Sarepta Therapeutics, Inc. (SRPT) Earnings Call Transcript & Summary

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.

And the next question will come from David Hoang with Deutsche Bank.

This is [ Sean ] for David. I guess one question that I have is around the ambulatory status. So can you comment on ambulatory status of patients, if there was any patients during the 3-year window who transitioned from ambulatory to non-ambulatory. And my second question is more broad. So how do you think this 3-year data set could impact prescribing patterns and commercial uptake as we progress through 2026?

Yes. Answering the second question, of course, it's all about education so that both the patient community and the caregiver -- and the physician community, both treating physicians and referring physicians have a balanced understanding of the profile of this therapy, including the benefits. Not only the immediate benefits of the therapy when launching it over a sort of 12-month period, but seeing the diverging benefits in trajectory when you have a disease-modifying therapy that's changing the future for these patients. So that will all come down to education and we certainly are strong believers that education works in so far as it allows for an informed group to consider therapeutic options. So more to come on that as it relates to the first question, I will turn it over to Dr. Richardson today.

Thanks, Doug. So I think this also relates to the last question about milestone analysis. So we had 2 patients in the treated arm who lost ambulation over the 3 years which is roughly about half the number that lost ambulation in the external control. We see a similar signal on other milestones. We just -- as I said, the absolute numbers are relatively small now to be able to come out with a formal analysis.

And the next question will come from Gil Blum with Needham & Company.

Thanks for the comprehensive update. Maybe this is just one question as it relates to the NSAA change in the treatment arm from year 2 to year 3. So it does appear that there's a certain level of decline, obviously, not nearly as much as seen in the external control. Can you put the decline in context? Is it like within error margins? Or how should we view this?

Sure. Again, Dr. Richardson.

Thanks for the question. So I think, again, what we're seeing is largely a stabilization of the treatment trajectory of patients. And so we do see patients who are declining post treatment, but if you look at the individual trajectory, they are overall declining less steeply if they are declining than the external controls. So I think that to see no decline in the [ NSAA in treated ] patients is not a realistic treatment expectation, but I think to see a greatly modified disease trajectory is a realistic expectation.

And the next question will come from Anupam Rama with JPMorgan.

This is Priyanka on for Anupam. It might be too early to tell, but are there noticeable differences in treatment effect in those who were treated at a really young age, like 4 years versus the relatively older population of 7 years?

Dr. Richardson, do you have that information?

We haven't completed an analysis of these by age yet, but historically, we have seen across our data sets, good treatment effect both in younger patients and patients those with an older age. There tends to be different sensitivities depending on the timed function test or whether we're looking at the NSAA, which is related to how sensitive those particular tests are to the age group and whether that age group can expect to lose that particular function.

And just to remind everyone that Dr. Richardson is speaking to the functional test manifestations. But remember, while the average boy is diagnosed somewhere in the 4, 4.5 year range, this disease is causing damage even in utero. So even by the time a boy is born, they're beginning the process of damaging their muscles. And remember also that the therapy like ELEVIDYS and any other therapy that is possible today with respect to Duchenne muscular dystrophy cannot bring muscle back that has been damaged. It can only slow or stop future damage. That is -- I mean I'm talking even broadly about other therapies as well. So the concept of early intervention, just Occam's razor tells us that it is going to be beneficial to get to patients as soon as reasonably possible to stop the damage that could occur from disease.

[Operator Instructions] Our next question comes from Yanan Zhu with Wells Fargo.

Great. Thanks for the update. Maybe a quick question for the company and a question for the doctor. Is there any planned muscle biopsy in year 3 and also in future, if not, perhaps anything planned in future years? For the doctor, I was wondering, could Dr. Proud comment on patient interest for ELEVIDYS in ambulatory population at your practice? And how has it evolved since the initial safety update in early 2025? Do you think it could recover to pre-safety update level with enhanced education and promotion?

Sure. Let's turn first to Dr. Proud, and then we'll turn back to answer the first part of your question.

Sure. So interest from my patients in clinic, I don't -- I have not seen a shift as far as any sort of decline in interest. I think that my patients know based on the dialogue that I have with them routinely that my primary objective for them is to pursue a dystrophin-restoring therapy as the foundation for their treatment. And so as ELEVIDYS is a dystrophin-restoring therapy, that would be something that we would have a dialogue about. So I've not necessarily seen any change over time or decrease in that level of interest. I think that data like -- the data that has been shared today is certainly something that they will be eager to discuss with me if they make decisions on their treatment moving forward.

Dr. Richardson, can you just confirm my understanding that there wouldn't be biopsies associated with these year 3 patients. Is that correct?

That's correct. There's no biopsies in the 305 EXPEDITION protocol.

So we understand there's a lot of reasons why it would be very difficult. First, it is unbelievably intrusive to do a biopsy. It is one of the most difficult parts of a clinical trial for these families. So limiting the number of biopsies to those that are absolutely required is an important overarching goal Second of all, if you -- one of the issues we have with the long-term follow-up on the study and studies like it is this is a onetime therapy. So these families that are participating and staying in the study for multiple years are really doing an enormous service to other families since they'd fully receive the benefits of the therapy if one burden them with additional biopsies would very likely cause either reluctance to enter studies like this or frankly higher dropout rates than would be acceptable. So I think it would be very difficult to do that.

Yes. No, I just wanted to remind that we did do multiple time points of biopsies previously in EMBARK. And so the 1-year results for the later time points were actually consistent to somewhat higher in terms of expression over time. So we've looked in series at multiple time points previously and saw consistency and actually some growth over time.

And the next question will come from Andy Chen with Wolfe Research.

This is Brandon on for Andy. And the work that you've done, we're curious to know, are you able to quantify the group amid the DMD community that leads with hesitancy to take the therapy because of more of a safety concern? Or is it broadly the skepticism around how efficacious the drug could actually be?

Well, I think it's -- generally speaking, I think we would say -- and I'll turn this to Patrick if he has any additional direct objective market research on this. But broadly speaking, it really is an information deficit issue. We just need to provide fully balanced information on the benefits and the safety profile of this therapy. But Patrick, you can provide any additional color that you have on that.

Yes. I mean you're hitting the nail on the head. And this data is extremely important, and we're going to factor all of this into our conversations both with physicians as well as patients and families. And just to remind you, this is the first time we've had this type of data for a gene therapy. And so we are going to lean in and balance our discussion as we talk about both safety and efficacy.

I am showing no further questions in the queue at this time. I would now like to turn the conference back over to Doug Ingram for closing remarks.

Thank you for that. And let me just say thank you to a few folks before we conclude, I want to thank, once again, echo Dr. Richardson and Dr. Rodino-Klapac. Thank you to both the families that participated in this study as well as our investigators who have committed themselves to these patients and made a significant role in these studies. I want to thank specifically Dr. Crystal Proud for her willingness to take time out of her very, very busy schedule to provide her valuable perspective and insight on the meaningfulness of these results. And I want to thank all of you for joining us today and for your very thoughtful questions. We really appreciate that and look forward over the course of this year to providing additional updates on all of the work that we're going to be doing, including, as we've talked about today, our various education plans to talk about not only these results, but the broader issue of the benefits of this therapy and the entire profile of this therapy, ELEVIDYS. We also, as you will remember, have some really interesting results from the rest of our pipeline, including our siRNA therapies, both DM1 and FSHD, which will happen before right around the very late first quarter of this year. So looking forward to updating you across the year as we continue to serve the communities that we serve and execute on our plans. With that, have a wonderful day, everybody.

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