Sarepta Therapeutics Inc (SRPT) 2021 Q2 法說會逐字稿

Good afternoon, ladies and gentlemen, and welcome to the Sarepta Therapeutics Second Quarter 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, operator, and thank you all for joining today's call. Earlier today, we released our financial results for the second quarter 2021. The press release is available on our website at sarepta.com, and our 10-Q was filed with the Securities and 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 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 quarterly report on Form 10-Q 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.

I'll now turn the call over to our President and CEO, Doug Ingram, who'll provide an overview of our recent progress. Doug?

Thank you, Mary. Good afternoon, everyone, and thank you all for joining Sarepta Therapeutics Second Quarter 2021 and investor conference call. With a large multi-platform genetic medicine pipeline, which spans RNA, gene therapy and gene editing. And with 3 approved therapies, we have a significant number of important initiatives underway in 2021. And I and my team are very pleased to share with you this evening our progress in the achievement of our milestones. I am particularly proud of this team's focus on execution and the consistent achievement of our goals this year, which you will see reflected in our results.

Now as pleased as I am with our quarterly performance, I am going to dispense with my usual order and start by updating you on the important and very positive developments for SRP-9001 this quarter. I am delighted to share with you the progress we have made with respect to SRP-9001 and the positive outcome of our recently completed meeting with FDA's Office of Tissue and Advanced Therapies. I'll be referring to that division going forward as OTAT.

Now as a reminder, earlier in the second quarter, we announced the 12-week results of our first 11 patient cohort for Study 103, also known as ENDEAVOR. To remind you, Study 103 is our trial evaluating the expression and safety of our commercially representative material. This is an extremely important study as it has confirmed the performance of our therapy using the material process with which we intend to launch SRP-9001.

We were pleased to report that on every biomarker, our commercially representative material performs as well as or better than the clinical supply material we used in our prior study. Armed with the positive Study 103 results, we scheduled a meeting with OTAT to review our CMC and our plans for Study 301. That is our proposed pivotal trial for SRP-9001.

I would like to thank OTAT for what was a very productive and informative meeting. And based on that meeting, we are on track to commence Study 301 as proposed to the division, both in the United States and then globally, and we believe we should be able to initiate Study 301 in September of this year. The initiation of Study 301 is an important moment, not merely for this program, but for families living with Duchenne.

Following receipt of the final minutes, I will provide detailed information regarding our study design and some of the reasons we are so confident that our program will be successful.

Now we've taken a deep dive into Part 1 of Study 102. And we are not only very confident in the performance and transformative potential of SRP-9001. But we are also very confident that 301 is well designed with a high probability of success of showing that performance. Again, once we have the final minutes and are ready to initiate the trial, I will share with you the details of the trial and the data-driven basis for our confidence in this program.

Looking forward, Study 102 is proceeding and remains blinded, and we will have a readout of the second phase of that study, including 1-year and 2-year functional results in the first quarter of 2022.

Staying with our pipeline updates, let me now move to limb-girdle muscular dystrophy. As you know, we have seen very robust results from our first 2 cohorts. And our proof-of-concept study for SRP-9003, that's our gene therapy being developed to treat LGMD Type 2E. I can now report that we have already solicited and received written feedback from both the FDA and EMA regarding our plans for SRP-9003, both confirming the possibility of using protein expression as an endpoint for accelerated approval in the U.S. and for conditional approval in Europe.

From here, we need to gain alignment with the FDA and EMA on the precise clinical and regulatory approach appropriate for LGMD2E and then appropriate for the rest of the LGMD pipeline. And based on the written feedback we have received, we are investing time now considering how we might move our entire LGMD sarcoglycan platform forward together. With the successes that we've seen with our gene therapy approach to LGMD, we are expanding our portfolio. Dr. O'Neill will provide additional color on our license to another rh74 mediated gene therapy in this instance, 1 to 3 LGMD Type 2A or calpainopathy.

Moving now to our RNA franchise. You will recall that earlier this year, we announced positive results from Part A of our MOMENTUM trial, studying our next-generation version of our Morpholino platform, a peptide conjugated PMO or PPMO SRP-5051, which is designed to be an enhanced version of our PMO technology for Duchenne patients who have a mutation amenable to exon 51 skipping.

Dr. O'Neill will review the positive results of that study at 30 mg/kg, and we'll provide our plans to commence our pivotal phase of our trial for SRP-5051 later this year. The advancement of our PPMO technology solidifies our singular leadership in evidence-driven RNA technology to treat rare diseases where steroid blocking can provide benefit.

Our PMO is predictable and a durable platform that has already produced to 3 FDA-approved therapies that can in turn improve the lives of nearly 30% of Duchenne patients in the United States and at least for now, to a lesser extent outside the United States. Our next-generation PPMO, if confirmed in upcoming trials, will greatly extend the reach and impact of our RNA platform.

As Dr. O'Neill will share with you, our PPMO platform has the potential of being a leap forward in the treatment of Duchenne. With the PPMO platform, we have the technical ability to construct therapies for well over 80% of Duchenne patients. And with profoundly greater dystrophin production, the opportunity exists to expand our reach far beyond the United States with approvals globally.

And even as we develop our PPMOs for Duchenne, we are exploring additional genetic diseases where steric blocking may provide benefit. We will work with the neurology division at CDER and that's the division within FDA responsible for our RNA platform to gain alignment on Part B of SRP-5051 trial. And once confirmed with CDER, we will commence our Part B pivotal trial before the end of this year as we also advance additional constructs for other mutations.

Now let me comment on our quarterly performance, serving the Duchenne community with our 3 approved RNA therapies. In addition to continuing to adapt to this pandemic, the team is focused on serving our patients with EXONDYS and VYONDYS, and launching AMONDYS, which, as you know, was approved back in February of this year. And their success is reflected in our quarterly numbers.

I am pleased to report that in the second quarter, we achieved net product revenue of approximately $142 million, that represents a nearly 27% growth over the same quarter last year. Since our first approved therapy nearly 5 years ago, we have enjoyed long-term compounded annual growth of about 20%. And as a testament to the value of our therapies to the lives of those living with Duchenne, even considering that each of our therapies requires weekly infusions amid a troubling pandemic environment, the adherence rate for our therapies remains well over 90%, an extremely impressive and telling metric.

Based on this success, we have today increased our full year net product revenue guidance. At the commencement of this year, our guidance was in the range of $537 million to $547 million. Today, we are raising that guidance to between $565 million and $575 million, representing at the midpoint, a growth of more than 25% over last year. Our Chief Commercial Officer, Dallan Murray will provide more color on our quarterly performance in a moment.

Now the progress we've made in 2021 demonstrates execution by our team of professionals across our entire fully integrated commercial stage genetic medicine organization, while not currently reflected in our stock price, I am proud that the Sarepta team has executed this year and achieved nearly every one of the ambitious goals we have set for them, driving performance of our on-market therapies, and advancing our industry-leading genetic medicine pipeline.

To summarize, let's consider the accomplishments so far in 2021, and I'll do this chronologically. First, additional evidence-driven confidence in the probability of success of SRP-9001. Even though Part 1 of Study 102 did not achieve statistical significance on the pooled primary endpoint due to titering issues and baseline imbalances in the prespecified subgroup analysis of the 4- to 5-year-olds where the baselines were in line we saw not merely strong statistically significant benefit, but perhaps the best results so far in a trial for Duchenne.

Moreover, an analysis of the complete data set from Study 102 only bolsters even more our confidence in the transformative potential of SRP-9001. And more than just that, the study has informed the design of our next trial, greatly enhancing its probability of success.

Next, we received FDA approval for and launched our third RNA therapy to treat Duchenne. Of course, that is AMONDYS. Now serving a record percentage of patients. As Dallan will detail in a moment, our performance across all 3 of our RNA-based therapies, EXONDYS, VYONDYS and AMONDYS even in these challenging times, has been exceptional.

We also reported over the course of this year, several positive clinical data readouts that bolster not only our approach but the intrinsic value of both our gene therapy and RNA platforms, consider exceptional functional improvement and durability results for SRP-9003, our LGMD2E gene therapy. We also reported impressive clinical results for SRP-5051, the first of our candidates from our next generation, PPMO platform. We also reported exceptional clinical results from the first cohort of Study 103, confirming the performance of our commercially representative material for SRP-9001.

And frankly, the culmination with enormous work and investment to advance our gene therapy manufacturing process over the last few years. And as you have heard today, we have completed a productive meeting with OTAT, regarding our pivotal trial for SRP-9001, that is, of course, Study 301. And we are on track to initiate that trial in September of this year in the United States and then around the world as well.

Looking forward to the rest of the year, in addition to initiating Study 301 and continuing Study 102 for SRP-9001, we will engage the FDA and Ministries of Health to align on our clinical and regulatory pathway for our LGMD portfolio. And separately, we will align with the FDA and other ministries of health around the world with the goal of advancing our PPMO SRP-5051 and to a pivotal trial to start this year. I look forward to updating you as we progress and to continue to execute on our milestones over the remainder of this year.

And with that, let me turn the call over to Ian Estepan, who will provide an update on the financials. Ian?

Thanks, Doug. Good afternoon, everyone. This afternoon's financial results press release provided details for the second quarter of 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. Total net product revenue for the second quarter of 2021 from our PMO exon skipping franchise was $141.8 million compared to $111.3 million for the same period of 2020.

For the second quarter of 2021, individual net product sales were $112.5 million for EXONDYS 51, $22.4 million for VYONDYS 53 and $6.9 million for the newly launched AMONDYS 45. The increase primarily reflects higher demand for our products in the launch of AMONDYS 45. As Doug said, due to the strong performance, we have increased our 2021 revenue guidance range for our RNA franchise.

In the quarter ended June 30, 2021, we recognized $22.3 million of collaboration revenue compared to $26 million recognized in the same period of 2020, which primarily relates to our collaboration arrangement with Roche. The reimbursable co-development costs under the Roche agreement totaled $17.7 million for the second quarter of 2021 compared to $8.9 million for the same period of 2020.

On a GAAP basis, we reported a net loss of $81.4 million and $150.8 million or $1.02 and $1.93 per basic and diluted share for the second quarter of 2021 and 2020, respectively. We reported a non-GAAP net loss of $121.2 million or $1.52 per basic and diluted share in the second quarter of 2021 compared to a non-GAAP net loss of $117.9 million or $1.51 per basic and diluted share in the second quarter of 2020.

In the second quarter of 2021, we recorded approximately $19.5 million in cost of sales compared to $13.3 million in the same period of 2020. The increase in cost of sales is primarily due to increasing demand for the company's products.

On a GAAP basis, we recorded $239.6 million and $188.5 million in R&D expenses for the second quarter of 2021 and 2020, respectively, a year-over-year increase of $51.1 million.

This increase is primarily due to an increase in milestone and manufacturing expenses. On a non-GAAP basis, R&D expenses were $189 million for the second quarter of 2021 compared to $160.4 million for the same period of 2020, an increase of $28.6 million.

Now turning to SG&A. On a GAAP basis, we recorded approximately $72.3 million and $73.7 million for expenses for the second quarter of 2021 and 2020, respectively, a decrease of $1.4 million. The year-over-year decrease was driven primarily by a decrease in compensation, personnel and professional service expenses.

On a non-GAAP basis, the SG&A expenses were $54 million for the second quarter of 2021 compared to $55.1 million for the same period of 2020, a decrease of $1.1 million. On a GAAP basis, we recorded $16.2 million in other expenses net for the second quarter of 2021 compared to $12.4 million in other expenses net for the same period of 2020. The increase primarily reflects an increase in interest expense incurred on the company's term loan debt facility due to an increase in the outstanding balance, partially offset by a reduction of interest expense, incurred on the company's convertible debt related to the adoption of ASU 2020 06.

In February 2021, we entered into an agreement to sell the rare pediatric disease priority review voucher or PRV we received from the FDA in connection with the approval of AMONDYS 45. In April of 2021, we completed our sale of the PRV and received proceeds of $102 million with no commission costs, which were recorded as a gain from the sale of the PRV, and did not carry any -- did not have any carrying value at the time of the sale. There was no similar activity during the second quarter of 2020.

We had approximately $1.74 billion of cash, cash equivalents and investments as of June 30, 2021. As Doug just outlined and Gilmore will go over in more detail, we've progressed several pipeline programs this year. For this reason, we anticipate running multiple pivotal studies in 2022. We will continue to invest in our manufacturing scale-up in anticipation of delivering these therapies to patients. And with that, I'll turn the call over to Dallan for an update on our commercial activities. Dallan?

Thank you, Ian, and good afternoon, everyone. The team has yet again exceeded expectations across all 3 of our approved products in the second quarter of 2021. Due to the strong performance, as Doug mentioned, we have increased our guidance range by almost $30 million with the new guidance being $565 million to $575 million, up from the $537 million to $547 million.

As mentioned, total revenue reached approximately $142 million in Q2, representing double-digit growth over the previous quarter, and we approached nearly 27% growth versus Q2 of 2020.

The second quarter represents our strongest rate of revenue growth since the EXONDYS 51 launch phase. It's our 19th consecutive quarter of revenue growth since launch in 2016. To put that into perspective, that's 1 quarter shy of 5 years of consistent quarter-over-quarter revenue growth. Keep in mind that this consistent growth has been achieved without taking a single price increase at any point making this accomplishment that much more distinct and impressive.

Now transitioning to the details of our performance in the second quarter. Our revenue in Q2 was driven by strong performance across all 3 of our approved PMO-based exon skipping medicines. I'll review each in chronological order, beginning with EXONDYS 51. The team has continued to execute, driving revenue to over $112 million in Q2 2021, which represents roughly 8% growth versus Q2 2020.

We've worked hard throughout the COVID-19 pandemic to mitigate the risks to EXONDYS 51 and have emerged in a strong position. Our impressive performance from Q1 to Q2 2021 for EXONDYS 51, was a result of the team driving a robust rate of reauthorizations during the insurance changes we typically see at the beginning of each year. As such, we don't expect to see the rate of growth we saw in the second quarter the EXONDYS 51 to continue at the same rate.

It's important to be reminded that we now see the EXON 51 amenable population as mature and well penetrated in the ambulatory setting. Having had an approved therapy on the market for nearly 5 years, as a result, any growth that we see for EXONDYS 51 will be primarily driven by newly diagnosed or incident patients.

Moving now to VYONDYS 53. Although we're still very much in the launch phase, I'm happy to report we are seeing minimal competitive impact on the demand from both patient and physician community. Revenue totaled over $22 million in the second quarter, representing nearly 30% growth versus the first quarter of 2021, reinforcing our leading position, our expertise in Duchenne and the flawless execution of our team.

The team has done a great job in the second quarter of getting patients on therapy. And as we work through the start forms for the launch phase, we expect more modest growth in subsequent quarters due to a smaller base of start forms to work from. Overall, from what we're seeing to date, the vast majority of exon 53 treated patients are on VYONDYS 53, and the competitive launch has had limited impact on our overall launch trajectory to date.

And finally, AMONDYS 45. Perhaps our most exciting news coming out of the second quarter is our stronger-than-anticipated launch. While it's early days, we're seeing revenue from AMONDYS 45 tracking ahead of the EXONDYS 51 trend, which is even more impressive given the relative size differences of the 2 patient populations.

Adjusting for the relative population sizes, the rate of new patient start forms for AMONDYS 45 are in line with what we saw for the EXONDYS 51 launch. However, based on our deep experience in Duchenne, and constant improvements in terms of the execution of the team, the time to getting patients access to and on therapy has been faster for AMONDYS 45 than what we saw for EXONDYS 51. As a result, the team has delivered nearly $7 million in revenue in our first full quarter with AMONDYS 45.

The successful launch of AMONDYS 45 is our third since 2016, and represents the dedication of our team who work every day on behalf of patients. Our deep experience with Duchenne has enabled us to serve more patients, expedite access to drug and offer best-in-class support through SareptAssist. We are extremely proud of the team and will continue to apply learnings towards our #1 priority, which is serving the nearly 30% of Duchenne patients who may benefit from our PMO-based exon skipping therapies.

Now looking to the future, as Chief Commercial Officer, I couldn't be more excited about continuing to leverage our learnings to support the Duchenne community as we rapidly advance both our gene therapy and PPMO pipeline.

And now I'll turn the call over to Gilmore for an update on our research and development activities. Gilmore?

Thank you, Dallan, and good afternoon, everyone. In the second quarter, a great deal of progress was made in advancing both our RNA and gene therapy programs. Before beginning with our RNA-based PPMO program, SRP-5051, I want to echo Doug's sentiment that we are very pleased with our recent meeting with OTAT regarding the SRP-9001 program.

We remain on track to initiate our study 301 this September in the United States and globally. As you recall, in early May 2021, we announced positive clinical data from the 30 mg/kg arm of the MOMENTUM study for SRP-5051, evaluating safety and change from baseline at week 12 and for exon skipping and dystrophin expression in both ambulant and non-ambulant patients.

3 of the patients in their -- were in their late teens and 1 patient was 7 years old at the time of treatment. The results were impressive. The 30 mg/kg cohort showed a significant dose-dependent increase in exon skipping. SRP-5051 when dosed once per month at 30 mg/kg achieved approximately 11% mean exon skipping at week 12.

Compared to the PPMO 30 mg/kg dose at the 30 mg/kg dose, we observed a greater than fourfold dose-dependent increase in exon skipping at only a 50% increase in dose. Further, when compared to the current standard of care at (inaudible), we observed an 18-fold increase in exon skipping.

Now in terms of expression, the 30 mg/kg dose of SRP-5051 demonstrated more than 6.5% mean dystrophin protein expression as measured by Western blot, representing a greater than 100% increase in expression versus the 20 mg/kg cohort at only week 12. Here are some other notable aspects of the data.

First, the results were not driven by a single patient, all the patients responded well to therapy. Second, based on our predictive modeling, we should comfortably achieve greater than 10% dystrophin with once per month dosing over time. Third, baseline dystrophin levels are not a predictor of post-treatment expression. In fact, we observed that 2 patients with the lowest baseline had the highest level of post-treatment expression.

And fourth, safety. We continue to believe that the hypomagnesemia, observed in the study remains monitorable and manageable with magnesium supplementation and is not correlated with changes in renal function.

Our next step is to meet with FDA regarding Part B of MOMENTUM. And based on the outcome of that meeting, our intention is to dose Part B by the end of 2021. We are thrilled with the SRP-5051 results and the potential that SRP-5051 holds to offer individuals with Duchenne, a more convenient once per month treatment option with a manageable safety profile and superior dystrophin expression.

Now shifting to our gene therapy program, I will begin with our safety and biopsy results reported in mid-May from the first 11 patients in Study 103 using our commercially representative material for SRP-9001. These results are tremendously valuable because they've confirmed the characteristics of the commercially representation material for SRP-9001, which achieved robust transduction for a mean of 3.87 vector genome copies per nucleus.

In addition, we reported robust expression of microdystrophin, correctly localized to the sarcolemma membrane. And we have measured this 3 different ways with a mean of 55.4% by Western blot 70.5% positive fibers and intensity of 116.9% correctly localized to the membrane. Furthermore, we observed a consistent safety profile with our clinical manufacturing process with no clinical complement manifestations. It cannot be understated that the Study 103 results provide confirmation of our manufacturing process and analytics, positioning us to aptly serve the Duchenne population.

I'd also like to remind you about some critical findings from Part 1 of our ongoing SRP-9001-102 study. I want to emphasize that because of the studies stratified randomization design and the statistic analysis plan, we can state with confidence that the prespecified subgroup analysis of 4- to 5-year-old Duchenne boys stratum demonstrated that SRP-9001 treated boys achieved NSAA games that were both clinically meaningful and superior to placebo treated boys with statistical (inaudible).

This means that the SRP-9001 microdystrophin construct is functional in humans and confers physiological and clinical benefit, thus substantially increasing the probability of success for this program.

Now moving to our limb-girdle muscular dystrophy portfolio. Our 6 development stage programs have the potential to address approximately 70% of all limb-girdle patients. These programs are progressing well and we continue to hold a leading position in limb-girdle muscular dystrophy, grounded in differentiated signs and a deep understanding of the disease.

Currently, Sarepta has several programs in development to treat various subtypes of limb-girdle muscular dystrophy. And this morning, we announced the execution of a licensing agreement with Nationwide Children's Hospital for calpain 3, a gene therapy candidate to treat limb-girdle muscular dystrophy type 2A or calpainopathy. limb-girdle muscular dystrophy type 2a caused by mutations in the calpain 3 gene and is the most common form of limb-girdle accounting for 1/3 of limb-girdle muscular dystrophy diagnosis.

We are pleased to report that the preclinical research and safety studies led by [Dr. Sarissa Hank] at Nationwide Children's Hospital have provided early proof of concept for calpain 3 in limb-girdle type 2A and support further investment. We will apply the learnings from our SRP-9001 and SRP-9003 development programs to the calpain 3 program and our 5 other limb-girdle programs, all of which use the same AAVrh74 vector, designed to robustly deliver treatment to skeletal muscle makes an ideal candidate to treat muscular disease.

Now turning to SRP-9003, our lead limb-girdle gene therapy candidate in development to treat limb-girdle type 2, which demonstrated positive data earlier this year at the 2021 Muscular Dystrophy Association's Annual Clinical and Scientific Conference. We presented the first expression data from biopsies of participants in Cohort 1, the logos cohort, taken 2 years after a single administration of SRP-9003.

The result showed sustained protein expression in muscle tissue. We are thrilled with these results for the SRP-9003 program as they also provide read-through to our 9001 program and any program that utilizes rh74 and the MHCK7 promoter.

Now turning to our functional results for SRP-9003. Assessments were taken 2 years following treatment in Cohort 1 and 1 year after treatment and cohort through the high dose cohort. We were pleased to observe that patients continue to demonstrate stability in their North Star assessment for dysferlinopathies or NSAD, total score and improvements on timed function tests. The results from both cohorts continue to support a differentiated safety profile of the rh74 vector compared to other AAV serotypes.

In fact, between our SRP-9001 and SRP-9003 programs, we have dosed nearly 80 patients and have maintained a consistent safety profile. We also believe that the high-level expression observed with our construct led to durable outcomes that are critically important for patients receiving a onetime therapy. All these therapies are not a coincidence as the SRP-9001 was rationally designed. And then the learnings from this candidate have been applied and continue to be applied to SRP-9003 and our 5 other limb-girdle candidates.

The SRP-9003 results represent a solid foundation a virtual engine to build and advance a steady stream of additional sarcoglycan derived indications in limb-girdle muscular dystrophy. Now many of you are likely aware that in early September, the Cellular Tissue and Gene Therapies Advisory Committee is meeting to discuss the toxicity risk of adeno-associated virus or AAV vector-based gene therapy. With the results we have thus far from our SRP-9001 and SRP-9003 programs, we expect the discussion with (inaudible) vector-specific toxicities observed with other serotypes. We look forward to the meeting and expect that the shared learnings will be helpful and continue to drive the field of therapy forward.

Additionally, we look forward to sharing data from our gene therapy and RNA pipeline programs at the 2021 Annual Congress of the World Muscle Society being held virtually from September 20 to 24.

Finally, and most importantly, I want to thank all the patients, their families, study sites and 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 rare diseases.

I will now turn the call back over to Doug to open the question-and-answer session. Doug?

Thank you very much, Dr. O'Neill, and thank you for the rest of my colleagues. May, let's open up the lines for the Q&A now.

(Operator Instructions) Your first question comes from the line of Gena Wang of Barclays.

I have one question regarding Study 301. Doug, I know you will share detail about the trial design. But just wondering if you can share the high level of a trial design now and also regarding Study 102 crossover data in first quarter next year. Just wondering, have you defined prespecified natural history controller?

Yes. Thank you for that question. Gena, first of all, thank you for the first question because I'm going to get this question a lot in this evening, and this gives me an opportunity to frustrate everybody just once. So I am not going to provide details on Study 301 other than, of course, to let you know that it is a placebo-controlled, double-blinded trial, that will be our pivotal trial.

There are a lot of nuance behind that, the powering of it, the end, the age groups, et cetera. And we have really put a lot of thought into Study 301 informed enormously by Study 102. And I'm going to be -- I'm very excited to share that with you, and I'm very excited that we were able very recently to have met with the division and on that basis, gained confidence that we're going to initiate that trial in September of this year. But I'm going to frustrate you and not provide a ton of detail other than to know that it is obviously a robust, very well powered, double-blind, placebo-controlled trial.

On Study 102, of course, before the team is working on natural history sets and all of the statistics associated with that. It is a blinded trial. As you know, we'll have to fully lock all of that down and lock the natural history sets down before we unblind, but I think the team has still has additional statistical work to do before the stat plan is fully launched. And thank you for both of those questions, Gena.

Your next question comes from the line of Tazeen Ahmad of BofA.

So my one question, Doug, is about timing of your study. You're expecting to start in September. On the Pfizer call that happened recently, they didn't seem to make specific mention of what is happening with their DMD study, at least with U.S. enrollment. So I'm curious, if you end up on a time line where you're starting the study, at least in the U.S. patients around the same time, what's your view about overlapping clinical trial sites and whether or not it might impact the ability to enroll?

Yes. A couple of thoughts. One, I want to be clear. I'm going to avoid directly comparing to other programs as you can well imagine, I have probably a well-earned reputation for leaning towards the competitor. So I'm going to fight my natural instinct. But I will say the following, let me say the following: first, that there is no one else that has the amount of clinical data to inform their program and the confidence of their therapy like Sarepta does. As Dr. O'Neill, I believe, mentioned in his opening remarks, we have by now dosed at these levels, SRP-9001 and ambulatory, nonambulatory children and nearly 80 children, if not more than 80 by now. So we have an enormous amount of information that informs the confidence of our therapy and informs the next program and gives us a lot of confidence that we're going to do quite well.

And we've done Study 101. We've done Study 102 Part 1. We will have Study 102 Part II that will read out very early next year. We have Study 103 and the first cohort of that, of course, looks brilliant in the performance of that therapy from an expression and safety perspective and we'll start 301 and initiate that trial, if all goes well in September, and we feel very confident about that.

So we're in very good shape to drive SRP-9001 forward. And of course, the reason that we want to do that with enormous amounts of urgency is hopefully everybody that's near this rare disease knows, there are thousands and thousands and thousands of children literally hundreds of thousands of children around the world, who are having their muscle stolen from them day after day, literally unrelenting and unfortunately, invariably fatal. So we need to move fast, and we will do that.

On the specific question you asked a second part of your question that you asked. Again, there is an enormous need for therapies like this for this gene therapy for PPMO and others and therefore, understandably an enormous amount of interest and desire that we move fast, both from families who are living with and unfortunately, invariably dying from Duchenne muscular dystrophy and from physicians and investigators. So I stand by the proposition that I've had for some time that this program once we get going should enroll with significant rapidity.

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

Congrats on the progress. I'm just wondering with respect to Study 301, are there any additional gating factors to getting that study up and running both in the U.S. and internationally?

Any additional back and forth required with the agency? And can you confirm that, I guess, at this point, you're aligned on all the necessary potency assays are expected to be aligned shortly?

A couple of thoughts. One, just to initiate a study, and roll a study out around the world, there are lots of steps. So I want to say. I don't -- this is very -- the team has been, frankly, in my view, fantastic in their execution, but we have a lot to do to get this study fully enrolled around the world. So there's -- I don't want to create the impression that there's not a lot of additional work to do, there is. The team is very competent and confident in getting all of that done.

I'd say the biggest, the most significant issue for us to ensure that we could move rapidly and initiate this trial quickly, particularly in the United States, was to have that meeting with OTAT. And of course, we had that meeting, we'll say although I'm not going to give you the exact date, it was very recent. And as I said, a very positive meeting, very informative meeting, very well-prepared meeting on both sides, by the way. And as a result of that, we have an enormous amount of confidence that we're going to be able to initiate this trial very soon, and our goal is to have that done in September, and we feel confident about that.

As it relates to the potency assay, we've done a lot of work on the potency assay. As you may recall, back last year in September, we actually had been stalled for a short period of time it turns out based on potency assay on September 2020, that actually ended up being for us a blessing. It gave us an opportunity to have live dialogue with the division and to really understand at a fairly granular level what the division was looking for, not only then, but in the future on potency assays.

And so we've done a bunch of work since then. We've shared our perspective on the potency assays and our approach to potency assay with the division. They have agreed with our approach and endorsed our approach, and we've gathered the data. And we -- as I said before, there's a lot still left to do as 1 can imagine to get a trial up and running around the globe, but we feel very confident that we'll be initiating that trial this year. And frankly, we feel confident we'll be initiating in September.

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

Congrats on the progress. I'll ask one, but I will put a contingency in because you may not answer it. I guess, I wanted to get your perspective on like PPMO potential endpoints. Is there a potential for similar endpoint to PMO, or is it more functional? And then if you don't answer that, can you just talk about maybe some other indications where steric blocking is associated with PPMO? And where you might consider going there?

Yes. I will start with -- so on the PPMO, there'll be essentially 2 -- there'll be a functional endpoint, of course, as we will eventually need to confirm the benefits functionally to continue to have the therapy approved around the world. But our goal in the first instance with the PPMO is to seek an accelerated approval in the United States and potentially even a conditional approval in Europe on the basis of the robust expression that we're seeing. We have a well-understood pathway in the United States with the accelerated approval that way.

So it will be essentially 2 broad things. There'll be functional endpoints for the PPMO. And then there'll be -- I don't think that we've landed on or yet disclosed probably what particular end point that we'll use or it will obviously be -- there'll be some complications because with functional endpoints, we'll have to think about the functional endpoint for the ambulatory population and then a functional endpoint potentially for the nonambulatory population.

But we'll also have expression, and that will be dystrophin production, and we have a we have a well-understood pathway in the United States, and we'll have a dialogue with EMA on that basis as well. And then on additional indications, I turn this over either to Dr. O'Neill or Dr. Rodino-Klapac for that to maybe chat about some of the other possibilities.

Before we go on, I think it was -- Alethia had another question I want to answer. I just created confusion because I'm supposed to be the master of ceremony and called on 2 people. So I will start with Dr. O'Neill, will answer it or turn it over to Dr. Rodino-Klapac.

Yes. So we're actually very interested in leveraging the (inaudible) the arms muscle in muscular dystrophy and are looking at a number of tissues are targets of interest, both in -- with a muscle indication as well as potentially renal indications. But that's the kind of work that we're still performing in our discovery phase, and we will be leveraging our learnings from the ongoing 5051 and then applying those and accelerating those forward once we have absolute clarity on our 5051 progress and the PPMOs across the exon skip amenable population for Duchenne. Louise, I don't know if you want to add anything to that?

No, I think you covered it well, thanks.

We do have preclinical work ongoing, exploring a number of different disease areas where steric blocking might be interesting, that isn't Duchenne. And then, of course, I should say, just to remind everybody, we are working on PPMO 5051. But we've got a number of other constructs for additional mutations. And at least theoretically, we can build constructs with a high probability of success that could treat patients, at least from a technical perspective, could be well over 80% of patients that we can build therapies. There is a small percentage of very rare exons, very rare mutations where this start blocking the technology in exon skipping isn't available, but the good news is it's a very small percentage of Duchenne patients.

Your next question comes from the line of Anupam Rama of JPMorgan.

Congrats on the progress. Just on Study 301 and the initiation here in September, how do you think about getting sort of global sites up and running, particularly with the pandemic very variable in different regions and how you think about the enrollment curve here?

I think -- well, I'll say the broad strokes, again, I think enrollment, you raised an interesting point about limit on certain times every time we think we have clarity on this pandemic, new information comes out that forces us to continue to be humble in our prognostication about the future.

I would still broadly say that I am very confident, the team is very confident that this is going to be robustly -- a very robustly enrolled therapy. And even in the height of the pandemic, we have experienced that sites ex U.S. and U.S. but ex U.S. is the kind of thing. I think a lot of us are worried about, have been able to stay up and running and continue to execute without much of a problem.

In the absolute ranging most difficult part of the pandemic, we were running a very significant, as you know, in other trials, we were running a very significant global trial, which is the ESSENCE trial to confirm the benefits of VYONDYS and AMONDYS. And with very -- even in the most difficult times with very few exceptions, we were able to continue to execute and patients were able to get in and got their infusions. And this is going to be -- that's even more complicated because, of course, those infusions are weekly and then got their functional results. There were a few missed visits, but not very many.

So I think we'll be able to navigate through things, of course, I will say again what I've said to the team about 1 billion times, we have to remain humble in our prognostication about the pandemic. But I don't think that's going to be the limiter on things. I think the I think the most significant limiter is just our ability to get out, execute, get sites up and running, get them qualified and going and then I think recruitment will go very, very well.

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

In your meeting with OTAT, was there any discussion about the potential for 9001 approval on in the 4- to 5-year-olds with DMD just based on data to date? And then secondly, can you help us understand how these 2 limb-girdle micro-muscular dystrophy type 2A programs will coexist within your portfolio?

Yes. So I'll answer the first one, and I'll probably leave it to Dr. Rodino-Klapac to touch on the calpainopathy limb-girdle. So let's -- we're very straightforward about this. We were very clear about our goals. We ended the meeting with OTAT, we did -- we asked very specific questions. And in broad strokes, the specific question was, here's our CMC, review or CMC, Here's our protocol for Study 301. Do you object to us commencing Study 301, it's that discussion. We had absolutely no discussions, we didn't broach the issue of something else, like an accelerated approval for the 4- to 5-year-olds or the 4- to 7-year-olds based on the data we've seen already or coming up the data that we might see early next year in part to Study 102.

Just to remind everybody, we're going to get some really exciting data. Well, some interesting data at a minimum and hopefully exciting data in the first quarter of next year because we'll have 2 cohorts, 1 cohort with 1 year functional results in part 2 and another with 2 years functional results. That is not an issue that we broached with the agency. There were no discussions around that. This was really very, very much around Study 301 and the convention of Study 301.

And I'd say I'm very excited that we are -- we had a very, very productive, very positive meeting with the agency. And on that basis, we're going to initiate that trial very soon. And we believe it will be in September.

Now I'm limb-girdle, I'll turn it over to Dr. Rodino-Klapac to touch on calpainopathy.

Thank you for that question. I think that there was some confusion. We only have 1 LGMD2A program. We did have an option to doctors' (inaudible) program for quite some time. So we've been talking about it in the context of our portfolio and that we recently executed the license on that program. So it's just 1 LGMD2A program, which now surrounds out our portfolio. And we're really excited about it. Dr. (inaudible) been working quite tirelessly to complete the preclinical data, which shows efficacy both logically and functionally in (inaudible) mice at both -- in both young mice and old mice, and really gives us a lot of confidence moving forward in our development program for this program. So thanks for the question.

We're particularly -- we're very excited about the fact that this is another rh74 mediated gene therapy. Because, as you can imagine, with the amount of data that we've developed over the last few years. We are only more confident in the differentiated aspects of rh74 as the vector delivery mechanism for gene therapy.

Your next question comes from the line of Brian Skorney of Baird.

Congrats on getting clearance to go into Phase III. I guess I know the question is the most appropriate for Dr. Rodino-Klapac or Dr. O'Neill. But I know you guys have been exploring certain AAV redosing strategies. I think you have a partnership with Selecta and we've also discussed some other potential strategies in terms of tolerizing patients for redosing. Any thoughts on the progress there? I know based on the LGMD data, it also looks like there's really weaning of protein expression here, but sort of in the long term where are you in terms of looking at the potential for redosing AAVs.

Let me say a couple of preface remarks, and then I'll turn this over to Dr. Rodino-Klapac if she wants to make any broad statements. I suspect we're not at a stage where we're going to probably provide any detail other than this is important. There's a lot of reasons why this is important. It's important for redosing, it's important for knocking down neutralizing antibodies to bring in to frame the number of children that can benefit from our therapies.

It's important for the ability, if there was ever a topping up was needed, it would really be a fascinating opportunity. And we have a number of different programs that we've been advancing. And we're pretty excited about it from at least from a preclinical perspective. I doubt we're going to provide a ton more information than that. But if you have any other comments you'd like to make, Louise, please do.

Yes. I'll just reiterate our -- we've been very thoughtful about having a comprehensive strategy to be able to treat patients with preexisting antibodies and if needed, for the ability to redose and our -- we have both internal programs and then partnerships with Pfizer and Selecta that really will address the aspects of that. So knocking down antibody in patients would help them and that's potentially preventing antibodies in patients that are treated for the first time. So it's something that we're working very aggressively on.

I think this is important for the entire field of gene therapy eventually knocking down preexisting neutralizing antibodies is extraordinarily important. Now we are fortunate. We're in a fortunate position. But I think compared to many others. Our screen-out rate for neutralizing antibodies is relatively low. It's 15% to 17%, maybe maximum, that -- but that's still 15% to 17% of kids that until we find a solution for them would be screened out. So it gives us a real opportunity to bring those kids back in frame and if all works well, give them a much better life. So that's why this is extraordinarily important, including redosing as well.

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

Congratulations on a great quarter. Just a quick one from us. So the FDA is going to have an advisory meeting on the safety of AAVs, is there any potential for new guidelines coming out of this meeting that might require amendments to protocols?

Well, I will let Dr. O'Neill touch on that if he has additional comments. The one thing I would say is that this is not an issue that we just had a discussion with the division. We just had a meeting on the all parameters of CMC and protocol and the like regarding 9001 in our next study. And certainly, none of these issues were, any [strict word] were even part of that discussion.

And frankly, we don't have any data preclinical or clinical that would give us any concern around at least the issues as we understand them that are being raised in this upcoming advisory committee meeting. We're very interested in it. We'd love to provide whatever information we have, but we're not particularly concerned that this would have an impact on therapies that we're working on right now. Dr. O'Neill, do you have any other comments or contra comments?

No. I think you said it nicely. I would emphasize that it is our belief, and I think the data that we have and others have support the view that different serotypes in the AV group of capsids are different and behave differently and are differentiated. And I think we have a robust data set that show our differentiation and how we anticipate designing our protocols and how we design that is based on the empiric data sets that we have generated. And as Doug said, we have dosed around 80 or in excess of 80 patients by now. So those are the key things that we will use to drive our study designs.

And I will also say that we are looking forward to learning more from this advisory group. It is also probably worth reemphasizing the FDA guidance are actually relatively recently published. And I think I speak in broad sway. But as I said, different serotypes, different data sets. And so we believe and continue to believe that we will be designing our protocols around the empiric datas that we are generating from our clinical experience with our rh74 capsid. Thanks, Doug.

Your next question comes from the line of Ritu Baral of Cowen.

Doug, did I hear you right in your conversations with FDA around the LGMD sarcoglycanopathies will sarcoglycan levels be sufficient to drive accelerated approval? And does that apply -- do you think that applies to like all of the sarcoglycopathies? Could it apply to A and calpain as well?

Yes. Yes. So yes, I want to say dialogue, this is a written response. So we haven't had direct live dialogue with the division yet. But the written dialogue that we've had, the written and feedback that we've had from the division is that it is possible to use protein expression levels for 2E, presumably, it's beta-sarcoglycan levels as the basis for an approval. And that's obviously consistent both with the -- it's consistent with a number of guidances that exist at the FDA, both CBER and the neuro side of things.

So we're very excited about that guidance, and we're excited about the written feedback that we've got. And there really is no reason on the face of it why that wouldn't apply to the sarcs -- to all of the sarcs. They're very similar in a number of regards. And I think they -- and similar to a number of regards and in some ways, less complicated than some other gene therapies.

One of the issues with AAV-mediated gene therapy is that, of course, the packaging ability of AAV is limited. And a lot of times, the gene is larger than the packaging and you have to do interesting things like we have with microdystrophin through a lot of great work. The simpler thing with respect to each of the sarcoglycans is that the gene is actually comfortably able to fit inside the AAV. So we are making a gene that codes with the native protein in all of the sarcoglycans that's -- right now, that's alpha-beta and gamma.

We're making the actual native protein unaltered that is the sole cause of the disease that is causing the demise of these children and teens and adults, in some cases with respect to some of these sarcs. And so I think it's not unreasonable for the agency to have suggested to us that we can use protein as a surrogate endpoint reasonably likely to lead to clinical benefit for purposes of considering that.

Now there's still work we have to do. We have more conversations to have. We have to have a broader conversation both with MS -- by the way, I should say. And we've had similar feedback from EMA. So there's the opportunity for accelerated approval in the U.S. opportunity for conditional approval in Europe, as an example. And now from there, we've got to get more concrete about the plans and think about what this means for 2E, what the clinical program should look like, what the regulatory pathway will look like for that, both for the approval.

And then also, obviously, for the post-approval confirmatory data that we're going to need, and we need to do that not only for 2E, but for gamma and for alpha as well. And so that's one of the things we're working on right now.

Your next question comes from the line of Difei Yang of Mizuho Securities.

So just a clarifying question at the OTAT meeting, did the FDA provide any guidance with regards to how to construct the natural history cohort for Study 102?

That wouldn't be an issue that came up. The meeting was division, OTAT, was all about the commencement of our pivotal trial Study 301. And that, of course, isn't going to have a natural history cohort. It's a placebo-controlled trial. So that wasn't an issue that was -- we didn't broach the question and that didn't come up in the meeting.

Okay. And then do you -- of just to follow up on that, do you think eventually you'll need to have FDA spying on the natural history, the comparators arm?

Well, no, I think that's on us to make sure that it's done with -- it's done and done robustly enough that it's meaningful and insightful. But generally speaking, I think we are the we are the masters of our stat plan for purpose of 102. We just have to make sure that it's robust and it meets a statistical muster. And that's, of course, what we're doing. I say we have a great team on that. We have a strong stats team, and obviously, I think, a very expert development team that's considering all of those issues.

Your next question comes from the line of Tim Lugo of William Blair.

This is John on for Tim. Congrats on the quarter. I was just wondering if you could provide any updates on your views on longer-term competition or maybe even opportunity from CRISPER-based therapies in Neuromuscular disease.

Yes, I'll say that about -- so we're very excited about CRISPR technology. Let me be very clear about that. We're making significant investments in CRISPR/Cas9. Hopefully, everyone knows we have essentially 3 platforms. We've got our RNA therapy. We've got gene therapy. I think by now, we are, if not the leaders in portfolio of gene therapy. We are certainly one of the top couple of leaders in gene therapy.

And then we've got this gene editing innovation center in Durham, North Carolina, where we're looking at CRISPR/Cas9 and the ability to directly edit the genome as another long-term opportunity to bring a better life to people with genetic disease, including neuromuscular genetic disease.

And I'm excited about that. I'm very excited about, for instance, the fact that we have, as our leader of our Gene Editing Innovation Center Dr. Charlie Gersbach, who is brilliant. And I think one of the significant world leaders in CRISPR/Cas9 generally, and neuromuscular specifically, I will -- you'll note if you search of Google search his articles, you'll see that -- I say this all the time, it probably would embarrass Dr. Gersbach. But I know that Dr. Doudna, I think we all know, won the Nobel Prize for CRISPR/Cas9 was asked not too long ago. I think earlier this year, who she was excited about in the CRISPR/Cas9 space for the future. And our own Dr. Charlie Gersbach was one of the names she gave, and I think it was the only name she gave in relation to biotech. So we are very focused and very excited about it.

Now CRISPR/Cas9, certainly for full-body infusion neuromuscular disease is challenging today. So from our perspective, this is a research project right now. We are not yet ready to translate the fascinating work of CRISPR/Cas9 into a clinical program right now in patients because there are a lot of things that have to be unlocked before you consider full-body infusion. This is not trying to do CRISPR/Cas9 in, let's say, ocular or in the liver where it's sort of where these AAV-mediated therapies significantly go. This is asking a lot more of editing. And so we've got a lot more work to do.

So I don't -- I think CRISPR/Cas9 is exciting. I think it could be very exciting for neuromuscular diseases as well, potentially even including Duchenne muscular dystrophy. But I don't see this as a near-term competition to, for instance, gene therapy, which is right in front of us today. I think this is a research project that we've got some work to do before we can translate this into clinical programs.

But that is not to say we're not excited about it. We definitely are. We think there's going to be an enormous -- that the time is now for RNA and gene therapy. And we think gene editing is something that could be very exciting for the future where we actually directly go in and start thinking about how to edit the genome.

Your next question comes from the line of Matthew Harrison of Morgan Stanley.

This is Max Skor on for Matthew Harrison. So how should we think about the crossover arm in terms of the findings from Study 102 that is? Would you expect it to replicate some of the age differences and other factors compared to baseline?

Yes. Thank you for that. So no. The good news is that the 1 -- so there were two flaws in Part 1 of Study 102. One of the two, of course, is the titering as a result of the kind of PCR titering that was done in the Nationwide Children's Hospital material, which is a supercoiled PCR. We some of the kids were -- had less than the target dose and a significant number of 60% of the kids had less than the target dose. That's correct. Let's just be clear. That's correct that for the crossover patients fully corrected. We were using our current titering method. We do not have that issue.

The second and probably really significant, the problem with part one was this enormous baseline imbalance because even with those titering issues, when we had the baselines right, and we did in the 4 to 5 year olds, you saw a clinically meaningful and very strong statistically significant improvement in the kids that were on treatment was at 16 kids. So clearly, getting the baseline [life] is important. And the problem was in the 6 to 7 year-old is enormous delta between the active and the treated where the active kids were all very severe and the placebo kids were far more mild. I mean significant, like the p-value on that was 0.004. So 4x out of 1,000, you would have even had this problem.

The good news of the crossover is that we -- there's no way to look at a placebo arm anymore, of course, all the kids will be on therapy. Some will be on therapy through 2 years, some will be on therapy for 1 year. Sort of the good question that was asked previously, we need to make sure we build a strong natural hit before we ever [run blind] build a natural history model that is appropriate and matches and then we'll look at this therapy versus natural history.

So that's essentially self-correcting that second issue. The self-correcting on the part 2. And then on all the crossovers, the titering issue is corrected with our more precise titering that was used for all of the doses in the crossover.

Your next question comes from the line of Joseph Schwartz of SVB Leerink.

I was wondering beyond those 2 flaws that you were just talking about, Doug, how much have you been able to learn from your analysis of Study 102 that you can use to implement in Study 301 in order to improve the probability of success. Do you have any examples that you can give us to help us appreciate how the POS might rising going forward?

Well, we'll -- I'm going to -- apologies, I'm going to beg off the detail, and we'll talk about that a little bit later when I have the minutes and we're closer to initiating the trial because we will come back and talk about the trial, and how we become even more confident in the program in POS.

But I'll give you a summary answer, Joseph, and I know this is frustrating, but I'll give you a summary at least, and it is an enormous amount of insight that we got from Part 1 of 102. I mean -- we did a [step-sync], some of us, myself, certainly included, were watched for a while and then immediately realized that we had an enormous amount of opportunity in front of us. And I'd say 2 things that came out of that part 1.

In summary fashion, and we'll talk about some of this in more detail when we get the minutes and we talk about the 301 trial. One is that we're just very confident as the people in our program and the probability of success of the program and the transformative potential of SRP-9001. We feel very confident. For instance, if we didn't have the baseline issues that we had with those kids. Unfortunately, we would have had a very different outcome on Part 1 of Study 102. And the second thing I would say is that it has informed 301 in ways that should significantly increase the probability of success.

Your next question comes from the line of Colin Bristow of UBS.

This is Ting on for Colin. Congrats on the quarter. So we have a follow-up question related to the potential accelerated filing for 9001. We understand it was not discussed over the meeting you had with OTAT. Just want to get idea of where do you stand now on the[post-clinical] filing microdystrophin expression like biomarkers especially now with aducanumab's approval, where FDA did take a much more strict approach for this neurology diseases with high (inaudible). And post-clinical filing with a preliminary expression data from 301 and of course, with all the data you have with 101, 102, 103.

We also have a follow-up question, a separate question on the competitive landscape where we did notice Pfizer announce plans to start a Phase III trial in non-ambulatory patients with no age restrictions and Phase II for early symptomatic patients 2 to 3 years old. Any plans from your side to initiate studies in this population in near term?

Yes. I'm going to answer the second question first. Certainly, one of the things that's happened historically with -- for good understandable reasons, but not for good results is that the non-ambulatory patient population has been underserved in the clinical trial setting. We certainly will be looking to do trials in the nonambulatory population. And I should tell you right now in Study 103, and we've already dosed a lot of kids in 103, we are dosing nonambulatory patients and larger kids as well in Study 103.

So that is a big part of our plans. On the accelerated approval pathway, I'm going to say 2 things. I'm going to say 3 things. The first, of course, is that we understand that kids are getting damaged every day by this disease and that we need to think about how we can urgently move our therapies forward as fast as possible. And so I wouldn't -- no one should assume that we're not willing to be thoughtful and creative about things.

And the second thing I would say in broad strokes, unrelated to 9001 is that accelerated approval as a pathway has been an enormously valuable and innovative approach to bringing better lives to patients over the course of many years because accelerated approval has existed long before it was in the 21st Century Cures Act. It has brought a better life to your countless patients and we could literally just reel off the cancer patients and AIDS patients and others whose lives have been bettered or saved as a result of this wonderful approach, when it's appropriate.

But I will say this, finally, when I get to 9001, I want to say 2 things about it. The first is that just so we're very clear, we've had no conversations with the division about it and there's nothing that would have come out of our meeting with OTAT, that would have given us any reason to be more or less confident in that as a concept.

But the second thing I would say is that Study 301 is our pivotal trial. And we have built it as our pivotal trial, and it's robust and it's placebo controlled. And it's, from our perspective, very well powered. And if I was an investor, I would presume that 301 is the pathway to success from a clinical perspective and from an approval perspective, both in the United States and around the world. And I wouldn't want to overpromise on other things because that's our focus right now.

Our focus right now is getting 301 initiated up and running, fast enrolled, and confirming the results that we've seen already and what we presume are going to see in early next year. And so I just want to make sure we're not creating the wrong impression. I think 301 is our pivotal trial, that's what I think people ought to focus on as the pathway for approval right now for SRP-9001.

And maybe just -- this is Ian, just one quick point of clarification. I don't believe Pfizer started a pivotal study in the non-ambulant patient population. The last update, I think they gave was that they had an SAE in that population and they were doing a protocol change and adding sirolimus to their protocol before dosing more patients. So I don't believe they're in a pivotal study with that population.

No, I think their not even -- I think their Phase I study that was going to explore non-ambulatory patient. I probably didn't realize you had suggested they had started. I think that they are actually not moving forward right now because they're going to do a protocol amendment to add another prophylaxis. I think they already have Soliris if I'm not mistaken. I think they're now suggesting they're going to have (inaudible) as well as a prophylactic in advance of pretreatment.

Your next question comes from the line of Danielle Brill of Raymond James.

This is Alex on for Danielle. I just want to expand on your point on 103. When can we expect to see the expanded data set? And if you can comment how many patients have you dosed in those non-ambulatory and the older cohort?

So we were find an appropriate medical meeting down the road to provide additional information and insight in Study 103. So we haven't selected a medical meeting yet that will be very interesting to show that information. And I don't have the details, the number -- the complete number, but we've dosed a number of non-ambulatory patients in a number of large -- larger kids with Duchenne muscular dystrophy with SRP-9001. So that is proceeding very well right now.

Your next question comes from the line of Yun Zhong of BTIG.

And on limb-girdle 2E, it's very encouraging to hear the surrogate endpoint discussion. But you showed very positive functional data even after 1 year of treatment, then my question is, why don't you go for full approval with the functional data? Does the pathway relying on surrogate endpoint? Would that allow you to maybe avoid running a placebo-controlled study? Or would that allow you to talk to the FDA on potential approval maybe even before 1 year after treatment?

But we're going to have to at -- let's, at a bare minimum. We -- one has to dose children using the commercially representative material. So let's start there. Understand that the data that we have right now for the first 2 cohorts I agree with you completely, it's brilliant data. It's brilliant on expression. It's great on safety and it's great on functional signals as well. But that is in the clinical supply material.

We've got to get all of the work done process development, (inaudible) development and dose kids on the commercially representative material as a predicate approval that's as a first part. And then once we do that, why do -- why would we be interested in looking at expression as opposed to just looking at function. The short answer is, this is a very rare disease and it is more heterogeneous than Duchenne muscular dystrophy.

And so it would just be -- it would -- we would make people wait far too long in our view, if we had to wait for a statistically significant functional readout on 2E kid. This is to be direct, this is a perfect place for the use of a surrogate endpoint and accelerated approval. You've got a well-characterized disease, at least the mechanism of action of the disease is well characterized, which is -- it is a single gene mutation, a lack of a structural protein and that lack of structural protein is causing the demise and eventual fatalities for these patients, these kids and adults.

And we are able to deliver that exact protein the literal native protein in robust amounts to the muscle. So this is the kind of place where accelerated approval was intended where you can bring this therapy. Because it's going to have such a high probability of being clinically meaningful to patients. You can bring it to patients and then have an ongoing study that confirms those clinical results over time so that you don't have to wait to bring the therapy to patients. And so that's going to be our approach, and we've got more work to do with the FDA and EMA on that. But I am happy to say that at least at a philosophical policy level, the division agrees that, that is a potential both at EMA agrees and FDA, OTAT agrees as well.

There are no question at this time. I will now turn the call over to Doug Ingram for closing remarks.

Thank you very much. I will just extemporaneously say a few things, but not many because I know people it's getting late for everyone. Thank you very much for joining us this evening. I am very proud of the work this team has done, both to serve the patients that we have with the therapies available to us today. And I think the team has just done a brilliant job of that.

One of the -- people haven't asked questions about our revenue, but that revenue is impressive because it reflects commercial expertise and a field-based expertise that I got to tell you, I'm extraordinarily proud of and it's going to benefit us enormously when we launch some of these gene therapies. And as we don't take price increases as a company and we've priced all of our therapies at parity. It is a reflection of our ability to serve patients and bring better life to patients. So I'm really thrilled with that.

I'm obviously thrilled with the team for the great work we've done in advancing our portfolio and pipeline over the course of this year. We've made a lot of great progress, and we have multi platforms to do that on. We've got our RNA. We've got our PPMO next-generation version of the PMO. We've got our gene therapy 9001, 9003 and, of course, the list will go on with the sarcoglycans and the remainder of the LGMD and then we've got a bunch of therapies behind that, that we don't have time even to speak about today.

So I'm excited about that. I'm looking forward to updating people across the course of this year. And I want to echo the words of Dr. Gilmore O'Neill, I want to also thank the patients and their families, particularly those who have been willing to participate in the clinical trials that have created so much insight. And I think in the end, we'll provide so much hope to patients living with Duchenne muscular dystrophy limb-girdle and the other diseases that we're fighting to try to reduce the impact of hopefully save lives of people. So thank you for that. We look forward to additional updates over the course of this year.

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