Q4 2020 Sarepta Therapeutics Inc Earnings Call

[music].

Good afternoon, ladies and gentlemen, and welcome to the sort of the true but export quarter in full year 'twenty 'twenty earnings conference call. At this time all participants lines are in a listen only mode. After the speaker's presentation, there will be a question and answer session.

Operator: Good afternoon, ladies and gentlemen, and welcome to the Sarepta Therapeutics fourth quarter and full year 2020 earnings conference call. At this time, all lines are in a listen-only mode.

Operator: After the speaker's presentation, there will be a question-and-answer session. To ask a question during... You will need to press the star, then the one key on your touchtone telephone. If you require any further assistance, please press star zero. 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.

So ask the question doing.

You will meet the press the Star then the one key on you touched on the telephone if.

If you require any further assistance. Please press star Zero as a reminder, today's program is being recorded at this time I'll turn the call over to Mary Jenkins Senior manager of Investor Relations. Please go ahead.

Okay.

Yeah.

Okay.

Okay.

Thank you operator, and thank you all for joining today's call earlier today, we released our financial results for the fourth quarter and full year 2020. The press release is available on our website at throughout the Dot Com and our 10-K was filed with the Securities and Exchange Commission earlier the back again, joining us on the call today are Doug Ingram.

Mary Jenkins: 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. The press release is available on our website at SREPTA.com, and our 10-K was filed with the Securities and Exchange Commission earlier this year.

Mary Jenkins: Joining us on the call today are Doug Ingram, Ian Estepan, Dallan Murray, Dr. Gilmore O'Neill, and Dr. Louise Rodino-Kleipac. 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 the company's control. Actual results could differ, could materially differ from these forward-looking statements, and any such risk can materially and adversely affect the business.

On Alan Murray, Dr. Gilmore O'neill and Dr. Louise Rodino, Great day 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 jackets.

Actual results could differ material materially differ from these forward looking statements and any such risks can materially and it materially anniversary effect of the business. The results of operations and trading prices of Chris referenced common stock for a detailed description of the applicable risks and uncertainties. The encourage you to review the company's most recent annual report on form.

Mary Jenkins: The results of operations and trading prices for certain commodities. 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 FEC, as well as the company's other FEC files. 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. Now, I'll turn the call over to our CEO, Doug Ingram, who will provide an overview of our recent progress. Doug?

10-K filed with the SEC as well all of the company's other SEC filings. The company does not undertake any obligation to publicly update its forward looking statements, including any financial projections provided today based on subsequent events or circumstances and now I'll turn the call over to our CEO, Doug Ingram, who will provide an overview of our recent progress Doug.

Thank you Mary good afternoon, everyone and thank you for joining us Europe, the therapeutics fourth quarter and full year 2020.

Douglas S. Ingram: 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 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.

Investor Conference call I am pleased to share with you. This afternoon. The the progress that we've made across our multiplatform portfolio, including our performance serving the Duchenne community with the approved products.

Work, we are doing in gene therapy of including SRP nine 001 for D. M D.

And of course of the advancement of our RNA platform now.

Douglas S. Ingram: We have an enormous number of important milestones to achieve 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 goal.

Now 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 the team interrupted history to advance toward our goals to remind you in December of 2020, I announced the Dr. Louise Rodino quite back was named our chief sign.

Douglas S. Ingram: To remind you, in December of 2020, I announced that Dr. Louise Rodino-Klapak was named our Chief Scientific Officer, taking charge of our research efforts across gene therapy, gene editing, and RNA Therapeutics. Dr. Rodino-Klapack is a renowned leader in genetic medicine research, and organizing all of our efforts under her stewardship will ensure we maximize the opportunities in front of us. At the same time, I promoted Dallan Murray, a commercial leader with expertise second to none in rare diseases, D&D, and our RNA franchise.

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And RNA therapeutics Dr.

Dr. <unk> is a renowned leader in genetic medicine research on organizing all of our efforts under her stewardship will ensure we maximize the opportunities in front of us on.

At the same time of elevated to Chief commercial officer, Alan Murray of commercial leader with expertise second the nod in rare disease day M D and the RNA franchise and I also elevated Ian S Japan to CFO.

Douglas S. Ingram: And I also elevated Ian Estepan to CFO. Now, 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 D&D 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'm sure you all know Ian well and will appreciate that is nuanced knowledge of our company on all programs as the 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 of men 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 it's intellect judgment and commitment to ethics and compliance will serve us well as we advance over 'twenty.

Douglas S. Ingram: 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 in 2021 and beyond. Moving on to performance. 2020 was a challenging year for all of us and for the patient community, and launching a new therapy by August 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 ensured their access to therapy.

'twenty, one and beyond.

Moving to performance 2020 was the challenging year for all of US answer the patient community and launching of new therapy by August 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.

Douglas S. Ingram: 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 of 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.

$6 million in product revenue, that's a 20% to 25% increase from the same quarter of the prior year for the full year, we achieved product revenue of $455 $9 million, that's nearly 20% increase over the prior year you will also recall that our guidance for 2021.

Douglas S. Ingram: You will also recall that our guidance for 2021 is in a range between $537 million and $547 million, so we continue to see 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 Exodus 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 Amandus-45, the generic name for that is Casimirsin, and that's for the treatment of those Duchenne muscular dystrophy patients who have a mutation amenable to skipping Exxon 45.

<unk> is in a range between $537 million to $547 million. So we continue 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 the exon 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 of the U S foods of drug administration approved a modest 45 from generic name for that as CASM Pearson that's for the treatment of those duchenne muscular dystrophy patients.

You have a mutation amenable to skipping exon 45 of.

Douglas S. Ingram: Amandus 45, our third approved RNA therapy, will bring a treatment option to another 8% of the DND community. Together, our three therapies can treat nearly a third of all patients with DND. And with our RNA-PMO technology, we should be able to build constructs that can ultimately treat more than 80% of all DMD patients. 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 SRP5051, our therapy based on our next generation RNA technology, that's the peptide conjugated P The goal of the PPMO is to use a proprietary peptide to increase cell penetration.

The modest 45 hour of 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.

And with our RNA PMO technology, we should be able to build drugs drugs that can ultimately treat.

More than 80% of all the M D.

In the fourth quarter of 2020, we announced preliminary but encouraging results from the 10 Meg per gig and the 20 Meg per kg cohorts and our multi ascending dose study investigating SRP 50, 51 of our therapy based on our next generation RNA technology the peptide conjugated.

PMO.

Or P. P M O for sure the goal of the P. P. M. O is to use the proprietary peptide to increase cell penetration improved.

Douglas S. Ingram: Improving Exposure, Exon Skipping, and Dystrophin Production, and all with the goal of profoundly improving. We are on track to announce results from our next cohort at 30 minks per keg 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 and Study 102 in early January of this year.

Improving exposure exon skipping and dystrophin production and all with the goal of profoundly improving outcomes. We are on track to announce the results from our next trial award at the 30 Megs per gig in the second quarter of this year.

Moving to our gene therapy platform as you know we announced the results of part one of the SRP nine 001 study one of them to you in early January of this year.

While we did not achieve statistical significance on our primary functional end point, we did gain valuable insight.

Douglas S. Ingram: 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 end. So we are clear, the miss on statistical significance on the primary functional endpoint... has required a change in strategy in our regulatory filing strategy. But it does not impact our confidence or commitment to 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 PNase reduction, we did not achieve statistical significance on our primary functional endpoints.

And strong proof of concept on our secondary endpoints. So we're clear the missed statistical significance on the primary of functional endpoint.

As required a change in adoption in our regulatory filing strategy.

It does not impact our confidence of commitment and the program indeed quite the contrary consider the following while we achieved statistical significance on important biomarkers of Western blot.

T and the positive fibers intensity and creatine kinase reduction we did not achieve statistical significance on our primary functional endpoint.

Douglas S. Ingram: However, when one looks to the pre-specified subgroup analysis... the reason for this becomes immediately apparent. In the six to seven-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 compared profoundly different populations, making statistical significance practically impossible and rendering those results uninterpretable. However, in the 4- to 5-year-olds, the baseline characteristics were properly matched. In fact, the baselines on every functional measure were nearly identical.

However, when one looks at the Prespecified subgroup analyses the re.

Reason for this becomes immediately apparent in the six to seven year old age groups. The baseline characteristics were still enormously different the treated group was far more severe than the placebo group with a P value of literally 0.017 at baseline.

When we compare it profoundly different populations, making statistical significance practically impossible in reading those results uninterruptible.

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.

Douglas S. Ingram: And when they were appropriately matched, so we were actually comparing similar populations. In our pre-specified analysis, we strongly achieved statistical significance and a clinically meaningful benefit of the therapy over placebo. To be sure, for the first time in the history of DMD development... in a double-blinded, placebo-controlled trial of DMV patients... a therapy has shown this sort of statistically significant and clinically meaningful benefit on NSAA and DND. You better believe we continue to be confident in our therapy and in this program.

And when they were appropriately matched so we were actually comparing similar populations in our pre specified analysis, we strongly achieves statistical significance and clinically meaningful benefit of the therapy over placebo.

It is to be sure. The the first time in the history of DMD development.

That in a double blinded placebo controlled trial of DMD patients a day.

Therapy as shown on this sort of statistically significant and clinically meaningful benefit on N. S. A a N D. M. D. 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 would they traject with micro dystrophin than any other organization. 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.

Douglas S. Ingram: Second, we now have more in-depth, patient-level insight into these age ranges and how they correlate with microdistricts. We are confident that our unique insight will give us a much greater probability of success and a competitive edge. There is a lot to do this year to advance.

Our construct we are confident that the unique insight we can apply to our next trial will give us a much greater probability of success and the competitive edge now there's a lot to do this year to advance that.

Douglas S. Ingram: SRP 9001 First, as you will recall... Last year we commenced what we call Study 103, and that's our trial to evaluate our commercially representative material. We announced at the J.P. Morgan conference that all of our initial 11 patients in that study have been enrolled in DOE to better balance the number of 4-5 and 6-7 ages in that study.

That's R P nine year of zero one.

First as you will recall lash.

Last year, we commenced what we call study one of the route that's our trial to evaluate our commercially represented the material.

We announced at the J P. Morgan conference that all of our initial 11 patients.

In that study had been enrolled and dosed.

It's a better balance of the number of four to five of six to seven ages on that study we've updated all the R&D Easter weekend.

Douglas S. Ingram: We've updated our IND so we can add additional 4-5 year-old patients, and we'll commence that enrollment and dosing soon. However, just so you're clear, that will not delay the evaluation of and reporting out of the results of our first 11 patients in the second quarter of this year as planned. Next, we will complete the evaluation of Study 102, we will update our protocol for our next SRP 9001 trial, we will meet with the division to discuss and gain alignment on that protocol, and 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.

Additional for the five year old patients the more convention that enrollment and dosing. Soon however, just so you're clear that will not delay of the evaluation of and report out of 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 of data our protocol for our next SRP nine 001 trial, we will meet with the division to discuss and gain alignment on that protocol, we aim to commence the trial this year.

Our goal is the commenced that trial around the middle of this year, we the 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.

Douglas S. Ingram: 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 blind, and the last patient, last visit for the full results from part two of that study will occur at 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.

And finally, it is important to recall the study one or two remains blinded and the last patient last visit for the full results from part two 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 nine 001, we will see the impact of therapy at 96 weeks in 20 patients who were dosed at enrollment.

Douglas S. Ingram: 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 from those patients dosed at crossover. Those patients will have had a 48-week run-in period to judge their trajectory before they were provided therapy, and to compare those patients against natural history predictions.

And equally important we will have 48 week results from those patients dosed at crossover those patients will have had a 48 week running period, the judge trajectory before or 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 construct and the.

Douglas S. Ingram: Already we have substantially more insight and proof of concept on our program than any other concept, and that insight will greatly expand with the readout of part two of study 102. Let me now comment briefly on SRP9003.

The insight will greatly expand with the readout of part two of study one out of two.

Let me now comment briefly on SRP nine 003 that is our gene therapy intended to restore the protein beta circled the wagon in those patients who have limb girdle muscular dystrophy type two week.

Douglas S. Ingram: That is our gene therapy intended to restore the protein beta-sarcoglycan in those patients who have limb girdle muscular dystrophy type IIe. Last year, we announced very positive results in our proof-of-concept study with SRP 9003 in both our low-dose and our high-dose cohorts.

Last year, we announced very positive results in our proof of concept study.

S. R. P. Nine 003 in both of our low dose and in our high dose cohorts.

Douglas S. Ingram: 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 our other limb girdle programs, and this year, we will complete toxicology studies for SRP 9004 and SRP 9005. These are for limb girdle type 2D and limb girdle type 2C, respectively.

We will be updating those results at the 2021 M D. A clinical and scientific conference in March our goal of this year is to align with the FDA on the development path for SRP nine 003.

The commenced.

Pivotal trial this year we.

We will schedule that meeting with the agency once we have GMP material.

At least for use in our next trial.

Those discussions will inform our development strategy for our other limb girdle programs and this year, we will complete toxicology studies for SRP nine 004.

Sorry P 900 of five those are for limb girdle type two D limb girdle type two C respectively.

Douglas S. Ingram: And we will commence a proof-of-concept study using material from Nationwide Children's Hospital for SRP6004, our dual-vector therapy for the treatment of limb girdle type 2B in patients that are missing this spur. Beyond these programs, we continue the focused advancement of our gene therapy, RNA, and gene editing research under Dr. Rodino-Claibach. In summary, I am reminded of the importance of our mission on Rare Disease Day, which was recognized yesterday, February 28, with ruthless certainty every hour of every day.

And we will commence a proof of concept study using material from nationwide children's hospital for SRP 600 of for our dual vector of therapy for the treatment of limb girdle tied the two b in patients that are missing the spring.

Beyond these programs we continue the focus the advancement of our gene therapy, RNA and gene editing research.

Under Doctor Regina playback.

In summary, I am reminded of the importance of our mission by rare disease day, which was recognized yesterday.

February 28.

With the roof with certainty every hour of every day the rare disease patients that we serve are harm.

Douglas S. Ingram: The rare disease patients that we serve are harmed, and they were... 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 they worsen.

And if we are serious about our responsibility, we have little choice, but to be ambitious and to move with the sense of urgency to intervene.

Douglas S. Ingram: And when one is ambitious, there will be obstacles. As there were at the beginning of this year. But as we have shown before, we know what it takes to address and overcome obstacles, and we are doing just that. I have a passionate, expert team that is moving our programs forward. With $1.9 billion of cash as of the beginning of this year, augmented by strong revenue to reinvest in our programs and a razor-sharp 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 and solve problems.

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 it over overcome obstacles and we are doing just that.

Have a passionate expert team that is moving our programs forward with $1 9 billion dollar of of cash as of the beginning of this year on.

Baited by strong revenue to reinvest in our programs and a razor focused on our top priorities we of the strategy the talent and the resources to execute.

And we have of Michigan 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.

Ian M. Estepan: 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. Thanks, Doug. Good afternoon, everyone.

And with that let me turn the call over to Ian asked the pad.

We will provide an update on the financials Ian.

Thanks, Doug good afternoon, everyone the fab.

Ian M. Estepan: This afternoon's press release provided details for the fourth quarter of 2020 on a non-GAAP basis as well as on a GAAP basis. The press release is available on our website. Please refer to our press release for a full reconciliation of GAAP to non-GAAP financial results.

The news press release provided details for the fourth quarter of 2020 on a non-GAAP basis as well on the GAAP basis.

Press release is available on our website.

Please refer to our press release for a full reconciliation of GAAP to non-GAAP financial results.

Ian M. Estepan: We are pleased to announce that, in conjunction with our recent Amandus 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 Exondus 51 and Vyondus 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.

We are pleased to announce that in conjunction with our recent amount of 45 approval. We have sold the rare pediatric disease priority review voucher or <unk> 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 ease on this 51 and by all of US 53 was the $122 $6 million compared to $100.1 million for the same period of 2019 the <unk>.

Increase primarily reflects higher demand for our products going forward in 2021, we will be breaking out revenues for our RNA franchise, including exon 51 by one on just 53 and a modest 45 and I'd like to remind you as Doug mentioned earlier, our 2021 guidance for our RNA franchise inclusive.

Ian M. Estepan: Going forward, in 2021, we will be breaking out revenues for our R&A 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 R&A franchise, inclusive of Amondys 45, is $537 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 costs under the Roche agreement totaled $34.2 million for the fourth quarter.

Inclusive of the minus 45 is 537% 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 costs under the Roche agreement totaled $34 $2 million for the fourth quarter.

Ian M. Estepan: 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.

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 of 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 of approximately $22 $4 million and 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.

Ian M. Estepan: 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 gap basis, we recorded $207.2 million and $22.3.1 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 was primarily offset by a $58.1 million increase in manufacturing expenses due to the continuing ramp-up of our gene therapy programs.

Which reflects increasing demand for our products.

On a GAAP basis, we recorded $207 $2 million and $22 $3 $1 million in R&D expenses for the fourth quarter of 2020, and 2019, respectively, a year over year decrease of $15 $9 million the.

This decrease is partially related to of $64 2 million dollar 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 dollar increase in manufacturing expenses due to the continuing ramp up.

Of our gene therapy programs on.

Ian M. Estepan: On a non-gap 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-GAP R&D expenses was driven primarily by a continuing ramp-up of our gene therapy program. Now turning to SG&A, on a gap 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.

On a non-GAAP basis, R&D expenses were $188 million for the fourth quarter of 2020 compared to $135 $4 million from 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 a continuing ramp up of our gene therapy programs.

Now turning to SG&A on a GAAP basis, we recorded approximately $86 million and the $81 $4 million of expenses for the fourth quarter of 2020 in 2019, respectively, an increase of $4 $6 million the year over year increase was driven.

Ian M. Estepan: 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, 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 gap basis, we recorded $17.8 million in other expenses 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 the amortization of investment discounts due to the investment mix of the company's investment portfolio.

It was driven by an increase in stock based compensation, partially due to increases in head count 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 $6 million.

On a GAAP basis, we recorded a $17 $8 million in other expenses 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 the decrease in interest Inc.

Income and net.

And the amortization of the investment discounts due to the investment makes him the company's investment portfolio.

Ian M. Estepan: We had approximately $1.9 million in cash, cash equivalents, and investments as of December 31st, 2020. And with that, I'll turn the call over to Dallan for an update on our commercial activities.

We had approximately $1 $9 million of cash cash equivalents and investments as of December 31, 2020, and with that I'll turn the call over to down on for an update on our commercial activities Alan.

Dallan Murray: 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 Amanda's 45 Casimir, Sarepta's third RNA exon skipping medicine, which occurred last week on February 25th, 2021. The approval was based on a statistically significant increase in dystrophin production in skeletal muscle observed in patients treated with Amandus 45.

Thank you Ian and good afternoon, everyone. Despite the challenges posed by the COVID-19 pandemic to wrap the maintained its leadership position in Duchenne muscular dystrophy by continuing to serve patients and execute on our state of 2020 goals.

Firstly, we were thrilled with the FDA approval of a modest 45 CASM person <unk>.

<unk> 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 the modest 45.

Based on our unrivaled expertise in DMD and our commitment to serving this community with excellence and urgency of modest 45 was launched immediately after approval on.

Dallan Murray: Based on our unrivaled expertise in D&D and our commitment to serving this community with excellence and urgency, Amandus 45 was launched immediately after approval. All facets of our commercial, manufacturing, and medical organizations, including case managers, supply chain, and field force, jumped into action on day one to support the roughly 8% of patients who are amenable to skipping Exxon 45. Our goal is to facilitate rapid patient access to Amandus-45 by leveraging our industry-leading knowledge and proven experience in having successfully launched two other RNA medicines to treat DMD, Exondus-51 and Biondus-53. In total, Sarepta now serves roughly 30% of the DMV community.

All facets of our commercial manufacturing and medical organizations, including case managers supply chain and field force jumped into action on day, one to support the roughly 8% of patients who are of medical the skipping exon 45.

Our goal is to facilitate rapid patient access of a modest 45 by leveraging our industry, leading knowledge and proven experience in having successfully launched two other RNA medicines to treat the M D.

Exon 51 and buy on to 53.

In total swept and now serves roughly 30% of the DMD community.

Moving on now to exon 51, and by almost 53, we continued to provide uninterrupted supply of both products to patients and there have been few delays or stoppages as a result of the pandemic.

Dallan Murray: 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 the Exondys 51 or Biondys 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.

Due to the fact that a large majority of the exon 51 or bond of 53 patients roughly 90% are receiving weekly infusions in their homes.

We are encouraged that the majority of payers have demonstrated a willingness to work with the DMD community and have shown flexibility to allow for continued access to these important therapies. During this difficult time.

Any impact to date has largely been due to missed doses one to two doses of on average as a result of pandemic impact on either of immediate family or direct care team.

Dallan Murray: Any impact to date has largely been due to missed doses, one to two doses on average, as a result of the pandemic impact on either immediate family or direct care. 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 BYONDUS-53 continues on pace with minimal impact to date from any competition.

Our patients are determined to adhere to the weekly infusions and <unk> is determined to continue to monitor and support these patients.

The launch of buy on just 53 continues on pace with minimal impact to date from any competition.

Dallan Murray: And our team continues to execute on its goals and provide consistent and ongoing support to the Exxon 53 amenable patients. In addition, we have 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.

And our team continues to execute on its goals and provide consistent and ongoing support to the exon 53 of medical patients.

In addition, we have thoughtfully deployed measures to minimize the risk of transmitting COVID-19 the.

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 administered the 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 searches in the infections.

Dallan Murray: We continue to monitor the pandemic and are ready to react quickly with additional modifications to our strategy, especially in those places experiencing surges in infections. Patient safety remains our top priority, and we will continue assessing any and all efforts that will ensure patients feel safe and supported during this unusual time. Now I'll turn the call over to Gilmore for an update on our research and development activities.

Patient safety remains our top priority and we will continue assessing any and all of the 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.

Timothy Francis Lugo: Thank you, Dallan, and good afternoon, everyone. Doug has already shared the highlights from our most advanced gene therapy program. 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.

Thank you Devin and good afternoon, everyone.

Doug has already shared the highlights from our most advanced gene therapy programs.

I will focus my remarks today on sweaters upcoming presentations at this year's NDA 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 formats of scientific music.

The MDA will host its annual clinical and scientific conference as a virtual meeting from March 15th two March 18th 2021 of which to wrap the plans to host two symposia and presents 10 abstracts, which would include three podium presentations.

Timothy Francis Lugo: Thus, 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 will include three podium presentations. Podium presentations will show previously reported data from SRP 9001-102 Part 1, our microdystrophin program, and new, long-term, two-year functional data from study SRP 9003-101 Now, Doug covered the Part 1 results from our ongoing two-part SRP 9001-102 study.

The podium presentations would show previously reported data from SRP nine years of one one O. Two part one on micro dystrophin program and new long term two year functional data from study SRP nine Years' worth of three 101 for our limb girdle.

The muscular dystrophy type <unk> E program.

No.

Doug covered the part one results from our ongoing two parks SRP nine years of one 102 study.

Timothy Francis Lugo: But I do want to emphasize that first, because of the study's 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 SRP9001-treated boys achieved NSAA gains that were clinically meaningful and superior to placebo-treated boys with statistical significance. This means that the SRP9001 micro dystrophin construct is functional in humans and confers physiological and clinical benefits, thus substantially increasing the probability of success for this program.

But I do want to emphasize that first because of the studies stress side randomization design and second because of the statistical analysis plan, we can state with confidence that the pre specified subgroup analysis of four to five year old Duchenne boys demonstrated the SRP nine years of one treated boys achieved.

N S. A a gains that were clinically meaningful and superior to placebo treated boys with statistical significance.

This means that the SRP nine years of one micro dystrophin construct is functional in humans and confers the physiological and clinical benefit thus substantially increasing the probability of success for this program.

Moreover, the large amounts of biological and clinical data.

Timothy Francis Lugo: Moreover, the 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 studies. Now, let me talk about our RNA portfolio. We were delighted to announce last week's approval of Amandus-45 for the treatment of Duchenne boys who carry an Exon-45 skip amenable mutation in their dystrophin genes.

That we have collected from the SRP nine years of one 102 study will further inform and optimize the design of our future studies.

Now, let me talk about our RNA portfolio.

We were delighted to announce last week's approval of the modest 45 for the treatment of Duchenne boys, who carry on exon 45, skipping amenable mutation in their dystrophin gene.

Now you would be pleased to know that the essence study a placebo controlled confirmatory trial, which is designed to support the VI on the 53 and demand is 45 approvals remains on track.

Timothy Francis Lugo: Now, you will be pleased to know that the ESSENCE study, a placebo-controlled confirmatory trial designed to support the Viandis-53 and Amandas-45 approvals, remains on track. We expect data from this PMR trial in 2024. Notwithstanding our excitement about Amanda's 45's approval, which is our third FDA approval to emanate from our proprietary PMO technology, our goal is to continue to advance the science for patients with Duchenne. We have successfully leveraged our PMO technology to selectively skip exons and restore the dystrophin reading frame, thus creating a truncated but functional dystrophin protein.

We expect data from.

This PMA trial in 2024.

Notwithstanding our excitement about of monitors 40 fives 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 restored the dystrophin reading frame, thus, creating a dedicated bus functional dystrophin protein.

Based on this elegant approach and our deep understanding of Duchenne, we sat out of two engineered the next generation of this technology, which we called P. PMO with the sole purpose of safely delivering more of the PMO into sales.

Timothy Francis Lugo: 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 adds a positively charged cell-penetrating peptide, or CPP, to the PMO backbone. The addition of the peptide should increase failure uptake, and if we can safely drive more of the drug into the cells, we will see greater exon skipping and greater dystrophin production.

To do this P T Mo as a positively charged cell penetrating peptide or CPP two of the PMO backbone.

The addition of the peptide showed increased cellular uptake and if we can safety drives more drug into the cells, we will see greater on exon skipping and greater dystrophin production.

Timothy Francis Lugo: 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 toxicity. On December 7, 2020, we presented a clinical update of our ongoing Momentum multi-ascending dose study of SRP5051 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 SRP5051 in patients with Duchenne and determine the maximum tolerated dose or MTD.

This is no small feat however, as we and many others have tried approaches to increased cellular penetration that had been hampered by dose limiting toxicities.

On December seven 2020, we presented the clinical update of our ongoing momentum multi ascending dose study of SRP 5051 for Duchenne muscular dystrophy.

By way of reminder, momentum or SRP 50, 51, two of one has two parts.

Part day is to evaluate the safety and Tolerability of SRP 50, 51 in patients with Duchenne.

And determine the maximum tolerated dose of our M T D.

The dose levels for part D. R for 10, 2030, and 40 milligrams per kilogram administered once monthly.

Timothy Francis Lugo: The dose levels for Part A are 4, 10, 20, 30, and 40 mg per kg administered once monthly by IV, with each dose cohort enrolling 3 to 6 patients. Part B will evaluate SRP 5051 administered at the MTD and will include patients who complete Part A and an additional cohort of approximately 15 patients. In that update last year, we reported that we had achieved human proof of concept that conjugation of our cell penetrating peptides to our PMO chemistry does indeed increase cellular uptake of PMO in the muscle target tissue in association with an increase in downstream exon skipping and dystrophin expression.

The IV with each dose cohort enrolling three to six patients.

Part B will evaluate SRP 5051 administered at the MTV and will include patients, who complete pace 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 peptide to our PMO chemistry does indeed increased cellular uptake of PMO in the muscle target tissue in association with an increase in downstream exon skipping and dystrophin expression.

Timothy Francis Lugo: 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 PROMO-V 30 mg per kg at Tepperson cohort at 24 weeks. Please remember that at 12 weeks, the SRP50-51 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 atepersin group at 24 weeks. And, and this is important, those increased levels were observed with fewer doses of SRP50-51 4 versus 25 compared to atepersin and at an approximately 10x lower cumulative drug exposure.

These higher tissue exposures higher exon skipping and higher dystrophin expression were observed in the 20 Meg per kg cohort of our 50 51 201 momentum study at 12 weeks as compared to the promote the Turkey make boutique of 10 person cohort at 24 weeks.

Please remember that of 12 weeks. The SRP 50, 50, 120, Meg per kg cohort so increases in exon skipping of one six ex and an approximately five fold increase in percent of normal dystrophin as compared to the of 10% growth at 24 weeks and this is important.

Those increased levels were observed with fewer doses of SLP 50, 51, four versus <unk> 25, compared to a 10 person and as from approximately 10 ex lower cumulative of drug exposure.

Our next step will be announcing our 30 Meg per kg of expression data Inc.

Q2 of this year of 2021.

Once we have determined on MTBE, we will commence part b of the momentum study, which would include patients who complete part day and an additional cohort of approximately 15 patients.

Timothy Francis Lugo: Our next step will be to announce our 30 Mbps 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.

Finally, and most importantly, I want to thank all of the patients their families study sites and coordinators My R&D colleagues on 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'm on hand, the call back to Doug for Q&A Doug.

Thank you very much gilmar, let's turn it over to Q&A now operator.

As a reminder to ask a question of you wont need the breadth of star one on your telephone to withdraw your question press the pound key.

We ask that you please limit yourself to one question. Please standby, while we compile the Q&A roster.

Timothy Francis Lugo: Now I will hand the call back to Doug for Q&A. Thank you very much, Gilmore. Let's turn it over to Q&A now, operator. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key.

Our first question comes from the line of Alicia Young from Cantor. Your line is now from.

Hey, guys. Thanks for taking my question I know a lot's been made of how to interpret what the 19 zero one day of means for the next studies in DMD, but I just wanted to talk a little bit about what you think it means for limb girdle.

Operator: We ask that you please limit yourselves to one question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Alicia Young from Cantor. Your line is now open.

You know your general confidence level, there based on what you've seen.

Technology and then also you know how the perhaps spine and think about one of the core of key regulatory endpoints as ever of conversations with the FDA.

Unknown Executive: Hey guys, thanks for taking my questions. I know a lot has been made of how to interpret what the 9201 data means for the next studies in DMD, but I just wanted to talk a little bit about what you think it means for limb fertile, your general confidence level there based on what you've seen with this technology, and then also how to perhaps fine-tune, think about what are the core key regulatory endpoints as you have those conversations with the FDA to make sure that study is successful.

Make sure that the successful thank you.

Well. Thank you very much all of those questions relate the I mean first.

Our confidence in our cost structure and the way we build them.

Only increases over time, I would remind everyone that the.

The limb girdle program that we have limb girdle type of TUI and SRP nine 303 uses not only of the same.

On a capsid, which is already 74, but it also uses the same promoter is nine here of zero, while we have now treated patients that are well over 50.

Patients at the target dose and so we are of very stable.

The stable safety profile, we're seeing very good expression.

Unknown Executive: Thank you very much for those questions, Alethea. First, we have our confidence in our constructs and the way we build them, and that 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, but we have now treated patients who are well over 50 patients at the target dose. And so we have a very stable safety

And so this is the only increases our confidence level around SRP nine year olds or all three and so we're excited about that with respect to the the clinical and regulatory strategy as it relates to the nine drills or of one in particular, we have an enormous amount of insight that's come out of the study one of two 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 the work to really understand.

Douglas S. Ingram: We're seeing a very good expression. And so this only increases our confidence level around SRP 9003, and we're excited about that. With respect to the clinical and regulatory strategy as relates 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 the 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 nuances that we're seeing out of study 102, meet with the agency once that protocol is fully defined, then we'll update everybody on that.

On the data and we're coming to the end of that now to build the protocol. That's fully informed by studying one of two in the positive proof of concept in one or two on some of the new ones that we're seeing out of study of one or two to meet with the agency.

Once that protocol is is fully defined then well 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 then of course, the readout would probably up last patient last visit if all goes well by the end of next year and the readout. Shortly thereafter and it is our current base assumption that that would be the study upon which we would obtaining approval for some of the U S net around the world.

Okay.

Thank you. Our next question comes from the line of Brian Abrahams from RBC capital markets. Your line is now open.

Hi, there. Thank you so much for taking my question now that you've had more of an opportunity to digest. The the mono two data set and I think you mentioned maybe in January you're going to be looking at additional statistical analyses, including those that may get normalized baseline characteristics. I was wondering if you had any further learnings or insight that you'd be willing to share in.

Douglas S. Ingram: And 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.

Any maybe planned adjustments to the general approach you might take to the 301 design on things like inclusion criteria.

Douglas S. Ingram: And of course, a readout. We'll probably have the last patient, the last visit if all goes well by the end of next year, and then a readout shortly thereafter. And it is our current base assumption that that would be the study on which we would obtain an approval first in the U.S. Thank you. Our next question comes from the line of Brian Abrahams from RBC Capital Markets. Your line is now open.

Or analysis. Thanks.

Yeah, Brian. Thank you so that the the short answer is yes, we have an enormous amount of insight that's come out of one or two.

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 will do that once that protocol is fully designed the than the agency has bought into the the protocol, but we are convinced not only the theres a lot of insight here.

Unknown Executive: Hey there, thank you so much for taking my question. Now that you've had more of an opportunity to digest the 102 dataset, and I think you mentioned maybe in January, you're going to be 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 on things like inclusion criteria or analyses. Thanks. Yeah, Brian, thank you.

That we can greatly increase the probability of success in the next trial in a very new watch the way we have.

Already out of the study one or two significantly more insight and data that anyhow anyone else would have regarding a construct from.

Micro district for the use of Duchenne muscular dystrophy that'll help us design.

Our next study with tentatively called back study three of one and then we will have even more inside by the way of the end of this year you know I really do want to point out how important that is this remember studying one of the two is a blinded study what we saw in January was part one of that study and what we saw you know while I'm not going to deny.

Douglas S. Ingram: 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 already have, out of study 102, significantly more insight and data than anyone else would have regarding a construct for microdistrict therapy for the use of Duchenne muscular dystrophy.

I'm disappointed that we didn't hit statistical significance on the primary endpoint, what we saw on the secondary endpoint 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 the only 16 kids and in the 16 cohort.

Where the baselines were actually properly.

Compared we saw on not just the 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 gonna of part two of its going to the last patient last visit in the back half of this year and so by the end of this.

Douglas S. Ingram: That'll help us design our next study. We'll 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.

You are probably very early next year, we will have the results from part two and that is gonna be enormously insightful on top of this I mean thinking about what you'll have there. We will have four about 20 of the kids two years' worth of data that we can look at and the way their trajectory on therapy and then for the other 21 kids area of something.

Douglas S. Ingram: This, remember, study 102 is a blinded study. What we saw in January was part one of that study. And what we saw, while I'm not gonna deny it, I'm disappointed that we didn't hit statistical significance in the primary endpoint. But 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.

Very interesting there in some ways really interesting, which is we'll have.

A cohort of children, who will have.

We've been able to follow and do a run in for 48 weeks of the trajectory without of therapeutic intervention than we are of therapeutic intervention and then we get to judge when we unblinded what the impact of that therapeutic intervention was so well have even more insight. So short answer on your mommy Anthropologie.

But long answer we're trying to get short on your.

Question is we have developed an enormous amount of insight out of one or two that gives us not only of lot of confidence in the therapy, but really keen on understanding of how we ought 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 talk about it once that's done.

Douglas S. Ingram: And in that 16-kid cohort, where the baselines were actually properly compared, we saw not just strong statistical significance but also a very clinically meaningful benefit over placebo in only 48 weeks. And then at the end of this year, just to remind everybody, that study remains blinded. We're gonna have part two, that's gonna be the last patient, the 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 gonna be enormously insightful on top of this. I mean, think about what you'll have there.

Thank you. Our next question comes from the line of solving Richter from Goldman Sachs.

Your line is now open.

Good afternoon, Thanks for taking my question Jim.

You maybe.

Maybe an update on your gene editing portfolio you recently entered into a research collaboration with Gen event for LNP based editing therapeutics and you've had some other partnerships to day could you just walk us through you know when we should expect kind of on an update on programs meeting point yeah.

Douglas S. Ingram: We'll have, for about 20 of the kids, two years worth of data that we can look at and the way they're progressing on therapy. And then for the other 21 kids, we have something very interesting there, in some ways really interesting, which is we'll have a cohort of children who we've been able to follow and do a run-in for 48 weeks of trajectory without any therapeutic intervention. Then we have a therapeutic intervention, and then we get to judge, when we unblind it, what the impact of that therapeutic intervention was. So we'll have even more insight. So, short answer on your, well, long answer, apologies Brian.

Sure I will turn this over to Dr. Jim when we start getting quite back before I do I will point out that you will notice that we are you know our goal is to look at all of the modalities. We looked at gene editing of something that's very exciting from the future. In addition to.

On the partnerships and relationships that we have entered into over the course of the last 12 months to 24 months I should also note that we have built out of gene editing.

Center the.

What we called the gene editing innovation Center in Durham, North Carolina, all of which is under the leadership.

Dr. Charlie Gerspach from Duke University, who is.

One of the significant world leaders in the use of gene editing from of neuromuscular perspective, but perhaps.

Addition to that Luis you'd like to comment on our gene editing efforts.

Douglas S. Ingram: But the long answer, trying to get short on your question, is that we have developed an enormous amount of insight out of 102 that gives us not only a lot of confidence in the therapy but a really keen understanding of how we ought 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. Thank you. Our next question comes from Salveen Richter from Goldman Sachs. Your line is now open. Good afternoon.

Sure. Thank you Doug on I'd like to Jim.

That kind of went back on it about I'm trying to pick our spots and being really the two liter in the field and that's been working on space for quite some time.

And really we have the opportunity of just about the best in class on technology and part of that is really scanning the landscape for delivery.

The delivery technologies and that.

There are other ways that you can deliver of gene editing machinery and some of our agenda of that partner shop partnership with.

Unknown Executive: Thanks for taking my question. Just, you know, maybe an update on your gene editing portfolio. You recently entered into a research collaboration with GenEvent for LNP-based editing therapeutics, and you've had some other partnerships to date. Could you just walk us through, you know, when we should expect kind of an update on programs moving forward here? Sure, I will turn this over to Dr. Louise Rodino-Klapack before I do, I will point out that you will notice that we are, you know, our goal is to look at all of the modalities, you know, we look at gene editing as 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, of North Carolina, all of which is under the leadership of Dr. Charlie Gerspach from Duke University, who is, you know, 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, Sure. Thank you, Doug.

One of them I don't look at that you think of lipid nanoparticles on where certainly.

Open to making sure that we have the the best.

Delivery vehicle for gene editing and so we'll continue to.

Look at these research partners partnerships in the broad manner to make sure that we are about the best technology moving for the thank you for the question.

And I should also of note we have lipid nanoparticles we have.

Relationships to advance.

The 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 boats for gene editing and gene therapy, and maybe even the RNA as well.

Thank you. Our next question comes from the line of Ritu <unk> from Cowen. Your line is now open.

Hey, guys. Thanks for taking the question.

Doug have you ruled out breaking the blind on one of two to generate more data before you start three of one or do you have on.

<unk> to keep three of one adapted depending on what final one O. Two data will show and you know given enrollment is gonna be competitive how confident are you that you can enroll three of one in six.

Douglas S. Ingram: I'd like to just... Second, what Doug said about Charlie Gershbach and being, you know, really the true leader in the field and having worked in the G-Shen 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, [inaudible] 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 way to make sure that we develop the best technology moving forward.

Six months.

Yeah. Thank you for those both of those questions Ritu. So he brings a really interesting question, which is could you do an interim analysis on part two to gain even additional inside the the short answer is having thought about that we're not currently I'm of the.

A few that we should do that for a host of reasons the the.

The first is that we already are going to have.

Significant insight from part one of the study one of two that will help us design.

Louise R. Rodino: So thank you for the question. And I should also note, Salveen, that we have lipid nanoparticles; we have relationships to advanced, updated, and increasingly sophisticated AAV technology. And of course, we have a relationship to explore the use of exosomes as delivery devices as well, potentially for gene editing and gene therapy, and maybe even our next question comes from the line of Ritu Baral from Cowen. Your line is now open.

What we're calling study three of one right now I mean, we've got Scott no one let's be very direct nobody has the kind of insight that we currently have.

The the design that we all have for our next study will increase the probability of success. It will clearly put us in the like in the competitively positive advantage and that's already with the part one so we really do want to maintain that blind and get a readout on the study 102 at the end of the last patient last visit by the end of this year and probably the very early.

The following year have that readout, because that's going to be an enormously important.

Unknown Executive: Hey guys, thanks for taking the question. Doug, have you ruled out breaking the blind on 102 to generate more data before you start 301? Or do you have the option to keep 301 adaptive depending on what the final 102 data will show?

On a normal important set of data a vast amount of information in the rare disease and we just really want to maintain the blind as it relates to enrollment.

The 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 I think that won't be our significant issue I don't believe right now of our big issue right. Now is getting that protocol really fine tuned meeting with the agency of getting the agency blast at the.

Douglas S. Ingram: And given enrollment is going to be competitive, how confident are you that you can enroll 301 in six months? Yeah, thank you for those both those questions. So you raise a really interesting question, which is, you know, 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 the view that we should do that for a host of reasons.

Agents blessing them on that protocol in the approach and then really getting that kicked off and started in time to really start enrolling patients and I suspect that patient enrollment enrollment will be robust once we get that gallon.

Thank you. Our next question comes from the line of a new pump <unk> Rama from J P. Morgan. Your line is now open.

Douglas S. Ingram: The first is that we already are going to have significant insight from part one of study 102 that will help us design what we're calling study 301 right now. I mean, we've just got that no one, let's 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 and will clearly put us at a competitively positive advantage. And that's already with part one.

Hi, guys. Good afternoon. This is touched on the call from E com.

So one one question here in your remarks, I think he said you're expanding study one on <unk>.

On to better balance of one five year olds on the trial I guess, what is the rationale here of giving you're planning to run the real wine and what is the target and for one offs to me now.

Thanks, so much.

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 as to make sure that it's not a significant change or delay on anything so just to remind everybody of study why on three uses of the commercially representative material or new process that we would intend to launch the therapy with and it's our.

Douglas S. Ingram: So we really do want to maintain that blind and get a readout on study 102 at the end of this, you know, 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.

It's our goal to test the expression and safety and the similarity of that process and the great news on that was that we had all of the kids dose as you know by them by the end of last year as we reported out of J P. Morgan and that was about 11 children on what we've noticed is that there are more sixth and seventh of tourism.

Douglas S. Ingram: There is an enormous need for 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 it is right now. Our big issue right now is getting that protocol really fine-tuned, meeting with the agency, getting the agency's blessing on that protocol and the approach, and then really getting that kicked off and started in time to really start enrolling patients. I suspect that patient enrollment will be robust once we get that going. Thank you. Our next question comes from the line of Anupam Rama from J.P. Morgan. Your line is now open. Hey guys, good afternoon. This is Tess on the call for Anupam.

Fives and since this was intended to be.

On a look at the.

For the four to seven year olds with.

We've added we updated the India 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.

We will not delay us in the in the evaluation of the report out of those 11 patients. It's just an attempt to get a better balance overtime. So don't consider that a delay in anything it's not a delay on the report out on the second quarter, there shouldn't be any kind of delay on the start of three of one it's really just our effort to ensure that we have a nice balance of.

For the fives and sixes and sevens in that study.

Okay.

Thank you. Our next question comes from the line of the Bai Yun from Mizuho.

Your line is now open.

Hi, good afternoon, and thanks for taking my question just a quick on a quick one on the very high level. How do you think about gene editing relative to the AAV based gene therapy.

Unknown Executive: 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 end for Study 103 now? Thanks so much.

Is there a possibility that gene editing to leapfrog the virus based gene therapy and come to commercialization first.

Douglas S. Ingram: Yeah, 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 commercially representative material, our new process that we would intend to launch the therapy with, and it's our goal to test expression and safety and the similarity of that process.

Well I think the answer is no I don't think that we're going to see something that's gonna Leapfrog gene therapy right now for a host of reasons firstly raise of 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 is the.

Biopharmaceutical industry in the the short answer is net of course gene editing today is virus based as well. So you know what and I think that through power of gene editing. We may want to look as we are currently as you've seen both through Alan piece of extra zones about on the delivery device that would move it.

Douglas S. Ingram: And the great news about that was that we had all of the kids dosed, as you know, by the end of last year, as we reported out at J.P. Morgan, and that was about 11 children. What we've noticed is that there are more 6s and 7s than 4s and 5s.

Self away from a V as the potential so that already is going to require a lot of effort and focus and research to think about it a of he's been a very successful approach for delivery of.

Douglas S. Ingram: And since this was intended to be a look at, you know, 4 to 7-year-olds, we've added, we updated the IND. It would allow us to add some additional 4 to 5s, but it is no more than that.

Douglas S. Ingram: We haven't seen any data on this, so we will not delay 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.

Of gene therapy, and if we're going to move away from that over time that is going to take time.

There are so gene editing is really exciting, but I think just have poorly.

There is a different gene therapies right in front of US right today, we just as you saw.

Douglas S. Ingram: It's not a delay in the report coming out in the second quarter. There 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 4 to 5s and 6s and 7s in that study. Thank you. Our next question comes from the line of Desai Yang from Mizuho Mutual. Your line is now open.

The results of the 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 of placebo trial. So this is right in front of US gene editing is very exciting but believe me. We are theres a reason why we're putting a lot of effort.

Unknown Executive: And thanks for taking my question. Just a quick one. On a very high level, how do you think about, Relative to AAV Bay, gene therapy? Is there a possibility that gene editing just leapfrogged virus-based gene therapy? Commercialization? Well, I think the answer is no.

Third into the gene editing of why we've built this gene editing of innovation Center why we've wrapped our arms around the technology of of summer like Dr. Charlie Gerspach why we've entered into partnerships to look at other delivery mechanisms to empower of gene editing, but I think theres just the difference in time between the opportunity to bring therapies to the chilled.

Douglas S. Ingram: I don't think that we're going to see something that leapfrogs gene therapy right now for a host of reasons. First, you raise a really good point. Because what you've said is that, is it possible that 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.

And today with the 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.

On gene editing edits and that's very interesting on the other hand, let's be clear.

Douglas S. Ingram: So, you know, 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, for 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's been a very successful approach for the delivery of gene therapy, and if we're going to move away from that over time, that's going to take time.

You you are going to have to edit and create truncated forms of of the ultimate protein as well and you're either gonna do you really got to do that on an exon by exon basis or with respect of gene editing or you're going to have to do with what we are attempting to do with doctor of Charlie Gerspach, which is take a significant hotspot of gene editing.

You can put something back and 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 to 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 cash nine is it.

Douglas S. Ingram: So, gene editing's really exciting, but I think just temporally, there's a difference. Gene therapy's right in front of us right now. You know, we just, as 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 between four and five, we saw a really profound, never-before-seen benefit from a placebo trial. So, this is right in front of us.

Unbelievably exciting technology, there's a reason why those individuals one of the Nobel price worth, but it is a little bit it's a little ways out gene therapy is right in front of US today and offers the hope of transforming the lives of patients both in Duchenne muscular dystrophy and on a lot of other.

Areas as well.

Yeah.

Thank you. Our next question comes from the line of the the heat shallow part he from Guggenheim Securities. Your line is now open.

Douglas S. Ingram: Gene editing is very exciting. Believe me, we are. There's a reason why we're putting so much effort into gene editing, why we've built this Gene Editing Innovation Center, why we've wrapped our arms around the technology of someone like Dr. Charlie Gerspach, why we've entered into partnerships to look at other delivery mechanisms to empower gene editing. So, 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, you know, there are technological challenges in both areas.

Hey, good afternoon, and thank you for taking my question. So is the.

I'm trying to find an explanation for the high <unk> to VC and per cell in the crossover of patients, but micro dystrophin expression about the same as study one on one of the VC and was the one six threep.

Of our vision was $1 6 billion and could you also sort of talked to any difference in dose between on the first cohort of patients on study one of two versus the crossover of patients. Thank you so much.

I'm going to turn this the question over to Dr. Louise Rodino clay of banking can provide some insight into both I would think Luis will explain I think on the genome copies per nucleus I wouldn't over interpret the the.

The delta between those the genome copies of the probably the risk.

Douglas S. Ingram: Gene editing edits, and that's very interesting. And that's different than gene therapy, where gene therapy really is agnostic to the mutations, so there are differences. For a short answer, I think there's a difference in time.

Quite smaller numbers in the sense in the genome copy has been in the the western blot expression, but.

Luis the thoughts on both of those questions.

Okay.

Yeah.

I'm, sorry, I'm, turning it over to Mark when we say probably of all of you I think.

Douglas S. Ingram: I think gene editing today is 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 bit, it's a little ways out. Gene therapy is right in front of us today and offers the hope of transforming the lives of patients, both in Duchenne Muscular Dystrophy and in a lot of other areas as well.

I think Sheila you apologies apologies.

I would agree with you about the not over interpreting the.

Doctors have copy numbers on and.

And part two of them I would add that in part two as we mentioned in the first of all of us on patients on.

The heap the intended.

Dosing level.

Close to the part one.

On between discussed so in that respect we just we felt that any one on one and what we've seen kind of on our part to that the intent of quiet.

Unknown Executive: Thank you. Our next question comes from the line of Debjit Chattopadhyay from Guggenheim Securities. Your line is now open. Hey, good afternoon.

On target in terms of expression of.

Thank you Jim copies of them range as well.

Unknown Executive: Thank you for taking my question. So, I'm trying to find an explanation for the high 2.62 VCN per cell in the crossover patients but microdystrophin expression about the same as study 101, where the VCN was 1.63. I'm going to turn the question over to Dr. Louise Rodino-Claypack, who can provide some insight into both. I would think, you know, Louise would explain. I think about the genome copies per nucleus. I wouldn't over-interpret the delta between those genome copies.

Well there has the smell of a question.

No I think that thing because of the two questions. So just to remind everybody.

The <unk> question. So in the first part of the study there. The tighter Inc. Method that was use of the standard was a what's called Supercoil TCR. It turns out with the benefit of having developed the linear standard for Q PCR or we can look back and see that there were three large one of the large had the TARP.

<unk>.

On the target tighter in two of the lots were below the tighter range in the first group of patients that's about 60% of the patients were in the.

The lower loss on the crossover we use the linear tighter inc. For the purpose of the crossover.

Unknown Executive: It's probably the, you know, there's probably smaller numbers in a sense in the genome copies than in the western blot expression. But, Louise, thoughts on both those questions? I'm sorry. I'm turning it over to Louise. I think she's on mute.

And so so we are on we are right on the target.

The ring and targeted process Tiger target dose on the crossover patients.

I'm not sure I've got that the.

Completely wrong to actually release.

That's correct.

Yes.

Yeah.

Thank you we ask that you. Please limit yourself to one question. Our next question comes from the line of Gena Wang from Barclays. Your line is now thing.

Unknown Executive: Apologies. I would agree with you about not over-interpreting the vector genome copy numbers in Part 2. I would add that in Part 2, as we mentioned, the first 11 patients all received the intended dose as opposed to the Part 1 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 dosage level are quite on target in terms of expression and vector genome copies within range as well. Was there an additional?

Thank you for taking my questions. So one question regarding study one of the two.

Regarding the cross the Obama did you align with the FDA regarding pre specified match of history patient population of statistical analysis type price.

And of course, the school of law came on we know what the Doctor gentlemen, downtown to use Beacon regimen was that consistent across all of the patient.

Unknown Executive: 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 titering method that was used, the standard was a, 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 titering, two of the lots were below the titering, in the first group of patients, that's about 60% of the patients were in the, the lower lots, on the crossover, we used the linear titering for the purpose of the crossover patients, and so, so we are all, we are right on the target titering and target process, target dose on the crossover. Unless I've got that completely wrong factually.

Yeah, taking the second question first we allowed patients the patients that could be on a.

It had to be on a long term study doses of steroids, we allowed the patients to use the stay on their standard of care and they said there is.

Some of some.

People have daily dose on people use weekend dose that could play a role as well.

We can see and as it relates to the crossover that was all pre specified and then we can update it again before we on blind, but on the list Dr.

The Doctor, who we should be the quite back or Doctor Neil.

You can correct me, if I'm wrong, but I think all of that was all of that of analysis was in the protocol of the commencement of the trial.

Gary Mandel hearing, though that's the.

Curtis again on the language.

Unknown Executive: That was correct. Thank you. We ask that you please limit yourself to one question. Our next question comes from the line of Gena Wang from Barclays. Your line is now open.

The.

The protocol on the S E T.

Were created prior to the on blinding of Parkman.

The interim analysis.

Okay.

Okay.

Unknown Executive: Thank you for taking my questions. So I have one question regarding study 102 regarding the crossover. Did you align with FDA regarding the pre-specified natural history patient population for statistical analysis purposes? And for the steroid treatment, we know that Dr. Geron Lindell tends to use weak enrichment.

Thank you. Our next question comes from the line of Gil Blum from need him on company. Your line is now open.

Hello, everyone and thank you for taking our question so ex U.

You mentioned before the the the L. Jim the programs have certain similarities across them.

From from a regulatory perspective, there's positive data, though of continuing positive data for LNG and the TUI does that translate across the programs.

Unknown Executive: Was that consistent across all the patients? Yeah, taking the second question first, we allowed patients to, patients had to be on a long-term study dose of steroids. We allowed the patients to use their standard of care, and there is a, some people have a daily dose, some people use a weekend dose. That didn't play a role, as best we can see.

Thank you.

The positive data on the LG of the.

Programs has.

From a strictly regulatory perspective, it may it may not but from a confidence in the construct and the result of it definitely does I mean, we're seeing we see it and it doesn't vote both across all of the L. G M DS.

Unknown Executive: And as relates to the crossover, that was all pre-specified. I mean, we can update it again before we unblind, but unless Dr. Louise Rodino-Klepec or Dr. O'Neill, you can correct me if I'm wrong, but I think all of that analysis was in the protocol at the commencement of the trial. [inaudible] The protocol and the SAP were created prior to the unblinding of Part 1 intramenopathy. Thank you. Our next question comes from the line of Gil Blum from Needham and Company. Your line is now open.

But also of back onto the 901, because if you look at the safety profile. The understand of course of the significant part of the safety profile comes from the capsid itself. In this case, our age 74 and of course, our 874 as the capsid that we're using for.

All of our limb girdles as well as nine 001 for D. M D and so there's a value there and then seeing the positive expression results gives us a lot of confidence both in the tropism of already of 74 across all of the programs and also of the promoter itself. It's the same promoter into either the 900.

Unknown Executive: Hello everyone, and thank you for taking our question. So, as you mentioned before, Doug, the LGMD programs have certain similarities. From a regulatory perspective, if there's positive data or continuing positive data for LGMTQI, does that translate across programs? Well, the positive data on the LGMD... [inaudible] If I'm not mistaken, three of the five limb girdle programs. So there is an enormous amount of built-in confidence that we have. Now, with respect to the limb girdle and its pathway, I think that, you know, 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 Thank you. Our next question comes from the line of Tazeen Ahmad from Bank of America. Your line is now open.

One of its the same promoter in I think three of the five if I'm not mistaken three of the five limb girdle programs. So there is an enormous amount of on building confidence that we have now I think with respect of limb girdle and its pathway I think the we are going to be meeting with the division this year at 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 on 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.

Thank you. Our next question comes from the line of cuisine, a Mark from Bank of America. Your line is now open.

Douglas S. Ingram: Hi guys. Maybe just to change gears to your current franchise, just wanted to get a little bit of color, Doug, on what kind of penetration you have right now with Exondys and the targeted market. And can you give us an idea of how Golo Deerson's launch is going? And if you expect Kazimiersan will also have a similar type of ramp to what Exondys had at the beginning?

Hi, guys, maybe jokes on 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 Exxon. This on the targeted market and can you give us an idea of how go live here since the launch is going in a few weeks that caused the Nielsen.

We will also have the spend on.

On the type of ramp to what Exxon just had at the beginning.

Douglas S. Ingram: And maybe to tie it all up, how big of a market opportunity is the combination of the three drugs together? Thank you. Yeah, so thank you for that. I think you let me take them and gave us the stroke together.

And maybe the tie in all of that how big of the market opportunity with the three drugs together represents Inc.

Yeah. So thank you for the I think let me, let me take the broadest of strokes together and.

Douglas S. Ingram: And so first of all, with respect to Exondys, you know, we launched Exondys in late 2016. We are going to start getting to the flatter side of the curve with Exondys over the course, probably by the end of this year. And the reason for that is that there and then we'll be continuing to grow based on incident population, and we still find new patients. And if we could ever unlock new patient screening, we would definitely see a significant increase.

So first of all with respect to we saw on the sooner we launch the Exxon just in late 2016.

We are going to get started getting into the flatter side of the the curve with axon on this over the course, probably by the end of this year.

I'm now on the reason for that is that there and then we'll be continuing to grow based on the incident population and still we find new patients and if we could ever unlock new patient screening, we would definitely see a significant increase theres a total.

Douglas S. Ingram: There's still a ton of opportunity in Exondys, even over the long term, but the issue there is it's XUS, and we have to find an opportunity for XUS to get approvals, XUS, to really unlock that opportunity. We have XUS sales, but they come from what we call the MAP program, this access program that's responsive in nature.

There's still a ton of opportunity in exon this.

Even over the long term, but the issue there is it's ex U S and we have to find the opportunity ex U S to get on approvals ex U S to really unlock that opportunity we have the ex U S sales, but they come from.

What we called the map program of this access program. That's response of the nature of the problem ex U S is that there isn't the most countries of the concept of an accelerated approval pathway. So that hampers us until we get a read out on some of our confirmatory trials with exon isn't that I think give them another opportunity for growth goal of has done very well now.

Douglas S. Ingram: The problem, XUS, is that in most countries the concept of an accelerated approval pathway isn't in place. And so that hampers us until we get a readout and some of our confirmatory trials with Exondys, and then I think you have another opportunity for growth. And yet, the team did a brilliant job, and we had very good growth in Biondus.

Goal of those launch has been somewhat attenuated as a result of the pandemic itself. Obviously you know it isn't the you would rather not launch of new therapy, particularly of therapy that has to start with not only going into physician's offices, but going into.

The hospital for your first infusions of very typically you would love to not have to do that launch in the midst of of pandemic and yet the team did a brilliant job and we had very good growth in buy on us, but from my perspective, we should see my honest is the continuing of launch which is actually a positive because of lot of growth. There and then finally, if you look at CASM Ericsson now this is maybe the.

Douglas S. Ingram: But from my perspective, we should see Biondus as a continuing launch, which is actually positive because there's a lot of growth there. And then finally, if you look at Casamircin, now this may be just 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. I mean, kudos to our team, supply chain, commercial, MedAffairs, and the like, because we're able to immediately launch that. We're able to get start forms. We've got start forms already. We'll have Amandus in the warehouse by this week, by literally tomorrow.

Of the honeymoon period of having just gotten the approval. We just got approval last week and just so we're clear where we're ready to go just I mean on kudos to our team supply chain commercial Med affairs and the like because we were able to immediately launch that we were able to get start forms. We got start forms in already we'll have.

We will have.

I'm on the skin warehouse by this week by literally tomorrow, we will have it and insights. So I'm on this is going to I think looking at a modest obviously scaled down to the size of the patient population, which is smaller than exon. This I currently think that even with this pandemic.

Douglas S. Ingram: We'll have it in sight. So Amandus is going to, I think looking at Amandus, obviously scaled down to the size of the patient population. Smaller than Exsandus, you know, I currently think that.

Douglas S. Ingram: Even with this pandemic, and you know, Dallan's probably scared I'm going to say this, but I think its launch trajectory is going to look a lot like Exandus, and there's a lot of excitement and a lot of pent-up demand for therapy for Exxon 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-500s, and we're really in a big phase with two of the three therapies, and those two together are bigger than the other therapies. So there's a ton of headroom. If we just didn't leave the United States, you know, we're going to be getting up into the billion-dollar range over time, potentially.

Dallas is probably scared I'm going to say this but I think its launch trajectory is going to look a lot like Exxon does and there's a lot of excitement and a lot of.

Pent up demand for the therapy for exon 45 of 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, where we are already in the mid five hundreds and we're really in the launch phase two of the three therapies and those two together of bigger than the other therapy. So there's a ton of headroom. If we just didn't leave the United States.

You know, we're gonna be getting up into the $1 billion range over time potentially.

Douglas S. Ingram: And if we can open up, XUS will be significantly larger. And then the bigger opportunity than that, which I really want to hammer on this because I think people have underappreciated 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. We have 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 constructs safely that can bring therapies to these kids.

And if we can get if we could open up ex U S will be significantly larger than the bigger opportunity than that that I think is they really want the hammer on this because I think people of underappreciated.

<unk>, our RNA franchise is the opportunity to bring therapies to patients as exciting as these first three therapies arm is 29% of the patient population.

We 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 and precise way to build construct safely that can bring therapies to these kids. So we have the potential over time in addition.

Douglas S. Ingram: So we have the potential, over time, in addition to Exondys and Biondys and Amondys, to build therapies out for these kids, you know, in the US and hopefully around the world that can 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. As you know, we had the 10 mg and the 20 mg readout last year. And, you know, at least from a proof of concept perspective, we were pretty excited.

Two exon doesn't buy on to send them on this to build therapies out for these kids in the U S and hopefully around the world that could get us over 80% of 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 the platform approach because of those.

<unk> 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 in that big opportunity will either be the TMO, which were which were you know obviously of develops now and we're just launching of modest which of the PMO or it could be on peptide conjugated PMO. The P. P M O and where.

Gonna see the 30 Meg per kg readout on the P. P. M O in the second quarter. So that'll be really interesting to look at as you know we had the 10 Meg of the 20th of Big read out last year and you know at least from a proof of concept perspective, we're pretty excited we saw with the P. P. M O 110th of the drug exposure and five ex the dystrophin production of the very.

Douglas S. Ingram: We saw with the PPMO, we one-tenth the drug exposure and 5x the dystrophin production in a very short period of time. So either PBMO or PMO, there's a lot of opportunity to do a lot of good in the Duchenne community. And, of course, there are significant revenues with that as well.

Short period of time, so either P BMO or PMO, where there's a lot of opportunity to do a lot of good in the Duchenne community and of course, they are of significant revenues with that as well.

Unknown Executive: Thank you. Our next question comes from the line of Vincent Chen from Bernstein. Your line is now open.

Thank you. Our next question comes from the line of Vincent Chen from Bernstein. Your line is now open.

Unknown Executive: Thanks for taking the question. Thinking of 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'll evaluate the data and what you're hoping to see. I guess what comparisons are specified in the protocol and what would, from your view, an encouraging result look like? Well, we're looking at about two things, really. We're looking at... The first one, there are a bunch of examples that we're going to look at.

Hi, Thanks for taking the Watson thinking.

Thinking of the crossover data at the end of this year from study one of two I was wondering if you could provide a bit more color on how you will evaluate the data on what you are hoping to see because what comparisons of our specified in the protocol and what would the from from your view of what would an encouraging result look like.

Well, we're looking at both two things really were looking at.

The first of all.

A bunch of them.

So we're going to look at and of course, we can update on.

Unknown Executive: And of course, we can update it with more insight, more thought into it. In the broadest of strokes, we're going to be able to see, first of all, how it compares with natural history. We're going to have this trajectory analysis that we can look at as well, which is, we have, you know, we have a unique opportunity to look at children who are blinded the whole time. So let's be very clear. This is not an open-label study. This will be blinded till the end.

The more insight more on into the broadest of strokes, we're going to be able to see first of all we're gonna be able to compare against natural history.

Children, including children a bit on that.

Therapy for nearly two years, that's going to be exciting. We're gonna have this trajectory of analysis that we can look at as well, which is we have you know we have a unique opportunity to us too.

To look at children, who are blinded the whole time, so let's be very clear. This is not an open label study. This will be blinded till the end look at them trajectory over the course of 48 weeks without any therapeutic intervention and then the therapeutic intervention and then we see what that looks like over time, both using themselves of their own control and also using of <unk>.

Unknown Executive: We look at them trajecting over the course of 48 weeks without any therapeutic intervention and then with 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, you know, their trajectory over that 48-week period and then looking at their age.

L matched natural history set that would be pre specified to look at what you would have predicted out of the.

Out of the natural history set based on based.

Based on their trajectory over that 48 week period, including there and then looking at the age but beyond that Dr. O'neill of is there anything I'm missing here in the broad strokes.

Unknown Executive: But beyond that, Dr. O'Neill, is there anything I'm missing here in a broad stroke? I think, in broad strokes, you've hit it and obviously you also have, we'll have a second year of follow-up for the patients who were randomized to active treatment in part one. So you've got...

I think in broad strokes the patients and obviously you also have we'd have.

Second year of followed from the patients who had who were randomized to active treatment and.

In part one.

So you've got it.

Yes.

Right.

Okay.

Thank you.

Unknown Executive: Thank you. Our next question comes from the line of Tara Bancroft from Piper Sandler. Your line is now open.

Our next question comes from the line of Tara Bancroft from Piper Sandler Your line is now open.

Unknown Executive: Hi guys, thanks for taking the question. 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.

Hi, guys. Thanks for taking the question on so staying on the topic from Christine's question.

What do you think is there.

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 at a P. P. M. O. I know you said it could be one of the other and on the P. P. M O topic.

Unknown Executive: 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? Yeah, so going to the last question first, the data that we'll have in the second quarter will be the 30 meg per gig data. That's what that will happen in the second quarter on, you know, it's a really interesting question.

Have you started dosing in the 40 Meg per kg cohort, yet and will they be included in the data in Q2.

Yeah. So go to the last question first the data that will have on the second quarter will be the 30 Meg per kg data, that's what that's what will happen in the.

The second quarter on.

Interesting question, we have we have contracts the belt.

Unknown Executive: We have, we have constructs built. The great thing about RNA technology is that it's the conjugation of a peptide to a construct, the PMO construct. So we can build the PMO construct, and if we want to go 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.

For the the great thing about our RNA technology isn't that.

It's the conjugation of a peptide to construct that the PMO constructs. So we can build the PMO construct if you wanted to go Pee PMO, we simply conjugate the peptide to the preexisting construct we have of what a number of of built for all of the fairly significant.

Populations. So the real question for Us the Fork in the road is gonna be.

Unknown Executive: So the real question for us, the fork in the road, is going to be, you know, 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, we can seek accelerated approval via And if, when it all ends up, we think that PMO is the better answer, we'll start conjugating, we'll start creating those constructs and bringing them forward. And we've seen now that we have a fairly, you know, distinct approach. We can build the constructs with them; they're highly precise, and they have very good safety profiles in the PMOs.

You know what the data looks like and the P. P. M O and then we can make a choice and if the data looks great and the P. P. M out then we're on.

Obviously, you're going to start building the cost structure would peptide conjugation to them that we're going to start getting those kids on.

Therapy, and then hopefully seek accelerated approval via that mechanism and if.

When when it all ends up we think the PMA was the better answer will start college of getting all of this.

Creating those kind of shocks in bringing them forward and.

When you have seen now that we have a fairly.

The stink approach, we can build the construction of their highly precise the very good safety profiles in the PMO is of course of the P. P. M. O. That's exactly one of the day, we're looking at in the which is the safety profile of the P. P. P.

Unknown Executive: Of course, the PPMO, that's exactly one of the things we're looking at, which is the safety profile of 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. As everyone knows, we saw very encouraging results in PPMO last year, and then in the second quarter of this year, we'll see how it looks. Thank you. Our next question comes from the line of Brian Skorney from Baird. Your line is now open.

The about and then we.

We can bring those.

Forward with the accelerated approval pathway, which is very efficient, but we need the first decided if it's gonna be P. P. M O N PMO as everyone knows we saw very encouraging results from the P. P. M. All last year and then in the second quarter of this year, we'll see how it looks at 30 megs per kit.

Thank you. Our next question comes from the line of Brian <unk> from Baird. Your line is now open.

Unknown Executive: Guys, thanks for taking the question. Um, the question on the Essence study said it'll be read out in 2024. I guess, is that study now blinded until week 144? And I'm just wondering, with three years to go before the readout, how do you intend to maintain trial integrity in terms of keeping patients randomized, given that both Golda Durson and Kazim Erson are now available? Yeah, that's a great question. Yes, it's blinded.

Hey, guys. Thanks for taking on the question.

A question on the essence study said it will read out in 2024, I guess is that study now blind it out until the week 144.

Just wondering in terms of the three years to go before the readout, how do you intend on maintaining trial integrity in terms of keeping patients randomized given the political leaders on CASM or some of our are now available.

Yeah, that's of Great question, Yes, it's blinded.

Unknown Executive: And it's very difficult, so you're a very good point. We've done a great job. The team did a brilliant job.

And it's very difficult to your very good point, we've done a great job. The team has done a brilliant job of 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.

Unknown Executive: And more than that, the patients have done a wonderful job of being committed to this, this trial, but it is blinded and having a long-term blinded trial takes a lot of commitment. So there's no doubt about that. The trial integrity is not at risk as a result of the approvals of both Amandus and Biondus. It was one of the things we talked about early with the agency, as we were thinking about the accelerated approval approach for both Biondus and then Amandus.

Makes a lot of commitment.

No doubt on that the.

The trial integrity is not at risk as a result of the approvals of both of them on to send by on this it was one of the various things that we talked about early with the agency.

As we were thinking about the accelerated approval approach both for buy on the Savannah Bond is and the way we achieve that was to ensure even as the bond is I mean, it's by honest 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.

Unknown Executive: And the way we achieved that was, even as Amandus, I mean, Biondus was coming close to approval, we moved our recruitment XUS. So we moved to regions around the world that don't have access to a commercially available therapy, so that access to the therapy in those areas could be via this trial. And then we don't have to worry about what would be a very credible risk, which would be that 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.

Alible therapy, so that the access to the therapy in those areas can be via the.

On this.

This trial and then we don't have to worry about the what would be of very very credible risk, which would be you get a commercially available therapy.

I'm on Board and then you know Jim.

Children are moving over to commercially available therapy as opposed to being on the placebo controlled trial, but that risk is not.

Significant at all as a result of the actions that we took care of couple of years ago to start recruiting actually Louis.

Unknown Executive: Got it. And just, I just want to clarify, so that blinded data, so what we'll get from the blinded data in 2024, is that actually going to be week 144, six minute walk? Is that the primary now? I think that's right. Is that right, Dr. O'Neill? Yes, yes.

Got it and just I just wanted to clarify some of that blind. So what we'll get from from the blinded data and in 'twenty 'twenty four is that actually gonna be week 144, six minute walk is that the primary now.

I think that's right is that right Dr O'neill.

Yes, yes.

Unknown Executive: Thank you. Our next question comes from the line of Colin Bristow from UBS. Your line is now open. Hi, this is Ting. I'm on behalf of Colin.

Yeah.

Thank you. Our next question comes from the line of Colin Bristow from UBS. Your line is now open.

Hi, This is king on for Colin Thanks for taking all the question so.

Unknown Executive: Thanks for taking our questions. So we have a follow-up question on the PPMO and ahead of the data, like updates in the second quarter. So, based on your modeling, what extra skipping or distribution expression levels are you expecting or should we expect from the 30 mg per kg or even higher dosing cohort? Thank you. Yeah, well, you know, the short answer is we don't know yet. We haven't seen any of the data yet. So I want to be very clear. We don't know yet what we're going to see until we look at it.

So we have a full of question on the P. P M O and the.

How does that all line up gas Inc. Second Quad area. So based on the E. R modeling what exon skipping more on this.

True pressure on level are you expecting or should we expect from the they can make per cake or even the higher dosing cohort. Thank you.

Yes.

The short answer is we don't know yet we havent seen any of the Dallas. So I wanted to be very clear, we don't know yet what we're going to see until we look at it all we can do.

His model off of animal data and and of course that there is a lot of risk and decided in the.

Unknown Executive: All we can do is model off of animal data. And, of course, there's a lot of risk and decision and trying to correlate between animal data and human data and trying to figure out what the exact right model is. Is it weight-based? Is it allometric?

Trying to correlate between animal data and human data and trying to figure out what the exact right model is it is it wait base. If the dollar metric. It is some mix shift between what we do know is we know two things we know that at 20 megs per keg, which in the animal models wouldn't have yet been at.

Unknown Executive: Is it some mix in between? What we do know is that we know two things. We know that at 20 mixes per kid, 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. But we nevertheless saw at one tenth the dose exposure five times the dystrophin production. So we've already seen something that's really interesting, and frankly, it's interesting in a whole host of ways.

That's the part of the the dose response curve from of Dystrophin exon skipping perspective, we nevertheless saw at one test tends to the dose exposure five times of dystrophin production. So we've already seen something thats really interesting and frankly, it's interesting on a whole host of.

Way, so we're seeing five ex the dystrophin.

Unknown Executive: We're seeing 5x the dystrophin, and the dosing schedule is much better for the PPMO than PMO. It's monthly dosing, as opposed to weekly dosing. So already, a very interesting concept.

On the dosing schedule is much better for the P. P M of the PMO its monthly doses.

Most of weekly dosing so already a very interesting concept. The second thing that we know and we don't know of 30 mix per gig will be the place we see it.

Unknown Executive: The second thing that we know, and we don't know if 30 mgs 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 could see either 30 mgs per kg or something higher than 30 mgs 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 it in patients. Because all of the data that we had up until the 10 and 20 mgs per kg, of course, weren't over in Animal.

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 a sig Peter 30 makes particular, it's something higher than 30 of mix per gig, we see a steep increase in the amount of dystrophin, but we won't know that frankly until we you know we have evaluated biopsies and we begin to see that.

In patients because of all of the data that we had up until the 10 and 20 of mix per gig of course worrying.

We're in the animals.

Animals.

Unknown Executive: Thank you. Our next question comes from the line of Marty Oster from Credit Suisse. Your line is now open.

Yeah.

Thank you. Our next question comes from the line of Marty Auster from Credit Suisse. Your line is now open.

Unknown Executive: Hey everyone, and a solidly belated congratulations on the amount of approval last week. I had a follow-up from the prior question. I think, looking back at my notes from the December call on 5051, Doug, you talked about possibly being able to commence dosing of the 40 mg per kg arm by the end of Q1. Is that still potentially on track?

Hey, everyone and Oh, so they believe the congratulations on the amount of its 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 50 51, Doug.

Doug you talked about possibly being able to commence dosing of the 40 milligram per kilogram of arm by the end of Q1 is the.

That still potentially on track and if not.

Unknown Executive: And if not, are you waiting to kind of get that 30 mg per kg 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 to move forward? Thanks.

Are you waiting to kind of get the 30 milligram per kilogram, David before advancing is that something youre looking for on the biopsy side or something on the safety side to kind of make the determination to move forward.

Unknown Executive: We're looking to, yeah, so our updated view is we want to see 30 mgs per kg before we decide two things. We decide what the pathway is for a pivotal and also what the dose ranges should be and, you know, how much higher should we start thinking about going up in doses. So we're going to see the 30 mgs per kg and then make the decision on the 40 mix per keg right after we do that. We'll see the 30 mix per keg in the second quarter.

We're looking at yes. So we are in fact, the updated view is we want to see the 30th ex protect before we.

The side two things, we decided what the pathway is for a pivotal and also what the dose range that should be in and then you know how much higher should we start thinking about going up in dose. So we're going to see the 30th extra kick in then.

The make the decision on the 40 mix per kg right. After we do that we will see the 30 mixed breed CAGR of the second quarter.

Okay. Thanks.

Unknown Executive: Thank you. Our next question comes from the line of Joel Beattie from Citi. Your line is now open. Good afternoon. This is Sean Egan calling in for Joel.

Thank you. Our next question comes from the line of Joel Beatty from Citi. Your line is now open.

Good afternoon. This is Shawn Egan, calling in for Joel Thanks for taking my questions.

Unknown Executive: Thanks for taking my questions. It was great to hear about the pivotal trial for the beta-cycloglycan trial this year. When could you expect pivotal data for that study? Should we expect a similar cadence to study 3.0.1?

It was great to hear about the pivotal trial for the betas are cyclical I kind of trial of the fear.

When could you expect pivotal data for the study should we expect a similar cadence of the study 301.

Unknown Executive: 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 beta sarcoglycan. It is significantly different from SRP 9001 in one important regard, which is the issue with SRP 9001 and one of the reasons that we're taking the approach that we're taking, which is a placebo-controlled, blinded study.

Well, we don't know because we have to Steve we have to decide with the agency's involvement in the guidance what the right development pathway will be.

For the beta circle the wagon it is significantly different from SRP nine 001 and one.

Important the guard, which is the issue with SRP nine 001, and one of the reasons that where we've taken the approach that we're taking which is a placebo controlled blinded study while there's two reasons. One is that the DMT is large enough patient population that it is.

Unknown Executive: 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 achievable. The second thing, of course, is that with respect to microdystrophin, you do have a truncated version of the dystrophin, so expression alone wouldn't be sufficient. You have to also show function in that.

Feasible to do that it has its own ethical challenges and believe me it's required a lot of discussion with them.

Patient groups and the patient advocates around that but when you. It can be done. So it's executable. The second thing of course is that with respect the micro dystrophin you do have a truncated version of the the district and so expression of alone. It wouldn't be sufficient you have to also share a function of that there is a sense to that the agency has been clear about that it makes.

Unknown Executive: There's a sense to that, and the agency's been clear about that. With respect to beta-sarcoglycan, we're in a different place, and that's why I wouldn't assume in advance that it's the same cadence as SRP9001 in two regards. One, this is a much larger, much rarer population.

The sense.

With respect the beta start look like and we're in a different place and that's why I wouldn't assume in advance of it its the same cadence as SRP nine 001 for two regards one of this is a much more much rare population the.

Unknown Executive: The very concept of doing, you know, a blind and 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 and an ethical perspective. But the second thing that's important is that, with respect to beta sarcoglican and 2E, the gene that we are delivering creates the native protein. This is the native protein.

The concept of doing you know blinded placebo controlled trial I think it would be.

Probably it would be an understatement to say that that would be challenging from both the execution of perspective on an ethical perspective, but the second thing. That's important is with respect of data there.

Well I can and to E on.

On the gene that we are delivering creates a the native protein. This is the native protein so with respect to those two issues together of the discussion that we're going to half of the agency is around the ability to come up with a lean.

Unknown Executive: 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 in both our low-dose and our high-dose cohorts using the clinical 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.

Efficient executable approach to get these the therapy to patients that are waiting we are already seeing both on a low dose of arc.

Those cohorts.

I'm using the clinical supply from nationwide children's hospital that we're seeing very high expression in both we're seeing correlates of of really strong functional endpoint, we'll have an update on that by the way at M. D E and that that will be a very important update.

Unknown Executive: 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 that it's a native protein.

And so of course, our view is that given its native protein the the development pathway should be.

She'd be leaner and and it should be informed by the patient population and the fact that it's the 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 them to talk CMC with of the division and that'll happen this year.

Unknown Executive: But we'll know that when we have the discussions with the agency, and we'll have those discussions once we have CMP material to talk about CMC with the division, and that'll happen this year. Thank you. Our next question comes from the line of Danielle Brill from Raymond James. Your line is now open. Hi guys, this is Daniel Datta-Olin from Danielle's team. Thank you for taking our question. On PPMO, in your last update, you mentioned that there were COVID-related biopsy delays that might have contributed to lower SRP 50-51 muscle concentration in the 20 mg per kg cohort compared to the lower dose. I wanted to ask, with the improving COVID environment, can you comment on whether you're still experiencing similar delays that may make data interpretation potentially more difficult?

Thank you. Our next question comes from the line of Danielle Brill from Raymond James Your line is now open.

Hi, guys. This is of the Neal that the Olin on from Danielle. Thank you for taking the question.

On P. PMO in your last update you mentioned that there were college related to delays that might have contributed to lower the SRP 5051 muscle concentration in the 20 milligram per kilogram cohort compared to the lower dose.

Wanted to ask it missed the improving COVID-19 environment can you comment on the other who are still experiencing similar delays that may make it.

The interpretation of potentially the more difficult. Thank.

Unknown Executive: Thank you. Yeah, I don't, yeah, so to remind people there were out of the problem was the biopsy timing versus the dosing was out of the 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 mcg per kg cohort that we'll be reviewing in the second. Yeah, that is correct. We have not had COVID has not forced important out-of-window biopsies.

Thank you.

I don't Yeah could you remind people there were out of the problem was the biopsy timing versus the dosing.

It was out of window because of a delay of that resulted from the pandemic itself.

The Doctor O'neil, you can confirm but I don't believe that will be an issue for the 30 Meg per kg cohort that we'll be reviewing in the second quarter.

Yes that is correct, we have the south how COVID-19 has not force them.

Important cash window of biopsy.

Unknown Executive: One thing I should comment on, I made an error earlier and I apologize, I'm going to correct myself. The kids roll off of the ESSENCE study, and I believe it's two years, so they won't, it won't be, the study will read out, but kids will be rolling off the study, so it's, I believe two years of blinded grad, if I'm not mistaken, not 144 weeks Apologies for that error. Thank you. Our next question comes from the line of Joseph Schwartz from SVV Larynx.

Yes.

One thing I should comment on I've I've made in the air earlier, and I apologize I'm going to correct myself the kids roll off of the asking the study and I believe it's two years, so they won't it won't be.

On the study will readout of the kids are kids will be rolling off the studies. So its I believe two years of blinded that of I'm not mistaken marriage of about 100 portfolios.

For the programs.

All of these from that that are on my phone.

Yeah.

Thank you. Our next question comes from the line of Joseph Schwartz from SBB Leerink. Your line is now open.

Unknown Executive: Your line is now open. Hi, thanks. This is Kelly Gerskis on behalf of Joe Schwartz. Maybe just one more on the PPMOs. You touched on this, but we're hoping you could expand on the regulatory path you envisioned for 5051 and the other PMOs waiting in the wings. Might there be a creative way to do a single trial with multiple PPMOs in the future? Thanks. Yeah, so first, a couple thoughts on that. The big issue with the PPMO is finding the right doves.

Hi. Thanks. This is kind of curious this on for Joe Schwartz on maybe just one more on the P. P M on it.

Touched on that's what we're hoping you can expand on the regulatory path do you envision Burger.

On the other P&L of is leading in the range might there be accretive way to do a single trial with multiple P b and those in the future.

Yeah. So first a couple of thoughts on that but the big the big issue with the P. P. M O. It's 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 of we're going to use of the PMO or a P. P. M. O. So one of the things that's exciting about.

Unknown Executive: 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. Now, we can do that for 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 where 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.

This RNA platform that we have is that we can precisely build constructs that are that are very predictable and their ability to reduce the 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.

The likely to lead the clinical benefit and therefore, we have the ability to use the accelerated approval pathway that is the pathway with the we've been able to officially use for exon. This way on this and now I'm on this so it's you know, it's our belief that regardless of whether it's the PMO or a P. P. M on the so long as we can induce the.

A substantial amounts of dystrophin that are reasonably likely to lead the clinical benefit we will be able to use the sufficient accelerated the pathway to reliably bring contracts forward now that we can do that up to about 50.

Unknown Executive: Then 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.

50, 55% or so of the D. M D patient so a significant number of additional patient populations. Then we have about 30% or so of patients with very rare of exxon's, where the we would still use the accelerated approval pathway, but our goal is to a buildup of sufficient amount I think were getting there the submission.

Unknown Executive: So a lot of potential opportunity, whether it's PMO or PPMO, to do a lot of good for patients. That is, of course, our Thank you. Our next question comes from the line of Hartaj Singh from Oppenheimer. Your line is now open. Hi, this is Jackie Yan for Hartaj.

Sufficient amount of experience on both the dystrophin production and the safety of this side of things that we can do essentially a basket study where the collection of the potential mutations that can get us to that next 30% of patients that would benefit from our therapy and I think that would work similar.

Unknown Executive: Thank you for the questions. Just on the $1.7 billion potential milestones from your agreement with Roche, Roche, could you just remind us what proportion of that amount is going to be clinical milestones and what proportion is going to be, you know, commercial milestones? Thank you. I'm not sure if we've disclosed that. Ian, you can confirm, or if we have, we can disclose it again, but I don't believe we've disclosed the nuances of our milestones. Am I incorrect in that assumption?

Really whether we had a P. P M O or a PMO so a lot of potential opportunity, whether it's PMO or the P. P. M out of do a lot of good in D. M D.

That is of course our goal.

Thank you. Our next question comes from the line of Mark types of things from Oppenheimer. Your line is now open.

Hi, this is Jackie and thank.

On the question.

Just on the.

The one point of $7 billion of potential milestones from your agreements with the withdrawn.

Can you just remind us what proportion of that.

I'm gonna be clinical milestone and it will.

Propulsion.

Kind of be more commercial milestones. Thank you.

I'm not sure if we've disclosed that the yeah.

And you can confirm or if we have we have we can disclose again, but I don't believe we've disclosed the nuances of our milestones of my incorrect on that assumption and the.

Unknown Executive: That's correct, and the milestones are mostly related to regulatory and commercial milestone achievements, so they're on the back end of the development program. Thank you. At this time, I'm not showing any further questions.

That's correct and the milestones are mostly.

Related to.

The regulatory and commercial.

Milestone achievements, so they're there on the back end of life.

And the development program.

Yes.

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.

Douglas S. Ingram: 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, and 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 this year. From a commercial and serving the patient community perspective, we'll continue to serve the community with Exondus.

Oh, Thank you all very much for joining us this.

This evening. This after the end of this evening and thank you for your you're probing.

Probing and insightful questions. We obviously of a lot to do over the course of 2021 of <unk>.

Number of very important milestones across this year.

From a commercial and serving the patient community perspective, we will continue to serve the committee with exon. This will continue the launch of my on this and we're very very excited about the opportunity to launch them on this which is already occurring as I've said earlier, we will be.

Douglas S. Ingram: We will continue the launch of Vyondus, and we're very, very excited about the opportunity to launch Amondus, which is already happening. As I've said earlier, 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 30 mg per kg next quarter.

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 the sheer staying with R&D with RNA. We're very excited about the opportunity to update on the P. P. M O where the 30 megs per gig next quarter that could be a very exciting.

Douglas S. Ingram: That could be a very exciting evolution of our RNA technology, and in either regard, either PPMO or PMO, we have an enormous opportunity to do a lot of good in DMD. As I said a number of times tonight, we can serve, over time, up to 80% of the DMD community, both in the United States and, hopefully, over time, outside the United States, which is an enormous opportunity. On the gene therapy side, you know we have an enormous opportunity.

On.

The evolution of our RNA technology in either of regard either P. P. M on where PMO, we have an enormous opportunity to do a lot of good in D. M. D. As I've said, a number of times Tonight, we can serve overtime up to 80% of the DMD community both of the United States and hopefully over time ex U S, which is an enormous opportunity.

On the gene therapy side, you know, we have an enormous number of milestones and a lot of work to do this year with respect to SRP nine here of zero. One we are very focused on that as that could be a significant transformative event for patients with duchenne and.

Douglas S. Ingram: 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 Lynn Girdles and we'll continue to focus this year and I look forward to the opportunity to update everyone on milestones over the course of 2021.

The results of the study 102, when you really look at it carefully gives us increasing confidence about the potential of nine year on year, one to bring a better of longer life. The kids with D. M D and beyond that of course, we all of our limb girdles.

We'll continue to focus this year and I look forward to the opportunity to update everyone on the milestones over the course of 2021 and with that thank you have a good evening and of course, everyone stays safe.

Operator: 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.

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

Yes.

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