Sarepta Therapeutics, Inc.

Good afternoon, ladies and gentlemen, and welcome to the Sarepta Therapeutics Fourth Quarter and Full Year 2021 Earnings Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session, and instructions will follow at that time. If anyone should require assistance during the conference, please press star then zero on your touch-tone telephone. As a reminder, today's program is being recorded. At this time, I'll turn the call over to Mary Jenkins, Senior Manager, Investor Relations, please go ahead.

Thank you, Mel, and thank you all for joining today's call. Earlier today, we released our financial results for the fourth quarter and full year 2021. The press release is available on our website at Sarepta.com, and our 10-K was filed with the Securities and Exchange Commission earlier this afternoon. Joining us on the call today are Doug Ingram, Ian Estepan, Dallin Murray, and Dr. Louise Rodino-Klaypak. 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 take a moment to review our slide in the webcast, which contains our forward-looking statements. These forward-looking statements involve risks and uncertainties, many of which are beyond Surreptice control. Actual results could materially differ from these forward-looking statements, and any such risks can materially and adversely affect the business. The results of operations and trading prices for Surreptice common stock. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report on Form 10-K filed with the SEC, as well as the company's other 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. And now I'll turn the call over to our President and CEO, Doug Ingram, who will provide an overview of our recent progress. Doug?

Thank you, Mary. Good afternoon, everyone, and thank you all for joining Sarepta Therapeutics' fourth quarter and full year 2021 investor conference call. Among the thousands of public and private biotech companies currently existing in the United States and around the world, Sarepta sits in a select and small group of fully integrated commercial stage biotech enterprises with a proven track record of translating brilliant science into approved therapies and then supporting the patient community and physicians in gaining and maintaining access to those approved therapies. This operational focus and commitment to patients was on full display throughout 2021. We have greater than 40 programs in our pipeline of potentially life-enhancing therapies focused on rare genetic diseases across multiple platforms, including RNA, gene therapy, and gene editing. But more than that, in 2021, we entered pivotal registrational trials for our lead programs in both our RNA and gene therapy platforms. Encouraging data from our Momentum Part A study, we commenced Part B of the study, a pivotal trial for SRP5051, our next generation RNA-based PPMO for the treatment of Duchenne patients with exon 51 amenable mutations. Additionally, we commence dosing EMBARQ, the pivotal registrational trial for SRP9001, our microdystrophin gene therapy to treat Duchenne muscular dystrophy. EMBARQ, which includes sites both in and outside the United States, is currently the only truly global trial dosing a gene therapy for the treatment of Duchenne. And we translate our development activity to approved therapies. With the approval and launch of Amandus 45 in February of 2021, we now have three approved therapies serving the Duchenne community. In the fourth quarter of 2021, we enjoyed our 21st straight quarter of strong quarter-over-quarter revenue growth. Fourth quarter total revenues, which consist primarily of our net product revenue plus our collaboration revenue, reached $201.5 million. And net product revenue for our three RNA-based therapies reached $178.7 million, a 46% increase over the same quarter of the prior year. For the full year 2021, total revenue reached $701.9 million, and net product revenue was $612.4 million, a 34% increase over the prior year. Since 2017, first full year launch for Exondus 51, Sarepta has recognized sustained growth with a compounded annual product revenue growth rate of over 40%. And our growth continues. We entered 2022 in a position of financial strength with our total revenue guidance at over $880 million and our net product revenue guidance of over $800 million, a 30% growth, over the prior year. Additionally, we entered 2022 with $2.1 billion in cash on our balance sheet and the financial discipline to make the most. And our pipeline continues to perform. In the first quarter of this year, we announced statistically significant functional results and continued confirmation of our differentiated safety profile for SRP 9001 from Part 2 of Study 102. With the objective conviction that comes from consistent results in what is the largest body of clinical evidence in Duchenne today, we continue to enroll in those patients in the Embark and the Momentum studies while also advancing our deep multi-platform pipeline. Now, our strategy has taken us far over the last five years, but it is all only the beginning. As we look to the future and to our strategic plans, If our late-stage clinical programs are successful, we should achieve profitability by the end of 2024. And by 2025, our yearly revenue is $4 billion. And if our pipeline is successful, by the end of this decade, our yearly product revenue could approach $10 billion generated from our internal programs alone. We have the strongest team in Sarepta's history, and I believe at least, one of the most astute and strategically-minded teams in all of genetic medicine and biotech. And we stand ready to continue executing, translating our programs into life-enhancing therapies for the patients that we serve, and also benefiting the investors that have placed their trust in us. And with that, let me turn the call over to our head of R&D and our chief scientific officer, Dr. Luis Rodino-Klapak, who will give us an update on our research and development activities. Luis?

Thanks, Doug. My decision to join SORUPTA four years ago was driven by the strong foundation of the R&D organization and SORUPTA's unmatched dedication to science and to patients. Since that time, the R&D group has grown in breadth and depth to become a truly integrated team focused on propelling disruptive scientific endeavors and vast pipeline floors. Today, the R&D organization totals nearly 300 employees, grounded in a mission to translate the very best science into the very best treatments for patients in the shortest time possible. I am proud to lead such a strong and committed team of scientists. Together, we as R&D have achieved great things, and this is an especially exciting time for our organization. We are fostering and leveraging our internal research capabilities, capitalizing on our current strengths. We're also ensuring we are positioned for sustained growth into the future. As a fully integrated organization, we have expertise in the manufacturing of our RNA and gene therapy assets. All of our research-grade materials are produced internally, and we have developed and validated the analytics to characterize and release these materials. I'm particularly proud of our competency in this area as it's a capability unique to Sarepta. We are creating efficiencies and streamlining development of our pipeline candidates using a consistent manufacturing process. We've also established internal GLP capabilities at our Genetic Therapy Center of Excellence, or GCCOE, in Columbus, Ohio. This affords us maximum flexibility, agility, and speed for preclinical studies. Additionally, in the past few years alone, we've created an internal innovation engine driven by your subject matter expertise that has resulted in the advancement of over 50 therapeutic candidate constructs across gene therapy, gene editing, and RNA. In collaboration with our business development and alliance management functions, we are continuing to invest selectively in best-in-class disease-modifying approaches, supplementing our internal R&D toolbox. With these approaches, our goal is to further enhance our delivery platform so that we can reach more patients with our therapies faster. We are also investing in next-generation technologies to ensure that we are developing best-in-class therapies, not only for today, but for the future, and that we are continually fostering an R&D culture of scientific inquiry, creativity, and sustained focus on innovation. As an example, in 2021, we successfully advanced our partnership with GenEdits. while encouraging initial in vivo results. One of the most significant challenges when developing a non-viral delivery mechanism is establishing good muscle tropism. The results from this collaboration demonstrated the potential of GenEdit's polymer nanoparticles to deliver therapeutic cargo to muscle tissue, following systemic administration to allow for targeted non-viral systemic delivery of genetic medicine. Our partnership with GenEdit reflects our strategies to leverage a variety of therapeutic modalities to treat rare neuromuscular diseases. As a result, we have a large pipeline of programs at various stages under development, both internally and externally, each of which is evaluated for probability of success and unmet needs using the same set of criteria. Our translational functions within R&D, including quantitative pharmacology, genomics, preclinical safety, and translational biology, span the continuum from discovery through clinical development. These internal capabilities, which are supplemented by external resources, ensure tailored monitoring for our trial participants from both a safety, advocacy, and patient experience perspective. Our innovative scientific mindset is not only reserved for research. Our development organization, comprised of development sciences, regulatory affairs, and pharmacovigilance, takes pride in a creative approach rooted in specialized experiences of genetic medicine and neuromuscular disease. prime examples being our success with our PMOs, as well as the initiation of our Phase III global trial for SRP9001, our lead gene therapy program for Duchenne, which includes sites in the U.S. Now, turning to updates on our late-stage clinical programs. In January of this year, we announced top-line data from SRP9001-102, or Study 102 Part 2, which further amplifies our confidence in the therapy's potential to alter the trajectory of the disease with an emphasis on improving function, quality of life, and preventing premature and early death. Driving this transformative effect is the underlying strength of our construct, combined with our deep understanding of Duchenne, neuromuscular disease, and our science. To remind you, Study 102 is a double-blind, one-to-one randomized placebo-controlled trial evaluating SRP9001 microdystrophin in 41 participants with Duchenne. between the ages of four to seven. Study 102 uses SRP 9001 clinical process material and has two primary endpoints, microdystrophin expression at 12 weeks and change in MSAA total score at 48 weeks compared to placebo. Data from part one of study 102 were shared in January of 2021. We evaluated the 48-week results of 20 patients on therapy against 21 patients who were randomized to placebo. In part two, the study remains blinded to the participants and investigators. All participants in the placebo group crossed over to active treatment, FRP9001, and all participants were followed for another 48 weeks while safety and efficacy were evaluated. In part two, the goal of the primary analysis was to look at the 21-patient placebo crossover cohort versus the propensity score weighted external control. The external control included inclusion and exclusion criteria and rigorously matched baseline characteristics for age, NSAA, rise time, and 10-meter walk-run. In this regard, we show that the external controls are nearly perfectly matched against the crossover patient baselines. As a reminder, the propensity score method was prospectively defined and shared with the FDA prior to database lock and unblinding of the Part 2 data. It's important to understand that in the absence of a placebo arm, the propensity score method is scientifically rigorous and widely used to match controls across multiple factors relevant to prognosis. It provides as close an approximation as possible of what would be expected to occur in a randomized trial setting with a well-balanced placebo control group. And now to the data. SRP 9001 treated participants in the placebo crossover group scored a statistically significant two points higher on the mean NSAA at 48 weeks compared to the propensity score weighted external control, achieving an impressive p-value of 0.0009. Mean NSAA scores from these Part 2 participants improved 1.3 points from baseline for the SRP 9001 treaty group. The NSAA scores in the external control group with an N of 103 patients declined 0.7 points from baseline. It's important to note that these children were on average 7.24 years of age at the time of baseline NSAA and over 8 years old at the last functional test. As a scientist with a passion to change the lives of patients, I'm thrilled with these results. They demonstrated consistency with our previous studies, Study 101, Study 102, Part 1, and Study 103, having just over 80 patients across these two trials alone. Based on these results, we would expect the treatment benefit to continue to increase over time due to the progressive nature of Duchenne. Across these studies, we have seen sustained functional improvements compared to natural history, with the longest now in year four follow-up. The safety for study 102, part two, is entirely consistent with the safety results in part one of the study. The most common adverse event has been vomiting. There were no treatment-related serious adverse events and no discontinuations due to an adverse event. We continued to generate data from Studies 101, 102, and 103, including two-year data from Part 1 of Study 102 and one-year data from Study 103. We planned to perform an integrated analysis of the one-year data from Studies 101, 102, and 103 for all patients who received the target dose. Our plan is to share the totality of these data with regulators and then present all of these results at a medical meeting thereafter. In parallel, we are actively enrolling in BARC, a 120-patient, global, double-blind, placebo-controlled Phase III trial, the largest study of its kind in Duchenne. In BARC is a multi-center clinical trial evaluating commercially representative SRP 9001 material in patients with Duchenne between the ages of 4 to 7. Now, continuing with our gene therapy franchise, SRP9003 is our lead LGMD program in which a full-length beta-sarco-glycan cDNA uses the same AAV RH74 capsid and the MHTK7 promoter as the SRP9001 program. It is generating promising expression and functional data in the ongoing SRP9003-101 study to treat LGMD2E with SRP9003 clinical process materials. We look forward to sharing the impressive body of data we've generated to date at the upcoming MDA Clinical and Scientific Conference. When we are ready to test commercially representative SRP9003 material in a clinical trial, we will discuss with OTAP the design of a registrational study for SRP9003. In parallel, we are enrolling patients in Journey, our global, multicenter, longitudinal natural history study of LGMD2E, 2D, and 2C patients. As a reminder, we've received written feedback from both the FDA and EMA regarding our plans for SRP 9003, confirming the possibility of using protein expression as an endpoint for accelerated approval in the U.S. and for conditional approval in the U.S. Turning now to our RNA-based platform. In the fourth quarter of 2021, we initiated Part B of Momentum, a multi-arm global ascending dose study of SRP 5051 infused monthly assessing dystrophin protein levels in skeletal muscle tissue following SRP5051 treatment. SRP5051 is our next-generation PPMO to treat patients with Duchenne who are amenable to exon 51 skipping. The study is enrolling between 20 and 40 patients between the ages of 7 to 21 amenable to exon 51 skipping who are naive to SRP5051. Additionally, those previously dosed in Study 5051-201 Part A or Study 5051-102 who meet the entry criteria are eligible to participate. Both ambulatory and non-ambulatory patients are also eligible for participation. In May of 2021, we announced results in Part A of the momentum study, showing that after 12 weeks, 30 mg per kg of FRP 5051 dose monthly resulted in 18 times the exon skipping and eight times the dystrophin production as a Teplerson, weekly for 24 weeks. Moving forward, we anticipate Part B of Momentum to serve as a pivotal study for SRP 5051, and we plan to seek accelerated approval if the trial is successful. Part B is enrolling on PACE, and as we've guided, we anticipate it to be fully enrolled in the second half of 2022. In conclusion, I'd like to thank my colleagues who on a daily basis dedicate themselves to the advancement of our programs for the betterment of patients around the globe. Thanks as well to our partners in science, clinical trial investigators, and the patient community for their commitment as we work together to propel the science forward. I will now turn the call over to Dallin for an update on our commercial activities. Dallin?

Thank you, Louise, and good afternoon, everyone. 2021 represented an incredible year of execution, whereby our team delivered net product revenue growth of more than 30% and $150 million over that of 2020. This strong growth was driven over the course of the year by exceeding expectations in all three of our approved RNA-based PMO therapies. In 2021, compared to the prior year, we delivered nearly 8% growth of Exondus 51 and more than 160% growth of Vyondus 53 in the face of a competitive market. Additionally, we recognized $68.5 million in revenue from Amondus 45 after launching within just 24 hours of approval in the first quarter of 2021. This success was generated by mission-driven collaboration across all of our field teams and their deep commercialization experience gained over nearly six years since the approval of Exondus 51. The flawless execution in the field is supported by cross-functional partners throughout Sarepta who are all intensely dedicated to serving the Duchenne community. I'll begin by highlighting some of our 2021 achievements. The team got off to a strong start setting the stage for the entire year by successfully navigating the reauthorizations process starting in January of 21 and maintaining more than a 90% success rate in reauthorizations throughout the year. This robust start coupled with continued high adherence rates served as the foundation for four more quarters of revenue growth for Exondus 51 in 2021. For Vyondus 53, we ended 2021 in a strong position in market share, maintaining our leadership role in the Duchenne space and growing at a robust triple-digit rate over 2020. Further, the team continued to demonstrate their operational launch excellence with the launch of our third RNA-based PMO, Amandus 45. As we mentioned in the past, the penetration rate of start forms in the Exxon 45 market was similar to that seen in 2016 in the Exxon 51 market when we launched Exondys 51, the key difference being a much faster conversion rate exceeding the Exondys 51 launch and our own expectations, allowing us to surpass the revenue of Vyondys 53 with Amondys 45 within one calendar year. I'll take a moment to focus on Amondys 45 because its performance relative to Vyondys 53 requires further explanation. The literature suggests Exxon 45 and Exxon 53 have similar prevalence. However, with experience, it's becoming clear that the Amandas 45 population is larger than the Biondas 53 population. Therefore, Amandas 45 appears to be a greater opportunity than we originally thought. So we anticipate a strengthening growth trajectory of Amandas 45 in the coming quarters. That said, we're very pleased with the performance and continued growth of Biondus 53. Despite the entrance of a newcomer in the US Exxon 53 market, the revenue trajectory of Biondus 53 saw minimal impact throughout 2021. As the Exxon 53 market reaches full penetration, we expect the growth rate to continue modestly in coming quarters. As mentioned in prior quarters, the vast majority of Exxon 53 treated patients continue to choose Sarepta with Cliontis 53. Overall, our deep experience with Duchenne has enabled us to serve more patients, expedite access to drug, and offer best-in-class support services through Sarepta Assist across all three of our approved therapies, serving nearly 30% of individuals living with Duchenne in the United States. Turning now to our performance in the fourth quarter of 2021, the team executed and grew the RNA-based PMO business by a robust 46% over the fourth quarter of 2020. Total net product revenue for the fourth quarter was $178.7 million, bringing the total net product revenue for the year to $612.4 million, reaching the upper end of our 2021 guidance of $605 to $615 million. As a reminder, the final net product revenue guidance reflects two increases over the course of 2021 and represents an overperformance of greater than $70 million over our original guidance. This outperformance of 2021 was mostly driven by Amandas 45, and we believe our 2022 net product revenue guidance of greater than $800 million accurately captures the performance of all three of our approved therapies. I'll now outline individual net product revenues for the fourth quarter of 2021 for our three approved RNA-based PMO therapies. Beginning with Exondys 51, which totaled roughly $119 million, representing approximately 11% growth over the fourth quarter of 2020. Biondis 53 revenue totaled nearly $25 million, representing roughly 66% growth versus the fourth quarter of 2020. And Amonda's 45 revenue totaled nearly $35 million, representing greater than 30% in sequential growth over the third quarter of 2021. I'm proud of what we accomplished in 2021. And most importantly, I'm grateful for our team's enduring commitment and unwavering efforts to serve nearly 30% of the Duchenne community who are amenable to one of our three approved RNA-based therapies. As a fully integrated biotechnology company, we look forward to working in close collaboration with our R&D colleagues as they discover and develop therapies for an even larger proportion of the Duchenne population, as well as advance our deep portfolio of therapies in gene therapy, RNA, and gene editing. And now, I'll turn the call over to Ian Estepan for an update on our financials.

Ian. Thanks, Alan. Good afternoon, everyone. This afternoon's financial results press release provided details for the fourth quarter and full year 2021 on a non-GAAP basis as well as a GAAP basis. Please refer to the press release available on SREPTA's website for a full reconciliation of GAAP to non-GAAP financial results. Beginning in the fourth quarter of 2021, due to recent SEC comment letters issued to a couple of biotech companies, upfront and milestone payments associated with the company's license and collaboration agreements Settlement and license charges and collaboration revenue, along with related transaction costs incurred, are no longer excluded from non-GAAP expenses and income. Although collaboration revenue slightly confounds our core business operations, to conform with these updates, non-GAAP financial results for the fourth quarter and full year 2020 have been updated to reflect this change for comparable purposes. For the three months ended December 31st, 2021, The company recorded total revenues of $201.5 million, which consists primarily of net product revenues and collaboration revenues, compared to total revenues of $145.1 million for the same period of 2020, an increase of $56.4 million. Total net product revenue for the fourth quarter of 2021 from our PMO Exxon Skipping franchise was $178.7 million, compared to $122.6 million for the same period of 2020. For the fourth quarter of 2021, individual net product sales were $119.1 million for Exondus 51, $34.7 million for Amondus 45, and $24.9 million for Vyondus 53. The increase in net product revenue primarily reflect higher demand for our product and the launch of Amondus 45. And I'd like to remind you, as Doug mentioned earlier, Our 2022 product revenue guidance for our R&A franchise is greater than $800 million. In the quarter ended December 31st, 2021 and 2020, we recognized $22.7 million and $22.5 million, respectively, of collaboration and other revenues, which primarily relates to our collaboration arrangement with Roche. The reimbursed co-development costs under the Roche agreement totaled $18.6 million for the fourth quarter of 2021, compared to $34.2 million for the same period of 2020. On a gap basis, we reported a net loss of $122 million and $189.3 million or $1.42 and $2.40 per basic and diluted share for the fourth quarter of 2021 and 2020 respectively. We reported a non-GAAP net loss of $66 million or $0.77 for basic and diluted share in the fourth quarter of 2021 compared to a non-GAAP net loss of $133.2 million or $1.69 for basic and diluted share in the fourth quarter of 2020. In the fourth quarter of 2021, we recorded approximately $31.7 million in cost of sales compared to $22.4 million in the same period of 2020. The increase in cost of sales is primarily due to increasing demand for our products. On a gap basis, we recorded $197.3 million and $207.2 million in R&D expenses for the fourth quarter of 2021 and 2020, respectively. a year-over-year decrease of $9.9 million. This decrease is primarily due to decreases in milestone payments made in the fourth quarter of 2021 related to our license and collaboration agreements compared to similar activity during the fourth quarter of 2020, as well as the decrease in clinical trial expenses due to the timing of expenses incurred. On a non-GAAP basis, R&D expenses were $175.5 million for the fourth quarter of 2021 compared to $191.4 million for the same period of 2020, a decrease of $15.9 million. Now turning to SG&A, on a GAAP basis, we recorded approximately $78.1 million and $86 million for expenses for the fourth quarter of 2021 and 2020, respectively, a decrease of $7.9 million. The year-over-year decrease was driven primarily by a decrease in professional services expenses. On a non-GAAP basis, the SG&A expenses were $60.1 million for the fourth quarter of 2021 compared to $65.2 million for the same period of 2020, a decrease of $5.1 million. On a GAAP basis, we recorded $16.1 million in other expenses net for the fourth quarter of 2021 compared to $17.8 million in other expenses net for the same period of 2020. The decrease primarily reflects a reduction of interest expense incurred on our convertible debt related to the adoption of ASU 2020-06. We had approximately $2.1 billion in cash, cash equivalents, and investments as of December 31st, 2021. Based on our current assumptions, we believe our balance sheet provides us runway beyond the readout of study 301 and into 2024. And with that, I'll turn the call back over to Doug to start the Q&A. Doug?

Thank you very much, Ian. Mal, let's open the line for questions and answers.

Sure thing. Thank you. Ladies and gentlemen, if you have a question at this time, please press the star and then the number one key on your touchtone telephone. Again, that will be star then the number one key on your touchtone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the hash key. And as a reminder, please leave it yourself to one question. Your first question comes from the line of Dejit. Chattopadhyay of Guggenheim. Your line is now open. You may ask your question.

Hey, good afternoon. Thank you for taking my question. The prepared remarks indicated consolidated analysis of all patients who received the correct dose and then engagement with regulators. So would this include all 33 patients in Study 103? Will you supplement with biopsy data from the EMBARQ study? What would be the timing of the engagement, and how closely is Roche aligned with the strategy?

First of all, everything we do is in concert with and consultation with our partner, Roche. I should say that to begin with. I'll make a few comments, and then, Luis, you can provide additional commentary. So, obviously, a couple things to know. So we have a number of different analytics and data. We want to share that information first with the agency and have some discussions. And then we will share that in an appropriate medical meeting down the road that includes additional information out of Part 2 of 102, the data from 103, and this integrated analysis that you've made reference to. The integrated analysis will be an integrated analysis looking both at safety and function for those children who were dosed at the target dose across the various studies that we have. And I will remind you that we have a wealth of insightful data, all very consistent, but just If you've just taken bark and put it to one side right now, which is we're continuing to dose and move with, we already have across all of these studies over 80 children that have been dosed with SRP9001. So that's the current plan. We'll package that together. We'll provide that to the agency. One of the things that you should know is that our regulatory professionals have suggested strongly to us that we share that information and have that dialogue with the agency before we discuss it externally. So we'll do just that and then we will, of course, find an appropriate medical meeting. On the timing of those discussions, as I said before, I'm not going to provide a lot of detail around that right now and provide the blow by blow other than to say we're gathering the information now. We'll have that submitted to the agency in the not too distant future. We'll have those discussions. And then when we get to a place where we have some clarity on those discussions, we will provide an update certainly to the investment community and, of course, as I said, following the submissions of the agency of that information, we'll find a medical meeting to discuss some of that data about which we are pretty excited. The one thing I do want to say, because we're talking a lot about discussions with the agency this year, I want to remind everybody that while we are certainly going to have discussions with the FDA about the state of our information and creative ways in which we might get therapies to children even sooner than our pivotal trial. Our base case assumption and the assumption that you should make is that Embark is our pathway to an approval for SRP 9001. And it's a pretty exciting pathway to remind you. We will, around the middle of this year, we will have fully dosed SRP 9001 and Embark. That means we'll have a readout around the middle of next year, 2023, and we will very shortly thereafter submit our BLA in our base case scenario. And given all of the information that we have to date, including the consistency of the information we have to date, both expression, function, and safety, we are very, very confident and convicted in Embark, and that's why we're moving as fast as we can to get Embark fully dosed. But with that said, at least if there's additional detail that I have omitted.

I think you covered it really well. I think the only thing I would add is that there was one question around for the integrated analysis for study 103. So there we would include the patients that are four to seven that were consistent with studies 101 and 102. If you recall, we also just older non-ambulatory patients, which we'll certainly look at that data, but it won't be included in the one-year integrated analysis.

Thank you. Next question comes from the line of Brian Abrahams of RVC Capital Markets. Your line is now open. You may ask your question.

Hey, guys. Thanks so much for taking my question. Congrats on all the progress. I guess just following up to that first question, recognizing that Embark is the base case, I'm just sort of wondering, as you've gathered the data, whether there's been any evolution in your level of confidence in the feasibility of a faster path for approval, how the change in FDA leadership and some of the pledges around the accelerated approval path might impact your views there, and then where you might stand with respect to commercial supply in terms of supplying the market if you were to get an accelerated approval versus after the Embark readout. Thanks.

I'm going to be a little careful on the first question because it could reveal a lot about data that we don't yet have. I'll just broadly say that we have an enormous amount of conviction around our program and our data, both safety, function, and expression. I think the leadership changes at the FDA certainly will have no, to the best of our belief, have no negative implication on any strategy that we might have or any faster pathway and actually might I think Dr. Califf is a very good choice for the head of the FDA and has shown historically a commitment to the use of what is a tremendously valuable pathway to translate science to therapy to save lives, which is the accelerated approval pathway. And just to remind you, that is a pathway that saved a lot of lives over the years, both in cancer and in HIV, and as well as in neurodegenerative diseases and the Shen patients. So we're excited about that. Luis, have I missed anything there?

No.

Got it. Thank you. There was one final thing. I think you asked about commercial material. Again, just to remind you, I want to be careful because in my enthusiasm, I may keep sounding like I'm pivoting off of our base case. Our base case is assumptions. is that Embark will be the basis for our approval, and we're moving like mad to get that fully dosed, and that will, in a very short order, have a readout, which will be in the middle of next year. But in the event that we had a faster pathway to an approval, we will have all of the commercial material that we'll need to serve the community at that point. We will be ready in the event that we had a faster approval. Apologies, Luis. I think I might have cut you off.

Thank you. Okay, thank you. We have the next question comes from the line of Annapurna Rama of JP Morgan. Your line is now open. You may ask your question.

Hey, guys. Thanks so much for taking the question. Doug, maybe more of a housekeeping question. This question came up at the conference and in subsequent discussions, but where are you in terms of your contract and your future with Sarepta? Thanks so much.

So just by way of background for those of you that I know, I joined Sarepta in late June of 2017, and I joined pursuant to a five-year agreement. With that said, let me be clear. I have one of the strongest teams, I think, first and certainly in Sarepta history, but more than that, I think in all of biotech. I say that referencing not only my direct reports, but the broader team that is Sarepta, the extraordinary professionals. And I ask a lot of them. I'm asking them to be dedicated and passionate and committed to our patients and to the future of Sarepta. And I can't ask more of them than I ask of myself. So the avoidance of doubt is my every intention to stay at Sarepta beyond my five-year agreement and to continue to drive with my colleagues towards a better life for these patients. And frankly, you know, quite directly, where would I go that would be as exciting and challenging with as much opportunity to do good and to do well at the same time as Sarepta. We've got an enormous pipeline. We've got multi-platforms. We're in pivotal trials in our two late stage platforms. We've had extraordinary growth. We're sitting with $2.1 billion on the balance sheet so that we can continue to execute. If you look into the future, just look where we could go, right? If all is well, we'll be profitable by the end of 2024. If our late-stage programs are successful, and I have to say I, for one, am very, very confident in where we're headed, we will approach $4 billion in the next few years by 2025. And if you look out into the future, by the end of this decade, if our pipeline performs, we could be approaching $10 billion. So I'm extremely excited about the future of the company. I'm thrilled to be working with the people that I work with. There are a few things that are as – as rewarding while at the same time challenging as working at this company and serving these patients. So I have every intention of continuing to lead this company with my colleagues. So thank you for that question.

Thank you. We have the next question comes from the line of Tazin Ahmed of Bank of America. Your line is now open. You may ask your question.

Hi, guys. Good afternoon. Thanks for taking my question. Doug, I was hoping to get a little bit more granular on, you know, your $10 billion in peak sales by the end of the decade. What are the components that go into that? And how would we think about if D&D gene therapy is approved, the contribution of that versus the contribution of either PMO or PPMO? Thank you.

So I can't go into a ton of detail because we haven't provided a lot of granularity, but I'll give you the broad strokes on this. First, know this. A lot of times when people create strategic plans, they have essentially yet unidentified development programs or the like that might make up their future revenue projections and goals. That is not us. Everything that I'm talking about comes from the internal programs that we have today, even as we continue to look for new opportunities as an organization. First and foremost, the success of our plans rely on the success of 9001, of which we are very excited. And if we're successful there, as I've said, together with our other programs, we'll get to approaching $4 billion by 2025. And then we have the Lynn Girdles and some other programs coming on behind it. Our current assumptions, and I think it's a conservative assumption and we're challenging ourselves there, is that with the success of 9001 gene therapy, that it would have a significant cannibalizing effect on our existing RNA therapy, even though our RNA therapy would remain viable in a lot of places, and there will be different places where cannibalization wouldn't occur. So we're assuming a significant amount of cannibalization, and we would still get to something around $10 billion by the end of this decade. We'd still get even with significant cannibalization to about $4 billion by 2025. And again, we're doing a lot of work right now to test the thesis that there is a significant amount of cannibalization in the event of 9001 success, because there may be a very real opportunity for a commonative benefit of RNA and gene therapy together. So those are kind of the broad strokes of the strategic plan for us.

Thank you. Next question comes from the line of Jeannie Wang of Barclays. Your line is now open. You may ask your question.

Thank you. I have one question regarding the MDA presentations in two weeks. I know you have three presentations. Just wondering specifically, you know, regarding Dr. Jeremy Wendell's presentation on the study 102, wondering will we see two-year data from the drug arm with propensity score weighting analysis with external control? And also regarding the 50-51 PPMO Part A data, will we see longer follow-up data from that data upset?

Yeah, I'll let Luis answer some of the detail, but let me answer the broad strokes in the first part of it. So, as I've said before, we have a significant amount of additional analytics done and being completed after which we're going to collect them all together and share them with our regulatory agency. And then we're going to find a medical meeting to have that discussion thereafter. We have been strongly encouraged by our regulatory professionals to avoid presenting any additional data until we have those discussions with the FDA for a host of technical reasons. And we certainly want to have the most successful meeting that we can with the division when we can have it. And the second issue for us is that that having presented the main primary information and material information at J.P. Morgan, we want to make sure that we put this all together in one medical meeting and we don't look like we're trying to essentially promote individual pieces of data across the year. So the short answer is that Dr. Mendel's presentation will be essentially the data that you've seen before. He has additional commentary, as you can well imagine, direct insight, and then we're going to, in short order, gather all of our information, additional information out of Part 2, additional interesting analytics around it, the two-year data, 103, the first cohort of 103, about 20 patients, and integrated analysis. We're going to provide that all to the agency in the form of a well-thought-through briefing book, and then we'll find a medical meeting and we'll disclose all of that information and have a discussion about where we are. sometime this year, as soon as it's reasonably possible to do that. Louise?

Yeah, so just to add on 5051, there won't be new data from Part A. It'll be what was previously presented. This is obviously a live audience, and this would be nice to be able to present this and interact with people at MDA around this data. As you know, we're now enrolling Part B of the study, but Part A readout will be similar to what was presented previously.

Thank you. The next question comes from the line of Alicia Young from Cantor. Your line is now open. You may ask your question.

Hey, guys. Thanks for taking my question, and congrats on all the progress. I just actually wanted to talk about, I know, you know, obviously you have the base case of drugs being approved, you know, roughly a year or so. But if it's not, can you talk a little bit about how you're thinking about kind of like launching into this group of people with gene therapy? Obviously we know the cadence of your kind of, losses currently as they stand, but I guess, you know, how should we think about, you know, kind of early sets of patients that might be interested in this treatment and just how to think about the overall population in general? I'm sure you guys have been thinking about it.

Yeah, I mean, a lot of it's going to be subject to discussions with the division, obviously. First and foremost, you know, whether there is even a faster pathway, and that's very much an open issue. As I've said, you know, many times I've I really would. My primary investment thesis, and I will say it's personally my investment thesis, as everyone knows. I've been a significant investor in Sarepta personally over the years. I bought additional stock. Last year, I bought on the assumption that Embark is going to be wildly successful, et cetera, et cetera, at a very personal level. But we need to have additional discussions with the agency. First question is, is there a pathway that would be even faster than Embark? Second question, Question is, what is the size of the patient population inside of that? That is going to be subject to discussions with the division. Is it a subset of patients? Is it more than a subset of patients? Those are all discussions that have not occurred yet, but we need to have them. The one thing I can say to you is that we will be well prepared to launch the therapy under any of those various scenarios. either a subset or a larger one, or, of course, we'll obviously be prepared for our base case assumption. So we'll be prepared in a number of regards. We'll be prepared commercially. Dallin and his team are well aware of the various possibilities, and we'll be prepared to make the most of this therapy and to get it to patients as soon as possible, and we'll be prepared prepared from a supply chain perspective, from a manufacturing perspective, and from an inventory perspective in the event. So it's difficult to say exactly what that launch would look like, first because it's only theoretical right now, and second because it would require additional discussions even if we were successful.

Thank you. Next question comes from the line of Colleen Bristow of UBS. Your line is now open. You may ask your question.

Hi, this is Ting for Colin. Thank you for taking our question and congrats on progress. So we have a follow-up question on the ongoing or anticipated conversations with FDA. Could we know when do you expect to be in a position to provide an update on their potential filing for 901? And also, when we think of your estimates of the potential of like your long-term goal of achieving 4 billion by 2025, how should we think of your estimates of the potential launching time for 901? Thank you.

Yeah, so let me answer the second question first. When we talk about our strategic plan and we talk about the revenue potential out of our platform, we're assuming our base case scenario. We're assuming that Embark, which is our pivotal trial, well-controlled, well-powered, 120-patient, placebo-controlled, blinded study, is the pathway to getting this therapy approved first in the United States and then around the world. And it is on that basis that all of our plans, from our strategic plan perspective, have been built. And then going to the first question, you know, we're not going to provide detail on sort of the blow-by-blows and discussions. We obviously still have to gather information, create a briefing book, submit that, have a meeting. That meeting may be one or a few meetings. The one thing I will say is we'll do it as expeditiously as is reasonably possible, ensuring that we have the data to have a very successful and thoughtful discussion with the agency. And when we are at a point in those discussions where we have sufficient clarity that we can provide additional color, we'll do that at that time. So I would be generally confident it will occur over the course of this year, but I can't give you more detail on the exact timing of that.

Thank you. We have the next question comes from the line of Matthew Harrison of Morgan Stanley. Your line is now open. You may ask your question.

Thanks. Good afternoon. I guess I was just hoping to just clarify one point about the set of information that you're going to provide to the FDA. And I guess my question is, Have you asked them specifically on the kind of information you're going to provide to them in this package, or has this sort of solely been designed by you and your regulatory folks? Thanks very much.

Yeah, it's been designed by us. I mean, let me be clear. You know, the briefing book and the information that we share will obviously be constructed by us. we have provided to them historically some of the statistical analysis plans that we're using. So they should have in advance a good understanding of the kind of information that we'll be discussing. But it is essentially on us to ensure that we have a robust package that can inform our discussions. With that said, I will also give enormous kudos to both our development folks and scientists and regulatory professionals who have a very keen understanding of what might be required to ensure, not that we'll ultimately be successful in finding a pathway faster than Embark. I don't want to suggest that because, again, I will say over and over again that I think everybody ought to assume that Embark is our pathway and it's an exciting and very, coming up very quick pathway, but that we will have a very good, well-informed, robust discussion based on what I believe to be very scientifically rigorous analytics.

Thank you. We have the next question. It comes from the line of Ritu Baram of Colwyn. Your line is now open. You may ask your question.

Good afternoon, everyone. Thanks for taking the question. So, Deb, 2024 break-even implies, obviously, some revenue from 9001. And assuming you're filing on the Embark data, that kind of gives you no time for any potential reimbursement delays, which has been super challenging for gene therapies. Can you talk about maybe lessons learned from other people's mistakes and what sort of groundwork you're laying now in advance to get reimbursement out of the gates to meet 2024 break-even, 2025 4 billion revenues?

Yeah, I mean, I would say broadly speaking, Dallin and team spend an enormous amount of time laying the groundwork for, you know, laying the groundwork to ensure that we can launch this as appropriately as possible, serving this community. No one, this is going to be immodest of me, but I say this on behalf of my commercial medical affairs colleagues, no one is as prepared to launch and support a Duchenne muscular dystrophy therapy at Sarepta. This is a, this is a honed team that knows what it's doing. And, you know, while we are still in a very nascent field of gene therapy, you know, we do have the benefit of looking over our shoulder at what others have done, seeing what they've done that's been good and mirroring it. And to the extent that our colleagues in other companies have, haven't had the benefit of seeing others and have stumbled to be able to benefit from from that and learn and, and certainly, I think, you know, the artist has done a really good job with his old gentleman, there's learnings in there. And I think we're, we've had some time to get ourselves ready and to prepare for that. But Alan, do you have any other additional thoughts? No, I think everything that micro microscope on this.

Yeah, no, absolutely. Everything that Doug said, and I think our forecast assumptions are based on our experience launching three PMOs, so that those assumptions incorporate everything we've learned in the Duchenne market in the last several years.

One mistake we could make is to assume that launching a gene therapy is identical to launching one of our RNA therapies, but the good news is that Dallin and his team don't do that. They've thought a lot about the ways in which gene therapy, capacity issues, centers for excellence, and the like, and all of the pre-work associated with having discussions with payers long in advance need to happen. And that's happened a bunch. I mean, we've had a significant number of interactions with payers, and we have much more to come. But I will also say, I mean, look at our track record. If one wonders whether we know how to translate therapeutic approvals into meaningful therapies for patients, getting them access and keeping them maintained on access and getting great revenue growth. Amandus is a brilliant example of that. A lot of times a company gets an approval and then they launch a couple of months later, three months later, four months later. These folks literally launched essentially within it was either 24 or 48 hours. And we had our first start form within I think 24 hours. And our future our first infusion with them on this within days, literally within days, we we translated that to being a patient impact amazingly fast. And I think we have the opportunity to do the same. So I, I think, you know, we have lofty goals, but I think our strategic plan is realistic.

Thank you. We have the next question comes from the line of Brian Scorney of Beard. Your line is now open. You may ask your question.

Hey, good afternoon, everyone. Maybe departing from 9001 for a minute, I was just wondering on the limb girdle programs, I think you've said that the rate-limiting step here has been CMC. So I just wanted to see if we could get an update on where you are in terms of building out a CGMP production here, and when could we possibly see initiation of a pivotal program? Thanks.

Yeah, so you're exactly right. The rate-limiting step or the commencement of a pivotal trial, I mean, we still have to have further discussions with the agency to confirm and agree on the development program itself, but the predicate to all of that is the CMC. And in relation to the CMC, it's really more than anything else assay work. You've got additional assays that still need to get billed. They will. They'll get built. It just takes time. It reminds me a lot of sort of where we were with 9001 in 2019. You'll recall in 2019, I was telling people, you know, we're building our manufacturing process, but we don't have the, for them, this is not the case with 9003, but 9003 is just about building assays for the most part, but With 9001, you'll recall I was telling the external world, you know, the yields aren't yet where we need them to be from a manufacturing process perspective, but we're going to get there. It's the same answer with these assays. We have additional assay work to do. It's an engineering and empirical process. We don't have any significant inventive steps here. We know exactly how we need to get there. It just takes some time. So once we have that CNC process, complete, we have the assays complete, then we can have a discussion with the agency and start what we would hope to be the pivotal trial for 2E. Beyond 2E, I can tell you a couple of additional things. We're working really hard on the other sarco-glycans and trying to get them in a place where they could be as close to 2E as possible. That's a big effort for us right now. And we'll also start a pilot program for 2B, which is dysprolinopathy um, if I'm not mistaken, Louise, but this year we'll start our pilot program, which can be really, really interesting. We're doing a pilot program because this for lidopathy is a little bit different than the other programs, including, um, the circle glycans. It's a dual vector approach. So it has that, um, difficult, you know, that different technical aspect to it. And we want to do a pilot program and see its, its effect before we move into a, um, a pivotal trial, but we've got a lot going on. One of the reasons we raised additional resources last year was, number one, to ensure that we were well-funded, but also to ensure that we were moving the glint girdles along, as well as with the success of 5051, ensuring that we're moving the other PPMOs along as well.

Thank you. Next question, we have the line of Eka, the dowry of Oppenheimer. Your line is now open. You may ask your question.

Hello, this is Eka Ghigori, dialing in for Hartaj Singh. Thank you for taking our question. One from us on the limb girdle muscular dystrophy program also. So some key opinion leaders we have spoken with have emphasized that the natural history for LGMD is fully defined And that there's a strong I'm at need with the lack of trials as well as difficulty of conducting trials in this ultra rare disease. Our question is, if you could elaborate on this points and also on your on your conviction in this interrupted the entire lgbt portfolio.

Thank you. Sure, at least you want to take this one?

Sure. I'll emphasize that we are currently doing a natural history study in limb girdle called Journey, and that's for the sarcoid ligands 2E, 2D, and 2C to help inform that. We do have natural history data in 2E, for example. We've previously shared data where we've shown the comparison of our one-on-one patients in comparison to natural history. We're certainly, for some indications like disferlinopathy, there is actually a wealth of natural history data. So where there is an absence of data. We're making sure that we are doing studies and it's well informed. It's certainly a newer field than Duchenne in terms of natural history, but we are making sure that we're making the best decisions for patients and gathering natural history data where we need to and then being creative in terms of our approach to making every patient count in our trials and maximizing the amount of information we get from that. Thank you for that question.

Thank you. We have the next question comes from the line of Jill Blum of Needham & Company. Your line is now open. You may ask your question.

Good afternoon, and thanks for taking our question. So maybe focusing a little on the PPMOs here. So you guys have never taken a price increase on your PMO franchise, but considering the potential for an improved clinical benefit with 50-51, would there be discussions around this? Is this even something you're considering? Thank you.

Well, we haven't gotten to a point where we thought about the exact pricing for the PPMOs and certainly if it is successful, could be a significant and profound benefit to patients even over our current PMOs in a number of regards, of course, you know, just to remind everybody what we've seen so far, and this all has to be borne out in our pivotal trial, which is Momentum Part B. Just to remind you, we saw 6% distrofin. We saw 18 times more exon skipping, about 8 times more distrofin than exon. We saw it in half the time in 20% of the does. So the product profile could be significantly different. Now, with that said, we haven't made those decisions, and we'll look at that carefully. I can give you our current general philosophy, which doesn't speak exactly to what our pricing will be for PPMO, but should give everyone a steer on who we are as a company. We're a company that believes in pricing our therapies appropriately to ensure that programs like this can be successful for patients and will spur additional innovation. But once launched, we don't believe in trying to meet our goals, for instance, by unnecessarily or inappropriately raising price, and that's why, to your very good point, We've launched Exondys, what will this year be six years ago? And we have never taken a single price for Exondys. Then we got Amondys and Vyondys approved, and there was at least an argument that could be made for pricing them at a premium to Exondys, maybe in part because they are a smaller patient population. And we didn't do that. We priced them all at parity. So generally speaking, You know, our goal is to price our therapies appropriate at inception and to not use, to use our performance and our commitment to the patient community and serving the community as the basis for our success and not using things like unnecessary or, you know, gratuitous price increases as a way of satisfying our obligations. And so far it's worked. Just, you know, by the way, I'm you know, I'll go back and I'll give, I want to give an enormous credit to our commercial and medical affairs group and everyone that's supported them because we've had 21 quarters of consistent, sequential, strong quarter over quarter growth. We've grown 40% CAGR over the last five years. We'll do over $800 million in product net product revenue this year. And so I think that the philosophy that we have has worked well for us. Now, What the exact price for the PPMO will be is something that we'll decide when we get closer, but one should assume it'll be, you know, we're not going to take advantage of the benefits of the PPMO. We'll make sure that we price it appropriately to serve the community and justify future innovation.

Thank you. Next question comes in the line of Joseph Schwartz of SVB Securities. Your line is now open. You may ask a question.

Hi, thanks very much. Could you provide us with any Phase III enrollment statistics for 9001, such as the proportion of sites that have been activated or patients that have been enrolled and dosed so far? And maybe also describe the impact that your new inclusion and exclusion criteria has had on enrollment. What percentage of patients do you see screening out on this criteria?

Yeah, so here are the broad strokes. Louise can give anything that I've missed. In broadest of strokes, we're not giving details on numbers of sites activated dead or patients dosed, other than to say we're dosing patients. I think someone's asked me recently if we were dosing patients in the U.S. Yeah, that has been, I think, for a lot of people, a significant challenge. And the short answer is yes, we're dosing patients in the U.S. We are on track to complete the dosing of our study in the middle of 2022, which is our goal. So that's great. We've got more sites to initiate, and we're working well to do that outside of the United States and even some additional sites in the United States. So we've got more work to do, but the team is executing well, and we're on track to hit our goals. On the inclusion-exclusion criteria, Louise can give some of the data on what she thinks the the the percentage of patients that might be excluded from that might be but broadly speaking, there's such an extraordinary need and demand for this therapy both from families and investigators are well aware of this that I don't believe that is going to be an impediment to the robust enrollment of this of this study. Louise.

That's correct. We've not seen a significant influence of the revised inclusion exclusion criteria for 301 that was informed on our earlier studies. The demand is high and the recruitment is on track.

Thank you. We have the next question comes in the line of Judith Frommer of Credit Suisse. Your line is now open. You may ask your question.

Hi. Thanks for taking the question. And just to follow up on the last one, just kind of given the, you know, continued clinical holds placed on AAV gene therapies, any impact, positive or negative, you can sense at an enrollment site any hesitancy maybe from investigators or patients, obviously, you know, kind of different AAV here. And then tied to that somewhat, within the long-term guidance, can you make any comments on competition for your gene therapy?

So I will say a couple. On the last one, let me say that our long-term strategic plan, base case, assumes robust competition. Whether or not that's accurate or not is something we'll all find out over time, but we're trying to be thoughtful and conservative in our strategic plan approach, so we actually assume in our plan and our revenue assumptions robust competition for our therapies, even including our gene therapy. So that's built in. On the first part of the question, I don't believe Luis, you can correct me, that there has been any significant impact from the issues that have occurred with our colleagues at other companies, both Pfizer and Solid, with respect to AEs, SAEs, and the like, and the most recent very difficult situation that occurred with Pfizer. I think that investigators are fairly well informed that SRP 9001 is substantially different than those others and has performed different than those others. from a safety perspective. And I think patients are generally pretty sophisticated in this space and generally are aware of that. But Louise, you might have more color on this than me.

I agree with everything you said. The physicians are eager, as well as the patients for 301. They ask good questions. I think one thing that we're seeing is that the PIs are becoming increasingly sophisticated and ask the right questions, which is good to see as we're tracking along in development. as well as IRBs that are asking the right questions. So I think we're in a good space in terms of education of the community of knowing the right questions to ask and being informed. So it's all positive from our perspective.

Thank you. The next question comes from the line of Sylvine Richard of Goldman Sachs. Your line is now open. You may ask your question.

Hi. Thanks for taking the question. This is Tommy on for Sylvine. Our question is on the genetic collaboration. Seeing as non-viral delivery has had some setbacks in the past, what is giving you confidence that their platform could be successful? Thank you.

Luis, you might want to take this one.

Yeah, thank you for that question. I think, as I mentioned, with non-viral delivery, one of the challenges is beginning to muscle in the first place. So the non-viral delivery mechanisms have been very efficient in going to places like the liver, as you would expect. And so one of the hurdles to get over this was to efficiently deliver to muscle. And so when we delivered, which ended up systemically and saw expression in muscle, we were thrilled with the progress on that. Now, we have a ways to go. It's early, but this is the first time we really saw measurable expression in muscle. And so we're excited about where that could go. Again, it's early. It's research, but we're excited.

Thank you.

That's a very good question. One thing you should know is that we're taking a number of different approaches simultaneously. To your point, this is a very challenging concept. AAV has been successful. There are lots of interesting opportunities if one could either enhance AAV, something we're working on, or find an alternative to AAV, but it's challenging. So this So gen ed, it's exciting. There are other approaches we're taking as well in the hope that we can advance the science of genetic medicine.

Thank you. We have the next question. Sorry, go on. No, no, go ahead. Sorry about that. Thank you. So for the next question we have from the line of Yoon Zong of BTIG, your line is now open. You may ask your question.

Hi. Thanks very much for taking the question. So My question is a follow-up one on PPMO platform. And with a better clinical profile, how possible do you think the platform can potentially expand the patient population, convincing those patients who are not committed to receiving exon-skipping therapies to get on treatment? And given that you said that exon is 51 and maybe even bion is 53, the sales are nearing plateauing. I know that you're very confident in the gene therapy program, but if you do decide to work on additional candidates, how fast do you think you can move the next one into the clinic?

Well, we're moving, from a preclinical perspective, we're moving as fast as we can. Obviously, everything takes more time than one would like when you're dealing with often ferocious neurodegenerative diseases like Duchenne muscular dystrophy, but we're moving fast. As far as the potential opportunity for the PPMO, I think it's enormous. Enormous in many ways. First, remember, with our first three therapies, we treat about 29% of the Duchenne muscular district, the Duchenne community. We can, both with our PMOs or PPMOs, treat easily 50% of the patients and theoretically up to over 80%. There's challenges when you get to the really rare exons, but we can treat a significant number of patients and And we can make a bet on the PBMO platform that gets us to a significantly greater percentage of patients than just 29%. Beyond just that, the XQS is on a name patient basis, a managed access program, very much a responsive program. And while patients do benefit from our therapies outside of the United States, the vast majority of all of our sales will happen inside of the United States with our PMOs. And that relates in significant ways to sort of some of the history with the PMOs, the way they were approved, and the like. I think with a PPMO and certainly with a therapy that if it's successful could make, you know, 10% or so over the course of a year of truncated but functional dystrophin, which the literature would say would be a profound change in trajectory of disease potentially. I think the XUS opportunity becomes far more viable, and that would really expand the potential for this therapy to treat patients around the world. And then, therefore, as a result of that benefit, I think would really greatly enhance the long-term revenue associated with the PPMO. So there's a lot of exciting opportunities in the PPMO, and we're moving as fast as we can with respect to them.

Thank you. We have the next question comes from the line of Ji Changshu of Berenberg. Your line is now open. You may ask your question.

Great. Thanks very much. Good afternoon. I want to ask about your 2025 revenue aspiration of $4 billion. I think if you just look at the consensus right now, it's $2.2, $2.3 billion. What do you think is missing here? What do you think that Delta can be accounted for? Thank you.

I'm not 100% sure where they're deriving their number. I can tell you we're deriving our number with an understanding of the prevalent population that's much better than certainly the literature. And it's a very thoughtful, bottoms-up approach to building our revenue guidance. They might be assuming complete cannibalization of the RNA franchise with the launch of 9001. That would be, I think, an inaccurate assumption. So I can't say with precision. I suspect, frankly, that we've just done significantly more modeling than one would expect from folks. This is all we do is these genetic medicines.

It's also partially being driven by probability of success.

Thank you. Thank you.

They may just be discounting it. That's a good point.

Sorry about that. So we have the last question comes from the line up. Your line is now open. You may ask your question.

Hey, thanks for letting me back in again. So any progress with EMA with respect to SRP 5051 and the threshold of district and expression for potential MMA submission? Also, are you expecting top line by the end of this year?

I'm really sure. I take those questions.

There's certainly something that with, you know, 5051 in terms of the levels that we expect that we will revisit and have discussions with regulators both in the United States. And then with EMA, this study will be enrolled this year. And so we'll, we'll look towards dystrophin expression at 28 weeks thereafter. So we'll provide guidance as we as we track towards that.

I will say that, you know, having been personally involved in and involved in the discussions with CHMP and EMA, and I do think we would have a different I suspect anyway, they should say they'll all be subject to discussion. I think we would have a different dialogue with the division with EMA and then then ultimately CHMP with a therapy that was making six to 10% district family. I think the probability of success wouldn't be much higher for an approval or conditional approval.

Thank you. I am showing no further questions at this time. I would now like to turn the conference back to President and CEO Doug Ingram, sir.

Thank you very much. So I'll be brief. You know, yesterday was Global Rare Disease Day. It is a time when we reflect on those around the world who are living with a rare disease, very often a rare genetic disease. The external world can often seem chaotic and uncertain. particularly these days, and that can be particularly distracting. But reflecting on rare disease days and on our mission to bring a better life to our patients and their families that live with very degenerative disease, it reminds us that we don't have the luxury of getting distracted. And fortunately, we don't have to be distracted. We have the team, we have the science, we have the programs, we have the revenue, we have the balance sheets, and we have talent to stay focused and to execute our plans for the benefit of our patients and thus to the reward of those of our investors who place their trust and their resources with us. We will continue to execute in 2022 and I look forward to additional updates with you across this year. With that, have a good evening and thank you for joining us today.

Thank you, ladies and gentlemen. That concludes today's conference call. Thank you all for participating. You may now disconnect.