Hi, everyone. Thanks for joining us today, for the Sarepta Fireside Chat at TD Cowen's Second Annual RNA Therapeutics Summit. With us for the Fireside Chat, we have Sarepta CEO, Doug Ingram. Also, on the line if we need him, we have CFO Ian Estepan. Thank you so much, Doug, for joining us today. Busy times for you guys, but I did wanna take the time today to focus on what is really your foundational technology, from back in the day, and the foundation for your base business, the PMO and PPMO DMD therapies. There's been a lot of discussion about your newly approved DMD gene therapy, ELEVIDYS, certainly. It turns to, you know, what will become of your close to billion-dollar DMD PMO franchise and your PPMO pipeline for DMD going forward?
Doug, let's start on a high level. What are the aspects of AAV gene therapies as you see it, that you think RNA therapies, particularly your PPMOs, could address?
Well, let's step back a bit on this. There's, sort of, layers of questions here. I may answer a lot of questions in my first-
Sure
answer, and then we'll go back and go into any detail you like.
Yeah.
It's a fascinating question, and it's a question we'll only be able to definitively answer over time with empirical evidence. We're in an interesting place right now, right? We have three oligonucleotides. We're doing nearly $1 billion in sales. Our guidance right now is $925 million for the year, and they've really been fantastic. Never mind the revenue, they. Well, one of the things that I think some have missed is, you know, from what was back in 2016, perhaps a controversial beginning of this journey with oligonucleotides, they've done an immense amount of good. We had some real-world evidence that we provided last year that showed what the PMOs can do, both in delaying ambulation, slowing down pulmonary function, and correlating to mortality. They've done a really good job. Let's...
There's this interesting bar there, and then, of course, we now have ELEVIDYS gene therapy with an enormous amount of hope, making extraordinary amounts of shortened but functional dystrophin. There's sort of three questions from my perspective. The first question, of course, with respect to our PPMO, and, for those who don't know, and I'm sure everybody does, the PPMO is our next generation version of our PMOs, conjugated with a peptide, the goal of which is to enhance delivery. There would be two big values to that. One value is just convenience. The PMOs, even though we have this enormously high compliance rate, over 90%, they're weekly infusions, either at home or, you know, a minority of them in the hospital, weekly infusions.
The PPMO would be once a month dosing, and then, of course, with an enhanced delivery of this positively charged peptide, you could get significant increases in the amount of dystrophin you're making. One of the big limitations of oligonucleotides is that they make very little amounts of dystrophin, and it turns out even a little does far more than people would have envisioned, delaying ambulation and the like. The first question for us is: Where are the PPMOs versus the PMOs? We'll begin to get a hint of that at the end of this year, right? We have a study going on called MOMENTUM Part B. We'll see those results. We'll need to look at both expression and safety for both, because there's a very high bar on safety.
The PMOs have just been extraordinarily safe. We need to look at both of those issues. We're very excited based on what we've already seen early on, and we'll talk about that, but that's our first issue. The second issue, which is at higher bar, I believe, yet again, will be your very question, our gene therapy, ELEVIDYS. You know, this is gonna be a very high bar, of course.
given what we've already seen with ELEVIDYS. How it competes directly with ELEVIDYS, if it does, in fact, compete directly with ELEVIDYS, is gonna be an empirically driven question. We need to see what kind of expression we get from it, we need to see the risk-benefit of the expression, and then we need to see the functional results over time so that patients can make decisions. I don't think it's unreasonable to envision a world in which both could exist independent of one another. We've seen this already, right? We've seen it with SMA, with SPINRAZA and ZOLGENSMA. ZOLGENSMA was, you know, a remarkably transformative gene therapy, and yet there still is a place in the world for SPINRAZA.
The third question, I apologize, this probably gets to the question you were actually asking.
It's okay.
is, you know, where does the PMO reside in a world in which our gene therapy is successful, and it doesn't directly compete with it from an efficacy perspective, an expression perspective, and the like? That probably is a potentially likely scenario, given that ELEVIDYS makes, you know, upwards of 50% of normal, so makes it, you know, more than an order of magnitude, more than the PMO.
What would the PMO really do to compete directly with it? That'll be an interesting question that we'll have to look at. Even if that's the case, there still is a potentially interesting place for the PPMOs. I can think of sort of broadly three areas. Today, of course, it's a no-brainer. The label we have is limited with ELEVIDYS. Let's assume a world in which that label is much broader. You still have neutralizing antibody-
positive patients. That would be available. If you came up with there, with PPMOs that address earlier mutations, there are mutations that are excluded from gene therapy that could be of interest.
like null, the null mutations, the highly immunogenic.
Right, those sorts of early mutations .
Yeah
that exist around exon 8 and 9 for us.
You mean early in the sequence?
Yeah.
Early. Yeah, yeah.
Yeah, those ones. But we don't have constructs built for those, but that's a possibility. There's also, of course, even in a world in which gene therapy has been wildly successful, and the PPMOs are wonderful and better than the PMOs, but, you know, objectively may be difficult to compete, there still will be family choices. There will still be moments where families will choose a chronic therapy over a one-time therapy. I envision that occurs, and it occurs, I think, at times with SPINRAZA, even though ZOLGENSMA has been so successful. There are obviously access issues, payer issues, that might drive-
chronic therapy. All of this is broadly to say we don't yet know, there is a lot of potential in this, and we need to just let the data and evidence drive us. Down the road, long term, there are things that the PPMO could do that the gene therapy will not do.
which is work in smooth muscle, as an example.
Smooth muscle has dystrophin, but the AAVs don't deliver to smooth muscle, so that's not one of the most significant issues for Duchenne muscular dystrophy, but it's an interesting one down the road. Of course, we always have the idea of combinative or adjunctive therapy, where we can build over time an evidence set, an evidence set we don't currently have available to us, but an evidence set that could suggest that the combination use of Zolgensma, of ELEVIDYS. You can see where I'm thinking now.
Not yours.
ELEVIDYS and our PPMOs could add some enhanced value, and we have seen that.
Yes
as an example, Zolgensma and SPINRAZA.
Your comment on the payers, is that in any way driven by the last few weeks of conversations with payers or your, the discussions around PPMD about coverage at this point? Or, you know, has that informed the ramp at all?
No. well, no.
Okay.
We're a little bit in the honeymoon period, where I, you know, I'm falsely imagining it's going to be easier than it really is going to be. Look, payer issues are always significant, but we're in a... now we're talking about ELEVIDYS.
Yeah.
The data set for ELEVIDYS is more than an order of magnitude, more substantial and robust than, for instance, when we successfully launched EXONDYS. We started discussing ELEVIDYS with payers years ago. We had recent granular discussions before approval with payers that covered 220+ million lives. I think we've been in a really good position to have very thoughtful discussions.
... with payers. No, I actually think it's going to go very well.
Okay.
I don't misread that. I, you know, I think, you know, as it sits right now, we're in that kind of honeymoon period, where I think it's gonna go well. Ironically, maybe in this world, payers were emailing us congratulations when ELEVIDYS was approved. You know, one other thing to sort of proof point on that, I know I'm lingering on gene therapy.
apologies, but, you know, I think we did a really thoughtful job of doing the cost-effectiveness analysis, the pharmacovigilance work, and then the pricing of this therapy in the context of that I think has made those discussions go very well right now.
As you know, we had created a cost-effectiveness model.
We did a really objective approach. We had it published in a peer-reviewed journal. We priced below the bottom of that, and we didn't price at the top end of current gene therapy pricing. I think we're not getting enormous, you know, payer pushback on those issues. I think it's gonna go very well.
They see the cost-effectiveness of a gene therapy as being greater than, say, the existing PMO right now, EXONDYS, VYONDYS, AMONDYS. Is that a takeaway from your point of view?
I think. Yeah, I would look at it if I judged it in one way, I would say that definitely is the case.
I wouldn't say the existing payers with the existing data set for the existing oligonucleotides, 'cause remember, we've now have six years of great data that justifies the benefits of those therapies.
We're in a good place today. If you look at the launch of EXONDYS or the launch of VYONDYS, and you compare the data sets available there with the data sets we have for ELEVIDYS, the cost effectiveness, the pricing.
I see. Yeah.
the way we looked at it, which is just much more evolved, and I think payers have appreciated.
Understood. Doug, you've talked to a few aspects of, I guess, the world in general.
Yeah
as we, as we live in it for comparing and contrasting PPMO versus ELEVIDYS, neutralizing antibodies, early mutations, family access, et cetera. What about the inherent clinical profile of ELEVIDYS and where PPMOs? Where does the science take you? You talked about smooth muscle. What sort of pathologies within DMD are related to smooth muscle? One of the questions, really hypothetical at this point. Nobody is talking about it all that much post-approval, but duration of effect. You know, how are you looking at data generation for durability, and how PPMOs could sort of roll into that?
Yeah, it's very interesting that you ask that. If you look at scientifically... First thing is before we think about ways in which they could address issues in gene therapy, we first have to acknowledge, interestingly enough, that they are very different modalities that ultimately do basically the same thing, right? The oligonucleotides, through a very different mechanism, put messenger RNA back in frame, and then make shortened but functional forms of dystrophin. The ELEVIDYS doesn't do that, but what it does is deliver a gene cassette that makes a shortened but functional form of dystrophin. It just makes it in much greater abundance. The differences in the sort of the Duchenne and the like are maybe threefold, or well, one is the same and two are different.
One is, you know, could we get dystrophin into the brain, right? There's not... Cognitive issues are not degenerative, so that doesn't exist, but there definitely is a cognitive aspect.
Yeah
to a minority of Duchenne patients. Neither of these therapies are going to do a brilliant job of getting. Well, first of all, we don't know if getting dystrophin into the brain is even meaningful at this point. We have no idea, right? Because it's not degenerative. Neither of these are going to address that issue in any event. You know, I did raise the issue of smooth muscle. Smooth muscle is really, you know, you hear very little about this being an issue. It may very well be that it's not a significant issue because, unfortunately, the Duchenne patient dies, and he dies, you know, much earlier in life than perhaps smooth muscle issues become a major issue.
There may be, in the long run, some value to protecting smooth muscle, given that if all goes well and ELEVIDYS is as successful as we all hope it will be, we'll be greatly extending life, and then, you know.
GI and other smooth muscle-related issues could be meaningful.
Doc, are you keeping?
And then the-
track of this? I'm sorry to interrupt...
No
Are you keeping track of this as part of your endpoints in the studies? Because what you're saying is reminding me of cystinosis, and how it wasn't until there was an actual treatment that they found out patients in their 20s and 30s lost the ability to swallow.
We all.
Are you keeping G.I. motility and stuff?
In the study itself.
For instance.
I do not believe that's the case, because we're looking at too short a period of time.
Okay
to see a significant issue. This is beyond; this is at best theoretical. You know, I think most physicians don't even talk to these kinds of issues. This is something that we'll be thinking about, if we're thinking about it at all, when a Duchenne boy is now in his 30s. He's not a Duchenne boy; he's a man in his 40s. He's a late middle-aged man. I like to think, from my vantage point, to think young middle-aged man. Et cetera. Then, of course, then there is the durability issue. You know, again, that's something we're going to have to live with over the long term. The interesting thing about gene therapy for muscle, and about ELEVIDYS, and about shortened dystrophin, delivered by a gene cassette, is that, you know, muscle's a hard place to get to.
Fortunately, we get there now, right? Three genome copies per nucleus on average. It doesn't turn over very, very fast. It's not like the liver.
Yeah
the durability we've seen, both empirically in the patients, we've only been able to look at them for 4 or 5 years, but we haven't seen any kind of functional durability issues. In the animal models, both non-human primate, golden retriever, and the, you know, mouse model, for what it's worth, we just have not yet seen any signal of durability. Does that mean there won't be a durability issue in 10, 15 or years? No, it certainly doesn't mean that. It's something we're going to have to keep an eye on. You could envision a world in which either the PMO or PPMO could intervene if there was a durability issue, or theoretically at least, be dosed early and actually participate in reducing the risk of a durability waning-
out there in the later years, right? You could envision that. There is a thesis, you know, there was at least one paper, Dr. Voit did some work in a rat model some years ago, where he suggested that the use of a PPMO, actually, in the rat model strengthened the muscle membrane and actually reduced any risk of the loss of the gene cassette as it was making dystrophin. That there wasn't this synergistic value of having both, the PPMO and the gene therapy, but we need to do more work on that before we can stand here.
Doc, you said there was no evidence of durability for preclinical, do you mean that the data has been rolling off, or do you mean that the studies have just not gone out that far to show durability?
They I mean that it's been as durable for as long as we've been able to look.
Okay.
If you think about it.
Thank you.
for a mouse, not very long, cause the natural life of a mouse isn't.
Yeah
very long. For a golden retriever, I believe we've looked out to 7 years with these kinds of gene cassette constructs. In the non-human primate, the last time we looked, or I looked at least, it was out to 9 years, and we just did not see a waning of durability yet.
That's what I mean.
Got it. Nothing representative of a 30-year-old DMD patient, essentially? Yeah.
Right. Not yet, not yet.
Got it.
Not yet.
Great. Well, I want to use the H2 of this to discuss the MOMENTUM Part B data. As you mentioned, Part B is going to be coming out. What are we looking for in terms of this top-line data? Your Q monthly, 30 milligram, 30 mgs per kg developed mean exon skipping of about 11%, mean dystrophin expression of 6.5%, and you'd previously said your model suggests you can achieve 10% with chronic dosing. I think the readout will still be six months. Do you think you can get closer to the 10% with aspects of the study? What should we be looking at?
We don't know yet, to your very good point, we had, you know, over 6% dystrophin in a very short period of time, 24 weeks. As we know, with this chronic dosing, we've seen that you get greater dystrophin over time.
The model suggested that if that data was, in fact, representative of the larger data set we're gonna see at the end of this year, you could be seeing 10%. Let me contextualize what that is. That is a massive home run. Let's be very clear about this. That should not be the bar. For those who don't know, 10%, you know, with, you know, at a year with EXONDYS, you know, we're seeing the 1 to 2%.
This is multiples higher at monthly dosing than what we're getting with, you know, much higher doses at weekly dosing, so it really would be significant. We don't need, for instance, 10% to be successful. There was a paper in 2018, it really ought to, in a very real sense, be considered one of the definitive answers to the question that was asked back in 2016.
which was, "Can small amounts of dystrophin really make a difference?", right?
That was the debate back in late 2016. Amthor answered it. Unrelated to us, we had nothing to do with the study, didn't fund it, didn't even know it existed until it was about to come out. That answer was absolutely, even dystrophin at less than 1%, is correlated to phenotypic change. If you get above 5%, it's transformative. That's what the data shows, empirically based on natural history. You know, anything substantially greater, and I don't know how to define exactly what substantial is, other than to say it's greater than 1 or 2%.
it doesn't have to be as high as 10% with a good safety profile. Remember, we have to also have a good safety profile.
Right. Right.
With the convenience of monthly dosing, could really give us something that would be a substantial step forward in the treatment of Duchenne, at least with respect to oligonucleotides.
It sounds like anything between the 6-ish seen and the 10 would be a home run and an approvable, with.
safety, an approvable profile for you guys.
I would be popping champagne at 5%.
Okay.
5% would be amazing. I mean, really would be amazing. 5%, we could reliably get 5% on, you know, average.
That, that's big. I mean, if you look at the Amthor paper, that would suggest, you know, you're not, you're not just creating a phenotypic change...
you have a really potentially transformative therapy. Of course, if the safety is good and the like.
But, like, just because you're popping champagne, does that mean you're gonna turn around and file for approval three months later?
Yes. If I'm popping champagne, we're filing for approval. Whether we get it or not, will be a discussion with the agency.
Right.
We obviously have a lot of very good precedent for the use of dystrophin, truncated dystrophin, as a surrogate endpoint.
in the neurology division, but yes.
Got it.
Let me just one thing to add, just as it relates to this 5%, to put it in context, I think different people use different ways of quantifying dystrophin. You can see different numbers. I think Doug's 5% is in comparison to our PMO specific.
Right? Because if you use a different way of quantification, someone else could say, "Well, we have 5%," but you can't compare those different methods, so it's 5% compared to how we actually quantify dystrophin.
Okay, got it.
That is really important, and there's a host of reasons for that. You cannot compare against programs, unfortunately.
The way there's two different ways individual companies do western blots, are different. We have an exceptionally rigorous, and I would argue, particularly conservative approach, that was driven through the neurology division in the FDA some years ago. You have to have a comparator. You use a comparator pool. We have a very conservative pool that against which, and it's only our pool, and therefore really have to look at it intra-programmatic.
To Ian Estepan's point, when I say 5%, I'm comparing that against what we see.
Sondys
EXONDYS, VYONDYS, AMONDYS.
Okay.
It's not what you might see in some other-
It's not even giving you. Like, your own assays are still not telling you what the differential clinical profile could be between ELEVIDYS and SRP-5051.
No.
Okay
you're gonna have to really understand that we're gonna have to live with these therapies for a while.
Okay. Like you said, data in hand, 5%, you would turn around and file?
Correct. Well, let's go back to safety for a second, 'cause I skipped over that.
Yeah
as you see it right now, as the DSMBs have progressed, what is the hypomagnesemia real-world monitoring and supplementation going to look like? As we think about forward programs, can that be engineered around?
Yeah
the next direction you take it?
We don't currently engineering the construct in a way that avoid hypomagnesemia.
You don't think-
We don't have a basis yet to believe that to be the case as it relates-
Okay
to the use of peptides. We don't know that.
I mean, maybe it can be, but we don't have any empirical evidence that justifies it. We were surprised to see hypomagnesemia itself. It's hard to find in animals, by the way.
Just to put this in context, so the... You know, it's definitely the case that we see a dose-dependent increase in hypomagnesemia with the use of the PPMOs. No doubt that that has been the case.
What we don't see, which is very good news, 'cause hypomagnesemia could mean a lot of things. One thing it could mean is some significant, you know, kidney damage-related signal. We don't see that right now. That is not what we have seen. We, you know, the signals of kidney function look good.
whatever this may be, it doesn't appear to be the case, and it appears on its face to be both monitorable and manageable, through the use of oral supplement magnesium. What do we have? For our Phase 3, let's talk about what we have and what our aspiration will be, it's gonna depend on seeing the data. What we have right now is the way we monitor, the way we manage is the use of magnesium supplementation. That's BID. I think 200 mgs BID, if I'm not mistaken. It's just an oral magnesium supplementation. It's, it's pretty straightforward, not particularly, you know, burdensome or difficult. We have a blood draw at the time of infusion. That's a nothing.
I shouldn't be, you know, but essentially it is. Then we do one at 7 to 10 days after infusion, and that happens every month. That's the current protocol. The goal would be to understand this more, live with it, and then determine if patients that aren't seeing any kind of hypomagnesemia issues seem to be very well controlled, whether you can actually start eliminating some of those blood draws over time. We need to kind of get through the phase 3 and really understand it better before we would confidently say that.
Got it.
As it stands right now, the clinical profile, again, is, you know, is that those numbers of monitoring.
The last two questions in... You have exactly 2 minutes, Doug. Sorry about that. Given the data that drives approval is going to be expression, and given you said, you know, this is, the compare and contrast is going to be a longer-term, empirical data-
driven decision, how and when do you think you're gonna know what to invest from a commercial standpoint, from a corporate focus standpoint, in your PPMO versus ELEVIDYS and your gene therapies? You know, looking beyond, where do you think PPMOs can be taken into next? Last year, Ian mentioned that there were potential kidney applications. Are there other muscle applications?
Yeah.
How are you thinking about that?
Let's go first. On the investment thesis of ELEVIDYS versus PPMO, it's never about investing in ELEVIDYS. We are fully committed to ELEVIDYS.
We're as confident and convicted on ELEVIDYS as we could possibly be, we're going to continue to invest aggressively to bring that therapy to as many patients as possible. On the PPMO, it's gonna be very data driven. You know, the expression and safety profile alone is gonna give us a very insightful view on what this could mean over the long term. We already know that even small amounts of dystrophin provide a benefit. We'll make some investment decisions once we see, the results of MOMENTUM at the end of this year. When we think about next steps, the next steps, of course, is if we're excited about it, do we go into... We already have constructs built. How many additional
Right
related constructs do we go into? We'll make that decision, and we'll think about it next year. On other therapeutic areas, we can't make significant investment in other therapeutic areas until we know that this PPMO platform is really meaningful, and we'll start knowing that at the end of this year. There are a number of places we can go. I mean, there are things like You know, kidney's a perfect place for it. We have some kidney diseases that we've looked at very deeply. Pompe is one that people talk about often with respect to the PPMOs, and we've done a lot of interesting preclinical work there. Translating that to something that would get to a clinic is a decision we're not gonna make until we know what momentum looks like.
at the end of this year.
Okay.
Then we can make some interesting investment decisions on this part of the platform.
Great. Well, with that, we are at time. Doug and Ian, thank you so much. Appreciate all of the insight and look forward to your Q1 for ELEVIDYS and how the base business gets along with it.
Thank you so much. Thank you very much.