Sarepta Therapeutics - Q4 2025

Transcript

Operator (participant)

Good afternoon, 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 Ian Estepan, Sarepta's Director of Investor Relations. Please go ahead.

Ian M. Estepan (Director of Investor Relations)

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

Doug Ingram (President and CEO)

Thank you, Ian. 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, 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. 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 and, 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, four 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 LGMD2E. Over 1,200 patients have already been treated with ELEVIDYS. 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. 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 two infusion. 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.

While it is challenging to perfectly model the exact shape of the revenue curve of a one-time 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. 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 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-$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. 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. 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 programs 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.

Louise Rodino-Klapac will discuss later in this call. With that, let me turn the call to our Chief Commercial Officer, Patrick Moss. Patrick?

Patrick Moss (Executive VP and Chief Commercial Officer)

Thank you, Doug, and good afternoon, everyone. As pre-announced 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.

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 robust and growing body of data for ELEVIDYS.

Two-year data from EMBARK Part Two has recently been included in our promotional efforts. The three-year EMBARK top-line data was shared last month and will be presented at the upcoming MDA Conference. Both the two and three-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. 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. 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 newer 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.

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 one-time 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. 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. 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. 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?

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

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 one 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 One 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 Ten Meter Walk/Run, when compared to a pre-specified 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 Ten 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 Ten 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 show 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.

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, a known side effect of all AAV gene therapies. Cohort 8 will enroll approximately 25 US participants who are non-ambulatory. 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 & Scientific Conference, which will take place in Orlando, Florida, from March 8th through March 11th. 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. 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 αvβ6 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 a 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've accepted our application. 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 months-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 28th.

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

Ryan Wong (Interim CFO)

Provided details for the fourth quarter and full-year on a GAAP basis as well as a non-GAAP basis. 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 in cap to 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-$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. We anticipate recognizing $325 million of non-cash collaboration revenue tied to Roche declining an option for a specific program. We expect total collaboration, contract manufacturing, and royalty revenues in 2026 to be in the range of $450 million-$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 non-cash 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 on 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. Consistent with cost reduction targets we announced last July, we are reaffirming our 2026 non-GAAP OpEx outlook of $800 million-$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 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 to our key value inflection points. We remain committed to disciplined financial execution and to delivering sustained and non-GAAP operating profit and positive cash flow. Now I'll turn the call back to Doug for closing remarks. Doug?

Doug Ingram (President and CEO)

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. 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. 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. Because of that commitment, we now have 4 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. That impact compounds 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've 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 4 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, after a lot of thoughtful consideration, I have informed the board that I intend to retire as CEO. 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. We stand at one of the most exciting moments in our entire history. However, I have family commitments that require my attention. I will explain them, even though I normally, I'm a relatively private person. I'll explain. When I joined Sarepta, I had no personal connection to muscular dystrophy. 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. Subsequent to that partnership, in a fairly shocking and certainly ironic twist of fate, my personal commitment to muscular dystrophy has deepened, as 2 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. With that, let's turn the call to questions. Can we open the call for questions now?

Operator (participant)

As a reminder, to ask a question, press star one one on your telephone and wait for your name to be announced. To remove yourself, press star one one again. In the interest of time and as a courtesy to other analysts, we ask that you please keep your questions to one. One moment while we compile the Q&A roster. First question is from Anupam Rama with JP Morgan. Please proceed.

Anupam Rama (Managing Director and Senior Equity Analyst)

Hey, guys. Thanks so much for taking the question. 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 know, you're still, you know, coming out of a tough period for ELEVIDYS in 2025. You know, you've got to defend your PMO franchise. You've got to deliver on the Arrowhead assets, right? How do you think about continuity with somebody like Ian M. 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?

Doug Ingram (President and CEO)

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 an important part of this company.

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. You know, I can at least commit to all of you that I and the board understand where we are as an organization, and we're gonna 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 now. 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. We have a lot to execute and a great team, and whoever we ultimately choose to be the successor CEO, I'm confident will 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.

Patrick Moss (Executive VP and Chief Commercial Officer)

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

Doug Ingram (President and CEO)

Thank you, all, I really.

Operator (participant)

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

Brian Abrahams (Managing Director and Co-Head of Biotechnology Equity Research)

Hey, good afternoon. Thanks for taking my question. Doug, thanks for the heartfelt message, 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 gonna be looking for over maybe the first half of this year that might suggest initial receptivity? 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? Thanks.

Doug Ingram (President and CEO)

Yeah, they're both are very good questions. I'm gonna turn this over to Patrick for a more detailed answer. In the broadest of strokes, the ultimate signal is gonna be embedded in the first and foremost enrollment forms, and then ultimately in infusions. 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, you know, it's remarkable how much data we have on the completely trajectory-changing benefits that come from this therapy, and really being able to contextualize that and for having people fully understand that is an exceptionally important issue.

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

Patrick Moss (Executive VP and Chief Commercial Officer)

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

Brian Abrahams (Managing Director and Co-Head of Biotechnology Equity Research)

Thanks very much.

Operator (participant)

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

Paige Thompson (Analyst)

Hi, this is Paige Thompson for Ellie. Thanks for taking our question. 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? If not, what levels could we see that read well to higher doses?

Doug Ingram (President and CEO)

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

If you think about the mechanism 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, you know, 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.

If you have a very safe therapy or relatively safe therapy, and you have great muscle concentration at, you know, at low doses, then, you know, Occam's razor, the rest will come, including the knockdown, the downstream splicing, and the functional benefits and the like. 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. I turn it over to Dr. Rodino-Klapac to provide her views.

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

Yeah. Thank you. 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. 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. So we using siRNA, we are not limited by that.

Taken together those two things, so both the 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. That's what we're 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'll further evaluate.

Operator (participant)

One moment for our next question. That comes from the line of Andrew Tsai with Jefferies. Please proceed.

Andrew Tsai (Managing Director and Equity Research Analyst)

Hey, thanks. I appreciate the updates, Doug. Wishing you and your family all the best. 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 second half, or do you need to do more dose expansion work? I'm also curious, your guys' latest thinking on the accelerated approval pathway for these indications. In DM1, I think one company's going after accelerated, the other, full approval, so I would love to know what your guys' stance are. Thanks.

Doug Ingram (President and CEO)

Thanks. I'll turn this over to Louise.

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

Yeah. First, on the phase III, 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. 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. We are, as you would predict, moving as fast as possible in terms of the potential for an accelerated approval. It'll 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. We are taking our fastest approach, regardless of whether we ultimately end up getting an accelerated versus a traditional approval. We'll do so and make sure that we are collecting the appropriate data, functional data to support both.

Andrew Tsai (Managing Director and Equity Research Analyst)

Thanks.

Operator (participant)

Our next question comes from the line of Joseph Schwartz with Leerink Partners. Please proceed.

Joseph Schwartz (Senior Research Analyst)

Thanks so much, and 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?

Doug Ingram (President and CEO)

Yeah, let me say one thing, and I'll turn it over to Patrick to answer the details. I don't think that our view has changed. Whether what the current state in the market may be before more education occurs, you know, it may be different than that. Just to be clear, we think there's this an enormous opportunity. As we said, the vast majority of the addressable ambulatory patient population remains to be dosed, and we're confident that those, all those patients would benefit. We won't get all of those patients, I'm not unrealistic, but 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.

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. We have work to do there. In the interim period, I think, Patrick, maybe you can talk to how you see, you know, physicians and stratifying patients and excluding and including patients and the like.

Patrick Moss (Executive VP and Chief Commercial Officer)

Yeah. In addition to that, Doug, what we see is with Duchenne, it's obviously a rare disease that impacts the entirety of a family. It's really each patient, they have a unique situation. There's, you know, travel, schedule, siblings, all of that, you know, is contemplated as the physician and the patient and the family decide whether they're gonna move forward at what rate.

Doug Ingram (President and CEO)

We do see, I think, you know, some physicians without more information leaning younger. 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. That practice may also, over time, impact the patients that physicians see as amenable for this therapy.

Joseph Schwartz (Senior Research Analyst)

Thank you.

Operator (participant)

Thank you. Our next question comes from the line of Yigal Nochomovitz with Citigroup. Please proceed.

John Wolleben (VP and Equity Research Analyst)

Hi, this is John on for Yigal. Thanks for taking our question and 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?

Doug Ingram (President and CEO)

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

Patrick Moss (Executive VP and Chief Commercial Officer)

I would turn them over to Roche.

Doug Ingram (President and CEO)

We're excited. As you all know, our partner is launching that therapy in Japan. Japan is an extraordinary opportunity, very large population, very advanced healthcare system, you know, understands the value of therapies and how to price therapies as a culture. 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. We're very excited about not merely the opportunity, but the ability to do some good in Japan.

John Wolleben (VP and Equity Research Analyst)

Got it. Thank you.

Doug Ingram (President and CEO)

Thank you.

Operator (participant)

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

Tommy Smith (Analyst)

Thanks for taking our question. This is Tommy on for Salveen. We're just hoping for some more details on ELEVIDYS' quarterly dynamics. Your guidance of the 1Q being flat to 15% down, how do the rescheduled infusions play into that? Just checking on some of the math, assuming $900 million in PMO revenue, giving you an ELEVIDYS range of around $300 million-$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.

Doug Ingram (President and CEO)

Yeah, I'll give the broad strokes, and then again, Patrick may have more color for you. As we look across the year, First thing to consider on a quarterly basis, if we say we're gonna be flat to slightly down, is that given the, this rare disease and given the cost per patient, you know, 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. It doesn't just become additive, but, you know, ultimately, it, the patients will be there.

I think we 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. There's two things to know on those ranges, the sort of 1.2-1.4. It does relate to the, to ELEVIDYS, far more than the PMOs. The PMOs are very stable, they're easier, I should say, to forecast because they are chronic therapies. You're tend to be forecasting on the margins of a therapy, as opposed to what you have to do with a one-time therapy like ELEVIDYS, which is basically you start new every quarter, you have to forecast that way.

$1.2 billion implies that we're at steady state with no new educational efforts of any benefit. 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 more enrollment forms, and that gets you up toward the $1.4 billion. 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 these patient educational liaisons that we're gonna 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.

The enrollment to infusion time is itself something in the, you know, four to the very lowest, four months to even six months. 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, you know, significantly into the second half of this year and then very significantly, really, in 2027. That's kind of the delta between the $1.2-$1.4. Patrick, you may have other metrics that you think I've missed.

Patrick Moss (Executive VP and Chief Commercial Officer)

Well, I mean, you hit most of them, I'd really start out to say that with ELEVIDYS, the quarter-to-quarter dynamics, as you mentioned, they can be noisy, right? We have to consistently look at performance over the longer arc rather than each quarter. You know, with, you know, the identification and, you know, screening of the patients and ultimately dosing, that can lead to that variability. 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.

Doug Ingram (President and CEO)

Yeah. One other thing to know, you 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. 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 looked brilliant. The two-year data looked, you know, 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. There's another big issue as well on this issue of sort of educating and information, and that is that. This, I find this really troubling, and that is that you have a much better chance of getting infused with ELEVIDYS if you're middle class, English speaking, well educated. There is a real delta that exists where, you know, 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, that can talk to people where they are. We have other thoughts about how we can support people that are struggling but have, you know, children with Duchenne, which is very, very common, frankly. That is a, 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 to muscles that desperately need it.

Operator (participant)

One moment for our next question. That comes from the line of Tazeen Ahmad with Bank of America. Please proceed.

Tazeen Ahmad (Managing Director)

Hi, good afternoon. Thanks for taking my question. 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? Is that assumption also embedded in the $1.2 billion-$1.4 billion guidance that you've provided? Thanks.

Doug Ingram (President and CEO)

Probably that thesis is probably not fully embedded in the 1.2-1.4. To your interesting point, physicians 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, we've 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 as a predicate to getting the gene therapy, and there'll 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, you know, fully benefit. This is a very complicated disease, as we all know, and I think, you know, having adjunctive therapies with a gene therapy like our 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.

Patrick Moss (Executive VP and Chief Commercial Officer)

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.

Tazeen Ahmad (Managing Director)

Okay, thank you. Doug, best wishes to you and your family.

Doug Ingram (President and CEO)

Thank you so much, Tazeen.

Operator (participant)

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

Mitchell Kapoor (Director and Senior Biotechnology Analyst)

Thanks so much. 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, you know, the early trends you're seeing in 2026 for ELEVIDYS so far. Obviously guiding to flat to down 15% for the quarter, but 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 number.

Doug Ingram (President and CEO)

Sure, Patrick, I'll turn this to you. I'd caution reading too much into really any single quarter. I mentioned before, ELEVIDYS is not a product that, you know, 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, you know, the new data, expanding the field sales force, 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, again, that time from enrollment form to infusion is still around six months.

Tazeen Ahmad (Managing Director)

Thank you.

Operator (participant)

Moment for our next question. It comes from the line of Michael Ulz with Morgan Stanley. Please proceed.

Michael Ulz (Executive Director and Biotechnology Equity Research Analyst)

Good afternoon, and thanks for taking my question. Doug, let me add my best to you and your family as well. Maybe just to 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. Then, should we anticipate vHOT as well? Thanks.

Doug Ingram (President and CEO)

I'll turn this to Louise.

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

Yep. In terms of PD for DM1, we will have early DMPK knockdown data, and for FSHD, it'll be DUX4 targeted gene correction in terms of the early data for that.

Michael Ulz (Executive Director and Biotechnology Equity Research Analyst)

Great. Thanks.

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

Mm-hmm.

Operator (participant)

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

Biren Amin (Managing Director and Senior Research Analyst)

Yeah. Hi, guys. Thanks for taking my questions. 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, you know, clear for acute liver injury. Would FDA also want to see ALT/AST elevations in a trial? What bar would be acceptable on ALT/AST elevations? 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? Thanks.

Doug Ingram (President and CEO)

Sure. I'll turn this to Louise.

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

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

Operator (participant)

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

Kostas Biliouris (Managing Director and Senior Biotechnology Analyst)

Thanks for taking our question. Doug, congratulations on a terrific career, and sorry to hear about your family members. You had a non-event 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? Thank you.

Doug Ingram (President and CEO)

Sure. Louise, take that?

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

Without having read that publication, a few things to note. 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 a 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.

Doug Ingram (President and CEO)

Yeah.

Kostas Biliouris (Managing Director and Senior Biotechnology Analyst)

Thank you.

Doug Ingram (President and CEO)

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, you know, without a dose-limiting toxicity, they didn't see enormous differences in muscle concentration. Dyne did, but then because Dyne's therapy is a DMO, 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 steric blocking that occurs with the exon-skipping modality of a PMO. Maybe I'm missing something we need to look at, but I, you know, 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, you know, frankly, Occam's razor for an siRNA would tell you that's what you're going to see.

Kostas Biliouris (Managing Director and Senior Biotechnology Analyst)

Thank you. Congrats again.

Doug Ingram (President and CEO)

Thank you so much.

Operator (participant)

Our next question comes from Ritu Baral with TD Cowen. Please proceed.

Josh Bleichman (Senior Equity Research Analyst)

Hi, Doug. This is Josh Bleichman on the line for Ritu. We send our best wishes to you and your family, and thank you for taking our question. How strong has physician and patient interest been in ENDEAVOR Cohort 8 recruitment? Can you give any color on the current extent of enrollment?

Doug Ingram (President and CEO)

Sure. Louise, you want to touch that?

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

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

Josh Bleichman (Senior Equity Research Analyst)

Great. Thank you.

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

Mm-hmm.

Operator (participant)

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

William Pickering (Senior Research Analyst)

Hi, thank you for taking my question. Doug, wishing you and your family well. For DM1, could you clarify if the initial disclosure will include cohorts 3 and 4? How much follow-up do you think that you need to see a splicing benefit? In the Avidity The New England Journal of Medicine 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. 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.

Doug Ingram (President and CEO)

Louise, do you want to touch on that?

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

Yeah. For DM1, to your point, we'll have the SAD cohort data. We'll have early data on MAD, which will be primarily safety data for that. In terms of the splicing panel, the CASI-22 for DM1, that'll be second half of this year. The DEX for 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.

Operator (participant)

Our next question comes from the line of Brian Skorney with Baird. Please proceed.

Luke Sergott (Equity Research Analyst)

Hi, team. 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. Thank you.

Doug Ingram (President and CEO)

Yeah, 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, you know, 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 is not something we've done. But with that said, Louise, thoughts?

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

Yeah. I, based on, you know, as I mentioned, we're early on in this, 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. We'll be analyzing all of that, working with our KOLs to inform our phase 3. It's early for us to commit ourselves to a threshold in terms of what we think will be meaningful for the phase 3.

Operator (participant)

Our next question comes from the line of Gil Blum with Needham & Company. Please proceed.

Gil Blum (Senior Analyst)

Good afternoon, everyone, hope things go well for you, Doug. It's always, you know, it's not great to hear that the people in your family are having issues, especially with an indication like this. The one question that we have is just a really 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? Thank you.

Doug Ingram (President and CEO)

The short answer is we need to have more conversations with the agency about that. There have been suggestions and telephone calls with the agency that they might want to see a patient dose with the, you know, prophylactically with sirolimus. On the other hand, we'll have had a significant amount of prophylactic dosing with our DMD therapy, and it is exactly the same passage, so it should be quite relevant. 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 an ultra-rare disease, you know, if we're required to dose a patient, we certainly would do that.

Louise, if you have more color than that, let me know.

Louise Rodino-Klapac (Executive VP, Chief Scientific Officer, and Head of Research and Development)

Yeah. No, I just add that they specifically wanted to see data from Cohort 8 first and subsequent to that. We'll have that conversation once we have that data in hand.

Gil Blum (Senior Analyst)

Thank you, and our best wishes again.

Doug Ingram (President and CEO)

Thanks.

Operator (participant)

Thank you. Our next question comes from Sami Corwin with William Blair. Please proceed.

Sami Corwin (Research Analyst)

Hi, thanks for taking my question. Doug, you know, we're 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. Regarding the ENDEAVOR trial, do you plan on sharing when enrollment in Cohort 8 has been completed? Thank you.

Doug Ingram (President and CEO)

Yeah. I'll save the second part of that question. Louise can answer that. On the first one, when we think about co-competition, I think the only credible near midterm potential competition on the exon skippers is Dianne's EXONDYS 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 Dianne is capable of getting an approval any time in the near term, it's going to be on the basis of an accelerated approval. It'll be a completely flat playing field with respect to that.

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. You know, I think we'll have real competition, and I think they'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, you know, it's extraordinarily well-tolerated. Families absolutely fiercely are committed to these PMOs. I think it will be, you know, real competition, and we'll be selling the benefits of our therapy and, you know, Dianne 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 (participant)

Thank you. As a reminder, ladies and gentlemen, if you do have a question, simply press star one one on your telephone to get in the queue. Our next question comes from David Hong with Deutsche Bank. Please proceed.

Sean Kim (Analyst)

Yeah, this is Sean on for David, and thank you for taking our questions and our best wishes to you, Doug, 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? Thank you.

Doug Ingram (President and CEO)

Yeah, a couple thoughts on that. First, before I talk about the mechanics of it, understand that, you know, this is fantastic. You know, we've been working towards this day, and the patient community has been working for this day for a very long time. It was a really significant moment to get DMD added to the newborn screening panel. I also wanna give an enormous amount of credit and kudos to Secretary Kennedy himself, who really, you know, spearheaded this after consultation with specific, you know, folks from the patient community, understanding the significant value of having this out there, particularly so that the earliest possible day patients can benefit from existing therapies, including, for instance, our PMOs, EXONDYS, AMONDYS, and VYONDYS. That was explicitly discussed with Secretary Kennedy.

I want to give a lot of kudos to HHS for their willingness to do that. On the timing of this is going to be a really significant opportunity, but it is not gonna be a near-term opportunity. Don't envision that this is gonna 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, Dianne, would do a much better job than I will of exactly that timing. 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 4 years and older. To really see the benefit of this for the very young patient, we need to lower that age range. We're working on that and, you know, 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've proved it over and over again, which is really important, by the way.

Let's be very clear, you know, one of the things that, you know, 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 at one year and two year and three year, and taking all that data and then looking at the safety for the very young kids and looking at the expression you get with the very young kids. We think there's a very compelling argument. To really fully get the benefit of this, we're going to need to adapt that label, and that, you know, that itself will take some time and some discussion. Both of those issues are gonna delay the opportunity, but the opportunity is coming, and it is a really big deal.

You know, it's very easy to have to criticize, in this situation, I would just wanna give enormous kudos to HHS, and I really wanna 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. It's important because, as we say over and over and over again, to the point of almost being trite, time is muscle. At any stage in this disease, if you can get in there and treat, you can save muscle that will otherwise be forever lost.

That's true of a three-year-old versus a four-year-old, or a two-year-old versus a five-year-old, just as it is true of a nine-year-old versus a 12-year-old, or an 11-year-old versus a 14-year-old. This is a, it's a, it's a big deal.

Operator (participant)

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

Brandon Folkes (Senior Analyst and Managing Director)

Hey, this is Brandon for Andy. Sorry to hear the unfortunate news, and thank you for taking our question. 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? Thank you.

Doug Ingram (President and CEO)

Yeah, 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...

Brandon Folkes (Senior Analyst and Managing Director)

Mm-hmm.

Doug Ingram (President and CEO)

has a very sophisticated healthcare system, it's a very large population, has a lot of patients that can benefit from this. I think our partner, Roche, and their subsidiary, Chugai, you know, I think will do a brilliant job of serving the community in Japan. 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.

Brandon Folkes (Senior Analyst and Managing Director)

That's what she's asked. Thank you.

Operator (participant)

Thank you. This concludes our Q&A session, and I will pass it back to Mr. Ingram for closing comments.

Doug Ingram (President and CEO)

All right. Well, thank you all very much for spending time with us today. I'm just gonna end with the way I started. The, you know, 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, you know, worked with the community itself, to the fact that we restructured our convertible debt to remove any overhang. 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. 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, you know, very resilient PMOs that people love, as well as ELEVIDYS, which, you know, the evidence on ELEVIDYS and its benefits grows, you know, quarter-to-quarter-to-quarter, and we're gonna make sure that everybody that can benefit from that knows it. 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. Then, you know, finally, we have this, you know, extraordinarily exciting siRNA pipeline that, you know, 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, starting next quarter, not next year, folks.

You know, 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. 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, bringing better lives to these patients as well. Over time, I think that we'll get the benefit of all of this extraordinary work as well. Thank you very much for your time. Look forward to updating you across the course of this year as well. With that, have a lovely evening.

Operator (participant)

This concludes our conference. Thank you for participating, and you may now disconnect.