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. [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 fourth quarter and full year 2020. The press release is available on our Web site 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?.

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 the 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 to Chief Commercial Officer Dallan Murray, a commercial leader with expertise second to none, in rare disease, DMD and our RNA franchise. And 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 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 and all with the goal of profoundly improving outcomes. We are on track to announce results from our next cohort at 30 mgs-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 67-year-old age groups, 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, that we compare it profoundly different populations making statistical significance practically impossible and lending most * results uninterpretable.

However, in the four to five 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 four to five and six to seven ages in that study, we've updated our IND, so we can add additional four to five year 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 one or two, 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. And 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.

And 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] [ph]. Beyond these programs, we continue to focus 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 harm and they worsen.

And 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. And when one is ambitious, there will be obstacles as there was 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..

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 Web site. 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 a 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 and diluted 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 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 at $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?.

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 D&D, and our commitment to serving this community with excellence and urgency, AMONDYS 45was 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 to roughly 8% of patients who are amenable 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 miss 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. And 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 and 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?.

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 which 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 four to five 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 on 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 53and AMONDYS 45 approvals remained on track. We expect data from this PMR trial in 2024.

Notwithstanding our excitement about AMONDYS 45s 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 exon 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 called PPMO, with the sole purpose of safely delivering more of the PMO into cells. To do this, PPMO as a positively charged cell penetrating peptide or CPP to the PMO backbone.

The addition of the peptide should increase cellular uptake. As 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 quarter 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 and this is important dose increased levels were observed with fewer doses of SRP-5051 four versus 25 compared to 10%, and 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 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 with rare diseases.

Now, I would hand the call back to Doug for Q&A.

Doug?.

Thank you very much Gilmore.

Let's turn it over to Q&A now, operator?.

[Operator Instructions] Our first question comes from the line of Alethia Young from Cantor..

I know a lot been made of how to interpret what's 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?.

I mean, first, we have -- our confidence in our constructs and the way we build them, only increases over time, I would remind everyone that the limb-girdle program that we have limb-girdle Type 2E and SRP-9003 uses not only the same capsid, which is RNA 74 but it also uses the same promoter as 9001.

We have now treated patients that are well over 50 patients at the target dose. And so, we have a very safety profile, we're seeing very good expression. And so this only increases our confidence level around SRP-9003 and so we're excited about that.

With respect to the clinical regulatory strategy as relates it to 9001 in particular, we have an enormous amount of insight that's come out of Study 102, some of which we've shared, some of which we're still working on and we'll share when the protocol is complete. And so our goal here is to continue to work to really understand the data.

And we're coming to the end of that now, to build a protocol that's fully informed by study 102 and the positive proof of concept in 102 and some of the nuance that we're seeing out of Study 102 to meet with the agency, once that protocol is fully defined, then we'll update everybody on that.

And then, of course, our goal is to commence our next trial this year, somewhere around the middle of the year with the goal of having all of those kids dosed if all goes well before the end of this year and of course the read out, probably have last patient, last visit, if all goes well by the end of next year, and then read out shortly thereafter.

And it is our current base assumption that would be the study upon which we would obtain an approval first in the U.S. and around the world..

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

Now that you've had more of an opportunity to digest the mono two data set, 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..

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, we tentatively call that 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, were 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.

And then, at the end of this year, just to remember, right, everybody, that study remains blinded, we're going to have part two, that's going to be last patient last visit, in the back half of this year.

And so 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 and 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.

And then 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.

And then we get to judge when we unblinded 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 competence in the therapy, but really keen understanding of how to design the next protocol and fine tune it.

And 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..

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

Just, you maybe an update under 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?.

Sure, I will turn this over to Dr. Louise Rodino-Klapac. Before I do, I will point out that you will notice that we are -- our goal is to look at all of the modalities, we look at gene editing that's something that's very exciting for the future.

In addition to partnerships and relationships that we have entered into over the course of the last 12 to 24 months, I should also note that we have built out a gene editing center, what we call the Gene Editing Innovation Center in Durham, North Carolina, all of which is under the leadership of Dr.

Charlie Gersbach from Duke University, who is one of the significant world leaders in the use of gene editing from a neuromuscular perspective. But perhaps, in addition to that, Louise, you'd like to comment on our gene editing efforts..

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. And really, we had the opportunity to develop a best-in-class technology.

And part of that is really scanning the landscape for delivery technologies, and that 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. And we're certainly open to making sure that we have the best delivery vehicle for gene editing.

And so we'll continue to look at these research partnerships in a broad manner to make sure that we develop the best technology moving forward. So thank you for the question..

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

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

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?.

Yes, thank you for both those questions, Ritu. So you raised a really interesting question, which is, could you do an interim analysis on part two, to gain even additional insight. The short answer is having thought about that we're not currently of a view that we should do that for a host of reasons.

The first is that we already are going to have significant insight from part one study 102 that will help us design what we're calling study 301 right now, and we just got -- that no one gets to be very direct. Nobody has the kind of insight that we currently have.

And the design that we'll have for our next study will increase the probability of success, it will clearly put us in a competitively positive advantage. And that's already with part one.

So we really do want to maintain that blind and get a readout on study 102, at the end of this last patient last visit, by the end of this year and probably very early the following year have that readout, because that's going to be an enormously important set of data, a vast amount of information in this rare disease, and we just really want to maintain the blind.

As it relates to enrollment, there is an enormous need in Duchenne muscular dystrophy. And so I remain quite confident that we can enroll with rapidity, physicians and investigators are very excited about the opportunity to work with us. And so I think that won't be our significant issue.

I don't believe right now, our big issue right now is getting that protocol, really fine tuned, meeting with the agency getting the agency blessing on that protocol and the approach and then really getting that kicked off and started and in time to really start enrolling patients.

And I suspect that patient enrollment will be robust once we get that going..

Our next question comes from the line Anupam Rama from JPMorgan..

This is [Tes] [ph] on the call for Anupam.

So one question here, in your remarks Doug, I think you said you're expanding study 103 to better balance four and five year olds in the trial, I guess what is the rationale here, given you're planning to run 301? And what is the target and for 103 now?.

Yes, thank you for that. And I really appreciate that question, because I want to make sure that the reason I mentioned it at all is to make sure that it's not a significant change or delay in anything.

So just to remind everybody, study 103, uses the commercially representative material, our new process that we would intend to launch this therapy with. And it's our goal to test, expression and safety and the similarity of that process.

And the great news on that was that we had all the kids dose by the end of last year, as we reported out to JPMorgan that was about 11 children, what we've noticed is that there are more sixes, sevens and fours and fives.

And since this was intended to be a look at four to seven year olds, we've added -- we updated the IND, it would allow us to add some additional four to five, but it is no more than that. We haven't seen any data on this. And will not delay us in the evaluation and the report out of those 11 patients.

It's just an attempt to get a better balance over time. So don't consider that a delay in anything. It's not a delay in the report out in the second quarter. It shouldn't be any kind of delay in the start of 301. It's really just our effort to ensure that we have a nice balance of four to fives and sixes and sevens in that study..

Our next question comes from the line of Difei Yang from Mizuho Mutual..

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?.

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.

So and 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. And 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, we just did you saw had the results of a placebo controlled trial, at least part one. And, again, I would remind us that when we got the baselines, right, in the four to five, we see a really profound, never before seen benefit out of a placebo trial.

So 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.

And then, of course, there are differences in, there are 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.

And you're either going to do, you're going to have to do that on an exon by exon basis, or 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. And that's different than gene therapy, where gene therapy really is agnostic of the mutation. So 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 both in Duchenne Muscular Dystrophy and a lot of other areas as well..

Our next question comes from a line of Debjit Chattopadhyay from Guggenheim Securities..

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 VCN was 1.63.

And could you also sort of talk to any difference in dose between the first cohort of patients in study 102 versus the crossover patients?.

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 is 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?.

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?.

I think those are the two questions and just to remind everybody about Debjit's question. So in the first part of the study, the tittering 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 tittering for the purpose of the crossover, patients and so, we are right on target tittering and target dose on the crossover patients. And if I've got that completely wrong factually release..

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

So I have one question regarding study 102. Regarding the crossover, did you align with FDA regarding pre-specified natural history patient population for statistical analysis purpose and therefore the treatment, we know that Dr. [indiscernible] tend to use weekend regimen.

Was that consistent across all the patients?.

Yes, taking the second question first. We allowed patients that could be on a long-term steady dose of steroids. We allow the patients to use their standard of care and some people have daily dose, some people use weekend dose that play a role as best we can see.

And as it relates to the crossover that was all pre-specified and we can update it again before we unblind, we should even [indiscernible] correct me if I'm wrong. But I think all of that was all meta analysis was in the protocol at the commencement of the trial. .

Protocol on the SAP were created prior to the unblinding of part one interim analysis..

Our next question comes from a line of Gil Blum from Needham & Company..

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?.

Well, the positive data on the LGMD programs not from a strictly regulatory perspective, it may not but from a competence in the construct and the result, it definitely does. And we're seeing -- we see and it does in both across all of the LGMDs, but also back on to 9001.

Because if you look at the safety profile, understand of course, there was a significant part of the safety profile comes from the capsid itself in this case r874 and of course, our 874 is the capsule that we're using for all of our limb-girdles as well as 9001 for DMD and so there's a value there.

And then, seeing the positive expression results gives us a lot of confidence both in the [tropism] [ph] of r874, across all of the programs, and also the promoter itself. It's the same promoter in 2E, that's a 9001 and it's the same promoter, and I think three of the five, if I'm not mistaken, three of the five limb girdle program.

So, there is an enormous amount of building confidence that we have. Now I think, with respect to limb girdle and its pathway, I think that we are going to be meeting with the division this year, once we have GMP material released from our commercial representative material.

And then, we'll figure out what the pathway is for that limb-girdle and I suspect that that pathway will inform the pathway of the other limb girdles as well. And so that conversation will be an important one for us to have this year..

Our next question comes from the line of Tazeen Ahmad from Bank of America..

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 the EXONDYS and the targeted market? And 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.

And maybe to tie it all up, how big of a market opportunity with the three drugs together represent?.

Yes, so thank you for that, I think, let me take them [indiscernible] together. And so first of all, with respect to EXONDYS, we launched EXONDYS in late 2016, we are going to get -- start getting to the flatter side of the curve with EXONDYS over the course probably by the end of this year.

The reason for that is that there and then we'll be continuing to grow based on incident population and still refine new patients. And if we could ever unlock new patient screening, we would definitely see a significant increase.

There's still a ton of opportunity in EXONDYS, even over the long-term, but the issue there is ex-U.S., and we have to find an opportunity ex-U.S. to get approvals ex-U.S. to really unlock that opportunity. We have ex-U.S., but they come from what we call the map program, this access program that's responsive in nature. The problem ex-U.S.

is that there isn't in most countries the concept of an accelerated approval pathway. So that hampers us until we get a readout on some of our confirmatory trials with EXONDYS that I think give another opportunity for growth. Golo has done very well.

Now golo's launch has been somewhat attenuated as a result of the pandemic itself, obviously, it isn't the -- you would rather not launch a new therapy, particularly a therapy that has to start with not only going into physician's offices, but going into a hospital for your first infusion is very typically, you would love to not have to do that launch in the midst of a pandemic.

And yet the team did a brilliant job and we had very good growth in VYONDYS. But from my perspective, we should see VYONDYS has a continuing launch, which is actually a positive, there's a lot of growth there.

And then finally, if you look at casimersen, now this may be this the honeymoon period of having just gotten approval, we just got approval last week.

And just so we're clear, we're ready to go, just kudos to our team, supply chain commercial med affairs in the light, because we're able to immediately launch that we're able to get start forms, we got start forms in already, we'll have AMONDYS in warehouse by this week, by literally tomorrow, we'll have it in site.

So AMONDYS is going to, I think, looking at AMONDYS obviously scaled down to the size of the patient population, which is smaller than EXONDYS. I currently think that even with this pandemic, Dallan is probably scared, I'm going to say this, but I think its launch trajectory is going to look a lot like EXONDYS.

And there's a lot of excitement and a lot of pent-up demand for therapy for exon 45 amenable kids that have been waiting a long time for this therapy.

On the size of the market, if you just look at this RNA alone, I mean, we are already in the mid five hundreds and we're really in a launch phase two of the three therapies and those two together are bigger than the other therapy.

So there's a ton of headroom, if we just didn't leave the United States, we're going to be getting up into the billion dollar range over time potentially. And if we can get, if we can open up ex-U.S. will be significantly larger.

And then, the bigger opportunity than that but I think is, I really want to hammer on this because I think people have under appreciated our RNA franchise is the opportunity to bring therapies to patients as exciting as these first three therapies are, this is 29% of the patient population.

There are well over 80% of children with Duchenne Muscular Dystrophy whose mutations are amenable to this kind of exon skipping technology. We have a very reliable, consistent, precise way to build construct safely, that can bring therapists to these kids.

So we have the potential over time, in addition to EXONDYS and VYONDYS and AMONDYS to build therapies out for these kids in the U.S., and hopefully around the world that could get us over 80% up to maybe, I think, around 55% or so we can do it in a very straightforward way from 55% to over 80%, we have to find a platform approach because those mutations are fairly rare.

We've already had some early dialogue with the agency about how we could do that. But we have a big opportunity there. And that big opportunity will either be the PMOS, which were, obviously develops now. And we're just launching AMONDYS which is a PMO, or it could be a peptide conjugated PMO.

The PPMO and we're going to see that 30 mg-per-kg read out on the PPMO in the second quarter. So that'll be really interesting to look at. As we had the 10 mg and the 20 mg read out last year and at least from a proof of concept perspective, we were pretty excited.

We saw the PPMO, 1/10th of drug exposure and 5x, [indiscernible] production in a very short period of time. So either PPMO or PMO, where there's a lot of opportunity to do a lot of good in Duchenne community. And of course, there are significant revenues with that as well..

Our next question comes from the line of Vincent Chen from Bernstein..

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? And what would, from your view, what would an encouraging result look like?.

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.

And of course, we can update a 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 have been on the therapy for nearly two years, that's going to be exciting.

We're going to have this trajectory analysis that we can look at as well, which is 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, look at them trajecting over the course of 48 weeks without any therapeutic intervention and then therapeutic intervention.

And then we see what that looks like over time both using themselves as their own control, and also using a 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?.

I think in broad strokes, you've hit it and obviously you also have -- will have a second year of follow for the patients who were randomized to active treatment in part one. So you've got it..

Our next question comes from the line of Tara Bancroft from Piper Sandler..

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?.

Yes. Going to the last question first. The data that we'll have in the second quarter will be the 30 mg-per-kg data. That's what will happen in the second quarter on, it's really interesting question. We have constructs built for -- the great thing about RNA Technology is that, it's the conjugation of a peptide to construct that PMO construct.

So we can build the PMO construct. And if you want to go to PPMO, we simply conjugate the peptide to the pre-existing construct. We have a lot, a number of them built for all the fairly significant populations. So the real question for us, the fork in the road is going to be what the data looks like in the PPMO. And then we can make a choice.

And if the data looks great in the PPMO, then we're obviously going to start building the constructs with peptide conjugation to them. And we're going to start getting those kids on therapy, and then hopefully, she can celebrate an approval via that mechanism.

And if that when it all ends up, we think that PMO is the better answer, we'll start conjugating, we will start creating those constructs and bringing them forward in, when you can see now that we have a fairly distinct approach, we can build the constructs, they're highly precise, they have very good safety profiles in the PMOs.

Of course, the PPMOs, that's exactly what we're looking at, which is the safety profile, the PPMO. And then, we can bring those forward with the accelerated approval pathway, which is very efficient, but we need to first decide if it's going to be PPMO and PMO.

And then when those we stop very encouraging results in the PPMO last year, and then in the second quarter of this year, we'll see how it looks at 30 mg-per-kg..

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

Question on the ESSENCE study, you said it'll read out in 2024. I guess is that study now blinded out until week 144.

And 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?.

Yes, that's a great question. Yes, it's blinded. And it's very difficult, you have a very good point.

We've done a great job, the teams had a brilliant job and more than that the patients have done a wonderful job and being committed to this, this trial, but it is blinded and 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.

And the way we achieve that was to ensure even as AMONDYS, I mean, its VYONDYS was coming close to approval is that 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, so that the access to the therapy in those areas can be via this trial, and then we don't have to worry about the -- what would be a very, very credible risk, which would be you get a commercially available therapy on board.

And then, children are moving over to commercially available therapy as opposed to being in a placebo controlled trial. But 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..

Got it.

And just I just want to clarify so that blind so what we'll get from the blinded data in 2024, is that actually going to be week 144? Six minute walk is that a primary now?.

I think that's right. Is that right, Dr.

O'Neill?.

Yes..

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

Hi, this is [indiscernible] on for Colin, thanks for taking our questions. So we have a full question on the PPMO and half of the data like updates in second quarter.

So based on your modeling work, [indiscernible] more dystrophin expression levels? Are you expecting or should we expect from the 13 mg-per-kg or even higher dosing cohorts?.

Yes. The short answer is, we don't know yet. We haven't seen any of the data. So I want to be very clear. We don't know yet. What we're going to see until we look at it. All we can do is model off of animal data.

And of course that there's a lot of risk and trying to correlate between animal data and human data and trying to figure out what the exact right model is, is it way base, is it allometric, it is some mix in between. What we do know is we know two things.

We know that at 20 mg-per-kg, which in animal models wouldn't have yet been at that steep part of the dose response curve from a dystrophin and exon skipping perspective, we nevertheless saw at one-tenth, the dose exposure, five times a disrupt in production. So we've already seen something that's really interesting.

And, frankly, it's interesting in a whole host of ways, and we're seeing 5x, the dystrophin, the dosing schedule is much better for the PPMO than PMO, its monthly doses, it's a post a weekly dosing, so already a very interesting concept. The second thing that we know and we don't know if 30 mg-per-kg will be the place we see it.

But at least in animal models, you do start seeing a steep increase at the right dose.

So there is a potential that we see either 30 mg-per-kg or something higher than 30 mg-per-kg, we see a steep increase in the amount of dystrophin, but we won't know that, frankly, until we have evaluated biopsies and we begin to see that in patients, because all of the data that we had up until the 10 and 20 mg-per-kg, of course, were animals..

Our next question comes from the line of Marty Auster from Credit Suisse..

Congratulations on the amount of approval last week. I had a follow up from the prior question. I think looking back at the my notes from the December call on 5051. Doug, you talked about possibly being able to commence the 40 milligram per kilogram arm by the end of Q1.

Is that still potentially on track? And if not, are you waiting to kind of get that 30 milligram per kilogram data before advancing? Is that something you're looking for on the biopsy side or something on the safety side to kind of make that determination going forward things?.

We're looking -- yes, so we are in fact updated view as we want to see that 30 mg-per-kg before we move on to decide two things, we decide what the pathway is for pivotal, and also what the dose ranges should be in. And then, how much higher should we start thinking about going up and dose.

So we're going to see that 30 mg-per-kg and then make the decision on the 40 mg-per-kg right after we do that. We'll see the 30 mg-per-kg in the second quarter..

Our next question comes from the line of Joel Beatty from Citi. Q - Shawn Egan 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?.

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? Well, there's 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. And believe me, it's required a lot of discussion with patient groups and patient advocates around that but it can be done. So it's executable.

The second thing, of course, is that with respect to micro-dystrophin, you do have a truncated version of the dystrophin. And so expression alone, it wouldn't be sufficient, you have to also show function of that there's a sense to that agents, you've been clear about that it makes sense.

We just make the beta-sarcoglycan and we're in a different place. And that's why 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, blinded, placebo controlled trial, I think would be probably it would be an understatement to say that that would be challenging from both an execution perspective than an ethical perspective.

But 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 by the way at MDA.

And that will be a very important update. And so of course, 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.

But we'll know that when we have the discussions with the agency and we'll have those discussions once we have GMP material to talk CMC with the division. That'll happen this year..

Thank you. Our next question comes from the line of Danielle Brill for Raymond James..

This is [Dr. Olan] [ph] on for Danielle. Thank you for taking our question.

On PPMO in your last update, you mentioned that there were college related biopsy delays that might have contributed to lower SRP-5051 muscle concentration in the 20 milligram per kilogram cohort compared to the lower dose, plus the improving COVID environment? Can you comment on whether you're still experiencing similar delays that may make the interpretation potentially more difficult?.

So to remind people there were out of -- the problem was the biopsy timing versus the dosing was out of window because of a delay that resulted from the pandemic itself. Dr. O'Neill, you can confirm, but I don't believe that will be an issue for the 30 mg-per-kg cohort that we'll be reviewing in the second quarter..

Yes. That is correct. COVID has not forced important out of window biopsies..

But one thing I shouldn't comment on, I made an error earlier and I apologize, I'm going to recollect myself. The kids roll off of the ESSENCE study and I believe it's two years, so it won't be -- study will read out but kids will be rolling off the study.

So it's, I believe two years of blinded data, if I'm not mistaken, my apologies for that error on my part..

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

Hi, this is Kelly Girskis on for Joe Schwartz. Maybe just one more on the PPMOs.

You touched on this but we're hoping you can expand on the regulatory path you envision for 5051 and the other PMOs waiting in the wings? Might there be accretive way to do a single trial with multiple PPMOs in the future?.

Yes. So first couple thoughts on that. The big issue with the PMO is finding the right dose. And then beyond that our current working assumption is that the regulatory pathway will be the same or similar whether the construct we're going to use is a PMO, or a PPMO.

So one of the things that's exciting about this RNA platform that we have is that we can precisely build constructs that are very predictable in their ability to induce exon skipping and therefore dystrophin production.

And the other thing from a regulatory perspective is that we have the ability to avail ourselves of the use of dystrophin as a surrogate endpoint reasonably likely to lead to clinical benefit, and therefore we have the ability to use the accelerated approval pathway, that is the pathway that we've been able to officially use for EXONDYS, VYONDYS and now AMONDYS.

So, it's our belief that regardless of whether it's a PMO or PPMO, so long as we can induce substantial amounts of dystrophin that are reasonably likely to lead to clinical benefit, we'll be able to use this efficient accelerated pathway to reliably bring constructs forward. Now, that we can do that up to about 50%, 55% or so of DMD patients.

So a significant number of additional patient populations, then we have about 30% or so of patients with very rare exons, we would still use the accelerated approval pathway.

But our goal is to have built up a sufficient amount, I think we're getting there, a sufficient amount of experience on both the dystrophin production and the safety side of things that we can do, essentially a basket study with a collection of potential mutations that can get us to that next 30% of patients that would benefit from our therapy and I think that would work similarly whether we had a PPMO or a PMO.

So a lot of potential opportunity, whether it's PMO or PPMO would do a lot of good in DMD. That is, of course, our goal..

Thank you. Our next question comes from the line of Hartaj Singh from Oppenheimer..

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 going to be clinical milestones? And what proportion are going to be for commercial aspect?.

And 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?.

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..

Thank you. At this time, I'm showing no further questions. I would like to turn the call back over to Doug Ingram for closing remarks..

Thank you all very much for joining us this evening, this afternoon or this evening. And 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.

And we're 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, staying with RNA, we're very excited about the opportunity to update on the PPMO with a 30 mg-per-kg next quarter. That could be a very exciting evolution of our RNA technology and 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, that 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.

And 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.

And 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.

And 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..

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