Earnings Call Transcript - SRPT Q4 2020

Operator, Operator

Good afternoon, ladies and gentlemen, and welcome to the Sarepta Therapeutics Fourth Quarter and Full Year 2020 Earnings Conference Call. At this time all participants' lines are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. 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.

Mary Jenkins, Senior Manager, Investor Relations

Thank you, operator, and thank you all for joining today's call. Earlier today, we released our financial results for the fourth quarter and full year 2020. The press release is available on our website at sarepta.com and our 10-K was filed with the Securities & Exchange Commission earlier this afternoon. Joining us on the call today are Doug Ingram, Ian Estepan, Dallan Murray, Dr. Gilmore O’Neill, and Dr. Louise Rodino-Klapac. After our formal remarks, we'll open up 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 slides 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 will turn the call over to our CEO, Doug Ingram, who will provide an overview of our recent progress.

Doug Ingram, CEO

Thank you, Mary. Good afternoon, everyone and thank you for joining Sarepta Therapeutics fourth quarter and full year 2020 investor conference call. I am pleased to share with you this afternoon that the progress that we have made across our multi-platform portfolio, including our performance serving the Duchenne community with our approved products, the work we are doing in gene therapy, including SRP-9001, for DMD and, of course, the advancement of our RNA platform. We have an enormous number of important milestones in 2021. And I am very pleased that we have what I believe to be the strongest, most committed, and focused team in Sarepta's history to advance toward our goals. To remind you, in December of 2020, I announced that Dr. Louise Rodino-Klapac was named our Chief Scientific Officer taking charge of our research efforts across gene therapy, gene editing, and RNA therapeutics. Dr. Rodino-Klapac is a renowned leader in genetic medicine research, and organizing all of our efforts under her stewardship, we'll ensure we maximize the opportunities in front of us. At the same time, I elevated Dallan Murray to Chief Commercial Officer, a commercial leader with expertise second to none, in rare disease, DMD, and our RNA franchise. I also elevated Ian Estepan to CFO. I'm sure you all know Ian well and will appreciate that his nuanced knowledge of our company and our programs is only matched by his passion and commitment to our mission and the DMD community. Finally, I am pleased to announce that I have elected Ryan Brown, formerly our Chief Compliance Officer and then Interim Head of our Legal and Compliance Function, to be our permanent General Counsel. I have known and worked with Ryan for many years, and his intellect, judgment, and commitment to ethics and compliance will serve us well as we advance over 2021 and beyond. Moving to performance, 2020 was a challenging year for all of us and for the patient community, and launching a new therapy VYONDYS 53, just as the pandemic struck was not without its obstacles. Nevertheless, our commercial team in concert with medical affairs and our supply chain rose to the challenges, worked to keep our patients safe, and to ensure their access to therapy. So, for the fourth quarter of 2020, we achieved $122.6 million in product revenue; that's a 22.5% increase from the same quarter the prior year. For the full year, we achieved product revenue of $455.9 million, and that's a nearly 20% increase over the prior year. You will also recall that our guidance for 2021 is in a range between $537 million to $547 million. So, we continued strong growth. And to remind you, we have priced all of our RNA therapies at parity and we have not taken a price increase on any of our therapies since the approval of EXONDYS 51 back in 2016. So, our growth comes directly from our ability to serve our patient community. Now moving to our RNA platform, as you will have seen on February 25, the U.S. Food and Drug Administration approved AMONDYS 45; the generic name for that is casimersen. That's for the treatment of those Duchenne Muscular Dystrophy patients who have a mutation amenable to skipping exon 45. AMONDYS 45, our third approved RNA therapy will bring a treatment option to another 8% of the DMD community. Our three therapies together can treat nearly a third of all patients with DMD. And with our RNA PMO technology, we should be able to build constructs that can ultimately treat more than 80% of all DMD. In the fourth quarter of 2020, we announced preliminary but encouraging results for the 10 mg-per-kg and the 20 mg-per-kg cohorts in our multi-ascending dose study investigating SRP-5051, our therapy based on our next generation RNA technology, that's the peptide-conjugated PMO, or PPMO for short. The goal of the PPMO is to use a proprietary peptide to increase cell penetration, improving exposure, exon skipping, and dystrophin production, all with the goal of profoundly improving outcomes. We are on track to announce results from our next cohort at 30 mg-per-kg in the second quarter of this year. Moving to our gene therapy platform, as you know, we announced the results of part one of SRP-9001 study 102 in early January of this year. While we did not achieve statistical significance on our primary functional endpoint, we did gain invaluable insight and strong proof of concept on our secondary endpoints. So, we are clear, based on statistical significance on the primary functional endpoint has required a change in adoption in our regulatory filing strategy. But it does not impact our confidence or commitment in the program. Indeed, quite the contrary, consider the following. While we achieved statistical significance on important biomarkers, Western blot, protein positive fibers, intensity and creatine kinase reduction, we did not achieve statistical significance on our primary functional endpoint. However, when one looks at the pre-specified subgroup analyses, the reason for this becomes immediately apparent. In the 6-7 year old age group, the baseline characteristics were so enormously different, the treated group was far more severe than the placebo group with a p-value of literally 0.017 at baseline, making statistical significance practically impossible and lending most results uninterpretable. However, in the 4-5 year olds, the baseline characteristics were properly matched. In fact, the baselines on every functional measure were nearly identical. And when they were appropriately matched, so we were actually comparing similar populations in our pre-specified analysis, we strongly achieved statistical significance and clinically meaningful benefit of the therapy over placebo. This is, to be sure, the first time in the history of DMD development, that in a double-blinded placebo controlled trial of DMD patients a therapy has shown this sort of statistically significant and clinically meaningful benefit on NSAA in DMD. You better believe we continue to be confident in our therapy and in this program. Second, we now have more in depth, patient level insight into these age ranges, and how they traject with micro dystrophin than any other organization, and we will use this insight to refine our strategy and the protocol for our next trial, which we intend to commence this year. We are not only confident in our construct, we are confident that unique insight that we can apply to our next trial will give us a much greater probability of success and a competitive edge. There's a lot to do this year to advance SRP-9001. First, as you will recall, last year, we commenced what we call study 103. That's our trial to evaluate our commercially representative material. We announced at the JPMorgan conference that all of our initial 11 patients in that study have been enrolled and dosed. To better balance the number of 4-5 and 6-7 year olds in that study, we've updated our IND, so we can add additional 4-5 year old patients and we'll commence that enrollment dosing soon. However, just so you're clear, that will not delay the evaluation of and report out the results of our first 11 patients in the second quarter of this year as planned. Next, we will complete the evaluation of study 102, we will update our protocol for our next SRP-9001 trial. We will meet with the division to discuss and gain alignment on that protocol. We aim to commence that trial this year. Our goal is to commence that trial around the middle of this year with enrollment complete by the end of 2021. Our baseline assumption is that if successful, this will be the study to support our approval in the United States and around the world. And finally, it is important to recall that study 102 remains blinded and the last patient last visit for the full results from Part II of that study will occur before the end of this year. This will be an extremely important and insightful moment. And it's going to provide us all with an enormous amount of information on the performance of SRP-9001. We will see the impact of therapy at 96 weeks in 20 patients who were dosed at enrollment, and equally important, we will have 48 week results for most patients dosed at crossover; those patients will have had a 48 week run-in period to judge trajectory before they were provided therapy and to compare those patients against natural history predictions. Already, we have substantially more insight and proof of concept on our program than any other constructs. That insight will greatly expand with the readout of Part II of study 102. Let me now comment briefly on SRP-9003 that is our gene therapy, intended to restore the protein beta-sarcoglycan, in those patients who have limb-girdle muscular dystrophy type 2E. Last year, we announced very positive results in our proof of concept study for SRP-9003 in both our low dose and in our high dose cohorts. We will be updating those results at the 2021 MDA clinical and scientific conference in March. Our goal this year is to align with the FDA on the development path for SRP-9003 and to commence a pivotal trial this year. We will schedule that meeting with the agency once we have GMP material released for use in our next trial. Those discussions will inform our development strategy for other limb-girdle programs. And this year, we will complete toxicology studies for SRP-9004 and SRP-9005; those are for limb-girdle type 2D and limb-girdle type 2C respectively. We will commence a proof of concept study using material from Nationwide Children's Hospital for SRP-6004, our dual vector therapy for the treatment of limb-girdle type 2V in patients that are missing dysferlin. Beyond these programs, we continue to focus on the advancement of our gene therapy, RNA and gene editing research under Dr. Rodino-Klapac. In summary, I am reminded of the importance of our mission by Rare Disease Day, which was recognized yesterday, February 28, with a ruthless certainty every hour of every day. The rare disease patients that we serve are harmed and they worsen. If we are serious about our responsibility, we have little choice but to be ambitious and to move with a sense of urgency to intervene. When one is ambitious, there will be obstacles, as there were at the beginning of this year. But as we have shown before, we know what it takes to address and overcome obstacles, and we are doing just that. I have a passionate expert team that is moving our programs forward with $1.9 billion of cash as of the beginning of this year, augmented by strong revenue to reinvest in our programs and a razor focus on our top priorities. We have the strategy, the talent, and the resources to execute. And we have a mission that motivates us to get up each day to work hard to solve problems and to stay focused on the patients who will be the beneficiaries of all of that effort. And with that, let me turn the call over to Ian Estepan who will provide an update on the financials.

Ian Estepan, CFO

Thanks, Doug. Good afternoon, everyone. This afternoon's press release provided details for the fourth quarter of 2020 on a non-GAAP basis, as well as a GAAP basis. The press release is available on our website. Please refer to our press release for a full reconciliation of GAAP to non-GAAP financial results. We are pleased to announce that in conjunction with our recent AMONDYS 45 approval, we have sold the rare pediatric disease priority review voucher or PRV for $102 million. We expect the transaction to close in the next quarter after all regulatory conditions have been satisfied. Now moving to net product revenue for the fourth quarter of 2020 from our products EXONDYS 51 and VYONDYS 53, was $122.6 million, compared to $100.1 million for the same period of 2019. The increase primarily reflects higher demand for our products. Going forward in 2021, we will be breaking out revenues for our RNA franchise including EXONDYS 51, VYONDYS 53, and AMONDYS 45. And I'd like to remind you as Doug mentioned earlier, our 2021 guidance for our RNA franchise inclusive of AMONDYS 45 is $537 million to $547 million. In the quarter ended December 31, 2020, we recognized $22.5 million of collaboration revenue, which relates to our collaboration arrangement with Roche. The reimbursable co-development clause under the Roche agreement totaled $34.2 million for the fourth quarter. On a GAAP basis, we reported a net loss of $189.3 million and $235.7 million, or $2.40 and $3.16 per basic and diluted share for the fourth quarter of 2020 and 2019, respectively. We reported a non-GAAP net loss of $145.1 million or $1.84 per basic and diluted share in the fourth quarter of 2020 compared to a non-GAAP net loss of $116.9 million or $1.57 per share in the fourth quarter of 2019. In the fourth quarter of 2020, we recorded approximately $22.4 million in cost of sales compared to $15.6 million in the same period of 2019. The increase in cost of sales is primarily due to an increase in royalty payments to BioMarin Pharmaceuticals and the University of Western Australia, which reflects increasing demand for our products. On a GAAP basis, we recorded $207.2 million and $223.1 million in R&D expenses for the fourth quarter of 2020 and 2019 respectively, a year-over-year decrease of $15.9 million. This decrease is partially related to a $64.2 million decrease in upfront milestones and other expenses in the fourth quarter of 2020 as compared to the same quarter in 2019, which is primarily offset by a $58.1 million increase in manufacturing expenses due to the continuing ramp-up of our gene therapy programs. On a non-GAAP basis, R&D expenses were $180.8 million for the fourth quarter of 2020 compared to $135.4 million for the same period of 2019, an increase of $45.4 million. The year-over-year growth in non-GAAP R&D expenses was driven primarily by the continuing ramp-up of our gene therapy programs. Now turning to SG&A, on a GAAP basis, we recorded approximately $86 million and $81.4 million of expenses for the fourth quarter of 2020 and 2019 respectively, an increase of $4.6 million. The year-over-year increase was driven by an increase in stock-based compensation, partially due to increases in headcount and stock price. On a non-GAAP basis, the SG&A expenses were $65.2 million for the fourth quarter of 2020 compared to $65.8 million for the same period of 2019, a decrease of $0.6 million. On a GAAP basis, we recorded $17.8 million in other expenses and net for the fourth quarter of 2020 compared to $4.8 million in other expenses net for the same period of 2019. The increase primarily reflects the interest expense on the company's debt facilities, as well as a decrease in interest income and amortization of investment discounts due to the investment mix of the company's investment portfolio. We had approximately $1.9 million in cash, cash equivalents and investments as of December 31, 2020. And with that, I'll turn the call over to Dallan for an update on our commercial activities.

Dallan Murray, Chief Commercial Officer

Thank you, Ian, and good afternoon, everyone. Despite the challenges posed by the COVID-19 pandemic, Sarepta maintained its leadership position in Duchenne Muscular Dystrophy by continuing to serve patients and execute on our stated 2020 goals. Firstly, we were thrilled with the FDA approval of AMONDYS 45, casimersen. Sarepta's third RNA exon skipping medicine, which occurred last week on February 25, 2021. The approval was based on a statistically significant increase in dystrophin production and skeletal muscle observed in patients treated with AMONDYS 45. Based on our unrivaled expertise in DMD, and our commitment to serving this community with excellence and urgency, AMONDYS 45 was launched immediately after approval. All facets of our commercial manufacturing and medical organizations, including case managers, supply chain and field force, jumped into action on day one to support the roughly 8% of patients who are amenable to skipping exon 45. Our goal is to facilitate rapid patient access of AMONDYS 45 by leveraging our industry-leading knowledge and proven experience and having successfully launched two other RNA medicines to treat DMD, EXONDYS 51 and VYONDYS 53. In total, Sarepta now serves roughly 30% of the DMD community. Moving on now to EXONDYS 51 and VYONDYS 53, we continue to provide uninterrupted supply of both products to patients, and there have been few delays or stoppages as a result of the pandemic. Due to the fact that a large majority of EXONDYS 51 or VYONDYS 53 patients, roughly 90%, are receiving weekly infusions in their homes, we are encouraged that the majority of payers have demonstrated a willingness to work with the DMD community and have shown flexibility to allow for continued access to these important therapies during this difficult time. Any impact to-date has largely been due to missed doses, one to two doses on average, as a result of pandemic impact on either immediate family or direct care team. Our patients are determined to adhere to their weekly infusions and Sarepta is determined to continue to monitor and support these patients. The launch of VYONDYS 53 continues on pace with minimal impact to-date from any competition. Our team continues to execute on its goals and provide consistent and ongoing support to the exon 53 amenable patients. In addition, we've thoughtfully deployed measures to minimize the risk of transmitting COVID-19. These measures include sending personal protective equipment to all of our patients who have requested supplies to help ensure that they are protected when nurses administer their weekly infusions at their homes. We continue to monitor the pandemic and are ready to react quickly with additional modifications to our strategy, especially in those places experiencing surges in infections. Patient safety remains our top priority and we will continue assessing any and all efforts that will ensure patients feel safe and supported during this unusual time. Now I'll turn the call over to Gilmore for an update on our research and development activities.

Gilmore O’Neill, Head of Research and Development

Thank you, Dallan, and good afternoon everyone. Doug has already shared the highlights from our most advanced gene therapy programs. I will focus my remarks today on Sarepta's upcoming presentations at this year's MDA meeting in March and the progress we've made in advancing our RNA portfolio. Let me start with this year's MDA meeting. You will not be surprised to know that COVID-19 continues to disrupt the format of scientific meetings, plus MDA will host its annual clinical and scientific conference as a virtual meeting from March 15 to March 18, 2021, at which Sarepta plans to host two symposia and present 10 abstracts, which would include three podium presentations. The podium presentations will show previously reported data from SRP-9001 Two-Part I, our micro-dystrophin program and new long-term two year functional data from study SRP-9003-101 for our limb-girdle muscular dystrophy Type 2E program. Now, Doug covered the Part I results from our ongoing two parts, SRP 9001-102 study, but I do want to emphasize that first, because of the studies stratified randomization design, and second, because of its statistical analysis plan, we can state with confidence that the pre-specified subgroup analysis of 4-5 year old Duchenne boys demonstrated that SRP 9001 treated boys achieved NSAA gains that were clinically meaningful and superior to placebo treated boys with statistical significance. This means that the SRP 9001 micro-dystrophin construct is functional in humans and confers physiological and clinical benefit, thus substantially increasing the probability of success for this program. Moreover, a large amount of biological and clinical data that we have collected from the SRP-9001-102 study will further inform and optimize the design of our future study. Now, let me talk about our RNA portfolio. We were delighted to announce last week's approval of AMONDYS 45 for the treatment of Duchenne boys who carry an exon 45 skipping amenable mutation in their dystrophin gene. Now, you will be pleased to know that the ESSENCE study, a placebo-controlled confirmatory trial, which is designed to support the VYONDYS 53 and AMONDYS 45 approvals remains on track. We expect data from this PMR trial in 2024. Notwithstanding our excitement about AMONDYS 45’s approval, which is our third FDA approval to emanate from our proprietary PMO technology, our goal is to continue to advance the science for patients with Duchenne. We have successfully leveraged our PMO technology to selectively skip exons and restore the dystrophin reading frame, thus creating a truncated but functional dystrophin protein. Based on this elegant approach and our deep understanding of Duchenne, we set out to engineer the next generation of this technology, which we call PPMO, with the sole purpose of safely delivering more of the PMO into cells. To do this, PPMO has a positively charged cell-penetrating peptide or CPP to the PMO backbone. The addition of the peptide should increase cellular uptake. If we can safely drive more drug into the cells, we will see greater exon skipping and greater dystrophin production. This is no small feat, however, as we and many others have tried approaches to increase cellular penetration that have been hampered by dose limiting toxicities. On December 7, 2020, we presented a clinical update of our ongoing momentum multi-ascending dose study of SRP-5051 for Duchenne muscular dystrophy. By way of reminder, momentum, or SRP-5051-201 has two parts. Part A is to evaluate the safety and tolerability of SRP-5051 in patients with Duchenne and determine the maximum tolerated dose or MTD. With dose levels of Part A, Part 4, 10, 20, 30 and 40 milligrams per kilogram, administered once monthly by IV with each dose cohort enrolling three to six patients. Part B will evaluate SRP-5051 administered at the MTD and will include patients who complete Part A and an additional cohort of approximately 15 patients. In that update last year, we reported that we had achieved human proof of concept that conjugation of our cell-penetrating peptides to our PMO chemistry does indeed increase cellular uptake of PMO in the muscle target tissue in association with an increase in downstream exon skipping and dystrophin expression. These higher tissue exposures, higher exon skipping, and higher dystrophin expression were observed in the 20 mg-per-kg cohort of our 5051-201 momentum study at 12 weeks, as compared to the PROMOVI 30 mg-per-kg at 10% cohort at 24 weeks. Please remember that 12 weeks, the SRP-5051 20 mg-per-kg cohort saw increases in exon skipping of 1.6x and an approximately five-fold increase in percent normal dystrophin as compared to the 10% group at 24 weeks. As an approximately 10x lower cumulative drug exposure. Our next step will be announcing our 30 mg-per-kg expression data in Q2 of this year 2021. Once we have determined an MTD, we will commence Part B of the momentum study, which will include patients who complete Part A and an additional cohort of approximately 15 patients. Finally, and most importantly, I want to thank all the patients, their families, study sites, coordinators, my R&D colleagues and our partners who have done so much work under incredibly difficult circumstances caused by the pandemic to maintain our urgent mission to deliver new, highly effective therapies to people with rare diseases. Now, I would hand the call back to Doug for Q&A.

Doug Ingram, CEO

Thank you very much, Gilmore. Let's turn it over to Q&A now. Operator?

Operator, Operator

Our first question comes from the line of Alethia Young from Cantor.

Alethia Young, Analyst

I know a lot has been made of how to interpret what the 9001 data means for the next studies and DMD. But I just wanted to talk a little bit about what you think it means for limb-girdle, your general confidence level there based on what you've seen with this technology? And then also, how perhaps fine tune, think about what are the core key regulatory endpoints as you have those conversations with the FDA to make sure that they are successful?

Doug Ingram, CEO

First, our confidence in our constructs and the way we build them increases over time. I would like to remind everyone that the limb-girdle program, specifically limb-girdle Type 2E and SRP-9003, utilizes not only the same capsid, RNA 74, but also the same promoter as 9001. We have treated over 50 patients at the target dose, and we maintain a solid safety profile. We're observing good expression, which further boosts our confidence in SRP-9003, and we are excited about that. Regarding the clinical regulatory strategy for 9001, we have gained a substantial amount of insight from Study 102, some of which we've shared, and some still need work and will be shared once the protocol is complete. Our aim is to continue analyzing the data carefully, as we near the end of this study, to develop a protocol informed by Study 102's positive proof of concept and the nuances we've observed. Once the protocol is fully defined, we will update everyone. Our goal is to initiate the next trial this year, around mid-year, with the intention of dosing all the children involved before the year ends. If all goes well, we expect to have the last patient visit by the end of next year and readouts shortly thereafter. We currently assume that this study will be the basis for obtaining the first approval in the U.S. and globally.

Brian Abrahams, Analyst

Now that you've had more of an opportunity to digest the mono two dataset, and I think you've mentioned maybe in January, you've been looking at additional statistical analyses, including those that may normalize for baseline characteristics. I was wondering if you had any further learnings or insights that you'd be willing to share and any maybe planned adjustments to the general approach you might take to the 301 design, things like inclusion criteria, or analyses.

Doug Ingram, CEO

So the short answer is yes, we have an enormous amount of insight that's come out of 102 and it will help us tune the next study. We're not yet in a place where we want to discuss that and provide additional detail. We'll do that once that protocol is fully designed and then the agency is bought into the protocol. But we are convinced not only that there's a lot of insight here but that we can greatly increase the probability of success in the next trial in a very nuanced way. We have already at study 102, significantly more insight and data than anyone else would have regarding a construct for micro-dystrophin for the use of Duchenne muscular dystrophy, that'll help us design our next study, which we tentatively call study 301. And then, we'll have even more insight, by the way, at the end of this year. I really do want to point out how important that is. Remember study 102 is a blinded study, what we saw in January was part one of that study. And what we saw, well, I'm not going to deny, I'm disappointed that we didn't hit statistical significance in the primary endpoint, what we saw in the secondary endpoints confirms our belief in the value and the benefit and the transformative potential of this therapy. When you look at the four to five year olds, that's only 16 kids, and in that 16 kid cohort, where the baselines were actually properly compared, we saw not just a strong statistical significance, but also a very clinically meaningful benefit over placebo and only 48 weeks. At the end of this year, remember, that study remains blinded, we're going to have part two, which is going to be last patient last visit, in the back half of this year. By the end of this year, probably very early next year, we will have the results of part two and that's going to be enormously insightful on top of this. Think about what you'll have there, we'll have for about 20 of the kids, two years worth of data that we can look at, and the way they're projecting on therapy. For the other 21 kids there, we have something very interesting there, in some ways really interesting, which is we'll have a cohort of children who will have truly been able to follow and do a run-in for 48 weeks or trajectory without a therapeutic intervention, then we have a therapeutic intervention. When we unblinded, we'll get to judge what the impact of that therapeutic intervention was. So we'll have even more insight. So short answer on your long answer policies. But long answer trying to get short on your question is, we have developed an enormous amount of insight out of 102, that gives us not only a lot of confidence in the therapy, but a really keen understanding of how to design the next protocol and fine-tune it. We will do that and we'll get that blessed by the agency and then we'll all talk about it once that's done.

Salveen Richter, Analyst

Just, you maybe an update on your gene editing portfolio, you recently entered into a research collaboration with Genevant for LMP-based editing therapeutics and you've had some other partnerships to date, could you just walk us through, when we should expect kind of an update on programs moving forward here?

Doug Ingram, CEO

Sure, I will hand this over to Dr. Louise Rodino-Klapac. Before I do, I want to highlight that our aim is to explore all modalities, including the exciting potential of gene editing. We've formed several partnerships over the past 12 to 24 months, and I should mention that we have established a Gene Editing Innovation Center in Durham, North Carolina. This center is led by Dr. Charlie Gersbach from Duke University, a prominent figure in the field of gene editing, particularly related to neuromuscular applications. Now, Louise, would you like to share some insights on our gene editing initiatives?

Louise Rodino-Klapac, Chief Scientific Officer

Sure, thank you, Doug. I'd like to just second with what Doug said about Charlie Gersbach and being really the true leader in the field and having worked in Duchenne space for quite some time. We had the opportunity to develop a best-in-class technology. Part of that is really scanning the landscape for delivery technologies, and there are other ways that you can deliver gene editing machinery, and so our Genevant partnership was one way to look at that using lipid nanoparticles. We're certainly open to making sure that we have the best delivery vehicle for gene editing. We will continue to look at these research partnerships in a broad manner to ensure that we develop the best technology moving forward. Thank you for the question.

Doug Ingram, CEO

I should also note, Salveen, that we have relationships to advance updated and increasingly sophisticated AAV technology with the nanoparticles. We also have a relationship to explore the use of exosomes as delivery devices, potentially for gene editing, gene therapy, and possibly even RNA.

Ritu Baral, Analyst

Doug, have you ruled out breaking the blind on 102 to generate more data before you start 301? Or do you have optionality to keep 301 adaptive depending on what final 102 data will show? And given enrollment is going to be competitive, how confident are you that you can enroll 301 in six months?

Doug Ingram, CEO

Thank you for your questions, Ritu. You raised an interesting point about possibly conducting an interim analysis on part two for further insights. After considering this, we believe it is not the right approach for several reasons. Firstly, part one of the study, 102, will already provide us with substantial insights that will inform the design of what we are calling study 301. Our insights are unique and will give us a competitive advantage, increasing our chances of success. We want to keep the results of study 102 blinded until the last patient visit, which we expect to complete by the end of this year or very early next year. The data we gather from this will be crucial in this rare disease area, and maintaining the blind is important. Regarding enrollment, there is a significant need in Duchenne muscular dystrophy, and I am quite confident we can enroll patients quickly. Physicians and investigators are eager to collaborate with us, so I don’t foresee this as a major challenge. Our primary focus right now is on finalizing the protocol, meeting with regulatory agencies for approval, and ensuring we can start enrollment promptly. I believe that once we begin, patient enrollment will be strong.

Anupam Rama, Analyst

This is Tes on the call for Anupam. I have a question regarding your remarks, Doug. You mentioned expanding study 103 to improve the balance of four and five-year-olds in the trial. What is the reasoning behind this, especially considering you're planning to run study 301? What is the current target for study 103?

Doug Ingram, CEO

Thank you for your question. I want to clarify that the reason I brought this up is to assure everyone that there is no significant change or delay. To remind everyone, study 103 uses commercially representative material, and our aim is to assess expression, safety, and the similarity of this new process. The good news is that all the children were dosed by the end of last year, which we communicated to JPMorgan, and that involved about 11 children. We have observed an increase in the number of participants aged 6, 7, 4, and 5. Since the study focuses on 4 to 7-year-olds, we have updated the IND to include some additional 4 to 5-year-olds, but no more than that. We have not seen any data regarding this yet. This will not postpone our evaluation or the reporting on those 11 patients. It's aimed at achieving a better balance over time, so please do not view it as a delay of any kind. There will be no delay in the report expected in the second quarter, nor will it affect the start of study 301. Our goal is simply to ensure a good mix of 4 to 5 and 6 to 7-year-olds within the study.

Difei Yang, Analyst

Just a quick one, on a very high level, how do you think about gene editing relative to AAV-based gene therapy? Is there a possibility that gene editing just leapfrog the virus-based gene therapy and come to commercialization first?

Doug Ingram, CEO

Well, I think the answer is no. I don't think that we're going to see something that's going to leapfrog gene therapy right now for a host of reasons. First, you raised a really good point because what you said is that, is it possible that the gene editing would leapfrog this virus-based gene therapy that we have in front of us today as a biopharmaceutical industry? And the short answer is that of course, gene editing today is virus-based as well. I think that to empower gene editing, we may want to look, as we are currently, as you've seen, both through LNPs and exosomes, about a delivery device that would move itself away from AAV as a potential. So that already is going to require a lot of effort and focus and research. To think about it, AAV has been a very successful approach for delivery of gene therapy. If we're going to move away from that over time, that's going to take time. So gene editing is really exciting. But I think just temporarily there's a different, gene therapy is right in front of us right today. You saw had the results of a placebo-controlled trial, at least part one. Again, I would remind us that when we got the baselines right in the 4 to 5 age cohort, we saw a really profound, never before seen benefit out of a placebo trial. This is right in front of us. Gene editing is very exciting but believe me, we are, there's a reason why we're putting a lot of effort into gene editing, why we built this gene editing Innovation Center, why we've wrapped our arms around the technology of someone like Dr. Charlie Gersbach, while we've entered into partnerships to look at other delivery mechanisms to empower gene editing. But I think there's just a difference in time between the opportunity to bring therapies to children today with gene therapy and to look down the road at gene editing, as well. There are differences in technological challenges in both areas, gene editing edits and that's very interesting. On the other hand, let's be clear, you're going to have to edit and create truncated forms of the ultimate protein as well. You're either going to do that on an exon-by-exon basis with respect to gene editing, or you're going to have to do what we are attempting to do with Dr. Charlie Gersbach, which is take a significant hotspot of gene editing, where you can put something back in frame and create a therapy that could treat about 50% of the children. That's different than gene therapy, where gene therapy really is agnostic of the mutation. There are differences. Short answer, I think there's a difference in time. I think gene editing today, it's a really exciting research program. CRISPR-Cas9 is an unbelievably exciting technology. There's a reason why those individuals won the Nobel Prize for it. But it's a little ways out. Gene therapy is right in front of us today and offers the hope of transforming lives and patients in Duchenne Muscular Dystrophy and a lot of other areas as well.

Debjit Chattopadhyay, Analyst

So I'm trying to find an explanation for the high 2.62 VCN per cell in the crossover patients, but micro-dystrophin expression about the same as study 101, whether the VCN was 1.63. Could you also sort of talk to any difference in dose between the first cohort of patients in study 102 versus the crossover patients?

Doug Ingram, CEO

I'm going to turn this question over to Dr. Louise Rodino-Klapac who can provide some insight into both. I would think, Louise will explain, I think on the genome copies per nucleus, I wouldn't over interpret the delta between those genome copies, probably, despite smaller numbers in a sense, in the genome copies than in the western blot expression. But Louise, your thoughts on both of those questions?

Louise Rodino-Klapac, Chief Scientific Officer

I would agree with you about not over interpreting the vector genome copy numbers in part two. I would add that in part two, as we mentioned, the first 11 patients will receive the intended dosing level as opposed to the part one patients which we've discussed. So in that respect, we feel that study 101 and what we've seen so far in part two at the intended dosing level are quite on target in terms of expression and vector genome copies within range as well. Was there any additional question?

Doug Ingram, CEO

I think those are the two questions and just to remind everybody about Debjit's question. In the first part of the study, the titration method that was used, the standard what's called supercoiled qPCR. It turns out with the benefit of having developed a linear standard for qPCR, we can look back and see that there were three lots; one of the lots hit the target, the target tittering. Two of the lots were below the tittering in the first group of patients. That's about 60% of the patients were in the lower lots. On the crossover, we used the linear titration for the purpose of the crossover patients, and so we were right on target titrating and target dose on the crossover patients.

Gena Wang, Analyst

I have a question about study 102. Did you work with the FDA to define a specific natural history patient population for statistical analysis regarding the crossover? Also, we know that Dr. [indiscernible] tends to use a weekend regimen. Was this consistent among all the patients?

Doug Ingram, CEO

Yes, regarding the second question, we permitted patients to remain on a long-term stable dose of steroids, utilizing their standard care methods. Some patients take daily doses while others use them on weekends, and this might influence the results as we observe. Concerning the crossover, that was predefined, and we can provide updates before we unblind the study. If I'm mistaken, please correct me, but I believe all the meta-analysis was included in the protocol from the start of the trial.

Gil Blum, Analyst

So, as you mentioned before, Doug, LGMD programs have certain similarities across them. From a regulatory perspective, there's positive data, continuing positive data for LGMD 2E. Does that translate across programs?

Doug Ingram, CEO

The positive data on the LGMD programs may not come from a strictly regulatory perspective, but it definitely boosts our confidence in the construct and the results. We're seeing positive outcomes across all of the LGMDs, as well as with 9001. If we examine the safety profile, it's important to note that a significant portion of this profile is influenced by the capsid, which in this case is r874. This capsid is used for all our limb girdle treatments, along with 9001 for DMD. Observing positive expression results provides us with substantial confidence in the tropism of r874 across all programs, as well as in the promoter itself. The same promoter is used in 9001 and, if I’m not mistaken, in three of the five limb girdle programs. We have built a considerable amount of confidence here. Regarding the limb girdle and its regulatory pathway, we plan to meet with the division this year, once we have GMP material released from our commercial representative. This meeting will help us clarify the pathway for limb girdle, which I suspect will also inform the pathways of our other limb girdle programs. Having this conversation will be crucial for us this year.

Tazeen Ahmad, Analyst

Hi, guys, maybe just to change gears to your current franchise, just wanted to get a little bit of color on what kind of penetration you have right now with EXONDYS and the targeted market? Can you give us an idea of how go of your sales launch is going, and if you expect casimersen will also have a similar type of ramp to what EXONDYS had at the beginning? To tie it all up, how big of a market opportunity with the three drugs together represent?

Doug Ingram, CEO

Thank you for that. Let me address both points together. To start, we launched EXONDYS in late 2016. By the end of this year, we expect to see more stable growth for EXONDYS. This is due to our continuing efforts in patient outreach and potential new patient screening that could greatly increase our numbers. There's still significant potential for EXONDYS long-term, especially internationally, but we need to find ways to get regulatory approvals outside the U.S. Right now, our ex-U.S. opportunities mainly rely on a responsive access program. The lack of an accelerated approval process in many countries hinders our expansion until we have results from confirmatory trials that may open new growth avenues. Golodirsen has performed well, although its launch was somewhat impacted by the pandemic. Ideally, we would have preferred to introduce a new therapy without the complications of the pandemic. Fortunately, the team managed well, and we have seen positive growth in VYONDYS. I believe that the VYONDYS launch will continue positively, indicating strong potential. Regarding casimersen, which just received approval last week, our team is prepared for a quick launch. We already have start forms in place and will have AMONDYS ready for distribution very soon. Given that the patient population for AMONDYS is smaller than for EXONDYS, I estimate that its launch trajectory could resemble that of EXONDYS, with significant demand from families waiting for treatment for exon 45 amenable children. In terms of market size, our current pipeline places us in a strong position, and we are just in the beginning stages with these three therapies. Together, they represent a larger opportunity compared to other treatments. If we focus solely on the U.S. market, we could potentially reach the billion-dollar mark over time, and expanding internationally would greatly enhance that potential. An important point I want to emphasize is the opportunity within our RNA franchise. Our current therapies target only 29% of the patient population affected by Duchenne Muscular Dystrophy. There are over 80% of affected children whose mutations could benefit from this exon skipping technology. We have developed a precise and reliable method to create constructs safely that could help these children. Our goal is to extend our therapies beyond EXONDYS, VYONDYS, and AMONDYS, potentially addressing 55% to over 80% of the population. We need to adopt a comprehensive approach to target these rarer mutations, and we’ve already begun discussions with regulatory agencies on how to proceed. We see significant potential with either the PMOs we currently have or with peptide conjugated PMOs, with results from the PPMO expected in the second quarter. Last year’s data from the lower doses gave us encouraging proof of concept, with a fraction of the drug exposure showing substantial production increases in a short timeframe. Both PPMO and PMO avenues present serious opportunities to benefit the Duchenne community and could also generate significant revenues.

Vincent Chen, Analyst

Taking the crossover data at the end of this year from study 102, I was wondering if you could provide a bit more color on how you evaluate the data and what you're hoping to see, I guess, what comparisons were specified in the protocol? What would, from your view, what would an encouraging result look like?

Doug Ingram, CEO

Well, we're looking at both two things, really. We're looking at the first one; there's a bunch of things we're going to look at. Of course, we can update with more insight, more thought into in the broadest of strokes; we're going to be able to see, first of all, we're going to be able to compare against natural history children, including children who have been on the therapy for nearly two years, that's going to be exciting. We'll have this trajectory analysis that we can look at as well, which we have a unique opportunity just to look at children who are blinded the whole time. So let's be very clear, this is not an open label study; it will be blinded till the end. We'll look at them trajecting over the course of 48 weeks without any therapeutic intervention and then a therapeutic intervention. We see what that looks like over time, both using themselves as their own control, and also using well-matched Natural History set that would be pre-specified to look at what you would have predicted out of a natural history set based on their trajectory over that 48 week period, including and then looking at their age. But beyond that, Dr. O'Neill, is there anything I'm missing here in the broad strokes?

Vincent Chen, Analyst

I think you've covered the main points, and you'll also have a second year of follow-up for the patients who were randomized to active treatment in the first part. So you have it.

Tara Bancroft, Analyst

And so staying on the topic from Tazeen's question, what do you think is the next PMO, in terms of which candidate you think could get approved next, or do you think it's actually more likely to be a PPMO? I know you said it could be one or the other. And on the PPMO topic, have you started dosing in the 40 mg-per-kg cohort yet? And will they be included in the data in Q2?

Doug Ingram, CEO

Going to the last question first, the data we expect in the second quarter will be the 30 mg-per-kg data. It's an interesting question. We have constructs ready; the great aspect of RNA Technology is that we can conjugate a peptide to create the PMO construct. We can build the PMO construct and if we want to transition to PPMO, we simply add the peptide to the existing construct. We have several constructs prepared for significant populations. The key decision point for us will be based on the PPMO data. If the results are promising in the PPMO, we will begin developing constructs with peptide conjugation for those patients, and ideally, we will celebrate an approval through that route. If we determine that PMO is the better option, we will start conjugating and advancing those constructs. We currently have a distinct approach that allows us to build precise constructs with strong safety profiles in the PMOs. We're focusing on the safety profile of the PPMOs, which we can advance under an accelerated approval pathway that is very efficient. However, we first need to establish whether it will be PPMO or PMO. Last year, we received very encouraging results in the PPMO, and we will see how the 30 mg-per-kg data looks in the second quarter of this year.

Brian Skorney, Analyst

Question on the ESSENCE study, you said it'll read out in 2024. I guess is that study now blinded out until week 144? I'm just wondering, in terms of, with three years to go before the readout? How do you intend on maintaining trial integrity in terms of keeping patients randomized, given that both golodirsen or casimersen are now available?

Doug Ingram, CEO

Yes, that's a great question. Yes, it's blinded. It's very difficult; you have a very good point. We've done a great job; the team's had a brilliant job. More than that, the patients have done a wonderful job committed to this trial. But it is blinded, having a long-term blinded trial, it takes a lot of commitment. So there's no doubt on that. The trial integrity is not at risk as a result of the approvals of both AMONDYS and VYONDYS; it was one of the very things we talked about early with the agency as we were thinking about the accelerated approval approach, both for VYONDYS and then AMONDYS. The way we achieve that was to ensure that even as AMONDYS, I mean, its VYONDYS was coming close to approval, we moved our recruitment ex-U.S., so we moved to regions around the world that don't have access to a commercially available therapy. The access to the therapy in those areas can be via this trial, and then we don't have to worry about what would be a very credible risk, which would be you get a commercially available therapy on board. Children are moving over to commercially available therapy as opposed to being in a placebo-controlled trial. That risk is not significant at all, as a result of the actions that we took a couple of years ago to start recruiting ex-U.S.

Colin Bristow, Analyst

Hi, this is someone calling in for Colin. Thank you for taking our questions. I have a follow-up regarding the prior question. Looking back at my notes from the December call on 5051, Doug, you mentioned the possibility of starting the 40 milligram per kilogram arm by the end of Q1. Is that still on track? If not, are you waiting for the 30 milligram per kilogram data before moving forward? Are you looking for something from the biopsy or safety side to help make that decision going forward?

Doug Ingram, CEO

We're updating our view and want to see the 30 mg-per-kg data before deciding on two key things: the pathway for pivotal and the appropriate dose ranges. After evaluating the 30 mg-per-kg results, we will decide whether to move to 40 mg-per-kg. We expect to see the 30 mg-per-kg data in the second quarter.

Shawn Egan, Analyst

This is Shawn Egan, calling in for Joel, thanks for taking my questions. It was great to hear about the pivotal trial for the beta-sarcoglycan trial this year. When did you expect pivotal data for the study? Should we expect a similar cadence to study 301?

Doug Ingram, CEO

Well, we don't know because we have to decide with the agency's involvement and guidance what the right development pathway will be for the beta-sarcoglycan. It is significantly different from SRP-9001-101 important regard, which is the issue with SRP 9001, and one of the reasons that we've taken the approach that we're taking, which is a placebo-controlled, blinded study? There are two reasons. One is that DMD is a large enough patient population that it is feasible to do that; it has its own ethical challenges. Believe me, it's required a lot of discussion with patient groups and patient advocates around that but it can be done. The second thing, of course, is that with respect to micro-dystrophin, you do have a truncated version of the dystrophin. Expression alone wouldn't be sufficient; you have to also show the function of that. We've been clear about that, it makes sense. We just make the beta-sarcoglycan and we're in a different place. I wouldn't assume in advance that it's the same cadence as SRP-9001 for two regards. One, this is a much rarer population; the very concept of doing a blinded, placebo-controlled trial, I think would be probably an understatement to say that that would be challenging from both an execution perspective and an ethical perspective. The second thing that's important is with respect to beta-sarcoglycan and 2E, the gene that we are delivering, creates a native protein. This is the native protein. So, with respect to those two issues together, the discussion that we're going to have with the agency is around the ability to come up with a lean, efficient, executable approach to get this therapy to patients that are waiting. We've already seen both in our low dose and our high dose cohorts using the clinical critical supply from Nationwide Children's Hospital that we're seeing very high expression in both, we're seeing correlates of a really strong functional endpoint; we'll have an update on that at MDA. That will be a very important update. Our view is that given its native protein, the development pathway should be leaner and it should be informed by the patient population and the fact it's a native protein. We'll know that when we have the discussions with the agency; we'll have those discussions once we have GMP material to talk CMC with the division. That will happen this year.

Jackie Yan, Analyst

Hi. This is Jackie here for Hartaj. Thanks for the question. Just on the $1.7 billion of potential milestones from your agreement with Roche, could you just remind us what proportion of that amount is going to be clinical milestones? And what proportion are going to be for commercial aspects?

Doug Ingram, CEO

I'm not sure if we can disclose that. Ian, you can confirm, or if we have we can disclose again, I don't believe we've disclosed the nuances of our milestones. Am I incorrect in that assumption?

Ian Estepan, CFO

And that's correct, the milestones are mostly related to regulatory and commercial milestone achievement. So they're on the back end of the development program.

Doug Ingram, CEO

Thank you all very much for joining us this evening, this afternoon or this evening. Thank you for your probing and insightful questions. We obviously have a lot to do over the course of 2021, a number of very important milestones across this year. From a commercial and serving the patient community perspective, we will continue to serve the community with EXONDYS, we will continue the launch of VYONDYS. We are very, very excited about the opportunity to launch AMONDYS which is already occurring; as I've said earlier, we will be — our therapy will be in warehouses this week, and we will be serving the community literally this week with that therapy. So I'm very excited about that over the course of this year, we have a number of opportunities to update on the PPMO with a 30 mg-per-kg next quarter. That could be a very exciting evolution of our RNA technology in either PPMO or PMO. We have an enormous opportunity to do a lot of good in DMD, as I said a number of times tonight, we can serve over time, up to 80% of the DMD community, both in the United States and hopefully over time ex-U.S., which is an enormous opportunity. The gene therapy side, we have an enormous number of milestones, a lot of work to do this year with respect to SRP-9001. We are very focused on that as that could be a significant transformative event for patients with Duchenne. The results of study 102, when you really look at it carefully gives us increasing confidence about the potential of 9001 to bring a better longer life to kids with DMD. Beyond that, of course, we have our limb-girdles; we continue to focus this year and I look forward to the opportunity to update everyone on milestones over the course of 2021. With that, thank you. Have a good evening and of course, everyone stay safe.

Operator, Operator

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.