administer our drugs to the CNS using subcutaneous administration, low-volume administration, very infrequent. That's an example of bicycle. We have other approaches that we've been licensed as well to overcome the blood-brain barrier. For muscle targeting, we're actually in the clinic. For cardiac -- going after a cardiac myocyte target phospholamban for heart failure. That is partnered with AstraZeneca you may wonder, well, if you're prioritizing the wholly owned pipeline is a partner, well, we have a long-standing research collaboration with AstraZeneca and there was one target slot in the research [ cover ] remaining. They jumped at it. The data was really compelling. We have our own. That's now an IND tox study for cardiac muscle targeting, and we have targets coming for skeletal muscle for neuromuscular diseases.

For blood brain barrier, we are manufacturing our first BBB targeting drug for CNS diseases dementia, which will start IND tox studies in the second half of this year. And we hope to be in the clinic next year for our first BBB strategy. So I see us continuing to evaluate technology and in-licensing technology when it makes sense to like we had in the past. But right now, we're in pretty good shape with what we have. We have a lot of opportunity.

Starting here with TRYNGOLZA, you have the June 30 PDUFA for sHTG as you mentioned. Could you speak to your field team in preparation as you move from the ultrarare FCS indication to a much larger market here?

Yes. So as I mentioned earlier, this is a big, big opportunity for Ionis. We're leading the field, leading the way in targeting this indication severe hypertriglyceridemia. As I said, millions of people, multibillion-dollar product opportunity, and we're way ahead. And we're creating this market opportunity.

The FCS launch, the first indication, just for level setting for everybody, where we launched January last year for familial chylomicronemia syndrome with about 3,000 people in the United States devastating disease cause due to high -- very high triglycerides [indiscernible] demand for TRYNGOLZA and growing quarter-over-quarter, week-over-week, actually. That sets us up for a successful severe hypertriglyceridemia launch because we were in the market. Most of the physicians that manage FCS patients manage sHTG. We're out there talking about the Phase III data and setting us up to really take advantage of our leadership here.

We're ready to launch. We've had our final meetings at Ionis for launch readiness. We're ready to launch. Our field team that's approximately 200 or so field patient -- physician facing the field team is trained they're in the field. They're promoting FCS in the FCS indication and they're educating on severe hypertriglyceridemia. And our medical team has been in the field educating on the Phase III data from CORE and CORE2 in severe hypertriglyceridemia. They've been doing that for quite some time. And our drug supply is ready to go, and we're looking forward to an on-time approval on June 30, and we'll be -- we'll have a drug in channel within a few days and ready to launch.

So the other thing I'll say, Salveen, is that that's a starting point, a couple of hundred field-facing teams or patient-facing teams -- customer-facing teams, team members. We'll look at how the launch goes, and we can always modify that and upsize it as we need to.

You set a new WACC price of $40,000 for the drug effective April 1, applied to FCS as well as sHTG, remind us on the rationale behind not waiting until sHTG approval and how the integration into the 2027 payer cycles improves access post launch?

Yes. So our $40,000 WAC price for sHTG, again, level set for folks, we're going from a rare indication, a WACC price of $595,000 down to $40,000. That decision

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2 years of research

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demand research. It was the right time to do this. First of all, we had our Phase III data. Our HCP demand research was complete. And now earlier this year, we completed our payer research, which was extensive.

Obviously, what our goal was to do was to retain as much value for our shareholders for Ionis,while threading that needle to make sure access for patients was optimal, to avoid headaches for prescribers to write prescriptions and get patients access to the drug. In other words, no payer blocks, and we believe that based on all that work, we threaded the meal very nicely with a $40,000 flat price.

We implemented this on April 1 because our work was done. Secondly, because to coincide with 2027 payer budget cycles, which really begin April and May. And what we wanted to do was to make sure that TRYNGOLZA with the proper $40,000 with the proper price for a large highly prevalent disease indication, was on the radar. It was in the budgets for payers, so that we didn't have any roadblocks in the 2027 budget cycle. So it's there. It's getting there. It's getting embedded in the budgets for 2027.

And thirdly, it allowed us to talk to payers as we approach the PDUFA date and to talk about what their exposure is, right? And how we're going to be able to manage that with them to ensure for a smooth launch from a payer perspective. So really, all that came together and has been very well received by the payer community. So that sets us up for a nice smooth launch.

Could you lay out how you're thinking of quarterly dynamics this year as the volume from sHTG offsets the pricing headwind in FCS?

Yes. We -- so we have guided toward a $100 million, $110 million revenue goal for TRYNGOLZA for this year. And that reflects the significant of what I just took you through substantial reduction in price right out of the gate. So right now, we have a $40,000 WACC price for FCS, right? And that will go right into the sHTG launch. That is going to drive revenue down initially until that volume accelerates in the second half of this year. We're expecting the volume to accelerate pretty rapidly.

But still, the volume has to overcome the deficit in revenue that will get because of the drop in price. We expect that to really start beginning to take off in the fourth quarter of this year as that volume really overcomes and really takes shape. And then next year is going to be a big year for really accelerating revenue growth for the company as we work towards our $3 billion plus product U.S. peak product sales opportunity in the U.S.

What are you looking to see in competitor arrowheads Redemplo's Phase III data in the third quarter is it possible that their construct or use of siRNA could result in different hepatic fat increases versus TRYNGOLZA?

There's so much to take care of to ensure that this launch is as successful as possible. And as I said, we're in great shape to make sure it is successful. That's what we're focused on, we're really not looking for any data from any competitor Phase III data or whatever to influence what we're expecting to do. I mean we expect there to be a competitor in this space. And our $3 billion plus product market opportunity, peak sales opportunity reflects that, that we're not the only ones in this space.

Our data is groundbreaking, as I said, and we've set a very high bar on the reductions of acute pancreatitis, reductions in triglycerides that I just took you through, all with excellent safety, tolerability and the convenience of self-administration once per month using a simple low-volume auto-injector. But let me talk about the hepatic fat that you referred to because it's important to discuss. So what we reported in -- at AHA last year was a small increase, particularly at the 80-milligram dose in liver fat in patients with severe hypertriglyceridemia. I want to emphasize that we're expecting approval for 50 milligrams and 80 milligrams. Both were highly efficacious the 80 milligram dose showed a little bit better efficacy, particularly in the normalization of triglycerides down to a certain level, but both were highly efficacious and 50 milligrams barely move the needle on liver fat, it was very, very small. 80 was small too, but it was higher with the effects were dose dependent. There was no clinical sequelae associated with that increase in liver at 80 milligrams.

There was no correlation with ALT elevations. All of our demand research, the $3 billion-plus product market opportunity, that I referred to before, assumes that is there. That's based on -- that was included in our payer research, I was included in our HCP demand research. It's -- and in the eyes of HCPs, they shrug it off. They don't think it's anything to be concerned about, particularly since there's no adverse events associated with it. It's just an observation, and it's also well recognized as an on-target effect, right?

We know that our competitor -- a competitor of ours -- the competitor program that you referred to, the siRNA, showed in their Phase II study, dose-dependent increase in liver fat. By knocking through this mechanism targeting APOCIII. It wasn't statistically significant, but it was under powered. And it will be underpowered in their Phase III study, too because it's really relative to our study, there are very few patients that are undergoing MRI. So we think it's comparing apples to oranges. The bottom line is we're focused on our study, there's no clinical sequela associated with this.

And then the final thing I want to say is that as we continue to monitor these patients long term in the open-label extension. We're seeing exactly what you would see in an adaptive on-target response is that a return towards baseline, right? So these patients are continuing to be treated. No adverse events are emerging with long-term treatment, and we're seeing the liver fat -- the liver to be able to handle this and the triglycerides and deliver return towards baseline. So we're going to present that data at an upcoming medical congress. So stay tuned.

And how are the competitive dynamics between both drugs playing out in FCS maybe talk to what you're seeing in terms of new patient share and switches. And is there a read-through from that sHTG.

The FCS launch continues to go great. I mean, as I said before, the demand is -- continues to accelerate. Each week, my team tells me that this week was better than last with new patients coming out of TRYNGOLZA. And that, again, sets us up really well for severe hypertriglyceridemia it really reflects the product profile. I mean the efficacy and the feedback we're getting from the patient community and HCPs has been overwhelmingly positive. That's great.

I can't speak in detail about our competitor because I am not that familiar with it. But I'm sure that the vast majority of patients that they're identifying like us, our newly identified patients. I mean this is -- we've just scratched the surface in FCS. And this, we had the first FDA-approved medicine for FCS. So it's all about patient identification and getting patients onto new drug, I think, for both programs. I mean we're seeing a handful of patients switching from theirs to ours. And I think they said the same thing back and forth, but this is almost all newly identified patients for both programs. But TRYNGOLZA continues to go really well with respect to patient demanding new patients getting on drug and reauthorizations and prescribers expanding to more and more patients because of their positive experience.

Overall, what gave you the confidence here to raise your peak sales estimate from $2 billion to greater than $3 billion? And how much of this raise is due to the change in price, which could insinuate increased volumes?

Yes. And so in January of this year, we increased our peak product U.S. sales for TRYNGOLZA to be $2 billion plus. And that was based on the HCP demand research, how many patients do you have, how many -- how aggressive are you going to treat, how excited are you got the data, that was based on the Phase III data, which we then have.

More recently, we've upped that peak product sales to more than $3 billion in the U.S., and that's because of pricing. The HCP demand and the data is now in hand. But once we finalize the pricing that I referred to earlier of a $40,000 WACC that gets us into a net expectations for a net price that's meaningfully higher than what we were projecting in January. And that really is what drove that second increase in peak product sales for TRYNGOLZA to $3 billion plus. It's about pricing.

Okay. Moving to WAINUA, clearly addressing ATTR cardiomyopathy, which is a large blockbuster opportunity here. We're going to see data in the second half of the year with your partner, AstraZeneca. And you've disclosed that Cardio-TTR transform has 57% of patients on a stabilizer. I guess, a, speak to how you're thinking about the overall success of the study, but also in the context of the combo arm here and a really large end there. Do you expect statistical significance on top of tafamidis in the context of that trial?

So like TRYNGOLZA, we're developing -- we've developed a new for 2 indications, right? A rare hereditary indication called ATTR polyneuropathy, that's approved and that launch has gone very well. The feedback from the patient community and physicians have been very, very positive for the drug.

The second indication, we can call it rare, but we all know it's very -- it's much more prevalent, the ATTR cardiomyopathy, which includes hereditary but also wild-type patients, patients that don't have a mutation in the TTR gene. Cardio transform our Phase III study is the largest study ever conducted by far in ATTR cardiomyopathy, and that sets us up for the richest data set for not only the primary endpoint, but secondary end points.

And our -- we're expecting Phase III data, as you said, second half of this year and everything is going very well in the conduct of the study and execution. The study is reasonably derisked for its primary endpoint. We're excited. AstraZeneca is excited to get that data to get the NDA submitted, assuming positive outcome by the end of this year and to get that drug launched next year. Because of the size of the study, we will also have the potential to show benefit in secondary endpoints, right? And the most -- the one that people are most focused on is the combination with tafamidis, a stabilizer. First, let me make sure we're all aware that nobody has ever tested the hypothesis that a silencer and a stabilizer will cooperate and show additivity, right?

We're going to be the first to test that hypothesis. If that's the case, and it's reasonable to assume that it will cooperate. We're in the best position to show the -- to generate the strongest data set to reflect added benefit in combination. We're powered for the primary endpoint. Of course, all secondary endpoints have some powering associated with our powering for the combination isn't very high. It's a secondary endpoint. It's down in the hierarchy, we presented the higher -- statistical hierarchy already. But we believe that if they cooperate together, the mechanism is that we're going to have this strongest data set that could be convincing to prescribers that patients that are being treated with stabilizers today, and we don't know that all patients on stabilizers are progressing right?

This doesn't reverse the disease, they're progressing, which means heart failure, heart attacks, strokes, that they're going to advocate for combination usage with the science. We're going to be in a position to have that data and convince physicians that combination is worth doing to help patients. Our $5 billion plus product peak product sales guidance that we and AstraZeneca have stated does not assume combination benefit. That's an upside to that. So we're very much looking forward to that data. And like you said, we'll have the data in the second half of this year and everything is going well for the study.

And noting that you have an auto-injector for the Medicare Part B channel, do you still expect most of when you are treated patients to go through Part D? And within Part D, how are you thinking of pricing relative to the stabilizers? And is this an avenue to compete against AMVUTTRA in the Medicare Advantage segment?

Yes. So our primary -- we expect that the vast majority of patients on WAINUA will be going through the Part D route self-administered using a simple low-volume auto-injector. That's a big differentiator for WAINUA, which does not have to be treated by a health care provider in a clinical setting or what have you, using a prefilled syringe, we and AstraZeneca felt that there could be value in the physicians that prefer to be able to administer the drug themselves and maybe go through the Part B route for WAINUA to provide dosing flexibility an option for physicians to do that if you want to do it, the vast majority of patients.

And this has really resonated in the polyneuropathy launch. Self-administration is -- has been very well received. The convenience especially when you get into the much more prevalent cardiomyopathy indication, which we're going to be getting to not just centers of excellence, but rural settings and global settings. That it's going to be the primary driver for the value of WAINUA. But it does provide dosing flexibility as far as pricing, the price for polyneuropathy is out there. We haven't disclosed the pricing for cardiomyopathy. That will come when we get approval.

On the neurology side, you mentioned Angelman. What gives you the confidence in your primary endpoint here and ability to manage the heterogeneity in this population and essentially results in a positive outcome? And could you discuss your decision to remove the 40 milligram cohort from the Phase III study and any impact there to data timing?

Yes. We're very proud of our success in neurology 3 approved medicines today, including polyneuropathy for ATTR. But for CNS diseases, SPINRAZA and QALSODY for SOD1-- we recently reported positive Phase II data for our towel program in Alzheimer's disease with Biogen. And Zilganersen, we expect to prove for Alexander's disease in September. Right behind that is our Angelman's program, Obudanersen, which we expect to complete enrollment this year with a Phase III data next year.

Confidence a proven platform. This is the same platform that produced those FDA approvals that I referred to earlier. Our Phase I/II data, where we showed really, really, what we believe is highly clinically meaningful benefit across many different measures of clinical measures, including communication, cognition, motor function in Angelman using various different instruments. So and the study is we're going to complete enrollment later this year. So execution-wise, gives us confidence, too. But it's really the platform in our Phase I/II data. We chose expressive communication as our primary endpoint because that's where we saw the greatest magnitude of benefit in our Phase I/II study, although we saw a benefit in cognition and motor function, it was expressive communication that really stood out. It was dose dependent.

And also, what's very important is that we know the natural history, which is very well established in Angelman Syndrome. The natural history for progression of expressive communication is essentially 0. So the signal to noise in showing benefit compared to placebo on expressive communication should be highly advantageous for us. We don't we're not going to see a lot of noise in that endpoint. Of course, we have secondary endpoints on cognition and so forth and so on, but that gives us a lot of confidence, too.

And that's why we chose that as the primary endpoint. We removed the 40 milligram dose because we didn't feel like we needed it. The Phase I/II long-term extension data, which we reported some new data from last year showed that 80 milligrams was outperforming 40 milligrams, right? So let's just go to 80. It's good. It's well tolerated. It's safe, long-term treatment and allowed us to get to the Phase III data faster, right? We can enroll the patients quicker. Patients that were on 40 milligrams were moved into the open-label extension for the REVEAL Phase III study, and they move them up to 80 milligrams. Didn't really have much impact on our trial. But there's only a handful of patients -- a handful of patients at the time.

You've partnered neuro pipeline assets with Biogen, notably the tow targeting BIIB080 and the next-generation SMA assets Zilganersen.

Can you remind us of the economics to Ionis and yourself on the recent data releases for these assets, particularly the Phase II tau data?

Yes. So very quickly on Zilganersen, that's a follow-on to SPINRAZA that we provided to Biogen once per year intrathecal dosing with even greater efficacy of SPINRAZA, the economics from the mid-teens to the high 20 -- mid-20% range on royalties and about more than $500 million in development and commercial milestones. The tau data, we're very excited about that we reported with Biogen. That data is going to be presented at AAIC in July. And what you're going to see there is unprecedented improvements in cognition.

By targeting tau, you're also going to see reversal of tau pathology, so the neurofibrillary tangles that gets -- people are all aware of, we're actually reversing that by PET imaging and of course, tau reductions, all good tolerability, no area, of course, the antibodies and abilities to produce. The economics there are SPINRAZA like low to mid-teens and royalties and a few hundred million dollars in development and commercial milestones.

We believe tau is a breakthrough for Alzheimer's disease, obviously, we need desperate, desperately need new mechanisms to tackle in addition to a beta approaches. We think tau is the solution. we actually are also developing a blood-brain barrier approach to tau at Ionis that we expect to move into IND-supporting tox studies later this year.

Great. Well, with that, Brett, thank you so much. Really appreciate the time today.

Thanks, Salveen.

Good luck with all these data sets.

Yes. Thank you.

Good afternoon, welcome to the 2026 Annual Shareholders Meeting Corporate Update. My name is Brett Monia. I'm Chief Executive Officer of Ionis and Board Director at Ionis, and I couldn't be more thrilled to provide an update on the remarkable progress we have made at Ionis to drive accelerating value for all Ionis stakeholders over the last few years, and more importantly, how we are set up to drive even greater value in the years to come.

Of course, I will be making forward-looking statements during my presentation. So please take this under consideration in any interest you have in Ionis going forward. The field of oligonucleotide therapeutics has emerged as one of the most exciting and important new approaches to drug discovery and drug development in the pharmaceutical industry. And we're proud of the fact that Ionis pioneered this field. Accordingly, we have a rich history in discovering and developing transformational RNA-targeted medicines for a whole range of medically important diseases.

In support of this, we created the industry-leading medicinal chemistry and keep manufacturing capabilities here within Ionis. We were the first to optimize and validate oligonucleotide therapeutics of any kind to liver for diseases related to liver-derived factors as well as to the central nervous system for human therapeutics. We are at the forefront of validating, optimizing mechanisms of action of RNA-targeted therapeutics, whether it be mechanisms that result in the degradation of the targeted RNA to block the production of toxic proteins, such as through an RNase H mechanism or to modulate and improve splicing mechanisms, so that we can replace proteins, upregulate proteins that are lacking in loss of function diseases. And this has led to us leading the way in discovering and developing first-in-class medicines for a range of serious diseases.

We had remarkable progress across the business over the last several years. And this has set us up very well for accelerating growth, accelerating value creation for years to come. One of the most important decisions we made and a decision that has played out extremely well, great success is the evolution of Ionis from a research and development organization to a fully integrated commercial stage biotechnology company, creating a commercial organization of excellence and has always matched the excellence, we've always exhibited in research and development. And this is based on a truly groundbreaking technology, technology that continues to advance forward with state-of-the-art APOCIII type approaches creating a high-value, innovative pipeline.

We have consistently, especially over the last few years, delivered breakthrough clinical results that have enabled highly successful drug approvals and commercial launches and all of this is setting us up to drive revenue growth -- accelerating revenue growth, positive cash flow and value creation for everybody involved in the Ionis sphere. Over the last few years, we've had remarkable success. And just over the last 3 years, some of those achievements are shown in this slide. Six positive as Phase III data readouts that have resulted in 4 approved medicines and medicines with brand names that you can read there on the slide.

We're expecting 3 more approved medicines by the end of this year. Two of these approved medicines and independent launches, commercial launches have been -- are independent. Our first independent launches in Ionis' history, Tryngolza for familial chylomicronemia syndrome and DAWNZERA for hereditary angioedema and there's a lot more coming, and we've created a remarkable pipeline with 11 medicines in late-stage development and many more, of course, at mid stage just getting started from in the clinical pipeline. We're very proud and very pleased with the on-time approval last August of DAWNZERA, as a prophylactic treatment for hereditary angioedema.

Now although there are prior to DAWNZERA's approval, prophylactic treatments for this devastating genetic rare disease -- we also recognized, and as far as we moved on forward that the unmet need for patients is still vastly large. There's a lot of unmet need here for patients, and we felt that on DAWNZERA fill the needs of those patients. DAWNZERA is a very novel mechanism of action. Of course, as the first and only RNA-targeted treatment to prevent severe swelling, HAE attacks, which can be failed in these patients. And we're pleased that the launch is going very well, because this is a market where existing prophylactic treatment existed prior to the approval of DAWNZERA, as I mentioned. We're moving in to a market where the goal is to switch patients from their existing prophylactic treatment where they're dissatisfied to DAWNZERA.

And in fact, in this launch, we're seeing the majority of our patients switching from other prophylactic treatment to DAWNZERA. Also patient have managed their disease through other means such as on-demand treatment or even treatment naive patients. We're seeing a growing number of repeats with subscribers or prescribers and launch is gaining significant momentum, and we're proud of the fact that our first quarter results, we achieved 128% improvement over our first quarter launch. And I can tell you that the launch for DAWNZERA continues to be quite strong. We look forward to presenting an update on our Q2 earnings later this year.

Now moving on from DAWNZERA, which, of course, is being -- which is a disease hereditary angioedema, it's managed by allergists and immunologist very different than the bulk of our pipeline today. I want to drive -- I want to turn attention to our leading therapeutic areas of focus, cardiometabolic diseases and neurological diseases. Two areas where we have proven value time and time again from our pipeline, 2 areas that we pioneered, and we've developed drugs and our developing drugs for both rare and prevalent these indications, several of which have multiple -- several of which have blockbuster potential.

Now I want to start by providing some of the progress we're making in cardiometabolic diseases and now I'll move over to neurological diseases, some highlights in neurology as well. Starting with cardiometabolic disease and starting with olezarsen. Olezarsen, a transformational medicine or disease indications, all disease indications related to severely elevated triglyceride. There's a high unmet need for better treatments to manage patients with high triglycerides. And we're developing olezarsen, and you'll see this in a moment, our brand name for olozarsen for its first indication is called Tryngolza. And I may go back and forth between Olezarsen and Tyngolza, here and there.

The first indication is a rare, severe genetic disease call familial chylomicronemia syndrome or FCS. In the U.S., there's about 3,000 people suffering from this debilitating disease. As I mentioned, it's a genetic disorder, which is a consequence of severely elevated triglyceride through certain mutations in the genome of people. These patients -- these people suffer from a whole host of comorbidities, but what is most significant is the risk of a potentially fatal and recurring, if not fatal, acute pancreatitis attack.

And then there's a second indication, severe hypertriglyceridemia. This is not a rare disease. This is a disease that affects millions of people in the United States alone, it too is defined by very high triglyceride levels. In this case, triglyceride, the definition of sHTG in the U.S. are triglycerides above 500 mg/dL, normal triglyceride below 150. Although this is not a genetic disease and it's not a rare disease. These patients suffer from the same most significant risk that FCS patients suffer from the risk of a potentially fatal acute pancreatitis attack. They also suffer from risk of ASCVD cardiovascular diseases. And although there are some generic treatments for high triglycerides for SHTG today, they're grossly inadequate. They cannot get triglyceride for the most part, the vast majority patients cannot get patients triglyceride down in any meaningful way that puts them at risk for acute pancreatitis.

Late 2024, we were thrilled with the first FDA-approved medicine for a drug medicine for familial chylomicronemia syndrome in the United States. That is Tryngolza. And last year, we launched Tryngolza in January. It was our first year of launch and our first independent launch in our history. The approval of Tryngolza for FCS was based on remarkable groundbreaking results, efficacy results, substantial reductions in triglycerides and in acute pancreatitis with a very attractive safety profile, and offers the convenience of once per month administration using a low-volume auto-injector. Patients can administer themselves very simply.

In addition to the U.S., we're also launched in the EU with a commercial partner, and the launch was also a great start. We reported our Q1 revenue of $27 million, which was substantial growth compared to the first quarter of our 2025. The launch continues to go exceptionally well, and we're looking forward to provide an update DAWNZERA in our Q2 earnings in a few months.

Turning attention to severe hypertriglyceridemia now, Tryngolza and Olezarsen for this large indication, which represents Ionis' first potential multibillion-dollar wholly owned medicine. As I said, there are more than 3 million people with sHTG in the United States, and there's about 1 million or more than 1 million, slightly over 1 million people that we refer to as high-risk patients. Patients that have had AP event in their history and chances of having the other event is very high or the triglycerides are so high. Above 80 or so such that they have chylomicronemia, that put them at even higher risk for acute pancreatitis as well. What we demonstrated, presented and published last year was groundbreaking results from our CORE and CORE 2 Phase III studies evaluating Olezarsen in sHTG.

We showed a highly -- a substantial and highly statistically significant clinically meaningful reductions in triglycerides. Many of the patients in our study, we were actually able to normalize their triglycerides from very, very high levels down below that 150 mg/dL target, that I mentioned before and nearly 90% of patients, we were able to get them below the definition of severe hypertriglyceridemia, below 500 mg/dL. But what was really grounded, what was really remarkable and unprecedented was the first time anyone ever demonstrated that you can reduce acute pancreatitis events.

By lowering triglycerides in people with sHTG, 85% production in acute pancreatitis in our study after only 12 months of treatment, groundbreaking results. Like -- I guess like for FCS, we will -- and we administer Olezarsen, Tryngolza and using a simple once-per-month self-administration auto-injector. We're well ahead of any potential competition to be first to the market using this mechanism of action targeting APOCIII for sHTG. Our field team is fully deployed already. Of course, marketing FCS, but also educating severe hypertriglyceridemia and not surprising considering the groundbreaking results for this study and the unmet need. The FDA granted not only priority review, but also breakthrough therapy destination for this program and granted us with a PDUFA date of June 30, 2026.

As I said, this is the potentially the first multibillion-dollar wholly owned product opportunity for Ionis in our history. And recently, we increased peak product sales in the United States guidance beyond greater than $3 billion. We have an exciting cardiometabolic pipeline, we've just scratched the surface. This pipeline will continue to grow and expand. Today, we have 6 medicines in clinical development in cardiometabolic diseases. I highlighted Olezarsen. I also wanted to highlight the fact that we have a follow-on molecule that is on the verge of starting as a Phase II study in severe hypertriglyceridemia. That's ION775, in target APOCIII, but with this drug is our first advancement of an Ionis discovered using Ionis know-how in chemistry siRNA into the clinic -- and in this case, as a follow-on molecule to Olezarsen. The efficacy of a Olezarsen and sHTG is tough to be -- that's really not the objective. The objective is to relax dosing such that we can get to maybe even once per year dosing to add convenience for patients.

And then we have several other from our wholly owned pipeline that will be starting Phase I study shortly in our partnered pipeline is very exciting as well. I want to highlight 2 programs in which we're expecting Phase III data in the second half of this year. Eplontersen, which is already approved under the brand name WAINUA for hereditary ATTR polyneuropathy is in Phase III development for ATTR cardiomyopathy, where we're expecting data in the second half of this year.

That's a co-development, co-commercialization partnership with AstraZeneca. And then, of course, pelacarsen, pelacarsen in development, Phase III development with our partner, Novartis, for Lp(a)-driven cardiovascular disease and another cardiovascular outcome trial with data expected in the second half of this year.

Turning attention to our leading neurology platform, our leading neurology portfolio, a portfolio that has a strong track record in delivering first-in-class neurology medicines, breakthrough treatments like SPINRAZA, the first ever FDA-approved medicine for spinal muscular atrophy, like QALSODY, the first disease-modifying treatment for any cause of ALS and the first FDA-approved medicine for a genetic cause of ALS, QALSODY. And then WAINUA, as I already mentioned, on the market for hereditary ATTR polyneuropathy. And we're well positioned to deliver a steady cadence of medicines in neurology. We have a strong pipeline of wholly owned as well as partnered medicines, and we're anticipating our first independent launch in neurology in the second half of this year, and I'll get to that in a moment.

We have a focused strategy to expand our wholly owned neurology portfolio. Our wholly owned pipeline is the priority. And we're really excited about the innovations we're making in science to further extend our leadership in neurology in various ways, including moving to once per year dosing using an intrathecal route of delivery or using approaches that allow us to deliver our drugs to CNS by subcutaneous or intravenous administration, overcoming the blood-brain barrier.

We are very proud of the data we reported last year, Phase III data for zilganersen for the treatment of a severe commonly fatal -- typically fatal neurodegenerative disease called Alexander disease. Zilganersen, our data demonstrated the first -- to be the first and only investigational medicine to demonstrate clinically meaningful disease-modifying impact on patients living with Alexander disease. This is an ultra-rare disease indication. We received in the U.S. and EU orphan designation. And again, like for sHTG with TRYNGOLZA, olezarsen, we received breakthrough therapy designation and priority review for zilganersen with a PDUFA date of September 26 -- September 22, 2026, later this year. And we're prepared to launch. And this launch represents, again, our first independent launch for Ionis in neurology.

And coming up right behind zilganersen for Alexander disease is another really exciting wholly owned program that we're in Phase III development for Obudanersen for Angelman syndrome, a very promising medicine addressing a disease, a neurodevelopmental disease with incredibly high unmet need.

There's more than 100,000 people in major geographies today with Angelman syndrome, and there are no effective treatments for this disease today. We reported multiple times updates on the HALOS Phase I/II study in patients with -- treated with Obudanersen with Angelman syndrome, which we showed consistent and meaningful improvements in a range of clinical outcomes at only 6 months of treatment.

And I'm pleased to say that we also shared long-term data from our long-term extension that continues to support the benefits that Obudanersen appear to be delivering on from the 6-month HALOS Phase I/II study, certainly supporting continued development -- Phase III development.

Again, another breakthrough therapy designation for an Ionis discovered medicine. We expect to complete enrollment in the REVEAL Phase III study this year with data expected next year. And this is what our neurology clinical pipeline looks like today. I said it was robust. It was deep and broad, and I think the slide really reflects that.

Today, we have 13 medicines in clinical development, more than half of which are wholly owned today. I touched on already zilganersen for Alexander disease and Obudanersen for Angelman syndrome. And you can read the rest of the programs that are in Phase II development for devastating genetic diseases.

And I guess I'll just highlight one other program, which we just began clinical testing on in Dravet syndrome, ION337. We just got that started over the last month or so. And our partner pipeline also is very exciting, of course. We're expecting Phase III data for ulefnersen for ALS driven by mutations in the gene called FUS later this year.

We reported just today, our partner, Biogen reported breakthrough therapy designation for salanersen, a follow-on molecule for spinal muscular atrophy, a follow-on molecule SPINRAZA that supports once per year intrathecal dosing with faster onset of action and potentially even greater efficacy than SPINRAZA in SMA.

And we also reported positive Phase II data with our partner, Biogen for Diranersen targeting TAU in Alzheimer's disease just 2 weeks ago, and we will be presenting that Phase II data with Biogen at AAIC in July. There's a lot going on at Ionis, a lot of positive momentum, a lot of success of late and 2026 was set up to be a highly eventful year with many value-driving events, clinical events, Phase III events, I've already mentioned some of them.

In January of this year, we and our partner, GSK, reported very positive Phase III data for bepirovirsen in chronic HBV, which was presented and which the data was presented in detail last week at EASL and published simultaneously in the New England Journal of Medicine data which showed for the first time unprecedented results on functional cures for people living with chronic HBV, functional cures on the order of 20% in the overall population, really remarkable.

I already mentioned pelacarsen, eplontersen Phase III data later this year and ulefnersen Phase III data. We're also expecting Phase III data for sefaxersen later this year in IgA nephropathy with our partner, Roche. And we've initiated Phase III studies now for sapablursen, [indiscernible] for SMA, as I mentioned, and so on.

And we're also expecting more Phase II data this year. Along those lines, our regulatory affairs group is very busy with new submissions, approvals and so on. The most important, of course, is the approval of olezarsen in the U.S. for severe hypertriglyceridemia, zilganersen, U.S. approval for Alexander disease and bepirovirsen U.S. approval for chronic HBV, which we expect this year. And of course, following this our product launches.

These are exciting times at Ionis. Few companies can boast the steady cadence of new medicines that we expect to reach the market in the near term as we can here at Ionis, building on the success of WAINUA in ATTR polyneuropathy, TRYNGOLZA for FCS, DAWNZERA for hereditary angioedema. We're expecting 3 new product launches this year. I already mentioned, olezarsen for sHTG, zilganersen for Alexander disease, bepirovirsen for chronic HBV.

And assuming positive Phase III data later this year, we can anticipate new launches next year for pelacarsen for cardiovascular disease, eplontersen for ATTR cardiomyopathy, IgA nephropathy and the FUS-ALS that I mentioned and then Phase III data for obudanersen for Angelman syndrome next year as well.

So obviously, with so much success from our pipeline and our commercial launches, wholly owned and partnered, we're in a very good position to continue to drive and accelerate the driving -- the drive for revenue growth for Ionis over the relative near term.

At peak sales, just for the medicines that I just highlighted on the previous slide, we anticipate more than $5 billion in annual peak product revenue for Ionis, matched with partnered royalty revenue that goes beyond more than $2 billion, summing up to more than $7 billion in product revenue just from those near -- relative near-term programs that I just highlighted on the previous slide.

I also want to highlight the fact that the guidance to this revenue is also probabilized such that we do not assume every program is going to be successful in Phase III or on their launches as we hope them to be. So this is a relative conservative estimate of revenue growth for the company at peak for those programs in the relative near term. Very, very exciting for the company. It's going to continue to drive value for all of our stakeholders.

And based on the pipeline performance, the launch performance and the revenue growth that we anticipate, that's again probabilized, we are well on track to achieving breakeven cash flow in 2028 with positive cash flow, accelerating cash flow and for following breakeven and growth -- continued growth for years to come, driven by the product launches, some of which I highlighted already, royalty revenue. We're in a very strong financial position today, building on that foundation and of course, disciplined expense management.

So to conclude, Ionis has had a great deal of success over the last few years. But more importantly, we are positioned to drive far greater value in the near term this year, next year and for years to come, accelerating growth. And that's based on our leadership in cardiometabolic and neurological drug discovery and development, the steady cadence of positive clinical trial results we've delivered, successful product approvals we've delivered and the launches we have delivered and will continue to deliver and the fact that we're retaining so much more value for the company today as a fully integrated commercial stage successful biotechnology company. This is driving accelerated revenue growth, which is producing a clear path to sustained positive cash flow with breakeven cash flow in 2028.

So that's my presentation, and thank you very much for your attention. And now we can open it up for Q&A session.

Great. So I think several people have figured out how to submit questions online. We have a number of questions in the queue that we'll go through. [Operator Instructions]

The first question comes from Tom. He's asking about our strategy for China. He wants to know since we still have some rights to some of our drugs that we haven't licensed out to -- for China market, if and how we plan to commercialize olezarsen or these other drugs in China? And the second part of this question is, big pharma has done several deals for siRNAs with Chinese companies in the last year. How are these deals impacting your business model?

Thank you for the question. So our focus for our independent wholly owned launches is to focus on the U.S. market for now, we will be emerging to commercialization of our own products outside the U.S. eventually.

But today, we are relying on partnerships for commercialization of our products today. China is not a top priority for us, honestly. We have excellent partnerships for TRYNGOLZA already for the major -- for the global -- for the geographies that we have prioritized, EU, Japan, Middle East, LatAm, Canada.

China is not a top priority, but we continue to discuss potential commercialization partnerships for China for all of our wholly owned programs. And there's interest, but it's just not the highest priority right now. Impact of China, big pharma partnerships with China really has been none. We have seen nothing that has come out of China that we can't match or exceed with respect to science and innovation.

As I mentioned in my presentation, we have a follow-on molecule for olezarsen, TRYNGOLZA that's supporting once every twice a year, once a year dosing, subcu dosing with remarkable efficacy based on Phase I data.

We're doing the same thing for our other wholly owned programs, follow-on programs. We've seen nothing coming out of China that matches our innovation. I'll also tell you, we're doing the same thing in neurology. We have follow-on programs, as I mentioned, for salanersen that supports once per year intrathecal dosing, new approaches that are going to allow us to dose subcutaneously for CNS diseases overcoming the blood-brain barrier.

I've seen nothing in CNS that's going out of China that matches the expertise or the advancements we're making here at Ionis and CNS diseases. So nondismissive, but paying very close attention to it. But so far, no concerns.

Next question comes from James. He's asking, it appears that Ionis recently received patents for half-duplex ASO architecture and family of technologies. Can you elaborate a bit on what this architecture technology is about? And how do you plan to use it? Also, how would you -- how would this compare to standard siRNA in terms of potency like knockdowns and dose duration?

So these are double-stranded approaches that we -- our outstanding research team uncovered the potential for that they have shown remarkable durability and potency in animal models that, in many cases, not in all cases, but in many cases, match the durability and potency that we see with state-of-the-art antisense and state-of-the-art siRNAs.

We don't know how we're going to use this technology today. We don't -- we're looking at it much, more carefully. We have a lot more to learn about this technology. But it's just another example of Ionis innovation from our research organization. We think it has the potential to be as good and potentially better for certain applications, but we still have a lot more work to do here.

Our next question, actually a slew of questions comes from Denis Reznik asking on behalf of Gary Nachman from Canaccord Genuity. We'll break this up into a couple of parts. There's the first part. This has deal with TRYNGOLZA and olezarsen. Please provide an update on sHTG discussions with the FDA as we get closer to the upcoming PDUFA date.

Any color you can provide on how labeling discussions are progressing and what patients should be covered in the indication will sHTG AP data be included somewhere and any potential updates to warnings and precautions.

A long question. So I'm sorry to say that my answer is quite short. It's -- we don't comment on -- we're obviously in labeling discussions at this stage with a PDUFA date of June 30. And we don't comment on labeling interactions with the FDA at this stage in -- as we approach approval. All I can say is that our discussions with the FDA are going very well.

The second part related to olezarsen is how will payers be treating the sHTG indication? Will they be largely sticking to the label? And will they be requiring any sort of step edits or prior authorization documentation prior to approving TRYNGOLZA for use in the different sHTG patient groups of varying risk profiles?

Yes. We don't expect payers to support nor would we promote any off-label use for the indication, sHTG, as defined by triglycerides, 500 and above. I mean, we're talking millions of people in the United States. There's -- the opportunity here is enormous. So we don't expect that. We're not going to promote that nor we expect payers to support that.

But the other part of your question was on what step edit. -- sorry. step edit. So most of the patients -- many of the patients that have sHTG are already being treated with generic medicines inadequately fibrates, omega-3 fatty acids some even statins and those sorts of things.

These patients are -- all the patients essentially in our Phase III trial were on these drugs already. So although I wouldn't necessarily call it a step edit, the vast majority of the patients that we're going to be targeting initially, certainly, the high-risk patients are already on these drugs. Olezarsen and TRYNGOLZA demonstrated the results that I highlighted, the groundbreaking results on top of these medicines already.

For newly diagnosed patients, would they have to go on a generic fibrate or something like that? Possibly, maybe not, we'll see. That's something that we're going to have to work through. I don't -- whether it's required or not, it wouldn't take long after a couple of months, it will be clear that these patients are not getting to target and they're going to need to get on to TRYNGOLZA for their treatment. So we don't -- more important -- most importantly, we don't see this as a barrier to achieving our peak product revenue goals of $3 billion plus at peak in the U.S.

Thanks. Continuing on with questions from Denis at Canaccord. What are your expectations for the pelacarsen Phase II readout in Lp(a)? And what are you hoping to show with the outcomes data? And what's the latest timing of that data?

So the timing and data of the data has not changed. Our -- what we're guiding to us in Novartis in the second half of this year. We're very confident that, that data is going to come out in the second half of this year. We're looking forward to it.

As far as expectations, just let me remind everybody that there has been a baseline demographic paper published by Novartis in clinical trial design and study rationale and design rationale. The study is powered to achieve a 20% relative risk reduction in the total population, a 25% risk reduction in patients that are at greater risk in the study, higher Lp(a) in the study.

What I -- what do we expect to be a clinically important outcome in this study would be clinically significant -- clinically significant benefit on outcome, which is a composite of mortality and hospital CV events in the study compared to placebo.

Why is that? Why is the magnitude of risk reduction not so important because the unmet need here is enormous. There's 8 million to 10 million people in the United States suffering from cardiovascular disease, heart attacks and strokes at very high Lp(a) levels, and it's not manageable with any medicines that are out there today, showing benefit in this patient population would be groundbreaking for the cardiovascular field, where there's a desperate need for treatments for Lp(a) treating cardiovascular disease. And that's what I expect in the study. I expect it to be positive.

Follow-on, if the data are positive, how soon can this be filed for regulatory approval?

By the end of this year.

Next question is on WAINUA for ATTR cardiomyopathy. What should investors expect to see in the top line results, specifically with the combination subgroup that would be considered meaningful compared to the HELIOS-B data? And if positive, how soon can it be filed?

So this is a co-development, co-commercialization partnership with AstraZeneca, a partnership that is now over a decade old, a great partner. We work very closely together on this program. We're looking forward to the outcome of this study, which started in 2020, largest study ever conducted in ATTR cardiomyopathy, positioned to deliver the richest data set, not only in the primary endpoint, of course, but in the secondary endpoints, including the combination with tafamidis subgroup that you referred to.

The reason for your question and for the benefit of others, of course, is that nobody has ever shown -- has ever designed a study that can actually determine whether or not the combination of a silencer with a stabilizer will provide added benefit versus either agent alone or versus tafamidis alone, most importantly, which is the standard of care in the market today.

All patients on tafamidis are progressing. Some are progressing a lot faster than others, but they're all progressing, although tafamidis provides benefit to these patients. That's why the combination group is so interesting. It can we actually add further benefit in the combination group.

We have not worked through the -- what we're going to share in our top line announcement. But what I can say is that we believe that -- well, we will present the data at a medical congress as soon as possible after the data comes out and publish in simultaneously in a reputable journal. So all I can say is stay tuned for that. What we share with respect to secondary endpoints in top line results is something that we're going to have to work through with our partner.

And if positive, how soon could this be filed?

Also, we expect to file by the end of the year.

All right. Next, we have a slew of questions from James. First one is, when do you plan to start clinical trials for your first BBB crossing drug?

We plan to initiate our first BBB crossing drug, which I can tell you is a wholly owned neurology medicine, complete to start and complete -- well start IND studies this year to complete them sometime next year to enable a first in-human study second half of next year.

Next question is, it seems like Ionis' siRNA chemistry is much more potent than the competition. Can you elaborate more on this? And also, can the concept of MsPA chemistry be applied to your siRNAs?

Yes. We have a remarkable medicinal chemistry toolbox, MsPA is one of those tools, and we have been and can certainly apply it to siRNA as we do with single strand as we do and have with single-stranded antisense.

And all I can say about our siRNA capabilities are that we've seen nothing that's out there that can beat what we have done. Whether we're better or not, that has to be determined. We get a lot more experience in the clinic. But right now, you're right, early clinical returns have been extremely supportive of our capabilities.

I want to emphasize that this. I don't know of any company that has the expertise to do both, state-of-the-art single-stranded antisense for applications where antisense works best and double-stranded siRNA applications for applications where siRNA could work best. And we're developing both mechanisms depending on the target, depending on the application.

And as I said earlier, we have several SIs in the clinic already, and we're expecting to have more later this year and next year.

A question from James. What is your strategy for follow-on drugs with your more advanced chemistry and technology?

For all of our wholly owned programs, that we have achieved a key inflection point, let's say, proof of concept in the clinic as an example. Based on the advancements we're making in science, we have a high priority. We prioritize follow-on programs if we believe those advancements can be applied to a follow-on molecule that will meaningfully differentiate versus the existing molecule or competition, emerging competition.

We recognize the fact that there's a lot of smart people in the world out there and -- everybody watches what Ionis is doing because we tend to be first in the diseases we target and the targets we go after. So follow-on molecules to build a franchise around an indication is a top priority for the company.

And I gave you an example already. I'll give you 2 examples. One example was the follow-on we have with TRYNGOLZA, which is now about to start Phase II testing in sHTG supports once per year dosing. And I mentioned the follow-on to SPINRAZA, that's in Phase III development with our partner, Biogen and Ionis discovered medicine that supports once per year intrathecal dosing with potential for even greater efficacy than SPINRAZA in SMA. We're going to do that for all of our programs.

James has more questions on the technology. It looks like you've developed several technologies that can compete with competitors' modalities. Do you have plans to showcase these technologies? And what are your strategic plans for them to showcase them to investors?

Yes. So to be determined how best to do that, we -- of course, we published a lot at Ionis. We present at a lot of scientific conferences. Our research team is very active in doing that. But I understand the question, can you pull it all together and really present the overall strategy and the progress you're making overall.

To be determined, we have been incredibly busy with the late-stage pipeline and the launches that I highlighted earlier and even our mid-stage pipeline today. But we are looking forward to maybe a component of our biannual Innovation Day that we've been holding to really do a real focus on science and the advancements we're making there.

And maybe in the second half of this year, we can do a podcast or some sort of webcast and focusing on science. So I guess the bottom line is something we want to do. We just need to find the right time to do it.

Another question from James. Are you building your own internal ligand or peptide library? And so can you elaborate on the strategy for this?

All I can say is yes. We have our own programs internally. We also have a strategic partnership with Bicycle Therapeutics using very small low-molecular weight peptide-like molecules for muscle targeting as well as for blood-brain barrier where we have exclusive rights for all oligonucleotide strategies, ASOs, siRNAs.

It's working really well. Our first Bicycle siRNA is actually in Phase I testing today for a heart indication, targeting cardiac myocytes, that's with AstraZeneca. And -- but we have our own internal programs too. I just can't talk more about them. It's a very, very competitive space, as I'm sure you know.

And one more question it looks like from James is, do you or GSK have plans to develop a follow-on drug for Hep B using MsPA, assuming that this chemistry would have better efficacy and dosing?

Not at this time, but I wouldn't rule it out for the future. What I can say is this, the groundbreaking results that GSK reported from the Phase III studies at EASL and published simultaneously on functional cure rates in the order of 20% to 25% just the beginning.

GSK is committed to -- as groundbreaking as those results are and important for the HBV community, that's the beginning. GSK is committed to this drug, bepirovirsen in this area and are already in clinical testing with combination approaches that sets bepirovirsen up to drive even greater functional cure rates.

So you can see some of that on clinicaltrials.gov, but also there's more in the works, I can tell you that's being planned. So the question really is about how are you going to ensure growing success and real leadership in chronic HBV for many years to come. GSK is doing all they can in that space with respect to combination approaches and further clinical trials involving bepirovirsen.

A question from Howard. Do you have any updates on the development of oral drugs?

We're not pursuing oral drugs at this time. It's -- we've been down that road many times. We've invested extensively. I think we've done the by far the most substantial work and the most innovative work in oligonucleotide oral delivery, whether it be ASOs, siRNAs and so on.

It's just really problematic. Instead, several years ago, we pivoted to less frequent dosing. As I mentioned for certain targets, we're on the cusp of potentially delivering drugs once per year using a low-volume subcutaneous injection once per year.

And in the CNS, once per year, intrathecally or even subcutaneously, which will, if subcutaneous administration works for CNS diseases, that too will be extremely infrequent. That's not going to be a frequent dosing regimen.

We questioned the value of oral drugs versus once per year dosing or twice a year dosing. I mean that's very convenient for patients and doesn't cause the burden of oral delivery often frequently every day or so. So we've pretty much moved away from oral delivery.

Another couple of questions from Tom. Where do you think stand with respect to your collaboration with Metagenomi and other gene editing efforts? Will you bring a gene editing drug into the clinic in the next year?

Our partnership with Metagenomi continues to go well, very well. We have late-stage programs in research, drug discovery research. We haven't disclosed -- Ionis has not disclosed targets that we've prioritized yet. We expect to have a candidate by next year, probably the first half of next year, our first candidate involving gene editing.

I want to emphasize again that -- or I want to emphasize that the know-how of Ionis with respect to chemical modification of nucleic acids and understanding nucleic acid biology and drug discovery, nucleic acid-related drug discovery is something we're taking full advantage of with Metagenomi in developing state-of-the-art gene editing approaches.

And just general know-how of understanding how to discover drugs involving nucleic acids. So it's going well. We expect our first candidate discovery efforts are going well. We expect candidate not too far down the road. And as far as when we initiate clinical studies, that's to be determined, but it's not going to be next year.

Next last question from Tom is, how many Phase I trials do you plan on initiating in the next 12 months? And can you tell me what the targets for these drugs are?

I can't talk about targets at these targets at this stage where until they reach posting on trials or we start the Phase I study. I did mention already, we just started Dravet syndrome Phase I/II, first-in-man first inpatient study. So we refer to that as Phase II study. That's underway.

We expect additional first-in-human starts this year. Typically, we move 3 to 5 new drug candidates into development each year, and that has a trickle-down effect of a similar cadence of new clinical trial starts each year. So that's the ballpark for new trial starts for Ionis, and we're well on track for that this year as well as next year.

We have a couple of questions from Ted, who's asking about tissue delivery. First question is, where do things stand with Ionis targeting skeletal muscle, skeletal muscle targeting drugs entering the clinic in the next year?

Potentially, we have several late-stage drug discovery programs using the Bicycle technology, coupled with an ASO or an siRNA for muscle targets for neuromuscular diseases that are, as I said, in late-stage drug discovery. They have the potential to get through tox next year, assuming everything goes well and maybe get into the clinic in the second half of next year. That's to be determined. We don't have the drug candidates yet. But if everything goes smoothly, I wouldn't rule out a clinical start next year.

Second question that Ted has is about -- where do you think stand with Ionis' inhaled drug programs and Ionis any inhaled drugs into the clinic soon?

We have our first medicine using Ionis advanced chemistry, MsPA chemistry, in particular, using an antisense oligonucleotide with that chemistry incorporated for a target. I don't believe we've disclosed the target yet. That candidate, it looks great in preclinical models. That's our first reentry into pulmonary disease in the inhaled route of delivery.

We're hoping to start IND tox studies in the second half of this year, and then you could do the time line. The tox goes well, if we complete it next year in enough time in advance, maybe we can start a clinical study end of next year. Maybe it will be 2028. We'll see about that. But pulmonary is advancing forward nicely.

All right. I think we have one more question, and it's from Denis on behalf of Gary Nachman from Canaccord. Where are you currently with the Angelman study in terms of enrollment completion? Is there any color that you can provide on the baseline characteristics enrolled thus far in terms of age, gender, location and maybe how it compares to the original Phase I/II trial you ran?

Yes. So let me back up. Our Phase III program for Angelman syndrome has a pivotal study for people, I believe, between the ages of 2 to 18, nearly about 200 patients or so, give or take, all being dosed at 80 milligrams quarterly in that study. And that's the dose that showed the best evidence of efficacy in our Phase I/II HALOS study across all measurement tools as well as all clinical measures for each of those tools, Bayley-4, SAS-CGI as examples.

Very encouraging data there. We expect enrollment is going really well. There's a lot of enthusiasm for our Phase III study. And we expect to complete enrollment this year with Phase III data next year. We haven't provided more granularity than that, but we'll certainly announce when we complete enrollment for that study.

And the other part of the question, but I think pretty much covered it. I'm sorry, that's what I was going to say. In addition to the pivotal study, we also have additional studies going in parallel for the newborns between newborn to 2 years of age as well as in adult patients.

And in our Phase I/II HALOS study, we actually showed good evidence, strong evidence that even the adults were benefiting, not just the teen the 2- to 18-year olds in the study. And of course, we all know based a lot on Ionis research, drug discovery and development that the earlier you can treat neurological diseases, the better you are.

So we believe that the greatest benefit will actually be getting to those newborns as quickly as possible. And that's why we initiated the infant study, which is now underway.

And the second part of these questions are about the competitors' readout this year. So he wants to know what are the read-throughs that we could expect from the trial readout later this year for the competitor drug? And is there anything you could do to change your Phase III trial after seeing those results?

So let me just start by saying that we're pulling for all modalities to have success for the treatment of these devastating diseases that we're tackling, right? We think options for patients is best. It's best for all parties, patients, HCPs as well as sponsors.

It just lends to greater success for everybody. But I will also say that let's not forget the fact that Ionis has been in CNS diseases for multiple decades now with great success. I talked about the drugs that are already approved and the proof of concepts and the drugs to be approved later this year as well as proof of concepts that are coming that we've already achieved in neurological diseases.

We're using a chemical platform in our Angelman's program that's essentially identical to SPINRAZA and QALSODY and TAU, all the drugs that have shown value, zilganersen for Alexander's disease. So it's a proven platform. The competitor that is going to have Phase III data later this year is a very different platform, very different approach, very different dosing in the study.

But we are very much looking forward to the results later this year because it will be the first randomized controlled study using an oligonucleotide approach for Angelman syndrome. Can we learn from that?

Sure, we can learn from it. Can we modify our study in certain ways within limits. Within limits, we could potentially do we expect to? Probably not. We like the design of our study. It's very well designed. It's based on our Phase I/II ALS study, which was very successful. And it's using a platform that's proven. But certainly, we'll be paying attention to it, and we're very hopeful that they have success.

And we have time for one last question from Ted. Is there a priority review voucher associated with the approval of the Alexander disease drug?

No, there's not. We do have breakthrough therapy designation, priority review. Okay. Well, those are all great questions. I really, really want to thank everybody for listening and your participation in our shareholder meeting today.

I very much enjoyed it. And I think you agree with me that based on all the progress that I've summarized for all of you today and additional successes we've had that I didn't have a chance to get to that many of you are aware of, Ionis is really, really well positioned to really drive value, tremendous value, accelerating value for all Ionis stakeholders, our shareholders, HCPs, the medical community and most importantly, to the patient community.

So thank you for listening. Really proud of the update we've been able to give today and stay tuned. There's a lot more coming from Ionis.

Thanks, everybody. Luca Issi, Senior Biotech Analyst here at RBC Capital Markets. And today is our great privilege to have Ionis Pharmaceuticals as part of our 2026 Global Healthcare Conference. Representative of the company, we have Holly Kordasiewicz, who is the Chief Development Officer; Holly, thanks so much for joining us. How are you doing today?

Great. How are you?

Good, good, good, good. Yes. We have a list of questions. But maybe before we go into the specifics, it will be fantastic if you can maybe talk a little bit big picture about what progress has the organization made over the last few months and kind of most importantly, Ionis?

Yes, absolutely. So it's been an exciting time. We had our first 2 independent launches last year with TRYNGOLZA in FCS and DAWNZERA and HAE. We're, of course, planning for 2 PDUFA this year. For again, we have TRYNGOLZA for sHTG coming up in June. Hopefully approval and then launch. And then at the end of the year, we have Zilganersen for the treatment of Alexander's disease, which is our first wholly owned neurology program that we'll be launching.

Following behind that, we then have 5 Phase III readouts this year. The first is bepirovirsen, of course, this was positive. The data is going to be presented later this month at EASL, we then have 2 cardiovascular outcome trials reporting out later this year. One is cardio transform for ATTR-CM and then, of course, pelacarsen, the HORIZON study looking at Lp(a) lowering. And then behind that, we have a robust mid-stage pipeline that's advancing, and of course, our partners at Biogen just last week announced the tau program and that they're going to be advancing that into Phase III clinical testing. So busy times but lots of opportunities for continued growth in 2026 and beyond at Ionis.

Got it. Got it. Super helpful. I'm going to start asking you about your questions now. I know you're not going to answer. But I'll ask anyways. Obviously tau data fresh off the press. Biogen presented the top line data last week. It sounds like the data is good enough for them to actually pursue a Phase III trial. Just tell us a little bit more about what is your reaction to that top line data? And is there any context you can provide in terms of like what benefit they have shown in terms of [ CDR ] sum of the boxes or ADAS-Cog and how does that benefit kind of compares to the a-beta antibodies, like I think that's some of the questions we're getting from investors. So any comments would be much appreciated.

First to start, I will be excited about this program and this data for the 80 patients and community. This is a new mechanism of action. So here, we are using an oligonucleotide to lower tau. So we're lowering intracellular tile because we're stopping production of tau. So a new way to go after the disease. In our Phase I study, we had robust reductions in CSF tau, which is our pharmacodynamic biomarker as well as reversal of tau PET. So it was the first time in an AD brain, where we actually showed clearance of pathological tau. So that biomarker data in the CELIA Phase II study, which Biogen just reported on last week, it replicated. So we have those nice reductions in CSF tau and tau PET. And then it also showed, and this is what it was designed to do, a benefit on cognitive endpoints. And they were unprecedented. It is the first time anyone has shown this with tau. They are in line with what has been shown with amyloid therapies and, in some cases, exceed it. So very encouraged by the data. It met Biogen's prespecified endpoints for going into a Phase III.

So excited that they're advancing that. They have the data that gives them confidence to do that as well as the data needed to select dose and design that next study.

Got it. Got it. Super helpful. Any context on how placebo has formed in that trial. Obviously, we're seeing, especially in small data sets, sometimes placebo underperformed or overperformed can magnify the benefit or underrepresent the benefits. Is there any context of what placebo has shown in that trial?

So fortunately, in the space, we have lots of data on how this should perform in this patient population. And there's nothing in either the biomarker data or the cognition data that says it's not performing as expected.

Got it. That's super encouraging. What about the lack of dose response, if you will. I mean, obviously, Biogen have mentioned that the cohort that showed the best cognitive benefit was actually the lowest dose, which is obviously a little counterintuitive. I guess, what's the best way to rationalize that. If I recall it correctly, the lowest dose is also the one that has the smallest end. So could that have been confounding and amplify the benefit? Or how should we think about that part.

I think so. So all doses showed a benefit. That's the important point is all those has showed a benefit. And there's overlapping of all of that data. And so this isn't unexpected given the doses that were used in the target engagement that we observed. And that will all become clear once the totality of the data is presented at AAIC in July.

Right? I guess we stay tuned for dead data that is obviously coming. Maybe just pivoting to severe hot progress. Obviously, the PDUFA date is only 6 weeks away. How do you feel about it? Are you guys already in discussions with the FDA?

It's progressing as planned. We feel excellent about it. Of course, this is Phase III study where we had beautiful data, efficacy data. Here, we had an 85% reduction in AP events in people with high triglycerides. And so that we also received a breakthrough therapy designation based on that data. and that gives us a lot of confidence going into the discussions with regulators. Everything is on track for that PDUFA date on June 30.

Got it. Got it. That's actually helpful. I think when you look at the data set, there's maybe a little bit of a worsening in liver fat. And again, it's -- the magnitude of the increase in liver fat is relatively modest. But how should we think about how that data will be potentially reflected on the label? Do you think that that's going to only be in the diverse sections of the label? Could there be something more? Could this be like a REMS or a black box warning or how should we think about the...

No. So. it is well tolerated in CORE-1 and CORE-2 studies and in the ASCEND study. So we do not expect any monitoring or anything like that. This is -- to be clear, this isn't a safety signal. This is a biomarker signal that does not correlate with any sequelae or any other safety signals or biomarkers. This is information that has been shared broadly with HCPs. They have no concerns about this given, of course, the benefit profile that we see with TRYNGOLZA. And so taken together, this is not of a concern. This is on mechanism. This isn't unexpected, given that we are drastically lowering triglycerides over 70% in the Phase III studies, that rapid clearance of triglycerides it's going to end up in the liver.

Another important thing is that we're following these individuals over time from the CORE-1 and CORE-2 studies, they were all able to roll into an open-label extension where we're continuing to monitor this for over 2 years. And over time, we're seeing stabilization and then coming back towards baseline.

Got it. Got it. That's actually helpful. For severe hypertriglyceridemia, how are you thinking about the TAM. Because I think, obviously, there are a lot of patients out there that have severe hypertriglyceridemia. However, when you look at the patients that have severe hypertriglyceridemia and a history of acute pancreatitis is the TAM is much smaller, maybe like single digits type of percentage when you reflect on the 3 million versus the one that have historic pancreatitis.

So is this going to be a aimer prevention type of drug for patients that don't have the historic pancreatitis will receive the therapy? Or do you think the scenario the payers will restrict the access to this drug to primarily the patients that have historic pancreatitis up? How we think about it versus secondary prevention?

Yes. So we've set this program up specifically not to restrict access. So there's 3 million patients that have high triglycerides over 500. Within that 1 million patients, we consider a high risk. And those are the original patients that we'll be focusing on. Everybody over 80, which then puts them at severe risk and then over 500 with history of acute pancreatitis, and that's still 1 million patients. So that's where we'll be starting. But we will get to all those patients then at 500 and above that do have risk of acute pancreatitis.

Got it. Got it. That's helpful. Maybe pricing, it feels like your thinking around pricing has evolved over time. And you now obviously have settled to $40,000 as the -- your WAC. However, your competitor last week came forward with $45,000 WAC. And again, I think they have an argument that maybe their drug is dosed less frequently, and they could have some pharmacological properties that are different versus your molecule? Like -- what's your take on what was your reaction to Arrowhead actually pricing their drug of $45,000 versus $40,000?

So our approach is entirely data-driven. So we first did HCP research. We're using our CORE-1 and CORE-2 data. So with our Phase III data, we took that out to understand demand once we understood demand with existing Phase III data in hand, we then were able to talk to payers and work out the pricing implications based on that as well to find a price that would get us the broadest access to the most individuals, so not limiting the access but still having a favorable price. And then that's where we learned it on the $40,000 WAC.

And so for our -- for the other company, they don't have Phase III data yet. They don't have information in sHTG. And so we did a data-driven approach.

Got it. Got it. That's helpful. Obviously, the company has guided peak revenues. And I think that has been a little bit of a moving part. I think you guys started with $1 billion, then I think JPMorgan was $2 billion, I should say, $1 billion plus, then became $2 billion plus and now most recently is $3 billion plus. Walk us through like some of the assumptions in your model that got you there? Is it just simply a function of price? Or there are other variables, including either access or discontinuations or walk us through the evolution from $1 billion to $3 billion. That's a big delta.

So the first [indiscernible] it was demand eased on the data. So the Phase III data was excellent. We had an 85% reduction in acute pancreatitis events. This leads to a number needed to treat in 1 year in the high-risk group, the over 80 of 4. So only 4 patients need to be treated at 1 to prevent an acute pancreatitis attack and only 20 patients in that larger population. So with that really remarkable efficacy data, we then took that out and did the demand research. And it was the initial demand research that led us from that $1 billion to the $2 billion. And just the sheer number of patients, the doctors are planning on prescribing this for. Then once we got to the $2 billion, then we did the pricing work. And we had initially assumed a lower price.

And then once we had done that work in hand to make sure that we weren't restricting access to the broader patient population that we would still be able to get the drug to everybody that we need to get it to, and that's where we increased it from $2 billion to greater than $3 billion.

Super clear.

And just to say it, this is a population that didn't exist before we had this drug and the way that we're now thinking about it. So this growth isn't unexpected given that we're just learning as we're doing this and generating the data.

Yes, yes. And certainly conversations with payers and what not, obviously influence some of these assumptions, so makes to sense to me.

Maybe, again, going back to your competitor, I think investors are under age their seats waiting for the SHASTA-3 and SHASTA-4 data. Again, their trial is designed slightly different than your trial, ruble smaller trial. There's also some differences around randomization. So we're not -- what's your take? Do you think that Arrowhead had a chance of hitting the second -- key secondary endpoint of reduction in acute pancreatitis in a statistical significant fashion?

I think they have a good chance it's going to be really hard to beat. It's a high number, but I think they have a good chance at it. And that's actually favorable in that having 2 people out or 2 companies out on the market is only going to help, as we just discussed, that this is a new market, it's a growing market. And so having more voices out there to help raise awareness is going to help those patients.

And we certainly have seen that movie over and over again with more players, there's also often market expansion there. So it's sometimes it's not about market share, but it's more like market expansion.

So maybe if I can pivot to Angelman, which I know it's your bread and butter, if you will. Maybe just talk about big picture of what data have you seen so far? Maybe just remind us about differentiations versus Ultragenyx and maybe just walk us through what's next year. Maybe if I can, quickly, things that comes up in conversations with investors a decent amount. Can you just refresh our memory for why Biogen ultimately decided to pass on that program.

Yes. So first of all, this is a neuro development disease. So this is not a degenerative disease like some of our other CNS programs where we see decline. These are individuals who they develop cognitively to about the age of a 2- to 4-year-old and then they stay that way for the rest of their lives, and they have a normal lifespan. So what we've seen in our Phase I study, which is our open-label HALOS study, it was an improvement across domains and across measures. So these individuals have motor, communication, cognition, this function. And across the board, we saw benefits across all those various domains. As you would expect, if you were restarting neuro development, which is the mechanism that we think will be happening by targeting the underlying cause of the disease.

We also saw this across measures that were physician administered, physician reported and parent reported. So it's nice in an open-label setting to see consistency in the data across different ways of collecting it. So we have a benefit across these different domains, a restarting of development that appears to be happening in individuals that really just have stable development once they hit that peak at about 2- to 4-year-old neurotypical development.

And so with that, that gave us confidence to go into the Phase III study. The Phase III study is enrolling right now. We plan to complete enrollment for that this year. It's a 1-year primary endpoint in the REVEAL study, and so then that will read out next year. And then in terms of Biogen and why they passed, there was risk in the endpoint. They wanted to derisk that. They wanted more information. We did not want to give any more time. This is a program that we very much wanted back. We wanted to build our neurology portfolio. We had pivoted as a company from just an R&D company to an R&D who is going to then take things through commercialization. We saw this as a really attractive fit, as you can imagine, with Alexander disease, which is launching later this year, assuming approval. And so in total, this is something we want back. We didn't want to negotiate. They want to negotiate and so it's ours.

Got it. Got it. Got it. That's super helpful. What's your take on the Ultragenyx approach? I think it's fascinating to me that there are splitting alpha actually between 2 separate endpoint, right? So obviously, they have daily store cognition and they're spending most of the alpha on the Bayley-4 cognition, but they also spend some of the alpha who MDRI, which is more of a composite endpoint. You obviously, you have a different approach here because you have a separate primary endpoint using expressive communication as a primary point. Have you -- are you potentially considering doing something similar where you split the alpine, -- you maybe have kind of 2 shots on goal? Or what's your take there?

So we'll see the data. So right now, we are focusing on our primary endpoint, which is expressive communication. This is the #1 thing that is most important for caregivers. There was a listening session last year with the parents overwhelmingly said, I want my child to be able to tell me when something is wrong to tell me what they want. These individuals, most of them are nonverbal. So as you can imagine, it's very difficult for the family. So that's the main thing that they care about. It was also the thing that we saw the greatest effect on earliest and it had the most stable natural history, so the most stable baseline. So it gives you the biggest delta for, in effect, in a Phase III study.

And so with that, we have confidence that we have a meaningful endpoint. It's also clinical meaningfulness. The expressive communication is if someone is communicating, they're going to score higher on it. So it has inherent meaningfulness in that. That's very different than some of the other endpoints, which are building blocks, how do you judge the clinical meaningfulness of building blocks, where clinical meaningfulness of communication is implicit. And so that taken together, we're happy with where we're at. But of course, we'll see the data. We'll see the data. This is one of the benefits of coming second is that we can see that readout and then adjust based on data as necessary.

Got you. Can you expand on adjusted necessary? Like I mean, I guess, what are you primarily focused on is to see the data from Ultragenyx? It sounds like their data is coming late this summer. So like what are you primarily focused on? And do you have optionality in your protocol to amend the protocol and maybe make the protocol -- maybe your trial either longer or bigger like talk us through on some of the moving parts there and how you're thinking of potentially adjusting your trial base their data.

So we're looking for the placebo effect. So nobody knows the placebo effect in Angelman syndrome at this later time point. There has been shorter studies, but there haven't been 1-year long studies with these clinical endpoints in Angelman. So that's the #1 thing to look at because all the data generated to date is open label. And so seeing that will be very meaningful. And then, of course, how the different responses are. Now if they don't have a robust response, that's -- that's not surprising, given that they're using a very low dose, but we will pay attention to that as well. And then in terms of adjusting things like our SAP can be easily adjusted.

Got you. And especially because they're going to probably read out at the time where your trial is not fully enrolled yet. Would that be a fair assumption at this point or not necessarily?

No, not necessarily. We're not giving out any of those kind of data.

But you're saying...

Can change.

But you're saying that the trial will be -- your trial to fully enroll second half of this year? Is that...

We haven't given the details this year.

Okay. Okay. Okay. That's helpful. Maybe one last question on Angelman. Maybe just remind us the commercial opportunity here, should it tryouts work? How many patients are out there? Maybe I know it's preliminary at this point, but just any commentary at high level or how you're thinking about pricing?

Yes. So this is a -- there's 100,000 individuals, we think, in the U.S. in major markets, and this is a rare neurological disease. So we expect it to be similar to previous to other rare programs that we have, assuming positive Phase III data in efficacy.

SPINRAZA type of pricing or too early to comment...

Too early to comment. We're within that rare neural range.

Okay. Okay. That's helpful. You mentioned cardio transform. I think a lot of people are obviously eager to see that data. I think you presented recently the baseline characteristics. I think you highlighted that -- this is much more of a contemporaneous population. So like there's a lot more patients on tafamidis to baseline or more patients on SGLT2 are baseline and what not. So -- just maybe just remind us how you design your trial and at the end of the day, how confident are you -- I believe you now have 3x the number of patients that Alnylam had on HELIOS-B on tafamidis baseline, I think it's 819 but they only had 259 patients tafamidis -- is 819 patients tafamidis baseline, a large enough sample size that you think you can actually hit the stats as add-on to tafamidis.

Yes. So that is not the expectation. So it is not powered for statistical significance on the secondaries. We did release the study design recently. And as you can see, at 6 in the hierarchy. So it is in the secondary hierarchy, but it is 6. So everything else would have to hit to get there. And so we are encouraged, though, by the size of the study. We intentionally designed this as a very large study, as you mentioned. We have more folks on tafamidis than there were in the total previous studies. And this will give us information about how it's behaving.

So the expectation for this study is on par with what the previous silencer data has looked like. And then anything with tafamidis is going to be on top of that and upside.

Got you. Got you. Okay. That's helpful. You mentioned earlier LOI's probably one of the biggest catalyst in medicine maybe to is going to be the next cholesterol, who knows. However, I think you powered a trial to show a 20% to 25% benefit depending on what sub populations you're looking at. However, it feels to me that some of the recent commentary from Novartis kind of implies that maybe the benefit could be a little more modest. So maybe instead of 20% to 25% relative risk reduction, this could be more like in mid 10% or 15% relative risk reduction. Should that be the case? Do you think that, that would still be a commercially viable product?

Yes. So nobody knows what the rate risk reduction is going to be. That's the trial that we're doing right now. This is another first for Ionis, where we're asking for the first time, if you lower the largest untreated risk factor in cardiovascular disease, what kind of benefit can you have? And so we'll find that when the trial reads out. The question on is 10% to 15% enough yes, and that's really from research and talking to KOLs and getting feedback from the community on what they would need to see to treat. And the answer is that 10% to 15%. So that's where that shift is coming from. And it's really based on the fact that with the human genetics -- this is very clear that this is an independent risk factor. So you can control everything else, you can get the LDL down extremely low, and you still have this risk that's coming from the Lp(a).

So because there's nothing to treat it because this is an on mechanism directly on target treatment that they would then do that.

Got it. Got it. That's actually helpful. That's actually helpful. Maybe just fill into the out of PDUFA date did you have upcoming Alexander disease a small indication, maybe just talk about what would an approval for the community, which would be obviously huge given the unmet medical need. And then I mean how confident are you in approval, again, technically, I believe the p-value was 0.0412, so relatively close to the 0.05 kind of magic number. So like how do you feel about probability of approval at this point?

We hit that tag on a primary endpoint that's clinically meaningful for patients. in an ultra-rare patient population. So very excited about that. We got breakthrough therapy designation because of that. So confident going into this that there's a path forward. and a very clear one and straightforward one, given that we have that beautiful data.

And what this means for the community is an excellent question and most important, the outpouring from the community has been just overwhelming when we announced this data. They have nothing. This is a progressive neurodegenerative disease that affects children that affects adults. It is almost always ultimately fatal. It affects most systems. And so there's motor, there's cognition. There's across the board effects that these families are dealing with in these individuals. You hear the parents talk about it.

And the kids game a new developmental skill and then they lose it because the disease progresses. And so they work so hard to get something and then they lose it. And what we've shown in the data is a stabilization. And then if you have that stabilization in the motor endpoint, which is the primary endpoint that once they make those gains, they can keep them.

And then we also have in the secondaries, they all favored zidinersen and that -- so that targeting of the underlying disease is providing that broad benefit for the individuals. So with that, in totally, very excited about this program and to get this to patients. We have an EAP open. It's enrolling very well, lots of enthusiasm brand to continue to try to get this to as many folks as possible.

Got it. I have a lot more questions, but limited time. Thanks. Appreciate your time. Thanks, everyone, for joining, and we'll talk soon.

Thanks again.

So conversation, I think, is not surprisingly going to start with just the commercial opportunity for olezarsen in sHTG. And you've got an important FDA action date coming up here, June 30. So maybe just talk about how you're positioning for your first major launch as a company. Commercially, you've launched this drug Tryngolza for an ultra-orphan indication, but now you're migrating to [ sHTG ] with a very big market, a more complicated probably end market, I would imagine. And so maybe just level set in terms of how Ionis is getting ready for kind of a transformational event for you as a company.

Yes, sure. Let me begin with FCS because that's the current indication for Tryngolza. Patients with a genetic cause of severely elevated triglycerides. The commercial launch for Tryngolza has been very, very strong, very positive. And the HCP demand -- patient demand, for patients that have FCS has been very, very strong and continues to get stronger and stronger week by week. That's been driven by the overall therapeutic profile of the medicine as well as the sentiment from both patients as well as HCPs who are managing these patients.

These patients are feeling really good. They're seeing their triglyceride plummet. Many of them into -- well into the normal range, and they're seeing a prevention of acute pancreatitis, which, of course, they live in fear of all the time. That launch will continue through the expected sHTG launch that you referred to on June 30, a PDUFA date June 30 with priority review and breakthrough therapy designation. We reported Phase III data for sHTG last year that was just groundbreaking with an 85% reduction in acute pancreatitis and triglyceride reductions on top of standard of care that exceeded 70%, really, really groundbreaking results. And we're leveraging that data. We've leveraged that data to get priority review.

This is a multibillion-dollar product opportunity for Ionis, is a wholly owned program, and it puts us into prevalent diseases for wholly owned programs and launches that you referred to. We are well prepared to launch into this multibillion-dollar product opportunity. We have trained -- we have hired and trained our field team. They've been out in the field educating on severe hypertriglyceridemia for cardiologists, endocrinologists, with the specialists, but also they've also been identifying accounts. Physicians who are managing these patients at high numbers with high numbers, high volumes of patients that are being handled by these physicians. So we're targeting these patients. We're identifying the high prescribers, and we're going to be ready to launch in June, assuming an on-time approval on June 30.

When we think about the key learnings from the FCS launch and how they're applicable to sHTG, I recall when you were initially launching FCS, there was a lot of discussion we had about patient finding, right, genetic component to the disease. Here, when we think about something much more broad, right, those early adopters of Tryngolza for FCS, how important are they to sHTG early adoption? And maybe just talking about how much broader you need to reach now with the sHTG indication with that disease?

Well, it's very important because the physicians who manage FCS patients are also managing sHTG patients. And we built tremendously positive sentiment in that community. Because they see the efficacy and the excellent safety, the tolerability that Tryngolza is offering. And what we're hearing from those physicians is this is great for my FCS patients. I've identified more FCS patients. I want to put them on Tryngolza. When can I get access to Tryngolza for my severe hypertriglyceridemia patients, which, of course, on a volume basis, we're seeing many more of there. So it's launching from FCS to sHTG has provided a big advantage for us. And of course, we are first to market in FCS. We're going to be well ahead of any competition first to market in sHTG, which has been -- which is going to be really important.

Okay. In third quarter, there will be some competitor data for another APOCIII-modulating agent. And you have about a 1-year head start to the competition. And I'm just kind of curious how you view the competitive dynamic, right? Like is 1-year first-mover advantage material? Or ultimately, hey, this is a big market, 2 players more than enough to support 2 players, and it may actually be advantageous to have 2 companies out there investing and building out this market opportunity.

In the United States alone, there's more than 3 million people with severe hypertriglyceridemia. About 400 or 1,000 of those patients today are being treated ineffectively really with generic fibrates and fish oils. So this is a growth market. This is an untapped market and a market with high unmet medical need, and there's room for multiple players and more players in this space that deliver effective medicines will only grow that market out even further.

With that said, there's -- we're really thrilled, and we believe it's a big advantage to be first to market. Because it allows us to identify those high-volume treaters and get to those high-volume treaters. Those treaters who are treating the patients that are at the highest risk for acute pancreatitis or cardiovascular disease, which will be the priority to get those patients in as quickly as possible. So we're going to access to those patients more rapidly and secure those patients. As I said, the experience with Tryngolza and FCS has been wildly positive. So we're expecting that sentiment to translate to sHTG. Patients will stay on drug, and we'll continue to accelerate that by really over a year advantage at the market. In addition, it allows us to set up accounts with payers and build a relationship with payers, set price, which we did for our WACC price for sHTG. So there are lots of different advantages that we're taking full advantage of as first to market for sHTG.

So these drugs are effectively being positioned as pancreatitis-sparing drugs, right? Ultimately from the core study results. And so as you think about these individuals who had past events, right? I would imagine they are that initial first adopter, right, of the therapy, most highly motivated. Is that your sense? Are these patients -- is your feedback from physicians, KOLs that these are the types of patients who might be more asking about when a therapy like this can become available? Are they because of these past events perhaps under the care of a specialist who might be aware of clinical stage data as opposed to maybe more of a community-based doctor?

Out of the gate focus will be on the high-risk patient population. One segment of that high-risk patient population are patients that have had a history of acute pancreatitis. The other segment of that population is patients that have triglycerides 880 milligrams per deciliter and above. They're at high risk for their first time AP event, if they haven't had one yet. The motivation by patients that have had an AP event in their past is extremely, extremely high as it is HCPs, of course, because there's nothing they can do for patients that come to an ICU with an AP event. It is incredibly painful. Patients don't want a second event. So they are highly motivated.

However, HCPs that are managing patients with triglycerides and above, whether they've had an AP event in the past or are also highly motivated because they want to prevent that first AP attack from happening. Once you have AP attack, the chance of having additional attacks goes up exponentially, leading to organ dysfunction and destruction. So it's -- HCPs are highly motivated whether or not they have had a history of AP or not, but certainly, patients that have had AP, they don't want another one.

All right. Great. Maybe just help reconcile you revised the pricing in advance of the sHTG launch for pricing to be more in line with a broader market opportunity that is sHTG. I guess just trying to understand that versus some comments recently about wanting to wait -- payers wanting to wait until they see a final label to have more meaningful discussions. Is that just mechanical, right? Like payers just need to fundamentally have a label? Or are there specific label outcomes that you feel like are going to drive access relatively PA to label, like a PA that matches study entry criteria? Because if that were the case, that would suggest broad access, I would argue.

So let me start with the $40,000 WACC price that we announced for sHTG that went into effect on April 1, how we got there. That price was the product of 1.5 years, maybe even 2 years of research with payers and HCPs. We first had to -- once they have the Phase III data to understand which HCPs are going to prescribe Tryngolza to which sHTG with what priority based on the Phase III results. As I mentioned, the Phase III results were groundbreaking.

We then took that HCP demand research to payers to understand where their limits would be with respect to putting in place blocks of -- NDC blocks or other blocks that would delay access for patients due to price being too high. We believe that we've threaded the needle perfectly to maximize access and to maximize value with a $40,000 WACC price. The conversations, the discussions we've had with payers have been deep, intense, very positive, very productive. We are aligned on the $40,000 WACC price. We do not believe the label is going to impact access in any way. We kind of know what the label is, and that's what we presented to payers.

We received breakthrough therapy designation, which basically gets translated to the ultimate indication saying, which is patients with sHTG as defined by triglyceride 500 and above as an adjunct to diet, and that's the label we expect. We do expect acute pancreatitis to be in the label probably in the clinical trial section because the results were so statistically significant and was a prespecified secondary endpoint. And it's important to have it in there. With that said, we don't think that that's going to drive adoption because everyone is aware of the AP data already for publications and presentations. And certainly, the payers are aware of it, and that has resonated extremely well with them to prevent ICU hospitalizations, prevent potential fatal outcomes and so on. So payers are...

The last point you made, the omission of the language that is in some triglyceride lowering therapies front page to say this drug has not been studied for pancreatitis reduction, whereas you've now studied it. I imagine that label language will be deleted from a [ Tryngolza ] label for sHTG. Is that right? And sales reps not sort of alluded to the fact that, that label language is now...

Yes, absolutely. We do not expect -- obviously, it was studied for AP outcome, and it was highly successful. So it will -- that statement will not exist in the label. In fact, we'll have AP data that we expect to have in the clinical trial section of the study. The other point I think might be worth mentioning is guidance, clinical trial or clinical treatment for FCS and sHTG, the guidelines. The Tryngolza is indicated in the guidelines for FCS, and we expect that Tryngolza will be in the guidelines for sHTG pretty quickly after approval as well. The guidelines were adjusted very quickly. And Tryngolza singled out as a treatment for FCS, we think a similar same thing will happen for sHTG.

That recommendation presumably will be tied to the pancreatitis outcome benefit. I know there's some theoretical possibility, right, that in like a comorbid diabetic patient lowering trigs might actually have cardiovascular benefit, but that hasn't been studied. I doubt it will ever be studied. But if you can speak to how you'd envision guidelines and recommendations evolving within the launch of the product?

I think the guidelines will be focused on the triglycerides. If patients are above 500, they need an APOCIII inhibitor and Tryngolza will be the first one out there by a long shot to be the treatment for to manage sHTG. It will not be in the guidelines for managing cardiovascular outcome because we didn't study that outcome, as you pointed out.

With that said, although the high-risk patient population that we're focused on is primarily patients that are above 80 and/or have a history of acute pancreatitis. There are a lot of patients that have triglycerides well above 500 that have cardiovascular disease -- and that -- those are the other comorbidities that round out the million-plus high-risk patient population. Cardiologists recognize that having triglycerides that high puts them -- predisposes them to cardiovascular risk, and they're going to want to get their triglycerides down to the normal range, which we achieved more than 80% of the time in our sHTG Phase III trial. So we do believe that, that's going to be an added benefit for the sentiment towards prescribing Tryngolza is also those patients that have a history of cardiovascular disease because they recognize that this is a contributor to cardiovascular disease.

Okay. And then just circling back to price. I believe both you and your competitor have declined to speak specifically about kind of what gross to net would look like over time. But can you just maybe remind us about payer mix? Because I imagine with the government plan patients, there will be some mandatory rebating that needs to be offered. And I imagine like rare orphan comps and maybe even oncology drugs might be a good proxy for the spread between gross and net. So any high-level commentary that you can offer?

Sure. I mean what we can say is that when we first discussed the market opportunity in the U.S. for Tryngolza and sHTG in January of this year, we assumed the net price that we announced of $10,000 to $20,000. We're still doing our market research. So we have a lot more work to do, a lot more payer research to do. That was a net price that was used in the U.S.

As we developed our HCP demand research and then had our payer engagement research completed, we settled on the $40,000 WACC price. That's going to bring us in meaningfully higher than our original net price, which is the main driver behind our upgrading our peak product sales in the United States beyond $3 billion. We upgraded it from $2 billion to above $3 billion. And that's because our net price will be higher in that $10,000 to $20,000 range. Other than that, we're not -- we're really not going into more detail about net pricing and rebating at this time. Okay.

And maybe a few questions just on safety. Olezarsen safety looks pretty pristine. Do you think this is going to be easy drug to administer. Monitoring requirements can sometimes add a layer of complexity for the drug. Do you think this will be a drug that has many safety monitoring requirements tied to it in the sHTG setting?

Yes. No. I mean, first of all, FCS has no monitoring. It's a clean drug and no monitoring was required. That's one of the reasons why the launch has gone so well in FCS. And we don't expect monitoring in sHTG. Why would we? It's a very clean profile, extremely clean profile, and we don't see the need for monitoring at all. And right now, all of our discussions with the FDA have been going very smoothly, and that supports my conclusion.

Yes. Because what I wondered is there's obviously going to be a lot of work done to determine patient triglyceride level at baseline. I imagine they may look at something like liver fat at baseline and whether or not there might be any sort of requirement to follow and look at how both of those clinical measures are over time, presumably the same measurement.

We don't expect hepatic fat to be measured at all in the real-world setting on the market at baseline or any other time. Let me level set here a little bit. So in our Phase III study, we reported a small increase in liver fat in patients with sHTG that was dose dependent. It was small, but most importantly, there was no clinical sequela, no clinical outcome, no adverse events or reactions related to that, right? So there's nothing to monitor. There's no correlation with ALT.

MRI imaging of a lab observation that has no clinical consequences is just not something that would be required. It's just an observation. It's also an on-target effect. We know that from a competitor program that has a silencer that reported in Phase II, a dose-dependent increase in liver fat. And it makes complete sense. What we're working through using the APOCIII mechanism of action are 2 pathways that are substantially and rapidly lowering triglycerides in circulation. One is to break down the LDL particle, the triglycerides into fatty acid. The second is to clear through the liver very rapidly. And the liver does a very good job of clearing out the fat that much is true. But there was some residual liver fat that we saw in the -- at the 12-month time point in the Phase III study.

What I can tell you, though, is that we continue to monitor these patients that are in the open-label extension, and we're seeing as expected that the liver continues to compensate and clear out the liver triglycerides, we're seeing a return to baseline at 1 year, which further continues to get to baseline at 2 years, and we're going to report that data at a medical congress later this year. So we don't expect any monitoring.

Is it crazy to think, I think, with the WAYLIVRA liver fat went down, it was not GalNAc-mediated ASO, is it just noise?

I don't think it's noise. I think WAYLIVRA is a very different class of molecules. As you mentioned, WAYLIVRA, which was a first-generation non-GalNAc molecule was not directed precisely and exclusively to the liver. It was also used at a very high dose, a dose of 15-fold higher than what we used for Tryngolza. That's because it's not a GalNAc. WAYLIVRA is probably affecting APOCIII in other tissue beds, including the GI tract, which if you inhibit APOCIII in the GI tract, you will block chylomicron absorption and other aspects of triglyceride metabolism. So we think that it's a different animal entirely and that it's broadly distributed, whereas Tryngolza is distributed precisely to the hepatocyte and that's where we're getting our...

Okay. And then lastly, just the status of your semiannual APOCIII modulating therapy, when could we get an update on next steps? And how quickly could something like that move through development?

Quickly, the high priority for us is to focus entirely on less convenient -- or less frequent dosing, semiannual dosing or once a year dosing. And that conclusion is supported by the Phase I, II -- the Phase I data that we reported last year in patients with mildly elevated triglycerides, we are following cessation of dosing. We're seeing a lasting lowering of triglycerides in APOCIII that's approaching a year in duration with very, very high potency.

We're going to start the Phase II study in sHTG patients very soon and we expect to wrap that study up pretty quickly, and we're already discussing next steps to initiate Phase II development. So we're moving that forward rapidly. It's an entire -- the focus is entirely on less frequent dosing. It's going to be hard to match to exceed the data that we've already generated in Tryngolza. So it's really less frequent dosing.

Okay. Maybe shifting gears to DAWNZERA and HAE launch. This one is exceeding our expectations so far in the early going. And I know you guys have been firm that you think this is an underappreciated therapy and a big value add to the HAE setting. So maybe early observations in the launch. Anything exceeding your expectations? I know this is largely a switch market as you frame it. And so I imagine the early adoption is primarily coming from switches. So anything you can say to help us better understand what's going on in the early days there.

Yes. The demand by patients and HCPs has been very high for DAWNZERA as prophylactic for HAE. As you know, there are several other products already on the market for HAE prophylaxis. So this is a switch market, unlike Tryngolza, where we're first to market and the launch execution has gone exceptionally well.

We're very pleased with the demand. We have a free drug program to get patients on top of DAWNZERA as quickly as possible. It's about a month of free drug, and then that allows them to get the experience and then they're moving over to commercial very rapidly. So we're really, really thrilled with execution on free drug as well as on commercial drug. But we're thrilled about the demand for the drug and the compliance. Patients are staying on drug. It's reporting very, very positive experiences.

What has really been a surprise to us was -- has been how much the mechanism of action has really resonated with HCPs. They are so used to antibodies and small molecules and treating these patients their whole careers. Something new. We're targeting RNA for the first time, something different. And of course, the profile has supported that as well. It's a switch market. We're seeing switches from all other available prophylactic treatments today. The majority, of course, are Takeda [ TAKHZYRO ]. So because that's the majority of patients that are being managed today is on that medicine. So we're seeing switches from all the other prophylaxis we're seeing switches from on-demand treatment. We're also seeing newly-diagnosed patients coming on to DAWNZERA. So we're really pleased with the launch. It's going to be a big year for DAWNZERA.

And you mentioned the free trial program. What does the conversion rate look like once you're in that program? And do you have a line of sight? Is there a big queue of patients that are entering into the free trial program?

It's very high, the conversion. We haven't reported the specific numbers. We're not going to do that right now. It's competitive, but it's very, very high. And that's because the patients are getting great experiences with DAWNZERA on treatment.

Okay. Maybe we've got 5 minutes, so just some quick hitters here. But we know it timely given you published baseline demographics, I think, over the weekend. How would you kind of level set investors now that we have that data out there, see differences, your trial versus HELIOS-B and what that either portends in terms of added risk or opportunity, a lot of focus on the [ tafamidis ] combination data sets, right, to sort of be incremental for the [ silincer ] class?

Well, first of all, as by far the largest study ever conducted in ATTR cardiomyopathy. We're very well powered for a positive outcome. The first time that was approved for ATTR cardiomyopathy, just greatly supports our -- the likelihood for a highly positive outcome because we're getting TTR lowering as good, if not better, excellent drug profile and our study is more than double the size of any study that's ever been conducted in this patient population to date. So we're very well powered for the primary end point.

The baseline demographics that we reported this weekend really not a whole lot of surprises. There are more similarities between our program and the HELIOS-B study than there are differences. As we've signaled well in advance, the demographics continues to shift in cardiomyopathy. We've been saying that we're going to have more patients on baseline tafamidis that we're going to be adding on to in our study, and that's what we reported, about a 56% at baseline patients on tafamidis. It is not that much more than HELIOS-B, but more.

We also have some more -- a higher percentage of patients with a higher percentage of patients with New York Heart Class III, higher percentage of patients that are hereditary, because it more rapidly progresses. None of that puts any of the primary outcome, at any risk because our study is so large, it's so well powered. We actually think it is the real-world setting that is going to generate data that is going to resonate really well with cardiologists in managing patients. Because those are the demographics that patients -- that these physicians are managing today.

Patients are on tafamidis. They want to know, if they're not doing well. They're progressing. What evidence do you have that combination is going to actually provide further benefit. And our secondary endpoints are laid out, and we're going to have a very sizable subgroup in combination usage that we're going to be able to report on. So if there is a complementary mechanism between a silencer that stabilizes 50% to 70% and then knocking down the rest with a silencer, we're going to have the data to convince HCPs that combination is the way to go.

And if you generate that data, can you talk about that as like a Ionis-Astra company-specific benefit that could allow you to swing the competitive pendulum and potentially fulfill the promise on -- I think eplontersen. And you'd be the only company, I think, that could promote, right? This data and presumably gets at least in the clinical Section 14 of the label.

That's correct because it is a prespecified secondary endpoint. We elevated it to that. It's upside. It's significant upside. Our base case, AstraZeneca has reported this as well as $5 billion product opportunity for Wainua, assuming we replicate the other silencer that has come out that data. We're well positioned to do that. Additional data that is favorable, including combination usage is the key differentiator and is key revenue upside for this program. So that will be a very significant upside.

Okay. Where do you expect given some of the recent announcement on the prefilled syringe and for Part B, where this market is going to go, right, for you? You think it's going to be more of a Part D drug, more of a Part B, as in boy, drug?

So let me first start by saying that the ability to self-administer Wainua by patients themselves once a month has resonated incredibly well in the polyneuropathy launch and will be magnified many, many folds exponentially in a much larger cardiomyopathy indication. The ability to self-administer is a big, big differentiator. With that said, AstraZeneca felt that flexibility optionality would be very nice to have. So there are like those centers of excellence that do buy and bill. So they came out as they pushed forward a prefilled syringe that would be administered by a physician as a Part B approach for using a buy-and-bill strategy.

It's really just optionality that they can have. The primary driver for Wainua going forward will be the advantage we have with self-administration using a simple once-per-month injection, that is room temperature stable, can be carried around, taken on vacations and so on. That will still be the main driver.

Maybe 2-word answer. What are you most excited about between tau, Lp(a) and Angelman?

All of them. Pelacarsen is a big deal. We're looking forward to the data in the second half of this year. We're looking forward to the tau data in midyear this year. What we're hoping to see is data that supports moving to Phase III development. That's the first tau lowering drug ever in history, another first potentially for Ionis. And we love the Angelman program, but it's a little bit further out. We're expecting to complete enrollment second half of this year and then to get the Phase III data next year for that program. So I'll leave it there. And we're excited about all 3 of them.

All right. So thank you. With that, we're out of time.

Thanks, Jason. My pleasure.

Good day, and welcome to Ionis' First Quarter 2020 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin.

Thank you, Sabrina. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to view the press release and related financial tables we will be discussing today, including a reconciliation of GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call. .

With me this morning are Brett Monia, Chief Executive Officer; Kyle Jenne, Chief Global Product Strategy Officer; and Beth Hougen, Chief Financial Officer. Holly Kordasiewicz, Chief Development Officer; Eugene Schneider, Chief Clinical Development Officer; and Eric Swayze, Executive Vice President of Research, will also join us for the Q&A portion of the call. I'd like to draw your attention to Slide 3, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. And with that, I'll turn the call over to Brett.

Thanks, Wade. Good morning, everyone, and thank you for joining us today. Ionis entered 2026 with significant momentum, which continued to accelerate through the first quarter of this year. Our performance to date highlights our strong execution across the business, which positions us to fuel substantial growth for years to come. We are very pleased with the continued success of Tryngolza. Demand continues to grow, reflecting both a compelling clinical profile and strong launch execution by our team. The launch of Tryngolza is now also underway in Europe through our partner, Sobi, expanding access to this transformational therapy for people with FCS. We also continue to advance our launch of DAWNZERA. We're very encouraged by the strong early trajectory and the breadth of prescribers across patient segments.

Outside the U.S., DAWNZERA received European approval earlier this year and our partner Otsuka has now initiated launch activities across the region. Together, Tryngolza and DAWNZERA give us a strong foundation of a successful commercial execution as we look ahead to 2 additional independent launches this year with more to come. We are on track for the launch of olozorsen in severe hypertriglyceridemia, which represents our first independent launch in a broad patient population. We are pleased to have received priority review by the FDA with the PDUFA date of June 30, reflecting the significant unmet need in SHTG and the groundbreaking results from our landmark core and CORE 2 studies.

In these studies, we demonstrated profound and highly statistically significant reductions in triglycerides and acute pancreatitis events, along with favorable safety and tolerability. Today, based on HCP demand and payer research, we are increasing our annual peak sales estimate for olezarsen from greater than $2 billion to now greater than $3 billion, positioning olezarsen to become Ionis' first wholly owned multibillion-dollar medicine as the new standard of care for treating patients with severe hypertriglyceridemia. Zilganersen for Alexander's disease is our second planned independent launch this year and the first from our industry-leading neurology pipeline. Zilganersen is the first and only medicine to demonstrate clinically meaningful and disease-modifying benefit in Alexander's disease, a devastating and orphan fatal leukodystrophy with no approved treatments today. We submitted our NDA in January. And based on the results of our pivotal study, the FDA accepted our NDA with priority review and a PDUFA date of September 22.

Overall, we are on track to have 3 independent medicines for 4 indications on the market in 2026. Tryngolza for FCS and SHTG, DAWNZERA for HAE and Zilganersen for Alexander disease. This marks a major step in Ionis' Evolution is a fully integrated commercial biotech company. Complementing our wholly owned portfolio is our partner pipeline, a rich pipeline that continues to advance toward multiple value-driving events this year. Bepirovirsen our potential first-in-class medicine for chronic hepatitis B is on track to launch in the U.S. and Japan this year by our partner, GSK. And just this week, the per version was granted Breakthrough Therapy designation and and accepted for priority review by FDA with a PDUFA date of October 26.

Next month at EASL, GSK will present the unprecedented results of the Phase III program in which bepirovirsen achieved statistically significant and clinically meaningful functional cure rates in patients with chronic hepatitis B. We also remain on track for data from 2 major cardiovascular outcome trials from our partner pipeline this year. The pelacarsen Lp(a) HORIZON trial in patients with elevated Lp(a) and cardiovascular disease and the eplontersen cardio transform trial in transthyretin-mediated cardiomyopathy. Including these programs, along with pepireversen, we expect 5 partner-led launches by the end of next year, creating a diversified stream of royalties and milestones for Ionis with multibillion dollar potential well into the next decade. In addition to our commercial and pipeline achievements, we also delivered strong financial results in the first quarter.

As a result of this strong Q1 performance and outlook for the balance of the year, today, we are announcing a significant improvement to our financial guidance, which Beth will cover in details in a few moments. Ionis has achieved a great deal of late. Our pipeline and our launches are delivering tremendous value, and we continue to strengthen our financial position. But even more importantly, we are well positioned and committed to build on the success to drive far greater value for patients and our shareholders. And with that, I'll turn the call over to Kyle.

Thank you, Brett. As we enter 2026, Ionis is capitalizing on the exceptional launch momentum we generated in 2025 to drive even greater impact. We are set up for continued success with our independent launches. Tryngolza, demand is accelerating. DAWNZERA early launch metrics are tracking extremely well. And enthusiasm continues to build for our upcoming olezarsen launch in SHTG and zilganersen launch in Alexander's disease. Bingo continues to build on the strong performance from last year. Q1 was our strongest quarter in terms of demand with patient starts increasing significantly versus prior quarters and patients on treatment are doing extremely well. .

Our patient finding initiatives continue to identify appropriate FCS patients, and we are successfully converting prescriptions to patients on treatment. We are seeing ongoing expansion in both breadth and depth of prescribing with more clinicians initiating Tryngolza and existing prescribers writing additional scripts. Prescribers span a broad mix of specialties, including cardiology, endocrinology and lipidology, which is exactly the prescriber base we want as we prepare for the broader SHTG population. Physicians remain highly satisfied with Tryngolza's overall profile. Efficacy, safety, tolerability and the patient experience, and that is translating into an accelerating rate for new patient starts.

Additionally, we are highly encouraged by the updated ACC and AHA clinical practice guidelines, which singles out olezarsen as the recommended treatment to lower triglycerides and reduce pancreatitis risk in patients with FCS. Outside the U.S., our partner, Sobi, is now in the early stages of launching Tryngolza for FCS in Europe. This is expanding access for FCS patients and will bring in additional revenue over time. Following the groundbreaking CORE and CORE 2 data and SHTG, we conducted extensive market research with high-volume lipid specialists, cardiologists and endocrinologists. That work consistently showed a clear understanding that preventing pancreatitis is the key treatment goal in SHTG and that current options fall short. Strong recognition of all olezarsen's differentiated clinical profile, especially the acute pancreatitis data and the very low number needed to treat.

And HCPs have stated a high intent to prescribe across a range of patient types with initial use expected for individuals with triglyceride levels above 880 milligrams per deciliter, or above 500 milligrams per deciliter, with a history of acute pancreatitis or other high-risk comorbidities, including progressive cardiovascular disease and type 2 diabetes. In line with our commitment to patient access and to a successful transition into the broader SHTG market, we recently announced an important pricing decision for Tryngolza. Effective April 1, we set the new annual wholesale acquisition cost to $40,000, which applies to the current FCS indication and will be maintained for the anticipated SHTG indication across both doses. Importantly, by establishing a new price ahead of the June 30 PDUFA date, we are integrating olezarsen into 2027 payer contracting cycles, positioning us for accelerating access following approval.

From a go-to-market standpoint, our full U.S. field organization is now in place, trained and deployed. Today, that team is focused on supporting Tryngolza for FCS and deepening our relationships with the key specialists who also treat SHTG. With this expanded footprint, we are positioned to engage approximately 20,000 high-volume SHTG prescribers across the country. The DAWNZERA launch is gaining significant momentum in what is largely a switch market in the U.S. We are seeing increasing adoption across all patient segments. Patients switching from existing prophylactic therapies, patients who were previously using on-demand treatment and treatment-naive patients. Our free trial program has been very effective with high conversion to paid therapy rate to date.

Just as importantly, feedback from both physicians and patients has been consistently positive, highlighting DAWNZERA's strong efficacy, its differentiated RNA-targeted mechanism, the positive switch data, which HCPs described as "differentiating and motivating" and DAWNZERA's patient-friendly profile that includes a self-administered auto-injector that can be stored at room temperature for up to 6 weeks. We are also seeing a growing base of repeat prescribers, which is a key indicator that Dawnzera is providing a substantial benefit for patients. While it will take time to fully transition appropriate patients off legacy therapies, especially in a well-established market like HAE. The launch fundamentals give us confidence that DAWNZERA will contribute significantly to the increase in our commercial revenue in 2026 and beyond. Outside the U.S., DAWNZERA is now approved in the EU and our partner Otsuka has initiated launch activities.

Over time, we expect ex U.S. markets to become an important contributor to the global DAWNZERA franchise. Finally, we are preparing for our first independent launch from our neurology portfolio with Zilganersen for Alexander's disease. On the back of the positive Phase III results, we now have FDA priority review with the PDUFA date set of September 22, and our expanded access program is underway. On the commercial side, our focus has been on continuing to strengthen current relationships and build new relationships with a highly specialized community of leukodystrophy and rare neurology HCPs, further advancing partnerships with patient advocacy groups, and ensuring the right support infrastructure is in place for diagnosis, treatment and ongoing care.

Our medical affairs team has been engaging with top leukodystrophy centers, sharing data and helping to build awareness of Alexander's disease. Our marketing and access teams are finalizing the launch strategy, and we will hire the customer-facing team closer to approval. Zilganersen is not only an important medicine for people living with Alexander's disease, but it's also a template for how we will commercialize future rare first-in-class neurology therapies emerging from our pipeline. With 2 independent launches building momentum, 2 additional launches anticipated this year, and a strong pipeline behind them. We believe Ionis is well positioned to change the lives of patients around the world. With that, I'll turn the call over to Beth. ?

Thank you, Kyle. The strong operational execution you've heard about this morning translated into very strong first quarter financial results. We delivered year-over-year revenue growth and maintained disciplined expense management while continuing to invest in our current and upcoming independent launches. First quarter total revenues were $246 million, an increase of 87% compared to the first quarter of 2025. This increase was driven by year-over-year commercial revenue growth from Tryngolza and DAWNZERA and substantial R&D revenue, including approximately $95 million of milestone payments from multiple partnerships. Commercial revenue increased over 42% year-over-year in the first quarter, driven in large part from Tryngolza and DAWNZERA growth. Tryngolza delivered over $27 million in product sales reflecting continued strong demand that was offset by an anticipated decline in net price. DAWNZERA contributed meaningfully to commercial revenue, delivering $16 million in the first quarter. an increase of 125% compared to the prior quarter.

Collectively, our expanding commercial portfolio positions us for robust revenue growth. and is expected to represent an increasing share of total revenue year-over-year. Operating expenses for the quarter were in line with expectations and increased to 29% year-over-year, primarily driven by commercial investments supporting Tryngolza and DAWNZERA and launch readiness activities for olezarsen in SHTG and Zilganersen in Alexander's disease. We ended the quarter with cash of approximately $1.9 billion. The change in cash from year-end 2025 was primarily related to $633 million we used to repay our 0% convertible notes, which were due on April 1. The strength of our balance sheet is the result of our prudent fiscal management which enables us to make strategic investments as we advance and launch our wholly owned medicine.

Our Q1 performance underscores the value of our diversified revenue model, which combines growing commercial revenue with substantial and recurring R&D revenue from partner programs. Based on our strong year-to-date financial results, accelerating launch momentum and positive outlook for the rest of the year, we are improving our 2026 financial guidance. We now expect total revenue in the range of $875 million to $900 million, an increase of $75 million versus prior guidance, with total revenue weighted slightly more towards commercial revenues. For the first time this year, we are also providing product level guidance for Tryngolza and DAWNZERA. We expect Tryngolza product sales to be between $100 million and $110 million for the full year. and generally in line with 2025 full year Tryngolza revenue. Our guidance assumes a significant decline in second quarter Tryngolza revenue based on the updated price effective April 1 and and a steady return to growth after the June 30 approval for SHTG. We are projecting Denver product sales to be between $110 million and $120 million for the full year. Our guidance assumes DAWNZERA will continue to be a significant contributor to year-over-year growth in 2026, with revenue steadily increasing as the launch advances. We also anticipate significant R&D revenue from existing collaborations, including potential development and regulatory milestones across our partnered portfolio demonstrating that R&D revenue is indeed an important financial accelerator.

In fact, we recently learned that the first patient initiated treatment in the Phase III program for salanersen, which triggered a $45 million payment we will recognize in the second quarter. Over the balance of the year, we also are eligible to earn additional milestones tied to sapoblirson, Vibro pelacarsen and other partnered programs as they advance. We expect our 2026 operating expenses to increase in the low-teen percentage range compared to last year. This modest increase reflects our commitment to financial discipline as we bring multiple medicines directly to patients and advance our pipeline. The key drivers of expense growth will be sales and marketing investments to support Tryngolza and DAWNZERA and to ensure successful launches for olezarsen in SHTG and Zilganersen in Alexander's disease assuming approvals.

We anticipate our R&D expenses to remain steady this year, similar to last year. As late-stage studies reach completion, we are redeploying our resources towards the drugs in our pipeline that we expect to fuel our next phase of growth. Our focus on improving operating leverage is enabling us drop the full increase in revenue guidance to the bottom line. As a result, we expect a non-GAAP operating loss between $425 million and $475 millionm a $75 million improvement over our previous guidance. This is similar to our 2025 operating loss after adjusting for the one-time sapablursen license fee we earned last year.

We are projecting a 2026 year-end cash balance of greater than $1.6 billion. This reflects the repayment of the 0% convertible notes, which were due on April 1. The strength of our balance sheet, combined with our diversified revenue streams supports our continued strategic investments in ongoing and planned launches as we advance our wholly owned pipeline. Our financial outlook reflects accelerating commercial launches, a progressing pipeline and a diversified revenue base, positioning us for continued growth and keeping us on track for cash flow breakeven in 2028. And with that, I'll turn the call back over to Brett.

Thank you, Beth. First quarter and our outlook for 2026 underscore the strength of Ionis today. With 2 successful independent launches underway, 2 more independent launches anticipated this year, a robust pipeline advancing toward multiple near- and midterm catalysts and a solid financial position that supports the continued investments we are making to maximize the value of our commercial medicines and pipeline. With all these key elements in place, we're confident in our ability to accelerate revenue growth and deliver increasing value for patients and for all Ionis stakeholders. Now in closing, I want to highlight that this week at Ionis, we are holding our annual YWeek. It's a time when our employees come together to hear directly from patients and caregivers about their personal stories and reinforce our purpose, which is bringing better futures to people in need. I've never been prouder of the impact we are having on patient lives and clinical medicine, and I'm even more excited about the greater impact we are positioned to make in the near term and sustainably well into the future. And with that, we'll now open the call up for questions. Sabrina?

[Operator Instructions] the first question comes from Jessica Fye of JPMorgan.

So you once again raised peak expectations for Trungolza. Can you just spend a little time elaborating on what enabled you to increase it from at least $2 billion at JPMorgan to now at least $3 billion? And can you also talk about your expectation for gross to nets on Trungolza following this price reset?

Yes. Jess, thank you for the question. So our increase in peak product sales for Trungolza and SHTG and SCS combined in the U.S. to $3 billion was based on several factors. As you recall, we increased the price or the peak sales to $2 billion in January based really solely on the Phase III data and some preliminary HCP demand research that we had conducted. The demand was very high. Since then, we've completed our HCP demand research. But more importantly, we completed our payer research, which landed on our $40,000 annual WACC price, so price as well as priority review. Those are the biggest drivers of the increase in peak sales that we have put out today. As far as gross to net, we're not commenting on that at this time.

The next question comes from Mike Ulz of Morgan Stanley.

Congratulations on the progress. Maybe just a question on the Tungolva trajectory for the year. You mentioned return to growth in the second half, really driven by the SHTG launch. Just curious in some of your market research, are you picking up on maybe any pent-up demand? Could we anticipate a bolus early in the launch here, just given the groundbreaking data?

Kyle, would you take that, please?

Yes, Mike, I appreciate that. And I think what's important first is the strong performance that we saw in Q1 in terms of demand. We are -- it's the best quarter that we've had in terms of the FCS patient population, the number of scripts that were received and the number of patients that are starting on therapy. So that actually lends us a lot of confidence, not only in the FCS space, but also as we get closer to the June 30 PDUFA date in SHTG, I think it's indicating that there is a lot of interest in using olezarsen very broadly in this patient population. In terms of the launch in SHTG, we do know that there are a number of patients that are waiting, right, especially the patients that have a history of acute pancreatitis, patients that are above 880, and those are really the patients that we're going to focus on out of the gate. The trajectory, I think, is going to be modest at the beginning here in 2026.

I think the revenue guidance that Beth shared of $100 million to $110 million is consistent with that expectation, and we'll see it steadily grow over time with that focus being on the highest risk patient population. But some of the dynamics here, as typically seen is it takes some time for the HCPs to be educated on the label. We've got to get those patients into those centers in order to get the prescriptions and then get the execution of the scripts to turn into patients on treatment. So it will be a build over time, and it will accumulate, and we expect modest and steady growth throughout the back half of this year.

The next question comes from Gary Nachman with Canaccord Genuity.

Congrats on the progress. So again, on SHTG, -- just talk about how you expect the payer access to ramp up the timing of that, when you think it will really kick in -- and you got updated guidelines for FCS. Will you be able to get that for SHTG as well? And how long before you think you could expand to a less severe patient population over time?

Kyle, do you want to take -- do you want to start and I can touch on the guidelines. .

Sure. On the payer access piece, Gary, part of the price change decision that we made on April 1 to change the WACC price to 40,000 is directly with working with those payers, right? It fits into the annual review cycle as they're getting ready for their 2027 decisions to be made. So we believe that it will help us get ahead of SHTG a little bit, not only in 2026, but also will help us in anticipation of -- that being said, some payers or all payers will actually wait for the final label, right, before they make any payer coverage decisions. because they want to see what the indication statement is. They want to see what information is in the label, including acute pancreatitis and some of the other clinical study data. that will be included in the label. So it will take a little bit of time.

Some payers will say, we're not going to review anything for 6 to 9 months, for example, that standard policy with some payers. But we hope that we'll be able to get ahead of that with the payers that do review earlier by making that price change and also with our current interactions that we're having leading up to the SHTG approval. So we're going to work quickly, and I think we're in a good spot right now in terms of the way that we're approaching the payers. .

And Gary, to your other question, we were very pleased by the fact that the cardiovascular treatment guidelines for FCS, a single do Trengolza as the treatment of choice for this disease indication. And we applaud the aggressiveness that they are taking to update their guidelines for treatments. And we believe that SHTG will be part of that in the future, which, again, we believe Tryngolza will be a treatment of choice for severe hypertriglyceridemia. They've been very, very supportive of the new treatments that are coming out, and we think that they will move pretty quickly. We're also pleased by the fact that they have increased the -- or updated their guidelines on Lp(a) testing, which bodes well for a potential positive Phase III readout for pelacarsen and the subsequent launch. So -- it's great news for patients, and it's great news for our pipeline.

And in terms of the less severe patient population, we'll start with the over 880 and over 500 with history of However, those same physicians that are treating that patient population also have patients that are 500 to 880, for example. So the education will be ongoing. We're in the right segment HCPs in terms of our targets, right, focused on cardiology, endocrinology and lipid specialists. So they'll see a mix of those patients. So I think some of those patients will already be picked up, especially if they have comorbidities, type 2 diabetes and/or ASC -- but the broader population will take a little bit of time just for awareness and for more of the data and information to come out and more experience of using olazarsen in the SHTG population.

So there's a lot of optimism and a lot of excitement around the category and around the use of a product like this because they've never seen the triglyceride-lowering effects that they're going to see on top of standard of care and they've never seen the outcomes in acute pancreatitis like they've seen with the core and CORI data.

Next question comes from Jason Gerberry with Bank of America.

This is Chi on for Jason. On olezarsenSHTG, could you give us an update on the levels of liver fat you've observed in the core open-label extension studies -- to what extent those open-label extension study data have been incorporated into the NDA as the FDA reviews the totality of the safety data -- and when would you expect to present the updated OLE data later this year?

Yes. Let me start, Chi. Thank you for the question, and then I'll pass it on to Eugene. Maybe you can comment on where we are in the regulatory process for SHTG briefly. But we're very pleased with the ongoing open-label extension data that we're continuing to accumulate with respect to MRI assessment of hepatic fat fraction. As you recall, the increases in hepatic fat that we saw were relatively minor, interested with other modalities that have taken that silencing approach in lowering APOCIII in this patient population. And it's completely logical, based on the mechanism of inhibition of APOCIII which leads to a rapid and substantial clearance of triglycerides in large part through the liver. .

And we've always felt that the changes that the observations in liver fat that we've seen here, again, no clinical sequelae associated would be transient based on deliver just needing to have a little bit more time to clear out the delivery that's coming -- that's been shunted through delivered. And that's what we're seeing in the long-term extension data. We're seeing a return to baseline in liver fat. Again, no clinical sequelae associated with anything in the long-term extension. And we look forward to presenting the data in the second half of this year at a major medical congress. So stay tuned for that, Eugene, you want to provide an update on regulatory?

Yes. The applications under review. Everything is going as planned. Of course, the emerging safety data has been provided to the agency as part of routine day 90 safety update. So that's under review now with no questions asked so far. .

I'll also add that the discontinuations in the long-term extension are extremely low. We're seeing excellent compliance with long-term treatment in the open-label extension. So stay tuned. We're very much looking forward to presenting the results.

The next question comes from Elly Merle of Barclays.

This is Tejus on for Eli. -- in FTE, you have a set of competitor readout coming up later this year. Curious just how you would frame those data in the context of the space and if any outcomes there would impact your peak sales view and SHTG.

We'd rather not comment on competitor data that doesn't even exist yet today. I mean, we're looking forward to seeing any additional data that comes out this year, next year and years to come in SHTG from other programs. All I'll say is that the Phase III data that we presented at American Heart Association and the late breaking clinical trial session last year is incredibly compelling. It's going to be -- it's a very high bar to me with respect to efficacy, with respect to safety, with respect to tolerability, 85% reduction in acute pancreatitis which has resonated very well in the HCP community, as Kyle highlighted earlier in his prepared remarks, 72% reduction in triglycerides on top of standard of care. We're focused on our program. We're ready to launch in June, and we're not -- and I'll just leave it right there.

I'll just add, this is a large market, greater than 3 million patients that are potentially addressable here. We have a lot of confidence in the greater than $3 billion peak that we've put out there. That's really based on the Phase III clinical trial outcomes that we have. It's based on our HCP demand research. It's based on the comprehensive payer research that we've done and also the final pricing decision that we made. So we stand behind the increase, and we're excited about launching this program and getting it to as many patients as possible after the June 30 PDUFA date. .

The next question comes from Jay Olson with Oppenheimer.

Congrats on the quarter, and thank you for this update. Maybe I'll shift gears to DAWNZERA. Can you talk about how you expect the competitive landscape to evolve in HAE and any feedback that you're getting from patients and physicians on DAWNZERA? And any color that you're getting on what percent of patients are currently on every 8-week dosing.

Yes, happy to, Jay. Thanks for the question. The competitive landscape obviously is evolving. I mean there was some recent announcement as late as this week related to some of the dynamics in the marketplace. Keep in mind that in the United States, over 75% of the patients are currently on a prophylactic treatment. This is a switch market as we understand the dynamics to be. And we are really pleased with the momentum that we're seeing in terms of the interest in using DAWNZERA, which is the first RNA-targeted therapy modality in order to treat these patients. The patient and HCP feedback has been extremely positive when they've been able to transition over to DAWNZERA or start as a naive patient. What led into this in terms of our market research is consistently being played out in the market. Really, this is about efficacy, it's about tolerability and convenience. And all 3 of those things are stacking up very nicely with the profile of DAWNZERA, and patients are responding very positively to the therapy.

Now the majority of patients start on a 4-week dosing schedule. This is to make sure that they get transitioned over that they're well controlled and then they have the option for the labeled indication to move over to every 8 weeks if they choose to do so. So as early in the launch as we are right now, you would anticipate that the majority of patients would be on a 4-week regimen. And we will expect over time that they'll be able to progress on to an 8-week schedule as they're doing well on therapy and we saw that in the clinical trial as well. So patients are doing great. Momentum is very strong, and we're encouraged by what we're seeing in terms of the metrics with the launch at this point.

The next question comes from Moritz Reiterer with Guggenheim Securities.

This is Moritz for David. I'll continue on, on era. Your 2026 guidance for DAWNZERA is essentially above what consensus was going into the quarter. So I was just trying to understand a little bit better what data drove this guidance number. And also if you could comment a little bit more on the current mix between new patient starts versus switches and how you expect this to evolve through the end of the year.

Yes, I'd be happy to touch on that. Thanks for the question. We had a very strong first quarter, $16 million in net product sales. This is a 128% increase over Q4 and I just spoke about the momentum that we're seeing in this market and the dynamics and also the receptivity by both HCPs and patients as they get started and gain experience with DAWNZERA. So all of those things that I just described are really what is encouraging us, and I think where we feel very confident that $110 million to $120 million in sales this year is very achievable. In terms of the new patient starts, the majority are switches, right? This is a switch market, greater than 75% of the patients are on a prophylactic therapy in the United States. .

So it's going to take time and time to build the revenues quarter-over-quarter. But it's happening the way that we expected it based on what we're seeing in the trends with Q4 as well as Q1. In addition to that, we are seeing some patients that haven't been on a prophylactic therapy before start on DAWNZERA. So those patients, in addition to those that are being treated with an acute therapy only today that are starting on DAWNZERA. Those 3 patient segments, I think, speak to the fact that the profile is very strong in what patients and HCPs are looking for. We have a differentiated mechanism of action. And our sales execution and market access teams are doing a great job in terms of supporting these patients to get started and stay on treatment.

The next question comes from Yaron Werber of Cowen.

This is Steven on for Yaron. Congratulations on the progress. On the collaborative revenues for the rest of the year and for maybe 2027. Can you talk about what you're projecting because those came out a bit higher, I think, than consensus may have. Further on zilginersen, can you talk about how many patients awareness efforts have found any new updates to the size of the market. You had mentioned before that about 50% of patients have been identified. Any updates on sizing there would be helpful.

Do you want to start and then Kyle, take the second part. .

Sure. So on the collaborative revenue for this year, the way to think about is we've raised our revenue guidance for the total year to $875 million to $900 million. That is slightly weighted towards commercial revenue, so you can think about that split being slightly more weighted towards commercial revenue versus R&D revenues. Obviously, we've already realized and recognized $95 million in milestones plus our ongoing collaborative revenue, which put us well over $100 million, closer to $130 million, $140 million for the first quarter. We've got a host of other milestones that we could potentially earn over the remainder of this year, plus our ongoing collaborative revenue from renew a cost share and amortization.

So that is all the items that really give us confidence in the overall collaborative revenue for this year. And then for '27, we've got think about it this way. There's some very large potential milestones for approvals coming in '27 with the Phase III data that we're expecting to see from from pelacarsen, in particular. And those milestones are likely going to drive collaborative revenue in '27.

And our launch preparations are going really well, right?

Yes. For Zilganersen, I just -- I want to just reinforce the excitement that we've got around this program. This is going to be our first anticipated neurology launch program and to be able to potentially bring this therapy to patients living with Alexander's disease, I think, is really an exciting opportunity for the community and also exciting for Ionis. In terms of the approach here, we're really going to be focused on the patients that are currently on the clinical trial in helping get those patients moved over so that they can maintain treatment. The second area that we'll focus on are patients that are going to be enrolled in our expanded access program, which is ongoing and going very well. .

And then as you asked, what about the patients that are currently being identified and how do we help get those patients on treatment. We believe that there are approximately 300 or so Alexander's disease patients in the United States. About 50% of those have been identified thus far. Some of them are on therapy that I just referenced. But we are doing some expanded work through our omnichannel and through our nonpersonal promotion campaigns to help identify more and more of these patients. And really, what we want to make sure of is that they have the opportunity to experience sogonersen as the patients in the clinical trial did to potentially have the positive outcomes that we're seeing in that trial.

So patient identification will be a key area of focus. And we're doing that while we're really making sure that we're going to take care of the patients that are on treatment today and those that are awaiting treatment that have already been identified.

The next question comes from Luca Issi of RBC Capital Markets.

A quick question on why now. What happened to for the quarter. Drug is actually down 35% versus the fourth quarter what drove the weakness here? And it looks like AstraZeneca is flagging the availability of the drug now as a prefilled syringe to be administered by a healthcare provider. Did that have a negative impact on gross to net? Any color there is much appreciated.

Yes. So in Q1, we continue to see very strong demand in terms of patients on therapy as well as new patient starts. So demand is still there. Oftentimes, you see some some January, February pressure as it relates to reauthorizations and the timing of those reauthorizations, which drove some of the pressure early in the quarter. But we expect to see that pick up in subsequent quarters and return to revenue growth as we move into Q2 and beyond in the U.S. You asked about the prefilled syringe. Really that's been put out there for optionality, right? It's flexibility of dosing and it's to allow HCPs to determine if they want to use the auto-injector or if they want to be able to treat these patients in some of the major centers with the prefilled syringe.

So it's really optionality for the program. That is not impacting the gross to net at this point. It's way too early to see any impact of that. And so I would just keep an eye towards future quarters. And again, this is the hereditary polyneuropathy space. The market is growing rapidly in the cardiomyopathy space and the eye towards cardio transform readout and getting ready for that launch is definitely where the line of sight is.

The next question is from Yanan Zhu with Wells Fargo Securities.

Great. So wondering for the FCS, you mentioned continued growth in demand. Could you help quantify that a little bit? In terms of percent growth, given that the price change making it difficult for us to appreciate. And then can you talk about how to think about SHTG in 2027, what kind of growth could we expect from the initial launch quarters in 2026. Obviously, you guided for peak revenue, $3 billion. Any sense that how long that might take? Any color would be super helpful.

Yes, and let me start and then I'll -- and Kyle already touched on what the expectations are for 2026 launch in SHTG -- you can cover that again, but maybe comment on 2027. But for FCS, as Kyle mentioned earlier, our first quarter of this year is our strongest quarter to date. -- on patient demand and gaining access to Tryngolza for FCS. And that's purely a product of patient finding and the great experiences, the HCPs and patients are having with Tryngolza in managing their disease from an efficacy standpoint and from a tolerability standpoint. So demand has never been higher. We're thrilled with what we're seeing, and we think that, that's going to bode quite well for the SHTG launch trajectory.

Yes. I think what's important, again, is to mention that in 2026, the revenue guidance is $100 million to $110 million for olazarsen this year. We expect that to grow steadily over time. As I also described, the focus initially is going to be on the high-risk SHTG patient population, over 880 or over 500 with history of -- and then as we get into 2027, I would expect that more and more patients will start to come on board that are broader than that, Type 2 diabetes, ASCVD, et cetera, as I described, and the launch momentum will build. And so will the patient base as we get these patients on as HCPs get experience in seeing the triglyceride lowering levels and seeing the reduction in acute pancreatitis that were demonstrated in Core and Core 2. And I think that experience and that evidence ultimately will help us drive the trajectory into next year.

The next question comes from Salveen Richter of Goldman Sachs. .

This is Mark on for Salveen. -- are -- you kind of touched on the Doner quarterly dynamics, but we were wondering what are the specific drivers for the quarter-over-quarter jump? And are there quarterly dynamics we should be aware for the rest of 2026? And how are you thinking of these dynamics going into 2017 and beyond?

Yes. The real quarter-over-quarter growth is coming from the switch cadence that we are expecting to see, right? This being a switch market, and we expect that to continue throughout the course of this year. But that's the big driver, right? We know that there's a need. We know that the profile of DAWNZERA meets the need of many of those patients being efficacy, tolerability and convenience. And we've got the data with the Switch data to help support how to move those patients over from existing prophylactic treatments over to DAWNZERA. And as HCPs are gaining experience, we're seeing more and more HCPs not only prescribed for the first time, but we're also seeing those that have used the treatment before, use it again and again. .

So I think that plus payer coverage tells us that we've got an optimistic outlook in terms of what 2026 looks like. And I think the $110 million to $120 million guidance is in line with that expectation.

And we have time for 1 more question, please. .

The last question comes from Myles Minter with William Blair.

Congrats on the car. Just on the TTR cardiomyopathy market, if I did settle for a potential generic entry from Vindemax in mid-2031 versus something like in 2035. Does that change the way you're AstraZeneca are thinking about the cardiomyopathy moving market moving forward? And how much emphasis you're going to place on that are stabilized of background therapy subgroup in cardio TTR transform.

The news that has been emerging this past week or so on genericizing tafamidis versus brand pricing is not come terribly surprising to us. is consistent with our product sales guidance that we've put out there with AstraZeneca previously. We believe we remain completely and believe that the filing or class will end up being the mechanism of choice for TTR amyloidosis. We believe that the silencer class will be utilized as first-line treatment. -- as well as in those patients that inevitably progress on stabilizers and combination usage to your question. We'll also be will be utilized very, very robustly, especially if there's data supporting that combination usage will add further benefit to these patients that inevitably are progressing on current treatments. .

And our study is designed to actually generate the data that we believe could be convincing to HCPs who are asking the question whether or not a combination of a stabilizer with a silencer will add further benefit to these patients. So -- it's the largest study ever conducted in ATTR cardiomyopathy and the combination subgroup is quite sizable. So we're looking forward to the data in the second half of this year. and we're prepared to submit the NDA by the end of this year and to launch next year. So thank you, Myles, for that -- thank you for the question, Myles.

Thank you, everybody, who joined us today and participated on our call. We're looking forward to an outstanding year and sharing our progress along the way. So until then, thank you, and have a great day, everybody.

Goodbye.

Thank you for attending today's presentation. You may now disconnect.

Great. Thanks very much, everybody. It's my pleasure to be here with Holly Kordasiewicz to talk about the Ionis neuroscience pipeline. Holly, instead of asking you to just give like some prepared remarks, do you mind if we just like get right into it? Is that cool?

Sure. Sure.

All right. Sweet. Thank you. Okay. So I am like super, super excited for this tau readout coming up later this year. But I think one of the things that's hard to really answer in research about tau is the whole correlation causation question, which was a question with amyloid for a long time. Obviously, the correlation piece was like somewhat disproven. But as it relates to tau, can you just talk about like tau as a target and put into context and then the evidence for tau is like a causitive part of the biology of Alzheimer's?

Yes. So first, we can start with the correlational pieces in the pathology. So tau pathology actually correlates better with cognitive decline than amyloid does. And so for there, that bit is already stronger. There's 2 ways that tau has been implicated in Alzheimer's disease. The first is, of course, the pathology and that correlation with the pathological spread of tau correlating with cognitive decline, but then also the function of normal tau. So the endogenous tau, if you lower that, you take that out in animal models, you can protect against AD and Abeta-driven AD. And so those 2 elements taken together suggest that tau is an important target for Alzheimer's disease.

Okay. Great. Sorry, I muted myself. So okay, makes sense. And I guess on the safety side, like what do we think the role of tau is actually in healthy brains? And do we think it has a role in adults? And do we think it's going to be okay to lower all forms of tau at the gene model?

Yes. Yes. So the short answer is yes. So we've seen absolutely nothing to date that suggests that partial lowering wouldn't be tolerated. There's nothing in the animal models or genetics. In fact, as I mentioned before, if you take a full knockout mouse with no tau and you cross it with an Abeta mouse, the Abeta mice do better. They have less disease. It also protects against excitotoxicity.

So it protects against genetic epilepsy. It also protects against chemically driven excitotoxicity. So tau full 100% knockout actually have a protective function in the animal models. In human genetics loss of function isn't associated with anything, any diseases, it's all gain of function or splicing mutations that are associated with tau-driven disease. So there's really nothing to suggest that there's going to be an issue with tau lowering. That said, of course, we want to be absolutely careful and continue to monitor this as we go through our clinical trials.

What do we think causes tau misfolding and aggregation? And when do we think that happens in the disease?

Yes. So excellent questions. We don't exactly know. So it probably happens early. And we do know that it shows up early in the disease course and that it progresses throughout the disease course. We also don't know how much is driven by tau pathology. And then as I mentioned, that other role of tau and the endogenous tau function leading to potential increased excitotoxicity and which of those elements are contributing more to the disease. It's possible it's both. It's possible. It's one driven at a different time period than the other.

Do we think it happen like with Abeta, right? I mean this is one reason why I'm really excited for the presymptomatic readouts, but like we think that, that starts at 0 like plus or minus 10 years, whichever way you want to directionally do it. Is tau -- do we think tau comes into play presymptomatically, too? Or does it really come into play when you have like MCI appearing?

Yes. So tau can -- you can have tau pathology early on. It is typically thought of it happening after and downstream of Abeta, but that's not consistent across all patients. So we can't -- it's not that simple of a pathology, and it's going to be different in different individuals based on what their underlying disease is. If it's more tau driven, if it's more Abeta driven, if it's more inflammation driven, what their ApoE phenotype is, all of that is going to change this.

Was it surprising to you that the antibodies for tau showed like nothing -- like I understand that they don't lower intracellular tau. But the whole idea of like stopping the spread from area to area like -- like are you surprised that they didn't even show a trend?

No. I mean there is some hints of stuff in the antibody. I don't think we can discern that much. But no, because trying to catch the tau pathology as it spreads between neurons is really hard to do. So we don't know exactly how it's transmitting from neuron to neuron if it is in that extracellular space so that it could be captured if it's moving through vesicles or other means between those neurons.

So to actually be able to capture that, to be able to prevent it from getting into those neurons completely so that you prevent that spread is hard to do because if you think about how tau seeding works, if you get a small seed in that neuron, then all that endogenous tau that's in that neuron can then misfold. And that's been shown over and over again in lots of different systems. And so to prevent all pathological tau from entering into a neuron to prevent that neuron from then misfolding its own intracellular tau is really tough to do.

Yes. Yes. Okay. Maybe talk about the data you have on PET and like how confident can you be that you're lowering tau enough in the right areas of the brain that matter with intrathecal delivery of an oligo.

Yes. So in our Phase I/II study, we were able to look at tau PET, and we were able to actually see a reversal in tau PET. So not just preventing a progression, but the tau PET that was there before treatment went away. And so because we were able to see that reversal of tau PET, that gives us confidence that we're targeting the brain regions that matter. And all the regions that had tau pathology have that reversal.

And so because of that consistency, it gives us a lot of confidence. Now that said, we know how our oligos distribute. We have a lot of preclinical data. We have a lot of experience with IT oligos. And so this is something getting distribution to the important brain regions was something we're confident going in and the tau PET is just really nice confirmation of that for the technology and then also exciting because it shows that reversal, which had never been shown before in an AD.

Yes. Yes. No, it's amazing. So I think you lowered tau PET maybe 60% of the hippocampus. Is that the right ballpark? With amyloid, I think we learned over time that like 70% is not enough, right? 80% like remember the whole aducanumab post hoc thing, which was best for a variety of reasons. But with amyloid, it's like you got to like obliterate it. Like do we have confidence that 60% is enough in the key area of the brain? Like what would you point to?

So that's the question that we're answering right now in the Phase II study in the ongoing CELIA study. That's the exact study we're answering. So we have looked -- Biogen did a really nice post-hoc analysis from the Phase I/II study where they compared the clinical data to an external control. So they use the TANGO studies. They did a propensity match control comparing it to our BIIB080 treated our tau oligo treated individuals and all those individuals that favored BIIB080 in terms of all their cognitive performance and functional performance. That said, it's a post-hoc analysis. It's small ends, but that was enough to give confidence that this could be in the right ballpark for having a benefit.

Yes. Okay. There are every 6 and every 3-month arms in this study. What would you say your confidence is that every 6 is going to be in like the right knockdown reduction range, given that it's been so hard to get uptake with these Abeta antibodies and people obviously wonder about intrathecal...

Yes. So you just got to that question that we were asking is how much tau do you need to lower and to what extent to have the biggest effect size. And so that's the key question that we need to answer. So we have a lot of experience dosing drugs in the CNS. We also know that our tau oligo lasts a long time. So from the Phase I/II study, we stopped dosing and then we looked at a 6-month recovery and it was flat in the high dose groups. There was no recovery over those.

Interesting. Okay. So that suggests every 6 months should be good enough.

Yes. So we had that gap between when we stopped the study and we started the LT specifically to look at this and it didn't recover. And so with that, that gives confidence that it could be enough. But again, if you need really significant reductions, you might want that quarterly dosing to get stronger reductions. And so that's why just to make sure we had all bases covered, we have both included in the study.

Are you giving a loading dose for the [indiscernible] arm?

No.

No. No loading dose. Okay. Okay. Okay. Interesting. Anything else you'd add on tau?

No, just that it's really exciting. The data readout is midyear this year and to see it.

Yes. I guess I have Biogen on the panel tomorrow, and I'll try to probably unsuccessfully pin them down on like the bar for success. But it's a big study, right? It's placebo-controlled. It's a long study. I mean, do you feel like this is well suited to like really answer the question and also show something statistical if you have an effect size that's in the ballpark of Abetas?

Yes. So this is do what it was supposed to do, which is to replicate -- replicate the biomarker data that we saw in the first study and then allow us to design a Phase III study. So it has all the different elements to it. We have the tau PET. We have the CSF markers. We have, of course, ApoE carriers, non-ApoE carriers that we can look at the different patient populations and how that they respond so that we can then design subsequent studies if there are benefits seen here. And as you mentioned, it's a big study. It's a long study. So I think we have the right time lines and we have the right patients to be able to ask the question.

Yes. And were patients in this study like is it basically the same population as the lecanemab and donanemab Phase III typically...

It's the early patient populations.

Okay. All right. I can't wait. Maybe switching gears to Angelman. Do you want to just sort of set the stage and talk about the Phase III and how it's progressing?

Yes. So the program is progressing really well. We recently refined the Phase III REVEAL design to focus exclusively on the 80-milligram cohort. So we initially had 2 dose levels -- but based on the positive efficacy and favorable safety tolerability profile from our Phase I/II HALO study, which was an open-label study that had both dose levels in it, we decided to focus on the higher dose level.

So this means we can now achieve the objectives for the study with 158 patients instead of the 210 we were originally planning, so a little bit smaller. And then the enrollment for that study is expected to complete this year so that we also have FDA breakthrough therapy designation. And then that means readout the following year in 2027 because it's a 12-month study.

Makes sense. We'll get the Ultragenyx data first. How are you thinking about like the read-through from that readout to yours? And what are the limitations of that read-through?

Yes. So for Ultragenyx, the thing I'm most looking forward to seeing is the placebo effect in this patient population. So we really don't have data on 12-month placebo effect in these individuals. Of course, we can model it. We can do all sorts of things, and we did do that as we powered our study, but to really see what that placebo effect is at 12 months will be really nice.

And that's an important question for the whole field, not just for us. Other than that, the molecules are very different. So the Ultragenyx molecule is a different chemistry. They have dose-limiting toxicity, so they're dosing it extremely low. And so because of that, I think the read-throughs are going to be limited other than really understanding the placebo effect.

Beyond the open-label data from both companies, which obviously looks like directionally supportive, is there any, I mean, I guess like asked in another way, right? Like with tau, you can look at tau lowering, with SMA, you can look at like other biomarkers. In Angelman, like do we have any hard evidence or anything we can ground ourselves in and knowing that you're normalizing like the actual underlying genetics?

Yes. So again, we have to go back to our knowledge of drug distribution, what we know about the preclinical modeling, how we understand our CNS oligos, which we have a lot of experience with. Based on all of that, we are at the mid and the high dose levels, achieving nice distribution to all the brain regions to get that restoration of UBE3A levels.

And we've been able to do that for other programs where we do have nice biomarkers, CSF biomarkers for. So I'm confident in that that's going to translate as well. That's also supported that we're getting the right target engagement in domains by all what we're seeing in the clinical endpoints. The important thing from our HALO study is that we're seeing benefits across domains and across tests. So it's not just one test. We were not cherry-picking any data. If you look at the Bayley, which is physician administered, if you look at the Vineland, which is parent reported, if you look at the CGI, which is physician reported, all of them tell us the same story.

They tell us the same story, and they tell us the same across different domains that we're having a benefit. And it's that consistency in the data that's giving us confidence here since we don't have that very hard CRISP biomarker that we have for some of the other programs.

Yes. Okay. Makes sense. You want to talk about the endpoint selection for Phase III? And I guess maybe just look in the backdrop of this, right, there's like a lot of consternation right now about the FDA and rare disease and like alignments and like is this -- whatever. So maybe just talk about your regulatory dialogue. Obviously, you're doing something different than Ultragenyx and like your confidence that this is kind of truly locked down.

Yes. So just to remind everybody, our primary endpoint is expressive communication as measured on the Bayley 4. So that's a physician-administered assessment. We chose expressive communication because it is by far the #1 thing that is most important for parents and caregivers. It is also something that if you're administering the Bayley, the individual has to communicate during the testing.

So they have to use gestures, sounds, words to score on the Bayley for expressive communication. So it's a very crisp endpoint that's going to be less subject to learning or bias or placebo effects or things that can happen than some of the other endpoints that are available. So it being a crisp endpoint, it being the thing that matters the most -- and it's also the thing that we had the biggest effect on in our HALO study and then it also has the lowest natural history. So there's really no change in expressive communication over a year time point in this Angelman patient population.

So it gives us the biggest delta. So taken together, it's the obvious right endpoint for us. We proposed this as the primary endpoint to the FDA, they agreed with no debate. One thing they did ask us to change is the Bayley 4. We had been proposing to use GSV scores. It's a score that has to be imputed. And so because of that, they wanted raw scores. We knew that they were going to likely ask for this because we know they didn't like it going in. So we conceded to that. They also asked that we not include parent input on the test that we really do just focus on the physician-administered assessment, which is fine. And so we agreed with that as well.

So everything that the FDA recommended, we agreed with, these were things that we knew we were probably going to have to concede to going into the discussion. So we were happy to make those concessions. And so with that said, we also have a controlled study. So this is a controlled study. So we have that head-to-head control. So you mentioned some of the other debates going on. Those are trying to use natural history comparators or external controls. This is gold standard controlled study in the patient population using the endpoint that's most meaningful for patients, doing it in a way that's directly consistent with FDA guidance and their feedback.

So because of that, I'm very confident in where we're at. And we've had a long lovely relationship with the FDA, very collaborative going all the way back to the days when we ran the SPINRAZA trial for SMA. And I'm confident in where we're at and that we have the right study design to be able to answer this question definitively.

Yes. Okay. That makes a lot of sense. Do you want to just talk about like, again, you mentioned the point on placebo arm, right, and that being like one of the natural questions. What's the effect size implied by the Phase I/II versus natural history? And when you did the powering in Phase III, like how much cushion did you give yourselves?

Yes. So we were pretty conservative in our powering because as we discussed about that placebo that we don't know. So we do have 90% power to see the effects that we're expecting based on the HALOS data, and we have powered that fairly conservatively, as I mentioned, because of the HALOs.

Okay. But not giving like numbers around it.

No, we're not giving numbers. This is a pretty competitive space.

Is it? Okay. I'm just joking. Okay. Sounds good. Anything else you would want to add on Angelman before I move on?

Yes. Just 2 other things. So we did add the under 2 cohort to our HALO study. So that will be open label. This is a really important patient population because these are the individuals who are first diagnosed. These are our youngest people in this patient population and the ones who could potentially have the biggest benefit because this is neurodevelopmental. So very excited that, that enrolled incredibly fast and is moving forward.

We also have our CHAMPION study that we've announced. And so this is to treat individuals with [ UPDID ] genotypes. So this is the final genotype that we haven't treated yet. So we've treated mutation and deletion patients in both our HALOS and REVEAL study. You can also get Angelman syndrome from UPDID mutations. And so those we're going to be capturing in the CHAMPION study. So that our total data package will have treated all age groups and all genotypes with Angelman syndrome when we go hopefully with a positive study to file.

Yes. Yes. Okay. That sounds good. Maybe just switching gears. Do you want to talk about like the platform? And obviously, there's been this explosion of the number of companies that say they have a brain shuttle. Maybe not all of those are of like equal quality or realness. But you guys -- I remember during your R&D Day in COVID, right, you had even like animal data for transferrin in muscle and like that was a long time ago. So where is Ionis in this space? And what are you doing to make sure you don't fall behind here?

Yes. So we're using, as you mentioned, novel targeting moieties and conjugation platforms to broaden our reach of our RNA medicines to new tissues, including muscle, but then also the brain. We've exclusively licensed the vector's VHH nanobody platform that allows us to systemically deliver our RNA therapeutics, both ASOs and SIs across the blood-brain barrier and using transferrin-mediated delivery. And so that's work in progress. We shared at Innovation Day last year, a really impressive nonhuman primate target engagement data. It's the best that I've seen out there. So very happy with it. And we're moving that forward into the clinic.

And is there anything more specific you can say about like how that would fit into a collaboration with like a Biogen? Like do you need them to be on board with this to move it forward for like tau or one of these targets?

So we're pursuing it now for an Ionis wholly owned program. If it is with a collaboration target, then we would, of course, need the partners and we'd be able to explore this as well as anything else we're working on. We're also working on bicycle technologies. So this is really exciting because these are really small peptides. We've already advanced this clinically for muscle targeting, and we're working on this for BBB as well. And the exciting thing about that is we could potentially get it down into a subcu auto-injector, which would be incredible.

Yes, that would be huge. Okay. Okay. Is that something you're working on for tau as well?

Yes, we're working on it for all the targets that are interesting for the CNS, of course.

Okay. Okay. I got one question from someone who's listening in on Angelman. What would the Bayley-4 data in HALO look like if no caregiver parent input was allowed?

Yes. So fortunately, we have the Oak Hill data that was published uses the Bayley-3, and they see a very similar response that we see. And the Bayley-3 doesn't use caregiver input. So it's a very similar response without it, which is why we were happy to concede to that.

It's not an analysis you can perform with your own data?

No, it's not.

Okay. Just like the scales don't work that way.

They don't capture it as consistently as they should the sites and everyone who's doing the test, exactly what came from the administration and what came from the discussions with the parents. And so we are capturing that, of course, now in the REVEAL study. But in the HALO study, we hadn't separated that out and requested that information while the test was being administered.

Right. Okay. Okay.

And asking for that information post hoc is not useful.

Right. I understand. That makes sense. So what CNS program or programs have we not talked about that you think at this panel a year from now or 2 years from now, you think could be a major focus for people.

Yes. Oh my goodness, we have so much stuff going on. So we haven't mentioned Zilganersen for Alexander disease. We had a positive Phase III there last year. So that NDA has been submitted, and we're looking forward to a launch later and approval later this year. So that's really exciting because that will be our first independent neurology launch for Ionis. And of course, it's always wonderful when you have disease-modifying positive Phase III data in a population that doesn't have anything.

So that's something to see and watch as we get through the approval and then the launch. There's also salanersen. This is in partnership with Biogen. This is basically like a yearly SPINRAZA. It's using our new NMA chemistry to increase the potency of splice modulating oligonucleotides. That's starting pivotal studies this year and the data from the Phase I study is just absolutely beautiful where they can reduce neurofilament to normal levels and keep it down for a year after a single dose.

And so that's a really remarkable chemistry and program that's moving forward that I think is going to be generating a lot of exciting data. We also are doing a similar program with Dravet using that same NMA technology that's going to start in the clinic soon. We, of course, have ulefnersen for FUS-ALS. This is a potential second ALS indication for Ionis. This is another genetic cause of ALS that Phase III data reads out this year. There's also the Huntington tominersen Phase II data that reads out this year. So that's in the lower dose, younger, earlier-stage patients. And then we have multiple mid-stage neurology programs in our wholly owned pipeline that are going to read out next year, including alpha-syn as well as [indiscernible]. A lot of really exciting stuff going on here.

On Alexander disease, I mean, the data there is really -- it's really awesome. How have you been like setting an expectation, if at all, on like the market opportunity for that drug?

So there's just a few hundred patients in the U.S. So it is an ultra-rare disease. So it is a small opportunity.

Okay. Okay. And then on salanersen, like the chemistry you used there, like is that the kind of thing you think could be extrapolatable to all types of targets, including targets that you knock down? Or is it going to be like more constrained?

No, it's only splicing. So it's fascinating. It only works for improving the potency of splicing. But across the board for our splicing, it so far has always performed.

Interesting. So SMA, Dravet diseases like that is not like the right thing to think about.

YES. And because they're already uniform, they're fully modified because we're modeling splicing and they don't have that DNA gap in there, they're already really long-lasting molecules. And then you add this on top of it, and that's where you get to that yearly dosing.

Okay. Okay. And maybe just lastly, like for any new IND you file now in CNS, like why wouldn't that just be a brain shuttle program at this point?

So we still have to show what technology works. Right now, the IT is working. We understand it. We know how to develop these and develop these quickly. And it's a known proven technology. And I hope that we'll be in the same place with brain shuttle, not too terribly long from now, and then that will be the answer, but we're just not there yet.

Okay. Okay. Interesting. Interesting. Do you feel like from -- like when you look at your shuttle technology and others, like like in your mind, is there like a material difference in like the expertise in targeting transferrin receptor or other -- like you know what I mean? Or is it feel -- because I guess like GalNAc and LICA became more commoditized pretty quickly. But I don't know where we're at with TfR1.

I think it's going to end up in the same place. Looking at the data, we played with a lot of these different things. The biggest difference that we can find is the size of what the ligand is and using a different size for more convenience and delivery. Other than that, they all tend to perform pretty similarly. And we, of course, make everybody else's molecules in breast. So I think it will be more like GalNAc. The biggest thing, though, is still understanding your cargo and understanding the safety profiles of your cargo and what you need to find good ASOs and SIs.

Makes sense. Okay. Great. Anything else you want to touch upon, Holly?

No, I think we hit it all.

Okay. What about muscle? Like what's next in muscle for you guys?

Yes. So we're moving muscle programs forward, both skeletal as well as cardiac. We had our first cardiac muscle program using our bicycle technology, which I mentioned. These are the very small peptides so that you can do subcu delivery for them. That's advanced into clinical testing. We have another that will be advancing later this year. And so it's moving.

Great. Awesome. All right. Well, thank you so much for taking the time. Really appreciate it.

Happy to.

All right. Thanks, everyone, for listening.

Great. Good afternoon, everyone. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very happy to have Ionis here with us today for a fireside chat, but we should call it a beachside chat since we are in Miami. Joining us from Ionis is Brett Monia, Chief Executive Officer. Brett, thank you so much for making the time and joining us today. Before we dive into questions, and I know there's a lot of programs to cover and a very catalyst-rich year for you. Maybe if you could give us an overview of the Ionis platform and portfolio and some of the key catalysts for the company over the next 12 to 18 months.

That sounds great. It's great to be here, Ellie. Thanks. Let me provide a brief intro on where we are today and where we're headed at Ionis. So as I think most people in the audience are aware, we're an RNA -- we're a genetic medicines company focused on novel treatments targeting RNA for clinical medicine, diseases where there's a high unmet need. And 2026 is really set up to be a big year for the company, a transformational year for the company. We have so much coming. And that's really built on tremendous momentum that we established last year in 2025. In 2025, we launched our first 2 independent medicines, the first ever FDA-approved medicine for familial chylomicronemia syndrome, FCS, Tryngolza. And as our first independent launch in our history, it was a spectacular success. Quarter-over-quarter growth, $108 million in total revenue for the year, clearly beating all estimates.

We also had our second independent launch with the August approval of DAWNZERA in hereditary angioedema, a prophylactic treatment for that disease, which really, really serves patients incredibly well, meeting the needs of patients. And that launch, too, is off to a very good start. We also had several pipeline readouts last year that is going to really serve us well this year. The breakthrough, the most notable Phase III readout we had was a wholly owned program of the second indication for Tryngolza to follow FCS, which was for severe hypertriglyceridemia, a disease that's not rare that afflicts millions of people in the United States that are in desperate need for new treatments to substantially lower triglycerides and avoid acute pancreatitis, and we hit it out of the park.

We shared the full data at the American Heart Association presented the data. And indeed, this is really set up to be a really big drug for the company, for patients, a blockbuster potential. And then also right around the same time, we announced positive Phase III data for a new medicine for the treatment of a neurodegenerative disease called Alexander's disease, a rare condition in which there are no effective treatment options that's commonly fatal. We showed highly statistically significant benefit in all endpoints in the study essentially, including the primary endpoint of motor function. And as I said, that momentum just sets us up great for this year. This year, we're looking forward to the approval and launch of Tryngolza for severe hypertriglyceridemia, a blockbuster opportunity, as I mentioned, wholly owned.

And just recently, just last week, we received priority review from the FDA, recognizing the importance and the unmet need here. So we're going to launch in July. And that's obviously a big event for the company. We're also expecting the Alexander drug -- Alexander's disease drug to be approved this year, and we'll launch that in the fall. And from our partnered pipeline, the beat goes on, we're expecting 5 Phase III readouts this year, one of which has already been achieved with our partner GSK for chronic HBV which is -- which was highly positive. We announced that in January with GSK. And then we're expecting the Phase III readouts for eplontersen for TTR cardiomyopathy and pelacarsen for Lp(a) cardiovascular disease, and IgA nephropathy drug and another -- a second ALS drug. We have one approved already. So great year last year. This year is going to be even better, and we're off to a fantastic start.

Great. Yes, definitely, we're probably the company with the most catalyst in my entire coverage, a lot going on. Maybe starting with Tryngolza and the commercial trajectory in FCS and potentially soon sHTG.an you give us more color on kind of the cadence of revenues you expect over the course of the year?

Yes. It's going to be really interesting. And very -- we're very much looking forward to it. It's going to be a big year for Tryngolza for severe hypertriglyceridemia. As I mentioned in my opening comments, the FCS launch is incredibly strong and quarter-over-quarter growth, beating all consensus estimates on total revenue. And this is continuing into this year with FCS -- with the FCS indication as we prepare for sHTG. The demand for Tryngolza continues to ramp up for FCS. Patient stories, physician experiences are so incredibly strong. We're seeing reauthorizations come in over and over again. Patients are staying on drug, and we're seeing continued growth demand -- patient demand for Tryngolza in FCS. Despite the emergence of a competitor that came late last year, we're continuing to see this go really well. We are experiencing some pricing pressure. This is a rare disease drug with a rare disease price and a competitor came in with a much lower price for FCS. So we're managing that effectively.

And it's different payers are requiring different things. All of them recognize the fact that we're just a few months away from launching in sHTG, which is really the key event. When we get to sHTG, when we get to the launch in July with approval in late June expected, we'll announce price, but there'll be a step down in price because we're going to go from a population that's estimated to be 3,000 in the United States to a population that's estimated to be 3 million in the United States. So it warrants a -- obviously, a significant step down in price. We're working through that right now. We'll announce price. Our job is to maximize value, highest price possible, while ensuring that patients -- more patients -- the maximum number of patients can access Tryngolza without physicians having difficulty in prescribing the drug or payers creating roadblocks for the drug to really maximize the full potential of this blockbuster opportunity. So that's going really well. We're managing it effectively, and there's a lot more to come.

Great. And feel free to answer this how you will. I know it's a sensitive topic, but price there's a lot of conversation amongst investors around how to think about the sHTG pricing. How is your thinking on price evolved over time? And to what extent are you thinking about how this price decrease will work in practice?

Yes. So I think it was almost 2 years ago when we first introduced the opportunity in severe hypertriglyceridemia, an opportunity that was not appreciated by really almost anybody. And we were making the case that this is a big opportunity, a big unmet need. Of course, everybody recognizes that now. But one of the questions we continue to get was price. How are you going to price it when you go from FCS. And we did some back-of-the-envelope estimations, large patient population. And what we put out there at that time was $10,000 to $20,000 price net, very important that that's a net price for sHTG. That was before we had data.

That was before we did really extensive market research, HCP demand research, payer research and so on. And now that we have the Phase III data, groundbreaking results, we've been able to go and do more informative HCP demand research and payer research. And we're coming to the conclusion there. We'll announce a WACC price. We're going to move away from net price announcements and disclosures. But we're going to focus on the WACC price. And we'll announce that, as I said before, when we launch the drug this summer. And again, we're threading that needle, maximize price while maximize the ability for physicians to prescribe without a hassle and payers to not provide roadblocks and access.

And the sHTG population is very large. How are you thinking about the initial focus population for the launch? And what you're expecting, frankly, from the initial cadence of the sHTG launch?

So as I mentioned, 3 million-plus people with severe hypertriglyceridemia. That's defined as triglycerides 500 milligrams per deciliter and above normal triglycerides or below 150. These patients suffer from many, many issues. Most importantly is the risk of a potentially fatal acute pancreatitis attack. It's not fatal, it tends to lead to additional AP attacks, which caused pancreatic -- eventually pancreatic failure if they continue. High unmet need. We showed an 85% reduction in acute pancreatitis attacks in our Phase III study, unprecedented. Number needed to treat to prevent an AP attack in the highest risk population was 4 patients. treat 4 patients, you'll prevent potentially fatal AP attack, really remarkable results. Out of the gate, that's the population we're going to focus on, is that highest risk patient population.

And that's based on what we're hearing also from the physicians, the cardiologists, the endocrinologists, the lipid specialists that manage these patients. First out of the gate are going to be those patients that have got a history of acute pancreatitis or have such high triglycerides that they're going to have an AP attack sooner or later. We want to prevent that first attack from happening. That's typically above 880 milligrams per deciliter. That's the high-risk population that's estimated to be about 600,000, 700,000 patients in the United States. And then when you add to that patients with other comorbidities. They may not have had an AP attack. They have sHTG, but they have cardiovascular disease or diabetes, that rounds up to about 1 million in the United States. That's the focus for us out of the gate. As far as revenue guidance and those sorts of things, we're going to be going from a rare disease price to a specialty price out of the gate.

So there's going to be some impact initially on revenue out of the gate as we make up for volume in this indication, which will start to really take hold in the second half of this year and then really accelerate next year. We estimate $2 billion plus in peak product sales in the United States alone, and we're very confident we're going to achieve that based on the profile of Tryngolza for sHTG, based on the fact -- based on what we've experienced with FCS, which has been highly, highly positive for this medicine based on the HCP demand, what we're hearing from it and based on the awareness, everybody in the cardiology and endocrinology community is aware of Tryngolza and they just can't wait to get -- to be able to treat their patients, sHTG patients with Tryngolza. So it will dip a little bit in revenue as we begin to get to that acceleration phase when we really increase volume.

So -- but dipping prior to the launch because we should see price decreases even before the approval in sHTG.

Well, we're getting some price pressure, as I mentioned before, in FCS between now and the late June PDUFA date, which we're managing effectively. And then we'll have a step down to the sHTG price at launch. So it will be a slow drop in revenue, but then we're expecting in the second half of the year for it to pick up.

Certainly a very exciting opportunity and could be a major growth driver for you. So we look forward to seeing that launch. Turning to some of the major clinical readouts this year. So you have a lot of them. Maybe starting with CARDIO-TTRansform, I guess, what's the latest on your expectations for what good data would look like and your thinking on how the patient population, whether it's the patients on baseline tafamidis or other factors in terms of sort of the severity of the disease might compare to other trials in the space?

Yes. So ATTR cardiomyopathy is a -- in our -- is a growth market. We've estimated 500,000 patients plus that have ATTR cardiomyopathy heart failure due to a buildup of TTR in the cardiac tissue. And -- but we don't really know what the prevalence is. This is clearly a growth market. There are several treatments out there today. There are 2 classes, stabilizers and silencer that's on the market will be the second silencer, assuming positive Phase III data in the second half of this year. And just a quick reminder for everybody that this same medicine is already approved in many geographies around the globe, including the United States for the hereditary form of polyneuropathy. And that launch is going very well. The demand is very high, continues to grow in patient demand quarter-over-quarter, going very well. I think that speaks to the profile of the drug.

It's a really, really effective and well-tolerated medicine. For cardiomyopathy, we have the largest study ever conducted in ATTR cardiomyopathy. We were pleased with the results of the first silencer that read out for Phase III in TTR cardiomyopathy and how well the launch has gone because that bodes really well for us because we're -- we have the same mechanism of action, very similar profile, virtually identical reductions in TTR in this population. So it greatly derisked the outcome of our Phase III study. But based on the size of the study and the design of the study, we're going to have several aspects of data that could be highly differentiating. Most notable, you highlighted the combination data, right? Tafamidis is the standard of care for TTR cardiomyopathy today in the United States. And there's been some usage of silencers -- a silencer plus stabilizers out there. But there's clearly going to be and there has been more recently pushback, particularly by payers to combine these data because they're expensive drugs, right?

And there's no data. There's absolutely 0 data supporting combination usage will create added benefit to patients. Everybody progresses on stabilizers. The breakthrough treatments, no mistake about it. But everybody is progressing and some -- many patients progress rapidly and quickly. So -- and adding another mechanism of action like a silencer to a stabilizer could really add benefit, but there's no data. All previous studies that -- were vastly underpowered. We have the potential to generate data for the first time that can show potentially if the mechanisms are indeed additive, we need to learn that. first time to really provide convincing evidence that combination adds greater benefit to patients with TTR cardiomyopathy, great unmet high unmet need.

Our peak product sales for eplontersen when we get to this market, we've announced it with our co-development and co-commercialization partner, AstraZeneca, to be $5 billion plus, $5 billion range. That's based on replicating the previous silencer, if you will. Having added data like combination data or other subgroup data, which we are in a good position based on the size of our study is just upside to that product sales revenue that have been projected. In addition, we have the ability -- patients have the ability with our medicine to self-administer, which is unique, right? It does not have to be administered by a health care provider. Ours will be the only silencer that can be administered by a patient themselves in the United States. That, too, is resonating incredibly well in the neuropathy, polyneuropathy launch. And we think that, that will be amplified in the cardiomyopathy launch.

Great. That's helpful. What are your latest expectations in thinking about whether you will reach statistical significance on the combination?

Well, that's a high bar. Our -- what we think will be a big win is if we can provide data that is -- that appears clinically meaningful and believable by HCPs that my patient is progressing, but they're getting some benefit from a stabilizer, show me the data -- and of course, we publish and so on that patients are going to do better. I'm going to fight for this. I'm going to advocate for this combination usage. And of course, once tafamidis goes generic, then the headwinds on using combination data, if there's data out there to support it or combination usage, if the data is out there to support it will be easier to justify.

With that said -- so that's our hope. Again, assuming the mechanisms are additive, we have to prove that. If we hit statistical significance, and that's a grand slam, if you will, right out of the gate. We're not necessarily, of course, powered for that. We're powered for our primary endpoint. Secondary endpoints, you don't typically are powered for. However, in case we underestimate the effect size of combination versus monotherapy in our study, we did make the decision to elevate the secondary endpoint on combination usage as a prespecified secondary endpoint. So we will have in our hierarchical statistical analysis plan just in case. But our guidance is we're looking to see if we can just have believable really meaningful data showing strong trends favoring combination usage.

Interesting. Well, certainly a large and growing market. So we look forward to seeing that data. Another major cardiovascular readout coming this year, Lp(a), massive population. How are you thinking about what would be clinically meaningful from a relative risk reduction here? Like if we see something like 15%, is that clinically meaningful? And how are you thinking about that readout?

Clinically -- clinical meaningfulness is always hinged on the unmet need, right? 8 million to 10 million people today have cardiovascular disease, often fatal myocardial infarction, strokes due to an independent risk factor, Lp(a), high levels of Lp(a) are at high risk for cardiovascular disease. And it's a big unmet need because no other treatments effectively lower Lp(a) to get them out of harm's way for an event, right? So we're in the Phase III study. We did the Phase II. We licensed the drug to Novartis. The HORIZON Phase III study will read out in the second half of this year, maybe by midyear. And we're expecting 80% plus reductions of TTR -- of Lp(a) that gets the vast majority of patients into the normal range of Lp(a) getting them out of harm's way. We hope and first to market by a significant length of time if the study is. So a groundbreaking study in cardiovascular medicine.

We -- the study is powered, designed to achieve a 20% relative risk reduction in the overall population, 25% relative risk reduction in a slightly sicker patient population based on slightly higher Lp(a) levels in the study. That's all been published now, the demographics for the study. Your question, what's clinically meaningful? Yes, sure, 10%, 15% is going to be a big deal. The unmet need is enormous. There's no other treatment. Physicians are seeing patients that have had 1, 2 cardiovascular events, sometimes in their 20s, 30s, 40s of age because of this independent risk factor, any statistically significant reduction -- statistically significant benefit on the primary outcome is going to be important and it's going to be meaningful for HCPs who are trying to manage these patients and they have no weapons and there's no ability to manage Lp(a) CVD. So it's powered for 20%.ow me stat sig, and I think we have a real breakthrough in cardiology.

Definitely exciting. We look forward to seeing that data. Turning to your tau program with Biogen. I guess, what are your expectations for data this year? And what would give you confidence to move forward?

Yes. Our 2 therapeutic areas of priority for Ionis are in cardiology, cardiometabolic diseases, we just talked a lot about that. And then in neurology, a platform that has delivered SPINRAZA for SMA QALSODY for SOD1-ALS, our Zilganersen program, positive Phase III data in Alexander disease that I mentioned in my opening. Next up is the Phase II data for tau. Tau is considered to be one of the most relevant targets for dementia, Alzheimer's disease. The problem is that approaches like antibody approaches have not been able to target intracellularly produce tau, only extracellular, mopping up the extracellular. But we know that tau intracellular causes a severe neurodegenerative disease as well as extracellular. And by blocking production, we're going to address both of those for the first time. In fact, we already did.

Two years ago or so, we reported results of Phase I/II in patients with AD, where we showed not only substantial reductions in tau and CSF, we showed reversal of tau pathology by PET imaging. Neurofibrillary tangles, reversal with evidence of improved cognition in that study. And that's exactly what the Phase II study that's going to read out midyear this year in studies called CELIA, a large Phase II study with the primary endpoint of being CD sum of boxes, which is the cognition primary endpoint in the study. We're looking at 2 dose levels. We're looking at dose intervals, 3 months or 6 months in intrathecal dosing. And it will be the first validation of a tau targeting approach blocking production in the neurology field. You asked expectations. I expect the study to be positive based on the Phase I/II data where we have already generated evidence of reversal of pathology and some evidence of improved cognition.

Okay. Great. Turning to Angelman's, not readout from you this year, but a readout from Ultragenyx, which I think a lot of investors view as a meaningful read-through to your program. How are you thinking about the size of the opportunity in Angelman's? And what gives you confidence that some of the Phase II data that you've seen or that Ultragenyx has seen could translate into a successful Phase III study?

Yes. So there's about 100,000 -- this is a rare disease, but there's about 100,000 people living with this severe neurodevelopmental disease, Angelman syndrome. There are no effective treatments available for this disease. We and others, 2 others sponsors have reported positive early clinical data. Same mechanism of different drugs, but utilizing the same mechanism of action to address the root cause of the disease, strong evidence of benefit in open-label studies compared to natural history data. Now we have the fortune of the natural history data in Angelman's is really strong. People have been working on this for years. So we have really good baselines to compare to, but it's still open label. With that said, we have a proven platform in neurology.

We know how to discover neurology drugs very effectively. And our Phase I/II data compared to natural history is very, very strong. We've seen evidence of benefit across all symptoms, whether it be communication, cognition, motor function, just whatever instrument you use, Bayley-4, CGI, ORCA, others, we're seeing very consistent benefit. And we're seeing now in long-term extension data that we reported last year, patients that are rolled over into the OLE from that study, continued benefit in endpoints. So the first readout is going to be the second half of this year. We're very much looking forward to it. We believe in our medicine. We believe in our trial design. And we don't believe -- we believe that our drug is called Obudanersen is really has a strong potential to really make a meaningful difference for the Angelman's community.

Great. Well, I know we're at time, but exciting year ahead and certainly a very large pipeline. So exciting things to come. I appreciate you making the time.

Thank you, Ellie. It was a pleasure.

All right. Everyone, welcome to this afternoon session of the first day of the 2026 Global Healthcare Conference here in sunny Miami. I'm happy to welcome everybody to my adopted hometown, as I said earlier. I'm Mani Foroohar, Senior Analyst [ Leerink ] Medicines. Very fortunate to be hosting Brett Monia, the CEO of Ionis Pharmaceuticals. Brett, how are you doing?

Great. It's great to be here, Mani. Happy to be in Miami.

I'm happy to have you. All are welcome. Let's chat a little bit. I know we spoke over breakfast this morning on some of these issues. So it's a little bit repetitive, you'll have to forgive me. But let's dive into where we are on the ongoing TRYNGOLZA launch and the transition to what's going to be an sHTG launch over the course of this year, but involves a little bit of label change, tinkering with pricing, contracting. Like how should we think about the tempo of that price evolution?

Sounds great, great topic. We're excited about the TRYNGOLZA program. Let me hijack that question very briefly and talk...

Hijack away.

A little bit, but I'll get to -- I'll be brief. We're set up for a great year in 2026. There's so many real game-changing events, some of which have already occurred, but we're really set up for a lot of them this year with the priority review for TRYNGOLZA achieved a week or so ago, sets us up really well. And then, of course, we had Phase III positive data with GSK, our partner for chronic HBV this year. And this builds on tremendous momentum from 2025, including our first 2 independent launches which both are off to a great start, including TRYNGOLZA for familial chylomicronemia syndrome. So that's a really short opening that 2025 was a pivotal year for the company. 2026 is set up to be a transformative -- really a transformative year for the company with so many game-changing events.

First, FCS. The -- our first independent launch in our history was an incredible success in 2025. We achieved product revenue of $108 million quarter-over-quarter growth, beat all estimates that were out there based on the profile of the treatment, based on our ability to find patients and gain access with payers and so on. Of course, that's just the beginning for TRYNGOLZA. To your point, severe hypertriglyceridemia is coming, and that's not a rare disease like FCS is. sHTG is estimated to affect more than 3 million people in the United States today. There's a high-risk patient population that we can talk about a little bit that are particularly on risk for acute pancreatitis, which can be fatal, which is about 1 million people in the United States today, inadequate treatment options available for this large patient population.

The FCS launch continues to go really well as we approach the sHTG launch. As I said before, we have got -- received priority review for sHTG with a PDUFA date of June 30. We're launch-ready. We've been -- we're in the field now preparing for the sHTG launch while we are promoting and doing sales on TRYNGOLZA for FCS. And that's going -- continues to go well. Despite the fact that there's a new competitive entrant into the FCS market, we've seen no meaningful impact on subscriptions for TRYNGOLZA for FCS patients nor on adherence persistence. It continues to go extremely well.

Where we have had some impact is on pricing pressure, right? As you would expect, since we're priced at a rare disease, we've been priced at a rare disease since the 1st of January last year, and that has gone extremely well. A competitor has come in with a much, much lower price. We don't fully understand why, but we're receiving some pressure on that. We're managing it effectively. Different payers are requiring different negotiations. Some none, none. They're saying, we'll just wait for the sHTG launch. And we're having discussions with them on what that price could look like for sHTG, and that's giving them a lot of comfort. Others, we are reducing the price. So we're going to have some impact there, but it's only a few months. With the June launch or a July launch, a June PDUFA date, it's not that far along.

What is that price going to be? For severe hypertriglyceridemia, we've been doing HCP research, HCP demand research for -- even before we had Phase III data that we announced last year at the American Heart Association. And then following the Phase III data, which was groundbreaking, 85% reduction in acute pancreatitis, 72% reduction in triglycerides on top of standard of care, truly remarkable data and then payer research as well.

Based on HCP demand, we increased our peak product sales in the U.S. for more than $2 billion for TRYNGOLZA and sHTG. We announced that in January. That's over -- that's increased from $1 billion plus. That's based on HCP demand. The payer negotiations are going well. And we're -- our focus, of course, is to ensure for the highest price possible to retain as much value as possible while making sure that we do not create roadblocks for prescribers to put in NDCs in place or other restrictions that prevent easy -- relatively easy access for patients to maximize population that get access to TRYNGOLZA for sHTG.

We're getting closer to the finish line. We're getting close. We think we're threading the needle very effectively on the ultimate WACC price. And we'll announce that price at approval and launch.

Almost as if you and I had this exact conversation hours ago. So let's dive into a little bit of those competitive dynamics. Looking forward to sHTG, you're going to have a year, perhaps a little year and change of headway before competitor launches. Competitors fairly publicly disclosed their top line WACC price at $60,000. You've given some commentary around net price. So it's a little bit of apples oranges. But let's talk about the size of this patient population and what parts of the sHTG population, starting from those who already have a pancreatitis event, very high 880-plus level of triglycerides 500, et cetera. Like which of those populations do you think are the sweet spot for TRYNGOLZA to launch into? And how does that influence pricing and contracting decisions?

Yes. First, we believe that having first-mover advantage, coupled with the amazing data that I just summarized for you that we presented last year is a big, big advantage there. And we think that we're at least a year, maybe 1.5 years now that we have priority review over competition for sHTG. I also mentioned at the beginning that this population, as defined by triglycerides 500 and above is over 3 million in the United States alone.

But to your question, the patients that are in the greatest need, the patients that are going to be prioritized by endocrinologists, cardiologists, lipid specialists, pancreatologists, out of the gate are going to be those that are at the highest risk for acute pancreatitis. Who are those? Those are people that have already had an acute pancreatitis event. Some of them multiple events, and they're losing function of their pancreas because of those multiple events with triglycerides above 500 or those that are above 880, which is a critical threshold of triglycerides that cause persistent chylomicronemia, and that puts them at high risk for an acute pancreatitis event. And docs want to prevent that first attack from happening even if they didn't have a history of AP.

As I mentioned, that's about 1 million people alone. Those are going to be the priority for physicians to target out of the gate because those are the ones in the greatest unmet need. We expect our label, though, to be broader than that. It's not just in the high-risk persistent chylomicronemia patient population. Guidelines say already, cardiology and endocrinology guidelines that if you have sHTG by -- as defined by 500 and above triglycerides, you need to treat patients as aggressively as you can to get them below 500. And there's going to be physicians that are going to want to prescribe to label. We expect label to be as an adjunct to diet for patients that have triglycerides above 500 period.

So it's a much broader population, and we'll work on that broader -- the broader component of that population in time. But out of the gate, it's that severe high-risk patient population with a history of AP or above 880 that we'll be targeting and that physicians will prioritize as well to get to TRYNGOLZA as quickly as possible.

So let's talk about a debate that's around the same competitive dynamic. How much of a difference is there between your once-monthly form factor and once every 3-month form factor presumptively will enter the market a year later. How meaningful is that? Is there a sub-published to patients, patients for whom there is a huge difference in terms of convenience?

Not in the research we've done, also not in common sense practice, in common sense thinking. Once per month administration is very convenient out of the gate. And we do not believe that there's any evidence that going to every 3 months administration offers any meaningful advantage from a patient convenience standpoint.

We are launched in FCS with an auto-injector, right? That means that you do not see the needle visibly, not a prefilled syringe. And that auto-injector has gone -- has resonated really well with the FCS patient population as it has for other launches we've done like WAINUA, for example, for TTR amyloidosis. Once per month is very convenient. What is far more important is the data, right? The data on 85% reduction in acute pancreatitis, 72% reduction in triglycerides, that's a very high bar for anyone to meet. And we believe that at the end of the day, the data is going to drive enthusiasm by practitioners in addition to being first to market and to set this market as we did in FCS, where we led the way. We've created this market opportunity in FCS. We identified the patient population as we did now -- as we're doing now in sHTG. And those are the big advantages is the product profile, which is going to be tough to beat and being first.

So let's talk about another point of differentiation or not, which is the debate around hepatic fat fraction. Obviously, this is one that's been discussed to what extent it's on mechanism, to what extent it may or may not be off mechanism. And what is the clinical significance of an elevated hepatic fat fraction seen in a proportion of patients in the CORE studies?

Yes. Let me level set for everybody, make sure we're all on the same page from the get-go. So what we saw was a small but dose-dependent increase in liver fat triglycerides in the liver of patients in our Phase III CORE and CORE 2 studies in sHTG, small but statistically significant, but small. We are 100% confident this is an on-target effect. Think about what we're doing here biologically, folks. We are very acutely, in other words, relatively fast and substantially reducing circulating triglycerides from the blood. And the clearance of those triglycerides is happening through 2 mechanisms.

One is breakdown through lipoprotein lipase. The other is clearing through the liver, right? And the liver does -- when you look at the magnitude of triglycerides reductions we're achieving, the liver is doing a pretty darn good job of clearing that out without a substantial increase in liver fat, but there's some. We've also saw it with a competitor -- a competitor program with an siRNA where they showed in Phase II dose-dependent increase in liver fat. Same thing. It's on -- we believe this is on target and makes complete sense.

With that said, we also went into this -- when we looked at the data, we also believe that this would be -- that the liver would be able to adapt to this, have an adaptive response. And once they got through that initial bolus of triglycerides that are cleared effectively, it would get around to the rest of the triglycerides in time. That's exactly what we're seeing in the long-term extension data. In 2 years out now, we have a sizable number of patients that are now -- have reached 2 years. We're continuing to monitor by MRI, and we're seeing return to baseline in patients. So we're going to publish and present that data later this year.

But what's most important, that's important. But again, it's not an adverse event. It's not a toxicity. It's an observation because there is no correlation with clinical sequelae. There's no correlation with ALT elevations. There's no toxicity correlations at all. It's an observation. And we're seeing it return to baseline with time. So we look forward to sharing that data probably in the second half of this year.

Great. Let's move to commercial opportunity and just wrap up this topic. You've talked about in the U.S. alone, $2 billion-plus opportunity for you guys in this indication, obviously, a sizable population. Give us a quick overview of the status of this indication for you guys, OUS and your economics that you draw in from there?

Yes. So we have -- our business model today, it will evolve, but today is to focus on our independent launches in the United States market -- U.S. market and then to partner ex U.S. for the time being. There will be a time, not too far down the road, probably where we will emerge from the U.S. market. But today, we have partners for commercialization of TRYNGOLZA and DAWNZERA.

For TRYNGOLZA, for FCS, we are now launched, approved and launched in Europe. Our partner is Sobi, and they're preparing for a launch in the broader we'll call sHTG population. Economics to Ionis is royalties in the mid-20% range or so. But what Sobi is doing is very thoughtful when it comes to pricing ex U.S. that will support pricing ex U.S. and addressing the patient population with the greatest unmet need is that they're focusing entirely on patients that have triglycerides 880 and above. Whether or not they have a history of AP, they're focused on that patient population, which instead of multiple millions of people is more in the 700,000 to 800,000 patient population range, which will allow them to command a higher price because it's the most severe patient population out there.

Sobi has said that ex U.S., this is a greater than $1 billion product opportunity in Europe alone. So we have a good partner. I should also mention that our first-generation molecule, I'll call it that, WAYLIVRA, which is approved in Europe for FCS, Sobi is our partner. So they know this space well. They've done a great job with WAYLIVRA. And the first patients that have come on to TRYNGOLZA in the FCS launch are switches from WAYLIVRA over to TRYNGOLZA. And they're doing a great job finding new patients as well.

So let's pivot off of this end market over to another partnered program in TTR, obviously, cardio transform long time coming, critical data set for you guys. Talk to me about how you see the combo with tafamidis opportunity now? What -- what a positive static benefit on top of tafamidis would mean for your commercial opportunity in the U.S. and EU in cardio transform?

Yes. So very much looking forward to the Phase III data in cardiomyopathy in the second half of this year. Just as a reminder to everybody, we are approved for the hereditary TTR polyneuropathy indication already. And that launch continued -- the patient demand for WAINUA for polyneuropathy continues to be very, very strong, very encouraging. But we're only indicated for one -- we only have one indication now. It's the hereditary polyneuropathy. We're looking forward to get into the cardiomyopathy indication, which is well north of 500,000 patients or so.

Our CARDIO-TTRansform Phase III study is the largest study ever conducted in TTR cardiomyopathy, and it's not even close. It's more than double the size of the next largest study conducted. There's one -- AMVUTTRA is approved, silencer, the first silencer for this indication is doing well. We're very pleased about that because we believe it bodes extremely well for our drug, eplontersen brand name WAINUA, based on sheerly on the fact that our product profile shows as good, if not better TTR lowering, excellent safety and convenience as a once-per month treatment that patients can self-administer at home and not rely on a health care provider to administer the drug like our competitor. We believe that the results of the first silencer actually greatly derisk the outcome of our study for the primary endpoint, which is what we're powered for.

Getting into the secondary endpoints to your question about combination usage. Today, we know that the one silencer that's out there today is being used to some extent with stabilizers, a combination approach. We believe that the 2 mechanisms will be complementary and offer greater efficacy. However, there are headwinds on that because there's no data. There's absolutely no data showing added benefit of a combination usage. So as these branded molecules are out there with branded pricing, it creates payer pushback, if you will. We believe that, that can all change with data. If you have data that delivers believable and meaningful evidence of benefit in combination usage that HCPs will advocate because we know that all patients are continuing to progress on stabilizers. These are not treatments that are reversing disease or halting the progression. These patients are still progressing. They want added benefit and complementary mechanisms has the potential to offer that.

We believe that we're set up to offer that data, to generate that data, which can go very well, which will resonate very well with HCPs and payers, if you can show them the data that covering 2 medicines will halt the disease or show added benefit versus either agent alone. We're not guiding towards stat sig. It's a secondary endpoint, but we are hedging our bets, if you will, that we could have really nice data in combination based on the size of our study. So we did elevate the secondary endpoint of combination to a key secondary endpoint. So it is part of a hierarchical statistical analysis plan in case we do hit it next year. Nevertheless, we will have the strongest data whether we hit stat sig or not in this study.

Let's pivot over as we have a couple of other studies talk about a partner study targeting Lp(a) with Novartis. It's been delayed a couple of times due to event rate. Admittedly, also Amgen has also seen delays. This has been something that's happened across the space. Talk about what you're expecting from the horizon based upon your conversations with your partner and how you think about the commercial opportunity at any particular level of event reduction, given the debate is, are we talking 15, 20, 18, et cetera? There's a lot of nuance on Wall Street.

Yes, there aren't a lot of independent cardiovascular risk factors left that aren't addressed by treatments today. Lp(a) is one of the last ones. We know that 8 million to 10 million people suffer from cardiovascular disease due to excessively high levels of Lp(a) causes atherosclerosis, strokes, heart attacks and is not effectively addressed with other agents that are out there today, PCSK-9, statins, anything that's out there today. What we're doing is targeting Lp(a) with pelacarsen, first mover advantage, at least 1.5 years ahead now with the delay you just referred to by a competitor program that's closest to get market first. Big market opportunity.

The study is powered to achieve a 20% to 25% relative risk reduction. and based on several assumptions, but that's what the study was powered based on based on the Lp(a) lowering that we're achieving, which is greater than 80% in the study. And that's obviously a multibillion-dollar blockbuster opportunity with attractive economics to Ionis, Novartis running that study.

The study has been delayed. As you mentioned, the competitor program was delayed, too, simply because -- I mean, as far as we could tell, we were blinded to the data, but it's just that the events are taking longer to accumulate to support the powering assumptions for this study than was originally projected. And a lot of assumptions go into that rate when you do something for the first time, an outcome trial for the first time.

The other contributor to the slower event rate is the fact that these patients' other risk factors are extremely well controlled. Their LDL-cholesterol is normal. Their diabetes is controlled, their hypertension is controlled. This is a pure play on Lp(a) CBD, which is good for the drug, because that's what we're doing. We're lowering Lp(a). We're normalizing it in this study. Is this a big market opportunity if we don't hit 20%, if we hit 15%, 12%? This is still a big market opportunity even in that situation because the unmet need is so big and there are no effective treatments on the market today.

We've popped around the pipeline a little bit. I do want to move forward to your own wholly owned rare disease assets as well beyond that sort of commercial. I want to touch base on Angelman Syndrome, where your pivotal data is coming somewhat later than your competitor Ultragenyx. Talk about how you're going to be interpreting that data. and how it would read forward to your data and how you think about what its implications, both scientifically and strategically?

Yes. We launched our Phase III study called REVEAL in Angelman Syndrome using Obudanersen, that's the generic name now, ION582 previously. And the enrollment is going very well. We're going to complete enrollment this summer in our Phase III study. We reported Phase I/II data a year or 2 ago, about 1.5 years ago, showing really strong evidence that we were improving outcome in patients with Angelman Syndrome across the measurements we've made using whatever instrument we made, Bayley-4, SAS-CGI, ORCA instruments on communication, motor function, cognition compared to a very strong natural history data. So that led us to make the decision to move into Phase III development. And we're going to have data next year for that program. This is over 100,000 people in the United States with this rare disease with no effective treatment options available.

We're very much looking forward to -- the competitor you mentioned who's going to have Phase III data in the second half of this year, and Mani, we're rooting for them. We want to see that be a good outcome in the study because we know we have a great drug, and we have a proven platform in CNS diseases, platform that is delivered SPINRAZA and QALSODY and our tau program, many more. But they are using a different chemistry than we're using. They're using a much lower dose than what we're using. Our dose is 5, sixfold higher. It's the highest dose that we tested in our Phase I/II study that showed the greatest benefit. So -- but we don't know why they're using a lower dose. Our data indicates equal potency in preclinical models. So we'll see. But we'll see what happens there.

Obviously, plenty of room. There's other advantages that we have with respect to dosing and that kind of thing. But at the end of the day, this is a big market opportunity, and we're looking forward to their data in the second half of this year. And moreover, we're looking forward to our data next year.

So we've walked through the pipeline, wholly owned assets, partnered assets. I want to look out a little further to the future. There's a lot of debate around how -- not to say commoditized, but how competitive oligo therapy has gotten. We've seen with the patents that yourselves and Alnylam built the [indiscernible] business as it is now, but this sub-industry on the back of. Many of them expired. The backbone chemistries are developed are fairly well known. And there are many companies everywhere from San Diego, Boston, China, Hong Kong, et cetera, moving assets in the clinic, especially for liver-targeted RNAi.

Talk about how you think about that increase in competitive intensity, how you stay ahead of that and what your strategy is to address what is going to be a more crowded pipeline space, especially in the liver?

Yes. What a difference a decade makes. Yes, it's -- as the lead pioneer in the space of oligonucleotide therapeutics, we're very proud of the fact how this has really taken hold and is producing such incredibly groundbreaking meaningful new medicines for the community.

For liver targeting, it has become somewhat commoditized. We're seeing a lot of other companies come in who really have no experience in oligonucleotide therapeutics, but it's relatively straightforward to develop an siRNA for a liver target, to your point. And we're seeing them come in unable to really beat efficacy or potency, but they're really focused on durability, less frequent dosing, right? What we have done to counter that at Ionis is for any program that's under our control or any partner we can convince, we have follow-on molecules that are doing the same thing, right? We have a TRYNGOLZA follow-on that's in Phase II development now that supports 9-month dosing, once a year dosing. We're doing the same thing for our other wholly owned drugs and for some of our partnered programs.

Where the real different -- so we're going to protect that in that way. But where we are also -- we are differentiating and extending our leadership is in innovation, right? We believe that we have the best platforms to expand, say, in CNS diseases using new blood-brain barrier penetrating technologies to allow us to target CNS diseases where we lead using subcutaneous administration, low-volume subcutaneous administration infrequently every couple of months or so, at least, maybe less frequent.

Muscle targeting. We have our first novel ligand, the Bicycle ligand targeting cardiac myocytes in the Phase I development now using siRNA coupled to a bicycle going after a genetically validated target with our partner, AstraZeneca. And we have a second one coming that's wholly owned by Ionis that will be in the clinic possibly by the end of this year, maybe early next year.

So it's all about innovation, Mani. It's -- you got to -- people are going to copy well you make sure you stay ahead of them and you become in your first to market and you continue to innovate to open up new opportunities. I think we're well on our way to lead -- continuing to lead in oligonucleotide therapeutics.

Great. And with that, I think we're out of time. And a pleasure to have you and looking forward to the conversation soon.

Great being here. Looking forward too. Thanks, Mani.

Good morning, everybody, and thank you for joining us for the 46th Annual TD Cowen Healthcare Conference. I'm Yaron Werber from the biotech team, and it's really a great pleasure to moderate the next fireside chat with Brett Monia, Chief Executive Officer of Ionis. Brett, good to see you.

Good to see you. Yaron, I forgot how cold it gets in Boston.