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

Good morning, ladies and gentlemen, and welcome to the Sarepta Therapeutics Program Update Conference Call. [Operator Instructions] As a reminder, today's program is being recorded. At this time, I'll turn the call over to Doug Ingram, President and Chief Executive Officer. Please go ahead.

Thank you, Michelle, and thanks, everyone, for joining us this morning. Next slide. Before we begin, I'll remind you to please look to our public filings for a discussion of the various risks and uncertainties that's associated with making forward-looking statements or predictions about the future. Next slide. We are very pleased to report the results from MOMENTUM Part B, the study examining the expression and safety of SRP-5051 our next-generation peptide conjugated PMO therapy for the treatment of Duchenne patients amenable to Exon 51 skipping. As you'll see SRP-5051, if successful, could be a significant advancement over the current gold standard oligonucleotide therapy for Duchenne. And with that, I will pass the call to Dr. Louise Rodino-Klapac, who will review the study results. I would also note that our Chief Medical Officer, Dr. Jake Elkins, is available as necessary for Q&A today as well. And with that, Louise?

Thank you, Doug. It's a pleasure to be here today. Next slide, please. SRP-5051 is our lead RNA-based PPMO therapy in development to treat Duchenne patients amenable to Exon 51 skipping. Duchenne is caused by a genetic mutation in the dystrophin gene. Most commonly, one or more exons or parts of the gene are missing, causing errors in the instructions for making dystrophin. Sarepta's PMO platform uses a phosphorodiamidate morpholino backbone chemistry that precisely target the specific sequence of a pre-messenger RNA that enables the translation of an internally truncated yet functional dystrophin protein. Sarepta is currently serving the Duchenne community with three approved products for one of our PMO platform. EXONDYS 51 for patients amenable to skipping exon 51, VYONDYS 53 for patients amenable to skipping exon 53 and AMONDYS 45 for patients amenable to skipping exon 45. All three of these drugs have consistently shown increased exon skipping and dystrophin production in patients. Peptide phosphorodiamidate morpholino oligomers or PPMO are Sarepta's proprietary next-generation PMO-based therapies in development and are specifically designed to increase tissue penetration. Next slide, please. To remind you, MOMENTUM is a global clinical study evaluating SRP-5051 in patients with Duchenne who are amenable to exon 51 skipping. The study evaluated dystrophin protein levels with skeletal muscle tissue at 2 dose levels, a high dose of approximately 30 mg per kg and a low dose of approximately 20. Safety and tolerability were also assessed. Part B of the study enrolled 40 new patients from the ages of 8 to 21 in the United States, Canada and the European Union. Approximately half the patients who participated in this study were ambulant and the other half were non-ambulant. Patients who were dosed in Part A and met the entrance criteria also participated in Part B. Throughout the study, we continued to administer a prophylactic magnesium supplementation and/or adjust the dose to manage hypomagnesemia. Next slide, please. In the first 4 weeks of the study, patients are monitored and receive a loading dose. We therefore experienced 24 weeks of dosing at the relevant therapeutic level. Now to the clinical results for our next-generation PPMO SRP-5051. We are quite pleased to see a significant increase in dystrophin in both treated groups. We have observed a 5.17% dystrophin production in the high dose group. This is over 12.2x more dystrophin than eteplirsen. We believe this greater production of dystrophin will also translate into improved clinical results for patients. Further, we continue to believe that we will observe accumulation of expression over time. We have observed the biggest increase in expressions from 48 weeks to 96 weeks of treatment with PMO. Next slide, please. Importantly, the data represented here shows that similar levels of expression were observed in both non-ambulatory and ambulatory patients. This reinforces that all patients with Duchenne can potentially benefit from dystrophin restorative therapy. Next slide, please. SRP-5051 administered monthly showed mean exon skipping of 11.11% at the high dose at week 28. Further, the results represent a 24.6-fold increase versus eteplirsen. Next slide, please. Now looking at immunofluorescence results. SRP-5051 demonstrated a mean of 50.68% dystrophin positive fibers or PDPF at week 28 and a 4.6-fold increase versus eteplirsen. Next slide, please. Now to the safety results. Next slide. It's important to note that mild to moderate hypomagnesemia and/or hypokalemia is very common and is generally asymptomatic or associated with only mild symptoms stable or resolved with supplementation. Hypomagnesemia, hypokalemia resolved with standard intervention and was not associated with any other clinically significant adverse events. With regards to estimated glomerular filtration rate or EGFR, the clients have been asymptomatic, nonserious and not associated with any other biomarker abnormalities of tubular injury. Several cases have resumed dosing. Cases have occurred in older non-ambulatory patients where causality is uncertain as some cases may be caused by background rate and/or other confounding factors such as concomitant medications. Post monitoring continues. Next slide, please. We are pleased to have achieved the study's primary endpoint and to demonstrate dystrophin expression at both the low and high doses and achieved 5.17% dystrophin expression at the high dose at 28 weeks. The safety profile seen in the study is consistent with the known side effect profile of 5051. Throughout MOMENTUM Part B, we continue to administer prophylactic magnesium supplementation and/or adjust the dose to manage hypomagnesemia. Importantly, no treatment-related discontinuations occurred in the study. Based on these results, we are requesting a pre-NDA meeting with FDA. We anticipate this meeting will occur in the third quarter of 2024. Sarepta's role is positively impacting the lives of individuals that Duchenne continues, ensuring patients can access meaningful treatments to manage this aggressive, debilitating disease. Next slide, please. Thank you for your attention. I'll now turn the call back over to Doug.

Thank you, Dr. Rodino-Klapac. Michelle, let's open the call for questions and answers.

[Operator Instructions]. Our first question comes from Gena Wang with Barclays.

I have two. One is regarding the efficacy part, the protein level when we compare to the Part A, at the shorter follow-up, I think at week 12, we did see like protein expression level was at 6.55%. Here, we have a longer follow-up -- update the protein level seems like a little bit lower than the Part A, so wondering what could be the reason there? And the second question is regarding the safety. It seems like there is a very high rate of the hypomagnesemia. So -- and also had some hypokalemia. So based on the current safety profile, do you think that, that will be sufficient for approval? Or will be some additional, say, dose finding studies that need to be done?

Thank you very much for your question. As in relation to the first question, I think as Louise explained to you, I won't jump on the line. The results of the study are leased in the hunt of what we saw previously and in many regards, maybe better than what we saw last time. And then -- so I'll let Louise to comment on that, and then Louise can comment on the safety profile and the positive risk benefit.

Sure. I think -- I mean, first of all, I'd just say that we're extremely pleased with the results of dystrophin expression. As we know from the literature, 5% expression has a significant improvement in the trajectory of patients. In terms of the results from Part A and Part B, I'd say Part B is entirely consistent, if not better, in terms of the fold increase that we saw in Part A in which we saw a small number of patients. This is a much larger sample size. Also, the potential to see increases over time continues as we have shown previously with PMO, we saw a large, almost threefold increase between the 48 weeks and 96 weeks. About 1/4 of the patients already are seeing about 10% expression in Part B. So just to summarize, we're thrilled with the results we're seeing. This is a large data set with dystrophin levels that are extremely beneficial to patients. In terms of safety, the hypomagnesemia is well controlled with the prophylactic supplementation, and I'll ask Dr. Elkins, if he wants to add anything regarding the monitoring and management of the hypomagnesemia.

Yes, thanks. I mean I'll just add that the monitoring is something that we're doing in the study and it's successful, and we haven't had people that need to come off the therapy. So we think that in terms of hypomagnesemia, hypokalemia, the lab abnormalities that we need to search for and address with the supplementation, but this has been adequate to control these events and allowing people to remain on the therapy.

Before you go on there, Michelle, just to really put an exclamation point on what Louise noted about dystrophin production. You should know the amount of dystrophin is important, the fold change is extraordinarily important because baseline characteristics can differ. When we look at this study versus our prior study, we saw in the prior one, it was brilliant. We saw in Part A, we got 18x exon skipping and 18-fold increase in dystrophin over eteplirsen. But in this study, we see a 24x fold increasing. I feel skipping in a 12x increase in dystrophin. And one of the things we have said is that our history shows and the evidence for -- these PMOs showed a -- the dystrophin builds over time already in this study, which was only 24 weeks essentially on actual therapy. A 1/4 of these kids were already over 10%. So we're very excited about the amount of dystrophin that's being made here. This is -- at this point, at least, really is unprecedented for oligonucleotide. Sorry, Michelle?

Our next question comes from Salveen Richter with Goldman Sachs.

Just a follow-up to the earlier point. How difficult is it to manage the hypomagnesemia in practice here? And then secondly, just speak to how you think the long strategy would play out with this drug and who the adopters might be in the context of coexistence with your other assets?

So I'll let Louise and Dr. Elkins answer the monitoring issue, and then we'll talk about where this fits in the paradigm thereafter I'll answer that. Louise?

The hypomagnesemia is very routine to monitor and to administer the prophylactic supplementation. It's become a routine part and it's very simple for the PIs and the families to manage. But Dr. Elkins if you want to add anything to that?

Yes. I mean, the prophylactic dose that we put the patients on is well tolerated. We're generally targeting one lab draw in between the monthly doses as part of the monitoring. So -- and this is something that has been very manageable for the physicians. And the thing that we really need -- that we hear from them is that increasing levels of dystrophin is very important, and this is their main goal and the monitoring regimen is something that they get used to it and that they find that this is easy to manage in the clinic.

Now on your other question, so the question, as I understand it, is essentially where will this fit in the entire paradigm of the treatment of children with Duchenne muscular dystrophy. Well, we've pondered this obviously, as you know, for a long time. There are three big pieces of information that one needs to really complete an analysis like this. The first one we're announcing today, which is what do the results look like from a next-generation peptide conjugated PMO SRP-5051. And as you've heard from Louise and others, we think it looks fabulous. We're seeing what would be a significant advancement over what is currently the gold standard for the treatment of children with exon 51 amenable Duchenne in the form of oligonucleotide. So we're really excited about that. We think that obviously the benefit risk, we think, is a positive one. We're very excited. There are two other pieces of information that we need. The next thing we're going to need, obviously, is to know what the label is going to look like for ELEVIDYS as everyone knows, it's not going to be a subject of our discussion today, but we're in the midst of a BLA supplement. With the goal of expanding hopefully, maximally the label for ELEVIDYS. And that label expansion will play a role in where SRP-5051 would fit into the larger paradigm, and of course, we're working on that. And then the other big piece of information that we need is the FDA's perspective on all of this and what is the pathway forward that would relate to timing and the like. And so we need all of those 3 pieces of information. We'll have that last piece of information in the third quarter of this year. We're going to do the entire analysis and look at exactly where SRP-5051 fits into the broader paradigm, and certainly, we would suspect before the end of this year, we'll come back and we'll chat about that. But what we have today is the first piece in many ways, probably the most important piece which is, what does this therapy look like in children with Duchenne muscular dystrophy who are exon 51 amenable. And from our perspective, we have safety profile that's manageable and monitorable and an amount of dystrophin that is in all regards, unprecedented at least as it relates to a non-gene therapy oligonucleotide. So we're very excited about where we are today.

Our next question comes from Brian Abrahams with RBC Capital Markets.

I guess how much do we know at this point about the pathophysiology of the hypomagnesemia? Is that something we have a better understanding of now that there's more data? And then I guess on a related note, can you maybe contextualize the GFR reductions, the potential relationship that had to the electrolyte changes that we're seeing and other any lab measures that you've done or can do to further tease out the degree of potential relationship that might have to 5051?

Good questions. Louise?

I'll start with addressing the pathophysiology. So we do know that there is a transient competition for absorption and reabsorption in the kidney, and that's likely from our early studies leading to the transient hypomagnesemia, both regards to the EGFR monitoring and other testing and I'll ask Dr. Elkins to address that.

Yes. Okay. So I mean, with regard to the EGFR monitoring, we do measure a number of renal biomarkers and other issues -- other urinalysis tests as part of the monitoring in the study. And we're not seeing any association of either the hypomagnesemia or EGFR changes with those biomarkers. So this is something that is seen primarily in all the patients. Some of them have start with high levels of EGFR and they come back even where the declines can still be in the normal range. So some of this may represent a regression to the mean that we see over time with the monitoring. We review with our experts, these events. And so it's something we're continuing to investigate and monitor closely in the study. But I think the important thing for now is that we're not seeing an association with them with any other markers of nephrotoxicity. They haven't been considered serious events by the investigator. They haven't been associated with any clinical symptomatology.

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

Morning, and congrats on the results. Just a quick one for me. It looks like a pretty big jump in activity from 20 milligrams to 30 milligrams. Do you find this surprising.

Louise?

Based on our nonclinical studies in our previous studies of Part A, we weren't surprised to see the difference between the 20 and 30 milligrams. It's just based on the essential the curve of dystrophin production based on the tissue concentration of the PPMO.

One of the things that is exciting. And I do agree with you, Gil. It's you really get a significant step-up with the 30 milligrams. But what is great is that at the lower dose, you're still seeing a significant improvement over the current gold standard. You're still seeing a 4.3x greater dystrophin production and almost 5x greater exon skipping. So all things being equal, we would have been pleased with the low dose. We're very excited about what we see when we move to what is approximately 30 milligrams per kilogram.

Our next question comes from Colin Bristow with UBS.

Congrats on the data. I was wondering if you could talk about the timing of the hypomagnesemia and hyperkalemia relative to the dosing and then within the patients, did you see these electrolyte changes moderate over time? And just in relation to this, can you remind me what was the frequency of EKG monitoring and whether you observed any EKG changes related to these electrolyte disturbances?

Louise?

Dr. Elkins, would you like to address that in terms of the timing of the hypomagnesemia?

Yes I mean, in general, what we see is that when people first start out on the treatment, there's more adjustment of the prophylactic regimen to keep the electrolytes within tolerable ranges. This is -- and over time, this looks to be successful, right? So we do think that over time that the monitoring, the frequency is going to be something that would become less frequent. We don't see any -- we haven't associated these events to EKG changes. There's no regular EKG monitoring that's required when there is an electrolyte abnormality [indiscernible] as managing according to standard of care -- with the standard of care repletion and the patients respond quickly to that. So yes, they haven't been associated with clinical ramps, and it's something that we think -- the main thing is finding that initial adjustment and getting people on the right prophylactic dose of magnesium in order to manage them over time.

Our next question comes from Ritu Baral with TD Cowen.

Doug, I'm going to ask you the same question I asked you in January. Just given ELEVIDYS path forward and potential label expansion, including potential full approval, where do you think that probability stands that these exon skippers still have an accelerated path forward on dystrophin expression. How will it -- how could it work? You have no clarity right now, but how could it work given ambulatory versus non-ambulatory and FDA's understanding of unmet medical need in the event of a full approval for some population in ELEVIDYS?

Yes. Well, I think there's maybe two subtle questions in there. Let me make sure. One possible question is just is the accelerated approval pathway more or less likely in the face of an ELEVIDYS. I really don't on the face of -- I see a difference there. I think this will, as it stand on its own. And the second question is, where does it fit into the broader paradigm. We have said for a long time, two things that are at tension with one another. One thing is that there will be cannibalization of the PMO over time to the extent there is success with ELEVIDYS, one could expect that. We've also said that we truly believe there is an opportunity for both of these modalities to exist and benefit patients. I think that -- well, to your point, I don't have yet clarity and we'll have more clarity this year. The probability of that, I think, increases with great results. And again, to editorialize a bit, I think these are great results. I think if this was equivocal then you might say, there isn't a path for the next-generation PMO, peptide-conjugated PMO in the face of ELEVIDYS, but at least this is a really fantastic results. Just to characterize this, remember, if you go back to the Amthor paper, which is kind of the current paper that really describes what it means for different levels of dystrophin. 5% is a bellwether amount of dystrophin that really correlates with a significant change in life expectancy, ambulatory status and the like. So that's exciting. But with all of that said, we have to do two more things. We have to see what the label for ELEVIDYS will look like. If, for instance, we didn't get the entire population or we had some other approval for the non-ambulatory population that may impact this opportunity. We have to see what the FDA says about all of this and what the pathway forward for this looks like, and that will reflect not only the amount of effort that goes into it, but the probability of success, the timing of it, that will play into this. And then we'll take all of that information plus the information that we're disclosing today. We'll do that analytic and determine where 5051 fits into the paradigm for the treatment of Duchenne patients. And we'll come back, and we'll have a discussion about that in the back half of this year.

Our next question comes from Danielle Brill with Raymond James.

Quick clarification for me. I wanted to know how many patients required dose interruptions in the trial and if any were dosed per protocol at 30 mg per kg every 4 weeks.

Louise?

I guess the second part of your question was about how many patients were in the 30 mg per kg was that the questions, I believe. So it's about half of the patients. Jake, do you want to take the first part of the question about any potential dose interruptions?

Yes. I mean in general, we've been successful in managing the patients with either a transient dose reduction or and sometimes missing one dose before starting on the treatment. This is relatively and frequent study. It's approximately 10% that maybe have -- go through this regimen of temporary reduction or missing a single monthly dose. But then as we've described, these patients are then successful at reescalating and getting back on the regular regimen of dosing. So again, it's something that we monitor, especially as we're getting people on their initial prophylaxis, and that seems to be stable and we're successful keeping the point of regimen over time.

And just one thing to quickly add because I think in the question, it sounded like the question was really around did patients stay on the 30 mg per kg dose. And obviously, if you look at the data and see the differential between the expression, between the 20 and the 30 , it's very clear that the vast majority of patients on the 30 -- remained on the 30.