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

Good afternoon, ladies gentlemen, and welcome to the Sarepta Therapeutics SRP-5051 Program Update Conference Call. [Operator Instructions] 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, Victor, and thank you all for joining us today as we discuss the clinical hold. In the United States, we're screening and dosing in MOMENTUM, our trial for SRP-5051, our PPMO candidate to treat Duchenne patients amenable to exon 51 skipping. Let me remind you that we may be making some forward-looking statements today. As we do those, please refer to our public filings for the various risks and uncertainties that come whenever one attempts to make predictions about the future. Now let me make a few points in advance of Dr. Rodino-Klapac providing real detail on this. First, as you've seen, after a serious adverse event of hypomagnesemia in the trial, the FDA is requesting information on all cases of hypomagnesemia, including a handful of nonserious grade 2 cases to assess the adequacy of the risk mitigation and safety monitoring program that we have. Our first priority, as you can well imagine, is patient safety and well-being. So we are going to work very diligently, and we intend to rapidly respond to the FDA's request for additional information. We are confident that we can provide clarifying information to satisfy the FDA's request in the next few days and to resume dosing in the U.S. very expeditiously. The study remains ongoing outside of the United States, and we remain on track to complete dosing in the second half of this year as previously guided. And with that, let me turn the call over to our Head of Research and Development and our Chief Scientific Officer, Dr. Louise Rodino-Klapac. Louise?

Thank you, Doug. Good afternoon. Today, we announced that the U.S. Food and Drug Administration has placed a clinical hold on SRP-5051, vesleteplirsen, our next-generation peptide-conjugated phosphorodiamidate morpholino oligomer or PPMO to treat patients with Duchenne muscular dystrophy who are amenable to exon 51 skipping. The hold in Part B of Study 5051-201, also known as MOMENTUM, follows a serious adverse event of hypomagnesemia. FDA is requesting information on all cases of hypomagnesemia, including a small number of nonserious grade 2 cases, to assess the adequacy of risk mitigation and safety monitoring plan. I'll take you through the events and how we plan on addressing this. Recall, MOMENTUM is a Phase II multi-arm ascending dose study of SRP-5051, infused monthly and will assess dystrophin protein levels in skeletal muscle tissue following SRP-5051 treatment. This study is designed to enroll up to 60 participants, both ambulant and nonambulant between the ages of 7 to 21 at sites in the U.S., Canada and the European Union to assess safety and tolerability. We have enrolled approximately 50% of the trial to date. The hypomagnesemia was identified through lab tests conducted as part of the monitoring outlined in the protocol of the MOMENTUM study and is similar to previous observed cases of hypomagnesemia in clinical trials of SRP-5051. The protocol for Part B of MOMENTUM includes prophylactic magnesium supplementation and monitoring of magnesium levels. Magnesium levels improved or return to normal following additional supplementation. We believe that the SRP-5051 may transiently interfere with magnesium reabsorption by the kidney. Importantly, we have not seen worsening of the hypomagnesemia over time or evidence of acute or chronic renal damage or evidence of persistent renal tubular injury associated with the hypomagnesemia. Furthermore, the cases of hypomagnesemia has improved or resolved while patients remain on treatment and do not appear to worsen over time. The SAE occurred in 1 patient 8 days after randomization to a high dose. He presented with grade 3 hypomagnesemia, along with grade 4 hypokalemia or low potassium and experienced mild to moderate tingling of extremities and muscular cramp. Without the need for hospitalization, he was given an IV bolus of magnesium and discharged on increased oral magnesium and potassium. Since it's resolved in 3 days and his magnesium levels have returned to normal, there was no evidence of complication suggested of renal tubular injury, renal insufficiency or changes in ECG. There's additional cases of grade 2 hypomagnesemia that were mostly mild and asymptomatic and resolved with increased oral magnesium. Our hypomagnesemia monitoring and management plan has effectively decreased the number of significant hypomagnesemia cases compared to our experience in previous studies. As a reminder, we observed that 20% of patients had grade 3 or 4 hypomagnesemia in Study 5051-102 in MOMENTUM Part A. Whereas in momentum Part B, we had a single grade 3 case and no grade 4 cases, which represents less than 5% of treated patients. The hypomagnesemia observed in SRP-5051 is dose-dependent. In order to further manage this, the Safety Review Committee has proposed modifications to the criteria for dose escalation. If the patient experiences grade 2 hypomagnesemia, they will be randomized to the low-dose arm. Both the low dose and high dose are predicted to be therapeutic based on the results from MOMENTUM Part A. While we take any adverse event seriously, we remain confident in the benefit/risk profile for SRP-5051. The results from Part A of the MOMENTUM study found that after 12 weeks, 30 mg per kg of SRP-5051 dosed monthly resulted in 18x the exon skipping and 8x the dystrophin production as eteplirsen which was dosed weekly for 24 weeks. The Safety Review Committee voted to continue dosing, concluding that the risk/benefit profile is unchanged and remains acceptable in the context of this devastating disease. The risk of hypomagnesemia, continues to be monitorable and manageable. There is no evidence of acute kidney injury, and we continue to undertake and enhance our early detection and prevention strategies. The study is ongoing. Globally, we have enrolled approximately half of the planned patients to Part B of MOMENTUM. And we remain on track to complete enrollment by the end of the year. We look forward to responding to the FDA's request in the next few days and working with the agency to recommence screening and dosing for MOMENTUM Part B in the U.S. as soon as possible. I'll now turn the call back to Doug for a brief Q&A. Thank you.

Thanks, Louise. Victor, let's open the call for questions and answers.

[Operator Instructions] Our first question will come from the line of Brian Abrahams from RBC Capital Markets.

Can you talk about the, I guess, the type of management and preventative plan you might expect in kind of a real-world setting commercially as you sort of think about how to put patients on the right doses? Any risk factors there? And then I guess just as a corollary to that, just wondering how to think about the overall kind of trial integrity if patients do end up missing doses, how to manage through that if most of these patients are being enrolled in the U.S. or outside the U.S. at this point?

Sure. Louise, do you want to take that?

Sure. As far as the real-world setting that will certainly be informed after the experience from our trial. Patients are on a daily supplement of magnesium and work with the investigators. Increases need to be made, we'll certainly take that into account and that will advise our management in the real-world setting if that occurs. As far as the second part of the question, could you repeat the second question?

Just trial integrity, if this takes -- it takes a little bit of time to work through this process with the FDA, what does it mean in terms of patients missing doses and overall trial conduct data interpretability?

We're currently enrolling outside of the U.S., and those patients are going through the protocol as planned. Certainly, in terms of the primary endpoint for the study being expression, we've enrolled over half of the study, and we don't need a large number of patients to meet that primary endpoint in terms of expression. So certainly, these patients that have to be paused dosing in the U.S. would not be included in that analysis, but we're working diligently to resolve this with the FDA very quickly.

Our next question will come from the line of Gena Wang from Barclays.

So maybe if you can walk us through in detail what is the current risk mitigation? And what additional you could do for the next step? And how long does that take you think that, that will resolve this issue?

Okay. We're going to hand it over to Louise. Just 2 things. Remember, the 2 things to consider is the -- whether this is monitorable and then is it manageable. On the monitoring side, I think we've shown quite directly that it's very monitorable. In the case that we found, was found making at the time completely asymptomatically through the monitoring program and looking for magnesium levels. And then on the manageability side, I think generally speaking, you can see that it is generally working very well. It was at less than 5% of children that had this serious adverse event, obviously. But beyond that, I think Louise has some additional mitigation aspects to the protocol that we're going to propose. Louise?

So we're monitoring. That has been working as intended in cases where we've had grade 2. The increased oral supplementation has worked well to reaffirm magnesium levels as a single SAE. IV magnesium was not the supplementation, also returning to levels to normal. Certainly, when we met at the Safety Review Committee, the analysis was that if we do have these patients that might be more sensitive, when we do reach Phase II, we would not randomize them to the high dose and keep them on the low dose. We see a recommendation from the SRC or the Safety Review Committee.

Our next question will come from the line of Joe Schwartz from SVB Securities.

This is Beth on for Joe. We were just wondering if you figured out maybe mechanistically what's driving these hypomagnesemia adverse events? Do you think it's something related to the peptide construct that you're using?

So Louise, why don't you give them a lead hypothesis.

Yes, it's a great question. So magnesium is primarily reabsorbed through the loop of Henle and the distal tubule which happens to be the primary site of PPMO localization. This is transient in terms of the concentration. And so the exact mechanism of how it may interfere we're working on, but it is specific to the peptide and the fact that we've looked for this in [ eteplirsen ] and has not seen the same phenomenon related to the peptide. But obviously, it's transient, very monitorable and manageable.

Our next question will come from the line of Anupam Rama from JPMorgan.

Just a clarification question in terms of geography. The FDA hasn't specified any portion of patients that have to come from the U.S. versus OUS for regulatory purposes and approvability purposes, right? So I'm just assuming that you can pick up your enrollment OUS to kind of meet the guidance for year-end enrollment?

Yes, that is correct. That is correct. Obviously, Louise, correct me if I'm in any way wrong, but that's certainly correct. Of course, we want to serve the patients in the U.S. as well even during the trial. So our goal here while we should be on track to meet our time line goals for the year, we still want to move as expeditiously as possible to satisfy the request for information from the FDA and to get off clinical hold in the U.S. so that we can dose patients in the U.S. and get kids that were being dosed and benefiting from this therapy in the U.S. back on trial therapy, but your point is well taken. There's no specific percentage of patients that must come from the U.S.

And our next question will come from the line of Ritu Baral from Cowen.

Apologies if it's a bad international signal. Louise, I just wanted to confirm that this patient with the severe event, this occurred while on supplementation, correct? And can you -- between the 5 or a handful plus this event, can you break out which events occurred while on supplementation versus not?

Yes, that's a good question. So just to confirm, this patient was already on supplementation as all of the other patients where they're all on prophylactic magnesium. After this event occurred, it's an SAE case, he received IV supplementation and not return to the levels to normal. In other cases, they increased the oral magnesium and that brought the levels back to normal.

And I know it's been said multiple times, but just so we're absolutely clear. So and all the kids have returned back to baseline. The mild cases were all asymptomatic. The serious adverse event was -- there was some sequela and maybe tingling and the like, but it was asymptomatic at the time of identifying it. And with additional magnesium supplementation, they all went back to baseline.

And our next question will come from the line of Tim Lugo from William Blair.

This is Lachlan on for Tim. I was just wondering if you had any discussion with the FDA when you met with them about the issue of hypomagnesemia? And if they had any suggestions or recommendations when you met with them a few months ago before starting Part B?

We had worked closely with the FDA and have their drug concurrence on the current protocol and the like. And so the current clinical hold is -- gives the FDA an opportunity to receive additional information and clarifications for us as we hopefully continue dosing in the United States. But Louise, is there anything additional to that, that you would add?

No, that's okay. That's correct.

Our next question will come from the line Gil Blum from Needham.

Just a quick clarifying question. How do you assess the patients seen sensitive to move to a lower dose? I mean, after first dose, you see low magnesium levels. I just want to understand that.

I'm going to ask our Chief Medical Officer, Jacob Elkins, to comment on that.

Okay. I just remind you that for all the patients, they go through a 2-month dose escalation period before they're eligible to be randomized to either the high or the low dose. So during this period of time, we are monitoring them carefully, and we have an opportunity to observe which patients may be more sensitive to this risk.

[Operator Instructions] Our next question from the line of Kristen Kluska from Cantor Fitzgerald.

I know in the past when you highlighted these cases that you noted that there were no occurrences or issues with highlighted markers of kidney function and that these levels have remained normal. Is that still the case with this latest update?

Technically, yes. But Louise, you can confirm that I'm right about that.

Yes, that's still the case.

Our next question will come from the line of Zhiqiang Shu from Bernberg.

Do you anticipate that following FDA's discussion to implement any sort of screening criteria for the remainder of the trial, such as baseline kidney function? And if so, what's the percentage of patients could even potentially screen out in the real-world setting?

Louise?

So we already prescreen patients for kidney function, although we're not seeing any abnormalities in kidney function related to hypomagnesemia. As Dr. Elkins suggested, we will monitor patients during the first 2 months of the study as they are dose escalating [ in a Phase II trial ]. So some sensitivity to hypomagnesemia, we would not randomize them to the high dose and closely monitor as we have been doing.

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

This is [ Tammy ] on for Salveen. And apologies if this question was asked already, I was having some connectivity issues. But relating to real-world use, can you speak to how monitoring patients there would work like the frequency that you would be checking for hypomagnesemia? And whether -- about the enrollment -- increasing enrollment ex U.S. to meet that complete time line, would you expect that there could be any payer like reimbursement headwinds in the U.S. as a result of potentially having more ex U.S. patients?

Well, so I'll answer the latter question, and then we'll move to the first. That issue, I don't think that is going to have any impact on the number of patients ex U.S. versus the U.S. It isn't something that would normally impact our discussions with payer. I think the data and the evidence is going to be beginning to drive our discussion and we'll have a very good data set. And then on the first part of the question, perhaps Louise would like to answer that?

Yes, I mean, regarding the real-world monitoring, this will be informed by the current information we have to date, the rest of the clinical trial. Certainly, there will be some type of magnesium [indiscernible] that will be necessary, but the data will guide us following those trials.

And our next question will come from the line of Gavin Clark-Gartner from Evercore ISI.

So you mentioned that the hypomagnesemia correlates with the dose. I'm just wondering if it's correlating with any other baseline characteristics, like maybe age, weight, BMI, ambulatory status, really just wondering if there's any way we could potentially prospectively identify patients who may be more likely to experience it?

Jacob, do you want to take that one?

Yes. No. I mean it's something we're definitely looking at closely. At this point, we don't -- we haven't identified any baseline predictors. But the thing that we're really focused on is sensitivity in the dose escalation phase, where changes in magnesium are likely to be smaller. It's something that we can identify and then have people that are -- [ the less the ] patients that are more sensitive to this issue would not undergo the dose escalation.

Thank you. And I'm not showing any further questions in the queue. I'd like to turn the call back over to Doug for any closing remarks.

Thank you, Victor, and thank you all for joining us today, and thank you for your questions. We look forward to providing further updates on MOMENTUM as we make progress with what is a very important program. Now speaking of upcoming updates, if you will indulge me, I'd like to discuss an update we'll have on an unrelated program. We will have a further update on SRP-9001 in the near future. As you know, we have additional and very important functional and safety data for SRP-9001 that we have been holding off sharing until we could first provide it to the FDA and give the FDA an opportunity to digest it and ask questions and the like. We have done that, that has occurred. So we are now able to present that data. And so I'm very excited. We all are very excited to present additional data on SRP-9001 at the ICNMD conference in Brussels, and that will occur on July 7. That data will include, among other things, the 1-year data for the 20-patient Cohort 1 of Study 103, and that's our study of SRP-9001 in the 4- to 7-year-old group using commercial therapy and at the target dose. We will present our integrated analysis of all the patients in the 4 to 7 range across studies 101, 102 and 103 at target dose. And then we'll have the 4-year data on the patients from Study 101. These children now are on average over 9 years old, and that means they are in what would be predicted to be the steep decline phase, probably among the steepest declines phase of Duchenne muscular dystrophy. So that data is going to be very insightful on the performance of SRP-9001. We will host an investor call around this presentation. So I mention this now, so if you're looking for that notification when it comes. At the same time, we do remain in dialogue with the FDA on the feasibility of an accelerated approval BLA for SRP-9001. Those discussions are ongoing, and we will provide an update on them as soon as they have concluded. And with that, please, everyone, have a good evening.

This concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.