All right. Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz , one of the Biotech Analysts here, and it's my pleasure to introduce the team from Sarepta Therapeutics, including Doug Ingram, CEO, and Ian Estepan, CFO. Just a reminder, the format for today is a fireside chat. But before we get started, I just need to read a quick disclaimer. "For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative." And with that, maybe Doug, I can just turn it over to you to give us a sort of quick background.
Sure. I'll try my best to be brief. I know these are all gonna come up in Q&A. Look, I have been at Sarepta now about six and a half years. Ian's been a few more years than me. We've had a very milestone-driven period of time at Sarepta, a lot of really important moments, but there are no more important moments than the moments we've had in 2023. It has been a very successful year for us thus far, and we have a lot to do in a very short period of time for the rest of the year.
As you all know, we had an approval for what I believe will be the most significant in vivo gene therapy so far, which is ELEVIDYS, with a limited label, and we've launched that. That launch is going exceptionally well right now. Our goal is to broaden that label as rapidly as possible. I am very happy to tell you that, of course, EMBARK is the basis for broadening that label. Our last patient, last visit in EMBARK will occur this week, so we're in great shape. We've said some time ago, we've not had a single dropout. That remains the case, and so we're in great shape there, which means that we will have results from EMBARK top line, sometime between the end of October into November, depending on, of course, the QC process.
Our goal is to rapidly provide that to the external world, but also to provide that to the FDA, so they can commence the review process even before we submit a BLA supplement, with the goal, in the first half of next year, to have a broad label for all ages, for Duchenne muscular dystrophy, including, of course, all ambulatory statuses. So that's where we are with ELEVIDYS. Of course, that is one of four products that we have approved serving the Duchenne community. We are doing very well with respect to our three PMOs. We continue to grow across all of those PMOs, and we recently reconfirmed our guidance for the year for the PMOs alone, which is EXONDYS, VYONDYS, and AMONDYS, and that was $925 million, with an... Actually, with a bias to exceeding that modestly as well.
A lot to do this year. We're very excited about the readouts the rest of the year, and we're very, very excited about the potential benefit we can bring to the lives of families with Duchenne muscular dystrophy.
Great. Congratulations on last patient, last visit. Maybe you told us about timelines for the data. Maybe just tell us what data we should expect in that update. How detailed will it be?
Well, we're, you know, gonna prioritize the top line, so it won't be everything. There'll probably be, you know, elements of expression and the like, that will take longer than the functional top line. Obviously, the most important two metrics for us is the primary endpoint functionally, which is NSAA, change in NSAA, and then, of course, the safety readout to confirm what, you know, we are very confident about, which is that the safety profile for ELEVIDYS is, as it has been for some time now, which is a laudable safety profile, given its potential benefit. Those results will be released probably sometime between the very end of October into the, you know, the first half of November, and then we will submit that to the agency at the same time, so they can commence a review.
We'll actually submit the formal BLA supplement probably by about January. That takes some time administratively, but we have a commitment from FDA leadership that they will actually commence the review in advance of the BLA supplement to work as fast as possible to expand the label to cover all age groups.
Let me steal your job for a quick second.
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In that question, maybe, are we gonna break out the 4- to 5-year-olds and 6- to 7-year-olds specifically?
I was also gonna ask, are you gonna share the P value, or just tell us whether it's stat sig or not? That would be another.
Oh, I imagine we'll tell you the P value. I mean, we have a pretty good history of, of being transparent.
But just to clarify, the P value, I think he was asking for the P value of the 4-5 versus the 6-7 versus the overall, and obviously, we're just planning on doing the overall.
Okay. Got it.
Yeah, let's make sure. I mean, I apologize for if that's what was implied. I'm not catching it only because I don't agree that it's actually relevant. So let me be very clear about this. We are studying. The goal of EMBARK is to prove, in a placebo-controlled trial, the mechanism of action of ELEVIDYS. We believe that the prior studies have already shown strong evidence of its mechanism of action, but EMBARK is a well-controlled, placebo-controlled, blinded study to do just that. We have narrowed that patient population down to 4- to 7-year-olds, not because we believe it works in 4- to 7-year-olds and not 3- and 8-year-olds, but because you have to reduce the population to something that's more homogeneous so you can see an effect.
The idea that going to subcategories, either 4s and 5s, and 6s and 7s, or 4 to 5s and 6 to 7s, is, I think, both unreasonable and is just an artifact of the fact that with respect to Study 102, Part 1, we had a problem with the balance in the 4- to 5-year-old group of kids. And I think that's created a false impression that there's something about 4- to 5-year-olds that would benefit from this therapy, and that by the time you turn 6 years old, somehow this structural protein that acts like a shock absorber is aware that you've just had a 6th birthday and stops working on your behalf. And that, of course, is not something we believe. So the primary endpoint is 4- to 7-year-olds.
We'll obviously do sensitivity analyses on that to ensure that we understand, you know, where the benefits are coming from, but that's, that's our plan.
Gotcha. And is there a particular delta in mind, you know, from physicians on NSAA, or is just... is this a situation where either it's stat sig or not, and there's no alternative, so physicians are going to use in all patients, or?
Well, I, you know, I earnestly believe that if you hit statistical significance in a delta in just 52 weeks in this degenerative disease, you will have proven out that we are changing the trajectory of this disease. Whether it's, you know, 1.5, 2 points, 2.25s, or 2.5 points, in my view, is entirely irrelevant, and it misses the point. This is a disease-modifying therapy. If this therapy works, and we certainly believe it does, it literally changes the course of the disease. So I've used this silly analogy before. I'll use it again.
If you were flying from Los Angeles to Japan and you were 1 degree off, you know, it wouldn't be very meaningful in 20 mi , but by the time you got to Japan, you'd be hundreds of hundreds of hundreds of miles away because you changed the course. That's what we're doing, whether it's 1.2, 1.5, 2, or 2.5. You see this in our data, by the way. This isn't merely logic, but it is logical. It's also in our data. Look at the kids, the first 4 kids. Those kids are now, you know, on average, the last time we presented their results, which is 4 years out, they were over 9 years old. If you've ever seen a kid with Duchenne muscular dystrophy over 9 years old, that boy is struggling.
He is in the steepest decline phase of this disease. Typically, he could even be in a wheelchair by 9.5 years old. These kids, 4 years after dosing, are defying gravity. They are. They had a nice benefit at 1 year. Now, 4 years out, versus natural history, they were almost 10 points on a 34-point scale better than natural history would have predicted, and they're 7 points over their own baselines, and they've been stable for years in a period of time in which Duchenne boys are not stable. So the point is, we shouldn't look at this therapy and say: Is this 1 point, or is this 1.3 points, or is this 1.5 points, or 2 points, or 2.2 points?
We should ask the simple question: Does ELEVIDYS, this structural protein that is intended to act like full-length dystrophin and protect the muscle when you contract, does it indeed do what it's supposed to do? And is the future of these kids different than natural history will predict? Have we changed the course of the disease? And if the answer is statistically significantly, yes, this is a profound change in the treatment of Duchenne muscular dystrophy.
To your point, which I think are all really well taken, if you look at the baseline characteristics of those first four patients, very indicative of what we're enrolling for in 301 too, right? So these aren't some very healthy patients that we enrolled in the first four patients, and now five years out, you know, are doing really, really well. These are patients exactly what we would have predicted for 301, using our inclusion, exclusion criteria, and we're seeing these results. So it just really highlights that it's a disease-modifying agent.
It's either 1 or 2 of the first 4 boys were exon 51 amenable. Exon 51 amenable boys are not known to be mild Duchenne patients. In fact, they're known to be typically more severe than the overall group, at least modestly more severe. So you would not have predicted that the patients that we chose would be where they are today. Naturally, as you would have predicted, they'd be falling off a cliff, if not already in wheelchairs.
Got it. Maybe you can just talk about the EMBARK study design and differences between 102 in terms of eliminating the potential risk of an imbalance and also the variability in the NSA and endpoint.
Yeah. So to remind you of a couple of things. So in Study 102, Part 1, we had this enormous imbalance. We were using age as the predictor for the prognostic for decline. And horrible bad luck, frankly, because the p-value was 0.004, if I remember it correctly. The 4- to 5-year-old boys were enormously imbalanced between the active arm and the placebo arm by 5 points on a 34-point scale. It was really just crazy where... And of course, in a way that would make it impossible to see a benefit. The kids on active therapy were all severe, and the kids on placebo were much milder. I think all but one of the kids, if I'm not mistaken, in the active group, had rise times over 5 seconds. Some of them...
really, really slow rise times, like predictive of being in a wheelchair in the next 18 months, and none of the placebo kids had it. As a result of which, those kids should have been falling off a cliff, the kids on active, they weren't. They were actually stable, which would have been genius, except that the placebo arm would have been predicted to be stable, and they were, so you couldn't see a delta. So when we go to EMBARK, we've solved for a lot of those things. First thing to know, EMBARK's a much larger study. It was intended to be 120 patients. We actually over-enrolled to 125 patients. We had assumed a certain level of dropout, I think about 17 potential dropouts. We could have still had power.
We've had zero dropouts, as I mentioned earlier, and our last patient, last visit is a few days from now. When we stratified on baseline characteristics, both for age, we're still stratifying for age. We don't want to lose sight of that, but we also stratify for NSAA baselines so that we will not have that problem a second time. We've also put in more stringent requirements to ensure less heterogeneity. We put in a hard floor, a hard ceiling on those kids, and then we all, across all of the ages, four, five, six, and seven, we've put in a requirement that they have rise times of under five seconds so that they're more similar to one another. So that should significantly reduce the standard deviation.
Interestingly enough, when we powered the study, we assumed the standard deviation that we were seeing in other studies, so about 3.5 points. And that would—we powered it to see a 2.1 to 2.2 point delta with a standard deviation of 3.5. But given the larger enrollment that we have, there are no dropouts, we've actually looked to see what number we would need and still have a power, and we would still see stats sig at 1.3 points, and with a 3.5 point delta.
We didn't play with the standard deviation, even though one could surmise that we would have a better standard deviation, given the rigor of this study, which I am quite confident is the most rigorous study ever done in Duchenne muscular dystrophy so far.
Maybe one just quick thing to add to all that you said was just that we did when we applied the 301 criteria retrospectively to the 101, 102, 103 data, we did see, in fact, what we would expect, which is a decrease in standard deviation and variability overall. So it was clearly a much more homogeneous patient population, and that's why you're seeing the decrease in variability. So we do feel really good tracking into EMBARK based on the adjustments we made.
Gotcha. When you share the data with the regulators, what gives you confidence that you can assuming it's positive, that you can expand into, not only all age groups, but also non-ambulatory patients as well?
We were, because we were told that. So I want to be very clear. Shortly after we were informed, like, no, that's not actually accurate. At the time, we were informed that the label would be limited initially to 4 to 5-year-olds. We were given a firm commitment by FDA leadership in the presence of the entire, of, you know, the broader division, and concurred in by the broader division, that in the event that EMBARK was successful, that the age limitations associated with the current label would be removed.
Gotcha.
The clinical reviewer herself, because sometimes there's some disconnect between what Peter Marks and CBER says versus what the division actually feels. It was in that conversation which Doug was referencing, the clinical reviewer herself said, you know, that they would prioritize the review of this application, you know, once we got the data to them. So it was really encouraging to hear that directly from the review team.
Well, then I will also can say one other thing on that topic. That there's nothing about that, that should be, precedent-breaking. In fact, it is entirely consistent with precedence. That is what the law would suggest, regulation would suggest, science would suggest, and all of the precedent would be, from the agency broadly. There are four PMOs currently approved, three Rs, one NS Pharma. All of them have studied a smaller population, and then even on an accelerated basis, obtained a broad label that covers all age groups, obviously, for the reason that, dystrophin should be broadly applicable. It is the single reason that these kids are, degenerating and dying, unfortunately. And even our confirmatory trials in all of our other PMOs do not require that we study broad deltas of age group.
We're studying a narrower age group with the understanding that, of course, if we've proven out the mechanism of action, it's applicable to all children, and children shouldn't have to wait for this therapy. So it's good to know that our regulators are being patient-centric and science-based and agree with us on that.
Got you. And just in terms of the timing of the review, you said filing January, expect the response in the first half. Is there any risk that that could slip or?
No. I bristle at the thought of it. No, we're not going to let that slip. You know, families are waiting for us.
Yep.
So we're not going to let that slip. And I think our colleagues at the FDA will be equally motivated. I think they'll understand that.
Makes sense. Maybe we can shift a little bit just to ELEVIDYS, you launched, I think, a little over two months ago. Maybe just talk about how early trends are going versus what your original expectations were.
Yeah. So I'm gonna apologize, I'm not gonna give numbers of patients or net sales. We'll talk about that obviously later over the course of, you know, next earnings call and the next earnings call after that. But the launch is going very well. It is for, in a number of ways. So one of the goals, we had an aspirational goal, and that was to have as many as 50 sites activated and able to infuse patients by the end of the year. And that would be enormous because there has not been a gene therapy that's been launched with that sort of capacity, site capacity. We're not there.
We're actually at, I mean, probably by today, 59 or 60 sites already activated, which speaks reams to the team, you know, to those who may wonder how we were able to do that. Frankly, it's been, you know, hard work for years leading up to this moment, probably nice, healthy paranoia to get us in a place, and then an enormous excitement and work from sites. I mean, it's not just us. That gets to the next issue, the level of interest and demand from physicians and patients has been extraordinary. I mean, people are very, very excited about this potential therapy. And then interestingly enough, the payer response has been generally very positive thus far in a number of ways.
I mean, first of all, I think the way we looked at the value proposition for ELEVIDYS ought to set the standard for the way that folks do it in the future. We did a pharmacoeconomic analysis to justify the value proposition for ELEVIDYS. We then showed our math, so this wasn't some black box exercise. We actually, in May, had published in a very highly respected, peer-reviewed journal, the pharmacoeconomic analysis that justified ELEVIDYS. We then priced that therapy at a price that was commercially viable and very acceptable to investors, but was actually below that pharmacoeconomic analysis, and peers could see all of that. And then we did a budget analysis, finding that at steady state, it's less than $0.10 per patient per month for a commercial payer.
So I think all of that went well in the discussions. I think payers generally, certainly the more sophisticated players, payers have become more sophisticated about Duchenne. So as an example, you, for those who were around back then, you may recall when EXONDYS was first approved, Anthem, one of the two largest healthcare organizations in the world, came out and had a policy that said that they weren't going to give any kids access to that therapy. Now, the good news is, by the end of 2017, to the best of my knowledge, every kid that was amenable, that was an Anthem kid, was on therapy. So we have a team that knows how to execute, but, you know, that was certainly an uphill battle.
Today, Anthem has issued its policy to label, so they are gonna rapidly give kids access, consistent with the label. And United, which is the largest managed healthcare organization in the world, has done exactly the same as well. And then a little bit more, specifically, I can tell you that when we're working with, physicians, given the narrow label that we have right now, one of the big issues are kids that are going to age out of this therapy, and that is a big issue. And so you know, you'll see, generally speaking, the kids that are getting dosed right now are kids that are very close to their sixth birthday, because physicians and the like, are really prioritizing, making sure those kids have access before it's too late.
It would be very easy for a disingenuous, I might argue, evil payer to simply delay things and have them age out of the label. But, you know, generally speaking, that isn't what payers are doing. They're working with physicians to give these kids access. So I give enormous kudos to the payer community for seeing the importance of getting these kids dosed and ensuring that they're not an impediment to that. So generally, you know, I don't want to pretend that there aren't tons of issues we have to work through. This is a battle-hardened team that knows how to work through issues, and work with payers and others and the like. But as we sit here right now, the launch is going very well. The distribution channel is going very well.
That may seem a weird thing to talk about, but, this is a brand-new distribution channel to, you know, have this high-value, single dose transported at, I think, negative 80 degrees, has all of, you know, has a number of interesting issues with it. But that's all going very, very well, which probably speaks to the team and speaks enormously to the, organization's, work that we've done really in the probably couple of years leading up to this launch.
Yeah, maybe just one thing to add to that really quickly, and it's implicit in what you said, but, you know, for all the patients who have been dosed right now, it's been a nice distribution between the payers and the commercial setting and state Medicaid and the like. There isn't one plan which is dominating, like if an Anthem came on and all the patients are getting dosed there. It's just distributed across, many different payers and state Medicaids.
That's a good point, too. The state... I mean, I shouldn't leave state Medicaids behind. Generally speaking, you know, we've seen very good response from state Medicaids. Again, not to suggest there aren't going to be issues. The team is gonna continue to earn their keep, but so far, things are going very well.
In terms of the sales ramp, you're minus sort of your expectations there in terms of timing, and is it the hurdle really the insurers? And if so, what sort of percentage of, you know, payers have policies in place today?
Look, the hurdles to getting dosed are many. There are a lot of different steps that one goes through. So one thing, let me answer the question and then come back. The broad answer is, of course, we're gonna see significant ramp, you know, toward the, sort of, back half of the year. We're getting close to that now, but sort of the back half of the year. And that's faster than most gene therapies. I mean, there are many of the, you know, few gene therapies that are approved. Many of them didn't dose for 4 months, 6 months. So the idea that we were able to dose within a month or so, of approval is actually quite impressive.
But really, to see the ramp, there are policies, there are codes that have to get put in place. There, the site readiness has been going very well, but the release process is very long. So remember, there are two issues. We make the material, and that's great, then it has to get released. That release process itself takes a lot of time from us, and then we have, as all gene therapies have had so far, we have a process where the agency actually has to independently release the therapy. They've been doing their job as well, but that adds, you know, some number of weeks on top of it.
But, you know, generally speaking, things are going well, and we'll get to steady state, you know, towards, not steady state, but we'll get to real ramp, you know, toward the back half of this year.
Do you anticipate any capacity issues, particularly if EMBARK's successful and you rapidly expand the label? Could that potentially be a hurdle?
Well, we're working hard to create material. So, you know, there are a number of different things that have to come together for the launch ramp. You know, one is site readiness, and that's not just site readiness, it's also the number of infusions each site can do every week. Remember, you can't just do as many infusions as you have rooms in availability in, let's say, you know, the hospital, because you have lots of follow-up. So how much follow-up you have relates to how much staff you have, so there's a lot of issues associated with that. Payer discussions play a role, and the like, and the release process for manufacturing certainly plays a role. So all of that together will define the, you know, the ramp.
Probably, you know, in the next year will define the ramp. I'm quite confident that it will be robust. But those... That's the multitude of issues that come together that will define that launch ramp over, you know, 2023 into 2024.
Can you talk about just manufacturing, sort of where you are and, and expanding that, and maybe some timeframes around that?
Yeah, I'll give you the. So the near term is that, you know, we're at Catalent right now. Catalent's being a good partner. We've made a lot of material with our colleagues at Catalent, and we're going through the process of releasing material now. To add additional capacity at Catalent, we've actually taken out an additional suite with them, so that's going well. We are working. Independent of that, we're working on a site. We have a single-use site with Thermo Fisher for adherent material, and we had made the strategic decision not to have that licensed at the time of launch because the concern we had is if we were trying to get two sites licensed at the same time, it would, you know, potentially slow down the approval process.
Remember, we had four, we had a GLP and three manufacturing site inspections just using Catalent. So now we're focusing on Thermo and getting Thermo licensed. That's gonna be an issue that we're gonna work on over 2024. So, that's great from an adherent perspective, and then we're really excited about the future. You know, we've got a suspension process. We've already run three runs at 250 L. We're running another run at 250 L, the back half of this year. We're gonna be running 500 L and 1,000 L early next year, starting next year. And the results we're seeing, at least so far, look tremendous. The product qualities are tremendous, and the yields are multiples greater than we get from adherent.
That's gonna be a really exciting part of the future of this therapy as we think about expanding out into other regions around the world significantly.
Great. So looks like we're out of time. That looks like a good place to wrap up. Looking forward to the data coming up, and thanks, Doug and Ian, for spending time with us.
Thank you very much.
Thanks for having me.
Thanks for spending time with us today.