Sarepta Therapeutics, Inc. (NASDAQ:SRPT) Evercore ISI HealthCONx Conference December 2, 2020 3:30 PM ET
Douglas Ingram – President, CEO & Director
Conference Call Participants
Maneka Mirchandaney – Evercore ISI
Great. Good afternoon, everyone. I’m Maneka Mirchandaney from the Evercore ISI biotech team. I am really pleased to be here with Sarepta. We’ve got Doug Ingram, who’s its President and CEO; and Ian Esteban, who’s SVP, Chief of Staff and Corporate Affairs. Thank you both so much for being here today. And Doug, to start — just give us a broad sense for where Sarepta is now? And what the vision is for the next few years?
A – Douglas Ingram
Sure. Thank you very much, and thanks for having us today. I mean if I started — its most — its broadest sense. We have to consider the fact we’re a rare disease company focused on genetic medicine to treat disease and bring a better life to patients. There are 7,000 rare diseases that exist. 80% of them are single-gene mutations, which means they are really prime candidates for the intervention of genetic medicine. As we sit here today, only 5% of those diseases have any kind of therapy, and many of those therapies are merely palliative. And yet genetic medicine has made these extraordinary strides over the last couple of decades at least.
And it’s time to start transforming that science into therapies that it can extend my life, I mean, I would say, as an example. 50% of rare diseases are children’s diseases. And they’re children’s diseases because they don’t — children don’t make it to adulthood with these horribly difficult, rare diseases. We are focused on — right now, the rare disease were focused on is neuromuscular and neurological. Our lead therapies are attempting to bring a better life to patients with Duchenne muscular dystrophy, which is a disease characterized by the lack of this structural protein called dystrophin. And the lack of that causes the generation and inevitable death of children who have the Duchenne muscular dystrophy.
And then also an umbrella of diseases called limb-girdles. We have 6 different disease areas we’re working under there, very similar to Duchenne, often children’s diseases and far more often than not diseases that result in the early demise of these kids. We have a platform approach. We’ve got an approach — an RNA approach, which is focused on literally editing messenger RNA to bring messenger RNA back in frame and make dystrophin for children who have Duchenne muscular dystrophy. I mean something that would have been science fiction 20 years ago, but really excited about that platform.
We’ve got a big focus on gene therapy. We have 27 programs in gene therapy. I think others might disagree, but we probably have the largest and most valuable platform and pipeline for gene therapy, 27 programs right now, with the leads in Duchenne muscular dystrophy and limb-girdle. And we have a Gene Editing Innovation Center, focused right now on CRISPR-Cas9. I think we all know about CRISPR-Cas9, and it’s impact in the fact that a couple of pioneers just won the Nobel prize on that basis. And we’ve got of group in Durham, North Carolina under the auspices of just a brilliant scientist, Dr. Charlie Gersbach out of Duke University, working on that. And then we’ve got — we’ve got 2 therapies that are approved for Duchenne muscular dystrophy, subpopulations. We’ll have a third therapy, if we are fortunate, that will be approved early next year, in February of next year, to treat another 8% or so of those kids, bringing the total percentage of the population that could be treated to 30%.
And we’re working right now, among a lot of other things, on a gene therapy for Duchenne muscular dystrophy, and we have a really important readout on that therapy early next year in the first quarter of next year on that therapy from a placebo-controlled and blinded study that we’re working on.
Perfect. Clearly, DMD gene therapy is the main area of focus for the company broadly. But before we get more data there, we’re going to get an update on your first PPMO program. So I wanted to actually start with that. Maybe you could just give us a quick sense for differentiation there and the first trial that you’re running for 5051?
Yes, it’s great. So just apologies for the uninitiated. And then I apologize for those who are initiated and find this far too basic for them, but I will explain it. So we have this technology. This is a Morpholino technology and oligo technology that’s brilliant. And we — what we do with that technology is we don’t find these concerts, we build them. This is really like a micro engineering project. We built them — nucleic by acid — by nucleic acid to essentially edit messenger RNA, put that back in frame and make dystrophin. And we do that very reliably, these therapies very reliably make dystrophin and they’re very safe. But they have a limitation to it. This is not the final place we want to be with respect to Duchenne muscular dystrophy.
This will change the phenotype of children with Duchenne muscular dystrophy and bring a better life to them, but we want to fully transform kids with Duchenne muscular dystrophy. There’s a reason why that cannot fully occur with our first technology, PMO, and that is they’re very precise and they’re very safe, but they’re also neutrally charged molecules. They circulate in the system for only about 4 hours, which means that they get into cells inefficiently.
And so they get into cells enough to make some dystrophin to slow the progression of the disease. But if we could get more of that therapy into the cell, we would almost certainly have far more, what’s called exon skipping in the dystrophin production and then a much better therapy for these kids that could more significantly transform them and extend their life and stop the degeneration, hopefully, or slow it down even greater than the current PMOs do.
That’s the peptide-conjugated PMO concept. So what we’ve done — the issue with the PMOs is that we since its neutrally charged and it leaves the body so quickly, if you just — you could increase the dose of this PMO significantly, you are likely not going to do much more than, frankly, just give the kids a lot of infusion that they can’t use because the therapy won’t get into the cell.
The peptide that we use, which is a proprietary peptide, is positively charged, it drags the PMO, at least in animal models, it drags the PMO into the cells, the muscle cells, in much greater abundance, which will occur — which will, at least in animals, creates far more exon skipping, far more dystrophin production. And that’s where we are right now. Our first therapy, as you know, it’s called 5051. It’s focused on about 13% of the population that have mutations that are amenable to exon skipping 51. And we’re in a multi-ascending dose trial right now.
The big issue for us, of course, is to ensure that we can continue to dose high because we’re very confident about what we’ll see if we can dose high enough without causing a safety signal that will stop our ability to continue to dose high with these children. And so the good news is that we’ve been able to dose already to 20 mg per kg, which is a very good dose, although we’re not done yet. We’re going to continue to dose through this.
And later this month, we will have an update where we’ll, for the first time, provide an update on what we’re seeing, most significantly on safety. What are we seeing? What are the lab results? Are we seeing the signals that would say that we can’t dose any higher? Or that we’ve hit the highest dose we can get to? And we know what signals we’re looking for, it’s renal signals. And then we’ll see as well what the tissue exposure looks like, are we seeing an increase in tissue exposure? Which would be certainly a strong indication that our mechanism of action works. And then we’re going to look at exon skipping as well, which is a marker for the kind of dystrophin we might be able to make.
And so to your point, you said you’ll definitely be showing the 20 mg per kg cohort. You recently announced you’ve gone higher to 30 mg per kg and potentially going even beyond that. How much data should we kind of expect in the upcoming readout later this month?
Well, it’s a small cohort. We don’t think we’ve made the number of patients. But of course, it’s a small cohort at each one of these dose levels. But it will be a very important readout because it will serve as, at least, the first step in our proof-of-concept that our PPMO can be a significant improvement over what already is the most significant therapy yet approved for Duchenne muscular dystrophy, which are our PMOs. And so the data that’s most significant for us is going to be safety, labs, what are we seeing from a lab perspective, what are the signals, are there signals with respect to the labs that tell us that there is a — that we’re already near an upper end to how high we can dose? That’s an important question.
And then what is the tissue exposure. Of course, we’ve seen it in animals over and over again, this increased tissue exposure, which would result in an increased efficacy, but are we seeing it already in patients. And then finally, exon skipping, of course, it’s really important. Exon skipping is that process by which you edit the mRNA itself that would result in the dystrophin. You could see exon skipping even before you can see dystrophin. And so looking at exon skipping is a nice marker for dystrophin production.
Got it. I think as we think about this platform, differentiated ASO technology could be quite valuable. I think with your DMD gene therapy and PMO programs, it can be a little nuanced to think about exactly how PPMO grows the top line. Like, obviously, it’s a technological improvement over the PMOs. But why was DMD the right place to look at here? And how should we think about — if you do have a differentiated platform, where you’ll go next with the technology?
So first and foremost — so we have a mission to serve patients who have rare diseases. Our — the core of our current mission is to bring a better life to kids with Duchenne muscular dystrophy. And that’s why you’ll see that we’re looking at that in every possible way we can. We even have the gene editing approach. Dr. Charlie Gersbach has been spending years looking at actually directly editing the human genome to potentially correct for and bring back into frame the gene that would result in dystrophin. So we — one of the reasons we’re looking at the PPMO for Duchenne muscular dystrophy is, it is central to our thesis for why we exist, to bring a better life to kids with Duchenne.
Second of all, we — there is a real opportunity for — as happy as we are with the PMOs and what they’ve been able to do for families with Duchenne muscular dystrophy. If we know the limitation that they have, and if we can solve for that limitation, we know what that could mean for kids who have Duchenne muscular dystrophy. I mean it might very well mean that we can stop talking about kids with this Duchenne muscular dystrophy and talk about adults and middle aged people with Duchenne muscular dystrophy. So we’re excited about it for that reason.
Then you raise a really good question, which is, okay, that’s fantastic. But you have this really exciting gene therapy, I hope you feel that way about our gene therapy. And if that’s successful, is there a place in the world for both the PPMO and the gene therapy? And that’s a great question. There’s a couple of ways to look — to think about that. First, of course, we’re going to be pursuing everything at the same time without being so arrogant as to drop things while we’re focusing, for instance, on gene therapy, as excited as we are about it.
But more than that, I think there will potentially be a significant place for the PPMO for Duchenne muscular dystrophy, even in the face of a transformative gene therapy, if gene therapy is transformative for a host of reasons. We already know that pretreating with a PPMO, at least in literature, and this wasn’t ours, this was someone else’s. Pretreating with a PPMO could actually enhance the benefits of gene therapy. So we know, as a pretreatment, it could be a real value.
We also know that, as it stands today, the science says that about 15% of kids are going to screen out of gene therapy because they’re going to have preexisting neutralizing antibodies. And so there’s going to be an opportunity for those kids to benefit from a PPMO, if they can’t yet get gene therapy. We’re trying to solve that limitation. But until we do, there’s an opportunity for PPMO.
There’s also going to be places around the world where gene therapy is not going to get yet to it, but the PPMO may be able to get to it. So there’s a significant places around the world where, just from a pure access and reimbursement perspective, gene therapy may not yet be available, but the PPMO could be. And then finally, and we’re doing the animal work on this now, and we don’t have an answer to say that this is definitely the case, but this is the — currently hypothesis.
There may very well be a world in which the best answer for children and then adults with Duchenne muscular dystrophy over the long term, is to get a significant onetime benefit from a gene therapy and then to have an ongoing benefit from an RNA and PPMO over time. So there’s a lot of value there. And then finally, of course, if the PPMO is successful, we can take the PPMO to other rare diseases that could benefit from steroid blocking. That’s the way our PMO technology works, and we’ll certainly do that, and we’re looking at that right now. But we need to get that proof-of-concept in Duchenne muscular dystrophy as a predicate to that.
Got it. Wanted to switch gears to 901, obviously, an extremely important update ahead. There have been a few recent updates on the regulatory and strategy side for this program. So maybe to start, just give us a sense for the recent updates on the manufacturing potency discussions that you had with the FDA? and where you, ultimately, landed on that? And then also on the decision to start Study 103 instead of 301 for now?
That’s great. So let me pull back for a second and talk about the things that we felt. From the beginning of this year, it was important for us to be able to establish as early next year as it’s possible. And there really are broadly 3 things that we were focusing on. With respect to SRP-9001, which is our gene therapy for Duchenne muscular dystrophy. We wanted to show: number one, that the therapy that we have is efficacious, that it’s transformative, that it’s benefiting these kids; number two, that it’s safe and well tolerated, an enormously important issue with respect to gene therapy; and number three, that the process that we’re going to be using to release that therapy commercially, both in the United States and around the world, is substantially the same and performs in the same way as the clinical material that we were using for our trials up to the commercial material that we now have.
And so we’ve done a number of things in service of that goal. The first one is we started a trial some time ago called Study 102, that’s a blinded placebo-controlled trial, 41-patient, 1-to-1 trial. And we’ll have a readout for that early next year, in the first quarter of next year. And if we’re successful, there’s always the if there — if we’re successful, we’ll have shown that the therapy is efficacious. And that it’s safe and well tolerated in a well-controlled trial.
The second thing we needed to do as we were starting this year, is to get the commercial material done and released and then to start a trial that would allow us to confirm to ourselves and, hopefully, others as well, that the commercial material operates and acts the same way as the clinical material. We have lots of reasons to believe that it will. We’ve got tons of CMC that tells us that such is the case. The processes are not that different. They’re both — there’s the same exact construct. They’re both adherent mammalian processes, but it’s a different process for scale up than for the clinical supply. And so we’ve got to show that the material acts the same way.
So we were sitting in the summer of this year in the midst of this pandemic. And we were going to start a large trial that we called Study 301, at least a larger trial, over 70-patient trial. It was going to be — and it is. We’re still going to do it. It’s a global trial, multi-site study, multi-region study, placebo controlled as well.
And then we were also going to do a cut from that study for biopsies of about 10 patients. So that early next year, when that study was running, we would have study to show how the material itself acts, essentially the commercial — what we call the commercial material validation study part of it. And what we realized in the summer of this year was that we’ll be launching this large multi-center, multi-country trial right as the potential second wave of this pandemic is hitting. Of course, it wasn’t hitting when we made that decision, but we were certainly worried about it. And unfortunately, for all of us, I think our worry is coming to fruition.
So in the summer, we divided that study into 2, the Study 301 and the Study 103. Study 301 is still multicenter, multi-country trial, which we’ll start as soon as possible, by the way, early next year. But a leaner study to get the commercial material validated that was far less risky and more executable in the midst of a pandemic, it’s a 10-patient open-label study using the commercial material.
We tracked into our meeting with the vision in early September with the FDA, and it was all on the papers. The FDA did — was unable to give us a live meeting, and the FDA objected to a particular potency assay that we were using. They just objected to the approach that we were taking to our release assay for potency, not the data itself or the fact that it wasn’t potent, but just the approach we were taking to approve that.
The danger of that or the risk there is that, that — if you went through a formal process to get that resolved with the agency, given how busy the agency is and the vagaries of the formal process, this could take months or really significantly longer than months to get resolved. And one of the things one knows with respect to Duchenne muscular dystrophy is that time is not on the side of the children that we serve. We don’t have time. Every single day, every night that a kid goes to sleep with Duchenne muscular dystrophy, they’ve been damaged by this disease. They’ve lost muscle that will not be brought back by our therapy. We can stop degeneration if our therapy is successful, but there’s no thesis that we can bring it back.
So we’ve got to move faster. I’m really proud of the team. We moved sort of heaven and earth, and we have had a very cooperative FDA to work with, and we were able to get an informal meeting 2 weeks after that disappointing news in early September that kind of stopped the progress of our programs. And we went into that meeting with really 3 goals: goal number one, find out what the agency’s concern is with this particular approach that we’re taking to the potency assay. Don’t argue about it, doesn’t suggest that we’re right, just find out what they think; and then number two, give them another assay that makes them — that satisfies their issues. Solve their issues in that meeting. Don’t solve it later, don’t solve it in 3 or 4 months, try to solve it that day. And number three, go for what we can get from the meeting and go for something that we need most acutely, which is a commercial validation study, which is Study 103.
And I’m really proud of the team. We went into that meeting, a very short meeting, and came out with all 3 of those goals achieved. We understood what the agency is concerned with, what were — we were able to propose an alternative approach. They accepted that alternative approach for purposes of Study 103. We proposed that we would start 103. They agreed that, that was acceptable. And of course, that’s where we are right now, and we’re tracking to that.
We will still start Study 301, but that’ll happen next year. But the good news is that we have not been significantly delayed in the program and certainly before the end of the first half of this year — of next year, we should have not only a readout on Study 102, by showing both function and safety, but we should have a readout on Study 103 showing the way this material performs, both from an expression and safety perspective.
So I guess COVID aside and then the rationale kind of makes sense, but COVID aside, could you hypothetically get Study 301 up and running now? Is there anything else needed from the FDA at all to kind of get that trial in place? And if you had to kind of guess, how much time do you think the 103 approach stays on the regulatory side in the U.S.?
So on 301, we’d have to go back to the agency and talk to them and get their concurrence before we start 301. And we won’t go back to them until early next year to talk about that. So we would like to see a quick readout on Study 103 and then commence 301 right around that time. So I don’t know precisely when Study 301 will start, but I think it certainly should start in the first half of next year, certainly. And then we should get a readout on Study 103, certainly in the first half of next year. So we really are in good shape from a study perspective right now.
Got it. So just thinking about the up to 10 patients that you’re going to be looking at in 103. I know you haven’t spoken formally to the FDA about the bridging strategy approach and what they kind of want from those patients. But as we think about expression and variability, how wide can that range be? Like what did you see in Phase I for the 4 people who, obviously, did respond and were seeing expression? And how variable is it based on where you biopsy? And how do you kind of control for some of those elements as well to try to minimize other factors that could affect the variability beyond just the product being given?
Yes. So first of all, we do see variability in expression. We have a 4-patient proof-of-concept study that was a predicate to our starting, what we call Study 102. And even in that study, we see variability. The good news is the variability is all in above that range that would be predicted to be therapeutically significantly beneficial. So the fact that there’s variability doesn’t surprise us. The good news is it’s not like we saw some really middling expression and then some very good expression. It was all a gray and some was extraordinary.
So it’s kind of all — from our perspective, it was all in the great to very great level, but there’s going to be variability. There’s going to be a variability for a host of reasons. And it’s unrelated to the product. This is all from the same [indiscernible], the same dose. It’s a patient-driven perspective in one sense. This is — again, the human eye is just a large organism, and you’re trying to get gene therapy everywhere, and there’s no reason to believe it’s going to be exactly the same in every patient. It’s going to act differently. And of course, then there are the vagaries of taking a biopsy. We don’t — you have a very good point. We get — we take a single — we take two biopsies and average them. And then that’s the marker for what we’ve done.
The biopsies are extraordinarily intrusive, by the way. These children who submit themselves to these trials are heroes. I mean it is not a small thing to ask a person to get a biopsy, and oftentimes, these are open biopsies, where they lose muscle as a result of this, and that’s the most precious thing for these children, let us remind ourselves, it’s muscle, preserving muscle.
So it’s a significant difference. You can’t take — you can’t sample biopsy over many different muscles in these children. So you’re going to see some variability just by the vagaries of when you happen to take or where you happen to take that biopsy. Even between the 2 blocks, when we take a biopsy, you will see some modest differences between those 2 blocks. So there will be some variability in the study, I would not be surprised at all. It’s not the therapy’s variability, it’s not the manufacturing variability, it’s patient variability.
And if you didn’t know I would [indiscernible] if you didn’t accept that variability, you’d have to say you couldn’t do gene therapy for these kids because the children are variable. But the great news is that the expression we’ve seen so far has all been up in the significant therapeutic area, and the kids have responded that way. I think, the first 4 kids, all of them, regardless of the expression, they all had nice expression and some had really nice expression. All of them have benefited functionally across every measure, both at 1 year and even now at 2 years, they continue to improve versus baseline and natural history.
So what we want to see out of 103 is the same range of variability in 103 that we’re seeing in 102. So it’s not that — we just want to see that they’re in the same range. And then we want to see that the safety signals are the same, The safety and tolerability from the commercial supply looks the same as the clinical supply. And certainly, all of our CMC would lead us to believe that, that is going to be the case. We’re very confident, not only have we done a lot of that work, but the work’s come out very well in that regard. But now we’d like to also see it in biopsies.
Got it. Just based on time lines for 102, and when you kind of completed enrollment, it seems like it’s potential — potentially reasonably likely that you might get those results before you get the 103 results. In that situation, do you go to the FDA after 102, assuming it’s positive and talk about the strategy then? Or kind of wait for the 103 results and go to them with the full package?
Yes. It’s a great question. It was an interesting debate internally on that exact topic. So you’re right. We’ll get the 102 results in the first quarter, and we’ll get this — the 103 results in the second quarter of next year. So there won’t be a large delay between them, but there’ll be a delay. And I think consistent with the philosophy that we’ve had for some time, and it’s frankly a philosophy I’m very committed to, I want to go sit down with the agency when we have the data in hand, and that really means 102 plus 103. I think it’s very difficult to ask a very busy — and some would argue, and I think they would all argue, a very overburdened division right now to try to engage with you in theoretical discussions about what the data might look like when it comes out.
I would much rather have that discussion about the path forward when we have the data in hand, and hopefully, compelling data in hand, both from the commercial validation study and, of course, from the readout from 102, the clinical functional efficacy study. So we’ll have that meeting after 103 reads out with the division.
Got it. And so if the bridging strategy works, with the current data package, you won’t have tested 901 yet in the nonambulatory population. Do you think that, that might restrict at all the kind of label you get in terms of age range and ambulatory status until you kind of run some data in that population as well?
Yes. It’s extraordinarily important that we don’t — that we not limit this therapy to ambulatory patients. Let’s just start. Let’s start with that, the why of that. If all the kids with Duchenne muscular dystrophy are in need of a transformative therapy right this minute, but there is no group that feels that with a more compelling sense of urgency than the nonambulatory patient group. They don’t have the time to wait. So we will start as soon as possible next year, a study on the nonambulatory patients. So that our goal is by the time we’re made to get approved for this therapy, we have sufficient data to satisfy the division that our label should not be restricted to a particular age group, but that all ages should be amenable for this therapy. So that is our goal right now. We haven’t started that study, but we want to start it as soon as possible next year so that we have these kids in scope when the therapy is approved.
Got it. You recently presented the 2-year update from — on the Phase I study. And I think the data there was pretty compelling. The patients now are all kind of in the 6- to 8-year age range, which, at least, based on natural history, you’d kind of expect some to start declining. What do you think is reasonable to expect for year 3 and beyond for those patients? And how frequently do you think you’ll kind of update that data set as well?
Well, we’ll eventually be updating it, but I’ve always tried to avoid updating that data set too aggressively while we’re in the midst of a placebo-controlled trial for a host of reasons. I don’t want to create the impression that we’re out of equipoise or — I also don’t want to create the impression that we’re trying to market these first for children. We’re in a placebo-controlled trial. Regardless of what’s going on with those children, the science is going to tell us what’s happening when we open this blinded placebo-controlled trial.
Certainly, our goal, over time, is — what we’ve seen right now is really exciting so far. Open-label for children, so we have to take that into consideration so we don’t overread it. But as you know, across all functional measures, these kids have improved significantly over the period of time that they’ve been watched versus baseline, but equally significantly versus natural history. They’re not performing like a Duchenne muscular dystrophy kid would be performing untreated. They — on the NSAA, which they composites for, every kid was performing and significantly better than baseline. They were about 5.5 points better on a 34-point scale at 1 year, which was extraordinary. And that’s all published in June of this year in JAMA Neurology.
And then we updated with the 2-year data, and the kids continued to improve. There were something like 7 points now in 2 years. They can’t keep improving, of course, because there is a ceiling to the NSAA. What we really hope, over time, is that this is eventually causing stabilization in these kids, and where natural history would have these cases significantly degenerating now by the time they’re 7 and 8 years old, that they’re actually stable. And then if that such is the case, the delta would just continue to grow, showing that this therapy is bringing a much greater benefit to these kids and a better life to the kids with Duchenne muscular dystrophy.
Got it. On Study 102, I know you haven’t given us all of the assumptions behind powering. But maybe just a quick overview on what you had pulled us for how well the trial is powered? And anything you kind of said on what you’re assuming for effect size and [indiscernible]?
Yes. So those are all great questions, some of which I’m not going to answer. I apologize for that. I’ve been very — we’ve been a little cagey on the powering assumptions themselves for competitive reasons, obviously. I will say we were informed in the approach that we took, both by what we were seeing in Study 101 early days, but also our own knowledge of the natural history of children with Duchenne muscular dystrophy. And at least as of the start of this study, we were powered at over 90% at the study. Now that’s exciting, but of course, as exciting as that might be, the real test is going to be when we unblind this and look at the data and produce it in early next year. But the good news is that it was robustly powered at its inception at over 90%. So that gives us some confidence.
Got it. So I guess, to your point, we kind of sit here, we see these NSAA plots, and I’m sure you’ve obviously seen them as well. But they’re a little all over the place, but we’re behind our desk. So we’re looking at a sheet of paper, which is obviously not a reflection of patients in the real world. So maybe you can talk a little about why the extense of variability in the plots that we’re looking at may not be an accurate representation of what we should expect from the patients that you’ve enrolled in 102? If there’s enrollment criteria in place? Or anything like that, that really should bring down that new deviation?
Yes, that’s a great question. I mean, first of all, there will be variability among the kids. There is — although the ultimate course of this disease is certain, there is variability year-over-year in the kids. And so there will be some variability in the powering of the study, presumed some variability in the study. So that, of course, is taken into account in the study — hold just once one second. I’m going to — I fear I’m going to lose you in a second from — my headset maybe dying. Well, if it does, I’ll stop and fix it.
But what we’ve tried to do in the design of the study is to reduce to the fullest extent possible, the amount of that variability. And I think we’ve done it in a number of very clever ways. One thing to start with is, we’ve excluded 2 phenotypes that we don’t intend to exclude from the launch of this therapy or the label because those patients definitively need the solutions, and there’s no reason why they wouldn’t get them. But there is 2 groups, exon 44 amenable kids with an exon 45 deletion and exon 8 amenable kids with I think a 2 through 7 deletion. Those phenotypes are associated with a slower progression. It’s still devastating, don’t get me wrong, slower is relative, but their phenotype’s slightly different. So we don’t — we didn’t want them in the study for fear that, that might actually influence the results in a negative way.
We then limited this — the population to 4- to 7-year-olds, so that we have a tight enough room that we can actually reduce variability. We then looked even more carefully. And one of the benefits of Sarepta over some others is that we’ve been doing this for a very long time. We have more patient-level data than I’m certain anyone else does in the industry, certainly. There are some academics, they have some great data as well, but in the industry, we certainly have the biggest data set of patient-level data and insight.
And actually, what we noticed is that 4 to 5 year olds are very similar to 6 to 7 year olds, but they’re not identical. 4 to 5 year olds can actually gain a point up to maybe even 2 points in the course of the year. 6- to 7-year old, that’s not going to happen. They’re actually coming over the top, and they’re declining, and they can actually decline pretty significantly.
So when we enroll the study, we make sure there’s a balance between 4 and 5 and 6 and 7s on each side of the active and placebo arm as well. And then finally, we’ve got ceilings in the study and floors in the study so that you don’t have outliers that are not trajecting like a typical Duchenne kid and might actually distort the results.
Even with that, there’s going to be variability. But again, as I’ve said, we’ve accounted for that in our powering, and still we have powering at over 90%. But I do think this study has been as tightly controlled as — really as reasonably possible to ensure that when this therapy is successful — but there’s 2 things about the therapy. It has to be transformative and successful, and we have to be able to see it in the trial. I mean those are actually, ironically, not as directly overlapping as it sometimes ought to be. And I think that we’ve done a very good job. The team has done a very good job of keeping this trial sufficiently tight that we should see the benefit that we’re hoping for.
Can you remind us what the extent of the blinded data is that you guys get from the trial? Is it safety, efficacy, dose? And if it includes some read on efficacy, is there a way to kind of look at the data that you’ve got so far and have a sense for is this range of variability, obviously, not knowing if it’s placebo or treated is in the range of what you would expect?
Yes. First of all, I don’t get any data on the study. So first start with me. I don’t have any study. So you — so I would take — you might take my enthusiasm with a grain of salt because this is a blinded study. I have no insight on the efficacy or safety of this study. Other than this, there is a DSMB, and I believe also there is a group in the company monitoring safety to ensure there are untoward safety signals that would require a pause in the study. And certainly, the study has gone — has moved to pace. So as it stands here right now, to the best of my knowledge, not being able to look at the placebo versus the active group, that we haven’t seen any what are called SUSARs. We haven’t seen any serious unexpected safety events that would require us to pause the study.
But beyond that broad signal, I haven’t seen the data at all and nor has anyone else. We’ve been very careful to maintain this blind, of course, are assiduous about it so that the data that comes eventually from this study is going to have high integrity. So we’re going to — unfortunately, for all of us, we’re going to have to wait and unblind this study and look at it together early next year.
Sounds good. On the safety side, obviously, you guys seem to, so far, have a differentiated profile compared to the AAV9 approach in. What’s cumulates thinking for why rh74 seems to have this better safety profile? And how to know that it’s something intrinsic to the vector as well — as opposed to some difference in manufacturing or other factors to consider?
So we’re sort of triangulate on some of those questions, right? And the best guess that we have, and we’re doing some work on it, but still it’s a guess, is it comes down to the capsid itself. There’s a — there does seem to be a differentiation between rh74, which is the capsid that we use, and we’re unique in that regard, and AAV9, which is the capsid that’s been commonly used in other areas, but with some consequences in those areas.
And it might have — and that might give us an enhanced — there’s a potential that it’s enhanced benefit from a safety perspective and maybe even an enhanced benefit from a tropism perspective because there does seem to be some issues about the ability to get good expression from some other programs that are looking at AAV9-mediated micro-dystrophin. And it’s still — there’s still a speculation and the reasons for that we do know some things. We know that rh74 circulates in the system less significantly — for a significantly lower amount of time than AAV9 does. So there’s — just be more opportunity for AAV9 to interact with and cause issues. We’ve seen, at least, in some of the results that we’ve seen so far, we’ve seen some complement-mediated aHUS out of these full-body infusions in 2 other programs.
We’ve also seen, at least in preclinical models, I don’t think it’s expressed itself yet in human clinicals, but we certainly have seen some narrow toxicities associated with AAV9 because AAV9, unlike rh74, significantly crosses the blood-brain barrier. [Indiscernible] on the again, preclinical models on the DRG, the dorsal root ganglion and plus other neurotoxicities. The rh74 doesn’t cross the blood brand barrier. So it doesn’t have those kinds of risks.
So it would have seem to be that it’s an rh74-mediated approach. I would say there are differences between all the programs and sort of all of the main aspects of the construct. We have a very different gene construct than the others. And we use a very differentiated promoter, MHCK7, a heavy chain promoter, that, at least in animal models, suggests that it’s more productive than other promoters. But the best guess that we have right now is that the differentiation that we’ve seen so far, and I should say it’s still so far, but what we’ve seen so far seems to be a capsid-related issue. And it’s certainly is confirmation of Louise’s decision to use rh74, which we are using liberally now. We use rh74 for all of our limb-girdle programs. That’s 6 different — or 5 of our 6 programs in limb-girdle are rh74. And we’re using — now from a research perspective, rh74 for some of our gene editing approaches as well. Since because we’re seeing really good results, both from an expression and so far from a safety and tolerability perspective.
So assuming 102 is positive, the 103 biopsies look good with expression in the range that you kind of hoped for, do you think you can take that package and go to other regulatory agencies beyond the FDA like in Europe or elsewhere in the world as well?
I think we look in — look, again, first, I want to be clear. We haven’t had the dialogue even in the U.S. about that approach. So I can’t say with any certainty that, that approach would be sufficient in the United States for a BLA filing. But it’s certainly something we’re going to discuss with the division when we have the data in hand.
Outside of the U.S., it’s going to be region specific. We’re sort of starting that process with our partners, Roche, around the world. There is — certainly, the case, there are going to be places around the world where Study 301 is going to be an important predicate to approval as opposed to sort of a bridging approach. So it won’t be consistent across the world. Even if we could do that in the U.S., it won’t be a consistent approach. I think there’ll be a lot of places around the world where Study 301 will be the driver for the approval.
Got it. Last question on manufacturing capacity. What’s kind of your latest thinking on how many patients you think you’ll be able to treat at launch? And then 3 to 5 years out How you’re thinking about continuing to build capacity on the manufacturing side?
While we haven’t given details — because we haven’t given forecast details as well right now, yet, we are very confident about where we are from a capacity perspective. And we are — we can say with a higher degree of boldness than we could say last year that we are confident if we are able to get — this therapy successful if the data goes the right way, if the FDA agrees with our approach and if we are able to launch this therapy. Even if we’re launching it alone without someone else helping to fulfill the needs of the community, then we can fully serve the community in the U.S. — and certainly U.S. and some ex-U.S. as well fully. And that we would have — we should have no issue with that. That says a lot because we were — we really started from a standing start to getting to a place where we had, had process development done and then the capacity built by really the beginning of this year.
And I think we’re in a good place right now to build inventory and be able to fully serve the community. There will be a time when we’re going to have to expand that. With our partner, Roche, we have an opportunity to go to places around the world that we could not have envisioned in a reasonable period of time getting to, for example, China is one obvious significant example. And you’ve got 50,000 to 60,000 children living with and dying from Duchenne muscular dystrophy in China. And that’s going to require really a rethink on manufacturing, but we can do that with our partner.
But for launch in the U.S. and then the initial ex-U.S. regions, we feel very comfortable about where we are from a capacity perspective and ability to serve the community.
Awesome. I know, there’s still quite a bit more going on in the pipeline. But I think that’s all we’ve got time for today. This has been really great. Thank you so much, Doug and Ian, for the time and very much looking forward to all of the updates ahead.
Thank you very much. Thank you for your questions, as well.