Sarepta Therapeutics Inc (SRPT) 2021 Q4 法說會逐字稿

Good afternoon, ladies and gentlemen, and welcome to the Sarepta Therapeutics Fourth Quarter and Full Year 2021 Earnings Call. (Operator Instructions) 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, Dallan Murray and Dr. Louise Rodino-Klapac. 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 on the webcast, which contains our forward-looking statements. These forward-looking statements involve risks and uncertainties, many of which are beyond Sarepta's control. Actual results could materially differ from these forward-looking statements, and any such risks can materially and adversely affect the business, the results of operations and trading prices for Sarepta's common stock. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent 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, a fully integrated commercial-stage biotech enterprise 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. And 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 SRP-5051, our next-generation RNA-based PPMO for the treatment of Duchenne patients with exon 51 amenable mutations. Additionally, we commenced dosing EMBARK, the pivotal registrational trial for SRP-9001, our micro-dystrophin gene therapy to treat Duchenne muscular dystrophy. EMBARK, 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 AMONDYS 45 in February of 2021, we now have 3 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 3 RNA-based therapies reached $178.7 million, a 46% increase over the same quarter in 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 EXONDYS 51, Sarepta has recognized sustained growth, with a compounded annual product revenue growth rate of over 40%. And our growth continues. We entered in 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 [dig the moat].

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 to date, we continue to enroll and dose 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 5 years, but it is all only the beginning as we look to the future and to our strategic plan. If our late-stage clinical programs are successful, we should achieve profitability by the end of 2024, and by 2025, our yearly revenue, $4 billion. And if our pipeline is successful, by the end of the 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. Louise Rodino-Klapac, who will give us an update on our research and development activities. Louise?

Thanks, Doug. My decision to join Sarepta 4 years ago was driven by the strong foundation of the R&D organization and Sarepta'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 Sarepta's scientific endeavors and vast pipeline floor.

Today, the R&D organization totaled nearly 300 employees grounded on a mission to translate the very best science into the very best treatments for patients in the shortest time possible. I'm 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 while also ensuring we are positioned to sustain 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 this material. I'm particularly proud of our competency in this area as it's a capability unique to Sarepta. We are creating efficiencies and streamlining the development of our pipeline candidates using a consistent manufacturing process.

We've also established internal GLP capabilities at our Genetic Therapies Center of Excellence, or GTCOE, in Columbus, Ohio. This affords us maximum flexibility, agility and speed for preclinical studies. Additionally, in the past 2 years alone, we've created an internal innovation engine driven by our 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 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 GenEdit following encouraging initial in vivo results. One of the most significant challenges when developing a nonviral delivery mechanism is establishing good muscle trophism. 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 nonviral systemic delivery of genetic medicine. Our partnership with GenEdit reflects our strategy 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, efficacy and patient experience perspective.

Our innovative scientific mindset is not only reserved for research. Our development organization comprises development sciences, regulatory affairs and pharmacovigilance, takes pride in the creative approach rooted in specialized experience about genetic medicine and neuromuscular disease. Primary examples being our success with our PMOs as well as the initiation of our Phase III global trial for SRP-9001, our lead gene therapy program for Duchenne, which includes sites in the U.S.

Now turning to updates on our late-stage clinical program. In January of this year, we announced top line data from SRP-9001-102, 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 the proven 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, 1:1 randomized placebo-controlled trial evaluating SRP-9001 micro-dystrophin to 41 participants with Duchenne between the ages of 4 to 7. Study 102 uses SRP-9001 clinical process material and has 2 primary endpoints: micro-dystrophin expression at 12 weeks and change in NSAA total score for at 48 weeks compared to placebo.

Data from Part 1 of Study 102 was 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 2, the study remains blinded to the participants and investigators. All participants in the placebo group crossed over to active treatment SRP-9001, and all participants were followed for another 48 weeks. Both safety and efficacy were evaluated. In Part 2, the goal of the primary analysis was to look at a 21-patient placebo crossover cohort versus the propensity score weighted external controls. The external controls 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 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-controlled group.

And now to the data. SRP-9001 treated participants in the placebo crossover group scored a statistically significant 2 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 treated group. The NSAA scores on 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 3 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 as compared to natural history, with the longest now year 4 of follow-up.

The safety for Study 102 Part 2 is entirely consistent with the safety results in Part 1 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 continue to generate data from Studies 101, 102, 103, including 2-year data from Part 1 of Study 102 and 1-year data from Study 103. We plan to perform an integrated analysis of the 1-year data from Studies 101, 102 and 103 for all patients to receive 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 EMBARK for 120-patient global double-blind, placebo-controlled Phase III trial, the largest study of its kind in Duchenne. EMBARK is a multicenter 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. SRP-9003 is our lead LGMD program, in which a full-length beta-sarcoglycan cDNA uses the same AAVrh74 capsid and the MHCK7 promoter as the SRP-9001 program. It is generating promising expression and functional data in the ongoing SRP-9003-101 study to treat LGMD2E with SRP-9003 clinical process material. 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 SRP-9003 material in the clinical trial, we will discuss with OTAT the design of a registrational study for SRP-9003.

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 Europe.

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 that's used [muscly], assessing dystrophin protein levels and skeletal muscle tissue following SRP-5051 treatment. SRP-5051 is our next-generation PPMO that treats 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 SRP-5051. Additionally, those previously dosed in Study 5051-201 Part A, or Study 5051-102, who meet the entrance criteria are eligible to participate. Both ambulatory and nonambulatory patients are also eligible for participation.

In May of 2021, we announced results from Part A of the MOMENTUM study, showing that after 12 weeks, 30 mgs per kg of SRP-5051 dosed monthly resulted in 18x the exon skipping and 8x the dystrophin production of eteplirsen, dosed 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 Sarepta 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 Dallan for an update on our commercial activities. Dallan?

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 3 of our approved RNA-based PMO therapies. In 2021 compared to the prior year, we delivered nearly 8% growth of EXONDYS 51 and more than 160% growth of VYONDYS 53 in the face of a competitive market.

Additionally, we recognized $68.5 million in revenue from AMONDYS 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 6 years since the approval of EXONDYS 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 of reauthorizations throughout the year. This robust start, coupled with continued high adherence rates, served as the foundation for 4 more quarters of revenue growth for EXONDYS 51 in 2021. For VYONDYS 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, AMONDYS 45.

As we mentioned in the past, the penetration rate of start forms in the exon 45 market was similar to that seen in 2016 in the exon 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 1 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 exon 45 and exon 53 have similar prevalence. However, with experience, it's becoming clear that the AMONDYS 45 population is larger than the VYONDYS 53 population. Therefore, AMONDYS 45 appears to be a greater opportunity than we originally thought. So we anticipate a strengthening growth trajectory of AMONDYS 45 in the coming quarters. That said, we're very pleased with the performance and continued growth of VYONDYS 53 despite the entrance of the newcomer in the U.S. exon 53 market. The revenue trajectory of VYONDYS 53 saw minimal impact throughout 2021. As the exon 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 exon 53 treated patients continue to choose Sarepta with VYONDYS 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 SareptAssist across all 3 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 million to $615 million. As a reminder, the final net product revenue guidance reflects 2 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 AMONDYS 45, and we believe our 2022 net product revenue guidance of greater than $800 million accurately captures the performance of all 3 of our approved therapies.

I'll now outline individual net product revenues for the fourth quarter of 2021 for our 3 approved RNA-based PMO therapies, beginning with EXONDYS 51, which totaled roughly $119 million, representing approximately 11% growth over the fourth quarter of 2020. VYONDYS 53 revenue totaled nearly $25 million, representing roughly 66% growth versus the fourth quarter of 2020. And AMONDYS 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 1 of our 3 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, Dallan. 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 Sarepta'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 3 months ended December 31, 2021, the company recorded total revenues of $201.5 million, which consist 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 exon 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 EXONDYS 51, $34.7 million for AMONDYS 45 and $24.9 million for VYONDYS 53. The increase in net product revenue primarily reflects higher demand for our products and the launch of AMONDYS 45. And I'd like to remind you, as Doug mentioned earlier, our 2022 product revenue guidance for our RNA franchise is greater than $800 million.

In the quarter ended December 31, 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 reimbursement 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 GAAP 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 per basic and diluted share in the fourth quarter of 2021, compared to a non-GAAP net loss of $133.2 million or $1.69 per 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 GAAP 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 agreement compared to similar activity during the fourth quarter of 2020, as well as a 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 in 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 31, 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. Now let's open the line for questions and answers.

(Operator Instructions) Your first question comes from the line of Debjit Chattopadhyay of Guggenheim.

The prepared remarks indicated consolidated analysis of all patients who received the correct dose and then the engagement with the regulators. So would this include all 33 patients in Study 103? Will you supplement with biopsy data from the EMBARK study? What would be the timing of the engagement? And how closely is Roche aligned with the strategy?

Well, 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, Louise, you can provide additional commentary. So obviously, a couple of things to know. So there -- 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 just take EMBARK 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 SRP-9001. So that's the current plan. We'll package that together. We'll have -- 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. And 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, I am -- 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 submission 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 the -- 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 in 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, Louise, 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 4 to 7 that were consistent with Studies 101 and 102. If you recall, we also dosed older nonambulatory patients, which we'll certainly look at that data, but it won't be included in the 1-year integrated analysis.

Next question comes from the line of Brian Abrahams of RBC Capital Markets.

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 new -- 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?

I'm going to be a little careful on the first question because it could reveal a lot of that data that we don't yet have. I'll just broadly say that we have an enormous amount of conviction around our programs 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 -- we believe have no negative implication on any strategy that we might have or any faster pathway, and actually might enhance it. 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 therapies that stabilize, 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 Duchenne patients. So we're excited about that.

Louise, have I missed anything there?

No.

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 assumption 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, Louise, I think I might have cut you off.

We have the next question, comes from the line of Anupam Rama of JPMorgan.

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 in your future with Sarepta?

So this by way of background for those who may not know, I joined Sarepta in late June of 2017, and I joined pursuant to a 5-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. And I'd say that referencing not only my direct reports, but the broader team that is Sarepta, 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 to the avoidance of doubt, it's my every intention to stay at Sarepta beyond my 5-year agreement and to continue to drive with my colleagues towards a better life for these patients.

And frankly, 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 got an enormous pipeline. We've got multi platforms. We're in pivotal trials in our 2 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, I'm 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 few things that are 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.

We have the next question, comes from the line of Tazeen Ahmad of Bank of America.

Doug, I was hoping to get a little bit more granular on 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 DMD gene therapy is approved, the contribution of that versus the contribution of either PMO or PPMO?

So I can't go to a ton of detail because we haven't provided a lot of granularity, but I can give you 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 limb-girdles and some other programs coming on behind it.

Our current assumptions, and I don't -- 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 combinative benefit of RNA and gene therapy together. So those are kind of the broad strokes of the strategic plan for us.

Your next question comes from the line of Gena Wang of Barclays.

The MDA presentation's in 2 weeks. I know you have 3 presentations. Just wondering specifically regarding Dr. Jerry Mendell's presentation on the Study 102, wondering will we see 2-year data from the drug arm with propensity score weighting analysis with external control? And also regarding the 5051 PPMO Part A data, will we see a longer follow-up data from that data [up set]?

Yes. I'll let Louise answer some of the detail, but let me answer the broad strokes on 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 and 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.

The second issue for us is that, that having presented the main primary information and material information at JPMorgan, 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. Mendell's presentation will be essentially the data that you've seen before. He has additional commentary, as you can well imagine, and direct insight. And then we're going to -- in the short order, gather all of our information, additional information out of Part 2, additional interesting analytics around it. The 2-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?

Yes. So just to add on 5051. This is -- there won't be new data from Part A. It will be what we've previously presented work. 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 we've presented previously.

The next question comes from the line of Alethia Young from Cantor.

Congrats on all the progress. I just actually wanted to talk about -- I know obviously, you have the base case of the drug being approved 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 launches currently as they stand. But I guess, how should we think about kind of early sets of patients that might be interested in this treatment? And just how to think about the overall population in (inaudible) you guys have been thinking about it?

Yes. I mean a lot of it's going to be subject to discussions with the division, obviously. First and foremost, whether there is even a faster pathway, and that's very much an open issue. As I've said many times, 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 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, in either a subset or a larger one or of course, we'll obviously be prepared for our base case assumptions. So we'll be prepared in a number of regards. We'll be prepared commercially. Dallan 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 will be aware -- we'll be 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.

Next question comes from the line of Colin Bristow of UBS.

This is Ting on for Colin. Congrats on progress. So we have a follow-up question on the ongoing or anticipated conversations with FDA. Can we know when do you expect to be in a position to provide an update on the potential filing for 9001. 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 9001?

Yes. 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 the -- on to the first question, we're not going to provide detail on the 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. The one thing I will say is we'll do it as expeditiously as it's 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.

We have the next question, comes from the line of Matthew Harrison of Morgan Stanley.

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?

Yes. It's been designed by us. I mean let me be clear, 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 have a -- 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 -- should give enormous kudos to both our development folks, 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. 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 at a 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.

We have the next question, comes from the line of Ritu Baral of Cowen.

So Doug, 2024 breakeven implies, obviously, some revenue from 9001. And assuming your 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 breakeven, 2025 $4 billion revenues?

Yes. I mean I would say, broadly speaking, Dallan and team spent an enormous amount of time laying the groundwork for -- 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 Duchenne muscular dystrophy therapy as Sarepta. This is a honed team that knows what it's doing. And while we are still in a very nascent field of gene therapy, 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 haven't had the benefit of seeing others and have stumbled to be able to benefit from that and to learn. And certainly, I think Novartis has done a really good job with Zolgensma. There's learnings in and there, and I think we've had some time to get ourselves ready and to prepare for that.

But Dallan, do you have any other additional thoughts?

No, I think everything...

Microscope on this.

Yes. No, absolutely, everything that Doug said. And I think our forecast assumptions are based on our experience launching 3 PMOs. So that -- those assumptions incorporate everything we've learned in the Duchenne market in the last several years.

I mean 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 Dallan 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. AMONDYS is a brilliant example of that.

A lot of times, a company gets an approval and then they launch a couple of months later, 3 months later, 4 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 first infusion with AMONDYS within days, literally within days. We translated that to being -- to patient impact amazingly fast and I think we have the opportunity to do the same. So I think we have lofty goal, but I think our strategic plan is realistic.

We have the next question, comes from the line of Brian Skorney of Baird.

Maybe departing from a 9001 for a minute. I was just wondering on the limb-girdle programs. I think you said that the rate-limiting step here has been CMC. So just wanted to see if we 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?

Yes. So you're exactly right. The rate-limiting step for the commencement of a pivotal trial, I mean it is -- 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. We've got additional assays that still need to get built. 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 we're building our manufacturing process, but we don't have the -- for them, this is not the case with 9003, but 9003's just [aducto re-assays] for the most part.

But with 9001 you'll recall, I was telling the external world, 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 CMC 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 this -- for 2E.

Beyond 2E, I can tell you a couple of additional things. We're working really hard on the other sarcoglycans 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 also start a pilot program for 2B, which is dystrophinopathy. If I'm not mistaken, Louise, by this year we'll start our pilot program, which could be really, really interesting. We're doing a pilot program because dystrophinopathy is a little bit different than the other programs, including the sarcoglycan. It's a dual vector approach. So it has that different technical aspect to it, and we want to do a pilot program and see its effect before we move into 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 limb-girdles along as well as with the success of 5051, ensuring that we're moving the other PPMOs along as well, and we are.

Next question, we have the line of (inaudible) of Oppenheimer.

This is (inaudible) dialing in for Hartaj Singh. 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 unmet 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 these points and also on your conviction, is it [interruptive] the entire LGMD portfolio?

Sure. Louise, do 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 sarcoglycans 2E, 2D and 2C to help inform that. We do have natural history data in 2E; for example, we have previously shared data where we've shown the comparison of our 101 patients in comparison to natural history. We're certainly -- for some indications like dystrophinopathy, 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 account in our trials and maximizing the amount of information we get from them.

The next question comes from the line of Gil Blum of Needham & Company.

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 of 5051, would there be discussions around this? Is this even something you're considering?

Well, we haven't gotten to a point where we thought about the exact pricing for the PPMOs. It 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. Just to remind everybody what we've seen so far (inaudible) borne out in our pivotal trial, which is MOMENTUM Part B. Just to remind you, we saw 6% dystrophin. We say 18x more exon skipping, about 8x more dystrophin in EXONDYS. We saw in half the time and 20% of the dose. 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 6 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, 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 gratuitous price increases as a way of satisfying our obligation. And so far, it's worked. Just by the way, I'll go back and I do want to give 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 5 years. We'll do over $800 million in product -- net product revenue this year. And so I think 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 will be -- we'll take -- 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.

Next question comes from the line of Joseph Schwartz of SVB Securities.

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?

Yes. So I'd give you the broad strokes and Louise can give anything that I missed or (inaudible). In broadest of strokes, we're not giving details on numbers (inaudible) or patient dose other than to say we're dosing patients. I think someone had asked me recently is we were dosing patients in the U.S. yet. 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. We're working like -- well to do that outside the United States and even some additional sites in the United States. So we got more work to do. But the team is executing well, and we're on track to hit our goals.

On the exclusion -- exclusioning criteria, Louise can give some of the data on when she think 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 study. Louise?

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

We have the next question comes from the line of Judah Frommer of Credit Suisse.

And just a follow-up on the last one. Just kind of given the continued clinical hold placed on AAV gene therapies, any impact, positive or negative, you can sense? And enrollment sites, any hesitancy maybe from investigators or patients, obviously, 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 the long -- 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 assumed 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, Louise, 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.

Yes, 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 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, they're asking the right questions. So I think we're in a good space in terms of education of the communities, of knowing the right questions to ask and being informed. So it's all positive from our perspective.

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

This is [Tami] on for Salveen. Our question is on the genetic collaboration. Seeing this nonviral delivery has had some setbacks in the past, what is giving you confidence that their platform could be successful?

Louise, you might you want to take this one?

Yes, thank you for that question. I think as I mentioned with nonviral delivery, one of the challenges is to [yank] the muscle in the first place. So these -- the nonviral delivery mechanisms have been very efficient at going to places that deliver 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 genetic systemically and saw expression in muscle, we're thrilled with the progress on that. Now we have a ways to go, it's early, but we're -- 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.

It's a very good question. One thing you should know is that we're taking a number of different approaches simultaneously because to your point, it's very -- 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 -- it's a genetic, exciting. There are other approaches we're taking as well in the hope that we can advance the science of genetic medicine.

We have the next question -- sorry, go on.

No, no, go ahead, sorry.

So on for the next question we have from the line of Yun Zhong of BTIG.

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 EXONDYS 51 and maybe even VYONDYS 53, the sales are nearing plateauing. So if you -- I know that you are 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 the 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 3 therapies, we treated about 29% of the Duchenne muscular dystrophy -- 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 we can make a bet on the PPMO platform that gets us to a significantly greater percentage of patients than just 29%.

Beyond just that, there -- the ex U.S. is on a name patient basis, the 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 the PPMO and certainly with a therapy that if it's successful could make 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 ex U.S. 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 that we're moving as fast as we can with respect to that.

We have the next question comes from the line of Zhiqiang Shu of Berenberg.

I want to ask about your 2025 revenue aspiration of $4 billion. I think you just look at the consensus right now is $2.2 billion, $2.3 billion. What do you think the Street is missing here? And what do you think that the delta can be accounted for?

I'm not 100% sure where they're deriving their number. I can tell you where we're deriving our number with an understanding of the prevalent population that is -- 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.

The last question comes...

They may just be discounting, but that's a good point.

So we have the last question, comes from the line of Debjit Chattopadhyay of Guggenheim.

So any progress with EMA with respect to SRP-5051 and the threshold of dystrophin expression for potential MMA submission? Also, are you expecting top line by the end of this year?

Louise, do you want to take those questions?

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

Well, I will say that having been personally involved in and involving the discussions with CHMP and EMA, and I do think we would have a different -- I suspect anyway, I should say. It will all be subject to discussion. I think we would have a different dialogue with the division, with EMA and then ultimately, CHMP with a therapy that was making 6% to 10% dystrophin. I think the probability of success would be much higher for an approval or conditional approval.

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. 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 rare 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 sheet, and we have talent to stay focused and to execute our plans to 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.

And 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.