Sarepta Therapeutics, Inc. Stock

All right. Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Michael Ulz, one of the biotech analysts here, and it's my pleasure to introduce the team from Sarepta Therapeutics. To my left, Michael Severino, CEO. To his left is James Richardson, the CMO. Just a reminder, the format for today is a fireside chat, but if anyone in the audience has a question, please raise your hand and we can try and address it in our discussion.

But before we get started, I just need to read a quick disclaimer. 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 turn it over to Michael to make some introductory comments, and then we can hop into the Q&A.

All right. Well, thank you, Mike. It's a pleasure to be here with you all today. And James and I are happy to tell you a bit about what's going on at Sarepta. I've just recently joined Sarepta. I've been here going on 2 months now, but it's been a very exciting and very rewarding 2 months.

I think Sarepta has a story that is very unusual, and I think we can actually say unique, even though that word is often overused in our industry, because it's a company that has a cadre of marketed products that are serving patients today and have been doing so for many years that offer us a number of benefits. First of all, they offer patient benefits, which is what's most important in our industry, but they also generate revenue that gives us a very strong and stable financial position and a very strong balance sheet.

And we can use that strong financial position to drive a very innovative, very promising pipeline that has the potential to expand our therapeutic footprint to drive growth, we believe in the near term and long term. And I'm sure we'll talk about that pipeline and everything that we're doing, for example, in the siRNA space. But as I said, this is a setup that you don't find in our industry.

And as someone who's spent more than 25 years discovering, developing, and commercializing therapeutics, when I looked at this opportunity, I was compelled by the interplay between those marketed products and a pipeline that I think holds tremendous scientific progress and can make a real difference for patients. And so I look forward to speaking to you all a little bit more about that as our session continues today.

Great, thanks for that introduction, Michael. I guess just as you mentioned, you've only been there for about 2 months. Maybe just talk us through, you know, your strategy near term, what's the focus, and then maybe just how that might evolve, like, longer term.

Yes. So near term, there are a number of important areas of focus. First of all, we want to continue to support and drive the business for our marketed products. As I mentioned, we have a cadre of marketed products. ELEVIDYS, people obviously are very familiar with, and our PMO franchise, both very important to the company. We recognize that there was some disruption, you know, particularly on the ELEVIDYS side in 2025.

And whenever you have a disruption caused by safety events like those that were disclosed in 2025, attention shifts very, very considerably towards safety, towards risk. And it's important in our industry, in our business, and for patients to focus on benefit risk. And ELEVIDYS clearly demonstrates a strong benefit for patients.

You see that in the initial registrational trials. You see it in the long-term studies, and we released 3-year data earlier this year that I think strongly makes that case for long-term benefit.

So getting that conversation shifted back towards benefit risk is absolutely essential because we need to keep in mind that, unfortunately, the condition that we're treating with ELEVIDYS is progressive, debilitating, and, unfortunately, life-shortening. And so one needs to look at benefit risk and the benefit that is delivered. And so we focused on recentering that conversation. We've expanded our commercial footprint. We've expanded our medical support for the product. And I think we are in that process of recentering, stabilizing, and continuing to support that business.

And driving that business as well as driving our PMO franchise is important to that longer term strategy that I described. But equally importantly, continuing to drive the pipeline is going to be absolutely essential. We have been serving DMD patients for a number of years, and we want to continue to serve DMD patients, in the near and long term. But we want to expand our footprint, as I've said, and we have a very promising siRNA pipeline.

I dug in deeply to the data behind our siRNA pipeline before I decided to join. I think it's truly differentiated. I think the delivery technology that we have available to us drives very high muscle concentrations for programs where that's relevant and also gives us the opportunity to penetrate deep brain nuclei in the CNS, for example, in our Huntington's program.

We have extremely potent constructs that can knock down genes effectively. And in our space where target validation is not an issue, in other words, we know what causes these diseases. The ability to deliver a therapeutic to the cell type of interest, to do it with high efficiency, to do it with good safety profile, to efficiently, in the case of the conditions we're talking about, knock down the gene very efficiently.

That is what's crucial to driving long-term success. Those sorts of data translate into the clinic and translate into late stage development with a much higher probability than most areas of drug discovery and development. So continuing to focus on that pipeline, driving it forward, driving through the near-term readouts, which we have coming, you know, later on, this year and beyond, as we move those programs, we believe into registrational studies, it's going to be a core focus. And if you look at those two elements of the strategy, supporting the ongoing business and driving the pipeline, we believe those can create a significant amount of value.

Everybody believes that they're undervalued, but I think we can make a strong case based on our cash flows, based on our pipeline. There is tremendous untapped potential in this company. And those two areas of focus are what will unlock that in the near term. And then give us the license in the longer term to continue to think about how we'd grow and expand our business. So that's what we're focused on right now.

Yes, makes sense. And maybe we could focus.

To start a little bit more on the pipeline, because there's some near-term updates, as you mentioned, and maybe just -- if we start with [ 1001 ], that's your FSHD program, and maybe talk about some of the early data you've shared this year and kind of what it means for the program.

Yes, certainly. So earlier this year, we shared data from the single ascending dose portion of the phase I trial. The trial has two components: the single ascending dose and the multiple ascending dose -- trial, components of the trial. Earlier this year we shared single dose data, and we saw good PK, not only systemic PK, but delivery to muscle. We saw dose-proportional increases in muscle concentration. So as we go up in dose, in a proportional way, we get more of the therapeutic into the muscle, which is not always the case.

There can often be a point of diminishing return as one escalates systemic concentrations. We saw a very good safety profile.

We saw no dose-limiting toxicity. And for the FSHD program, we saw very good early evidence of knockdown of the gene of interest, DUX4 knockdown in the biopsy samples. And that's critical because, you know, that's what drives that condition. And so we're going to continue to extend on those data.

We're going to have more data from that study coming later this year. We'll have data from the multiple ascending dose portion. We'll have data from higher doses as well, both this year and even higher doses next year as that study continues. And so that's a program that we're very excited about.

You mentioned the DUX4 knockdown. Can you maybe put that in the context of maybe what some competitors have shown?

Certainly. James, you wanna take that question?

Yes, absolutely. So, what we showed with the DUX4 gene regulated panels, so they can be expressed in a number of different ways, but we looked at both the panel used by Avidity, the same gene panel, and then the same gene panel used previously by Fulcrum. And we had seen in excess of 90% correction within the pooled single ascending dose data versus around 40% to 50% with the Avidity program.

I think that's super exciting. I think the other thing just to highlight from a PD perspective, the second half of this year is that there is an underlying challenge in FSHD with stochastic nature of expression that makes muscle biopsy a little more challenging from a PD perspective, so we're looking forward to showing some circulating data around DUX4 knockdown as well. That's just another compartment that balances out some of that stochastic nature you see in the muscle.

And when you share updated data later this year, can you maybe comment on what endpoints, what cohorts, et cetera, you might share? And what do you think the focus should be?

Can you say that, Mike?

Yes, you can go ahead and take that, James.

Yes, okay. So we are going to see 6 months out, up to the 8 milligram per kilogram dose for FSHD. So there's one higher dose from that in clinic that we won't be showing by this release, just because of timing. I think the important thing is just to repeat what we saw at a higher dose level the first half of this year.

So, again, just continuing on that hypothesis that Mike laid out that you can safely dose escalate. We know that's not something that has been shown across different programs in this space that have been dose limiting toxicities. That we continue to see this differentiating muscle concentration. And then from a PD perspective, as I've said, we'll look again at the DUX4 gene panels. I think that exciting new data will be circulating biomarkers of DUX4 correction.

And maybe just one thing to add, completely agree with everything that James has said. This is a condition where we know that more is better with respect to knockdown. Because DUX4 is a gene that should not be expressed outside of development. So in a normal adult or even child after the period of development, you shouldn't have DUX4 expression. And the expression of that gene is, by definition, therefore, abnormal. And the DUX4-regulated genes that are a consequence of that abnormal expression are what cause the pathophysiology, the morbidity, the long-term consequences of FSHD.

So if we can knock that down harder, we're quite confident that we're going to see that translate into very strong clinical results. And that's one of the things that I was referring to in my opening remarks when I say, target validation is very solid in this space. And the ability to predict from either preclinical data or early clinical data, what one is likely to see in later-stage studies is much more solid in this area than it is in most drug discovery and development.

It sounds like with multi-dose and higher doses, you might be able to drive that very high knockdown even higher, that kind of potential outcome here?

90-plus is very high, and so you get to the very desirable point where there's just not a lot of dynamic range left. But the ability to knock down, very substantially, we believe in the long term and to maintain that knockdown over time, we believe in the long term will translate into improved outcomes for patients.

Can you talk about some of those functional or outcome measures, and when might we see data on those endpoints?

Yes, we can certainly talk about them, and I'll let James give a little bit more detail in a second. The one thing that I would say is that we will look at functional endpoints in our early-stage studies, both in FSHD and DM1. I would really caution folks who look at the data not to over-index on those functional measures early on in a drug discovery and development program, because you have trials that just simply aren't large enough and aren't designed to show a difference on functional endpoints.

What these studies are designed to do is to look at the chain of events from PK, systemic PK, to muscle exposure to target engagement and biochemical knockdown at these targets and what is the consequence of that knockdown. When one looks at functional endpoints too early, you can essentially fool yourself by making decisions based on the variability.

So we'll look at those endpoints, but I would caution folks not to over-index on them until we get into larger, later stage trials. But James, you might want to talk about some of the endpoints that we will be looking at, both now and in the future as we move forward.

Absolutely, and I mean this is an evolving field, endpoint, generation validation in FSHD. What I would say as a company, we are extremely experienced in neuromuscular development, at working with neuromuscular outcomes. So I feel confident that we're going to, I guess what our focus really is right now is what are the best outcomes we can get for our phase 3 development.

And I'm very confident that we have the expertise in-house to use these data and use natural history data to make that decision, to be specific and on that question. I mean, endpoints we're looking at, I think like reachable workspace, I think that was challenging outcome in the Fulcrum phase III certainly will give it its due diligence. I'm not sure whether that's something they're still going to be persisting with long term and then measures of strength and measures of mobility, chiefly, so Timed Up and Go, 10-meter walk/run.

And I think what's going to be really interesting from these data is, as Mike says, not so much that we're going to really be picking out signals from noise but we will get an idea of how responsive to these endpoints are for use in a larger, more homogenous trial population.

Makes sense. Maybe we can shift gears now to 1003, that's your DM1 program, and maybe just talk about, you shared some early data this year, maybe highlight some of that and what you learned there.

Yes, certainly. So earlier this year as well, we shared data from the single ascending dose portion of that study. That study, while there are subtle differences, conceptually has a similar design to what I described before, which is there's an integrated single ascending dose and multiple ascending dose portion. And earlier this year, we showed data that have many of the same themes that we talked about in FSHD.

Good PK, good relationship between systemic PK and muscle concentration. The ability to see dose proportional increases in muscle exposure with a good safety profile, so with no dose-limiting toxicities identified. And we showed very early evidence of target engagement. And so we will have the multiple ascending dose portion of that study reading out later this year as well.

And that will continue to extend those observations and give us the ability to extend observations around target engagement, target knockdown, and the consequences of target knockdown, the PD consequences of target knockdown.

Maybe you can talk about what's a good outcome on some of those endpoints, knockdown, for example, other endpoints that are important there.

Yeah. Well, principle for DMPK, the gene that is responsible for myotonic dystrophy, for DM1. Again, we're in a situation where more knockdown is better. The exact specifics of how these genes are regulated are a little bit different, but still that basic theme that more knockdown is better, I think is quite clear and shown in the data.

And so we want to be able to drive knockdown that clearly differentiates us from others. We'll have more data later on this year, as I said -- as I mentioned, we have even higher dose cohorts coming early next year. And so making that PK/PD correlation, showing DMPK knockdown and the correlation to splicing correction, because what the abnormal form of DMPK does is it alters the machinery that regulates splicing and gives a detrimental and sort of a fetal splicing profile in the setting where that should not be the case.

And that's what's responsible for the downstream consequences in DM1. So showing that chain of events will be an important part of the data. It'll be coming later on this year. Showing that PK/PD relationship will be important. And that's important also as we have an eye towards even higher doses that can come early next year. And so it's going to be an important data set for us.

Yes, makes sense. And there's a lot of companies developing treatments for DM1, and Novartis actually shared some data recently from their phase III study, missed the primary endpoint, which was vHOT, so maybe just comment, you know, your thoughts there, how it impacts your thinking relative to your program, thoughts around vHOT, et cetera.

Certainly, I'll start and then I'll turn it over to James to provide some additional detail and color. Obviously, we're paying close attention to the space and we're well aware of the top line outcome of the Novartis study. One important caveat is there weren't a lot of data yet and that's typical in this space. What we know is that study failed to hit its primary endpoint. There was also a comment made that there were favorable indicators of movement in secondary endpoints.

The details of that will have to come out at a later time, probably in a scientific meeting is the way these things would typically proceed. So we'll learn a lot more.

But when we think about that outcome for that program, and its potential implications for our program, we think about a couple of things. The first is, what degree of knockdown were they able to achieve? And I certainly don't know within that specific study what they were able to achieve. But if you look at the earlier data, you would estimate that they're somewhere between about 30% and 40%, which is the range of knockdown that they've shown. And as I mentioned, this is a condition where with respect to knockdown, more is better.

So the first thing that we would look at is can we drive higher levels of knockdown with whatever dose it is that we ultimately carry forward into later stage development, whether it's one of the two doses that we'll update on later on this year or whether it's an even higher dose, you know, that we can update on early next year. And I think there is a very real opportunity for something that can deliver a greater degree of knockdown to have a larger benefit, to be able to show that benefit in late-stage studies.

Because the one thing I can tell you the Novartis result doesn't do is it doesn't shake our confidence in target validation.

And in so many areas of drug discovery and development, you can't say that. If you're working in immuno-oncology or some other area and there's a major failure, the first question that comes to mind is, is this even the right target? That's not a question that we worry about in these conditions because we know that the DMPK mutations are causal. The question then becomes, can you knock down the abnormal form to a sufficient extent? Can you do it consistently? Can you do it with a good safety profile? So we're going to be focused on that PK/PD and picking a dose for later stage trials that we believe will be truly differentiated with respect to the ability to achieve knockdown.

After that, then one has to think about questions regarding study design. So, was vHOT, video hand-opening time, was that the right endpoint? I'm not saying it was or it wasn't, but we'll learn more when those data are released more completely. Are there other features of study design? Stratification, so what was the nature of the baseline? You know, dystonia that existed in those patients. Does one need to control for that in ways that are different was done in the Novartis trial. Those are all things that we'll learn as the data come forward. Those are all things that we can build into our program.

But ultimately, we think the opportunity is very clearly there, and in particular, it's very clearly there for a differentiated program that can drive maximal or near-maximal levels of knockdown. So James, I don't know if you want to talk more about the specifics of study design and some of those endpoints.

I think you said a lot of it really, Mike, in that clearly there's very little doubt in the fundamental biology of DM1, which then leaves the speculation on Novartis around the drug, is it study design? From a study design perspective, I think it's quite likely that they've paid a pioneer's penalty here. We did it enough times in DMD. You're using outcomes often for the first time in a trial of treatment.

And you learn a lot from those studies. And I think that is a distinct advantage for companies like ourselves who are not yet locked down in our development plans. We're doing a lot of work in this space. As I said, a very experienced in-house team in the neuromuscular space.

We have well-networked in the KOL space and have plentiful natural history data, our own in-house clinical data, all of which to build on whatever we get to understand from the Novartis study to make sure, to Mike's point, that we are picking the right primary outcome for our studies. Study in the right population to show a change in that primary outcome. I think it's too early to throw out vHOT as an endpoint. It has a lot of appeal. It clearly does show drug response on a very subjective nature. You hear patients, you hear your PIs, patients know their myotonia changes.

How it responds, in a larger study over a longer time period is what I think we're learning at the moment, what Novartis have probably learned in this piece. And so I think we need to make a decision now, what is our best primary endpoint based on all of these data and our expertise and the population in which to drive a change in that.

But as said, I am for once happy to be in a position a little behind so we can learn on some of the others' experiences.

Makes sense. And maybe last sort of pipeline question before we move on, just any updates around the timing of the MAD data readouts for DM1 and FSHD and whether those readouts will be together or separated.

So, as we've said, we expect data readouts in the second half of this year. We're in the second half of the year, so in the coming months, we'll read out both of those studies. They're independent programs. They each have their own considerations, and they each have their own unique value propositions, and so our expectation is we would release each as it is ready. And so I think there will likely be separate data releases.

We want to make sure that folks are able to look at the data and absorb those data and understand what they mean for each program individually. They also have their own unique time frames. With respect to the FSHD program, as James mentioned, we're going to be focusing on a number of circulating biomarkers, including some novel biomarkers.

And so there's assay validation work that we're doing to make sure that we can bring forward a very comprehensive and high-quality data set.

So that program may be shifted a bit back in time within that window, so later on this year, but likely to be the second of the two. I think the DM1 program is likely to be the first. The exact timing is not yet determined because that's based on the progress in those programs, but we're well on track to release data from both studies in the back half of this year, as we've said.

They're great, we're all looking forward to those data. Maybe shifting your commercial program, you talked a little bit about, you know, kind of the history over the past couple years and some of the challenges, but if we start with ELEVIDYS and when we talk about some of the dynamics you're seeing, it sounded like you're getting to some stabilization and maybe some positive changes. Dynamics there as well, so maybe you could talk about those.

The key for ELEVIDYS is moving back to a balanced conversation around benefit-risk, as I described. And a number of factors have enabled us to shift that conversation back to that balanced conversation of benefit-risk. It's not just time from the events. It takes time for folks to absorb new data. There's sort of a natural arc of people's understanding new data like the safety data that were released last year, and an arc of their ability to sort of integrate that, together with their overall thinking, about the benefit-risk of the program.

We've also released new data, long-term data, the 3-year data as I described, which helps reinforce that long-term benefit, for both prescribing physicians and ultimately families, patients and their caregivers who are making these decisions. We've put a number of initiatives in place to expand our field force, to give them the new data that are available to facilitate those conversations.

Those conversations are going well.

We've dramatically increased the number of physician discussions that we've had. Subjectively, those have been very balanced with focus not only on safety but also on benefit, so those benefit-risk conversations are improving and I think becoming more centered in their focus. And with that we're seeing stabilization of demand and early positive signs as we said on our last earnings call.

And so overall, I would say that's going well. We would view it as a build off of this base and sort of a gradual build. So we're not expecting any dramatic inflection point in any particular moment in time, whether it's later on this year or early next year. But we do see signs of stabilization and forward momentum.

Yes. And that growth that you're seeing or sort of expect over time, is it kind of -- you said, I don't want to put words in your mouth, but like some growth here and then does it sort of stabilize at some point in the future and you kind of just, that becomes just a recurring revenue stream that's stable at a certain point in the future?

We would see it as a gradual -- a gradual build over time, as I said, and that's with respect to the currently indicated population. So nothing that I've described contemplates yet whether we return to the non-ambulatory population, and we can talk about that in a second. But with respect to the currently indicated population, we would see that gradual build over time. We certainly think there's durability in this franchise. We know that there is unmet medical need. We know that there are patients who can benefit from therapy.

And so we would see long-term stabilization.

We're not in a position today to give long-term guidance. But we do see that positive momentum, and we see ELEVIDYS being a very substantial contributor in the long term as well.

And as we think about, you know, what to expect the remainder of this year, should we be thinking flat-ish, or how should we think about the progression there?

Well, as we said on our last earnings call, the first half of the year benefited from a large number of patients that were already in queue, right? From 2025.

Obviously there were safety disruptions in 2025 and some patients dropped out, but many did not. And in particular, in the short term, there may have been a delay in making treatment decisions as those data became absorbed by the community. So that bolus of patients worked its way through the first half of the year and results in the first half of the year benefited from those patients.

What we're going to see in the second half of the year is demand that was generated earlier in 2026 at a period in time before we had our commercial initiatives in place, before we had centered that benefit-risk conversation.

So we're expecting that to be modestly lower than the first half, but stabilizing over time, and again we're seeing that long build off of that base.

What I would caution is that there's about a 6-month journey from enrollment form to treatment on average and so the effects that we're seeing on enrollment forms, the positive momentum that we're starting to see in the marketplace, it's going to take time for that to translate into revenues. That's more something that we'll see in 2027 than in the back half of this year.

Great. And you talked about label expansion into the non-ambulatory patients with ENDEAVOR data later this year. Maybe talk a little bit about that and your confidence in being able to expand the label.

So, the non-ambulatory population is not currently in our label. And we have a study ongoing, we have cohort 8 of the ENDEAVOR study, which is looking at the impact of sirolimus on hepatic [ artery ] in that population. And that will be an important component of future discussions around labeling for that non-ambulatory population.

The hypothesis in that cohort 8 is that sirolimus can be effective in reducing the incidence of acute liver injury in the non-ambulatory population. The specific hypothesis we built into that study is a 50% reduction in the incidence of acute liver injury, which would be quite meaningful. And when you broadly decrease the incidence of acute liver injury, what you're also going to do, although it's hard to study in a clinical trial, is you're going to reduce the likelihood of those severe cases, which are the ones that we're really worried about. So we're essentially looking at the base of the pyramid to determine whether we can improve hepatic safety, and that should, based on everything we know about drug discovery and development, reduce the likelihood of those more severe cases.

That study's underway, so we don't have data yet. It's enrolling as we speak. We expect to have it completely enrolled this year, with 12-week data in the first quarter of next year. And those will be important data for us and important data for us to discuss with the FDA around the potential to return to the non-ambulatory population.

And those data will form the centerpiece of those conversations. As we've said, we'll reach out to the agency. Our plan is to do that in the first quarter of next year with data in hand to have those conversations. And those discussions will really define what the path is to a return to the non-ambulatory population. It is a durable franchise.

That makes sense. And maybe we can last 2 minutes here. Just the PMO business looks like you've got some nice stability there, but you may be facing competition next year. So maybe just talk about some of the near-term dynamics and how you think things might evolve next year.

It is a durable franchise. These are products that have been on the market for a number of years. They've delivered clear patient benefits. Over that time period, we have extensive real-world evidence, which we've published in a number of settings, which demonstrates that, which shows, for example, prolonged time to ambulation, decreased rate of pulmonary decline, cardiac decline, even overall survival in a real world setting, based on that published evidence.

And those are things that matter to patients and to their physicians. And so we feel good about the benefit that those have brought long term. We also have supported those products extensively in the marketplace in terms of establishing reimbursement pathways, helping patients navigate a very complicated reimbursement landscape, other patient support systems, home infusion, all of those things matter as well and are contributors to that 90-plus adherence that we've demonstrated in the real world. And so we think that all matters to patients.

There are programs that are moving forward in this space. In 2027, Dyne will have a PDUFA date. We welcome drug discovery and development in this space as innovators. And we understand that over time we will move into a competitive marketplace. We think we're well-positioned to compete in that marketplace.

So for example, all of those things that I mentioned, the long-term experience, the data that had been published, the reimbursement pathways, the patient support systems, the home infusion, which is critical, for these patients to maintain them on therapy in a way that is not disruptive to their lives or their caregivers' lives. We think all of those things matter, and we'll add stickiness to this franchise. So we think we're well-positioned to compete in that longer-term marketplace.

Okay, great. It looks like we're just about out of time. Michael and James, thanks so much. Really appreciate your time today.

It's been a pleasure. Thank you.

Thank you very much.

Thank you. Good afternoon and welcome to Sarepta's second quarter 2026 earnings results call. As a reminder, today's program is being recorded. At this time, I'll turn the call over to Pam Thornton, Sarepta's Senior Director of Investor Relations. Please go ahead. Thank you.

Thank you. And thank you all for joining today's call. Earlier this afternoon, we released our financial results for the second quarter of 2026. The press release along with our slides and supplementary information are available on the investor section of our company website. We plan to file a form 10Q for the quarter today with the SEC. Joining me on the call are our CEO, Dr. Louise Rodino-Klapak, President of R&D and Technical Operations, Patrick Moss, our Chief Commercial Officer, and Ryan Wong, our Chief Financial Officer. Additionally joining us in the Q&A portion of the call are Ian Estepan, President and Chief Operating Officer, and Dr.

James Rodino-Klapak, police medical officer. Before we begin the formal remarks, I would like to note that during this call we will be making a number of forward-looking statements. Please refer to slide two of our presentation to view the formal text of these safe harbor statements. These statements involve varying risks and uncertainties, many of which are beyond directives control. Actual results could materially differ from these forward-looking statements, and such risks can adversely affect our business, our results of operations, and the trading price with Sarepta's common stock. We strongly encourage all listeners to review the company's most recent SEC filings for a detailed description of these applicable risks. Tarepta explicitly states that it does not undertake any obligation to publicly update or revise its forward-looking statements or financial projections based on subsequent events. Furthermore, please note that we will discuss non-GAAP financial measures during today's webcast.

Complete descriptions and reconciliations of our GAAP to non-GAAP financial measures are included in today's press release and the accompanying slide presentation available to investors on our website. And with that, I will now turn the call over to our CEO, Michael Severino.

Thank you, Tam. Good afternoon, and thank you for joining Sarepta Therapeutics' second quarter financial results conference call. This is my first earnings call as CEO of Sarepta, so today I'll offer a few opening remarks and then turn things over to Patrick, Louise, and Ryan to discuss our commercial highlights, pipeline progress, and financial results for the quarter in more detail. As someone who has spent a career evaluating preclinical and clinical data and translating scientific breakthroughs into meaningful treatments for patients, it's an honor to be here. Sarepta is uniquely positioned within biotech and has tackled some of the most challenging problems in medicine. Our scientific achievements have helped redefine what is possible for patients with Duchenne, from pioneering work in exon skipping to the development of Alevitis. A growing body of long-term data has established Sarepta as a leader in rare disease innovation. I see tremendous potential untapped value in the opportunity we have in front of us.

And that is what brought me to be a part of this team. We have a leading commercial portfolio in Duchenne with four approved therapies that are making a difference for patients today. These therapies are backed by a growing body of long-term data and real-world evidence supporting their use. We have an siRNA platform that has already delivered strong preclinical and early clinical data. As a physician scientist, I find these data compelling and have been impressed by both the potency of our siRNA and our ability to deliver to the cell type of interest with high efficiency, as evidenced by our ability to achieve high muscle concentrations in a dose-dependent manner in our SAD studies. Thank you. Based on these features and the strong predictive value preclinical models have in this space, I believe our pipeline has the potential to deliver best-in-class therapies across multiple neuromuscular and rare disease indications and drive our next phase of growth. Importantly, we have the financial strength to advance these programs independently, and we have a deeply experienced and talented team with a strong track record of delivering results.

We recognize that concerns around elevatist adoption, competition on the horizon for exon skipping treatments, and capital allocation remain. However, we are prepared to meet these challenges and have multiple upcoming milestones that can clarify our growth trajectory. These include Cohort 8 data, new data in the second half of this year, and new data in the second half of this year. from two of our most advanced siRNA programs in FSHD and DM1, and upcoming regulatory decisions around Vyondis and Amondis. Now, turning our attention to the quarter. You will hear more details from Ryan shortly, but I'd highlight three things from our quarterly financial results. First, we delivered another quarter of GAAP and non-GAAP operating profitability, reflecting the durability of our base business and disciplined execution. Second, we increased capital. cash and investments by approximately $197 million during the quarter, strengthening our ability to fund future growth.

And third, our commercial portfolio continues to provide a strong foundation as we invest in what we believe are significant long-term value and growth opportunities across our emerging SIs. RNA pipeline. Commercially, our PMO franchise has remained stable and 11 is performed in line with expectations with improving enrollment forms providing early evidence that our expanded commercial initiatives are taking hold. Now that we are in the second half of the year, we have narrowed 2026 total net product revenue guidance to $1.2 billion to $1.3 billion, with a midpoint being the appropriate reference. This is consistent with our prior expectation that results would trend toward the lower end of our original range. Patrick will provide more detail on our commercial performance, outlook, and growth initiatives in his section. Turning to R&D, we continue to make meaningful progress across both our Duchenne and SI RNA programs. In Duchenne, enrollment and dosing continue in cohort eight of the Endeavor study, and we expect to fully enroll the study by the end of 2026.

We were also pleased to see the FDA accept our supplemental NDA submissions of Amondus 45 and Vyondus 53 for review. Beyond Duchenne, our emerging siRNA platform remains central to SREPTA's future growth strategy. With important data readouts expected later this year from our FSHD and DM1 programs, Louise will discuss the biology-first approach that underpins these programs and why we believe our platform can deliver differentiated, potentially best-in-class therapies across multiple rare disease indications. In summary, our focus is clear and our future is bright. Our financial footing is sound, and we continue to execute in Duchenne. And revenue from our approved products enables us to advance our pipeline independently, which we continue to do with discipline and urgency. I'm excited to be on this journey with this team and look forward to creating long-term value for the company and the communities we serve.

Thank you. And with that, I'll turn it over to Patrick to discuss commercial performance for the quarter. Patrick?.

Thank you, Mike, and welcome to the team. Today I'll review our second quarter commercial performance, progress we are making to support physicians, patients, and families across our four approved Duchenne therapies and our outlook for the remainder of 2026. For the second quarter, total net product revenue was $329 million, consisting of $98 million from Elevitus and $231 million from our PMO franchise. PMO performance continues to reflect stable demand and sustained patient and physician competence supported by extensive real-world experience and evidence. Elevita's performance was in line with our expectations for the quarter, with sales remaining relatively steady and quarter-over-quarter growth in enrollment forms signaling that demand is increasing. We view that trend as an encouraging sign that momentum is building. Our focus is on sustaining that progress and supporting informed treatment decisions through continued science, education, and engagement.

Throughout the first half of the year, we completed the expansion of our commercial footprint. The strategy is set, our sales team is trained and deployed, and our initiatives are now fully operational. Our focus is now on execution, improving patient identification, expanding education for patients and families, and continuing to strengthen healthcare providers' confidence to drive demand. At a recent mid-year meeting, the energy across the team was clear. They are reaching more referring physicians, engaging more deeply at treatment centers, and participating in a more balanced discussion about the totality of evidence demonstrating a Levitas' benefit-risk profile. In Q2, our sales team delivered a record number of healthcare provider interactions. HCPs are engaging more deeply on the sustained functional outcomes and durability supported by Elevitus Embark Part 2 and, more importantly, the three-year data.

Enrollment form activity provides early evidence that these efforts are taking hold. A majority of Q2 enrollment forms were from HCPs who had interacted with our sales team in the prior 90 days, including a meaningful portion within 30 days. This pattern was consistent with Q1 and reinforces the importance of focused, timely engagement. The breadth of site activity expanded in Q2 as well, through both re-engagement and new interest. More returning sites submitted enrollment forms than in Q1, while submissions from referral sites outside our current network signal broader interest in 11S. Taken together, these indicators support our view that our sales team initiatives are taking hold. Understanding of the 11th Benefit Risk Profile is improving and competence is rebuilding across the Duchenne community.

In addition, our patient education team is bringing that same commitment directly to families, connecting with many who have turned to Sarepta seeking information that will help them navigate Duchenne and the treatment decisions they face with greater clarity and confidence. Turning to our outlook, as Mike mentioned, consistent with our previous direction of model towards the lower end of the $1.2 to $1.4 billion range, we are narrowing our 2026 total net product revenue guidance to $1.2 to $1.3 billion. The timing of revenue reflects how patients progress from enrollment form through the treatment journey. Elevita's revenue in the first half of 2026 was supported by patients who entered the pipeline following the late 2024 label expansion and progressed to infusion during the first half of the year. As a result, first half revenue benefited from the conversion of that backlog of demand. Elevitas revenue in the second half of 26 will reflect a period when enrollment form activity was lower before expanded commercial initiatives were fully deployed and beginning to take hold. We are encouraged by the quarter-over-quarter improvement in enrollment forms we are seeing today.

However, given the length and variability of the treatment journey, that activity is expected to contribute more meaningfully to revenue in 2027. As a result, we expect total net product revenue in the second half of 2026 to be modestly lower than in the first half. We also currently expect 11-ish revenue in the third quarter to trend lower than Q2, acknowledging that the quarter-to-quarter variability is the reality of a one-time gene therapy. We do remain confident in the long-term opportunity for Elevitus, and our team remains focused on sustainable execution. Now, turning to our PMOs. Stable demand, extensive real-world experience, a well-established safety profile, and adherence rates exceeding 90% continue to underscore the durability of this business. More than 1,800 patients worldwide have been treated with Sarepta's exon skipping therapies, underscoring their enduring value to patients and families. This year marks an especially meaningful milestone for Sarepta and the Duchenne community.

On September 19th, Exondus 51 will celebrate 10 years since its U.S. approval. For us, this is more than an anniversary. It represents a decade of SREPTA's leadership, close partnership with the Duchenne community, and progress that has helped us transform the treatment landscape. Over that time, Sarepta has helped establish exon skipping as a foundational treatment approach and build a substantial body of real-world evidence across important outcomes, including ambulation, pulmonary function, cardiac function, and survival. We are proud of the progress made over that past decade and deeply honored to have served the Duchenne community throughout that journey. In closing, our priorities remain clear. Execute with discipline, support informed treatment decisions through science and education, and drive sustainable growth across our Duchenne portfolio.

We remain confident in the long-term opportunity for Elevitus and the strength and durability of our PMO franchise. importantly, we remain deeply committed to transforming what is possible for patients and families living with Duchenne and bringing that same commitment to patients across other serious rare diseases. Thank you. And with that, I'll turn the call over to Louise. Louise? Thanks, Patrick.

And let me add my welcome mic. We're happy to have you on board. As we move into the few last months of 2026, we remain excited by the science that underlies our rare disease portfolio and the data we're preparing to share with you soon. Before turning to the individual programs, I want to briefly frame how we think about our next generation RNA platform. Our strategy is built on a simple premise, biology first. Rather than applying one delivery approach across all tissues, we select the receptor and delivery architecture that is intended to best address the key biological barrier in each disease. In muscle, that means leveraging Alpha-V Beta-6 Integrin targeting, which was selected for its strong muscle exposure and delivery characteristics.

In the CNS, where the dominant barrier is transport across the blood-brain barrier, we use a unique transferrin receptor based approach. Across both settings, our goal is the same, to move beyond systemic exposure and achieve productive intracellular delivery, engagement, molecular correction, and ultimately the potential for functional benefit. Combined, we believe this approach will distinguish our therapies from others in earlier and later stage development. This is also where siRNA biology is important. siRNA uses catalytic multi-turnover risk activity that continually silence. We believe this enables deeper and potentially more durable suppression of disease-causing RNA than a approaches that rely on antisense mechanisms that require RNase H, a rate-limiting enzyme. Together, biology-driven delivery and catalytic siRNA potency creates the foundation for our belief that these programs have the potential to be best in class. Building on the positive SADD data from our lead programs to treat FSHD and DM1, we remain on track to announce interim results from our Multi-Ascending Study, or our MADD study, in the second half of this year.

We believe these programs are differentiated through a unique targeting mechanism and high muscle bioavailability, positioning them as potential best-in-class therapies compared to more mature competitor programs in the space. To remind you, data from our readout this year showed high muscle concentration with alpha-V-beta-6 and a strong safety profile. Beginning with SRP1001, which is our siRNA-based treatment designed to reduce or knock down the production of the Dux4 protein in skeletal muscle in patients living with FSHD. FSHD is caused by abnormal activation of the DEX4 gene, leading to expression of the DEX4 Sex-4 is a transcription factor that affects the expression of multiple genes within muscle. It's normally expressed during embryonic development, but when reactivated later in life, it creates a toxic intracellular environment that contributes to muscle degeneration. underlying pathology is well understood and the pathological role of ducts or in the progression of the disease is well accepted Our therapeutic thesis is that deeper ducts for knockdown in muscle should translate into greater molecular correction and, over time, the potential for improved functional outcomes. The MAD data we plan to share will include safety, PK, Dux4-related gene panel, circulating Dux4-related biomarkers, PK, and preliminary functional assessments. Importantly, because FSHD is a slow, progressive disease, and this is an early study including six months of follow-up, the objective is not to definitively demonstrate functional benefit at this time, given the trajectory of the disease.

Rather, the goal is to establish the biological chain from tissue exposure to target knockdown to molecular biomarkers known to drive the underlying pathology of the disease, and also to select an appropriate dose to take on to the next stage of development. In summary, our goal is to generate the highest levels of knockdowns that improves biomarkers and leads to best functional outcomes. Confirming our ability to safely dose escalate and deliver a drug with proven biological efficacy efficiently to the target tissue would strengthen the evidence supporting SRP1001 as a potentially best-in-class treatment for FSHD and provide an important foundation for our discussions with FDA as we prepare for the next phase of the study. to advance a registrational study. Moving on to DM-1. SRP1003 is our siRNA-based treatment for DM1 designed to target and knock down or silence the DNPK mRNA in target cells. The early data we generated for DM1 is important for two reasons. First, our preclinical models are predictive of what we have seen in the clinic with respect to muscle concentration. And note, an increase in plasma exposure has translated into enhanced dose-dependent delivery to the muscle, resulting in robust target engagement.

And second, the DNPK knockdown observed to date has been directionally strong and supports the potential of siRNA to address the root molecular driver of disease. As you are aware, DM1 is driven by an expanded CUG trinucleotide repeat in DNPK transcripts, causing mutant DNPK mRNA to accumulate in the nucleus and disrupt normal RNA splicing. As a result, for any therapy to be therapeutically effective, it must reach the target tissue, enter the cell, and reduce nuclear-retained DNPK RNA. SRP 1003 is being developed to achieve exactly that, with the goal of driving downstream splicing correction. The results we plan to share from the MADS study will include safety, serum and muscle PK, BMPK knockdown, CASE 22 splicing index, and VHOD analyses. The importance of these results, should they be positive, will differentiate SRP1003 as a best-in-class treatment for DM1 and offer a clear path to a registration study. It's important to note that our FSHD and DM1 programs demonstrate why we believe delivery efficiency is a primary competitive advantage.

The key differentiator is not simply reaching the bloodstream, it's reaching enough muscle fibers, maintaining exposure long enough, achieving sufficient intracellular siRNA concentrations, meaningful target knockdown in the nucleus. Further, our non-clinical data has shown that targeting endocrine receptors via small peptides leads to enhanced skeletal muscle uptake compared to using a much larger TFR1 antibody-based approach. It's also important to note that based on data to date, our alpha-V beta-6 integrin targeting ligand provides superior muscle concentration compared to current transferrin-based approaches. without dose-limiting toxicity. More specifically, due to its role in intracellular transfer and trafficking, only approximately 5% of expressed TFR1 receptors are available on the cell surface for binding at any one time. versus alpha-V receptors available at any one time. This high level of surface availability and high levels of expression leads to a greater potential for ligands targeting alpha-V beta-6 to drive significantly higher muscle uptake than TFR1. These delivery characteristics help establish the rationale for advancing SRP1001 for FSHD and SRP1003 for DM1 in First in Human Studies and continue to support our confidence in the platform. In summary, we believe StorUP's next-generation RNA platform is differentiated by biology-driven tissue targeting, efficient intracellular delivery, and the catalytic potency of siRNA. focuses on connecting the full chain from tissue delivery to target engagement to molecular correction and ultimately to the potential for functional outcomes.

We are applying the same biology-first framework to our CNS programs. Our Huntington's program is ongoing, having dosed its first patients earlier this year. In these programs, our receptor selection is driven by the biological requirement for transport across the blood-brain barrier. If successful, the early CNS data would provide important validation of our transfer and receptor-based blood-brain barrier delivery approach. Our second generation DM-1 program is the first example where we aim to impact the CNS in addition to muscle to address the significant unmet need. We look forward to sharing this data as soon as it becomes available. Now, turning to Elevitus. We were pleased to announce in March that screening and enrollment were underway in cohort 8 of Endeavor for study SRP 9001-103.

To remind you, the purpose of cohort 8 is to assess prophylactic serolimus treatment as part of an enhanced safety protocol during treatment with olivudis in non-ambulant individuals with Duchenne. Data from cohort 8 will be used to determine whether administering serolimus prior to and after levodas infusion can help reduce acute liver injury or ALI. A known risk associated with AAV gene therapy is a class effect. The cohort's enrolling approximately 25 participants in the United States who are non-ambulatory and do since currently underway. As a reminder, the immunosuppression regimen will include 14 days of peri-infusion serolimus, to Levitas administration and will continue for 12 weeks after Levitas administration. Primary endpoints include incidence of ALI and elevatist dystrophin expression at 12 weeks. Participants will be followed for safety and functional outcomes for 72 weeks.

The approach with serolimus is based on preclinical data and shaped by real-world clinical experience, including guidance from independent specialists in Duchenne and liver health. The evidence base continues to build. As previously shared, there have been independent published reports on the use of serolimus to mitigate ALI with elevatus. Dr. Soslow and colleagues very recently published a study in human gene therapy demonstrating that none of the patients treated with prophylactic serolimus had ALI. We will also present what we believe are encouraging interim safety data from our Phase 4 indoor study at the Neuromuscular Study Group meeting in September that showed zero incidence of ALI in patients treated prophylactically with serolimus. We expect to fully enroll the Endeavor Cohort 8 study by the end of 2026. Based on observations that our study investigators are dosing participants sequentially, we now expect 12-week data from the full cohort in the first quarter of 2027.

Further, we continue to plan to meet with FDA in early 2027. In addition to safety, we continue to build the evidence-based through upcoming disclosures. At the Neuromuscular Study Group meeting, key de novo disclosures include microdystrophin and muscle MRI correlations with function. Next, the impact of treatment delay modeling, the Endure Phase 4 Interim Safety and Liver Safety, U.S. post-marketing safety, and finally, the promised mobility outcomes versus external controls. At the World Muscle Society meeting, we will highlight expression and safety data in 11 distributed patients under four, along with encore presentations that will embark three-year outcomes, cardiac functional data, pooled safety, and early intervention preclinical data. We look forward to sharing this data with the community. Moving now to Amondus 45 and Vyondus 53, our exon skipping therapies to treat Duchenne.

At the end of June, we were excited to announce that the FDA accepted our supplemental new drug applications for both therapies. The signing produced a target action date of February 28th, 2027. The SNDA submissions seek conversion of the accelerated approvals of Amandas 45 and Vyondas 53 to traditional approvals. The applications are supported by the data from the Essence confirmatory study, as well as substantial published real-world evidence and the favorable and consistent safety profiles of both exon skipping therapies. We look forward to sharing important updates with you in the coming months, including readouts from our FSHD and DM1 MAT studies, proof of biology from our Huntington's Disease Program, and data from the ENDEAVOR cohort 8 study. Thank you. And I'll now turn the call over to Ryan for an update on our financial performance. Ryan?.

Thank you, Louise, and good afternoon, everyone. We delivered a strong financial performance in the second quarter, and we are pleased with the continued operating discipline reflected across the business. Our results underscore the durability of our commercial DMD franchise, the progress we are making with our pipeline, and ability to fund our most important commercial and R&D initiatives from a position of financial In my remarks, I'll walk through the quarter's key financial highlights and how we are positioned for the second half of 2026. Beginning with second quarter revenue performance. Total revenues were $401 million, a decrease of 34 percent year-over-year, driven by the by the decrease in net product revenues, primarily levities to a lower demand. The total revenue in the quarter included $73 million of collaboration and other revenues, consisting primarily of contract manufacturing revenue from our partnership with Roche. Through the first half of the year, we have now recorded $659 million in total net product revenue and over $1.13 billion in total revenue.

Due to year-to-date total revenues decreased 17% compared to prior years. driven by lower elevatist product revenue, partially offset by higher collaboration and contract manufacturing revenue. Moving next to growth margins, total cost of sales for the quarter were $149 million, a decrease of 2% compared to the prior year period. The change every year is reflective of lower cost of goods due to the decrease in our product sales partially offset by higher cost of goods related to contract manufacturing revenues. On a year-to-date basis, total cost of sales were $248 million, a decrease of 11% year-over-year, driven by similar dynamics. Gross margins on net product revenues were 75% in the quarter and 78% for the first half of the year. Operating expenses continue to reflect our focus on disciplined cost management. combined R&D and SG&A expenses in the second quarter on a GAAP and non-GAAP basis for $199 million and $165 million, respectively. Non-GAAP expenses in Q2 decreased 44% compared to the prior year period, reflecting the benefit of our cost restructuring initiatives and the prioritization of our promising SR&A programs in our R&D portfolio.

First half combined R&D and extra expenses on a GAAP and non-GAAP basis for $462 million and $388 million, respectively. Year-to-date non-GAAP expenses were down 66% compared to the same period prior year. also driven by the restructuring and pipeline reprioritization, as well as the Arrowhead Collaboration upfront expense recognized in the prior year. This operating discipline translated into meaningful profitability for the quarter. delivered GAAP operating income of $13 million and non-GAAP operating income of $86 million. For the first half of the year, GAAP and non-GAAP operating income came in at a robust $372 million and $484 million, respectively. In addition to the results I just highlighted, our GAAP results include a $39 million litigation contingency charge to potentially resolve certain outstanding patent claims. From a balance sheet perspective, we ended the second quarter with $945 million of cash and investments. $197 million from the prior quarter. The robust cash increase in the quarter is a result of our strong operating performance. and includes a receipt of $40 million from the Roche commercial sale milestone earned in Q1.

For the first half of the year, if you exclude $250 million of collaboration payments made to Arrowhead in the first quarter, our base business has generated over $240 million in cash. In closing, I'll provide color on our outlook for the second half of 2026. First and foremost, we remain focused on discipline execution and prudent capital allocation as we advance our commercial and pipeline priorities. As you heard earlier on the call, we have narrowed our net product revenue guidance to between $1.2 and $1.3 billion, with the midpoint of this range an appropriate reference. In addition, we are revising upward our total collaboration and other revenue guidance between $550 and $600 million, which is an increase of $75 million from the midpoint of our previous guidance. This is driven primarily by higher contract manufacturing revenues. I'd like to highlight for modeling purposes, this increase in expected contract manufacturing revenues will also result in a roughly equivalent increase in cost of goods for products sold to Roche.

Now moving to expenses, given we are halfway through the year, we are tightening our non-GAAP optics guidance to $800 to $850 million, the low end of our previous range. And finally, from a cash flow perspective, looking back at the last 12 months, we have reset our cost structure, fulfilled our large collaboration obligations to Arrowhead, and refinanced the majority of our 2027 debt, while the base business generated nearly $400 million in cash. On a forward-looking basis, given the strength of our execution, we believe our medium-term liabilities and remaining 2027 notes are well-funded, and we remain in a strong financial position to fund our promising pipeline using cash flow from our business. With that, I'll turn the call back to Mike for Q&A. Mike? Mike Pazin- Thank you, Ryan. Operator, can you please open the call for Q&A?.

Thank you. At this time we will conduct the question and answer session. To ask a question, you'll need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. ask that you please limit your questions to one question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Anupam Rama of J.P. Morgan. Your line is now open.

Hey guys, thanks so much for taking the question. Hi Mike, how are you? Congrats on the new gig, man. So, when you look at the pipeline, what really excites you about what you have going on in the pipeline? Is it something particular about the Arrowhead products or something like what Cohort 8 do for the Elevitus franchise. I was wondering if you could expand on that. Thanks so much.

Certainly. Thanks for the question, Annapom, and I'm very happy to be here. There are a number of things that excite me about the pipeline, and so maybe I'll talk about them in two parts. The cohort eight data, I think, are very promising. The potential for serolimus to improve benefit risk in the non-ambulatory population, I think, can have a big impact over time. Obviously, we're still in the data generation. And as we said, we expect to complete that cohorts enrollment by the end of this year and have data in the first quarter of next year. But I think that's something that we're very much looking forward to.

But when I look at the earlier pipeline and the SI RNA programs that were advancing, I believe they have tremendous potential. First of all, What I would say is in this space, preclinical models and early clinical data have a very high degree of predictive power. This is very different than what we see in most areas of drug discovery and development. We essentially know the biology that drives these conditions unambiguously. And if we can achieve high levels of knockdown, we have a high degree of confidence, we have that we can achieve a benefit for patients in the long term. And when I look at both the preclinical data and the early clinical data, I see both the delivery aspects of the technology performing very, very well with dose-dependent increases in muscle concentration up to the highest dose tested in our SADD studies, without any dose-limiting toxicities. We have very potent RNA silencing technology.

As Louise pointed out, we are able to achieve very robust knockdown. And so I think there's a real opportunity to bring forward some tremendous therapies, not only in neuromuscular conditions, but also potentially in, in conditions like Huntington's, where our delivery technology also plays a key role in getting to deep brain nuclei in the preclinical models that we've studied. And obviously that clinical trial is now underway to see how those data translate into the clinic. So I just think there are a wide range of opportunities that can drive value for the company and value for patients in the future.

One moment for our next question. Our next question comes from the line.

Oppenheimer, your line is now open. Thank you for taking our question. Congrats on the progress and congrats on the new role, Michael. Welcome to Sarepta. A question for Michael. Based on our discussions, there is a high number of investors who are very interested in the DM1 and FSHD program. but are hesitating to underwrite the DMD pipeline risk. Although I understand it may be a little early for this question, but how are you thinking about the potential separation of the two businesses, the DMD pipeline and the DM1 FSHD programs? Thank you.

I think there's tremendous synergy between those aspects of what we do here at Sarepta in the big picture. So we're very committed to Duchenne. We've been in Duchenne for more than a decade now. Our marketed products, we believe, are making a tremendous favorable impact on patients. You see that in the long-term data. You see that in the preservation of function, increased duration of ambulation, reduction in progression of cardiac and pulmonary disease, and even overall survival across various aspects of our DMD portfolio. And so we think those programs are a real asset to the company.

When we look at their performance, we see very solid, very stable, and very durable performance, which I think is very consistent with that benefit that is being delivered. And importantly, the revenue that those programs generate is what allows us to drive the earlier parts of our pipeline, the SIRNA. programs in particular. And so they're really very complementary to each other. And I think as we move through the year, we have a number of data readouts that will clarify the long-term role of our DMD portfolio, which I think is very promising and will have a very bright future, as well as turn over new important data cards on the SI RNA pipeline, I think can open up some very new and very important venues for the company's future growth. And so, again, I think those areas are very synergistic.

One moment for our next question. Our next question comes from the line of Brian Abrahams of RBC Capital Markets. Your line is now open.

Hey, good afternoon. Thanks for taking my question and Mike, congrats on the new position. Welcome to this rep team. On the expense side, it looks like you've lowered your OPEX guidance for this year, and I think you've talked in the past about the 800-ish range being a good steady state to think about. I'm curious if we could talk a little bit more about the puts and takes around the OPEX run rate here. Is there any further wiggle room? and I guess how will resonance of the Elevitus commercial efforts as well as the competitive dynamics impact for the exon skippers potentially influence how you think about long-term OPEX. Thanks.

Ryan, do you want to take that? Yes, absolutely. Thanks for the question. Yes, so we've talked previously around, we're very comfortable in that $800 and $900 million range in terms of OpEx both being able to fund our commercial initiatives and to advance our pipeline. And as you saw, you know, we've, You know, we believe in the sort of durability of the CMD franchise. So although acknowledging that competitors are in the mix, We think there's high value in both our exon skipping and gene therapy programs. And so we're continuing to invest to to to in that durable DMV franchise. And then given the cash flow generation profile of our company, We feel really confident we can advance the SRNA program to value inflection points. And that being said, we continue to be very prudent about capital allocation.

You know, think about where the science leads us in terms of what has the highest probability of success and what's going to ultimately generate long-term value for the company as we think about where we invest. So that type of focus will continue to remain, even though we feel, again, very comfortable within that $800 and $900 million range to advance our programs.

One moment for our next question. Our next question comes from the line of Andrew Sy of Jeffery. Your line is now open.

Hi, thanks. Good afternoon. Congratulations, Mike. So, I have a question about the regulatory strategy for the SRNA programs, because given you guys have the desire to start pivotal studies, can you maybe talk about your latest thinking and whether you plan to pursue accelerated approval or full approval for both indications, and what do you envision your primary endpoint to be ultimately? Thank you.

And I'll ask Louise to address that. Sure. Thanks for the question. Now, for both FSHD and DM-1, in terms of the regulatory pathway, as we've described before, the way we've thought about it and set it up is that we have the ability to apply the for both accelerated approval and traditional approval depending on the regulatory framework at that time, the landscape, and the data that's generated. And in terms of the outcomes that we will use in our phase three trial, that's really what the MAD study readout will help us inform of that. Obviously, in these early studies, we're looking at a variety of endpoints and evaluating all of them, and it'll be a data-driven discussion. We'll also be looking at the landscape in general. It's a great opportunity for both of these communities that there's so much interest in this space and so many developers in this space. So it'll be both our internal data and the entire landscape that informs our approach to the next phase, and we look forward to having that discussion with regulators.

One moment for our next question. Our next question comes from the line of Ellie Merle of Barclays. Your line is now open.

Hey, guys. Thanks for taking the question. And Michael, welcome to Sarepta. Just a clarification on some of your elevatist commentary. You mentioned you saw a quarter-over-quarter increase in elevatist enrollment forms. Just to clarify, are you also seeing an increase in start forms in 3Q versus 2Q? Or if you could just characterize that trajectory. And then in your comments you said you expect modestly lower levitas revenue in the second half versus the first half, but more contribution from start forms in 2027. I guess just to clarify, should we be expecting revenues to grow in 2027 from that?.

So with respect to start forms, I'll say a bit and then I'll ask Patrick to provide some more detail. We're encouraged with the trends that we see. As you know, we spent a good portion of the first half of the year getting our expanded commercial footprint in place and putting our initiatives in place in order to have a balanced communication of benefit-risk around Elevitus. And we're seeing those efforts start to take hold. We are seeing improvement. in start forms, and we would expect those trends to continue. It's early to be talking about 2027, but we do feel quite confident in the nature of the benefit-risk discussions that we're having and the trends that we're seeing. Patrick, do you want to add a little bit more detail? Absolutely.

What I would say from a commercial perspective,.

perspective is the indicators that we're seeing today are moving in the right direction. Our strategy is set, our sales team is trained and out there and deployed, and our broader commercial initiatives are fully operational. With the enrollment form activity, it has stabilized and improved. Returning sites are engaging. And we are seeing interest from new sites. I would say all of this signals that these initiatives are taking hold and strengthening that patient pipeline, even though the associated revenue, it will come, but it's going to take time. And really, the team is just focused on consistent execution and helping those patients progress through the journey.

One moment for our next question. Our next question comes from the line of Nigal Nohomovic at Citi. Your line is now open.

Hi, this is Caroline on Fugol. Thanks for taking your question. With DM1 and FSHD data approaching, can you tell us what disease characteristics make a target particularly well-suited for the AlphaZ Beta 6 delivery platform and what additional muscle diseases could become attractive expansion opportunities if the upcoming data sets are successful? Thanks.

Certainly. Louise, would you like to take that? Sure. So for our platform for FSHD and DM1, we're using what really got us excited about working on these indications was the alpha-V beta-6 targeting ligand. And really because of the wide distribution across muscle, and that's why we selected it. We've also talked about the receptors available for high muscle concentration, and that's exactly what we saw translating the preclinical data to early clinical data, is that we were able to achieve high levels of muscle concentration in DM1 and FSHD without those lining toxicity. And so really when looking at an indication, why the alpha-B beta-C-1, why the alpha-B six is attractive is because you are broadly getting high levels of muscle concentration and so in terms of potential other indications it's really those affecting muscle diseases with widespread need in terms of the muscle pathology. And so in now speaking to the other part of the equation with siRNA, and FSHD have very clear pathological roles by toxic gain of function, mRNA, NPNPK, and then proteins with Dux4. And so there, the technology to reduce, we know that it's due to this toxic protein or mRNA, and we know that efficiently reducing that with the siRNA, the potent and siRNA is important.

So it's those two things together. It's the targeting technology, it's the siRNA, and the ability to do that. And so with the alpha-beta-6, you could target any muscle disease. With the siRNA, we're really looking at gait of function toxic diseases where you could get efficient knockdown of that indication. So we're... As you can tell, really excited about this platform generally and the potential in these indications and beyond.

Thank you. One moment for our next question. Our next question comes in the line of Ritu Borrow of TD Cohen. Their line is now open.

Good afternoon, guys. Thanks for taking the question, Michael. Great to have you. in the seat, I've got two questions. One is related to just the time lag to revenues for a Levitas. Given you guys mentioned that there is a quarter over quarter increase in demand, but that real revenue increases maybe not happen until 27. Does this imply that there is a longer time to fill, a longer time in the pipeline until revenue recognition than the previously indicated, I think, five to six months? Is that the lag we should be modeling going forward? And then with your cohort eight data in Q1 of next year, will you have expression data as part of that top line release beyond just liver safety? And if so, what should our expectations be both for expression and for liver safety? Thanks. Thank you.

Thank you. I'm happy to take those questions and I'll ask Patrick and Louise to provide some additional detail. With respect to the time lag between enrollment forms and revenue, it's generally about six months, as we have said previously. There can be some variability around that, but it's to around six months and I think that's very consistent with what we're saying now that we're seeing enrollment forms improving and given where we are in the year, that's going to translate into revenue meaningfully in the 27 timeframe. So there hasn't been any change there.

Patrick, do you want to add any detail? We say cohorts that have come in are not mature enough really to conclude whether the overall journey is getting longer or shorter. However, we continue to use that six months as the enrollment form to infusion for planning assumptions knowing that timing is going to vary from patient to patient.

And, Louise, do you want to take the question about the timing of expression data in cohort A? Sure. So, you asked about the endpoint. So, we expect to have the data on ALI. The primary goal of that study was to reduce that. We are collecting the biopsy data at this point. I'm not sure about the timing of that data, but the primary goal of that readout, especially with taking data to the agency, will be for the ALI, and we will, We will produce the biopsy data. I'm not sure on the timing of that at this point.

One moment for our next question. Our next question comes from the line of Mike Oles of Morgan Stanley. Your line is now open.

Good afternoon. Thanks for taking the question. And let me add my congratulations to Mike as well. Maybe just with respect to the RNA data updates expected later in the second half, should we expect those more towards year end? And will you share those updates together, or do you plan to separate them out If I remember correctly, I think FSHD may be a little bit ahead of DM1. Thanks.

Well, we've said that those data will be available later on in this year, and at this point we're not able to be more specific about the timing. We're going to look at each data set as they become available and make them public in an appropriate fashion. So I really can't comment today as to whether it would be at the same time or staggered. It depends on the availability of those data, but again, both are expected in the second half of this year and we're on track. to meet that timeline. Louise, is there anything you'd like to add? No, that's correct. Thank you.

Okay, and maybe just very quickly, just to add, Mike's exactly right. We do think about these programs as separate programs, though. Obviously, the timing on the SAD data, they were very close, and it made sense to release the data at the same time. But just generally speaking, we do think of these programs separately, so to Mike's point, when they become available is likely when we would release it. That's how we're thinking about it generally as a program.

One moment for our next question. Our next question comes from the line of Salveen Richter of Golden Saks. Your line is now open.

Great, thanks for the question. This is Matt on for solving. Maybe building on a prior question, could you provide any more color on the metrics being beyond start forms that you are seeing that support deeper elevatist penetration in the ambulatory patients? And how are you thinking of the longer-term trajectory now? And then also, you know, how might you be able to leverage some of your efforts here to support non-ambulatory use if that's eventually included back in the label? Thank you.

Absolutely. Now, our strategy is set, and as I mentioned, the sales team is out there. They've been trained, they're deployed, and the broader commercial initiatives are fully operational. So, we're seeing enrollment form activities stabilize and improve. We've got returning sites that are re-engaging, and we're seeing interest from new sites. seeing a directional alignment between healthcare provider engagement and enrollment form submission so when our sales teams goes in and speaks with an HCP we see enrollment forms result after it as I mentioned in some cases as soon as 30 days after that engagement those signals that to us that those initiatives that we put in place are starting to take hold, and it's strengthening our patient pipeline, even though the associated revenue contribution, it's going to take time. And Our team is just focused on consistent execution and helping those patients progress through the journey.

One moment for our next question. Our next question comes from the line of Baren Amman of Piper Sandler. Your line is now open.

Yes, hi guys, thanks for taking my questions. Maybe three-parter for me. On Amandus and Beyondus, SMBA, has the FDA indicated if there are any plans to hold an advisory committee meeting? So that's the first question. Second question on FSHDs, there's a direct transcriptional target of Dux4 that apparently to clinical disease severity. I wonder if you're looking at that in the current trial. And then the last one on cohort eight data, is there potential to revive the LGMD gene therapy programs after those cohort eight data? Thanks.

Okay, I'll start off and then I'll pass to Louise. With respect to the Amandus and Biondus reviews, the FDA has not indicated at this time that they have an intent to schedule an advisory committee. Obviously they can make that decision at any point, but to date they have not made any indication that they intend to do so.

Louise, do you want to take the questions about the endpoints? Sure. The second question, it was on FFHD and the CHUXIV. related genes. And so certainly we're looking at both a downstream DEX4 gene panel, but then also, I think your point was around the DEX4 biomarkers. And so our team is looking at multiple circulating biomarkers and evaluating them right now. So both Validate and the assays and then looking at them in our models. And so certainly that is something that we are actively looking at because having a circulating biomarker is a huge advantage in these indications. And then I believe the last question is on the limb girdle pathway following cohort 8 data.

And that's exactly right. So for LGMDQE, as we've discussed before, Right now we're on clinical hold, and in order to get off clinical hold and potentially submit to the BLA, that's based on the cohort 8 data as we've discussed with the agency. So as soon as we have that data, we'll be able to discuss the pathway to submit the BLA with FDA following that data as well.

One moment for our next question. Our next question comes from the line of David.

Your line is now open. Hi there. Thanks a lot for taking my questions. So I want to ask about the PMO franchise and your perception of the durability there. And in particular, how should we think about modeling the franchise next year, especially with Exondys, where we have a potential market entry?.

entry of a competing Exxon 51 skipper. Thanks a lot. All right, I'll start and probably pass it to Patrick for a little bit more detail. We have a tremendous amount of confidence in the durability of the PMO franchise. This is a franchise that has a very long track record, 10 years for the first approval. We and has delivered benefit to patients over that period of time. There's extensive real-world evidence supporting benefit as well as supporting a favorable safety profile. And so we feel that we are in a good position to enter a competitive market. and to maintain momentum in that franchise.

It's a bit early to predict exactly how those dynamics will play out from a modeling perspective, but we think any impact that competition would have would likely take some time to become. become visible. One has to overcome a number of hurdles when one enters a market like this. There are reimbursement pathways that need to be established, patient assistance programs that need to be put in place if the sponsor, in fact, intends to do that. For example, with our PMO franchise, We have home infusion support and a number of things that contribute in addition to the overall benefit delivered to the very high rates of adherence that we have observed, 90% or greater. And so we would expect that impact of competition if it were to come to be later on.

and 27. So Patrick, do you want to add any additional color? You covered it very well. Our position is grounded in that decade of experience supporting patients, families, physicians, and those treatment centers. As you mentioned, we've got a body of real-world evidence, established safety experience, adherence rate is exceeding 90%. And we've got a team that's very well versed in working through any reimbursement challenges with the providers and the institutions in order to get patients authorized and reauthorized and keep them on therapy. And so all of that points to the mature infrastructure that we have. have and we're going to lean into as we support our patients. One moment for our next question.

Our next question comes from the line of Mitchell Kapoor of H.C. Wainwright. Your line is now open.

Hi, this is Jaydon from Mitchell. Thanks for taking our question. So going back to Amandus and Beyondus, regarding those SNDA submissions, Do you have any thoughts on timing for converting Exondys to full approval? As you guys spoke about, as of next month, it'll have been on market for a full decade, but it's been on accelerated approval that whole time. And additionally, can you speak a bit on the recent Capricor ad comm meeting? Do you see this increased scrutiny of post-hoc data reevaluation as a negative read-through for Amandas and Beyondas, given that the data did not achieve traditionally accepted statistical significance in the trial. Thanks.

So, with respect to the Capricor adcom, I think the issues that were discussed at that adcom were particular to the package the Capricor brought forward and the FTH review of that package. Obviously, we don't comment on other sponsors' review process, but we don't see read-through to our package. our program. When we look at the applications, they are supported not only by the clinical trial data, but by extensive real-world evidence. And we believe together those present a strong package for conversion to traditional approval. With respect to the strategy,.

for Exondys. Louise, would you like to take that? Louise Cotterill, Sure. So for Exondys, we don't have a confirmatory study as part of that. We have a post-marketing commitment, which is our mission study, which is a dose-ranging study. And that study will be done by the end of this year. And so following that study, we'll have discussions with the agency in conjunction with the Viandus and Amandus as well. And so that's where we're at in terms of the preparation. conversion of Exondas to traditional gruel.

One moment for our next question. Our next question comes from the line of Andy Chen of Wolf Research. Your line is now open.

Hey, thank you for taking the question. Welcome, Michael. Regarding the MAD data in DM1 with the functional endpoint, I think, Louise, you mentioned that the goal is not, or the primary goal is not to establish functional efficacy with the data set. Can you please clarify the reason behind it? Is it because you don't have visibility yet and the sample size is too small for you to make a conclusion or is the empirical result tracking in such a way that you can't conclude that it's better than competition thank you.

Louise, do you want to address that? Yes. So for FSHD, it's really around the timing of the data. So as I mentioned, FSHD is a very slow, progressive disease, and this data is at six months. So we would not expect to see a strong signal at six months. So it's really about the timing of that. James, would you like to add anything around the disease itself and the way we think about functional outcomes in this indication?.

I mean, I think you've covered it, Louise. FSHD is a slowly progressive disease. We expect the treatment here to improve Symptoms we expected to stabilize the disease, similar paradigm to DMD, and we need time for the disease to progress to show the therapeutic effects of stabilization. This is very much in line with other developers' further advances in the field as well.

One moment for our next question. Our next question comes from the line of Brian Scorny of Baird. Your line is now open.

Hi, this is Luke on for Brian. Thanks for the question and also wanted to offer my congrats to Michael. So on the Huntington's program, I guess you have an idea of when we might see the phase one data and can you remind us if you're measuring protein knockdown and if you think the study could support some initial biomarker proof of concept?.

Luis, do you want to take that? So we expect the first proof of biology data early next year, and really this is early single ascending dose data. And what we're looking for in this study is safety and then early signs of disease. So are we getting past the blood-brain barrier? And to do that, we're looking at knockdown of pungent and that'll be in the CS path. So that's what we'll be looking for in terms of validation of the blood-brain barrier. platform along with safety and the ability to dose escalate.

One moment for our next question. The next question comes from the line of your zoo of Wells Fargo securities. Your line is now open. Well, hey, thanks for taking our questions and congrats.

to Mike, on assuming the CEO role. A question on cohort eight, is the ALI data, all that's needed from FDA to make a decision? And if that's the case, could the decision be a reinstate the indication And another question on the Biondis and Amondis, the SNDA. The review time seems to be eight months. I was wondering if that, it doesn't seem like either priority or standard review. Could you talk about what timeline is that and what might be the implication?.

Certainly. So with respect to cohort 8, Our strategy is to complete cohort eight, and as soon as we have the 12-week data, a approach the FDA to discuss the regulatory path. So we can't comment on that regulatory path today, but we will be engaging with regulators with data in hand to define that path. And we believe that the cohort A data is, when they are available together with other data sources like Endure can make a compelling argument for benefit risk in this population, but obviously that will be discussed with regulators and the exact nature of the path will be defined at that time. respect to the Amandus and Biondis review, it is a standard review. One moment, Garnet. Question. Oh.

No, I just want to clarify, it was 10 months from submission, not by.

Our next question comes from the line of Tazeen Ahmad of Bank of America. Your line is now open.

Hi, thanks for squeezing me in. I just wanted to clarify a comment that you made about the potential for an accelerated path for, let's say, DM1 in the future. As it relates to the competitive landscape, if, let's say, one of the programs that's ahead of you in development, let's say Novartis, is able to get an accelerated path, do you think that would lessen the chances that Sarepsa could have even with compelling data to get an accelerated path as well? Thanks.

Louise, would you like to take that? Sure. Certainly, as I mentioned, we'll evaluate the regulatory landscape as we proceed, and our study is designed to... be ready and available for both accelerated or traditional. Certainly having a traditional approval makes things change changes the landscape in terms of accessing an accelerated approval. And so it'll be facts and circumstances in terms of both the landscape and then where data as well and so we'll be looking at both to define that pathway and it'll be come out.

discussions with the agency when we do so. Yes, so I agree with Louise. The only thing I would add or perhaps emphasize is that these will be data-driven decisions, so it will depend on the nature of an approval in the space if that happens and the particular strengths of our data relative to that approval, but we will be prepared to go forward with that. forward for either an accelerated or a traditional pathway, depending on what is most appropriate at the time.

One moment for our next question. Our next question comes from the line of Joe Schwartz of Layering Partners.

Your line is now open. Hi, thanks for taking my question. Welcome, Mike. We appreciate you joining at such an important time. I look forward to seeing how you shape the company's future. For the next SRP 1001 and 1003 updates, what quantitative benchmarks does each program need to clear to justify pivotal advancement rather than continued exploration?.

Louise, would you like to take that? Sure. We're looking for...

two things out of these studies, or multiple things. We're looking for the ability to dose us glades safely, so get to a, appropriate for the phase three with very strong muscle concentration and significant knockdown. So, as I mentioned during my opening remarks, we want to get the highest levels of knockdown that we can in order to affect the biomarkers and also predict functional improvement. And that's all benchmarking back to our previous slide. preclinical data. And so we're looking for also concentration, knockdown, and the ability to dose escalate safely without any safety signals. And so that's what we're looking for out of these two studies.

Our next question comes from the line of Yun Zong of Wedbush. Your line is now open.

Hi, good afternoon. Thank you very much for taking the questions. So the first question I wanted to confirm because I thought the original guidance was for data from cohort eight to be available by year end. So was there a delay in terms of patient enrollment and did you have any challenge to enroll non-ambulance patient given the safety concerns? And secondly, can you remind us the efficiency of your Huntington's disease program candidate to cross the blood-brain barrier? And in terms of knockdown efficiency, what magnitude would you like to see, please? Thank you.

Louise, would you like to take those? Sure. So, for the cohort eight enrollment, and so in terms of enrollment, we're seeing the study progress well. We are seeing investigators dose sequentially their patient sources in parallel. And so, when we looked at the timing of when we would have the 12-week data, it would be available in Q1 of next year. And so when we have the complete data from the 25 patients, that'll be in Q1. So that's the reason for the data availability for cohort eight. In terms of Huntington's program, the knockdown that we're seeing is really based on our preclinical models, and that's both in murine models as well as the non-human primate model where we saw knockdown levels as high as 80 percent and really the what got us excited about this is the ability to knock down in deep brain-like regions the striatum as well as the caudate.

And so these are really what got us excited and what be looking for. Obviously, in humans, we can't have that degree of certainty in terms of knockdown within the brain, so we'll be looking at CSF knockdown as a surrogate for that.

I'm showing no further questions at this time. I would now like to turn it back to CEO Michael Severino for closing remarks.

Thank you, Operator, and thanks to everyone on the call for your time and attention today. As I said in my opening remarks, my first few weeks with this talented team reinforce my view that we have a bright future ahead of us, and my confidence in the potential of Sarepta has only grown. We have four marketed products that make a real difference in patients' lives today. We have a compelling pipeline of siRNA therapeutics that will drive our future growth, and we are executing for the future. from a position of financial strength, with the ability to advance our pipeline and initiatives independently, as evidenced by our strong balance sheet and operating profitability. number of important catalysts are on the horizon, which we believe can unlock long-term value for patients and shareholders alike. We appreciate your continued support and look forward to updating you on progress in the months ahead. With that, we can end the call, and I hope everyone has a very nice evening.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

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

[Call has ended.]

Great. Good morning, everyone. It's my pleasure to introduce the Sarepta team. With us, we have Doug Ingram, CEO; Ian Estepan, President and COO; Ryan Wong, CFO; and Louise Rodino-Klapac, President of R&D. Thank you for joining us.

Maybe we'll start here, Doug, with a question for you. You've announced your retirement as CEO by the end of the year. How are you thinking about working through the transition and the overall succession plan?

You can ask these folks if I've been winding down. I think you're surprised my intensity level has been going up. Right now, we're not transitioning anything. We got a lot to do as an organization. I did announce that by the end of this year, I will retire. There's an active process ongoing. When the Board makes its final decision on that, then I will obviously do everything in my power to ensure that, that individual is maximally successful both for the company and its investors and for patients as well. So I stand ready to do whatever they want for as long as the successor would like to ensure that we're successful. And I'm very confident that we will be.

You have laid out your priorities for 2026, notably stabilizing ELEVIDYS, advancing the pipeline and strengthening the financial setup. To start here, can you lay out the progress towards these priorities and what the key milestones for the company will be over the next 12 to 18 months?

Sure. Right. To your very good point, the strategy at Sarepta is quite straightforward. Let us start first with our 4 approved therapies. We have 3 PMOs, as you know, and our gene therapy ELEVIDYS. The goal there is to maximize that opportunity really first and foremost, for the patients who benefit from that therapy because even in our base case, we're going to do quite fine. But we would like to exceed that base case because that means even more children and young men with Duchenne muscular dystrophy are going to live better, freer lives because of it. That's -- and we're doing very well there, and we'll come back and talk about that. Let me just talk about each pillar.

That really leads to the state of play in the company from a financial perspective. We're in a really strong financial perspective. Just consider that we're cash flow positive, we were a little over $800 million, I believe, what was at the last quarter, maybe we were $770 million...

Something will be $900 million plus.

Yes. So we'll be significantly over $900 million. So we're cash flow positive. We're profitable usually on a GAAP and a non-GAAP basis. That will continue to be the case over the course of the intervening years, even as we fully invest in our pipeline. Just consider our sales forecast, we've said that we will do somewhere between $1.2 billion and $1.4 billion. Even if you assumed we were at the very bottom of our guidance, our cost structure is somewhere in the hunt of a little over $800 million.

So we're just a comfortably cash flow positive organization that isn't -- thank goodness given where our stock price is today, which if I can editorialize is so realistically goofy. In one sense, other than the employee morale, it really doesn't matter because we are not slaves to the equity markets to get our stuff done. And then, of course, where are we going in the future? We have a really exciting pipeline. Our siRNA pipeline is exciting. We have 5 therapies that are in the clinic dosing patients right now. We have a few more that are heading to the clinic soon. We have 6 research programs on top of that with our really exciting period of time.

Now let's talk about success in each one, and I'll do it real quickly, and then we can actually get to Q&A. So I'm not. Okay. I don't think they were taking bets on whether any of them would have a chance to talk to me. I'll be brief. From a sales perspective, the delta between $1.2 billion and $1.4 billion is really entirely ELEVIDYS and ELEVIDYS success. We've always said for the course of this year, you should really be modeling toward the lower part of the $1.2 billion to $1.4 billion for the simple reason that the actions that we're taking and the activities we're doing are going to be successful, but this is a very long cycle process. It's going to take some time. We've done great there. We more than doubled our sales force. They're out and being very productive, both from a reach perspective and a call perspective. That's going well.

Our promotional campaigns themselves are really powerful right now. We have a contract sales force in the field, and we have a group of what we call the patient education liaisons whose goal is to really educate patients and make sure they're prepared to have thoughtful discussions with their physician about the journey for -- particularly for ELEVIDYS. That's when we're out tons of green shoots of success there. I can give you interesting stats on that. That is going well. We're doing great financially.

And from an siRNA perspective, you saw that with DM1 and FSHD, we had very encouraging results from our SAD study that we announced a couple of months ago. We're really excited about getting a look at the next set of data, which is going to be even more robust. It will be multi-ascending dose, and it will be more patients and more biopsies and the like. And that will happen in the second half of this year. We've already started dosing our Huntington's program, which we're excited about. IPF is dosing, SCA2 is dosing as well. So we've made a lot of progress across that portfolio as well.

Can you touch on the leadership changes at the FDA and how -- and whether there's any risk to you from that dynamic?

We -- as we sit here today, we see no risk at all from changes at the FDA for two reasons. First of all, let's think about where we are with ELEVIDYS. We had a bunch of risk last year for abandoning our stock in the summer of last year, we had a really strange interaction with the FDA where they're pressuring this therapy off the market, notwithstanding the fact that we were able to get that therapy back on the market within 5 business days, I would suggest it would be very difficult for someone to replicate that success. It was understandable that we were -- people were worried about that relationship.

But from there, things just got very good for us. We negotiated the label. We negotiated a label update with the FDA that got out there to the physicians. We negotiated and got the blessings on Cohort 8, which is our pretreatment with sirolimus, which will be the pathway back for the non-ambulatory population. So there really aren't any open extent significant risks in the ELEVIDYS. So even with the change, it doesn't matter. On the PMO side, that really didn't exist as an organic risk anyways. And I think that what we're seeing so far in the changes at the FDA have been very positive. I think the acting commissioner, I have not interacted with him directly myself. But really universally, people are saying very good things about him. He comes from the food division, so he may not be steeped in the drug development process, but he understands how to run large organizations. He's apparently very rational and very reasonable and everybody that's interacted with us so far has come away saying he's a good steady hand at the FDA.

I think the same thing has been said about the [indiscernible] side as well and that change, and I don't know much about the CPR side. So I think there's a lot of hope for a stable FDA. And that's what we need. We -- I have been a big proponent for many years over the idea of really trying to modernize the FDA and get more thoughtful and mirror the FDA today within the current state of science and certainly in genetic medicine and rare disease. What we really need more than anything else right now at the FDA is a stable and predictable -- so we, for one, are very excited.

An important point. It didn't seem like the markets really fully discounted both the risk that I think were happening previously. And now I think a very strong tailwind now because of that exact point that you're making in terms of predictability. I think they're making dramatic improvements and trying to make sure that goalposts don't get moved, reviewing applications that previously have gone against what the agency had communicated previously and now actually factoring that in.

And hopefully, we'll see. We'll see in the next few months what happens with some of those applications that are getting reviewed. But I think that stability and that the ability to be able to predict what's going to happen should be really important for the investment community. So I think it's a much better backdrop.

And in the end, let's be very clear, this is what we want as an organization. We want the FDA to apply the standards that exist at the FDA and to review therapies in the totality of the evidence and to support those therapies where it makes sense to, but not to support therapies where it doesn't. So we're not looking for some cowboy country. We want an organization that applies standard and rigor. And I think there is some hope for that given some of the new leadership at the FDA at least on an interim basis.

That standard part is incredibly important because if you don't have that standard, then payers start weighing in and other factors start contributing to whether a drug gets utilized or not. And so making sure that the standards are met and the safe and effective therapies are going to patients is just critically important.

Starting with ELEVIDYS here. You've spoken about the information gap regarding ELEVIDYS and your initiative to drive penetration in the ambulatory patients. What are priorities for the expanded field team? And what leading indicators are you seeing with physician engagement that suggests a return to growth?

So the #1 overarching thing was to rebalance the discussion. If there was even a discussion. Remember, in 2025, we had 2 surprising and unfortunate fatalities associated with non-ambulatory, more advanced patients. And we spent the entire year focusing only on that, not talking about the benefits and the risk of the therapy and contextualizing those risks because you could really -- I would remind you, it's horrible for those families, but 2 out of nearly 1,400, I mean this is less than 1, whatever it is, 1/12 of 1% -- [ 0.12% ]...

And so that's the big thing to get the promotional material in the right place where we can have smart, thoughtful discussions about that. That's what they're doing right now. That's what the main sales force is doing. And then we have a contract sales force that's really trying to expand that reach into places around the country that are not the top centers but have opportunities for referral, have opportunities for neuromuscular physicians to get educated that maybe have never been educated before, so they can have thoughtful discussions. And that's the big focus there.

Some of the -- there's lots of interesting what Patrick Moss, our Head of Commercial likes to call the green shoots of success quite apart from the numbers of people in the field. You'll see something like 50% of start forms are coming from sites where a sales rep had visited that site within the last 60 days. You're seeing a significant percentage of sites. I think it's over 30% of sites that had either paused back last year or have never dosed a patient starting to send in start forms without getting into too much detail because I violate like there's one site that has enormous opportunity, but has been very slow, and they've actually put in multiple start forms over the course of the last couple of weeks. So that doesn't show up immediately in sales. Remember, it's a 6-month process to go from start form to infusion, and it could take even longer with the kinds of appointments you need to have and testing you need to have antibody testing, but it's a great sign for the future and a great sign for 2027.

With regard to the total revenue guidance, you spoke to the $1.2 billion to $1.4 billion, we estimate about $300 million to $500 million of it coming from ELEVIDYS based on historical performance of PMOs. What are the factors that influence whether or not you fall in this range?

It's all ELEVIDYS, and it's all the impact of our external activities, right? And there's still more to do. So for instance, we have this what I believe to be just absolutely knock out 3-year data on ELEVIDYS. And if you look at the 3-year data, you're not thinking about getting your dose, you just don't understand what you're looking at. That actually has to get into the promotional material. That's not even get in the promotional material. When we do ads and we share it with physicians, the impact there is just obvious. So we need to get that done. But it's all bad. And it's just -- the delta there is just that moving this up with such a long-cycle therapy is to use an absolutely worn out bromide is turning a tanker ship. So it's going to take some time. So I suggest a lot of the activity we're doing right now is going to go down to the benefit of 2027, not 2026.

And what does the FDA need to see from cohort 8, is that right? The sirolimus study to include ambulatory patients in the label? And what could the time line look post the top line data here in the second half?

I'll turn to -- Louise, you can talk about the study itself, and then we can chat about what we would expect to see.

So Cohort 8 of ENDEAVOR is an open-label study in non-ambulatory. So this is about the non-ambulatory population. And so by definition for the study, we're looking for a 50% reduction in the rates of ALI. That's what the FDA will be officially looking for as will we -- it's open label. So we're -- have the ability to look at the data throughout. And based on mechanism of action, all the tremendous real-world evidence we have with physicians using in the field, we would predict that we would certainly predict that we would achieve that. So we'd go back to the FDA after the end of the year and talk to them about bringing the patients back from the non-ambulatory patients back to the label and what the mechanism would be to do so.

It could. I think the -- if I'm not mistaken, I think success in the protocol is a reduction in the risk of ALI. Remember, ALI, if you reduce ALI, you're going to dramatically reduce even the theoretical medical risk of ALF, which is the ultimate thing we would worry about. I think it's by 50%, if I'm not mistaken, that would be the goal.

Now we'll see how this goes, and we'll get to watch this data over the course of the year. We do have data right now. We're thinking about the context with we discussed it. We have something called ENDEAVOR, where we get to collect data on patients in a more formalized fashion as they roll out of the study and as they're on commercial therapy and they're on commercial therapy as well. And there have been somewhere in the hunt of 11 or so of 14 patients that have been prophylactically dosed with sirolimus. Now I don't want to suggest that this is the standard we have to meet. I don't want to have -- I don't want to create this too high a standard for us. But so far, in all of those patients, there has not been any evidence of an increase in liver enzymes if one pretreats with sirolimus. So it gives us a lot of conviction that this approach we're taking is going to be a reasonable one to get nonambulatory patients back in the label.

And for those who may wonder why we care so much about this. I mean, look, if you want to be just dollars, sometimes you'd say the non-ambulatory patient population represents 50% of Duchenne. It is, in fact, an enormous opportunity. But there's a more important issue for us than that. And that is everybody abandon the non-ambulatory patient. Everyone always has abandoned the non-ambulatory population. Really nobody has ever treated these folks or even care to treat these folks.

And if we -- and it's going to get worse. If we don't win with this, if we can't safely dose these kids and bring them a better life, I pause it, no one will ever do it. Everybody is going to walk away from. Every current therapy in development right now is ignoring the heck out of these people. So the good news is there's a nice synergy there. It's going to be great for investors if we're successful. It's going to be great financially, but it's going to really be great for people that desperately need help and shouldn't be left behind simply because they're in the wheelchair.

And I think it's important, we've seen about 20% to 25% of sites dosing the ambulant patients with sirolimus also. And obviously, this is something that's not in our label, so we can't promote to it, but this is how the field is evolving based on the experience that we're seeing, which I think is important to the investment community also because if you're able to just limit the risk in ambling patients, I think that's obviously incredibly important from a patient perspective, but also from an investment perspective, if you're able to cut that risk. So hopefully, if the data continues to emerge and is very supportive, you continue to see that adoption.

And your partner, Roche, announced a new global Phase III trial here. Maybe talk about the read-through from that to your commercialization plan, but also why Roche has taken this viewpoint to kind of invest more in the program?

Well, I think a couple of things. Well, first, they have to do another study that get scientific advice. So with EMA and the CHMP, they realized that, that is the pathway. And I would say why they're joining it and investing is because they've seen the data that we've seen. And I think that our colleagues over at Roche are confident as we are about the way that this therapy is changing the lives of patients.

They've done quite well ex U.S. that gives them a really on-the-ground opportunity to see these patients up close to personal. And I think they realize the life-changing benefits of this therapy. And I give them kudos for understanding that and appreciating that. The study itself won't have any read-through. It's a placebo-controlled blinded study. It will take some time to read out. It seems like they've been fairly thoughtful in the approach they've taken. They've learned a lot from the work that we've done. So I'm confident in their study and its outcome, and it will just give additional evidence in support of this great therapy.

Maybe transitioning over to the Arrowhead platform here or that your partnered or your acquired Arrowhead platform. Regarding the siRNA programs, can you lay out how your constructs differ from the others here, so such as Avidity and Dyne and how you see those differences play out in the early data in FSHD, but also DM1?

So focusing on DM1 and FSHD, which are 2 advanced programs. So we use a targeting ligand called alpha v beta 6, and that's really the differentiator for these 2 programs, which are delivered IV. And really, that gives us the ability and why we did the deal in the first place to be most efficient in muscle getting into muscle, driving that siRNA in there. We know that siRNA itself is more potent in terms of the effect within the cell. You need 25 to 50x more molecules of an ASO versus an siRNA to have the same effect within it self.

We also have a large safety margins of 10x. And so what we've seen from our MAD data, from our SAD data and now going into [indiscernible] data is the ability to continue to dose up, which is important for getting maximal knockdown and then downstream biological effects within the cell. So I stop there if you want to add anything?

I agree with you.

As you move to higher and multiple doses, how are you thinking about receptor saturation or potential for dose-limiting toxicity?

So preclinically, we've not seen any evidence of receptor saturation. And again, this is where the alpha v beta 6 comes in. We don't have the same problems with the TFR that others have because of the use of that receptor for iron homeostasis. So we're not seeing things like anemia like others are seeing. So that really gives us the opportunity to continue to dose up, and we haven't seen that saturation that others may have...

Our NOL is significantly above where we're actually looking the best -- we feel confident about...

How much proof of concept do you think that initial data represented? And can you frame how to think about translation to the next data release and how the overall profile could ultimately land? And I think part of what I'm also getting at is did you show a selective group of patients here that we can take that overall view?

Yes, selective sounds like cherrypicking -- in cherrypick. Let me be very clear, we're really excited about the data, and we'll talk about the limitations of it. We're very excited about that data. And the reason we were so particularly excited about this early read is that it was very confirming of what one sees in the preclinical data. That's exactly what we had hoped we would see, which is the ability to dose escalate when others can't.

The ability to use the integrin receptor to drive up significant muscle concentration even at equivalent doses and then the ability to continue to drive it up and then the resulting knockdown that we saw in the early side. So there was really nothing in that early data that didn't completely confirm what we saw in the preclinical models. Now we have to be thoughtful about that. It's early data. It's just a single ascending dose. So it gave us a ton of confidence and now we need to see the MAD data.

We need to see it in multiple doses over time in a larger cohort of patients over other dose ranges. We'll have that in the second half of this year. And that looks great, then we're really -- we are really heading toward the very strong possibility that we will be the best-in-class both for DM1 and FSHD. But I would say we need that. I wouldn't over interpret the first one other than to say, it's really comforting that it was exactly what the preclinical models predicted.

And with that second -- I guess, the 6-month update in the second half, could you just frame what you'll show in terms of patients at each dose biomarkers early functional data and what you see as relevant benchmarks?

Sure. So we expect to have, as you mentioned, 6 months data in both FSHD and DM1 and the timing of that we'll see. So at our highest doses, as Doug mentioned, this is the MAD data. So again, we'll be looking for safety target engagement, PK, PD. In terms of FSHD, we'll be looking for the target circulating biomarkers, early evidence of function, 6 months, not a long time in FSHD, but we'll be looking at that. In DM1, then we will be looking at DMPK knockdown, CASI-22 splicing indices and then vHO, which is we can see at an earlier time point. So we're excited to see the data, as I mentioned, having multiple doses at higher concentration, I think, will be -- we're looking forward to seeing.

And it's all good with this data release. You talked about starting at these 3 posts. Maybe talk about those time lines.

Yes. I mean let's be realistic about what we can and can't see with these heterogeneous diseases, like people shouldn't over-index on some functional endpoint that relies upon degeneration. We need to be realistic. These are slowly degenerative diseases. And I think we're also excited about seeing something as soon as possible that you want to look at something in 6 months, that would actually take a couple of years to see in the placebo arm of the group. So just to be thoughtful. That's the beauty of vHOT.

A lot of complaints about vHOT. vHOT may not be a great model for predicting other declines in a short period of time. But it's clearly a functional manifestation of benefit or lack thereof, and it can be done very soon because it's not a degenerative issue, right? It's myotonia is not degenerative in nature. So let's just -- so really, if you're going to focus on the future, what should you really care about? You should care about safety. You should care about the ability to dose escalate with safety. You should care about muscle concentration and knockdown and downstream splice correction. And those -- that's the big one. And then going beyond that, there may be other biomarkers that will be fascinating, then there's vHOT. And then I would say the rest of it is exploratory, if that makes sense.

I think with respect to what -- we're going to move as fast as possible. That's the short answer. We're going to move as fast as possible. I don't think that we have the time lines in front of us today because we've got to do more work. We heard just the other day that I think our colleagues if I'm not mistaken. We're suggesting that they are going to go for an accelerated approval, at least in DM1. And I think it's a very interesting idea, and I think it is certainly not an irrational thing for them to be thinking about with these patients.

So we're going to take on all of that thinking, and we're going to fashion for ourselves the fastest possible approach. That will be our goal. But we need to get through some more of this. We are clearly going to start -- as an example, we're going to start pivotal trials next year as soon as possible after we get the readout this year and then what the exact pathway is to approval is at the end of those pivotals? Is it an interim accelerated approval on a well-confirmed biomarker. Those are things we'll have to figure out and then we'll have to figure out in concert with our regulatory colleagues at the FDA.

So just one thing to follow up, which Doug alluded to it, but just to say it more directly, knockdown is, to Doug's point, the most important thing to see because function will follow. You shouldn't have this toxic protein or toxic mRNA in either one in FDM1 or FSHD in your body. So if you're able to knock that down most significantly, that is eventually going to lead to the best functional outcomes, right? So whether you're able to see it in a heterogeneous disease in a very short period of time, that's challenging. However, knowing that the best knockdown is going to lead to the best function.

And it not to be personal. I have family members at FDM1? If I see in the multi-ascending dose confirmation of what I see in the single ascending dose, I'm not sitting around waiting for 2 years of functional data, so I can confirm what is obvious from using Occam's razor and good scientific analysis. And I'm sure that's where other people could be, and I would hope that's where our FDA colleagues will. That's why I frankly think Dyne's thinking on it is innovative, and I give them kudos for that.

Can you just speak to how you intend to leverage your teams and infrastructure for -- from the PMOs and ELEVIDYS for a potential launch here?

I don't think we've -- I think we're going to have to do a lot more. Like we've got a great team, and there's tons of parts of our team. We are neuromuscular experts as an organization. So there's going to be a ton of leverage there from a marketing perspective, promotional perspective, sales force perspective, MSL perspective, our PALs, there's going to be a ton of opportunity. But it would also be a mistake to be arrogant and imagine that there's no adaptation needed or no augmentation needed. So we're going to work those issues through [indiscernible] as well so that we are as prepared to launch in DM1 and FSHD and the unique elements of those different diseases as we were in DMD.

For your PMO franchise, speak to your confidence in the applications for the -- in the context of the confirmatory studies, but also how you strategically are thinking about the runway here in the context of competitors?

Yes. I think, first of all, as you all know, we've got sNDAs that have been filed, submitted on AMONDYS and VYONDYS to transition them to traditional approval. We are, at a minimum, confident based on our own analysis that these therapies will continue to benefit patients long into the future. Just to remind you, we had signals in our confirmatory trial. We have great real-world evidence. That's the beauty of having these therapies on the market. From an accelerated approval perspective for so many years, you get to actually see not in some stilted short-term experiment, but over a long term, what's really happening here. And they are significantly benefiting patients, keeping them out of the wheelchair and ambulatory and off event and out of emergency rooms and out of the hospital and a great mortality benefit across all these modalities. That's EXONDYS and VYONDYS and AMONDYS.

So we think the data for it is really powerful. I would remind you, patients love them. We've been -- some of these patients have been on for over 10 years, and they fight to stay on them. We have a well over 95% compliance rate on those physicians who also love them. And their safe is hey. I mean they have a really lawnable safety profile over these many, many years. So it would be irrational to deny these rational FDA would even be thinking along those...

Now with respect to competition, the primary competitor that we have -- will have a therapy that will compete with EXONDYS next year. They're going to seek accelerated approval. And in that context, I think that's rational for them to do that. And I think we'll be prepared for that competition. We have not focusing on them but focusing on us. We have a lot of things to say about our EXONDYS therapy.

Families have been on it for a long time. We have a 10-year safety record. We have great patient services. We know how to get these kids on therapy and keep them on this therapy. We do in-home infusions. So we make life easy for them on the therapy. And then, of course, Dyne will have its arguments and it will be a very credible, I think, competitor as well.

Great. Well with that, thank you so much.

Thank you. And we made forward-looking statements. So please just look at our SEC filings for the risks associated with that. Sorry to end on such...

Thank you very much.

Hello, and welcome to the Annual Meeting of Stockholders of Sarepta Therapeutics, Inc. Please note that today's meeting is being recorded.

It is now my pleasure to turn today's meeting over to Dr. M. Kathleen Behrens. Dr. Behrens, the floor is yours.

Thank you. Welcome to the 2026 Annual Meeting of Stockholders for Sarepta Therapeutics. It is now 10 a.m. Eastern Time, and the meeting will please come to order. My name is Dr. M. Kathleen Behrens, and as Chairwoman of the Board of Directors of Sarepta, I will be presiding over this meeting. Our Corporate Secretary will record the proceedings.

Today's meeting will follow the agenda that is attached in the documents section of the webcast. [Operator Instructions] Please note, only questions that are germane to the purpose of this meeting will be addressed.

Joining me today are the following current members of the Sarepta Board of Directors: Douglas Ingram, Chief Executive Officer; Richard Barry; Dr. Kathryn Boor; Michael Chambers; Dr. Stephen Mayo; Dr. Claude Nicaise; Deirdre Connelly and Dr. Hans Wigzell. Also present today are the members of the company's Executive Committee, Ian Estepan, President and Chief Operating Officer; Louise Rodino-Klapac, President, Research and Development and Technical Operations; Cristin Rothfuss, Executive Vice President, General Counsel; Ryan Wong, Executive Vice President, Chief Financial Officer; Diane Berry, Executive Vice President, Chief Global Policy and Advocacy Officer; Patrick Moss, Executive Vice President, Chief Commercial Officer; Alison Nasisi, Executive Vice President, Chief People Officer; and James Richardson, Executive Vice President, Chief Medical Officer. In addition, Stephen Briggs and Stacey Farese of KPMG, the company's independent registered public accountants, have joined us today.

The Board of Directors has appointed Computershare to serve as Inspector of Election. [ Gary Biever ] of Computershare will determine, first, the number of shares outstanding; second, the shares represented at the meeting; and third, the validity of the proxies and ballots. Mr. [ Biever ] will also tabulate the votes for this annual meeting. We have a quorum present, which allows us to proceed to the official business of this meeting.

We also have an affidavit from Computershare, the company's inspector of elections, certifying that the notice of Internet availability of proxy materials was mailed and deposited with the United States Post Office commencing on or about April 24, 2026, to each shareholder of record as of April 8, 2026. The company has not received notice from any shareholders as required under its bylaws of any other matters required to be considered at today's meeting, and therefore, no other proposals may be properly introduced by stockholders. I will now turn to the official business of this meeting.

The first matter to be voted upon is Proposal 1, the election of Class I directors for a 2-year term expiring at the 2028 Annual Meeting of Stockholders and until their successors are elected and qualified or their earlier death, resignation or removal. The current Board of Directors favors the election of the following individuals: Douglas S. Ingram; Hans Wigzell, M.D., PhD.; Kathryn Boor, PhD; Michael Chambers and Deirdre Connelly.

The second matter to be voted upon is Proposal 2, the advisory vote on the 2025 named executive officer compensation. The third matter to be voted upon at this meeting is Proposal 3, to approve the company's 2026 equity incentive plan. The fourth matter to be voted upon is Proposal 4, to approve the company's 2026 employee stock purchase plan. The fifth matter to be voted upon at this meeting is Proposal 5, the ratification of the selection of KPMG as the independent registered public accounting firm for the company for 2026.

We will now proceed to vote on the motions for Proposals 1 through 5. Stockholders who returned a proxy card or voted via telephone or Internet and do not wish to change their vote, do not need to take any further action. If you wish to vote at this meeting and have not yet done so, you may do so now by clicking on the Cast Your Vote button on the web portal and following the instructions there.

[Voting]

At this time, we will take questions from our stockholders. When submitting your questions, please indicate your name, business affiliation and whether you are a stockholder or a proxy for a stockholder. Please note, we will attempt to answer as many questions as time allows, but only questions that are germane to the meeting will be addressed.

The first question is actually not directed to the company. It's directed to large shareholders, and there are no large shareholders currently taking part of the meeting. So the question isn't appropriate nor can be answered here.

The second question we've received is around Mr. Ingram and Mr. Wigzell's reelection to the Board. The shareholder created a proposal requesting that they will no longer be on the Board, but Sarepta responded that their departure would be disruptive to our operations and the shareholder wants to understand why that would be disruptive when Mr. Ingram was -- stepped down from the Arrowhead Board, but there was no disruption from that perspective.

First of all, thank you for the question. Board composition and turnover is a very important subject for the Board to consider. I'm sure all of you are aware that it's been a very tumultuous 12 months for the company, actually 12 to 18 months for the company.

And the most important factors that the Board considers when looking at tenure for Board members would be the following items, in particular, in 2026. First is stability and retention of employees. Second will be performance. I'm sure all of you are very much aware that there are many things that the company needs to get done, in particular, in light of a lot of the turnover that we had last year and in light of the risk that we had for the company in July of 2025. Third, we are -- we have announced that Doug Ingram plans to retire later this year after a CEO search for his successor has been completed. It's extremely important that we retain both Dr. Wigzell, Dr. Ingram's continuity for a lot of the work that we are doing this year and in particular, for Doug Ingram to get the performance that we need for the company while we're undertaking a search for his successor.

So I hope that answers the question about why we -- why it was very important to us because of the work that both of these directors do and in particular, with the succession plan underway to retain them for us to be able to get the work done that we need to get done.

Third question is, given the results and the current state of the company, the 2018 equity incentive plan did not accomplish the purpose for which it was created. Why would shareholders accept significant dilution and approve the 2026 equity incentive plan put together by so many of the same executive consultants and directors in the 2018 plan.

Thank you for the question. Equity plans are not a mechanism to control stock price. No incentive plans can do that, particularly against exogenous safety events. What they do is align management with shareholders by making executive owners whose realizable value rises and falls with the stock. And over this period, the value of outstanding equity awards fell alongside shareholders. So management faced significant losses as well, as the plan has intended. The 2026 plan is a standard necessary tool to attract and retain talent and to keep that alignment intact going forward. Thank you for the question.

I do not believe there are any further questions, but we'll wait to see if there's any questions that come up in the next couple of minutes.

Two questions came in. I'd like to poll the directors that are up for election. If elected, will you commit to not seeking reelection in 2 years if the company is not ranked above the median relative peers over the next 2-year period. Please explain if you choose not to commit to this. Sure. Just to repeat the question, I'd like to poll the directors that are up for election, if elected, will you commit to not seeking reelection in 2 years if the company is not ranked above the median relative to peers over the next 2-year period.

I'm going to make a couple of -- this is Kathy Behrens. I'm going to make a couple of general comments. There are many things that we're engaged in as I speak to improve and enhance the company's performance. We've been very specific. Doug Ingram and the rest of the management team has been very specific about what our goals are in 2026 to enhance and improve performance. And I would say that we're very much underway in making significant progress with all of those benchmarks. We've, in fact, already reported our first quarter results. And from a financial perspective, we were exactly in the range that we had predicted for and anticipated for our shareholders.

The decision about which directors stay or get reelected or do not get reelected or stand for reelection will get made at a later time when we consider the other actions that are underway this year, in particular, our recruitment for successor CEO for Mr. Ingram, but we'll also obviously consider the performance of the company in all of the different areas that I just listed. At a later time and date, we will then consider who will stand for reelection and will not stand for reelection based upon many of the factors I just listed.

Next question. Mr. Ingram stepped down earlier this year, soon after being awarded a big pay package in December of 2025. I assume the Board didn't know of his plans when it awarded the package. In light of his departure, what steps will the Board take to [ rescind ] the package?

Thank you for the question. The timing of the December grant and February retirement announcement is a reasonable question. The grant decision was made through the Compensation Committee and Board's regular compensation process and was not tied to a planned departure. The award was discussed in June of 2025 after the employment agreement expired and the CEO no longer had unvested equity. The grant was delayed to December as the Board focused on restructuring and other mission-critical items. The Board was formally notified of the retirement in late February of 2026.

Why do members of the Board still believe that the reelection of Doug Ingram and Hans Wigzell is appropriate given the performance of the company over the long tenure?

I believe I answered that question at some length just a minute or 2 ago. Thank you.

And with that, I think that was the last question.

Thank you. Right. We will now close the voting polls with respect to the 5 proposals in the proxy statement. Since the voting polls are now closed, I move that the official business portion of this meeting be concluded. May I have a second?

I second the motion.

I would now ask Mr. [ Biever ] to summarize the tabulation of stockholder votes on the proposals raised at this annual meeting.

Thank you, Dr. Behrens. The preliminary tabulations of results are as follows: Proposal 1. Our preliminary tabulation of votes received immediately prior to and at this meeting indicate that the director nominees named in the proxy statement, Douglas S. Ingram; Hans Wigzell, M.D., PhD; Kathryn J. Boor, PhD; Michael Chambers and Deirdre Connelly have been elected to serve for the 2-year term expiring at the 2028 Annual Meeting of Stockholders.

Proposal 2. Our preliminary tabulation of votes received immediately prior to and at this meeting indicate that the advisory vote on 2025 named executive officer compensation has been approved.

Proposal 3. Our preliminary tabulation of votes received immediately prior to and at this meeting indicate that the company's 2026 equity incentive plan has been approved.

Proposal 4. Our preliminary tabulation of votes received immediately prior to and at this meeting indicate that the company's 2026 employee stock purchase plan has been approved.

Proposal 5. Our preliminary tabulation of votes received immediately prior to and at this meeting indicate that the selection of KPMG LLP as the independent registered public accounting firm for the company for 2026 has been ratified and approved.

I would like to thank all of you for attending Sarepta's 2026 Annual Meeting of Stockholders. The meeting is now adjourned with respect to all matters. I hope you enjoy the rest of your day. Thank you.

This concludes the meeting. You may now disconnect.

Good afternoon, and welcome to Sarepta's First Quarter 2026 Earnings Results Call. As a reminder, today's program is being recorded.

I would now like to turn the call over to Tam Thornton, Sarepta's Director of Investor Relations. Please go ahead.

Thank you, Antoine, and thank you all for joining today's call. Earlier this afternoon, we released our financial results for the first quarter of 2026. The press release, along with our presentation slides and supplementary information will be available on the Investors section of our company website. We plan to file our Form 10-Q for the quarter today with the SEC.

Joining me on the call today are Doug Ingram, our CEO; Dr. Louise Rodino-Klapac, President of Research and Development and Technical Operations; Patrick Moss, our Chief Commercial Officer; and Ryan Wong, our Chief Financial Officer. Additionally, joining us in the Q&A portion of the call are Ian Estepan, President and Chief Operations Officer; and Dr. James Richardson, our Chief Medical Officer.

Before we begin the formal remarks, I would like to note that during this call, we will be making a number of forward-looking statements. Please refer to Slide 2 of our presentation to view the formal text of these safe harbor statements. These statements involve varying risks and uncertainties, many of which are beyond Sarepta's control. Actual results could materially differ from these forward-looking statements, and such risks can adversely affect our business, our results of operations and the trading price of Sarepta's common stock. We strongly encourage all listeners to review the company's most recent SEC filings for a detailed description of these applicable risks. Sarepta explicitly states that it does not undertake any obligation to publicly update or revise its forward-looking statements or financial projections based on subsequent events.

Furthermore, please note that we will discuss non-GAAP financial measures during today's webcast. Complete descriptions and reconciliations of our GAAP to non-GAAP financial measures are included in today's press release and the accompanying slide presentation available to investors on our website.

With that, I will now turn the call over to our CEO, Doug Ingram. Doug?

Thank you, Tam. Good afternoon, everyone, and thank you for joining Sarepta Therapeutics First Quarter 2026 Financial Results Conference Call. We entered 2026 with a clear set of priorities, stabilize the business, restore confidence in growth, maintain financial strength and continue advancing a pipeline with the potential to define Sarepta's next era. In the first quarter, we made meaningful progress against each of these priorities.

First, our marketed product performance has stabilized following the disruption and uncertainty of 2025 with expanded field reach, increased physician engagement and a growing body of compelling evidence supporting the disease-modifying impact of ELEVIDYS, we believe that therapy is positioned to return to growth.

Second, Sarepta remains in a strong financial position. We ended the quarter with approximately $748 million in cash and investments, delivered positive GAAP and non-GAAP earnings, generated positive cash flow, excluding Arrowhead-related payments and remain on track for positive cash flow even under our base case assumptions. The financial strength matters. It allows us to fund our pipeline without relying on the equity markets. We are fully funding our programs in DM1, FSHD, Huntington's disease, the spinal cerebellar ataxias and our preclinical and research portfolio.

And third, we are making progress in what we believe is a potentially best-in-class portfolio of siRNA therapies, as Dr. Louise Rodino-Klapac will discuss shortly. We are especially encouraged by the early data from SRP-1001 in FSHD and SRP-1003 in DM1, and we look forward to additional readouts in the second half of this year.

Turning to first quarter performance. Total net product revenue was $331 million. That included $229 million from our PMO therapies, EXONDYS, VYONDYS, AMONDYS, and $102 million from ELEVIDYS. Starting with the PMO franchise, we were pleased that the FDA agreed that we could submit our clinical data and real-world evidence for VYONDYS and AMONDYS. We have submitted sNDAs seeking to transition those therapies from accelerated approval to traditional approval. That is an important step for patients, physicians and, of course, the durability of this franchise.

Turning to ELEVIDYS. Patrick will provide more detail on the commercial initiatives underway and the early signs of progress we are seeing. But I want to underscore the central point. Our confidence in ELEVIDYS is not -- is grounded in evidence, not in mere aspiration. To date, more than 1,300 patients have been treated with ELEVIDYS across clinical trials and commercial use around the world. The totality of the evidence continues to strengthen. The data show that ELEVIDYS is protecting muscle and changing the trajectory of Duchenne. It is giving boys and young men an opportunity that until now, this disease has never afforded them. We saw this in EMBARK, the only robust double-blinded, placebo-controlled trial demonstrating the benefit of a gene therapy in Duchenne. We saw meaningful benefits in year 1. We saw those benefits grow at year 2 and yet again, at year 3, boys continue to diverge on every measure from the expected course of untreated disease. That matters because Duchenne does not wait. Muscle damage is progressive, irreversible and cumulative. Every month of delay risks further loss, the evidence increasingly supports a simple but urgent message.

Physicians and families should evaluate ELEVIDYS now before additional irreversible damage occurs. We have also seen supportive muscle MRI evidence showing that ELEVIDYS dystrophin helps protect muscle from damage, resulting in less muscle loss and less replacement by fat and fibrotic tissue. This is exactly the kind of biological evidence one would hope to see from a therapy intended to alter the course of Duchenne. We are confident that as physicians and families better understand the disease-modifying potential of ELEVIDYS and the urgency of intervening before further decline, more patients will move towards treatment.

That said, we are still in the middle of our commercial and educational initiatives and the path from consideration to infusion takes time. For that reason, we are reiterating our full year guidance of $1.2 billion to $1.4 billion and would counsel prudence in raising estimates prematurely.

Now staying with ELEVIDYS, we are also advancing our ENDEAVOR Cohort 8 study, which uses sirolimus as a pretreatment. More than 25% of sites are already using sirolimus on their own initiative. In our interim analysis from the long-term real-world evidence study that we have ongoing, patients pretreated with sirolimus have shown no evidence of elevated liver enzyme to date. That gives us further confidence in Cohort 8 and in the potential with the success of that study and the concurrence of the FDA to resume offering ELEVIDYS to non-ambulatory patients.

Turning to the pipeline. Our focus is execution. We are rapidly advancing our siRNA portfolio including our DM1 and FSHD programs. The first data readout earlier this year showed encouraging signals that these may be differentiated, potentially best-in-class approaches for 2 very challenging diseases. We look forward to providing additional data later this year. We have initiated and are on track to dose our first patients in our Huntington's disease program, and we are progressing clinical trials in SO2 and idiopathic pulmonary fibrosis.

So to summarize, the business is stabilized. ELEVIDYS is supported by an increasingly compelling body of evidence. Our financial position is strong and our high-value siRNA pipeline is advancing across multiple programs. We believe Sarepta is well positioned in 2026 and beyond.

And with that, let me turn the call over to Louise, who will provide an update on our siRNA portfolio and broader development progress. Louise?

Thanks, Doug, and good afternoon, everyone. Our diverse and advancing rare disease portfolio has always been driven by a core fundamental truth, pursue the very best science and then follow where it leads. In March of this year, we announced positive preliminary data from our lead programs to treat FSHD and DM1, which are based on the potential of our alpha V beta 6 integrin targeting ligand to produce best-in-class therapies in these unmet disease areas. Importantly, our integrin receptors are highly expressed in muscle in addition to other tissues. They are also actively trafficked between the cell surface and the endosomal compartments through relatively well-understood pathways. Nonclinical data show that targeting these integrin receptors via small peptides leads to enhanced skeletal muscle uptake compared to using a much larger TFR1 antibody. It's also important to note that based on data to date, our alpha V beta 6 integrin targeting ligand provides superior muscle concentration compared to transferrin-based approaches without dose-limiting toxicity.

I will now summarize the early data from our FSHD and DM1 programs. SRP-1001 is an siRNA-based treatment designed to reduce or knock down the production of DUX4 protein in skeletal muscle in patients living with FSHD1. Study 1001-101 is our combined Phase I/II single ascending dose and multiple ascending dose randomized placebo-controlled trial in participants with FSHD1 aged 16 through 70. As previously shared, we believe our preliminary data from the Phase I/II SAD study supports the potentially differentiated attributes of SRP-1001, including a dose-dependent increase in plasma exposure up to the highest dose cohort, also superior delivery to muscle enabled by a differentiated approach with the alpha V beta 6 integrin, including no saturation of drug uptake, significant suppression of DUX4-related genes and a rapid and robust reduction in CK to support functional impact. Finally, a favorable safety and tolerability profile with repeated dosing, including no indication of anemia, which physicians have indicated represent an important therapeutic advantage. We look forward to sharing results from the MAD portion of the study later in the year, which we expect will include at least 6 months of follow-up for our 6 and 12 mg per kg MAD cohorts, which is equivalent to 4 and 8 mg per kg siRNA dosing.

This is with respect to safety, PK/PD data, including circulating biomarkers and DUX4 regulated genes as well as early functional data. We also plan to discuss our post Phase II with FDA to define an optimal registrational pathway.

Now moving to DM1. SRP-1003 is an siRNA-based treatment for DM1 designed to target or knock down or silence the DMPK mRNA in target cells. Study SRP-1003-101 is a first-in-human Phase I/II SAD/MAD randomized placebo-controlled clinical trial being conducted in individuals with DM1 aged 18 to 65. The early data we generated for DM1 is important for two reasons. First, our preclinical models are predictive of what we would see in the clinic with respect to muscle concentration. Of note, an increase in plasma exposure has translated into enhanced dose-dependent delivery to the muscle, resulting in robust target engagement.

Second, the demonstrated DMPK knockdown we observed was impressive and directionally strong. As you're aware, DM1 is driven by an expanded CUG trinucleotide repeat in DMPK transcripts, causing mutant DMPK mRNA to accumulate in the nucleus and disrupt RNA splicing. As a result, for any therapy to be therapeutically effective, we must effectively target and knock down or silence DMPK in the target cell. SRP-1003 is being developed to achieve exactly that. We look forward to sharing these results from the additional SAD and MAD cohorts in this study later in the year, which we expect will include multiple doses measuring mechanistic and functional endpoints with at least 6 months of follow-up for our 6 mg per kg cohort, which is equivalent to 4 mg per kg siRNA.

Specifically, we expect to share safety, serum and muscle PK, DMPK knockdown, CASI-22 splicing indices and VHA analyses. We will plan our IND submission for the U.S. study shortly after completing our MAD studies. We believe these trials, if successful, will support and provide a clear path to support registration.

In summary, enhanced muscle delivery, robust target engagement and maximal knockdown are well recognized as the gold standard for FFHD and DM1, and we're excited by the potential of our therapies to reach this standard. In terms of our other siRNA pipeline programs, we are on track for first patient in for Huntington's and our SCA2 trial is fully enrolled. We look forward to sharing data as it becomes available.

Now turning to ELEVIDYS. We are pleased to announce in March that screening and enrollment are underway in Cohort 8 of ENDEAVOR or study SRP-9001-103. To remind you, the purpose of Cohort 8 is to assess prophylactic sirolimus treatment as part of an enhanced safety protocol during treatment with ELEVIDYS in nonambulatory individuals with Duchenne. Data from Cohort 8 will be used to determine whether administering sirolimus prior to and after ELEVIDYS infusion can help reduce acute liver injury, a known risk associated with AAV gene therapy.

The cohort is enrolling approximately 25 participants in the United States who are nonambulatory and dosing is currently underway. As a reminder, the immunosuppression regimen will include 14 days of peri-infusion sirolimus dosing prior to ELEVIDYS administration and will continue for 12 weeks after ELEVIDYS administration. Primary endpoints include incidence of ALI and ELEVIDYS dystrophin expression at 12 weeks. The approach is based on preclinical data and shaped by real-world clinical experience, including guidance from independent specialists in Duchenne and liver health.

As Doug mentioned, in addition to EMBARK 3-year functional data, we also reported at MDA caregiver reported impressions from EMBARK through 2 years of follow-up, offering complementary perspectives on treatment impact beyond clinician reported and performance-based outcomes. We are pleased that our body of evidence for ELEVIDYS continues to grow with an unprecedented number of patients dosed as well as the years of follow-up. We remain steadfast in our commitment to serve the Duchenne community by generating clinical and real-world data to support understanding of long-term outcomes. This also includes our Phase IV observational study ENDEAVOR.

Now moving to AMONDYS 45 and VYONDYS 53. In March, we announced that we requested a meeting with FDA to discuss submitting supplemental new drug applications or sNDAs, seeking conversion of the accelerated approval of AMONDYS 45 and VYONDYS 53 to traditional approvals. This request was supported by data from the ESSENCE confirmatory study, substantial published real-world evidence supporting treatment and the favorable safety profiles of both therapies. Sarepta received feedback from the agency confirming that we are clear to submit our data from ESSENCE and real-world evidence as part of the sNDAs. We are pleased to share that we successfully submitted our sNDAs at the end of April.

In summary, we have numerous value-building milestones upcoming across our Duchenne and siRNA portfolio.

Thank you, and I'll now turn the call over to Patrick for an update on our commercial performance. Patrick?

Thank you, Louise, and good afternoon. Today, I'll summarize our performance in the first quarter for our on-market therapies, provide an update on execution of our 2026 initiatives and close with how that translates into performance for second quarter and the balance of the year.

For the first quarter, total product revenue was $331 million, including net product revenue of $102 million for ELEVIDYS and $229 million for the PMOs. For ELEVIDYS, first quarter results reflected measured demand, which we believe was influenced by the ongoing information gap within the ambulatory population. This reflects the dynamics we outlined last quarter as we advance efforts to rebalance the discussion around safety and efficacy to support informed decision-making for ELEVIDYS treatment.

Importantly, Q1 demand fundamentals have not deteriorated. Instead, we are addressing the information gap we know exists and are building momentum around a robust label and new data following the events of 2025. The PMO franchise continued to demonstrate durability with demand remaining stable and in line with expectations for mature therapies that are foundational for slowing the decline of Duchenne. We experienced seasonal dynamics in Q1, which contributed to the quarter-over-quarter decrease versus Q4.

Our focus for 2026 and beyond remains squarely on ensuring that patients and physicians have a balanced data-driven understanding of ELEVIDYS' benefit-risk profile. The treatment journey for ELEVIDYS has multiple touch points, including patient identification, referral, evaluation and payer review in addition to the time and information a family needs when deciding to pursue treatment.

While our commercial model supports all the touch points within this treatment journey, as discussed last quarter, we are actively implementing a number of initiatives to augment our execution, including expanding the number of field resources to support referring physicians, extending our reach within sites of care. In addition, the company is deploying new educational resources and tools to support patients and families.

We have increased our footprint fielding a contract sales force to focus on physicians who may be in a position to refer patients to a site of care for gene therapy or prescribe one of our exon skipping therapies. This team recently completed training and deployment in the field is underway. We expect the team to be fully operational as we enter the second half of this year. Expanding our footprint with a contract sales force has enabled us to deepen our efforts at sites of care with our Sarepta sales team. Our sales team will devote time to more robust interactions with prescribers at sites of care and engage with the extended care team.

In addition to my team's initiatives, the company is developing more educational resources and tools to aid patients and families in their preparation for a conversation with their clinician. In an age where information online is abundant and can be difficult to navigate, having clear resources and tools available to caregivers and patients is Sarepta's response to supporting the unique and very personal journey of each patient. All these interactions with referring clinicians, prescribers, supportive care providers, families and caregivers are grounded in clarity, repetition and transparency as we recognize the decision to treat with ELEVIDYS requires time and trust.

To date, a growing body of empirical evidence supports that ELEVIDYS is changing the trajectory at Duchenne. We integrated the long-term EMBARK data, including muscle MRI findings into our educational efforts and discussions with clinicians, addressing what matters most, preservation of muscle over time. Our efforts are having an impact and feedback from prescribers and the patient advocacy community affirms our approach. Safety must be considered within the totality of evidence, including the durable benefit of ELEVIDYS.

HCPs and the ambulatory population were directly affected by misperceptions of ELEVIDYS, so education remains essential and is a focal point of our work. We remain confident that all these initiatives should address the needs of prescribers and patients. But I do want to set expectations very clearly. The time from enrollment form to infusion is a 6-month process. Given this, it will take time to see the potential impact of my team's action to be reflected in sales. Last quarter, I said we are seeing green shoots, early signals that give us confidence we are headed in the right direction, and the team is squarely focused on delivering the efficacy message to drive demand.

For example, enrollment form activity is more geographically diverse. Sites have previously paused activity in 2025 are participating and submitting enrollment forms. Across the broader referral ecosystem, we are seeing more consistent HCP engagement, suggesting that awareness and understanding of the benefits of ELEVIDYS is resonating. We expect momentum to build progressively through 2026 with greater visibility into improvement most likely to emerge in the latter part of this year and into 2027.

Our efforts are substantive in responding to the needs of prescribers and patients and will improve with reach and repetition. Reestablishing momentum will lead to steady growth over time and not a sharp inflection. We believe our guidance assumptions for 2026 appropriately reflect a measured trajectory, accounting both for timing dynamics and patient decision cycles. Given this reality, we are comfortable with the Q2 consensus. And as Doug stated earlier, we reiterate the full year guidance of $1.2 billion to $1.4 billion and would counsel prudence in raising estimates prematurely.

Our long-term conviction in ELEVIDYS remains strong. As the only FDA-approved gene therapy for Duchenne muscular dystrophy, we have treated more than 1,300 patients in both the clinical and commercial settings with ELEVIDYS. The current and growing body of data demonstrates the disease-modifying potential of ELEVIDYS. And as a result, we believe ELEVIDYS has the opportunity to remain a cornerstone therapy in Duchenne for years to come.

And finally, a brief update on the PMO franchise. The PMO franchise remains durable in 2026, supported by long-standing physician experience, a well-understood safety profile, a continued commitment to preserving muscle function and exceptionally high rates of adherence with our therapies. Physicians continue to view exon skipping as an important treatment, particularly for patients who are not candidates for gene therapy or for those who choose to defer treatment. The robust body of real-world evidence that demonstrates meaningful benefits in survival and cardiac function reflects more than a decade-long commitment of Sarepta's scientific investment and leadership dedicated to improving outcomes for those with Duchenne.

In closing, our commercial focus in 2026 is clear: execute with discipline, educate with data-driven conversations, build momentum and support the unique needs of each and every patient. We are encouraged by the early rebuilding signals for ELEVIDYS, the stability of our PMO business and the long-term opportunity to support those with Duchenne and change the trajectory of the disease.

Thank you, and I'll turn the call over to Ryan. Ryan?

Thank you, Patrick, and good afternoon, everyone. On behalf of the Sarepta team, I'm pleased to report a strong quarter of financial execution to start the year, where our base business was profitable and cash flow positive. In my brief remarks today, I'll share highlights from the quarter and some perspective on how we're thinking about the rest of 2026.

Starting with the P&L. First quarter total revenues were $731 million, a decrease of 2% compared to Q1 of last year. The decrease in our net product revenues year-over-year was driven by lower ELEVIDYS sales and was partially offset by an increase in collaboration and other revenues. In Q1, we reported $400 million of collaboration and other revenues and consistent with previous guidance, this included $325 million of noncash collaboration revenue related to Roche declining a program option as well as $40 million of milestone revenue from the first commercial sale of ELEVIDYS in Japan.

Turning to gross margin. Total cost of sales for the quarter was $109 million, a decrease of 21% compared to last year, driven primarily by lower sales volume. On a unit sales basis, gross margins were 82%.

Moving now to OpEx. Combined R&D and SG&A expenses in the first quarter were $263 million and $224 million on a GAAP and a non-GAAP basis, respectively. Both included the $50 million annual Arrowhead collaboration license fee recorded to R&D. This was a significant decrease compared to the prior year quarter because of the cost restructuring initiatives enacted last summer and as the prior year quarter included the upfront transaction costs from the Arrowhead collaboration.

Putting it all together, in the first quarter, we delivered a GAAP operating profit of $358 million and a non-GAAP operating profit of $398 million. These results are reflective of the strength of our underlying business and the noncash collaboration revenue recognized during the period.

Shifting to the balance sheet. We ended the first quarter with $748 million of cash and investments, a sequential decrease of $206 million, driven by $250 million of payments to Arrowhead, the second DM1 milestone and the annual collaboration payment I just mentioned. Also, as noted earlier, excluding these planned payments, our base business continued to generate positive cash flow. Looking ahead to the remainder of the year, we are reaffirming our prior revenue and OpEx guidance as well as our expectation of profitability and to be growing our cash balance from here.

As you heard earlier on the call, we are very encouraged by the early data emerging from our FSHD and DM1 program. And if the data continue to translate clinically as they have so far, we believe they represent significant opportunities to benefit patients with unmet needs and create long-term value for investors.

In closing, I will highlight that our current operating expense outlook and medium-term planning fully contemplate advancing both programs through late-stage development. Leveraging the strength and durability of our commercial execution, we believe we are uniquely positioned to fund and execute these programs and our broader pipeline responsibly without placing strain on the balance sheet.

And with that, I'll turn the call back to Doug. Doug?

Thanks, Ryan. Let's open the call for questions.

[Operator Instructions] Our first question comes from Anupam Rama from JPMorgan.

This is Joyce on for Anupam. With your sales force expansion and ongoing initiatives to help close some of these information gaps, I was just wondering if you could comment on feedback you've been receiving regarding your 3-year EMBARK data and which parts of the data specifically have been especially resonating with physicians?

I'll turn this over to Patrick briefly can sort of comment on some of the advisory boards you've had and some of the direct interactions you've had with physicians on the 3-year data and other data.

Yes. Thanks, Doug. And so we've been having multiple ad boards and discussions with physicians, both myself and Ian and Doug, one-on-one, but also the field team as they're out there engaging. And what's moving the needle is the efficacy data as well as the MRI data. And once the physicians see both the divergence over time from natural history of patients that are treated with ELEVIDYS ties out with the MRI data, that's moving the needle and also reflects exactly what they were expecting from a therapy like ELEVIDYS as well as what they're seeing in their clinic.

And I think all that's exactly right and that more experience with it even than I have. But there are a couple of reasons that this has occurred. The first is the data itself is really impressive. If you look at the 1-year EMBARK data on every secondary measure, every time measure, we were statistically significant on this placebo-controlled and blinded well-controlled study. And then you look at 2 years on all measures, we are doing much better, ELEVIDYS is doing much better than untreated patients. And that gap grows even more in year 3, exactly what you'd expect from a disease-modifying therapy that's changing the trajectory of disease. And then from an urgency perspective, we have muscle MRI data, which is exactly what you'd expect to see, which is that if you get treated, you are going to save yourself from a lot of damage and the fat and fibrotic tissue that comes from that damage and the loss of muscle. So it's understandable that it's compelling when you talk to physicians about all of this data. And that's not even all the data that we have. We obviously have the 5-year data from our original cohort as well.

The other thing that's important to understand when you think about our initiatives is something that is both frustrating but in a big opportunity, which is when you do market research, what I've just told you now and what Patrick mentioned to you now isn't well understood that in large measure because of a lot of the important things that happened last year, but that were distracted us last year, there was a lot of focus away from what this therapy was going for patients. And as we sit here right now, both in the patient community and significantly in the physician community, there is a massive information gap around those issues. So when you sort of take that and you kind of shake off the frustration that comes from that and realize that's actual opportunity. And then you think about the initiatives that Patrick is putting in place gives us an enormous amount of confidence for the future. We more than doubled the size of our sales force. We have a contract sales force. We have grand data now. We have much better promotional material founded on that great data. We have great educational efforts in the patient community and the like. And we have the muscle MRI data that makes the point that you cannot wait that you will never catch up if you wait. There's an enormous amount of opportunity here to benefit patients and to get ELEVIDYS moving. Now with that said, I'm going to say what I said in my script, and I do want to be very careful. We are excited about where we are. We have -- these initiatives are in play. This is a long cycle process. And we are reiterating our guidance, $1.2 billion to $1.4 billion, and we'd ask you along with us to exercise some prudence in changing estimates until we get these initiatives going along the way. And the good news is that we're in a great place even in a base case situation to fully fund without the need to go to the equity markets, what is a very, very exciting siRNA pipeline.

Our next question comes from Konstantinos Biliouris from Oppenheimer.

One question on AMONDYS and VYONDYS sNDA, and sorry if I missed it. Can you clarify whether you have requested or received priority review there? And when should we expect a decision from the FDA?

Yes. This is -- these are sNDAs. We didn't ask for a priority review. So it's the regular time cycle. So we would imagine that the PDUFA date will be sometime in February of next year.

Our next question comes from Ellie Merle from Barclays.

Just two questions for me. You mentioned some 1Q seasonal dynamics. Can you just elaborate on what you saw there and how we should think about the appropriate run rate as we head into 2Q and beyond for both the PMO franchise and ELEVIDYS? And then a question on the Huntington's program. Can you walk us through what you see as potentially differentiating versus other silencing approaches in development and what we could expect from the proof of biology data next year?

Sure. I'll turn the first part of the call over to Patrick after which Louise can touch on the Huntington's program.

Yes. And what we do know and what we do see is quarter-to-quarter dynamics, they're noisy, right? And so it reflects just a small number of patients, either this quarter or the next quarter. And so when we look at it, it's not something we can be extremely precise on. But we do know things like illnesses, patient family dynamics do impact those quarterly, quarterly dynamics. And that's something that we do look at and evaluate as we provide our guidance.

Yes. One thing I will say about that as well is remember, the reason for all of that is that this is a onetime therapy. So with a chronic therapy, you kind of get this installed base and you're really just forecasting on the margin with a onetime therapy, you're forecasting new every quarter. And with a therapy like ELEVIDYS, which is a couple of million dollars net, a couple of patients that have the flu in the last week of the quarter can impact. So there's just a little more variability here as much as we have a nice line of sight. There's more variability here than you might see in a chronic therapy.

And then on the PMO side, there's lumpiness in the ex U.S. business as well as the beginning of the year, we do see insurance changes. And so that does impact the PMO side of the ledger.

And with that, we will turn the call to Louise.

Thank you. As you mentioned, we're very excited about the Huntington's program, and we think that we are potentially differentiating for several reasons. So the first is really the use of the mechanism of action, and that's using the TFR ligand in combination with the subcutaneous injection. And this really allows us based on preclinical data to get into the deep brain regions, which is essential for Huntington's disease like the striatum. And based on the preclinical data in mouse models as well as nonhuman primates, we have particularly high knockdown in these deep regions, and that's really what sets this program apart for us and got us excited. So it's early days. We are on track for first patient in, but we will be looking for proof of biology in terms of safety and then evidence of activity in terms of knockdown in the first data that we see, and that will be earlier next year. So I'm very excited based on preclinical data and very much looking for differentiation based on the mechanism of action and the dosing itself, which is much less invasive than some other programs.

Our next question comes from Andrew Tsai from Jefferies.

Congrats on the quarter. This is Matt Barcus on for Andrew Tsai. I just wanted to ask about what you guys are expecting in terms of the reduction of ALI segments in the non-ambulatory Cohort 8 TOS data set expected later this year? And I think you said you wanted to see a 50% reduction in ALI rates where I think the clinical rate is around 40%. But is it different in the real world? And might ALI rates in Cohort 8 actually mimic the real world setting?

Yes. So I'm going to turn this question over to Louise. But before I do, let me make a quick comment, which is that we do have some evidence before Cohort 8 that gives us some confidence around the success of Cohort 8. Dr. Steslow, as you may know, has pretreated a number of patients and presented that data, I believe, at World Muscle earlier of this year. And in that setting, the pretreatment with sirolimus completely abated any increase in liver enzymes. Also, we have the real-world evidence study, ENDEAVOR, I believe, and we've done an interim analysis there, early days, and I want to be very clear, the overlapping evidence because some of -- some of Dr. Steslow's data is in there as well. But in that setting as well, we've seen no increases in liver enzymes so far when a patient is pretreated with sirolimus. Obviously, we need to dose more patients. Obviously, we need to get Cohort A dosed and get the readout on there. But as you can imagine, given that, given our preclinical data and given the experience anecdotally from other physicians who've used sirolimus and other immunosuppression regimens, we feel a significant amount of conviction around the potential success of Cohort A and the ability to get back to offering this therapy to nonambulatory patients who desperately need a therapeutic option would have none, but for this therapy. But with that, I'll turn it over to Louise to talk about the clinical trial itself and what the standards are there pursuant to the stat plan.

Sure. And you are correct, we are looking for a 50% reduction in the incidence of ALI. The trial is an open-label trial enrolling approximately 25 patients. We do have the ability to look at the data and enhance the end if required. But regarding the ability to reach that 50%, I'm going to ask Dr. Richardson to just comment on it in the clinical trial versus the real world.

Yes. Thank you, Louise. And you're quite right that we have seen a different instance of ALI in the clinical trial setting versus the real-world setting. That's partly driven by the use of the research at the GLDH in the clinical trial setting. We'll be using that in Cohort 8. And so our primary analysis will be to look at a reduction of 50% or more versus our historical clinical trial rates, which include GLDH. We'll also be able to look at it without GLDH to make sure that there is no specific signal to that biomarker. And as Louise said, it's an open-label study, should we see anything that deviates from these original assumptions, we'll be able to adjust the sample size accordingly.

Our next question comes from Brian Abrahams from RBC Capital Markets.

This is Kevin on for Brian. Maybe following up on the sirolimus study. Can you talk a bit about your new end of 20 Phase IV ENHANCE study of patients receiving ELEVIDYS and sirolimus in the real world? Just curious how that fits with your potential regulatory strategy for non-ambulatory patients, whether maybe it was required by regulators and just your considerations on potentially just simply upsizing the current study versus running this real-world study in parallel as well.

Louise?

Yes. I'm going to turn it to James in a minute, but at the highest level, so the Phase IV study gives us the ability to look at the use of sirolimus in ambulatory patients as well as well as looking at gene expression based on this. So these two elements are important to looking at sirolimus in population other than the non-ambulatory population. But James, maybe you can give us a few more details about the study.

Yes, sure, absolutely. I mean this is a study looking at commercially dosed patients under the same sirolimus regimen as we're using in Cohort 8. It's not part of a broader regulatory strategy, but simply just asking the hypothesis about the use of sirolimus mitigation of ALI in a broader Duchenne population. The data could be supportive to Cohort 8, but it's not necessary for that non-ambulatory strategy, but we'll simply reaffirm the current hypothesis that sirolimus is equally well tolerated across a broad range of Duchenne patients, and we would expect a similar efficacy in terms of reduction of ALI.

Our next question comes from Mike Ulz from Morgan Stanley.

It's [indiscernible] Nova on the line for Mike. I guess just a quick one on guidance. I think on the prior call, you indicated that you're more comfortable with the low end of guidance, that would be more likely. I guess, given the positive green shoots you've seen early this year, I guess, would you be more comfortable that maybe the middle or high end of guidance might be more likely? And I guess, if not, what do you need to see to sort of get there?

Yes. Thanks for your question. You're exactly right. We guided $1.2 billion to $1.4 billion and sort of revised folks that they should be thinking towards the lower end of the $1.2 billion to $1.4 billion until we see more. The short answer is that we are making very good progress in our initiatives, but the initiatives are long-cycle initiatives. A number of them have already gone underway. As an example, our sales force is doubled and they're out in the field talking to physicians, and that's great. We've got great marketing material. We have additional marketing material coming out with our 3-year data as well. So that's going to be great. We've got educational efforts. We've got a contract sales force that will be getting in the field very, very shortly and has been trained up. But with all of that said and as excited as we are and the conviction we have about these tools, we want to speak cautiously for the time being and just be thoughtful. And so we're not changing our guidance. and we would caution others to be prudent in raising their internal estimates prematurely.

Let's get underway and get these initiatives going. And we do see some green shoots, and we certainly see when we -- qualitatively, when this information is understood by physicians and understood by patients, it has a meaningful impact, but it's going to take some time because these are all long cycle, essentially resetting people and getting to really understand the evidence set, both on safety and efficacy.

Our next question comes from Salveen Richter from Goldman Sachs.

This is Tommie on for Salveen. Maybe if we could get to the extent that you're available, the details on patient numbers at dose levels for the siRNA data by year-end? And especially, how will the functional measures for this data factor into how you're thinking about the registrational outlook and kind of competitive comparisons?

Great. I'll turn this to Louise.

Sure. So just for both studies. So for FSHD, we will have data from our 6 and 12 mg per kg MAD cohorts. And so those are our highest dose cohorts that's equivalent to 4 and 8 mg per kg siRNA. With respect to DM1, we will have our follow-up from our 6 mg per kg MAD cohort, which is equivalent to 4 mg per kg siRNA. So as I mentioned, we'll be looking at safety, biomarkers and early evidence of functional outcomes. And James, perhaps you can comment on how we're thinking about the functional data as it's early in terms of the follow-up and the number of patient numbers.

Yes. Thank you, Louise. I mean I think primarily, as you say, safety and the PD biomarkers will help us select the appropriate dose to carry forward into the Phase III program. Clearly, we're going to look at the functional data to understand what we think is supposed to be the most responsive outcome that help us select our -- and drive our design for our Phase III. But I would not, as Louise said, expect any significant movement in the functional measures at 6 months in FSHD. In DM1, we would expect to see a signal in VOD at this time frame. But similarly for the other time function tests, it's very early in this disease state and in the size of cohort to make any definitive conclusions.

Our next question comes from Tazeen Ahmad from Bank of America.

A couple on FSHD and DM1 or rather one on those. How do you think about comparing the data that you've presented so far to products that have already shown data that might be further ahead in development? Specifically, how should we be thinking about what the right endpoints should be in order to look at? I know that there's a Novartis study that's being debated as to whether or not in DM1, the right endpoint is being used. I'd love to hear your thoughts on that. And secondly, as you talk to FDA about the shift to get the PMOs to permanent approval, can you talk about if there's been any change -- any further change in who you talk to in the divisions that are relevant? Just trying to get a sense of continuity of people that you might be engaging with.

Yes. I'll turn this over to Louise.

Sure. Regarding the comparative data, as we mentioned in the disclosure call, in terms of what we're looking at and why we think that our program is differentiated is in terms of the amount of siRNA that we're getting into the muscle, and that's using the alpha V beta 6 targeting ligand. And so that truly in terms of comparison allows us the more you can get into the muscle, the more knockdown you can get, and that leads to better biomarkers and downstream functional markers. And so that's the way we're thinking about it with this early data is how can we get the highest level into the muscle so that we can have the most robust effect. We want to make sure that we are having a product that is giving us the best chance of efficacy and consequent function. So with regards to the functional outcomes, I'm going to turn that to Dr. Richardson in a second regarding DM1. On the PMOs, we're generally seeing the same -- interacting with the same individuals and the agencies that we have been for the PMO programs and for those sNDAs. But James, perhaps you can comment on the DM1 function.

Yes. I mean I think we're seeing in the DM1 space, what you commonly see as developers move into the disease space that we see an evolution in our understanding of the functional endpoints. And we also see a greater investment in natural history data. We've seen recently with Nick Johnson's group publishing from the NDM1 study which is building on our understanding of the appropriate functional outcomes. So I think from our point of view, the sponsor without calling other sponsor's program, we're in an advantaged position of being able to take these natural history data internally, be able to speak to people like Nick Johnson and others and take their opinion on the primary endpoints and then look at the functional data coming out of the cohorts we're seeing in Phase I and II, put that together and reach our own decision on what we think is the most appropriate primary and secondary endpoints for our Phase III study and obviously discuss that subsequently with the FDA.

Our next question comes from Joe Schwartz from Leerink Partners.

I have a question on the siRNA programs, which we'll have data on later this year. First, is there any data preclinical or otherwise, which suggests that deeper reductions in DUX4 expression would be expected to translate into greater clinical benefits for your approach in FSHD compared to competitor therapies with lower knockdown profiles? And then in DM1, what specific magnitude of splicing correction would you want to see in the upcoming MAD cohorts to prove that 1003's differentiated delivery can translate into a best-in-class clinical profile? And why wouldn't VHA improve fairly quickly for your approach since it has seemed to be fairly sensitive for other RNA approaches early on?

I'll turn this to Louise. I will note, and I think James did suggest that VHA may be an appropriate measure in the MAD, but that the other longer-term functional endpoints require more time in the disease. With that, I'll just turn to Louise to answer both of those questions.

Sure. On FSHD and the knockdown of DUX4. So if you recall, DUX4 is -- shouldn't be expressed at this time in late development. It's expressed early in development and then turned off. It should not be expressed in adults. So any stochastic expression is toxic. And so therefore, the greatest amount of knockdown gives you the greatest amount of benefit. So 100% knockdown would be fantastic. So obviously, more knockdown is better, and that's what we're looking for.

In terms of the target for being DMPK knockdown, the answer is similar in terms of what we're looking for. So we're looking for increases in muscle concentration leading to improvement in DMPK knockdown. We know that increased from preclinical data correlation of DMPK knockdown correlates with functional improvement. And so that's what we are looking for. And based on the data to date, we've seen dose-dependent increase in muscle concentration. We'll be looking at the DMPK knockdown with our MAD data later in the year. And then as Doug already mentioned, on the VHOT, we certainly would expect earlier signals, as you said, for VHOT is an early sign of function. James, anything to add to that?

No, no, just completely agree, just to distinguish between VHOT, as we said, which we do think we will see a signal with at this point and other functional outcomes, which will take longer.

[Operator Instructions] Our next question comes from Yigal Nochomovitz from Citigroup.

I had a question on SRP-1001 and the dose response with respect to muscle concentration. When you doubled the dose, you got about a sixfold super linear increase in muscle concentration. So I just curious if you could comment on that in terms of the mechanistic rationale and whether in the multiple ascending dose part of the study, you would also expect that kind of far exceeding linear dose proportionality at the higher doses?

Louise?

Yes, we certainly saw an increase there, which wasn't linear. We would expect to see it start to plateau based on the preclinical data. We did see a jump from the lowest dose, which wasn't unexpected based on preclinical data, but we would see it plateau at the higher doses, but certainly continue to increase based on the preclinical data.

Okay. And just one follow-up. With regard to the study that you mentioned for sirolimus in the real world where you didn't see any evidence of liver enzyme elevations. Could you just expand on that in the sense that where there were no Grade I or any abnormalities in liver enzymes in that real-world study?

Louise?

Yes. So this is our real-world data where we can go back and survey the results from investigators, and this is investigator calls in terms of ALI. So we see that 25% are using it, and we're not seeing any evidence of ALI as determined by the investigator.

Our next question comes from Ritu Baral from TD Cowen.

This is Joshua Fleishman on for Ritu. I wanted to start by asking what is the current progress of Cohort 8 recruitment? And are there any current time lines to enrollment completion? On the call, you guys also mentioned DM1 functional data, but what FSHD functional data will be included in the second half '26 data release? And then lastly, what are Sarepta's plans for additional BD deals, thinking about both time lines to a deal and potential disease areas?

So look, on Cohort 8, I'll just be quick on it and then turn the FSHD question to Louise. I'll touch on the BD. First, on Cohort 8, just so we're clear, we are right where we said we would be. We're dosing patients now. And our goal is to have the study complete and the data available by the end of the year. And so that -- we're on track for that.

With respect to business development, the good news is that we're in a great place as an organization. We are not required to do business development for our future success. We have a very straightforward strategy right now. We've stabilized the business. We have 4 approved therapies. They are performing well, and we think they'll perform as it relates to ELEVIDYS even better with our new initiatives. We are in a very strong financial position as an organization when we saw that we were profitable on a GAAP and non-GAAP basis, absent our Arrowhead payments, we were cash flow positive. We'll be cash flow positive going forward even in our base case assumption that allows us to fully fund our siRNA pipeline. And we're really excited about this siRNA pipeline. You've seen the DM1 and FSHD data early though it is, and we're excited to see that data later this year. We have Huntington's disease and IPF and multiple SCAs and 6 research programs. So we're in great shape there. With that said, we have a very active search and evaluation group that look for transactions, and we'll continue that. And we've got a very, very proactive Head of Business Development in Joe Zenkus, and we're constantly looking for opportunities, but we also have a very high bar for that. So that's where we are with that. And with that, I will turn the FSHD question to Louise.

Sure. So the question was what functional outcomes are we looking for in FSHD. So James, do you want to comment?

Absolutely. I mean, I guess to reiterate, the primary purpose of this study is to assess safety, PK and then the PD response. And I think we're particularly excited about also looking at circulating biomarkers at this point. We are obviously conducting functional assessments as part of the study, including reachable workspace, standard battery time function test and strength testing that you would expect. This is a slowly progressive neuromuscular disease, and this is not a point in time where I would expect a very strong signal from a functional endpoint perspective. But clearly, if we do see something at this point, that will be a fantastic upside. And anything we do see in terms of responsiveness of the various endpoints compared to one another will help us select the appropriate primary outcome for our Phase III study.

And then out of reachable workspace time function tests and strength, which of those will be included in the second half '26 data release?

Yes. I mean we will have data on all of these endpoints. I think that we'll be able to give a summary of the above. But again, as I said, I wouldn't be expecting a priority to see significant changes in any of them.

Our next question comes from David Hoang from Deutsche Bank.

So maybe one on ELEVIDYS. Do you have any sense of how many centers are currently offering ELEVIDYS? And maybe how does that compare to the number at the time of initial launch? And then just quickly on Cohort 8, could you talk about the regulatory path after you have the data in hand? Would this be like submitting an sNDA? Or just how should we think about the FDA interaction with cohort data -- Cohort 8 data?

I don't think we -- have we given information on numbers of sites historically, Patrick?

I mean we've talked about the number of sites that we've had just in the market. So we've got 75-plus sites that are available and offering up ELEVIDYS, and that has not changed over time. So it's still consistent out there.

We have also seen, again, in the green shoots category, we have seen sites that with some of the dislocation of last year, it paused that have picked up and have commenced submitting start forms again. So that's a positive green shoot as well. And with that, I'll turn the second part of the question over to Louise.

Sure. Once we have the Cohort 8 data in hand, we'll meet with the agency and then we'll determine the path forward after that. So we've committed to share the data with them as soon as we have it, and that we will meet with them and discuss.

Certainly, our hope -- we have to have a meeting with the FDA to figure out the exact regulatory process one has to go through. But in the event that the sirolimus data proves to be -- changed the risk benefit of this therapy significantly in favor of the non-ambulatory patient. We would hope that the agency would work with us to get this therapy offered to nonambulatory patients as fast as possible for the obvious reason. Duchenne generally is a disease that doesn't permit waiting. It's just not a therapy that can wait every day. These kids are damaged and no group of patients know that better than the nonambulatory patients who have a desperate need for intervention to save what muscle that they have remaining after they become nonambulatory and progress the disease. So with that said, we've got to meet with the agency, as Louise has said, but it is our very hope that the FDA will work creatively with us to get the indication back in the label so we can begin to have thoughtful conversations with physicians and families and offer this therapy to them.

Our next question comes from Andy Chen from Wolfe Research.

This is Brandon on for Andy. So you noted that ELEVIDYS for the business has stabilized. Does a return to growth assume only access in the ambulatory setting? Or does that growth assume that you're able to resume treatment in non-amb patients?

Yes. When we talk about return to growth, we're talking about in the ambulatory population right now. Obviously, with the success of sirolimus and Cohort 8, if it is successful, and we certainly have conviction that it will be and getting that back in the label, then, of course, we'll have to reforecast the post that. But when we talk about our initiatives right now and the return to growth, we're talking about the ambulatory population because obviously, non-ambulatory is not in our label, we would never promote to non-ambulatory as it is not in our label. So we're talking about ambulatory.

Our next question comes from [ Jay Wang ] from Mizuho.

This is [ Jay Wang ] on behalf of Roy here. I guess I just wanted to ask about the 20% you mentioned the sites that are already using sirolimus. I guess what's holding the remaining 75% from adopting this regimen, assuming it's going to help reduce ALI risk. Do you think it's because you're concerned about any immunosuppressing side effects or they're just not familiar with the regimen?

Our best guess would be that the education and information has to flow between physicians and thought leaders and the like. One of the things that we are not permitted to do is play a proactive role in that. We don't have sirolimus on our label. We can't promote to it. So the simple approach, which would be to go and share data with physicians is something that we are not permitted to do. So the spontaneous use of sirolimus in 25% of the physicians comes entirely from physician practice and from sharing of best practices among physicians. I would anticipate that it would grow, but we can't play a role in that growth. And so that will mute that growth until we get the Cohort 8 data out, we get the ability to get this in the label for non-ambulatory patients in particular.

Our next question comes from William Pickering from Bernstein.

For DM1 and FSHD, are you seeing any difference in half-life across the 2 drugs and any implications that might have on dosing interval in a Phase III trial? We read in the protocol documents that the FSHD half-life is expected to be twice as long as DM1 5 weeks versus 2.5 weeks. Hence the question.

Louise?

Sure. We're seeing similarities because we're using the same peptide across the programs. With respect to the timing interval, we are looking at 10 weeks versus 12 weeks in terms of the dosing interval. James, perhaps you'd like to comment on how we're analyzing that in the protocol.

Yes. No, just to reiterate what you said really, Louise, that we're not expecting differential half-life between the 2 products given that they are chemically very similar, same ligand and just different siRNA cargo. And the clinical data that we've seen is largely supported by our preclinical data, but we do think that we can probably drive a little bit better efficacy than we've seen already by reducing dosing interval for 10 weeks. We will see those results as part of the Cohort 5 CM1 and the subsequent FSHD Cohort 7.

Our next question goes to Mitchell Kapoor from H.C. Wainwright.

It's Jade on for Mitchell. So just on ELEVIDYS, could you comment on the recent FDA adverse event reporting system listed fatality due to cardiac breathing issues, which was reported 3 weeks ago? And if so, how much time the lapse between the patient receiving ELEVIDYS and this incident? How old is the patient? What was their ambulatory status? And do you have any information on the specifics of their DMP mutation?

Louise?

Yes. So that was a commercially treated patient treated with ELEVIDYS nearly 14 months post treatment. So based on the available information, we analyzed it and it was deemed to be unrelated to ELEVIDYS treatment.

Our next question comes from Brian Skorney from Baird.

This is Luke on for Brian. Just wanted to get an update on your efforts at addressing AAV immunity, maybe to treat lower titer patients or eventual retreatment.

Louise?

Sure. So we've -- this data will be presented. So we have preliminary data from our Apheresis study and some preliminary data from the study with Hansa as well, indicating there is some ability to reduce titers in patients that are antibody positive. So this is something that we've paused those studies for now, but something that we will certainly look to in the future and that we do see the potential to lower antibodies and have an effect, but it would need more clinical study.

This does conclude the question-and-answer session. I will now turn it back over to Doug Ingram for closing remarks.

Yes. Thank you for that. And thank you all for joining us this evening and for your very thoughtful questions. We are, as I said before, tracking through 2026 with an enormous amount of opportunity in front of us, and we have a very straightforward strategy to capitalize on that opportunity. We have 4, in my view, tremendous therapies, and our goal is to maximize the opportunity with those 4 approved therapies, first and foremost, for the Duchenne patients who benefit from them, but also for our investors.

The second, of course, is our very strong financial position. You will have seen that we were profitable on a GAAP and a non-GAAP basis. We have over $750 million in cash and investments. We were cash flow positive. If you exclude the Arrowhead payment, we'll be cash flow positive on a go-forward basis, even in our basis case with respect to our approved therapies. And all of that allows us to fund this very exciting siRNA pipeline and to do it very independently. We've got a lot there, DM1, FSHD, Huntington's disease, IPF, STAT2, STAT1, STAT3 the research programs. We're really excited about them. We've seen some great data on DM1 and FSHD to lead the way, and we're very excited at the second half of this year to share with you a more robust data still on both of those programs, which we think could potentially be best-in-class.

And the fourth pillar of our strategy is our employees. We have a really dedicated group of very seasoned expert folks who say what you will, have shown nothing but exceptional execution over these many years. And I think taking those 4 pillars into account, we have one of the most exciting opportunities in front of us that we've had as an organization in our long history. And I look forward over the course of this year to sharing more information on our execution and some of our milestones.

And with that, have a lovely evening, everybody.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

Good morning, and welcome to Sarepta's preliminary data readout of its Phase I/II studies for DM1 and FSHD. As a reminder, today's program is being recorded. At this time, I'll turn the call over to Doug Ingram, Sarepta's Chief Executive Officer. Please go ahead.

Thank you, Shannon. Good morning, everyone, and thank you for joining our first readout of our clinical data from our programs for FSHD and DM1. In a moment, you will hear from our President of R&D and Technical Operations, Dr. Louise Rodino-Klapac; our Chief Medical Officer, Dr. James Richardson; and during our Q&A session, our President and Chief Operating Officer, Ian Estepan; and importantly, our Chief Scientific Officer, Dr. Rachael Potter. But before that, let me make a very -- a few very short introductory remarks. Now first, I must remind you that we will be making forward-looking statements today, so please refer to our various public filings for the risks and uncertainties that come when making predictions about the future.

Sarepta has long been committed to improving and extending the lives of families with Duchenne muscular dystrophy. And with our 4 approved therapies and our ongoing research, we will continue that mission with all of the passion, dedication and expertise we have built and demonstrated to date.

If the results we present today are further confirmed in upcoming readouts, SRP-1001 and SRP-1003 hold the promise of changing the treatment landscape for these debilitating diseases. And we are as exhilarated by this new chapter as we remain fiercely dedicated to the Duchenne community that we serve. As we all know, both DM1 and FSHD are life-limiting muscular dystrophies without adequate therapy today. What is also common for both is that each involves a monogenic mutation that results in the presence of either a toxic mutant mRNA or toxic protein that causes system-wide downstream harm. In this context, the goal of a disease-modifying therapy is to remove as great an amount of the mutant protein or mutant mRNA as is possible.

As we contemplated the Arrowhead partnership back in late 2024, what got us excited about these programs from all of the animal models was the potential of the TRiM platform's unique approach to drive enhanced muscle concentration, often one of the crucial impediments to the effectiveness in muscle programs, to drive efficacy with a strong next-generation siRNA target engagement and to offer an improved safety profile, which in addition to a better [risk-benefit profile] should permit us to continue to dose escalate without the dose-limiting toxicities that have to set some other approaches that have been taken.

The clinical experience you will see today is, of course, early and thus limited, but consistent with the animal models, it strengthens the proposition that SRP-1001 for FSHD and SRP-1003 for DM1 could be best-in-class therapies to treat these difficult and life-limiting diseases. First, our clinical data to show -- data to date shows that the TRiM platform's alpha-V-beta-6 integrin targeting ligand drives multiples greater construct into the muscle than other approaches with dose-dependent increases in plasma and muscle concentration and no saturation of siRNA uptake to date.

While early and limited, we are seeing even at 1 dose, good target engagement and positive impacts on biomarkers. And to date, we have seen no dose-related safety signals that limit our ability to continue to dose escalate. Again, I will emphasize the obvious, these data are early. We will have more evidence later this year as we present our more cohorts and the multi-ascending dose data, but we are very excited with what we have seen to date, which strengthens our conviction in the potential of both SRP-1001 and SRP-1003. And with that, I will turn the call to our President of R&D and Technical Operations, Dr. Rodino Klapak. Louise?

Thanks, Doug, and good morning, everyone. Shortly, I'll turn the call over to our Chief Medical Officer, Dr. James Richardson, to go through the proof-of-concept data for FSHD1 in myotonic dystrophy type 1 or DM1. First, I'd like to take a few moments to highlight our rationale and our enthusiasm for the siRNA platform. Today is an important day for Sarepta and for the FSHD1 and DM1 patient communities as we share with you the progress we've made in advancing our programs and the foundational science that underpins them. From the very beginning and as we have assessed numerous approaches, programs and data, Arrowhead programs became the obvious choice for us as we thought about our future, grounded in making a difference in the lives of rare disease patients by leveraging the best science and continuing our leadership in neuromuscular rare diseases.

Our commitment, mission and values are steadfast, including our continuing leadership and long-term focus on rare diseases, including Duchenne, having achieved approval of 4 therapies to treat the disease and its ultra-rare genetic subtypes. Next, we are building on our expertise in neuromuscular disease to expand and treat neurodegenerative diseases with unmet needs. We are developing technologies where the foundational science is well understood, the proof of concept is established and the mechanism of action is validated and knowing that every day, we allow the science to lead our mission to serve patients. We believe the targeted RNAi molecular TRiM platform is applicable across a wide variety of tissue types and capable of deep and durable target gene knockdown.

The potential strength of this technology has been demonstrated in preclinical studies across multiple tissue types. This is why we have confidence that our TRiM-based therapies could be truly differentiated and best-in-class approaches. While RNA therapies hold tremendous potential, challenges in delivery and dose-limiting toxicity have been an obstacle for maximizing the therapeutic benefit of these molecules. To overcome delivery challenges we often see with RNA therapies, the TRiM technology employs proprietary tissue targeting ligands. This combination of siRNA chemistry and its ligand delivery platform are designed to enable us to achieve robust knockdown of overexpressed mRNAs and proteins associated with many neuromuscular and CNS-related diseases and reach areas of the body that are traditionally difficult to penetrate, including muscle and deep brain.

Specialized linker chemistries are designed to provide stability to prove efficacy and PK/PD structures such as lipids enhance delivery. Now this slide highlights the unique siRNA mechanism deployed by the TRiM platform. What you see in this graphic depiction is siRNA taken up by tissue and into an endosome by a specific ligand. That ligand is important for creating metabolic stability and efficient RNA silencing complex or RISC loading essential for enhancing efficacy. More specifically, native siRNA is rapidly degraded by nucleases and can activate immune responses. TRIM incorporates chemical modifications with the goal of improving nuclease resistance, reducing immunogenicity and maintaining high affinity for RISC.

RISC is a ribonucleo protein complex that uses siRNAs or micro RNAs as templates to recognize and silence complementary mRNA targets, which serve as a key regulator in gene silencing or knockdown. These modifications are designed to ensure the guide strand is loaded into RISC for efficient gene silencing, enabling greater potency since the catalytically active RISC cleaves multiple targeted mRNAs. Further, we are applying stabilizing chemistries at the 5 prime ends of both guide and passenger strands to resist 5 prime exonucleases during trafficking and loading. The 5 prime terminal phosphate on the guide is crucial for domain binding and RISC loading to drive potency and durability.

In summary, by targeting miRNA directly, we believe these therapies can target any disease-causing mRNA or protein, thereby increasing the number of potential drug targets. Importantly, using siRNA rather than, for instance, an ASO should be far more potent since the catalytically active RISC repeatedly cleaves multiple targeted mRNAs and is not limited to available RNaseH1 as is the ASO. As we all appreciate, greater muscle uptake has been associated with better efficacy and clinical outcomes. This slide shows we are encouraged by the potential of our targeting integrin alpha-v-beta-6 What's particularly exciting about these data is the ability of alpha-v-beta-6 integrin to highly express in muscle, making it optimal for targeted siRNA delivery, which we believe will result in enhanced efficacy and clinical impact to the patient.

As shown here from published literature, TfR1 was able to bind to only approximately 5% of available receptors at any one time versus alpha-v-beta-6 which was able to bind to approximately 40% of available receptors at any one time, resulting in higher muscle expression than TfR1. The binding capabilities of alpha-v-beta-6 led to how we established our goals for advancing SRP-1001 for FSHD and SRP-1003 for DM1 in our first-in-human studies. This slide summarizes why we're excited about the potential of our integrin targeting ligand to produce best-in-class therapies for FSHD and DM1. Like TfR1, integrin receptors are not exclusive to one tissue, but are highly expressed throughout the body. Also, like TfR1, they are actively tracked between the cell surface and endosomal compartments through relatively well-understood pathways.

Nonclinical data show that targeting these integrin receptors via small peptides leads to enhanced skeletal muscle uptake compared to using a much larger TfR1 antibody. Further, the peptide targeting integrin shows better muscle uptake compared to the TfR1 monoclonal antibody and siRNAs are more potent than ASOs due to the mechanism of action and stability of siRNA to categorically degrade more mRNA transcripts as compared to the RNA-H1dependent mechanism of ASOs. Lastly, it's important to note that nonclinical data supports a potentially large safety margin for siRNA integrin peptide conjugates. Others using TfR1 monoclonal antibodies to deliver siRNA to muscle have halted at lower doses and have seen some issues with anemia. The TfR1 fragment antibody appears to have the same limitations.

Now on this slide, you will see the preclinical validation of our scientific hypothesis and the power of the TRiM technology bearing out to support both our SRP-1001 therapy to treat FSHD1 and our SRP-1003 to treat DM1. The data demonstrates 2 important points in nonhuman primates and rat models. First, as we dose escalate across 5 doses, we see an absence of saturation, which means the drug has the potential to achieve maximal therapeutic effect. Secondly, a dose-dependent increase in plasma is observed, which should enhance -- enable enhanced muscle delivery and strong PD effect.

Now further preclinical supportive trend is shown here, specifically to SRP-1003 for DM1. An increase in plasma exposure has translated into enhanced dose-dependent delivery to the muscle, resulting in robust target engagement and maximal DMPK mRNA knockdown. Enhanced muscle delivery, robust target engagement and maximal knockdown represent the gold standard for our disease categories. We are thrilled to see our scientific hypothesis bearing out in this way as a potentially differentiated approach to tackling FSHD and DM1. And I'll now turn the call over to our Chief Medical Officer, Dr. James Richardson, who will share our single ascending dose or SAD study results. James?

Thank you, Louise, and good morning, everyone. I'm very happy to share with you the clinical results from our 2 lead siRNA-based programs to treat FSHD1 and DM1. Specifically, as these are first-in-human studies, we will discuss the data we observed on safety, muscle concentration and evidence of impact on pathways known to drive pathology in these 2 diseases. I also intend to highlight that these preliminary data build on our preclinical evidence that our proprietary approach could lead to potential best-in-class treatments based on the ability of the alpha-v-beta-6 ligand to provide superior muscle concentration to transferrin-based approaches without dose-limiting toxicity.

As you are aware, this is our first readout from these ongoing and actively enrolling studies, and these data are necessarily limited by the stage of development. The data available comes predominantly from the single ascending dose portions of both of these studies. For this upcoming FSHD section, we have data on muscle PK for cohorts 1 to 3 and DUX4 gene expression. The latter is analyzed as a pooled treatment arm due to the sample size availability. Overall, data availability is driven by the stage of the study recruitment, loss of data due to study conduct issues and the availability of muscle tissue for retesting as we transition from fit-or-purpose assays to validated assays suitable to support regulatory submissions.

These very promising data that will be built upon in the second half of this year when we plan to release data from the currently enrolling MAD cohorts. To begin with FSHD, it's important to understand the disease and its impact on the body. FSHD is a rare genetic disease and one of the most prevalent forms of muscular dystrophy. It causes weakness in the skeletal muscles that classically begins in the face and scapular girdle. And while progression is variable, progressive weakness in the upper limb, pelvic girdle and abdominal and leg muscles usually follow. It is an autosomal dominant condition, meaning that the child and affected parent has a 50% chance of inheriting the disease.

So 10% to 30% of cases occur in the absence of a family history, secondary to spontaneous mutation in the gene. No treatments currently exist. What this slide shows -- if we can move on to the next slide. Thank you. What this slide shows is that FSHD is caused by genetic mutation of the double homeobox protein 4 gene, also known as DUX4 on chromosome 4 that leads to abnormal activation of the DUX4 gene and expression of the DUX4 protein. DUX4 is a transcription factor, meaning that it has an impact on the expression of multiple other genes within the muscle. It is normally only expressed in muscle during embryonic development and its later activation in FSHD essentially switches the intracellular environment of that muscle fiber back to the embryonic stage. An environment that is helpful during embryogenesis is toxic for muscle fiber in a child or adult and leads to muscle degeneration.

This underlying pathology is well understood and the pathological role of DUX4 in the progression of the disease is well accepted. Our lead program, SRP-1001, is designed to reduce or knock down the production of DUX4 protein in skeletal muscle in patients living with FSHD1. Our Phase I/II clinical trial is a combined single ascending, multiple ascending dose, randomized placebo-controlled trial in participants aged 16 through 70. For your orientation, we normally dose this product by total drug dose, but to allow better comparison to other products in development, we show here the siRNA doses. So for example, for Cohort 1, the 1.02 mg per kg siRNA dose shown here equates to our per protocol total drug dose of 1.5 mg per kg. These are the baseline characteristics showing balance across cohorts with a baseline clinical severity score representing moderate disease.

Let me now share the clinical data. So here, you see the plasma exposure at 4 dose levels up to an siRNA dose of just over 8 mg per kg, roughly 4x the siRNA dose of the further advanced clinical siRNA program in this disease space. This dose-dependent linear increase in plasma exposure supports our hypothesis that we can dose escalate without saturation or toxicity. As mentioned, and as you should all appreciate, delivering drug to the muscle in a robust way should make an important difference in what constitutes clinical relevance and impact to patient health. Building on the dose-dependent changes in plasma exposure, what you're seeing here on the left is a dose-dependent increase in muscle concentration up to an siRNA dose of 4.08 mg per kg. A single dose of SRP-1001 measured at 42 days after dosing, mediates a sixfold higher concentration of siRNA than multiple doses of a transferrin targeting ligand siRNA approach measured 30 days after the last dose.

Earlier in the presentation, Louis spoke of the power of our alpha-v-beta-6 integrin targeting ligand. These data support our scientific hypothesis that this approach enables much greater siRNA muscle delivery with no evidence of receptor saturation. This is distinctly different from what has been observed in transferrin targeting ligand approaches used in FSHD and DM1, where absolute muscle concentrations are significantly lower. The potential to drive high muscle concentrations without concerns that will saturate the receptor and without dose-limiting toxicities offers a potentially differentiated approach that may be of important therapeutic relevance in treating FSHD.

As discussed, DUX4 protein leads to a misregulation of a number of genes, creating a myotoxic environment for the muscle. What you're seeing here on this slide is pooled data from the 3 lowest single ascending doses looking at the correction of erroneously expressed DUX4 regulated genes following the administration of SRP-1001. From left to right, you see a 4, 6 and 8 gene composite panel. Importantly, the 4 and 6 gene panels are comparable to Avidity 4 gene and ReDUX panels being composed of the same DUX4 regulated target genes. You see a single dose of SRP-1001 is providing suppression equal to or in excess of 90% across all 3 panels when adjusted to placebo.

To our understanding, this represents the greatest DUX4 gene reduction in the field observed to date. Creatine kinase is a well-established biomarker of muscle injury and therapeutic effect. This pool analysis of the 4.08 mg per kg and 8.17 mg per kg doses of SRP-1001 versus placebo shows a 33% reduction in creatinine kinase, providing a proximal measure of the impact of SRP-1001 on muscle health after a single dose. SRP-1001 has demonstrated a favorable safety and tolerability profile to date. Of note, the majority of adverse events were mild to moderate and most have resolved. One serious adverse event unrelated to treatment was reported.

This was chest discomfort, 78 days post a single dose of SRP-1001 in a patient with multiple RISC factors for coronary artery disease. The diagnosis made by the treating physician was of an unstable angina or missed acute coronary syndrome. With this early exposure, there is no discernible dose-dependent or idiocratic safety signal. No treatment-emergent events have occurred in 20% or more of patients and no treatment-emergent adverse events led to death, study drug discontinuation or study discontinuation. The strong safety profile so far exhibited by SRP-1001 provides a foundation for which we will continue to dose escalate, supporting our hypothesis that higher dosing could result in greater knockdown and therefore, greater functional benefit.

So let me summarize what we've observed in the available clinical data to date and what we believe supports the unique attributes of SRP-1001. Favorable safety and tolerability profile, dose-dependent increase in plasma exposure up to the highest dose cohort, superior delivery to muscle enabled by differentiated approach with the alpha-v-beta-6 integrin, including no saturation of drug uptake and potentially unprecedented suppression of DUX4 regulated genes with a rapid and robust reduction in CK.

Moving now to DM1. DM1 is the most common form of adult onset muscular dystrophy. It is caused by a repeat expansion in the DMPK gene and presents as a multisystem disorder that affects skeletal and smooth muscle as well as the eye, the heart and in particular, normal electrical conduction within the heart, the endocrine system, the gastrointestinal system and the central nervous system. There is currently no cure and there are no disease-modifying treatments available. As I just mentioned, DM1 is driven by an expanded CUG trinucleotide repeat in DMPK transcripts, causing mutant DMPK mRNA to accumulate in the nucleus and disrupt normal RNA splicing.

As a result, for any therapy to be therapeutically effective, it must effectively target and knock down or silence DMPK in the target gene. We believe our therapy SRP-1003 has the potential to achieve exactly that. Study SRP-1003, 101 is a first-in-human Phase I/II randomized placebo-controlled SAD/MAD clinical trial being conducted in participants aged 18 to 65. Today, we have data available from Cohort 1, and we'll be focusing on the muscle concentration. We have also seen impressive impact on DMPK knockdown in this cohort. Right now, we're seeing a 50% reduction placebo adjusted. But given the small end, some variability in placebo and that 50% would actually exceed our preclinical predictions, we believe it is more appropriate to defer a definitive assessment until the MAD data is in hand. These are the baseline characteristics showing balance across the cohorts.

Next slide. Like we saw with FSHD, we see a dose-dependent increase in plasma exposure. While we are limited today by the availability of muscle samples, given the use of identical targeting ligand and identical target organ in skeletal muscle and now with a very similar plasma exposure profile, we believe that with the availability of additional samples later this year, we will replicate the dose-dependent increase in muscle concentrations seen in FSHD in DM1. Focusing on the muscle concentration provided at the lowest dose of SRP-1003, we observed a manyfold higher muscle concentration than seen at comparable doses of a clinical stage transferrin monoclonal antibody targeted siRNA and a Fab tansferrin-targeted ASO-mediated approach.

We know from published data that the mAb approach shows a very modest increase in concentration with increasing dose, which likely explains the limited improvement in PD markers with dose. Conversely, a Fab approach has shown a more robust increase in muscle concentration with increasing dose, but again, a limited dose-related response in PD. This is likely driven by the reduced efficiency of the ASO approach versus the efficiency of siRNA. SRP-1003 has demonstrated a favorable safety and tolerability profile to date. The majority of adverse events were mild to moderate in severity, 9 adverse events were assessed as related to study drug. All were mild and resolved without sequelae. No adverse events occurred in 20% or more participants.

One unrelated fatal serious adverse event occurred in Cohort 1 due to a cardiac arrhythmia. The event occurred several weeks after a single low-dose administration of SRP-1003 and is aligned with a recognized RISC in the natural history of DM1. The investigator, sponsor and an independent corner each concluded the event was unrelated to SRP-1003. Subsequently, more than 60 patients have been treated with either SRP-1003 or SRP-1001 without a further adverse event of arrhythmia or any other emergence of a pattern suggestive of a treatment-related safety signal. Further, it is important to note that because the fatal event occurred early in the study, it was included in and reviewed as part of the subsequently approved clinical trial application by regulators in the U.K., EU and Canada. Based on these observations, there is no indication to date of a dose-related safety signal that would preclude continued dose escalation.

In both diseases, the alpha-v-beta-6 ligand has shown the clinical potential to drive higher muscle concentrations without dose-limiting toxicity. In FSHD, this differentiated delivery is driving early evidence of an impact on key markers of pathology. In the coming year, we will have the opportunity to present data from the MAD cohorts from both programs, along with data from further validated markers of the therapeutic impact, building on this promising early data in both FSHD and DM1. Before turning the call over to Doug for closing remarks, on behalf of Sarepta, I'd like to extend our thanks and gratitude to the FSHD and DM1 patient communities and the clinicians who participated in these trials. Participation in clinical trials is how science moves forward, especially for diseases without treatment. We are grateful for your participation and courage. Doug?

Thank you, James. SRP-1001 for FSHD and SRP-1003 for DM1 represent the first clinical readouts from our Arrowhead partnership. To remind you, we have 5 programs in clinical development right now. We have FSHD and DM1. We have IPF, SCA2 and Huntington's disease. We have 2 other programs in animal testing, and we have 6 research programs that make up this portfolio of siRNA. Our 5 clinical programs alone offer potential therapy to as many as 160,000 patients in the United States and multiples greater than that worldwide.

Looking forward, we plan to present updated data on SRP-1001 and SRP-1003, including more PD and PK data from the MAD arms of these studies in the second half of this year. With respect to Huntington's disease, a devastating and largely untreated condition impacting as many as around 40,000 patients in the United States, we will commence dosing in the second quarter, and we anticipate having proof of biology data to present in the first half of 2027. And with that, Shannon, let's open the line for questions.

[Operator Instructions] Our first question comes from the line of Anupam Rama with JPMorgan.

Can you clarify or maybe I misheard, did you comment that you're planning on dosing higher for 1001 in FSHD? And can you speak to the plans for this?

Yes. Thank you for that question. James, maybe you could highlight where we are in our dosing in the -- for FSHD in terms of the MAD dosing.

Yes. No, absolutely. Thank you for the question. So the data we largely presented here was cohorts 1 and 3, which is a maximal dose of around 4 mg per kg of siRNA. We have opened and actually fully recruited both a SAD and MAD cohort up to 8 mg per kg of siRNA.

Our next question comes from the line of Konstantinos Biliouris with Oppenheimer.

Congrats on the promising data here. Maybe one question on the differences between the number of patients across the different markers. From what I understand, based on the differences, some of the patient data are not shown. Can you talk a little bit about those patient data and whether we should expect to get those data in the second half of this year? Congrats again.

Sure. Just to clarify your question. So you're just asking for both programs, how many patients we've dosed and what we expect later this year? Just clarifying.

Yes. Just in some biomarker data, the number of patients between slides is different. Maybe why, in some cases, the number is lower than others, what happened to these patient data?

Sure. James, would you like to highlight that?

Yes. No, of course. So just to answer the first part of the question. So we dosed 36 patients in DM1 and 56 patients in FSHD. What you're seeing here is the available data we have. We have been transferring across to a fully validated regulatory-ready set of assays. That's caused some data dropout, particularly where samples have been insufficient to rerun the second time, now though have been inappropriate to run. So that's what's driving the difference in delta. I think overall, though, we've only included numbers that I think are represented overall of our data, and I think we're very confident in the conclusions that we've drawn.

Our next question comes from the line of Brian Abrahams with RBC Capital Markets.

I was wondering if there's anything more you could tell us on the baseline characteristics for the patients in the FSHD part of the study. Maybe just how that compares to studies from competitors on things like disease severity and clinical scores. And then just, I guess, how you think functional outcomes will end up looking relative to competitors, just given the higher PD effects you're seeing on the DUX4 related genes -- DUX4 regulated genes.

Thanks for that. James, would you want to highlight the FSHD baseline characteristics?

Yes. So our inclusion criteria for the clinical severity score was between 3 and 8, with a mean of around about 5 across the cohorts. We're using a 1 to 10 scoring scale. Avidity, I think, is a 1 to 15 score. But if you translate between the 2, we have fairly similar populations, I think both moderately severe. And I think that otherwise, the populations are fairly similar. So I think that, obviously, the sample size will be relatively small and the time follow-up will be relatively short for functional outcome. But I mean, a, we're very confident that these PD markers will carry through to function and I think could be reasonably comparable to what you've seen from the Avidity program.

Let me also comment briefly, Brian, to your point. And really, we're talking more at a sort of a predicted theoretical level. And one of the things that gets us excited about these programs is the opportunity to drive more functionality in patients both with DM1 and FSHD. And so what gets us excited about these things is these features should, as we confirm them in multi-ascending dose and beyond, should translate into enhanced efficacy. So we all know that one of the most difficult things in muscle-directed therapies is getting to the muscle and getting into the muscle. And so seeing really enhanced muscle concentration validates what we would imagine based on the preclinical work and one of the reasons we got so excited about the Arrowhead deal, it should result in efficacy.

The same with the idea that using the integrin receptor, avoiding things like anemia that come with using the transferrin receptor and therefore, avoiding some of the dose-limiting toxicity that you might otherwise have should allow us to continue to dose up, which again should -- if all is consistent with what we've seen preclinical result in enhanced efficacy. And finally, the fact that we're using an siRNA approach and in the case of the TRiM platform, a next-generation version of the siRNA approach, we think is going to enhance efficacy because, as we know, siRNA is a really potent, efficient way to knock down through the use of RISC, which has a real fast recycling ability and the fact to knock down a ton of mRNA.

So again, we don't want to -- we can't predict exactly what we're going to see going forward, but we have a lot of excitement about what we're seeing so far. And it really does relate the overall RISC benefit, but really to the potential benefit of this therapy.

Our next question comes from the line of Andrew Tsai with Jefferies.

So like you said, we're going to get more MAD data in second half 2026 now. So what exactly are your go/no-go thresholds or criteria to advance both assets into pivotal studies? For example, if you see strong DUX4 or continue to see that or if you see strong splicing vHOT changes, is that enough to you? Or are you waiting for longer-term outcomes data like 6-minute walk, for instance?

Thank you for that question. I'm going to make a few comments, and I'll turn it over to James. I think what we're seeing so far is that we're extremely excited about what we had. I think what we're seeing now in the SAD data was really one of the things that we are looking for in terms of muscle concentration. Doug spoke to it, but the fact that we are achieving these high levels of muscle concentration at low doses with just one dose was really significant, and we're not seeing dose blending toxicity.

So we continue to dose up. And our preclinical data shows that there's a correlation with muscle concentration and the PE effect, which we're seeing early signs of clinically. So in terms of hurdles and what we would like to see to move these programs forward, I think we're really happy where we are. Obviously, we're going to -- we're excited to see the MAD data as well. And I'll have James talk about what we're looking for in terms of data from that. But in terms of where we're at right now, we're really pleased with the status of the SAD data. James, do you want to add?

Frankly, I mean just very much the same. I think we're fantastically excited by the PK and the PD data we've seen already at dose. We'll be adding more data at higher doses, assuming we continue to see the same pattern. I think that we would be -- it would be a very easy decision to move this forward. I think specifically in on both programs, in terms of the biomarker versus functional data, I think given the nature of FSHD and the well-established natural history supporting the use of both the gene suppression biomarker and circulating biomarkers that we'll be presenting later this year.

They are likely to be the stronger sign to move the trial forward rather than efficacy, which is going to be, I think, in a slowly progressing disease, a lagging marker. But I think based on what we've seen so far, we're extremely likely to move these programs forward. For DM1, again, very well-established data supporting the predictiveness of biomarkers like CASI and then early functional change like vHOT. These will be things that we're looking at in the second half of the year and will, I'm sure, give us the reassurance that what we've seen today is indicative of what we think are going to be differentiated therapies in the market.

Our next question comes from the line of Ellie Merle with Barclays.

Can you just elaborate a little bit more on what you're seeing on the DMPK reductions? I think you mentioned a 50% reduction, but just could you elaborate on which cohorts that was seen in and your expectation for what you might see at higher doses?

James, do you want to reiterate?

Yes. Thanks, Louise. So we saw a placebo-adjusted change of just over 50% in Cohort 1. I think based on the fact that the sample size is relatively small and that these estimates are a little higher than what we are predicting, we are, A, extremely excited, but B, keen to validate these findings in a larger sample size with that data later in the year.

Our next question comes from the line of Yigal Nochomovitz with Citigroup.

Can you hear me? I just had a question on the way you did the bucketing for these biomarkers, the [CS4, the CS6 and CS]8 for 01. Obviously, there's some unique ones there in the list in the footnotes and then there's some that are overlapping, obviously, across all of the different buckets. So could you just help elaborate on the significance of the way you did that analysis and how one should interpret them perhaps differently or the same? I mean, obviously, it all points in the same direction to a very good effect. I'm just wondering if there's any specific interpretations regarding the choices of the biomarkers for each of those groups, [CS4, CS6 and CS8].

Yes. Thank you for that. I'm going to have Rachael comment on the gene panel.

Thank you. Yes. So we wanted to evaluate a comprehensive look across the 4, 6 and 8 gene panels. And again, as James mentioned, the 4-gene panel is the same as the Avidity panel and the 6 gene panel is the same as the ReDUX panel. All of these have similarities across them. The 8 gene panel has 2 additional genes included. But importantly, they're all DUX4-related genes. And some are more tightly and specifically linked to DUX4 activity while others show greater biological variability.

And as DUX4 is a transcription factor, it directly affects gene expression related to cell cycle, apoptosis, inflammation and immune response. So that's why we're looking across all 3 panels to capture pathway level modulation and reduce the impact of variability from individual genes to give us a comprehensive look.

Our next question comes from the line of Ry Forseth with Guggenheim.

This is Ry from Debjit's team. For the TRiM platform, how might we think about skeletal muscle concentrations as a proxy for brain and/or cardiac tissue exposure? And for the DM1 muscle concentrations, can you differentiate between nuclear versus cytoplasmic exposure? And for the second half data, will you have foci reduction data in the context of DM1?

Sure. I'm going to take that in 2 parts. So just I'll comment on the first part of your question on the TRiM platform, and then I'm going to turn it to Rachael to talk about the second part with DUX4. So in terms of the TRiM platform, for these 2 muscle programs, we're using alpha-v-beta-6. In terms of other programs that we are looking at, we're using different targeting ligands using the transferrin receptor in some cases, with the subcutaneous delivery.

And so for each program, we're being very specific about which targeting ligand we're doing. In terms of any potential cardiac programs, that would be a different targeting ligand as well. So we're being very specific and thoughtful around both the target tissue, the route of delivery and the intended efficacy of that particular therapy. For Huntington's, for example, we are using a subcu delivery with the transferrin receptor to be able to get into the deep brain regions. Rachael, do you want to comment on the DUX4?

Yes. So your question was about the nuclear versus cytoplasmic knockdown. And so what we've seen in our previously disclosed data with Arrowhead is that there is an equivalent reduction in knockdown in animal models in the nucleus versus the cytoplasm. So we're confident that this knockdown is nuclear. We've also tested in a DM1 animal mouse model that has human mutant DMPK in the nucleus, and that shows a greater than 50% reduction in the nucleus that corresponds to a 75% restoration of missplicing. And so we're very confident in the siRNA approach is effective at targeting the nuclear DMPK and root cause of the disease. And then in terms of the DM1 foci reduction, we're evaluating the opportunity to look at this, but we have data preclinically that demonstrates a nice reduction in the RNA foci.

Our next question comes from the line of Ritu Baral with TD Cowen.

This is Joshua Fleishman on the line for Ritu. Congratulations on today's data. Could we please go into more detail on the loss of participants due to study conduct issues? How many patients and what specific issues with conduct? And then I'm curious for the second half '26 data, what specific functional endpoints should we be expecting for FSHD?

James, I'm going to turn that one to you.

Yes. Thank you, Louise. So thank you for the question. So the participants excluded were essentially excluded based on missed dosing. So we had a very small number of missed doses due to administration errors in both the DM1 and FSHD study. So these patients have been excluded on the analysis you've seen. It's as I said, I think it's 3 patients in DM1 and a similar number in FSHD.

And the second part was on the functional outcomes in the MAD.

So in the MAD study for FSHD, we should be looking at a wide range of functional outcomes. I think essentially the standard panel, including Timed Up and Go, Reachable Workspace, 6-minute walk test. And I think that measures of muscle strength. So I think these will all be interesting signals. I think as I said earlier, for FSHD is a slowly progressive disease. The significant changes in functional outcome are likely to be seen over a longer-term, larger study and a lot of our decision-making will be made from a biomarker perspective, building on what we've seen, I think, which is the very high muscle concentration with the alpha-v-beta-6 approach and I think really impressive PD data within FSHD.

Within DM1, again, similar, I think, battery of TFTs -- sorry, time function tests, including Timed Up and Go and 6-minute walk test and obviously, vHOT being the, I think, differentiated outcome between the 2 programs being something that I think we will likely see a signal on. We've already seen some positive signs in vHOT based on a very small number of single ascending dose. I'd be confident that we'll be able to produce more robust vHOT data in the DM1 program at the end of this year as well.

Our next question comes from the line of David Hoang with Deutsche Bank.

I'm just curious about the correlation or maybe the relationship between the DUX4-related gene knockdown and the CK reduction that you're showing here. And the knockdown, I think, is obviously pretty impressive. CK looks maybe more along the lines of what competitors have shown. Any thoughts on this relationship and would potentially -- you expect CK reduction to deepen with multiple doses?

Yes. Thank you for that. So just a few comments on the knockdown. I think what we're seeing in terms of the DUX4-related genes, we're really pleased with. As you mentioned, I think the level of correction that we're seeing is significant. I'll turn to James to talk about the CK levels in DM1 in FSHD patients and what we think although we're encouraged by that signal, we think that there are -- we're looking at the totality of data and not CK in isolation. But James, would you like to make a few comments on in FSHD?

Yes. So I mean, I think that first and foremost, that the sign in CK, I think, is an incredibly strong signal of proof of concept with this treatment, which I think after a single dose administration is really, really something to be excited about with this program. I think in terms of the biomarker itself, there is some inherent variability with that at both the patient level and a visit-to-visit level. I think that you can often find yourself confounded with treatments in the neuromuscular space with CK because obviously, an effective treatment increases the patient's ability to ambulate and do tasks that they may not have been doing historically and that itself can drive the CK up.

So I think that CK should be viewed as to me, a more qualitative proximal signal of the drug acting on muscle health and something that really supports the continued development of the program. I think in terms of an objective biomarker that is less variable from patient to patient and is something that I think is less prone to the subsequent therapeutic effects of the drug in terms of increased mobility and the like, I would veer towards the gene suppression. I think that in both ways, is extremely strong and promising data for a single dose administration program. I would probably limit the comparison between programs based on the CK given the variability of that biomarker.

Our next question comes from the line of Mike Ulz with Morgan Stanley.

Maybe just one on FSHD. Can you just talk about the dosing frequency you're exploring in the MAD cohorts? And just given some of the potency we're seeing early on here, is there opportunity to even lower that frequency in the future?

Thank you. James, would you like to take this one?

Yes. So the current dosing paradigm is 12 weekly in the MAD study based on the data we're seeing here, we're going to amend that to 10 weekly. That would be also true in the DM1 program.

And just Mike, beyond that, just so we're clear, yes, there is a potential to have an enhanced more moderated frequency of these therapies. But we are taking a careful look at that because if you think about the 2 issues, basically convenience and efficacy, we really want to ensure as we go forward that we're prioritizing efficacy. So we might have an enhanced benefit over frequency versus other programs, but we're going to take a careful look at this, and we're always going to choose maximal efficacy over convenience, if that makes sense, Mike.

[Operator Instructions] Our next question comes from the line of Uy Ear with Mizuho.

Congrats on the early data. It looks very promising. Maybe just help us understand the regulatory pathway that maybe you're considering would you -- after the MAD data, would you either start a Phase III immediately? Or would you perhaps consider another route such as maybe an expansion cohort that could be registrational?

Yes. Thank you for that question. James, would you like to comment?

Yes, absolutely. I think that we are continuing to learn and understand both our science here and the regulatory environment. But from -- in terms of a development plan perspective, we think that the most appropriate way is to move forward to Phase III and do that in such a way that gives us the flexibility to pursue multiple different regulatory approaches to approval, and that would be true globally.

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

This is Tommy, on for Salveen. Congratulations on these results. We just had a follow-up on the registrational trial question. Wondering just checking in at this point, how you're thinking about regulatory discussions to that end and potential to accelerate your time to market. And then just a quick one. You mentioned that you had been doing some assay work. Maybe if you could go into more detail behind that and your confidence in these now.

Sure. First, James, maybe you could comment on any other comments in terms of the registrational trial. And Rachael, if you just want to comment generally on the assay approach across the board.

Yes. So we'll be looking at the MAD data later on this year and then taking that along with the protocol for the Phase III that we're currently working up to global regulators, including the U.S. to kick off Phase III trials in '27 in both indications, assuming the data remains as strongly positive as it currently is.

Can I just -- before Rachael goes, let me just amplify what Dr. Richardson is saying. We have a lot of work to do. We want to start a Phase III next year. Nobody on this call will be surprised to hear that we want to find the most urgent, but thoughtful pathway to bring these therapies to patients waiting for them. DM1 and FSHD like DMD are debilitating degenerative diseases, and we want to get to them as fast as possible. With that said, we're going to learn from others, but we're going to do our own work as well. We have a unique expertise broadly in muscle programs.

We need to learn even more about DM1 and FSHD to match what we already know about DMD. And on top of that, we need to talk to regulators. So we've got a lot of work to do, but you won't be surprised to know that our overarching goal is to get these therapies -- get the evidence for these therapies as rapidly as possible and get to these patients, both in the U.S. and around the world as rapidly as possible. But we don't have a lot of detail on that because humbly, we've got a lot of work to do before we commence our Phase III in both of these programs. I'm sorry, and then Rachael, I apologize for jumping in before you.

Thanks, Doug. We work to transition the assays that were fit for purpose from our partners into regulatory approved and validated assays. And so that was what was mentioned for the PK and the PD assays as we move forward.

Our next question comes from the line of Andy Chen with Wolfe Research.

This is Emma on for Andy. You touched on the targeting ligands, but can you share any additional insight on how consistent muscle uptake is across the different muscle groups, just given how these diseases affect different regions?

Yes, it's a great question. So obviously, the strongest data we have is from preclinical data. So Rachael, perhaps you could touch on what we're seeing across multiple muscle groups preclinically.

Thanks, Louise. Yes, we see a consistent uptake with the integrin-based approaches across lower limb and upper limb skeletal muscles as well as the diaphragm and the cardiac muscle. And so it's very consistent across the skeletal targeted approach.

Our next question comes from the line of Yun Zhong with Wedbush.

Congratulations on the positive initial data. Just wanted to confirm, did I see it correctly that you pulled different doses of siRNA when looking at gene panel analysis. Did you see a dose-dependent target gene knockdown? And have you seen any signals suggesting that the knockdown efficiency may approach in plateauing, please?

So for the -- for that target gene knockdown based on the number of samples, we did a pooled analysis across different doses. The N is too small to do a dose response at this point. So when we look to -- for the additional MAD data, we'll be looking for that. But right now, we've pooled just based on the N. Rachael, anything to add to that?

No. That's all.

Our next question comes from the line of Biren Amin with Piper Sandler.

On FSHD, did you measure for circulating DUX4? And if so, what were your observations in the SAD portion? And for the fatal arrhythmia event, I know the patients are predisposed, but have you done hERG channel studies with 1003.

Yes. So we'll take that in 2 parts. First, Rachael, could you comment on the circulating DUX4 assay potential for that? And then James, you can comment on the second part of the question.

Thanks, Louise. We are working on a circulating DUX4 assay, and we will -- we anticipate that data to be ready in the second half of 2026.

And James on the cardiac arrhythmia?

Thanks, Rachael. Thank you, Louise. Yes. So I mean, as you've rightly pointed out, I mean, cardiac arrhythmia occurs in roughly 4% of the DM1 population or fatal cardiac arrhythmia in [indiscernible] of the population annually. It's the leading or second leading cause of death in that population. It's tragic, it's not entirely unexpected. Yes, we have done studies with SRP-1001. We had ECG studies in nonhuman primates with no obvious cardiac toxicity and a tenfold safety margin at the highest dose.

Our next question comes from the line of Yanan Zhu with Wells Fargo.

This is [indiscernible] on for Yanan. So on DUX4 gene panel, I know the number is small, but can you comment on the error bar for the placebo group? It seems a little bit high.

Rachael ?

Thanks, Louise. The DUX4 expression is known to be stochastic and episodic in muscle, which introduces inherent biological variability, particularly in the small early phase cohorts. So as a result, the downstream target gene expression can fluctuate in untreated or placebo patients. And so this variability has been well recognized across the field and is often larger than differences attributable to assay platform or normalization strategy. So that is why we are adjusting for placebo approach. And so that's what's shown in the data.

Our next question comes from the line of William Pickering with Bernstein.

Congrats on the data. I have 2, if I may. So the first is on FSHD. To what do you attribute the very large jump in muscle concentration of the drug when you go from 2 MPK to 4 MPK. It looks like it's going from like 5 to 28, which is like a sixfold increase. So do you think that's reliable? And then for DM1, do you have the DMPK knockdown data for the 2 MPK and 3 MPK cohorts? I believe you said it was 50% for the 1 MPK, but just wondering how that data looked like at the higher dose cohorts.

Yes. Rachael, do you want to comment on the increase in the muscle concentration for FSHD?

Yes, happy to. So the muscle concentration in our FSHD program corresponds to what we've seen preclinically. So we were very happy to see that dose-dependent increase with the increasing dose. And importantly, we don't see any saturation demonstrated preclinically or with this early clinical data. So we're very happy to see that.

With the preclinical data, also, I want to highlight that we've seen this dose-dependent increase in muscle concentration and the relationship between the knockdown and higher magnitude of effect with the reduction in DUX4 regulated gene. So there's consistency that we're seeing preclinically into the clinical program that gives us confidence in the muscle concentration data here that we're showing.

And James, do you just want to comment on DMPK?

Yes. So as regards to Cohort 2 and Cohort 3, as we said at the start, we have had some issues with sample availability for retesting our validated assays. So we don't have DMPK data currently for -- [indiscernible] insufficient samples. Hopefully, we'll be able to provide more robust, and I'm sure we will have more robust DMPK data later this year from the MAD studies.

Can I just emphasize something that Dr. Richardson made during the presentation that we are in a lower dose, we're seeing already a greater than 50% knockdown placebo adjusted for DMPK, but you will see that it is not on any of our slides. I mean we want you to see that to know that we are seeing a very encouraging effect on knockdown for DM1, which, of course, is exciting. But we don't want you to pivot and anchor to 50%. We're going to have MAD data later this year, and we don't frankly want to set a bar for ourselves that is too high.

These are small ends. It's exciting that we're seeing such great knockdown, but really we should wait for the MAD study to get a look at DMP knockdown and the effect of DMP knockdown of multiple doses and multiple dosing. So I say that only because I don't want people to start thinking that that's the beginning, 50%. I want you to wait for the MAD data. But good news. we're seeing a nice significant impact on biomarkers. And then we'll see the full extent of the increase in knockdown as we look at the MAD data across doses and across multiple dosing.

Our next question comes from the line of Gavin Clark-Gartner with Evercore ISI.

I just wanted to follow up on the one death that happened. Could you just give us some more details on how everyone concluded this was unrelated to dosing? And was this on the first dose where this happened? Or was this like a subsequent dose in the MAD? And it's probably worthwhile to share some details on like the patient history of arrhythmia, severity of arrhythmia and maybe just a reminder on ABV6 cardiomyocyte expression.

James?

Yes, sure. Thank you for the question. So I mean we thoroughly investigated this, obviously, as you would expect, as part of our due diligence before acquiring these assets from Arrowhead. We agreed with their independent conclusions and those from the investigator and the coroner who performed an autopsy following the death, this was unrelated to treatment. I think there are really 3 key reasons for this, why we're confident that it was unrelated. I mean, first and foremost, the lack of biological plausibility, particularly at this low dose, single-dose exposure. As you rightly point out, this was the first low-dose cohort of 1.5 mg per kg or roughly 1 mg per kg of siRNA.

I think secondly, and importantly, arrhythmia is one of the most, if not the most common causes of death in DM1, an annual fatality of around -- around 4% and some cohorts have reported as a cause of death up to 40% with secondary to cardiac arrhythmia. -- sorry, that would be overall rate. I think thirdly, if you look across the data, we now dosed 60 patients subsequently at increasing doses with this platform across DM1 and FSHD without any further adverse events of arrhythmia without any other concerns from a cardiac perspective.

And I think with that and with that data package, because this data -- because this event occurred early, all that data was provided as part of the clinical trial application submitted and reviewed by regulators in Europe, the U.K. and Canada, and all of them subsequently approved the study with the current protocol. The patient in question, apart from having DM1, which as we know, is an extremely strong RISC factor for arrhythmic death had no other indications prior to her passing away, which is not unusual in this disease state. I think there was a follow-on question about alpha-v-beta-6 expression on cardiac tissue. Maybe I could hand that to Rachael.

Thanks, James. The alpha-v-beta-6 integrin ligand does target both skeletal muscles, upper limb and lower limb skeletal muscles as well as the diaphragm and the heart. We have not seen any indication of arrhythmia in nonhuman primates and with ECG studies. we have a highest safety margin at our highest dose of greater than tenfold. So we haven't seen any abuse arrhythmic signs preclinically either.

I'm sorry, let me just jump in to make sure that we've answered one of the parts of the question you had. This was the lowest dose, okay? And it was a single dose. And I know I'm just repeating what Dr. Richardson will say more eloquently, but as someone who's been involved a little bit in this disease. Just remember, 80% of DM1 patients have cardiac involvement, longitudinally, 30% to 40% of DM1 patients have arrhythmia.

And for those who are severe patients and as I understand this patient was a severe patient, the RISC in any year of sudden death from arrhythmia is somewhere in the 3% to 5%. So it's not surprising at all that the investigator or the sponsor of the DSMB independent cardiologists all concluded this was unrelated or more importantly related to the disease as obviously, so did the various regulatory bodies who subsequently reviewed this as we went into other regions and dose escalated. And remember, we've dosed a lot of patients since then. So just to be very clear about this, this is -- arrhythmia is associated significantly with DM1 sorry.

And I'm currently showing no further questions at this time. I'd like to hand the call back over to Doug Ingram for closing remarks.

Thank you very much, everyone, and thank you, James, Louis, Rachael, for your answers, and thank you all for your questions. The evidence from our SAD study -- studies in DM1 and FSHD, including exceptional muscle delivery and target engagement and dose and safety validate our decision to acquire this broad platform of siRNA therapies from Arrowhead back in 2024. We will have our next readout for these 2 programs in the second half of this year. We're very excited about that. The data continue to mature, consistent with what we have seen so far. There is a very real possibility that SRP-1001 and SRP-1003 could become best-in-class treatments for both FSHD and DM1, respectively.

And that, of course, should drive significant shareholder value. But from my perspective, not only as the CEO of a mission-driven organization, but as someone whose immediate family has been upended by multiple diagnoses of DM1. These data offer far more than that. They offer the potential, the hope of bringing a better freer life to those living with DM1 and FSHD.

From personal experience, I cannot adequately express to you the heartbreaking and frightening experience that comes to families with a diagnosis of one of these debilitating muscular dystrophies. But I can at least take some comfort in knowing that with all of the impressive progress made to date by brilliant scientists and by dedicated and passionate organizations, organizations like Avidity and like Dyne and like PepGen and like Sarepta and others, there could be no more hopeful moment in history to get this painful diagnosis. We will fight for DM1 and FSHD communities with the passion that we bring to DMD, and I do look forward to updating you all as we progress across this year. And with that, have a nice day.

This concludes today's conference. Thank you for your participation. You may now disconnect.

Thanks, everyone, for joining us at the Sarepta fireside chat at the 46th Annual TD Cowen Healthcare Conference. I'm covering analyst, Ritu Baral. And with us from Sarepta today is Ian Estepan, President and COO. Thanks, Ian, for joining us.

Let's start with ELEVIDYS and its current commercial ramp. On the Q4 call, Sarepta guided to 2026 net product revenue of $1.2 billion to $1.4 billion, noting it was comfortable with the current 2026 PMO revenue consensus estimate of $900 million. Now this implies that '26 ELEVIDYS revenue will be between about $300 million and $500 million with $500 million floor run rate if nothing else changes, whether that be sirolimus, whether it be label reexpansion, et cetera. What has changed from January to -- for you guys to amend your estimates for 2026 at least?

Yes. Well, first off, thanks for having me. It's a real pleasure. And of course, we'll be making a number of forward-looking statements. So before I get to your direct question, I think it's important to actually take a step back and think about the dynamics because one source of confusion that we've gotten feedback on is really just understanding the dynamic of a onetime therapy versus a chronically dosed therapy.

So for example, if you just looked at our current quarter that we reported, we had $110 million, times that by 4, you should be at $440 million, right? And so you really have to understand the dynamic with a onetime therapy where you're starting it from 0 every quarter, right? There is not a built-in installed base.

It's all NRxs.

Exactly.

Queue of NRxs.

Exactly. And so -- and then the other dynamic that's important to realize is the long turnaround time, which is around 6 months. So right now, we're kind of working through start forms that were written during the summer.

Got it...

And beyond...

And so that 6 months, is that longer than it was previously? And if so, for what reason?

It's traditionally been between 4 and 6 months. So it's still within that range. And so that's the dynamic that's really important because when you start from no patients each quarter, we're looking at the run rate from a start form perspective right now and using that as a base case to set our guidance. So we don't from -- so to your good point, where we obviously were comfortable around $500 million at JPMorgan. So we had about 4 to 6 weeks' worth of data from a run rate perspective from start forms, where we currently are and working through the start forms that are already in queue that's working for...

For the next 6 months...

In the next 6 months.

And then you extrapolate like if you sort of map out the next 6 months and then you flatline that, that's your $300 million?

Correct.

Okay. So if you accumulate like you take the area under the curve for the next 6 months, but then you get an inflection, that's the $500 million inflection...

Exactly. And so remember, from a calendar perspective, because there is such a long lead time, even if all the initiatives were hitting the ground running right now, right, you wouldn't see that translate to sales until 6 months later. So you're running out of just time from a calendar perspective. But from an opportunity perspective, everything is intact from the number of eligible patients who are available and the opportunity perspective.

So to that point, that $500 million assumes positive impact from the initiatives that you talked about, the ongoing sales force expansion. Can you walk us through the individual steps, like basically the delta on the sales force expansion, how long it will take to train and deploy them? Any color on where they're coming from? And is there, I guess, a unique element to expanding and detailing a $1 billion potential gene therapy that is different than $1 billion small molecules that we should keep in mind?

Yes. I mean the dynamic as it relates to the education that has to happen right now is as a onetime therapy, you are somewhat precluded from using another AAV approach going forward. Now that being said, there's a wealth of safety data and now with the 3-year EMBARK data, a wealth of efficacy data, which we see that as a drug-modifying agent, we're seeing exactly what one would expect in terms of increasing separation over time. So we're very pleased with the way that the data has panned out. Now from a sales -- so that's an important message these are the types of things that...

So the data that your reps are going out with is only going -- getting stronger over time.

Exactly. So that certainly balances the efficacy conversation. And then from a safety perspective, a lot of education to put everything in the appropriate context, right? The denominator is very important as you think about what is your overall risk from the therapy. So that's critical. And then obviously, just from -- I know that you were asking about the sales force, they're just now kind of hitting the ground running...

So they're trained...

The first wave has been hired and has been trained, but we're also doing a contract sales force that we're looking to expand to also. So about doubling from the number of reps that we currently have, and they'll be more focused on more of the peripheral sites and finding patients.

Got it. Okay. So the 50% more -- the first wave are Sarepta employees and they're -- they have hired a more technical detail. Is that fair to say? And then the doubling is actually this contract force. And you said their focus is.

It's more on the peripheral sites and patient finding.

So the lower volume sites. What sort of patient finding activity?

It's just a matter of, obviously, we've seen claims for a lot of patients, but that does not necessarily mean that they're having the conversations with physicians around -- around gene therapy or exon skipping. And so it's getting those patients in front of the physicians and getting them to a referral site and making sure they have balance in...

Got it. On your Q4 call, you guided to a slightly down Q1. What specific factors are driving that?

Yes. So from that perspective, now especially relatively late into the quarter, I think you know for each prescription has to be written specifically for each child, right? -- filled for each child because it's a weight-based therapy. And so we have good line of sight into the quarter and the kits have to be done about 2 weeks in advance. So we have good kind of line of sight from that perspective. However, what you can't account for is just the sicknesses, cancellations and things like that. And so the down 15% captures that aspect of which we just are just unknown until the patients actually get dosed.

So is that a conservative assumption of cancellations and sickness based on recent precedent like...

Yes. So we just wanted to factor in everything. We don't want to be in a position where we don't disappoint the Street. So we factored in everything in giving that guidance.

So you're assuming cancellations that maybe haven't quite happened yet.

Correct.

Okay. Got it. Got it. That's very helpful. In January, you emphasized that over the year, Sarepta's commercial goal is to detail ELEVIDYS efficacy data sets now, including the 3-year EMBARK data and less time on reestablishing comfort with the safety profile. Has that been the feedback of the sales force right now in the sense that when they go into the field that the pull on questions, the questions posed are more around the efficacy data sets? Or are they still getting questions on safety?

I think there's questions around safety, but it has to be put in context with efficacy, right? Risk benefit is always paramount whenever you're making any decision like this and even heightened as it relates to onetime therapy. So I think the efficacy data is important to balance out, but there could be any potential concerns around safety.

Got it. And what has reception been to that 3-year EMBARK data?

I think it's actually one of the best receptions one could hope for. And so what I mean by that is physicians were thrilled to see the data, but also encouraged that it was very consistent with their own experience, right? So they have been not surprised per se that they're seeing continued separation from what you would expect from natural history, but also to see that it was very consistent with what they've experienced.

So you're not seeing necessarily a ton of variability in terms of response where maybe I would have just an outlier of patients doing one thing, but it's not consistent with a larger data set. So people have been very pleased to see that their experience is very consistent with the larger data set that they didn't necessarily have access to.

Got it. Are you still seeing like new prescribers? Or really has everybody who's going to write ELEVIDYS at some point written at least one script?

We have seen new referrals, so not new prescribers. So sites that have not necessarily had a patient that they are now referring them to one of the bigger sites.

I see. Okay. And is this -- this is post 3-year EMBARK data?

This is post 3-year EMBARK data. Yes, Patrick just mentioned it on the call that we're seeing 2 dynamics that are somewhat encouraging not to overinterpret very small numbers, but that a couple of sites who haven't written in a long time have written and then referrals from a couple of physicians.

New referral sites to existing administration sites. Got it. So you previously guided to top line cohort 8 sirolimus pretreatment data in non-ambulant patients for ELEVIDYS treatment. You previously guided to second half. And then on the last call, you noted despite high patient and investor -- I'm sorry, high patient and physician interest, also investor interest, patient and physician interest, no nonambulant patient had yet been dosed, but you received the green light to start enrollment in late November. So is there -- are there gating items to that first treatment? Is it site activation?

Yes, exactly. This is logistics, right? So there's a nuance to it. So the agency agreed to the study design, but you still have to go through the contracting process and IRB approvals. So it's just logistics to get through even though the agency agreed in concept to actually get the sites to be to be able to dose.

How many sites?

Right now, there are 5.

There are 5 sites. Okay. Are they close to dosing?

Yes.

Okay. And the 5 are open...

Yes, they're -- 5 sites that are in the stages of opening. I know 1 site is definitively open right now.

As you think about that data, what do you want top line to include? Is it what liver biomarkers between all the enzymes, ALT, AST, GGT, bilirubin, like what's the most meaningful?

Yes, the real primary endpoint is the rate of ALI.

As defined by the -- the ALI definition is what on the other biomarkers?

It could be 2x, 3x normal at GGT.

And will you also be looking at like ALT, AST?

Yes. We'll be looking at all.

But it's GGT defined ALI. Okay. That's not usually how we think about drug-induced like DILI, right? It's usually like bilirubin and ALT. Is this a unique feature of an AAV associated liver injury that's sort of GGT focused?

Yes. It's GGT focused, especially because you often have variability as it relates to ALT and AST. So that's why don't typically...

In DMD patients.

Yes, in DMD patients.

Understood. That makes sense. What about bilirubin? Or is it like by the time bilirubin moves...

Yes, we look at it much earlier.

Okay. Before the bilirubin starts.

It's actually having an impact.

Got it. And then as part of this, you will be doing a biopsy to see the impact of sirolimus on potential expression. How are you taking the biopsy? How are you assessing the expression levels? And what's the current standard for assessment of muscle content-based adjustments to this analysis?

Yes. So obviously, from our perspective, we want to -- different companies do it different ways, which I think is actually important when you're comparing expression levels across programs. I think it's very challenging to do that. The normal control can be very different than one uses. And so that has an impact on the overall quantification.

That being said, we will do it in the exact way that we've done it always in terms of the EMBARK readout and the like, it's going to be completely consistent with the way that we've always done it.

When could we get the first indications of impact on efficacy? Will it be from that first top line data?

I don't know if we'll have the biopsies just because, as you know, it takes time to actually process and get it from both the Western blot and IF perspective. So I would expect that the real key to this, to your good point, we're very interested to see if there's an impact and there's a strong mechanistic reason as to why you might see increased expression when using an immunosuppressive regimen. That being said, we want to get the top line data out from a safety perspective to see if we've had an impact on ALI in the non-ambulant patient population.

What is the probability that this top line data is delayed into 2027?

We feel good from an enrollment perspective. Obviously, it's slated to the really back end of the year. So could you always have some level of slippage? Yes, but I wouldn't expect any major delay.

Was the non-ambulant indication in the label formally removed in the label update? And once you get that Cohort 8 data, could it restore that language? Or what sort of -- restore it quickly without sort of a review process, a formal review process.

We haven't defined that with the agency. Now it was, as you know, you've seen the label. So it was removed from the label. And the pathway to restoring it is not something that's been defined. I think it may have some level of impact. The data may have some level of impact on if the data is sufficient and what the pathway is. So we haven't had those formalized conversations. Now obviously, it could be an sBLA, but we're just going to have to see. So step 1 is just getting the data. Hopefully, it has a significant impact on ALI and then we'll engage with the agency to discuss kind of the pathway forward.

Have you ever had a -- as you were setting up Cohort 8, right, do you set an expectation for ALI or other, whether it's expression for thresholds that would restore the indication.

Not formally with the agency.

Has it been a discussion topic?

I think we want to look to reduce the risk by at least 30%. But again, we'll see where we net out from a...

So moving on to the Arrowhead assets. You noted that your initial FSHDDM1 data is still on track for 1Q. Could we please start by recapping which dose cohorts and what endpoints will be included in the first interim data set?

Yes. So before I do that, maybe let me frame the opportunity a little bit because I actually think you can get more insight from this readout than one would normally expect just because there's been so much work in the siRNA space and in the -- with ASOs that I think there's a lot more information that we can clean.

Specifically within DM1 and FSHD...

Within DM1 and FSHD specifically. Right. So when you take a step back and kind of look at the siRNA approach, which is currently in development, you did not see a dose response curve at all, right, with the mAb. And so there could be 2 reasons why that could be occurring, right? It could be the transferrin receptor or it could be the mAb itself and the interaction with the transferrin receptor. Now when you look at the ASO approach, you actually see a very good dose response curve from a muscle concentration perspective, right? So -- and since that's using the transferrin receptor also.

You mean the transferrin ASO approach?

Correct.

The Dyne approach, right?

I'm not calling people out by name.

I will.

So when -- you see that -- you do see a very good muscle concentration perspective. However, because of the ASO approach that you're dependent on RNAs to be available for knockdown to occur, you actually don't see that translate to a PD perspective, right? But with the siRNA approach with the mAb, you didn't see any dose response curve from a muscle concentration perspective. So of course, from a splicing perspective, you don't see...

Because enough doesn't get anyway...

And so it doesn't...

There aren't enough doors open or whatever mechanism...

You're just not getting enough into the cells, so you can't have more splicing. So you've seen flat from that perspective also. So what we really want to see is really focusing on the muscle concentration with an siRNA approach because if you're able to get more into the muscle, what you've seen from a preclinical perspective, you think that you can get a higher dose response curve, which will drive more knockdown.

And I think from a -- I think that's very important because, as you know, especially as it relates to DM1, the level of repeats is correlated to disease progression, right? And so if you have the congenital form or greater than 1,000 repeats, obviously, incredibly severe. If you have the classical form, you're between 200 and 500, obviously severe, but not as severe as the congenital form. So everyone knows that the level of repeat you have is correlated to disease severity.

So therefore, getting the highest knockdown will translate into the best overall efficacy. Now whether you can differentiate that at a year or something, who knows? However, but fundamentally, if you're getting the best knockdown, it will lead to the best clinical outcome. So with all that being said, going back to your question, what we're looking for -- and so it's very low doses, but what we're looking for is a dose response curve from a muscle concentration perspective, from a PK perspective to see because this is the big question is with using the TRiM platform and the siRNA approach, can we get more into the muscle, which would actually lead to higher knockdown.

And then mechanistically, the RNA stuff is figured out.

Exactly.

By precedent. Okay. And then the doses that will...

So it's 1.5 and 3 for DM1. And then for FSHD, it's 1, 3 and 6.

Got it. And how long are you treating them for?

So this is just a single dose when we're taking biopsies at 30 and 90 days.

Got it. And you have confidence that the expression will have happened and be sustained over 90 days or.

We'll see. Again, this is proof of concept, and we'll see what the correct dosing regimen will be as long as you're driving the knockdown, that's what's most critical.

Got it. What -- have you seen this sort of increasing muscle concentration with preclinical assays and sort of increasing knockdown with dose escalation in an intracellular basis with DM1 or FSHD, they don't really have good preclinical model. I mean there are some preclinical models...

Yes, [ Ritu ], I think we have good preclinical models, and that is certainly what we've seen from a preclinical perspective, the more you can get into the muscle, the more knockdown you end up getting.

Do you have -- are you going to disclose any updated preclinical DM1 or FSHD data before this?

No, the big focus has been on the clinical data. We haven't been doing a lot of preclinical work.

When you are -- when the program is mature enough for functional data, what do you see as the bar? Where has that been set for DM1 splicing and [indiscernible] in DM1?

I mean I think there's a danger, especially as you look at clinical data. [indiscernible] does respond very quickly, but it's to the point that I was trying to make earlier where because it responds quickly at 48 weeks, I don't necessarily know if you can see differentiation. But if you're driving the most knockdown, you're going to see from a long-term perspective because this is so tightly correlated to the number of repeats you have. And so I think knockdown and proof of concept from a functional measure, whoever has the highest knockdown will ultimately get the most share.

So Sarepta noted ongoing CASI-22 assay development delayed splicing data into second half. So what work remains on that assay? And what potential is there for further delays?

Yes, I don't -- I wouldn't expect any further delays. This is just around the validation. This validation work that's going on. The team has made good progress on that. So we'll have that data with some of the higher dose cohorts.

So Avidity before it was acquired, indicated that it had developed a proprietary DUX4-related gene knockdown biomarker. What bar do you see -- I'm sorry, we'll get to the biomarker next, but just what's the bar for the DUX4 down regulation, and we'll get to the biomarker.

I mean you've seen where they've been in kind of that 20% range. So we'll just have to see how this translates. Again, I think you can ultimately -- and there, you have to really, to your point, kind of compare how the assays that are being currently reviewed and how similar and different companies are doing. But ultimately, if you measure downstream knockdown, I think you'll -- if you get more into the cell, you're going to see more knockdown.

And what about biomarker approach for...

They have...

Yes, they have some proprietary.

Yes. So they have the [indiscernible]. Our team is working on that right now. Obviously, that's early. So...

Your team is working on using [indiscernible]...

I'm trying to validate it. Obviously, we don't have all the information. So the team is working on that now and looking to potentially use that as an assay. So that obviously just came out recently, and the team is just starting to work on it.

What does it sound like time lines will be to full top line data sets?

By full top line data sets, you mean in the.

All the cohorts.

By the end of the year.

Okay. So besides top line Phase I/II data, what else might gate a pivotal trial start in FSHD and DM1?

It's going to be a commercial manufacturing process.

How long do you think that will take?

Into '27.

Into '27. So really a next trial, maybe second half of 2027, assuming success.

In '27, we don't have exact visibility into. There's obviously more work to do from a commercial manufacturing scale-up perspective, but things are on track, and so we think in '27.

I do want to touch on your PMO franchise. Recently, a competitor announced what we see as kind of compelling pivotal data for a direct competitor, EXONDYS. If that drug is approved, what's strategy to counter their launch and maintain EXONDYS share? And what you plan on price?

Just to answer your last question first. I think this isn't a GLP-1 market, right? I don't think price is -- we have to make these viable and with such small populations, I don't think there's as much flexibility on price as real large indications.

Have margins improved with your PMOs?

They've been relatively stable. But as it relates to the competitive dynamic, again, and it goes back to the point I was making earlier just in terms of quantification. If you're using a different control, right, there was a competitor of ours whose drug was very close to ours, and they said that they had a 5% expression. But when you look at the full change...

6% or so, right?

No. So -- but when you look at the full change, it's actually identical, right? So quantification has a big impact. Now I do think on some of the new therapies, the dosing frequency could be important, right? So once monthly versus a weekly lessening the burden on the patient. I think that's where it could be more convenient from a competitive perspective.

But I think to your point around what is the team doing in advance of that, it's really educating around the long-term efficacy, the safety profile of the PMOs has been exceptional and driving good benefit from a long-term perspective on all key major milestones of disease progression. So loss of ambulation, time to event survival, mortality. We've seen good data coming out over 5 years from an overall survival perspective. So very compelling data. So really making sure that everyone is aware of that data educated in advance of any competitive entries.

Have you met with FDA to discuss potential full approval of AMONDYS, VYONDYS and EXONDYS?

We haven't had a meeting yet, it will be this quarter.

What's your base case in upside/downside cases for this meeting? -- most likely.

Most likely, I want to be very careful as it relates to -- it's always challenging to navigate the current regulatory landscape. Look, I mean, I think the data -- I'll say it a different way. I think the data wildly supports this drug remaining on the market.

This is in CEDAR, like all of this...

This is in CEDAR. And obviously, there is a very close comp in terms of NS Pharma and the last that they disclosed is that they're still discussing with the agency their protocol. That study didn't read out positively, and that was about 20 months ago. So it actually is current in terms of the current regulatory landscape.

And so I think it's as good of a proxy as one could possibly have. So we'll see. But I think the data from a scientific perspective and the way that both physicians and patients have responded, you have not seen any change in prescribing patterns or enthusiasm or utilization of the therapy.

This data hasn't told anybody anything. They didn't know already.

Exactly. We have a long history of experience over 10 years, and the data is very consistent with that.

Got it. Next presentation is mine, so I feel the ability to go over. Tell us a little bit about your third-generation PPMOs.

So the team is actually working on a combination approach using the TRiM platform in combination with the PMO. So they're very, very excited about that potential, but obviously, very early. So -- so we'll see.

Updates over 2026 potentially?

I think...

Was it 2027?

It may be more 2027. Internally, I think we'll start seeing whether it's viable from a preclinical perspective. And then depending on the data, we'll see if it makes sense to share it or not.

Great. With that, we are over time. Ian, thank you for all the insights.

Thank you for having me.

Yes. Look forward to the progress.

Good afternoon, and welcome to Sarepta's Fourth Quarter 2025 Earnings Results Call. As a reminder, today's program is being recorded.

At this time, I'll turn the call over to Tam Thornton, Sarepta's Director of Investor Relations. Please go ahead.

Thank you, operator, and thank you all for joining today's call. Earlier this afternoon, we released our financial results for the fourth quarter of 2025. The press release and slides are available on the Investors section of our website at sarepta.com, and our 10-K will be filed with the Securities and Exchange Commission next Monday.

Joining us on the call today are Doug Ingram, Dr. Louise Rodino-Klapac, Patrick Moss and Ryan Wong. After our formal remarks, we'll open the call for Q&A.

I'd like to note that during this call, we will be making a number of forward-looking statements. Please refer to Slide 2 on the webcast, which contains our forward-looking statements. These forward-looking statements involve risks and uncertainties, many of which are beyond Sarepta's control. Actual results could materially differ from these forward-looking statements, and any such risks can materially and adversely affect the business, the results of operations and trading prices for Sarepta's common stock. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent SEC filings. The company does not undertake any obligation to publicly update its forward-looking statements, including any financial projections provided today based on subsequent events or circumstances.

As noted on Slide 3, we will discuss non-GAAP financial measures on this webcast. Descriptions of these non-GAAP financial measures and reconciliations of GAAP to non-GAAP financial measures are included in today's press release and the slide presentation available on the Investors section of our website.

And I'll now turn the call over to our CEO, Doug Ingram, who will provide an overview of our recent progress. Doug?

Thank you, Tam. Good afternoon, and thank you for joining Sarepta Therapeutics Fourth Quarter and Full Year 2025 Financial Results Conference Call. As you will hear today, we've entered 2026 on a strong footing. There are three pillars to our strength. Our first pillar is our financial position. As our CFO, Ryan Wong will discuss in more detail because of the actions we took in 2025, we entered 2026 in a solid financial position with a large and growing cash balance, significant revenue, positive operating cash flow and removal of any near-term debt overhang. We exited 2025 with $954 million in cash and investments, growing $89 million in the fourth quarter. We anticipate under all reasonable scenarios to be cash flow positive and profitable on a non-GAAP basis this year even as we fully invest in our pipeline and our marketed therapies.

Our second pillar is our four durable life-improving therapies. As you will have seen, our three approved PMOs have remained stable even in the face of ELEVIDYS cannibalization. We read out the results of our AMONDYS and VYONDYS confirmatory study, ESSENCE late last year, and we have scheduled a meeting with the FDA for later this quarter to discuss the potential to transition those two therapies to a traditional approval.

When one considers the PMOs, it is important to recall several things. The PMOs have been serving the Duchenne community well for many years now, in some cases, exceeding a decade. Over these many years, they have been on the market. There has accumulated an exceptional body of published real-world evidence consistently showing the significant disease moderating benefits of these therapies across measures and across organ groups, and ESSENCE is supportive of the risk benefit of these therapies.

Patients and their physicians see significant value in the PMOs as represented by year-after-year compliance rates consistently over 90%. Indeed, families are fiercely supportive of these therapies. And importantly, the safety profile of the PMOs over the last decade is stellar. For these reasons, the evidence supports and we think the time has come to transition AMONDYS and VYONDYS to a traditional approval, although we do stand ready to provide additional reasonable prospective real-world evidence if ultimately required.

Moving on to ELEVIDYS. The unanticipated in two instances, tragic events of 2025 created uncertainty around ELEVIDYS in the middle of last year, but much of that uncertainty has been cleared by now. While short-lived FDA actions caused questions about the future availability of ELEVIDYS, that is now resolved with an updated label, updated precautions and monitoring and a traditional approval for all ambulatory patients for and over. The FDA has approved our sirolimus pretreatment study for non-ambulatory patients, which is an important step on the potential pathway back to treating non-ambulatory patients, assuming a successful outcome. That trial is already enrolling patients, and we expect results by the end of this year. Once we have the data in hand and assuming its success, we will discuss with the FDA the fastest possible pathway forward to resume commercial dosing in the non-ambulatory populations. Those results will also be an important element of moving forward with our BLA for SRP-9003 to treat LGMD 2E.

Over 1,200 patients have already been treated with ELEVIDYS and yet the majority of patients remain to be treated. That is an enormous opportunity. As we address the issues of 2025, we were left with little time to provide balanced information on the safety and efficacy of this simply remarkable therapy. And that information deficit has resulted in some patient and physician hesitation that must be addressed to ensure the greatest number of Duchenne patients benefit from ELEVIDYS. We have well-designed plans to address information deficits so that families and treating physicians are fully armed with accurate and balanced information to inform the decision to treat with ELEVIDYS. In a moment, Patrick Moss, our Chief Commercial Officer, will walk you through our plans.

Equally important, the overwhelming evidence that ELEVIDYS significantly alters the course of this disease has only grown over the last year with updated three-year EMBARK data that was universally positive in showing that the gap between ELEVIDYS-treated Duchenne boys and those who unfortunately have not yet been treated grows greater and greater with every passing year. These plans will take some time to execute given both the timing of the plans and the long-cycle nature of START Form 2 infusion. But based on the market research and advisory boards we have conducted, we are confident about our plans. We previously chose not to provide guidance on total net product revenue for 2026, due primarily to the uncertainty on the timing of our ELEVIDYS initiatives. However, we will provide broad guidance today to help investors model the year.

Now while it is challenging to perfectly model the exact shape of the revenue curve of a onetime therapy like ELEVIDYS, we believe there is a significant opportunity among the prevalent and incident population over the next three-year horizon. The delay and impact of our initiatives may affect near-term sales, but they should not impact the ultimate opportunity as we expect to pick up those sales as our initiatives result in better understanding of the disease-modifying benefits of this therapy and the compelling need to treat as soon as possible. But that is not to suggest that we will be satisfied before all patients and physicians have the information they need to make informed decisions about this therapy.

Regardless of our long-term sales, every day that goes by without treatment, a boy or young man loses muscle that he can never get back. Patrick will discuss this in more detail, but given the timing of the initiatives and the long cycle time for ELEVIDYS, we do not expect that we will begin to see the impact of our educational efforts until at least well into the second half of this year.

Looking at the first quarter itself, we should achieve revenue that's about flat to perhaps down 15% from the prior quarter. For total net product revenue for the entire year, we are providing a guidance range of $1.2 billion to $1.4 billion for our approved therapies. To be clear on our expectations, without our educational efforts, we would expect to track to $1.2 billion in net product revenue for the year. Depending on the timing of the initiatives, that could be as high as $1.4 billion if the initiatives more immediately showed impact. But given the long cycle times I just outlined and the resulting quarter-to-quarter variability, we believe that it is prudent to model toward the low end of the range at least for the time being. While we are being disciplined in our near-term projections, our confidence in the ultimate demand for ELEVIDYS and the transformational nature of this therapy remains exceptionally strong, and we believe our initiatives will support this opportunity.

Now the third pillar of our company is the strength of our pipeline. We have an exciting siRNA pipeline that is advancing. We have now five clinical stage programs, including our neuromuscular programs for DM1 and FSHD, our pulmonary program for IPF and our CNS programs for SCA2 and now for Huntington's disease. Given the unique approach we are taking with the Arrowhead TRiM platform, these programs hold the potential to be best-in-class. They also hold the potential to bring a better life to more than 160,000 patients in the United States and multiples of that number internationally.

We have two additional programs completing preclinical work for deadly CNS diseases, that's SCA1 and SCA3, and we have additional discovery programs with Arrowhead for high-value targets across neuromuscular and cardiac and CNS diseases. We are making good progress with our siRNA programs, and we will have some important updates this year, as Dr. Rodino-Klapac will discuss later in this call.

And with that, let me turn the call to our Chief Commercial Officer, Patrick Moss. Patrick?

Thank you, Doug, and good afternoon, everyone. As preannounced in January, net product revenue for 2025 totaled $1.86 billion, consisting of $966 million from our PMO franchise and $899 million for ELEVIDYS. For the fourth quarter, net product revenues for the PMOs totaled $259 million, which is relatively stable compared to the fourth quarter of 2024. Individual PMO net product revenues were $148 million for EXONDYS 51, $34 million for VYONDYS 53 and $77 million for AMONDYS 45.

Turning to the ELEVIDYS performance. Fourth quarter revenues totaled $110 million, impacted by the severe flu season and 6 planned infusions that had to be rescheduled in 2026. Now looking forward, it's important to recognize that the $500 million revenue floor for ELEVIDYS reflected a steady-state mix of incident patients along with a meaningful contribution from the prevalent ambulatory population. The safety events of 2025 reshaped the perceptions of gene therapy and of ELEVIDYS specifically. As a result, it has become more clear to us that 2026 serves as a critical reset year for the ambulatory patient population, where there's an information imbalance and the disease-modifying benefits of ELEVIDYS is less understood. Patients need and deserve a clear and comprehensive understanding of ELEVIDYS' risk-benefit profile to have informed and thoughtful conversations with their physicians. Physicians also deserve to be armed with a full understanding of the data and the totality of the evidence to help patients make the best treatment decisions.

Thankfully, we have a robust and growing body of data for ELEVIDYS. Two-year data from EMBARK Part 2 has recently been included in our promotional efforts and a three-year EMBARK top line data was shared last month and will be presented at the upcoming MDA conference. Both the 2- and 3-year data show sustained ELEVIDYS benefits over time with evidence of slow disease progression versus natural history.

I do need to emphasize something that matters, something that truly matters to patients, and that's the significance of the muscle MRI data. Our muscle MRI data is powerful in that it provides unbiased evidence showing the difference between those treated with ELEVIDYS versus untreated Duchenne. The muscle MRI data shows that the muscle decline is evident well before functional decline is observed and delaying treatment results in irreversible muscle damage that cannot be restored. This is empirical evidence that reinforces the importance of preserving muscle by treating Duchenne as soon as possible. Clinicians have affirmed their belief in the data and the disease-modifying effects of ELEVIDYS through feedback at advisory boards and conference discussions. Their clinical experience is consistent with the data, yet they believe, as we do, there is still work to be done to ensure patients have a balanced view of the benefit risk profile of ELEVIDYS.

Our new commercial initiatives are squarely focused on addressing the information deficit by reengaging with our customers with enhanced messaging and expanded footprint of our field teams. The traditional approval of ELEVIDYS creates a meaningful opportunity to strengthen our commercial messaging and engaging customers in new ways. We have updated our materials with substantial new data from the two-year EMBARK results to improve clarity and support a balanced understanding of ELEVIDYS benefit risk profile. And as a reminder, ELEVIDYS is the only FDA-approved gene therapy for Duchenne and has treated more than 1,200 patients across clinical trials and commercial settings with that number continuing to grow.

In addition to updating our messaging, the expansion of our customer-facing teams enables us to go beyond treatment centers to educate referring physicians, patients and their caregivers. Our teams are addressing treatment hesitancy through accurate and clear information with a repetition that supports informed decision-making. The decision by a patient and their caregiver to pursue gene therapy is an important one. Our outreach to clinicians, caregivers and patients is designed to address what's on their minds of each of these stakeholders and support them with educational efforts and resources and data.

We remain confident that our new 2026 initiatives will benefit patients while recognizing that it will take time for these efforts to translate into accelerated new patient demand. Unlike chronic therapies, which benefit from an installed base, ELEVIDYS is a onetime therapy and each treatment represents a new patient start. We continue to believe there is significant opportunity for ELEVIDYS and our confidence in capturing that opportunity is supported by emerging green shoots. A meaningful proportion of recent enrollment forms this year have come from sites that have not submitted since last summer and a growing percentage of enrollment forms have come from sites outside of our existing network. While this early traction from new sites is encouraging, we remain focused on executing our commercial initiatives to accelerate demand across the treatment network.

The PMO franchise remained stable in 2026, with demand declining modestly year-over-year as patients choose ELEVIDYS. This durability continues to be a testament to the clinical value of protecting muscle to slow the decline of Duchenne through the use of exon skipping therapy and the relentless operational excellence of the team. We are comfortable with the current consensus estimates for our PMO portfolio in 2026.

Now in closing, we are energized by the stability of our PMO business and the opportunity created by the traditional approval of ELEVIDYS. The robust long-term data included in our updated ELEVIDYS messaging, our expanded field force and demand from the Duchenne community support our efforts. Our confidence for 2026 is heightened by what we have witnessed, the ability to change the arc of the relentless decline of Duchenne. Our execution is driven by our commitment to serve patients, and we draw our inspirations from them, their families and the clinicians who continue to share their stories on how our treatments are changing what we know about Duchenne.

I'll turn the call over to Louise. Louise?

Thanks, Patrick. I'm happy to share with you our progress over the last several months, beginning with our positive top line three-year functional results from Part 1 treated in patients in EMBARK for study SRP-9001-301, our global randomized placebo-controlled Phase III study evaluating ELEVIDYS in ambulatory individuals with Duchenne.

Sarepta has led what is the largest and longest running Phase III trial, making ELEVIDYS the most studied gene therapy in Duchenne. We were thrilled to share the results last month, which showed that three years after treatment, patients who received ELEVIDYS in Part 1 of EMBARK demonstrated statistically significant, clinically meaningful and durable efficacy across all key motor function measures, which include North Star Ambulatory Assessment, time to rise and 10-meter walk run when compared to a prespecified propensity weighted untreated external control group. The mean NSAA score remained above baseline at year three for the ELEVIDYS-treated group, while the external control group continued to show the expected age-related decline below their baseline score.

Specifically, the ELEVIDYS group showed a 73% slowing of disease progression as measured by time to rise and a 70% slowing of disease progression as measured by the 10-meter walk run when compared to the external control group. The North Star Ambulatory Assessment showed a 4.39 point difference at year three between the treated and external control group with a highly significant p-value of 0.0002.

To put into context the importance of these results, please note that functional outcomes like time to rise and 10-meter walk run are prognostic for delayed loss of ambulation. Slowing disease progression is expected to help preserve functional abilities for longer and delay more debilitating stages of disease. The EMBARK data showed that as ELEVIDYS continues to slow disease progression and the cumulative benefits increase over time, a greater divergence from natural history occurs as patients in the external control group progress into the declining phase of the disease. Further, as Dr. Crystal Proud, a pediatric neurologist, EMBARK investigator and someone who has treated many Duchenne patients stated, she has witnessed the transformative impact of ELEVIDYS for her Duchenne patients who can now do many daily activities in ways we would not expect. In children who have not received treatment with ELEVIDYS as they get older, these functions decrease exponentially as the disease progresses.

Further, no new safety signals were observed in three years after treatment and no treatment-related serious adverse events were reported, which is consistent with our understanding of the safety profile of ELEVIDYS as evidenced by more than 1,200 patients treated clinically and commercially. These data support ELEVIDYS as a disease-modifying therapy, providing a clear and growing benefit over time in those treated versus those untreated.

I'd also like to provide a brief update now on Cohort 8, which is part of our open-label study ENDEAVOR for study SRP-9001-103. As a reminder, as of July 2025, we've treated 155 non-ambulatory patients with ELEVIDYS before dosing was paused. This new cohort, Cohort 8, was designed to assess the impact of a sirolimus treatment regimen on reducing acute liver injury or ALI, and known side effect of all AAV gene therapies. Cohort 8 will enroll approximately 25 U.S. participants who are nonambulatory. Our primary endpoints are dystrophin expression at 12 weeks and the effectiveness of sirolimus on the incidence of ALI. We initiated this trial in late 2025 and are currently screening patients for enrollment. We expect to share findings by the end of 2026.

Moving now to the 2026 MDA Clinical and Scientific Conference, which will take place in Orlando, Florida from March 8 through March 11. Sarepta's robust presence at this year's conference will include important highlights across our portfolio. Of note, the three-year EMBARK functional data, including cardiac safety data will be presented. We will also have several presentations from our PMOs demonstrating real-world evidence of long-term benefit along with our Phase III ESSENCE results.

Turning now to our PMOs and an update on our exon skipping therapies, VYONDYS 53 and AMONDYS 45 to treat patients with Duchenne amenable to exon 53 or 45 skipping, respectively. We believe the totality of the data we've generated to date with real-world evidence is compelling. Our meeting has been scheduled with FDA, and it will take place towards the end of Q1. We've also submitted a briefing book.

Moving now to siRNA. Our DM1 and FSHD programs continue to advance. As announced in November of last year, our Phase I/II single ascending dose and multiple ascending dose clinical study of SRP-1003 to treat DM1 is progressing well. Cohort 1 and Cohort 2 of the study are complete and Cohorts 3 and Cohorts 4 are fully enrolled and ongoing. Dosing in the final cohort, Cohort 5 at 12 mg per kg will be initiated by the end of the month.

For FSHD, enrollment in our SAD study is complete and Cohorts 5 and 6 of our MAD study are fully enrolled. We are excited by the potential of these programs to offer differentiated profiles, including better safety and greater muscle concentration over other therapies currently in development. Specifically, we look forward to evaluating our early proof-of-concept data to establish the alpha v beta 6 targeting ligand as a potential best-in-class approach for muscle penetration and corresponding ability to dose at levels required for maximum knockdown.

As previously communicated, we plan to announce our preliminary data available from our proof-of-concept studies for DM1 and FSHD programs at the end of this quarter. Of critical importance will be the safety and PK data. We expect to have serum and muscle PK to validate preclinical dose model prediction and evaluate dose response. Preliminary PD data will be valuable to further support our models to inform Phase III trial design. We look forward to sharing these early results with you.

Moving now to our Huntington's program, SRP-1005. We've initiated our trial for Huntington's disease using SRP-1005. It's an investigational siRNA therapeutic for the treatment of Huntington's disease. This program utilizes a subcutaneous route of administration, allowing for target engagement in deep brain regions like the striatum, particularly affected in Huntington's. The Huntington's gene located on chromosome 4 produces the Huntington's protein, which is vital for neuronal development signaling and survival. Last month, we announced the submission of our clinical trial application for study SRP-1005-101, also known as INSIGHTT to Medsafe, the New Zealand Medicines and Medical Devices Safety Authority. They have accepted our application, and our next milestone is to commence dosing in the first half of this year.

As you can see from this slide, we have numerous value-enhancing milestones coming up over the next 12 to 18 months. We are particularly excited about the promise of our advancing siRNA pipeline and continuing to add to the robust body of evidence for ELEVIDYS and our PMO exon skipping therapies.

In closing, I'd like to take a moment to recognize Rare Disease Day, which takes place on Saturday, February 28. We are reminded that when it comes to rare disease, we must look for the unexpected and think beyond the common answer of diagnosis. The zebra has become a symbol for rare diseases, reminding us that like a zebra stripes, every rare disease patient's journey is unique. To those living with rare disease, we see you and we are with you.

Thank you, and I'll turn the call over to Ryan Wong for an update on our financials. Ryan?

[Technical Difficulty] Provided details for the fourth quarter and full year on a GAAP basis as well as a non-GAAP basis. [Technical Difficulty] Available on Sarepta's website for a full financial results. My appreciation to the Sarepta team for their continued dedication and diligence in driving our goals forward. We took decisive actions to reduce our cost structure and proactively address our 2027 debt long-term financial resilience. Operating profit and [Technical Difficulty] 2026 with a solid foundation to execute against our goals of our 2025 performance and share some forward-looking perspective for 2026.

For full year 2025, total revenues were $2.2 billion, an increase of 16% year-over-year. This included $1.86 billion in net product revenue and $334 million in collaboration, contract manufacturing and royalty revenue from our partnership with Roche. Looking ahead to 2026, in addition to our net product revenue guidance of $1.2 billion to $1.4 billion, I can share further detail on our expectations for other revenues. As noted in our press release yesterday, ELEVIDYS is now launched in Japan. In Q1 2026, we expect to record a $40 million milestone payment from Roche upon the first commercial sale. Additionally, we anticipate recognizing $325 million of noncash collaboration revenue tied to Roche declining an option for a specific program. Altogether, we expect total collaboration, contract manufacturing and royalty revenues in 2026 to be in the range of $450 million to $550 million.

Moving on to gross margin. In the fourth quarter, total cost of sales were $399 million, a significant increase over the prior year. During Q4, we conducted a review of our raw material inventory and adjusted purchase commitments to avoid carrying materials that would expire before use. This review resulted in a $193 million charge consisting of $165 million in noncash reserves for excess inventory and $28 million in purchase commitment cancellation fees. For the full year, cost of sales totaled $840 million. Nearly half of this amount reflects failed production batches, inventory reserves and other period charges associated with recalibrating our go-forward manufacturing plans. Excluding these charges, our unit sales-driven margins were in the low 80% for the year.

Despite the immediate impact to margins in 2025, we expect improved margins and fewer period charges in 2026 as production volumes will be significantly lower than in prior years as we were building ELEVIDYS inventory for a broad ambulatory and non-ambulatory population last year. On a unit volume basis, we expect 2026 margins in the high 70% range.

Shifting to expenses. Combined non-GAAP R&D and SG&A expense in the fourth quarter were $413 million, driven in part by the $200 million second DM1 milestone under our collaboration with Arrowhead. For the full year, non-GAAP expenses totaled $1.85 billion with $884 million related to the same collaboration. Excluding Arrowhead, our core operating expenses were $965 million. And consistent with the cost reduction targets we announced last July, we are reaffirming our 2026 non-GAAP expense outlook of $800 million to $900 million. Rounding out the P&L for 2025, we reported a GAAP operating loss of $700 million and a non-GAAP operating loss of $492 million. Adjusting for restructuring and the Arrowhead transaction expenses, our underlying business would have delivered its second consecutive year of positive operating profit, $226 million on a GAAP basis and $391 million on a non-GAAP basis.

Turning to the balance sheet and cash flow. In the fourth quarter, we completed a second debt exchange transaction, refinancing an additional $291 million of the 2027 notes into 2030. This leaves a remaining $159 million stub that we believe is very manageable given the cash generation profile of our business. We ended the year with $954 million of cash and investments. Ex Arrowhead payments, our base business generated more than $330 million of positive cash flow in 2025. In closing, as we move through 2026, we will continue to focus our resources on initiatives that drive demand for our on-market therapies and advance our pipeline towards key value inflection points. We remain committed to disciplined financial execution and to delivering sustained non-GAAP operating profit and positive cash flow.

And now I'll turn the call back to Doug for closing remarks. Doug?

Thank you, Ryan. All right. Before we open the call to questions, I want to share an update regarding my own plans. By this summer, I will have had the privilege of leading Sarepta for some nine years now. It has been, without a doubt, the single honor of my professional life to serve along this extraordinary team. Over those nine years, we set audacious goals for ourselves, Chief among them, the goal of lessening the burden and extending the lives of boys and young men with Duchenne muscular dystrophy. And along the way, as you all know, we solved many thorny and scientific and technical problems even as we faced and overcame many exogenous and extraordinary obstacles, challenges that would have undone a less committed, less creative, less resilient organization. And yet this team that works with me and for these families never wavered. They innovated, they executed. They often pulled off what others saw as improbable or even impossible. But because of that commitment, we now have four approved therapies and thousands of boys and young men with Duchenne are living more vibrant lives today than would have been imaginable a decade ago. And that impact now not only for those families, but for those yet to be treated and for a generation of future patients who will benefit from the foundation that we have built.

Despite an unusual market dynamic that has not yet caught up, Sarepta is, in fact, stronger today than just about any other point in its history, right? We're on a strong financial footing with four approved therapies, bringing a better life to patients, an exciting pipeline of clinical stage siRNA programs and one of the strongest, most passionate and committed teams in our history. For that reason and after a lot of thoughtful consideration, I have informed the Board that I intend to retire as CEO, and I intend for that to occur by around the end of 2026. This decision was a deeply difficult one for me as this is the most meaningful and rewarding role that one could imagine, and we stand at one of the most exciting moments in our entire history. However, I have family commitments that require my attention, and I will explain them even though I normally a relatively private person, but I'll explain.

When I joined Sarepta, I had no personal connection to muscular dystrophy. But through my work at Sarepta, I have developed a zealous passion for our quest to improve the lives of those living with muscular dystrophy. I doubt anyone who knows me would disagree with that. That commitment required nearly my exclusive time in Boston and Cambridge, while my family primarily resides in California. As you know, in late 2024, we entered into a partnership with Arrowhead, and we gained access to a number of very promising therapies, including SRP-1003 for a devastating disease, DM1. Well, subsequent to that partnership in a fairly shocking and certainly ironic twist of fate, my personal commitment to muscular dystrophy has deepened as two of my members of my immediate family have been diagnosed now with myotonic dystrophy DM1. By the end of 2026, the time will have come for me to spend more time in California, focusing on family commitments and addressing the realities of DM1.

The Board and I have initiated a comprehensive search for my successor, both internally and externally. We will seek a visionary leader, someone capable of maximizing this team's potential, accelerating our opportunities and one who is unwaveringly committed to this extraordinarily important Sarepta mission that we have. When I eventually leave this role, it will be with complete confidence in this team and in Sarepta's trajectory, first and foremost, in fulfilling our mission to lessen the burden of devastating diseases and ultimately, in delivering the value that our science and execution warrant. Thank you for indulging me.

And with that, let's turn the call to questions. Can we open the call for questions now?

[Operator Instructions] In the interest of time and as a courtesy to other analysts, we ask that you please keep your questions to one. [Operator Instructions] First question is from Anupam Rama with JPMorgan.

Doug, I was wondering if you could speak to how you think about and how the Board thinks about internal versus external candidates as you go into your retirement. The company is in a place where you're still coming out of a tough period for ELEVIDYS in 2025. You've got to defend your PMO franchise. You've got to deliver on the Arrowhead assets, right?

And how do you think about continuity with somebody like Ian Estepan, for example, who's been forward-facing with the Street, forward-facing with the patient community, forward-facing with the KOL community, your partners know him versus bringing in someone externally who may break that continuity.

Well, thank you for your question, Anupam. Look, I will just say in the broadest of strokes that the Board is looking for both internal candidates, taking that very seriously and looking at external candidates at the same time. Certainly, we're at a very important point in our history. We have a lot to do and a lot of execution to do. And I think we will have to be very mindful that whoever we choose, whether internal or external, understands what we're up against and understands how to execute and understands how to lead this team and shares our cultural values, which while that sounds very soft, is an exceptionally important and important part of this company. And I think the thing that fuels us and allows us to keep going even in the face of oftentimes very challenging obstacles that occur when you're the leader is this patient focus that we have.

So I can at least commit to all of you that I and the Board understand where we are as an organization, and we're going to be very thoughtful that we choose a person that can continue to drive us forward and execute these plans and get the most out of this team. I mean I will just linger for a second. And hopefully, any Sarepta employees that are listening to this call will listen and hear me.

This is the most exciting time we have as an organization. And this is one of the most impressive teams I've ever had the good fortune of working with, and I've had a lot of teams in my many years. I've been doing this now for three decades, and I've had a lot of really impressive teams that have worked for me. None are as impressive as this team. So we have a lot to execute and a great team and whoever we ultimately choose to be the successor CEO, I'm confident we'll be a person that can drive our plans, can speak as a leader to this great team and can get the most out of an exceptional team. Thank you.

And Doug, I'm so sorry to hear about your family as well. And so our thoughts are with you.

Our next question comes from the line of Brian Abrahams with RBC Capital Markets.

Doug, thanks for the heartfelt message and my best wishes to your family as well. With regards to the kind of renewed efforts around messaging for ELEVIDYS, I guess what are some of the key metrics that you're going to be looking for over maybe the first half of this year that might suggest initial receptivity? And what are some of the takeaways we should think about from some of these signals you discussed with new sites initiating start forms and the return of some sites that hadn't prescribed since the summer?

Yes. Both are very good questions. I'm going to turn this over to Patrick for a more detailed answer. In the broadest of strokes, the ultimate signal is going to be embedded in the first and foremost, enrollment forms and then ultimately in infusions, but there are probably many signals we can get long in advance of that through the use of things like regional advisory boards and market research and the like to really see that people are beginning to fully embrace and understand the data on this therapy. I mean it is remarkable how much data we have on the completely trajectory changing benefits that come from this therapy and really be able to contextualize that and for having people fully understand that is an exceptionally important issue.

But with that, Patrick, you can provide certainly more detail than I can on this topic.

Great. And really, what we do is we consider there's value in promotion, right? And so our team is just beginning to get out there and promote the value of ELEVIDYS with our updated traditional label. And so our promotional efforts, they're rooted in the strong data, and that data continues to show the value of restoring dystrophin using ELEVIDYS. But one thing I'd also point out is that this is rare disease and more specifically a onetime therapy in rare disease. So each patient is a new patient. It's not a refill or a script renewal. So efforts do take time. And so a small number of patients can impact performance. And so all those various metrics we do evaluate as we're looking at our performance.

Our next question comes from the line of Ellie Merle with Barclays.

This is Tejas on for Ellie. For the siRNA readouts in 1Q, are there any particular benchmarks we should keep in mind when we think about target engagement? Should we think of these doses as getting to a therapeutic level? Or if not, what levels could we see that read well to higher doses?

I'm going to turn this call over to Dr. Rodino-Klapac. I mean I will say in the broadest of strokes, and again, I'm going to preview this and then Dr. Rodino-Klapac is both going to correct anything I say that is incorrect and also provide far more informed views.

But if you think about the main conceive of these therapies, particularly our muscle-directed therapies, DM1 and FSHD, the unique thing about these therapies is that they employ the integrin receptor in a very specific way, which at least preclinically would suggest a number of things that you can do this very safely and that at equivalent doses, you can get much greater muscle concentration, which means that ultimately, you should be able to dose escalate even more significantly with more headroom and you should get much greater and at the same time, safe knockdown and then downstream splicing, which means that in these early days of the readout, the two things we should be looking at most significantly is safety and is muscle concentration because if you have a very safe therapy or a relatively safe therapy and you have great muscle concentration at low doses, then outcomes razor. The rest will come, including the knockdown, the downstream splicing and the functional benefits in the life. So those are the big things to look at, and we'll have more than just that, but those are the big things to look at.

But I turn it over to Dr. Rodino-Klapac to provide her views.

Thank you. And I don't need to correct anything. I'll just add a few things and the fact that certainly, we are looking for muscle concentration. And based on our preclinical data, we feel and the data from the SAD data so far that we can continue to dose escalate. The important thing is also getting muscle concentration and also because we're using siRNA and we know how potent they are, we are not limited by the cellular machinery like an ASO where they're reliant on the RNase H in order to create knockdown. And so we -- using siRNA, we are not limited by that.

So, taken together, those two things, so both muscle concentration and the ability of siRNA to produce efficient knockdown we feel optimistic based on our preclinical data, we'll be able to continue to dose escalate and potentially provide best-in-class knockdown. So that's what we'll be looking for is consistency with the preclinical data. Most of the data will be the SAD data. Obviously, that's one dose, and we'll continue to get data throughout the year on the MAD as well, which we will further evaluate.

One moment for our next question, that comes from the line of Andrew Tsai with Jefferies.

I appreciate the updates, Doug, wishing you and your family all the best. So I also wanted to ask on the siRNA readout strategy in general. When would you guys be prepared to start pivotal studies? I think I heard you mention the word pivotal for DM1 and FSHD, would it be right after the full MAD data set in the second half? Or do you need to do more dose expansion work?

And then I'm also curious your guys' latest thinking on the accelerated approval pathway for these indications. In DM1, I think one company is going after accelerated and the other full approval. So I would love to know what your guys' stance are.

I'll turn this over to Louise.

Yes. So, first on the Phase III. So, in my script, I indicated, yes, we're working towards the Phase III. We'll be doing the -- continuing the MAD study, which will inform that. And at the same time, we are getting ready on the manufacturing side for Phase III, again, so that we can make sure that we are ready to go with commercial-ready material for that Phase III and can move as fast as possible. So we are, as you would predict, moving as fast as possible in terms of the potential for an accelerated approval. It will be facts and circumstances depending on where we're at with the state of the environment with other companies and where they are with approvals.

I think with FSHD, for example, there's early potential readouts that would not have a long delay between accelerated and traditional approval. So we are taking our fastest approach regardless of whether we ultimately end up getting an accelerated versus a traditional approval, and we'll do so and make sure that we are collecting the appropriate data, functional data to support both.

Our next question comes from the line of Joe Schwartz with Leerink Partners.

Please accept our condolences and best wishes, Doug, for you and your family. I was wondering if you could talk a little bit about how clinicians are currently risk stratifying patients for ELEVIDYS using things such as liver enzymes, age, weight, steroid exposure, concomitant meds, et cetera. How has your view of ideal candidates changed based on the experience that's building currently?

Yes. Let me say one thing, and I'll turn it over to Patrick to answer the detail. I don't think that our view has changed, whether -- what the current state in the market may be before more education occurs, it may be different than that. But just to be clear, we think there's this enormous opportunity. As we said, the vast majority of the addressable ambulatory patient population remains to be dosed, and we're confident that all those patients would benefit. We won't get all of those patients. I'm not unrealistic, but we will -- we can get a lot of those patients when everybody understands the context and understands the benefits of this therapy and understands the compelling need to dose as soon as possible. And I think the muscle MRI data maybe more than any other single piece of objective empirical evidence tells us that you need to dose as soon as possible to save muscle before it's lost. But we have work to do there.

And in the interim period, I think, Patrick, maybe you can talk to how you see physicians stratifying patients and excluding and including patients and the like.

Yes. In addition to that, Doug, what we see is with Duchenne, it's obviously a rare disease that impacts the entirety of the family. And so it's really each patient, they have a unique situation. So there's travel, schedule, siblings. And so all of that is contemplated as the physician and the patient and the family decide whether they're going to move forward and at what rate.

We do see, I think, some physicians without more information leaning younger. And so we've got to think about that and work with physicians, show them the data, understand the risk benefit of this therapy so that they and their patients can make better informed decisions across the entire ambulatory spectrum.

One additional thing that we cannot and will not promote because it is currently not in our label, but it is occurring exogenous to us is that about 25% of sites today, and I suspect that is growing, are proactively using sirolimus, either prophylactically before dosing or reactively if they see, for instance, an increase in liver enzymes. And that practice may also, over time, impact the patients that physicians see as amenable for this therapy.

Our next question comes from the line of Yigal Nochomovitz with Citigroup.

This is [ John Kim ] on for Yigal. Wishing you and your family the very best, Doug. One quick one from us. We're just wondering if you could provide some context on the size of the Japanese market, whether there's any important ordering dynamics to note? And then broadly speaking, any color on the potential for non-ambulatory patient treatment in Japan and what activities -- additional activities you would need to do -- would need to be done to be able to enable that?

Yes. Patrick, do you have any perspective on the size of the Japanese market other than the broad perspective that Japan is obviously one of the highest value countries from a pharmaceutical perspective that exists across therapies. But do you have any more information than that? Or should we turn folks to Roche for a better understanding of that?

I would turn them over to Roche.

We're excited, as you all know. Our partner is launching that therapy in Japan. Japan is an extraordinary opportunity, a very large population, very advanced health care system understands the value of therapies and how to price therapies as a culture. And of course, there are a lot of boys and young men in Japan who are living with Duchenne muscular dystrophy who will benefit from this therapy. So we're very excited about not really the opportunity, but the ability to do some good in Japan.

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

This is Tommie on for Salveen. We were just hoping for some more details on ELEVIDYS quarterly dynamics. So your guidance of the 1Q being flat to 15% down, how do the rescheduled infusions play into that? And just checking on some of the math, assuming $900 million in PMO revenue, giving you an ELEVIDYS range of around $300 million to $500 million. Maybe you can give some more detail on how the timing of that acceleration and kind of magnitude in the second half, as you said.

Yes, I'll give the broad strokes and then again, Patrick may have more color for you. As we look across the year, the thing to consider -- first thing to consider on a quarterly basis, if we say we're going to be flat to slightly down is that given this is a rare disease and given the cost per patient, a few patients move one way or the other on the therapy. Also, you'll know that six patients were delayed into 2026 from 2025, but also understand there's always this knock-on effect so that to the extent you're able to dose a patient in the first quarter that was delayed, that will almost inevitably delay another patient. So it doesn't just become additive. But ultimately, there'll be -- the patients will be there. I think we've already -- and Patrick, you'll correct me if I have this number wrong, but we've already dosed three of those patients who were delayed into 2026.

And then there's two things to know on those ranges, the sort of $1.2 billion to $1.4 billion, it does relate to the ELEVIDYS far more than the PMOs. The PMOs are very stable. And they're very easy -- they're not they're easier, I should say, to forecast because they are chronic therapy. So you tend to be forecasting on the margins of a therapy as opposed to what you have to do with a onetime therapy like ELEVIDYS, which is basically you start new every quarter, and then you have to forecast that way. So $1.2 billion implies that we're at steady state with no new educational efforts of any benefit. And our educational efforts should drive awareness and understanding of the risk benefits and should drive patients to get in front of the doctors and doctors to be starting in more enrollment forms, and that gets you up to the $1.4 billion.

But as we've said, you have to be thoughtful about the lead time on these. The initiatives themselves take lead time. We have already hired up our sales force. We have a contract sales force. We have educational -- these patient educational liaisons that we're going to be hiring. We have promotional material, but all of that requires training and getting out there and getting it through the process, and that takes its own time to be meaningful and impactful. But then the enrollment to infusion time is itself something in the four to the very lowest four months to even six months. So all of that suggests that for planning purposes, you should assume that while we'll get signals that this is really working in the next quarter or two to really see that turn into revenue is going to be something that's going to occur significantly into the second half of this year and then very significantly really in 2027. So that's kind of the delta between the $1.2 billion to the $1.4 billion.

Now Patrick, you may have other metrics that you think I've missed.

Well, yes, I mean, you hit most of them, and I'd really start out to say that with ELEVIDYS, the quarter-to-quarter dynamics, as you mentioned, they can be noisy, right? And so we have to consistently look at performance over the longer arc rather than each quarter. With the identification and screening of the patients and ultimately dosing, that can lead to that variability. But what we're focused on is to ensure that our team is out there executing on our plan. We're out there engaging with physicians, with payers. We're coordinating with the sites, supporting the patients. And all of that remains solid.

One other thing to know, we talk a lot about sort of getting the information out there and really educating people, getting to understand the risk benefit of this therapy and understand all of the efficacy data that we really had little time to do in 2025 for all of the reasons you know about. We were dealing with a lot of issues. We were working with the agency. We were getting the label updated and the like. And of course, it didn't allow us the time to really do this. Plus we have more data today than we ever did before. The one-year data look brilliant. The two-year data look exceptional. We just got the three-year data, and it's just the gap is growing and growing and becoming obvious that these patients really, if they understood this data, need to understand that they need to get in there and get infused.

But there's another big issue as well on this issue of sort of educating and information. And that is that -- and this -- I find this really troubling. And that is that you have a much better chance of getting infused with ELEVIDYS, if you're a middle class, English-speaking, well educated, there is a real delta that exists where people that are not in the middle class, Spanish speakers, other people in a different socioeconomic environment just may not even have access to any information to be able to make thoughtful decisions about this therapy. We are going to address that this year. We have some very good plans to address that and to really serve the full community, not pieces of the community.

One thing on the Spanish-speaking side, we're really focusing in on ensuring that we have a lot of field sales force that speaks Spanish, they can talk to people where they are. We have other thoughts about how we can support people that are struggling, but have children with Duchenne, which is very, very common, frankly. And so that is a sort of a big part of the efforts. It's not merely just more and more information, but really getting information to everybody whose lives will benefit if they understand what this therapy can do for them when they restore shock-absorbing dystrophin into muscles that desperately need it.

One moment for our next question, that comes from the line of Tazeen Ahmad with Bank of America.

I just wanted to clarify with regards to what you're seeing with PMO use, initially, doctors were saying that they wanted to keep the PMOs on board with patients even after the patients receive ELEVIDYS. Is that still what you're seeing? And is that assumption also embedded in the $1.2 billion to $1.4 billion guidance that you've provided?

Probably that thesis is probably not fully embedded in the $1.2 billion to $1.4 billion. But the interesting -- to your interesting point, physicians definitely on hold definitely want their patients to have the full armamentarium of gene therapy and a PMO. We have always taken the view, as you know, because we talked to investors about it over and over again over the long years even before we got launched is that, that may not happen a significant amount of time and the patients may be washed out of the PMOs, predicate to getting the gene therapy, and there will be a significant amount of cannibalization.

I would say at this point, there is more dual use of PMOs than gene therapy than I at least would have envisioned. And I think there's a real opportunity here for patients to fully benefit. This's very complicated disease, as we all know. And I think having adjunctive therapies with a gene therapy like a PMO makes a ton of sense, and I think that we might be seeing more, not less of that over time.

Patrick, you might provide more detail on that.

Right. Right now, we're seeing a handful of patients that have been treated with ELEVIDYS go back on PMO. It's not materially embedded in our forecast, but it is something, as Doug mentioned, that is an interesting proposition and something that the physicians are contemplating as they think beyond ELEVIDYS.

Okay. Thank you. And best wishes to you and your family.

Our next question comes from the line of Mitchell Kapoor with H.C. Wainwright.

And sorry to hear about your family, Doug, and wishing you and your family the best as you navigate this new journey and also your retirement.

I wanted to ask on the early trends you're seeing in 2026 for ELEVIDYS so far, obviously, guiding to flat to down 15% for the quarter. But I want to know what you're seeing on new patient starts, time to infusion, payer behavior, infusion center capacity. And if any of these factors or other factors are measurable performance signals that you're tracking in the next quarter or two to hit that $1.4 billion versus the $1.2 billion guidance.

Patrick, I'll turn this to you.

Yes. And I caution reading too much into really any single quarter. And I mentioned before, ELEVIDYS is not a product that performance unfolds in this like smooth linear quarter-to-quarter way. We are seeing consistent enrollment forms come in. However, it's early. And we're -- with our efforts and our messaging around the new data, expanding the field sales force and really expanding our footprint, we are expecting those efforts to materialize later in 2026. We do have early green shoots, as I mentioned, from prescribers that have paused in the past. But again, that time from enrollment form to infusion is still around 6 months.

One moment for our next question, it comes from the line of Mike Ulz with Morgan Stanley.

Doug, let me add my best to you and your family as well. Maybe just a follow-up on DM1 and FSHD data you're expecting to share later this quarter. Could you please clarify what PD data we should be anticipating from the slides, it looks like maybe splice correction, we shouldn't expect that, but maybe you can clarify what we might get? And then should we anticipate V-Ht as well?

I'll turn this to Louise.

Yes. So in terms of PD for DM1, we will have early DMPK knockdown data. And for FSHD, it will be DUX4 target gene correction in terms of the early data for that.

Our next question comes from the line of Biren Amin with Piper Sandler.

I also wanted to convey my well wishes to you, Doug, and your family. Maybe on the Cohort 8 data, what do you need for FDA to demonstrate safety? I expect it would be clear for acute liver injury, but would FDA also want to see ALT/AST elevations in the trial? And what bar would be acceptable on ALT-AST elevations? And I guess maybe just a second question would be, can you give us the status of ENVISION and when you would hope to restart that trial?

Sure. I'll turn this to Louise.

Sure. For the Cohort 8. So we're certainly collecting all liver parameters, which include AST and ALT, and that goes into the calculation of ALI in addition to GDC and others. So certainly, that will be part of the calculation, but that goes into the definition of how we define acute liver injury. So certainly, FDA and us, importantly, will be looking at that.

In terms of ENVISION, we expect in the U.S. to first look at some of the Cohort 8 data to help inform restarting that trial.

Our next question comes from the line of Kostas Biliouris with Oppenheimer.

Doug, congratulations on a terrific career and sorry to hear about your family members. You turn a nonevent press release into the most important conference call here.

Maybe one question from us on DM1, given the relevance. We saw recently a publication from Avidity on DM1. And although they saw drug concentration in muscle in a dose response manner, when it comes to splicing correction, the data were very inconsistent and without any trends across placebo and active arms. Any thoughts on whether this could also happen to your case, if it's a result of variability? And how should we interpret a potential outcome like that if there is muscle concentration, but then the biomarkers are not consistent.

Sure. Louise, take that.

Without having read that publication, a few things to note. So based on our preclinical data, we see a correlation between muscle concentration and correction. I do believe that there's some limitations with dosing in their case in terms of how high dose they can get. So that might have played into it. I haven't seen the publication. But what I can say from our preclinical data, we do see a correlation with muscle concentration and correction.

I may be missing the most recent data, but I was under the impression that at least at the doses that avidity was capable of dosing to without a dose-limiting toxicity, they didn't see enormous differences in muscle concentration. On the other hand, Dyne did, but then because Dyne's therapy is a PMO, that additional muscle concentration doesn't result in significant additional knockdown because of the requirement that you need the machinery inside of the cell to affect the steroid blocking that occurs with the exon skipping modality of a PMO. So maybe I'm missing something we need to look at it, but at least what we're seeing in our preclinical models is a very clear direct correlation between muscle concentration and the ability to knock down and then downstream splice correction, which, frankly, Occam's razor for an siRNA would tell you that's what you're going to see.

Our next question comes from Ritu Baral with TD Cowen.

Doug, this is Josh Fleishman on the line for Ritu. We send our best wishes to you and your family. How strong has physician and patient interest been in ENDEAVOR Cohort 8 recruitment? And can you give any color on the current extent of enrollment?

Sure. Louise, do you want to that?

Yes, certainly, there is a significant interest in Cohort 8. We are in process of screening and haven't dosed yet. We expect to do that soon, but we are on track, as I mentioned, to present data by the end of this year.

Our next question comes from the line of William Pickering with Bernstein.

Doug, wishing you and your family well. For DM1, could you clarify if the initial disclosure will include Cohorts 3 and 4? And how much follow-up do you think that you need to see a splicing benefit? In the Avidity New England Journal paper, the authors hypothesized that the 1 mg per kg dose didn't show a splicing benefit despite good DMPK knockdown because the biopsy was at day 45 as compared to biopsy at day 90 for the higher doses that did show a splicing benefit. So just wondering how you think about the length of follow-up you need to see the splicing improvement and if that informed the plan to wait until second half of the year to share that splicing data?

Louise, do you want to touch on that?

Yes. So for DM1 to your point, so we'll have the SAD cohort data. We'll have early data on MAD, which will be primarily safety data for that. For the -- in terms of the splicing panel, the CASI-22 for DM1, that will be second half of this year. The DUX4 target gene expression, we will have early data from that in this preliminary readout and then additional data from the MAD cohorts later on in the year.

Our next question comes from the line of Brian Skorney with Baird.

This is Luke on for Brian. Thanks, Doug, for your openness on the call and best wishes for you and your family.

We have a broader question on the DM1 indication. Just hoping for some insight on understanding of the importance of numerical splice correction data, just thinking about both clinical impact and the perspective of regulators. Is 20% plus still a reasonable sort of bar just in thinking about the current competitive landscape and how that's shaping up?

Yes. I'm going to turn this again to Louise, who may have some views on it. The one thing to know on some of this is we need to really understand and fully analyze the FDA's perspective on this. We'll need to have meetings with the FDA, and I do want to be clear that, that is not something we've done.

So -- but with that said, Louise, thoughts?

Yes. Based on -- as I mentioned, so we're early on in this. And so we'll be analyzing this first cohort of data to look at the correlation of muscle concentration, splice correction, which we won't have for DM1 just now. And so we'll be analyzing all of that, working with our KOLs to inform our Phase III. So it's early for us to commit ourselves to a threshold in terms of what we think will be meaningful for the Phase III.

Our next question comes from the line of Gil Blum with Needham & Company.

Hope things go well for you, Doug. It's always -- it's not great to hear that people in your family are having issues, especially with an indication like this.

The one question that we have is just maybe a clarification as it relates to the LGMD program. Would you need to dose any patients with sirolimus prophylaxis before coming back to that? Or is the data from the DMD study sufficient there?

So the short answer is we need to have more conversations with the agency about that. There have been suggestions in telephone calls with the agency that they might want to see a patient dosed with prophylactically with sirolimus. But on the other hand, we'll have had a significant amount of prophylactic dosing with our DMD therapy, and it is exactly the same capsid, so it should be quite relevant. So we'll have to have more discussions with the agency if there is some benefit to, for instance, dosing a patient. This is an ultra-rare disease. So we're not dosing a lot of patients prophylactically as a predicate to a BLA. This is ultra, ultrarare disease. But if we are required to dose a patient, we certainly would do that.

But Louise , if you have more color than that, let me know.

Yes. No, I would just add that they specifically wanted to see data from Cohort 8 first and subsequent to that. So we'll have that conversation once we have that data in hand.

Our next question comes from Sami Corwin with William Blair.

And Doug, sending our best wishes to you and your family as well. Regarding the PMO guidance, I guess I was curious what your internal assumptions are for competition with some emerging exon skippers and how a lack of conversion to full approval could impact that guidance?

And then regarding the ENDEAVOR trial, do you plan on sharing what enrollment in Cohort 8 has been completed?

Yes. So I'll save the second part of that question, and Louise can answer that. On the first one, when we think about competition, I think the only credible near midterm potential competition on the exon skippers is Dyne's exon 51 therapy. First of all, the transition from accelerated to traditional or if there was a lack thereof has no impact in a very real sense because remember, if Dyne is capable of getting an approval any time in the near term, it's going to be on the basis of an accelerated approval. So it will be a completely flat playing field with respect to that. And I think that in the event that they are able to get an accelerated approval and with respect to the PMO side of things, you would think that they might be able to.

I think we'll have -- that will be real competition, and I think there'll be an interesting play in the marketplace. They'll have some features that they'll certainly be promoting on their therapy. We have a decade of data on ours to support our therapy. And it's extraordinarily well tolerated. Families absolutely fiercely are committed to these PMOs. So I think it will be real competition, and we'll be selling the benefits of our therapy and Dye will be selling the benefits of their therapy. I think that's the real one sort of midterm potential competitor, and it's only for one of our three PMOs, which is, of course, EXONDYS.

[Operator Instructions] Our next question comes from David Hoang with Deutsche Bank.

This is [ Sean ] on for David. Our best wishes to you and your family. Just a quick question on the recent announcement of DMD being added to the federal recommended uniform screening panel. Can you give us a sense of how rapid individual states might be rolling out the recommendation in their newborn screening programs and how that will impact the demand for ELEVIDYS going forward?

Yes. A couple of thoughts on that. First, before I talk about the mechanics of it, understand that this is fantastic. We've been working towards this day and the patient community has been working for this day for a very long time. So it was a really significant moment to get DMD added to the newborn screening panel.

And I also want to give an enormous amount of credit and kudos to the Secretary Kennedy himself, who really spearheaded this after consultation with specific folks from the patient community, understanding the significant value of having this out there, particularly so that at the earliest possible date, patients can benefit from existing therapies, including, for instance, our PMOs, EXONDYS, AMONDYS and VYONDYS, that was explicitly discussed with Secretary Kennedy. So I want to give a lot of kudos to HHS for their willingness to do that.

On the timing of this, this is going to be a really significant opportunity, but it is not going to be a near-term opportunity. So don't envision that this is going to have some impact on our guidance this year for two reasons. One, it takes time. I probably can't tell you how much time per state my Head of Government Affairs, Diane, would do a much better job than I will have exactly that timing. But it takes some significant time to roll this out on a state-by-state basis. We already have a significant number of states that have newborn screening, but this will, of course, really expand it with it being on the federal RUSP.

The second thing to know, remember, at least as it relates specifically to ELEVIDYS is that ELEVIDYS is for the treatment of boys four years and older. So to really see the benefit of this for the very young patient, we need to lower that age range. And we're working on that and intend to engage in the FDA and have some discussions about that. We think the data that supports going to a younger age is really compelling. We've got not only great expression. We've already proven that our therapy is efficacious. We proved it over and over again, which is really important, by the way.

Let's be very clear, one of the things that is so heartening about our therapy is that we have so many clinical trials. And specifically, we have this very large placebo-controlled trial that showed data in one year and two year and three year, taking all that data and then look at the safety for the very young kids and looking at the expression you get with the very young kids. And we think there's a very compelling argument. But to really fully get the benefit of this, we're going to need to adapt that label and that itself will take some time and some discussions. So both of those issues are going to delay the opportunity, but the opportunity is coming. And it is a really big deal. And again, it's very easy to have to criticize. But in this situation, I just want to give enormous kudos to HHS. And I really want to give specific kudos to Secretary Kennedy for his willingness to lead in this area and to focus on trying to create a better life for young boys that have Duchenne muscular dystrophy.

And it's important because as we say we say over and over and over again, to the point of almost being trite, time is muscle. And at any stage in this disease, if you can get in there and treat, you can save muscle that will otherwise be forever lost. And that's true of a 3-year-old versus a 4-year-old or a 2-year-old versus a 5-year-old, just as is true of a 9-year-old versus a 12-year-old or an 11-year-old versus a 14-year-old. So this is -- it's a big deal.

Our next question comes from the line of Andy Chen with Wolfe Research.

This is Brandon on for Andy. Sorry to hear the unfortunate news. One from us. On the Japan launch, are there any early signs such as start forms or other signals that should give us confidence in a positive launch within that region?

Yes. We really aren't in a position to provide that information. I think Roche is a perfect group to provide information. I mean I am very excited about the launch, but that really comes more from the basic knowledge that Japan has a very sophisticated health care system. It's a very large population, has a lot of patients that can benefit from this. And I think our partner, Roche, and their subsidiary, Chugai, I think, will do a brilliant job of serving the community in Japan. So I'm excited about it, but I can't give any more detail than that broad stroke. And I think Roche can probably do a much better job of that than I can.

And this concludes our Q&A session, and I will pass it back to Mr. Ingram for closing comments.

All right. Well, thank you all very much for spending time with us today. I'm just going to end with the way I started. 2025, as we all will acknowledge, was a difficult year filled with a lot of unexpected obstacles that needed to be overcome. I'm proud of this team for having worked through that and stayed resilient in overcoming them. I'm also proud of us taking the decisions we took in 2025 that put us in a strong position. Everything from the way we worked with the community itself to the fact that we restructured our convertible debt to remove any overhang and we did a restructuring, which painful though it was, really allowed us to focus on the highest value programs, highest value to the patient community and to Sarepta, and I think we're entering 2026 in a really strong place.

We're strong financially. We have going on $1 billion in cash and investments. We'll be growing that cash balance over time even as we fully invest in our programs and our commercial launch. We have four therapies that are bringing a better life to patients every single day, really very resilient PMOs are that people love as well as ELEVIDYS, which the evidence on ELEVIDYS and its benefits grows quarter-to- quarter to-quarter, and we're going to make sure that everybody that can benefit from that knows it, and I'm quite confident that's going to have a big impact first on the lives of those patients and then with the benefit on those patients to our investors.

And then finally, we have this extraordinarily exciting siRNA pipeline that includes now Huntington's disease, where we've actually started our clinical trial in Huntington's disease, and we'll be dosing patients starting next year -- I mean, sorry, next quarter, not next year, folks. And we're dosing DM1, we're dosing FSHD, we're dosing SCA2. We're dosing IPF. We'll have a readout on IPF later this year as well. So we've got this extraordinarily impactful pipeline as well. And we've got a team that knows how to execute and make the most of this pipeline, bring a better life to these patients as well. And over time, I think that we'll get the benefit of all of this extraordinary work as well.

So thank you very much for your time. Look forward to updating you across the course of this year as well. And with that, have a lovely evening.

And this concludes our conference. Thank you for participating, and you may now disconnect.

Good morning, and welcome to Sarepta's EMBARK 3-year data top line results call. As a reminder, today's program is being recorded.

At this time, I'll turn the call over to Doug Ingram, Sarepta's Chief Executive Officer. Please go ahead.

Thank you very much. First, before we begin, I must remind you that we will be making forward-looking statements today, so please review our various public filings for the risks and uncertainties that come when one makes statements like that.

Now with that, first, thank you all for joining us as we present the 3-year top line results from EMBARK, which is the ELEVIDYS Phase III pivotal trial. The results from EMBARK year 3 are remarkably important. While we have seen longer-term results in Study 101, a small 4-participant proof-of-concept study, the results discussed today are the first time in history anyone has measured the disease-modifying impact of a gene therapy over a 3-year period in a large, well-controlled clinical trial. ELEVIDYS is different than some other therapies. It works not by providing palliative relief only, but by generating a functional shock-absorbing form of dystrophin, the goal of which is to restore protection to the muscle and thereby modify the trajectory of disease.

With 3-year results, we can confirm not merely the benefits of the therapy, something we have done repeatedly in past readouts, but we can test whether those benefits meaningfully diverge and widen against natural history over time, something one would predict for a disease-modifying therapy. That test has implications for the long-term value of commencing ELEVIDYS treatment as soon as reasonably possible to change trajectory and to avoid the irreparable damage that occurs daily without disease-modifying treatment.

Now with that, I will turn the call over to Dr. Louise Rodino-Klapac. Louise?

Thank you, Doug. It's a pleasure to be here today to share the newest results from the EMBARK study. Next slide, please.

As you have seen in our press release that was just issued, top line functional results in patients who were treated with ELEVIDYS and EMBARK Part 1 demonstrated a dramatic shift in disease trajectory out to 3 years. In a few moments, Dr. Richardson will take you through the data in detail. But briefly, on average, ELEVIDYS-treated patients remain above baseline 3 years after treatment as measured by the North Star Ambulatory Assessment, or NSAA. In addition, ELEVIDYS-treated patients have a 70% or greater reduction in disease progression relative to the propensity-weighted external control group. This is measured by Time to Rise and 10-meter walk/run.

This is a long-term data in a robust controlled clinical data set and demonstrates the power of a disease-modifying therapy targeting the underlying cause of Duchenne. These statistically significant benefits not only persist but continue to strengthen over time, creating a sustained and growing separation from the expected disease trajectory and the known relentless decline from Duchenne. Understanding the disease trajectory is important.

Next slide, please. In Duchenne, the course of the disease follows a well-understood and predictable path of decline as shown here via scores on the North Star Ambulatory Assessment, a composite measure of motor function skills. Individuals with Duchenne typically reach their peak physical function around age 6 and then decline as a result of increasing fibrosis, decreasing muscle mass and waning regenerative capacity. The aim of dystrophin restoration treatments like ELEVIDYS is to alleviate this constant downward pressure on the development and maintenance of these skills that produce this curve.

Next slide, please. As mentioned, Duchenne occurs because of the relentless underlying muscle pathology including muscle fiber loss and corresponding fat and fibrotic replacement. This process begins before birth and progresses over time, as shown in these cross-sectional images of skeletal muscle from 1 year of age to 8 years of age. This again highlights the importance of early treatment with dystrophin restoration to slow this progression.

Next slide, please. As shown in this slide, the goal is to stabilize or slow the decline resulting from the degenerative process of Duchenne. As a result, change from baseline alone is not adequate in measuring therapeutic benefit. Comparison to the expected disease trajectory is critical. As illustrated in this graph, the therapeutic potential of dystrophin restoration is demonstrated and grows over time based on the divergence of the external control decline contrasted with the stabilization or slowing of progression in treated individuals.

Next slide, please. We have the most comprehensive data set in Duchenne, with greater than 1,200 patients treated with ELEVIDYS clinically and commercially. ELEVIDYS has been dosed in a wide range of individuals from as young as 2 to adults with advanced disease.

Next slide, please. As a reminder, EMBARK is a double-blind placebo-controlled trial with the primary readout 1 year following treatment. At the end of year 1, the placebo patients crossed over and received ELEVIDYS and patients already treated received the placebo infusion, and all patients received the per protocol increase in corticosteroids around the time of dosing. Participants, investigators and the study team remained [ blinded ] for the second year.

After 1 year and external controls required in place of placebo for comparisons as all study participants have now been treated. Today, we're sharing the 3-year data from participants treated in Part 1 that are now enrolled in the long-term extension study, Study 305.

Next slide, please. Before looking to the new 3-year data, here's a reminder of the functional results for all Part 1 patients treated out to 2 years. All measures strongly favored ELEVIDYS and were statistically significant versus external control. The results known as Part 2 from EMBARK were just published in the peer-reviewed journal, Neurology and Therapy earlier this month.

Next slide, please. I'd also like to remind you of the muscle MRI data. Muscle MRI provides an objective approach to assess underlying muscle pathology, measuring the level of fatty infiltration and T2 signal to correlate strongly to and predict future physical function.

Lower levels of fat fraction in T2 indicate healthier muscle. In the absence of an external control, here, we are showing the 2-year data in 2 representative muscles versus the 1-year placebo data. We see modest to no increase in fat fraction from baseline to 2 years and levels of 2 years are well below what is seen at 1 year in the placebo patients. This is consistent across muscle groups.

Even though you see that improvement in NSAA and other functional measurements, you see the impact of treatment being delayed even 1 year. The damage to the muscle continues and you will never achieve the same level of fat fraction of patients treated a year earlier. We are pleased with the treatment effect in a blinded study and reconfirmed with MRI imaging, and this highlights the importance of treating as soon as possible to preserve muscle.

Next slide, please. Over the past year, we've also presented and published cardiac MRI data through 2 years in EMBARK, which have no new signals and cardiac function remains within normal range.

Next slide. I'm going to now turn the call over to Dr. James Richardson, our CMO, to share the new 3-year data from EMBARK in greater detail. James?

Thank you, Louise. It's my pleasure now to present to you the 3-year results from the EMBARK Part 1 treated patients. These prespecified analyses take data from the complete 2 years of EMBARK and then the first year of our long-term extension study, EXPEDITION, also known as Study 305. This is by far the largest long-term follow-up of patients treated with the gene therapy for Duchenne muscular dystrophy and is all conducted within the rigor of a clinical trial setting.

Next slide, please. We compared the 3-year functional data from the treated patients followed within our clinical trials to a propensity-weighted control. As you'll know, propensity weighting represents the gold standard of external control analysis. The outcomes analyzed were NSAA, Time to Rise and 10-meter walk/run. This was based on the availability of these measures in appropriate external control data sets.

These 3 measures are well established as clinically relevant and highly predictive of future disease progression and having served as the primary and key secondary endpoints in EMBARK Part 1, they were defined as the 3 co-primary outcomes in the prespecified year 2 and year 3 statistical analysis plan. That plan also includes all the technical aspects of the analysis, including the methodology and criteria for selecting the external control. The external control data themselves are taken from contemporary natural history of placebo arm sources.

All these studies were prospectively selected and represent current standards of care, including the use of chronic corticosteroid therapy. External control patients were initially selected out from this pool of data of over 1,200 patients based on inclusion criteria and align with the availability of the required data and the baseline characteristics of the EMBARK trial participants. Individual weighting is an implied to the data to further improve the comparability to the treated patients.

Next slide, please. This approach is yielding an extremely well-matched comparator as you can see in the table on the left here. The table on the right shows that a large number of external control patients were available for comparison at each time point, further speaking to the rigor of these analyses. You may note that 11 patients did not progress from the end of the EMBARK study into EXPEDITION. Thorough analysis of these withdrawals provide no evidence that this introduced any bias in the subsequent analysis.

Next slide. Beginning with NSAA. Here, we see a 4.39 point difference at year 3 between the treated and external control with a highly statistically significant p-value of 0.0002. This delta is a little under twice that observed at year 2, and it will more than twice over the published MCID. Even if we focus purely on the treated patients, we see that, on average, they're remaining above their baseline 3 years after treatment.

As a reminder, the mean age at this point for these patients is around 9. An age within the natural history of Duchenne when most patients undergo a rapid decline in the NSAA. In fact, we can see this rapid decline if we turn back to the external control, we have lost nearly 4 points from their baseline 3 years prior.

Next slide, please. Moving on to Time to Rise. There is extensive published natural history work, demonstrating time to rise as the most sensitive and earliest time function test to worsen in this age group, and there is a significant predictor of loss of ambulation. The relentless decline of Duchenne is demonstrated by the progression of the natural of external control group whose time to rise, which at baseline was only 3.5 seconds on average, has now increased by a further 8 seconds.

The resulting difference of 6 seconds between the control and the treated patients is again highly statistically significant with a p-value of less from 0.0001. This delta represents a slowing of disease progression of more than 70% and a threefold widening of the treatment effect between the treated group and control since year 2.

Next slide, please. As with NSAA and time to rise, we again observed a highly clinically and statistically significant difference in the 10-meter walk run assessment of 2.7 seconds with a p-value of 0.0039. This represents approximately 70% slowing of disease progression. And again, we see this widening treatment effect over time with a doubling in the separation between the treated population and external controls between years 2 and 3.

Next slide. No new safety signals were observed in year 3 of this cohort, and no treatment-related serious adverse events were reported. This is consistent with our understanding of the safety profile of ELEVIDYS gathered through over 1,200 exposures in clinical trials and in commercial use.

Next slide, please. EMBARK and the EXPEDITION study represent by far the largest long-term follow-up in a clinical trial setting of a gene therapy for DMD. Using a prespecified analysis, the results show definitive and profound slowing of the progression of the disease in patients who are now on average approximately 9 years of age, time at which the untreated natural history is one of significant loss of function. On NSAA, in stark contrast to the projected trajectory, patients remain above their baseline 3 years following treatment.

Disease progression as measured either by the Time to Rise or 10-meter walk/run is being slowed by approximately 70%. Equally important, there were no new safety signals. Long-term follow-up of patients will continue, and we'll work to present and publish these data and more data in scientific forums. While the data provides us with powerful information to inform changes in how we treat disease, none of these results are possible without the individuals and their families who participated in our studies.

We are incredibly grateful for all of their contributions along with the contributions of investigators and site teams and my fellow Sarepta colleagues, who continue to inform our understanding of Duchenne and ways to change the course of this terrible disease. And with that, I will turn the call back over to Doug.

Thank you, Dr. Richardson. I would like to now to invite to provide her perspective on these results. Dr. Crystal Proud, a well-renowned thought leader in the care and treatment of those with Duchenne muscular dystrophy. In addition to caring for children with general neurological conditions, Dr. Proud is a board-certified pediatric neuromuscular neurologist with an expertise in caring for children with Duchenne muscular dystrophy, spinal muscular atrophy, Charcot-Marie-Tooth neuropathy, other muscular dystrophies, congenital myopathies and MS.

Dr. Proud received subspecialty training at Stanford University in both child neurology and pediatric neuromuscular neurology, participating in clinical research trials for children with muscular dystrophy and SMA. Dr. Proud is currently the Chief of Neurology and Director of Neuromuscular Medicine at Children's Hospital of the King's Daughters, CHKD, in Norfolk, Virginia, where she works collaboratively to provide a comprehensive approach to patients with neuromuscular diseases. With her research focused on the development of therapeutic trials for spinal muscular atrophy and Duchenne muscular dystrophy, she is the primary investigator for several clinical trials evaluating novel treatments for patients with various neuromuscular conditions. She also serves as the Medical Director for the CHKD Novel Therapeutics and Gene Therapy Center with a commitment to optimizing clinical care and offering participation in clinical research to patients and families affected by rare disease. I am honored to turn to Dr. Proud for her perspective on these results. Dr. Proud?

Thank you, Doug. Thank you for having me here today. I think that these results are incredibly encouraging and, to be honest, are consistent with my continued expectations for the therapeutic program. They also mirror my observations personally from my treated patients within the clinical setting. The beneficial impacts of ELEVIDYS really have been very tangible and measurable and the distinction from my untreated patients is quite clear.

The results demonstrate that ELEVIDYS really is changing what was known to be the natural history for these boys with Duchenne muscular dystrophy, and treatment has led to differences in their abilities to walk, to run, to perform everyday activities that many of us can very easily take for granted.

So overall, I look forward really to the continued data update since we can look forward to a new horizon for Duchenne, and this continues to demonstrate that we're continuing to push the envelope of expectation and hope. So I'm incredibly encouraged to see these results today.

Thank you so much for that. And with that, let's open the line for Q&A.

[Operator Instructions]. And our first question is going to come from Brian Abrahams with RBC Capital Markets.

Really nice to see the patients in the study continuing to drive benefits over the longer term here. Maybe just a question just in terms of process. Just I guess, I'm curious if you could maybe walk us through any differences in the external control here versus in the 2-year cut. I think the press release suggests there's maybe some subtle differences.

And I'm just kind of wondering if that was due to the matching to this -- to the cohort that you have now that are in this open-label extension? And then I guess I'm curious how you're going to be using some of the learnings here to really hone in on the messaging to clinicians and centers around the efficacy benefits that you're planning to focus on this year.

Thank you very much for your 2 questions. I will turn the first part of the question over to Dr. Richardson. Before I do that, I'll answer the second part by just reminding everyone, we discussed this at JPMorgan that we have a real opportunity in front of us today to really rebalance the discussion, talk obviously about the safety of our therapy and the proper administration and monitoring, but also balance that with all of the wealth of efficacy data we have. That is going to be a big part of our strategic goals over the course of 2026 and beyond.

And to that goal, we have already -- we're in the process actually of doubling the size of our sales force, but we're going to have a much more robust and well-balanced promotional activity as well. We've got peer-to-peer discussions on that. We'll be talking to the community to make sure the community is aware of what we're doing so that we're fully transparent with them.

So we have a lot of things to do this year to discuss broadly with everyone who can benefit from it, HCPs and the community, the accurate and balanced information around this therapy, and there is no doubt, Brian, to your very good question, that the 3-year data and what it means for the long-term benefits of this therapy over time is going to play a significant role in those communications.

With that, I'm going to turn it over to Dr. Richardson to answer the first part of that question.

Thank you for the question. So just to reiterate the sources selected for external control and the methodology for years 2 and year 3 were both prespecified. I think the disparity that you're pointing out to simply the availability of patients in external control with 3 years of follow-up that otherwise meet the criteria for matching. So that's why we see a slightly lower number in the external control at that point. But as you can see from the baseline characteristics, they remain extremely well matched. And I think it's still a very significantly sized comparator.

And the next question is going to come from Andrew Tsai with Jefferies.

So given the trajectory that you're seeing, would you expect to see some kind of mortality benefit soon, especially for the older ambulatory patients? Or would that take a little bit longer? I'd imagine seeing something like that could really drive real-world adoption.

I will once again turn this over to Dr. Richardson.

Thank you for the question again. So I mean, I think that looking at these disease milestones, which obviously mortality is the most significant is something that we continue to do. It's really about the number of events that you see that will drive our ability to demonstrate a statistically significant difference. So I think that seeing that in mortality will take a number of years given the natural history of Duchenne. I think that we'll see it in other milestones like loss of ambulation sooner.

And our next question will come from Yun Zhong with Wedbush.

And it's very nice to see the positive data coming out from 3 years of treatment. My question is, so for those clinicians and patients that might be more concerned about safety rather than efficacy because efficacy apparently is very good separation from natural history studies. So will you be able to provide any additional safety data, maybe not necessarily from this study, but from additional studies in 2026 to address those patient and clinician concerns, please?

Yes, that's a very good question. James, do you want to take that?

So I mean, obviously, our safety team are constantly updating our understanding of the safety signals created both in the clinical trials and the real world setting. That's something that is communicated, obviously, in near real time with the FDA, will be reflected on one hand in future label updates if necessary, which I don't expect at the moment.

And then in terms of making them more widely available, yes, we certainly do have some publications in mind and presentations in mid for '26 that will continue to keep prescribers and the community I'm aware of the growing body of data we have regarding the safety of this drug.

And our next question is going to come from Ritu Baral with TD Cowen.

Thanks for the update this morning. I wanted to just focus on Slide 20 and the year 3 EXPEDITION trial, SAEs. Can you give any more detail on the 4 newly emergent SAEs as detailed on Slide 20? And in the footnotes, it clearly said something about excludes unresolved events that began prior to this period. Can you characterize sort of the ongoing unresolved events over the year? And then if there's any detail on the dropouts.

Once again, Dr. Richardson.

Yes, just to take that question, I think, in the parts that I heard. So first of all, the unrelated SAEs in year 3 were a variety of conditions, I think, assessed both by the company and the investigator is unrelated, included, for example, an appendicitis to give one example. The footnote around the continuing AEs or SAEs between years is mostly just an ability to be able to tabulate these data with, I think, any sense because we will have events across that period between year 1 and year 2, and we need to understand where we're going to capture that. It's not, I think, because of any very prolonged SAEs that we're seeing within these patients.

And our next question will come from Yigal Nochomovitz with Citi Group.

For Dr. Proud, I was just wondering if you could speak a little more to what struck you the most in the long-term data that perhaps wasn't apparent from your anecdotal experience with ELEVIDYS in your clinic?

Thank you for that question. So I think that my clinical experience really mimics the data that you've seen Dr. Richardson present here today. I've been able to observe higher North Star Ambulatory assessment scores than what I would otherwise have expected in my untreated patients.

I've been able to see my patients continue to rise from the floor in times that are quite impressive given their age at a time where I might expect for them based on the natural history data for us to be able to see a decline where they take longer to rise from the floor or longer to ambulate 10 meters. I'm seeing that those numbers have stayed quite low compared to what I would expect for their age.

This is really meaningful to me because this is how I provide prognosis to families and preparation for families. Once a child hits a 10-meter walk time of 10 seconds or greater, they are expected to be in a wheelchair in nonambulatory within the next couple of years. So these are things that really help to facilitate my conversations with families as they navigate this disease and we're changing expectations now based on these results. And so I'm incredibly pleased to be having a different dialogue these days with those families.

And just one quick one for the company. When you look at this data, I'm just curious if you did any sensitivity work around the conclusions, if you were simply to look at just the natural history components of the synthetic control or just, say, the RCT components, if things generally look the same that way.

James?

I'm not fully understanding that question. Could you repeat it, please?

Well, I believe you had an RCT component in the control and then 2 natural history control. I'm just wondering if you were to run the analysis, say, with just the natural history controls, would that still support the conclusions or...

Understood. Understood. We haven't done that analysis as of yet, but it's a good thought. I don't imagine it would make a difference, but we can certainly look at that.

And our next question will come from Kostas Biliouris with Oppenheimer.

Congratulations on the data. One question for Dr. Proud and one for management, please. Maybe for Dr. Proud, to what extent do the unfortunate deaths in nonambulatory patients last year impact your decision to treat ambulatory patients with ELEVIDYS currently, especially given this 3-year efficacy data.

And for management, now that you have 2-year data post dosing for all patients from the 2 groups, have you looked into how the NSAA trajectory compares between the 2 groups from year 1 to year 2 post dosing. You had shown this last year. I don't know if you have done these analyses this year again.

Yes. So I'll have James touch on the second of the 2 questions and then we'll turn to Dr. Proud for her thoughts.

I'm sorry, could you repeat that question?

I think the question that Kostas had is basically we had shown 2-year data for the Part 1. We'll have 2-year data for the Part 2. Have we done an analysis or a pooled analysis of those 2 to see what that might look like?

Yes. Sorry. Thank you. Yes, absolutely. So we have done a pooled analysis looking at all patients dosed up to a 2-year period. The Part 2 patients are obviously dosed a year older and assessed a year older. So it's a slightly different analysis set to what you might want to compare with just the Part 1 patients dosed on their own. Nonetheless, the results are highly concordant.

And then Dr. Proud?

Yes. So my conversations with families these days involve discussion around the updated prescribing information and making sure that my patients and families are aware of all of the potential benefits and the possible risks that go along with this therapy just like any other therapy that I might prescribe.

Of course, I'm optimistic as we are able to consider the future clinical trial landscape and the knowledge that we might gain from expanding the opportunity to older and nonambulatory patients by looking at the Cohort 8 data set that will eventually be generated through addition of sirolimus in hopes that this may reduce some of that risk that we had been noticing regarding liver events in the previous cohorts. So as we generate more data, that will then inform that continued dialogue that I have with my families but those safety events do not necessarily augment my capacity to be able to offer this to families.

And our next question will come from Salveen Richter with Goldman Sachs.

In the context of the data that you're seeing to date, maybe help us understand how long you think a patient should be treated on this drug?

I'm not -- apologies for that, Salveen. I'm not sure this is a onetime therapy. Right.

Yes. But the duration of benefit that you're seeing in patients, drug arm versus control arm year-over-year.

Yes, apologies for that. I mean James, do you have any thoughts on that. I mean I will say, generally speaking, obviously, we have not seen any diminution of effect either preclinically in our animals over a long period of time. And of course, now we have in a very small group of patients all the way up to published 5-year data.

And then, of course, now we have in these patients and a widening divergence of benefit versus external control as you're tracking the long-term benefits, we will only know together over the next, hopefully, 10 to 20 years. But Dr. Richardson, do you have any additional thoughts on this?

No. I think that captures it, Doug. I mean, as you said, we don't see any diminution of effect yet. We're clearly impacting the natural history over these 3 years that we're presenting and we'll continue to understand more about this as the data evolves.

I'll just say one more time. And of course, all -- if you really want to look over the very long term, the only thing we can do is look to some of our preclinical data. And again, we have seen continuing benefits from this therapy for as long as we've been able to look, which the last time I think I was updated was somewhere in the 9-year range. So very good long-term benefits from this therapy.

And as we can see, both in a pilot study, what was called 101, a small group of patients and now with well-controlled clinical trial prespecified results, we're seeing not only a maintenance of benefit, but a significant divergence of benefit versus external control, which is exactly what one would anticipate from a disease-modifying therapy like ELEVIDYS, which works by providing to patients a functional form of the very dystrophin that protects their muscles that they are missing, which is the sole cause of this disease.

And our next question will come from Uy Ear from Mizuho.

So maybe one question for management and one question for Dr. Proud. For management, how do you -- what do you expect to do with the data? Are you -- with respect to the label, are you going to the FDA and try to get this data inserted into the label? And for Dr. Proud, you mentioned sirolimus use, and I was just wondering, based on your conversations with your colleague, like how prevalent or do you see a trend moving into larger sirolimus use?

Yes, I will touch on the management question very briefly to tell you that these data -- the top line results are hot off the press. And so we haven't made any decisions, for instance, about whether one would benefit from an updated label. Of course, these results are very consistent with labeled indication that we have, which, as you know, is a traditional approval for all ambulatory patients 4 years and above.

So they will play a significant role in our future communications about the benefits and risks of this therapy, whether we choose to make a label update based on that is something that we have to assess later to decide if it was necessary or helped. And with that, I'll turn the second question on the use of sirolimus to Dr. Proud.

Yes. It's an interesting one. I think that we have a lot to learn about the potential benefit of adding sirolimus to our treatment paradigm. And of course, we'd like to try to mitigate risk as best we can. And so I think that what we'll have to do is really look towards the data to be able to inform us most comprehensively once we can analyze the impact of sirolimus addition to therapeutic protocols, then we can truly understand the benefit and whether or not this is something that we need to be incorporating into our clinical practice in the future.

I wonder if I could offer a little bit more color going back on a question I think that I missed around the patients who had adverse events between year 2 and 3 and patients who dropped out between year 2 and 3.

So I think first of all, just to clarify that the one serious adverse event in year 2 has resolved. So that patient is not still suffering an ongoing adverse -- serious adverse events in year 3. As regards to patients who dropped out, this was largely for personal reasons. And as I said during the presentation, the impact of this has been looked at fairly rigorously with a number of different ways, particularly looking at their performance in years 1 to 2 and the functional performance is very much in keeping with the other patients that continued on into year 3.

And if you conduct the analysis of all the patients, so a full analysis set is presented to you today and compare that to a complete analysis set for patients who have data in year 1, year 2 and year 3, we see no real discordance, which is not what you would expect if these dropouts were impacting the results overall. So apologies for missing that question first up and hopefully that satisfies.

And the next question will come from Kristen Kluska with Cantor Fitzgerald.

As you think about patients, physicians or caregivers that have been more hesitant about ELEVIDYS use, how much of this was ultimately driven by questions still around efficacy? And now that you have these data on hand, do you think that you could sway some that were on the fence prior?

I'm just going to answer that in the broadest sense, which is I think there is -- I think given some of the challenges of 2025 and the obvious requirement that we spend a lot of our time talking through the safety and the like, I think there's a real need in the community and in the patient community and the physician community to fully understand this therapy with respect both to safety and to the benefits of this therapy. And so I do think there is a real value that will come from additional education around this.

And we have plans throughout the course of this year and into next year to really educate physicians and patients and their families on the benefits of this therapy, all of the prior study results that we've seen and what we're seeing out there as well as the results of this year 3 from a pivotal trial EMBARK and the talk to them as well about not only the safety of the therapy, but also the administration of the therapy, updated practice, our label, as you know, we updated it late last year. It includes additional monitoring to support safety and it includes advice on more proactive reaction if there are labs that are different.

So we'll educate on all of these things. And there is no doubt that having an opportunity to really talk to families and physicians about the objective benefits of this therapy from our clinical trials is going to be meaningful to them. So there's a lot of educational opportunity in all of this.

And the next question will come from Biren Amin with Piper Sandler.

Thanks for sharing the data update. Maybe just a question on for the 3 year, did you measure left ventricular ejection fraction at year 3? And can you share details around stabilization and improvement of that endpoint? And also, was there any evaluation done on respiratory function like forced vital capacity?

Dr. Richardson.

So cardiac function was measured both with echocardiography and with cardiac MRIs in a subgroup. We haven't analyzed that data yet, but we'll be doing so in the coming weeks, and we'll be making that public when we have the opportunity. As regards to respiratory function due to the age of these patients, respiratory function wasn't measured in the EMBARK study. We are measuring in EXPEDITION. So we will have data on these patients as they stay in the study over the years, but there is nothing meaningful to share at this time given it's just happening in the EXPEDITION study.

And the next question will come from Sami Corwin with William Blair.

I was curious if you've seen any correlation on the individual level between microdystrophin expression or other biomarkers earlier on in this long-term functional benefit? And then I was also curious if you've seen any functional cardiac benefit over this longer duration of follow-up.

Dr. Richardson?

So I think that the association between dystrophin expression and function is more clearly seen as we have more patients over a larger period of time, but it's, I think, a complex relationship and a nonlinear one. In terms of cardiac function, I just refer back to my previous answer. So I think that -- I mean, I think, first of all, these patients are still relatively young to see a lot of cardiac decline even in the natural history. But we are certainly interested in continuing to follow these patients to both ensure that they're stable from a cardiac perspective and that over time as a natural history would predict a decline in cardiac function, we're seeing a treatment benefit with ELEVIDYS. But those data for year 3 are still pending analysis, and I think will become more interesting as well in subsequent years.

And the next question will come from Mitchell Kapoor with H.C. Wainwright.

This is [ Katie ] on for Mitchell. Looking at your data, it's mostly presented as means. And I guess my question is around the variability within that data set. Are there outliers on either end of that response? And have you considered presenting that data in terms of milestones in the future, something like TTR greater than 5 seconds.

Dr. Richardson?

The individual pattern of response is in general one of stabilization of their disease part as we would expect from a dystrophin-restoring therapy and a reduction in the frequency of patients with rapid decline. In terms of milestone analysis, yes, absolutely, we're super interested in milestone analysis. I think that in terms of loss of functions, whether that's timed function test or loss of ambulation, the absolute numbers losing those functions in the external controls are still relatively low, which is inhibiting our ability to produce [ analysis ] right now, but we are continuing to look at the data and I'm confident that we'll be able to show an effect on important clinical milestones in the future.