Sarepta Therapeutics, Inc. (SRPT) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Sarepta Therapeutics Update Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Douglas Ingram, President and CEO.

Thank you, Josh. Good afternoon, everyone, and thank you for joining Sarepta Therapeutics call to review the top line results for EMBARK. Our double-blind, placebo-controlled study intended to confirm the benefits of ELEVIDYS in children with Duchenne. Next slide, please. We will very likely make some predictions about the future or other forward-looking statements this evening. I would ask you to please review our public filings for the various risks and uncertainties that come with those sort of forward-looking statements. Next slide. In a moment, Dr. Rodino-Klapac will review the results and our path forward. But let me summarize at least our perspective on them now. Our perspective is that the EMBARK results have met the standard for substantial evidence of effectiveness confirming the mechanism of action of ELEVIDYS and showing that it alters the course of disease in Duchenne patients. The evidence is also clear that ELEVIDYS benefits Duchenne patients across the AGES studies. And there are no new safety signals that have emerged confirming the laudable profile upon which ELEVIDYS was approved in June. Importantly, we have already shared the top line EMBARK results with FDA leadership and have had encouraging early discussions with them. And on that basis, we are pursuing an application to expand the label of ELEVIDYS and they have confirmed they are open to evaluating an application to expand the label. Our goal is to expand the label to cover all amenable Duchenne patients without regard to age or ambulatory status. FDA leadership has also confirmed their goal of moving swiftly to review this new data and conclude its review on the label expansion. Hence, we will be moving rapidly to make a formal submission even as the FDA already has our top line to commence its evaluation now. And with that, let me turn the call to Dr. Rodino-Klapac, who will lead us through the top line down, Louise?

Thank you, Doug. I'm very pleased to share the results of our PMR study EMBARK. The data strongly supports the conclusion that ELEVIDYS demonstrates the treatment benefit that is clinically meaningful and similar regardless of age. Next slide, please. I'd like to briefly remind you of the EMBARK study design. Next slide. EMBARK is a Phase III double-blind randomized controlled trial with 1:1 randomization with 125 patients enrolled. Crossover occurs at 52 weeks, maintaining the blind to both the study teams and the patients. Biopsies are at 12 weeks at a subset of patients for an end of 31 of the 125 enrolled. The primary endpoint is change in NSAA from baseline to week 52. Key secondary endpoints are SRP-9001 dystrophin protein expression, time to rise and 10-meter walk run. The other secondary endpoints were also time performance test. The SV95C, which is measured using a wearable device, the 100-meter walk test and the ascending 4 stairs test. There were no dropouts to the study. Next slide, please. This slide demonstrates that this treated and placebo group demographics were very well matched at baseline. Next slide, please. Similarly, on this slide, treated and placebo group functional abilities were well matched at baseline. As you will recall, our stratification factors for this study were age and baseline NSAA and you can see the groups were well balanced at baseline. Next slide, please. I will now review the EMBARK top line results. Next slide, please. While it's not on the slide, I'd like to note that as expected, ELEVIDYS protein expression was highly significant [ a key ] is less than 0.0001, as the first key secondary endpoint. We look forward to presenting the full data set at a future medical meeting. Today, I will focus on the functional endpoints. And so first, I'm showing you this for slide and to allow you to digest it for just 1 minute. I'm sure you can see the compelling data that we see. All endpoints favor ELEVIDYS. We acknowledge that the primary endpoint of NSAA at 52 weeks did not reach statistical significance, although it favored ELEVIDYS, and I'll discuss this in more detail. However, there was a robust and clinically meaningful treatment benefit demonstrated across the secondary endpoints of physical function. All 3 key secondary endpoints strongly reached the systolic significance in all times secondary endpoints favored ELEVIDYS. The consistency demonstrated across these objective measures is strongly supportive of the treatment effect that it was simply not detected by the NSAA score at this 52-week time point. Next slide, please. Now let's look at the 4 spots broken out by age subgroup. The mechanism of action and totality of evidence supports the treatment effect that is independent of age across the breadth of the secondary endpoint. Even though we did not power the age subgroups, they were strongly significant for the key secondaries for each subgroup. In addition, there is consistency across all the secondary outcomes. We note the inconsistency in NSAA results for the 6 to 7 year olds, which was not present in the performance on the time function test. Next slide, please. Now I will show you each of the key secondary measures individually, starting with time to rise. On this slide, we see the time to rise by visit where the values or lease square means plus or minus standard error. The treated groups in purple demonstrate stability or improvement in their time to rise. In contrast, placebo patients in gold demonstrate increasing time to perform this skill in both age groups. We see significance in not only the overall population with P to 0.0025 but also in each of the age subgroups. Next slide, please. Now for the 10-meter walk run. Similar to the previous slide, the treated patients in purple demonstrate stability or improvement in performance. While the placebo patients in gold demonstrate more modest improvement or worsening in their function. Again, both the overall population and age subgroups are significant. Next slide, please. Here, we see the NSAA by visit with increasing scores indicating improved performance. As expected, ELEVIDYS treaty groups were stable or improved. However, despite the decline in performance evident on the time function test, the placebo group in gold showed stable to improved NSAA scores. This incongruity is particularly evident in the 6- to 7-year-olds and suggests the NSAA scores are masking meaningful decline as the time tests are able to detect. Thus, we were unable to detect a significant difference of 52 weeks. We expect we would detect a difference over a longer time period. Next slide, please. I'll now talk about the safety profile. Next slide. Regarding safety, Importantly, no new safety signals were identified with a profile consistent with our previous studies. Benefit risk is favorable and strengthened by this additional data from EMBARK. Next slide, now I'd like to discuss the clinical significance of these results. Next slide. Time tests are responsive to disease change and time derive was intentionally selected as the first functional key secondary endpoint. The time function tests are lost sequentially as DMD progresses. We know both from the existing literature and an analysis of our own clinical data preceding 301 that lengthening time to rise is the earliest sign of disease progression and the clearest marker of decline in the 4- to 7-year-old population. Lengthening time to rise is classically followed by increasing times in the 4-step climb and then the 10-meter walk run. The selection of time to rise and 10-meter walk run are key secondary endpoints in the 301 trial reflects the responsiveness to disease change in this population as demonstrated by natural history data. Time to rise, 4-step climb, 10-meter walk run and 100-meter run are all accepted registrational endpoints of global regulators and our primary outcomes in a number of contemporary DMD trials. Next slide. I'd like to take a minute to pause here. This slide is important to understand, as I will describe. The strong prognostic power of time to rise and the particular importance of the 5 second milestone is clearly demonstrated in its recently published natural history study drawn largely from the U.K. North Star Network. Here, patients are grouped by their baseline time to rise and then followed over time until they lose ambulation. Patients with a time to rise of greater than 5 seconds at baseline are seen to have a subsequently aggressive disease trajectory with early loss of ambulation. A rise time of less than 5 seconds was an inclusion criteria in our trial. We made this decision based on observations from our 9001-102 study, where a number of patients with a baseline of greater than 5 seconds deteriorated rapidly on the NSAA irrespective of treatment. While we still believe patients can gain benefit from treatment, we concluded that their exclusion would create a more homogeneous population for investigation over 1 year. Next slide, please. Understanding that all patients in EMBARK started with a time to rise of under 5 seconds, we looked at the impact of ELEVIDYS treatment on preventing progress to this important disease milestone. As you can see from this table, treatment with ELEVIDYS reduced the odds of progressing to a rise time of greater than 5 seconds by 91%, a hugely clinically meaningful treatment effect, driven, as you might expect, by the population were likely to decline to 6- to 7- year olds. Next slide, please. I'll next talk about our path forward and summarize. Next slide. As we have communicated, we are moving with urgency to provide these results to FDA as a BLA supplement to seek label expansion. We have provided this top line summary of the results to FDA and have engaged in productive and encouraging conversations with CBER on the data. In terms of next steps, we plan to submit an efficacy supplement to CBER as soon as possible, seeking label expansion to treat all DMD patients, and we'll submit a post-marketing requirement or PMR seeking transition from accelerated approval to traditional approval. Next slide. To summarize, the data from EMBARK exceeded thresholds for substantial evidence of effectiveness and the risk benefit of ELEVIDYS remains favorable. We are pleased with the consistency, the magnitude of response and the clinical meaningfulness of the results for EMBARK and from the body of evidence supporting ELEVIDYS. The data show ELEVIDYS is a disease-modifying therapy. And therefore, we believe all patients condition can benefit from treatment with ELEVIDYS. Following positive discussions with FDA leadership, they are committed to evaluating a labeling expansion to the full extent possible based on a review of the data and will do so rapidly. I will now turn the call back over to Doug to open up for Q&A.

Well, thank you very much, Dr. Rodino-Klapac. Before I open up the call for Q&A, I would remind everyone that we have an earnings call on Wednesday, and we'll talk about quarterly performance and any other issues there. So with respect, it would be great if people would limit their questions to this data and the EMBARK readout in our path forward. And with that, Josh, let's open up the call for questions.

[Operator Instructions] Our first question comes from Brian Abrahams with RBC Capital Markets.

I guess, first, I'm wondering if you saw any predictors of a better or worse response here. I noticed that in the baseline characteristics, you had more patients with large genetic mutations in the ELEVIDYS arm and then secondarily, can you talk about the biopsy results here relative to the prior studies? Did the biopsy data here support the potential for dystrophin expression to predict function across all age ranges. And to what degree has the FDA indicated that this would be important for confirmatory evidence to support full approval?

Great. I'm going to turn both of these questions over to Louise, but just to remember, Brian, the biopsy results we have right now are a small subset in EMBARK given that we did only a small sampling. We have to get the Part 2 as well. But as Louise said, not only were they strongly statistically significant and very robust, they're in the range of what we've seen previously. So it's all very consistent. But with that, Louise, perhaps she can answer both of those 2 questions better than I could.

Sure. Just starting the first question about any predictors, looking at mutations. So far, just looking at the baseline characteristics, they're well matched. We didn't see any things like mutation leading to prediction of the responses that we saw. With that said, the team is continuing to work on the data. This is the top line data and the team is continuing to do analysis. But I think so far, the data was very clear, and we were very pleased with the execution of the study and how well matched the 2 arms were at baseline. With regards to expression, as Doug mentioned, this was a subset of the biopsies. The expression data was consistent with what we've seen. Global regulators do not want us to biopsy every single patient. And so there was a subset in Part 1 as well as the subset in Part 2, and we will share this data at a future medical meeting along with the entire data set for the study.

One final thing to note is the lack of something you asked about any better or worse. Remember the significant open question in EMBARK was whether this therapy would work better for instance, in the 4 to 5 than in older patients, in this case, the 6 to 7s. And what we were very pleased with is that consistent with prior data and our hypothesis, there was no difference. And in fact, while we have not powered the key secondary endpoints for statistical significance in the subgroup analysis by age. As Dr. Rodino-Klapac noted in her presentation, we saw them strong statistically significant in both of the age groups in both of the key secondaries and almost identical in their statistical significance and in the clinical meaningfulness of both of those results. So it's very, very comforting that this therapy is working well across the ages and as one would expect it will, from our perspective, work across all of the agents into non-ambulatory as well.

Our next question comes from Tazeen Ahmad with Bank of America.

Doug, is there any way you can provide any color about the specifics of the conversation you had with FDA as it relates to the 4- to 5-year olds. Is the topic of whether the data that you've collected thus far to meet the criteria at least for the 4- to 5-year old to have permanent approval for the market? And then secondly, I just wanted to ask you, what in that conversation did you find encouraging to give you the view that a broad label here is something that the FDA is seriously going to consider?

Yes, thank you very much for your questions, Tazeen. I'm going to answer these very broadly, of course. First of all, the meetings we had was with, as we've said, senior representatives for the FDA, including but not limited to the Center Director, Dr. Peter Marks. We were not discussing whether we need the standards of the 4s and 5 staying on. I think that is an obvious win on that issue. And what we were really discussing was looking at the totality of this evidence, the ability to expand this label and from our perspective to expand it by removing artificial age limitations and removing the artificial restriction to ambulation as we don't think that's consistent with the mechanism of action or the data. And I would broadly say without going into a lot of detail, I would say everything about that meeting was encouraging. It was a very productive, very positive meeting. I want to be very clear. We still have a submission to have and a review to go through, but I was very encouraged by the discussions with the agency. They were very clear that they are very committed to moving rapidly, and they were very clear that they are very open to reviewing this application to look to expand the label, of course, supported by a full review. So it was a very, very encouraging meeting.

Our next question comes from Gena Wang with Barclays.

I'll just follow Tazeen's questions. How soon will the FD get back to you regarding the next step? And also, what was the FDA's feedback regarding, if we look at the Slide 14, you do have at the North Star, we do see 6, 2 years to 7 years old, the p-value is 0.9378. Any comments on that, I think everything else looks like very consistent only this one, we saw not much expiration there. And then also, what is the FDA comments on 2-year studies? Is there any way you can conduct 2-year study to prove the longer follow-up, you can see the North Star further separation?

There's a lot in there to unpack, Gena. So first of all, to be clear, there was no discussion about additional studies necessary nor do we envision that there would be the need. Again, without assuming in advance that they fully accept the exact analysis, I think everyone is tracking to the analysis of this data, so I'm going backwards in your questioning. And what that means is look very good. I'm glad you raised that. If you look at the 6- to 7-year-olds, you don't see separation between the treated children and the untreated children as it relates to NSAA. Then interestingly enough, if you look at the time to rise, the much more objective it turns out with the benefit of hindsight time test or you look at the 10-meter walk run, again, a very objective time test, you see that in the 6- to 7-year-olds, the treated kids are stable, which remember, is that long-term therapeutic goal here. In fact, that is a massive win. When you look at the secondary end points, what you see is that the untreated kids are unfortunately becoming much slower, both on time to rise and on the 10-meter walk run. And I would also notice that the same answer for the 4-step time. It's the same answer for the wearable as well, the SB-95. And I say, well, what's inconsistent about it. What's inconsistent is that we're not guessing. We're not looking at other data. We know that those untreated children are degenerating. We see it. We see it in time tests. We see that time to rise. We see it in the 10-meter walk run, we see in the 4-step time. We see it on the wearable but you don't see it on NSAA. And the reason for that with the benefit of hindsight is pretty obvious. It's not that somehow they're magically not degenerating in one measure versus another. It's that in a 52-week period in this population, NSAA is too course an insensitive a tool to detect the decline in the untreated kids that you see everywhere else. And I think when you look at the data together, it becomes really clear that, that is the case. Not to suggest that NSAA in the long run wouldn't show it. It just doesn't show it in this population in 52 weeks. And then on the timing of things, the short answer is they already have the top line data, and they are committed to moving as fast as possible. We are working on the formal submission part of this. It is my impression that they intend to begin to review the data even in advance of that submission. So we are very committed to moving as fast as possible. And I believe that our regulators are equally committing to moving as rapidly as possible, and that's extraordinarily important for patients. I would remind you, as Dr. Rodino-Klapac mentioned, when we look at time to rise, the single most predictive metric for early loss of ambulation is a child going over 5 seconds on time to rise. And in EMBARK, this therapy reduced the odds of that occurring by over 90%. So it is compelling that we need to move as fast as possible. This therapy was approved in June. By the end of this year, 200 kids who have lost ambulation that are not treated with ELEVIDYS. So we need to move as fast as possible. I am quite confident that our colleagues at the FDA are equally committed to rapidly reviewing this file and looking to, if they agree that the data supports it broadening this label and removing unnecessary restrictions in kids getting it.

Our next question comes from Gil Blum with Needham & Company.

So, maybe just on TTR in 10-minute to 10-MWR. Was any of this discussed in the earlier filing to the agency? And I want to give you confidence that the FDA will maybe reevaluate the tools for assessment here? I mean NSAA seems further established.

NSAA is an established metric as is time to rise as this 10-meter walk run, those other secondary endpoints have been used as primary endpoints in other studies. In fact, [indiscernible] is quite clear that particularly time to rise over 5 seconds is the single most important prognostic tool for determining if the kid will have an early loss of ambulation. And generally, what gives us confidence that we're confident because of 2 things. One, we're confident because of the comprehensive evidence in front of us; and two, we have confidence based on the fact that we've had very positive and encouraging interactions so far with FDA leadership.

Our next question comes from Ritu Baral with TD Cowen.

Doug, you mentioned something about the nature of the NSAA data in the older patients masking the benefits seen and the time to rise and the 10-meter walk. Looking at the 17 components of the NSAA, I'm sure you and Louise have looked at some of this aspect, like what in particular about some of these movements may be more difficult for the older boys independent of dystrophin and muscle function?

I'm going to let Louise' comment on this, I apologize, at least I'm going to comment first and we're probably going to do a better job of it for me. But just so we're very clear, for instance, rise from floor exist in NSAA. It's just simply as one can see from the data that in this 52-week period in the untreated group, the NSAA, while it will work in the long run, in this population in 52 weeks is to course to see, for instance, decline in the untreated group. As an example, if you look at a subset of kids that are one on the NSAA, remember, there's 0, 1 and 2. So 0 means you can't do it. 2 means you can do it flawlessly, 1 means you do it with some modifications. If you look at the kids that are in 1s, started at 1 and ended in 1s and then you looked at across treated and untreated group, you would see that the untreated group significantly declined versus the treated group, and yet they're both getting ones. Why is that? Is that a failure of NSAA, in a sense, it's not a failure of NSAA, but it is a failure of the tool in 52 weeks in this population. But Louise, you can do a better job than I'll do on the question.

Actually you took my answer. I think just to make the point that the NSAA, given that it's 0, 1 and 2, we just don't have the sensitivity in those time points like a 1 [indiscernible] for an example, with time to rise from floor doesn't show you the full breadth of the differences that we're seeing between the treated and placebo. But really is just the 52-week time point and this measure over that period, which is much more sensitive in the time test.

Have you either in the recent interactions or prior interactions had specific conversations with FDA on the 2-year time point from EMBARK, it's something that KOLs have mentioned repeatedly well before the data revenue?

To the best of my knowledge, the discussions that we had on these topics occurred after EMBARK. Am I correct on that, Louise?

Correct. We did not talk about the 2-year time frame proactively.

And if someone along the way asked a question about sort of looking at 2 years. It's just so we're very clear, the requirement of a study like EMBARK was that it must be placebo-controlled and blinded. It is nearly impossible consistent with good biomedical ethics to run a placebo-controlled trial for 2 years. We have actually done it in essence, but it is enormously difficult. It is challenged from an ethics perspective, and it wouldn't have been acceptable here. So we're very clear, 52 weeks for a blinded placebo-controlled trial is just about as long as one can do and get through IRBs and frankly, satisfy yourself that you're being ethical.

Our next question comes from Brian Skorney with Baird.

I guess as we think about through the FDA, do you think that they are going to call another AdCom to discuss any labeling changes here? And then on the statement around the secondary being statistically significant, I thought under the SAP, we would need to hit on the primary endpoint to evaluate secondaries for statistical significance. So is there something about the protocol that allows for a statistical evaluation of the secondary without adding on the primary as opposed to just a valuation for a nominal significance?

Yes, you can put the word nominal in front of it when you're a hierarchical analysis. But the fact is that we did hit p-value of 0.002. and 0.004 in both of the pre-specified key secondary functional endpoints. And then among all of our endpoints, every single secondary endpoint, favored ELEVIDYS and nearly all of them strongly hit statistical significance if we get statistical significance and time to rise. We had statistical significant in 10-meter walk and we hit statistical significance on the fore stair climb. We hit statistical significance on the wearable. And if you look at our key pre-specified endpoints, we're more powered to see stats segue in the subgroups of age, but we did. And we saw interestingly stats segue was almost identical between both of those groups and strongly shows. So we feel very good about the data. On the advisory committee, our perspective right now is there is no need for an advisory committee. And certainly, in our early conversations, there's been no discussions on that.

Our next question comes from Salveen Richter with Goldman Sachs.

Thanks for taking my questions. I just wanted to go back to 2 points that were raised earlier. So with regard to the FDA and the totality of benefit that they want to see, how much was there a discussion around the timed endpoints versus NSAA variability and the focus on the primary versus the inclusion of these secondaries? Just help us understand how they're going to think about this. And then the second point is you mentioned the confirmatory data that you just saw for the 4- to 5-year-olds. Is that enough to keep the drug on the market for this age group? I'm just trying to understand the discussion around what needed to be seen for that group?

Sure. Let me go to the first one first. So the discussion with the FDA largely mirrored the discussion that we've had today. So there, of course, was an enormous amount of discussion about the time test, the objective time tests, the statistical significance around them, the clinical meaningfulness of them. And the reason that the NSAA did not show statistical significance, which is related to the fact that the 6- to 7-year-olds didn't show the decline that they were, in fact, having. So it was all of those discussions together. And as we said, we had a very positive meeting with them on those topics. And then from our perspective on the level of evidence to justify confirming for the 4 to 5, the answer to your question is, is that enough? The answer is yes.

Our next question comes from Uy Ear with Mizuho.

I was wondering, first, just a clarification question. Did you say that the p-value for the secondary endpoints, they're nominal. Is that correct? And secondly, just wondering what your thoughts are with respect to payers? Like how would they look at this particular set of data, given that the primary endpoint did not hit statistical significance?

Yes. Thank you for your question. I'll answer the second question, and I'll turn the first question over to Louise. On payers, look, this team has a very good track record of working productively with payers. We have 4 approved therapies right now, and we've done very well, serving the community. So I'm confident, generally in our team's ability to work with payers, I'm specifically confident over the strength of this data. I think that this is about as good at that as we've ever seen in a therapy such as this. And as I've said before, it bears repeating, the literature is quite clear that there are 4 big prognostic indicators of early loss of ambulation, the most prognostic is time to rise in going over 5 seconds and then 10-meter walk run and then the 4-step climb. The fourth is the 6-minute walk test, the 6-minute walk test wasn't performed in this study. As it relates to all 3 of those, we strongly hit statistical significance, creating a very compelling point that this is very clinically meaningful and will change the course of this disease and keep these kids out of a wheelchair. And as we've mentioned before, on time to rise, the most prognostic being over 5 seconds, those kids on ELEVIDYS reduce their odds of an early loss of angulation by over 90%. So we will have, I believe, a very good discussion with payers once we've expanded this label. And with that, Louise, you can leave it to comment on the p. value again.

Sure. Yes, technically, when the primary is not met, then the secondaries used the word novel before it that does not negate the data in any way, and that's certainly not something that was brought up in our discussions with the FDA, who are very encouraged by the data specifically on these objective measures of time tests that was very encouraging and they're encouraged by the data.