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

I don't want to step on the 2-year data, I'll let that speak for itself when it comes out. And I think my team would be really unhappy if I jumped the gun on that. But let me say, all of the information that we have seen thus far in our trial continues to give us confidence that our original powering for Study 102 was appropriate. Remember, at the time that we powered 102, we had the benefit of our own -- we have a lot of natural history data and patient level and natural history data that informed our views. We put in -- we had the early reads on what we call Study 101, those kids that gave us some view on what this therapy might be able to do for these children and children who are in this age range, and then we were very careful about the design of the study. As you may recall, we actually have balanced the kids in the 4- to 5-year-old range versus 6- to 7-year-old range across the placebo arm and the active arm, which has helped -- which we believe will help, I should say. It's a blinded trial. It will help reduce standard deviation. We put in ceiling and floors to reduce standard deviation. And so at least from our perspective, and of course, it's all the -- it will all be proven right or wrong when we review the data when we unblind it in early 2021. But our perspective, as we're standing here right now, is that we feel very good about the powering of this trial. But the trial at the time that we went to 40 patients, it's actually 41 now, was over 90%, significantly over 90% power. So we feel good about where we are with the trial. And we feel great about the execution of the trial. One of the -- probably there are a number of risks we took with COVID-19. The first risk one would worry about is the manufacturing itself. The good news is we have made so much progress before COVID-19 hit us, but that has not slowed us down from a manufacturing perspective and release perspective. That's fantastic. The second one, of course, is Study 102. The great news is that those kids have all been dosed before COVID. In the main part of the trial, all had been dosed before COVID-19 hit, and we've been able to manage through those issues with Nationwide Children's Hospital and UCLA, so that we're in a good place right now. And that study will have last patient last visit in December, and we'll have a redound in early 2021. So we're in good shape there. We feel good about it. We feel good about the power.

Okay. Okay. Helpful. And then I guess second thing is some people have looked at, and I'm sure you've gotten this question, some people have looked at the various genotypes of the patients from the Phase I study and suggested that some of those patients had more favorable genotypes than others and tried to, I guess, look at those and make a conclusion about what it might have been if you had different genotypes. I mean any thoughts on how much of a driver those genotypes really are in terms of outcomes? And do you have any concerns about favorable or nonfavorable genotypes among the Phase I population as a good surrogate?

I think whoever is saying that is dead wrong. I mean, I think we have an exon 51 child, I believe, in Study 101. Ian will speak up if I misstating things, but these are very -- these are among the most serious genotypes in study. The 2 significant genotypes that result in a milder phenotype, which are not present in Study 101, of course, is exon 44-amenable kids and exon 8-amenable kids have a 1 through 7 deletion. They're not in there. And they won't be in our Study 102 either. So I think that's a false thesis. Look, it's 4 kids. Let me just say, we do have to be -- we have to follow the science. It's -- one might argue, it's only 4 kids, and it's open label. And 102 is going to tell us a lot. It's a well-controlled blinded study with 41 kids. With that said, I think those first 4 kids who suffer from Duchenne muscular dystrophy and do not fall into a mild phenotype for Duchenne muscular dystrophy appear on the face of it to act functionally distinctively different than one would have anticipated in age-matched kids and their trajectory. And so we're very excited about that. When you couple that with the expression, which would have predicted this, the functional benefit. And of course, the safety, we feel very good going into the readout on Study 102, very good.

Okay. Perfect. So one more question, then I'd like to move on to limb-girdle. But I think one of the other things you talked about manufacturing and your scaling there. Do you remain on track to be able to have thousands of doses available when you launch? Maybe you can just update us on your potential supply around the time of launch?

Yes. We feel great about supply right now. This was the big issue of -- it's probably our biggest issue last year was getting our process in place, getting our yields in place, getting the units in place so that we had the capacity. And we needed all of that. We needed the suites, we needed the units, we needed them installed, we needed them up and running, then we needed the -- more important even than that, we needed the process, right, so that we were getting the right kind of yields. And the short answer is that we're in great shape by then from a capacity perspective. We should be, by the time we're launching this therapy, in a place where we should be able to -- in the United States and in the initial countries around the world, we should be able to fully serve the community. Now there will be a day that will come in the next couple of years where as we think about expanding into other large areas with our partner, Roche, places like China, that we're going to have to think about additional capacity. But that, that's the modular easier part of this. The hard part of it is getting the process development and analytical development, right? And I'm very pleased to say that we're in a good place with that right now. So we feel very good about it. I mean we were -- as you may recall, I mean, this was the question of 2019, and we were like, we're going to get there. We feel good about where we're going. We know what's possible. It's just going to take us more experience and more turns and more process development to get to that place. But the great news as we sit right now is we feel very good about our process development, we feel very good about the yields that we're getting. And we always hope to get even more and more, better for cost of goods and the like, but we feel very good about it from a supply perspective and certainly a community perspective and the like and the cost of goods are acceptable, et cetera. And we feel great from an assay development work. Now we just need to sit with the agency. We need to get their concurrence. We need to adapt our thinking to what they want. And that's going to be our biggest goal here and then get our next commercial process trial going. Our goal is to try and do that as soon as possible.

Okay. Okay. Good. Helpful. So limb-girdle, I think 2 things maybe there. You, obviously, earlier in the year had data on high-dose patients. Maybe speak broadly to what that gives you in terms of your view on safety margin across the platforms. And then second, just talk about, from a pivotal study standpoint what needs to be done there.

Yes. So we are really excited. So just to remind everybody, this is what we've done. With limb-girdle 2E, limb-girdle is beta-sarcoglycan. It's a missing structural protein, very similar to dystrophin with one significant exception, which is that beta-sarcoglycan is the actual native protein that -- you don't have to edit it because the beta-sarcoglycan gene is sufficiently small that it comfortably packages an AAV. So we did a lower dose version. So it was 1/4 of the dose that we used with Duchenne muscular dystrophy, and we had those results out earlier in the year. And what we saw is even at 1/4 of the dose, we got great expression on immunohistochemistry. I think we were 51% protein positive fibers, and I think I'm going to get these numbers slightly wrong. This is off the top of my head, but on Western blot, I think we were in the mid-30s, maybe 36%, if I'm not mistaken, on Western blot. Ian, if I'm materially wrong, he'll correct me. And so -- and was safe and well tolerated from our perspective, so it looks good. And then we saw -- by the way, we also updated recently on the 1-year data on those kids. And even at the lower dose, they look significantly better than that natural history would have said. Now I will suggest that natural history is not as built out with 2E, it is an ultrarare disease versus Duchenne muscular dystrophy, but the kids looked brilliant compared to what we had in natural history. Two of these kids are 14 years old now, natural history would have suggested they'll be in fairly steep decline. One of those 2 14-year olds actually maxed the NSAD, the limb-girdle version of NSAA, maxed it out. So at least that kid -- nobody on this call will do better than that kid at that time point on an SAT. So we feel great about that. But then we did the next thing, which is we dosed up. And we dosed at the same dose as Duchenne muscular dystrophy, as SRP-9001, which, using our super coiled method would have been 2xE^14. And the great news is we saw a significant increase in expression, a dose-dependent increase in expression. These kids are really approaching normal. They're over 70%, I believe, on, I think, immunohistochemistry. So significant increase in expression. Expression is of the native protein, so approaching normal on the native protein. Safe and well tolerated generally speaking. We actually changed the steroid protocol for those kids in a similar way that we're changing it for 102, and we did see elevated liver enzymes with those kids. So generally speaking, it looks really good, and we're excited about that. We're excited about what we'll see there. So now the question is, how do we get to a pivotal trial, okay? And our view is we need to get into a pivotal trial with this limb-girdle and the other limb-girdles as fast as possible. This is an ultra-rare disease, like so many of the limb-girdles we're working on, we're able to -- it's a structural protein. It's the absence of a structural protein. We're able to restore that structural protein in its native form and at really significant amounts. And so we -- number one, we need to get GMP material out. We have GMP material runs going on right now. The big issue right now is just the assay development. You get the assay development done, we'll have that done by the end of this year. We need to have dialogue with the agency, as we you've heard earlier, it's difficult to have informal dialogue with the agency, but we need to have some dialogue with the agency and get the agency's view on what the path forward would be. We're not shy about saying that our hope at least, and I'm not suggesting for a second that we'd get this yet, but our hope is that you can do something like an accelerated approval pathway for these ultra-rare diseases and structural proteins based on the biomarker, which is the actual protein that's missing. And so we'll know that by early next year. And that will inform, not only 2E, but the rest of our limb-girdle programs. And then the second thing I would say about this high-dose cohort for limb-girdle 2E is that not only it has read-through to other limb-girdles, it has read-through to DMD, of course. It's the same vector, rh74, that's used in both. It's the same dose, it's the same promoter. So there's so much similar between these 2 that's seeing expression in safety and limb-girdle at much bigger kids, these kids are over 50 kilograms, gives us a lot of confidence about what we've already seen with DMD. And one of the things that's important and one of the things that you should be demanding, I think, patients and physicians and perhaps investors as well, of companies like us is that we talk to you about the genome copies per nucleus that we're getting so you can see that we're actually able to insert the vector in a high level. With DMD at 2xE^14, we were at 3.3 genome copies per nucleus. And lo and behold, we did the limb-girdle 2E high dose, we're at 4.2 genome copies per nucleus. So we can -- rh74 is working very well, both from a safety perspective, from a tropism perspective, it's really been impressive to say the least, and then the ability to release that cargo and then the kind of expression that we're getting post genome copy being at the right place has been impressive. So I think, overall, the data continues to break our -- in favor of the thesis that we've had around the way that we build these constructs and the use of rh74, particularly for these neuromuscular indications. Manufacturers going brilliantly right now, and now we just have to get to the point where we can release this material and start our next trial with the blessing of the FDA. And we've got some work to do to get that done, hopefully, in the next few months.

Okay. Perfect. And then I guess just one follow-up. Let's assume that you come to a conclusion around the potency assay and release criteria for the material for DMD. Does that have read through then to limb-girdle? Or are you going to have to have a similar discussion around limb-girdle?

We'll have to have a separate discussion about limb-girdle, but it will inform the discussion with limb-girdle enormously. Whatever we decide with the agency for the potency assay approach for DMD will certainly be -- will certainly inform our views. So it will accelerate our views in so many ways, because with respect to gene therapy and the newness of gene therapy, everything we do the first time, we're plowing a new field and where every step forward is a brand-new step. Things coming behind it will benefit from it, will move faster. I can tell you, I don't remember the exact number, I'm not going to say it because I'll probably get it wrong, but the length of time that it took us, as an example, to do the process development for DMD was cut significantly when we got to limb-girdle 2E. That ability to kind of move faster and faster from a platform perspective is going to be the thing that's going to make this a really significant engine. Same answer is going to apply to assay. So in the first instance, one of the first things we need to do with the FDA is really talk to them and figure out exactly what they want from an assay. That will be enormously enlightening for us, and we'll completely apply it to 2E, and then we'll apply it to the other limb-girdles. And then we'll apply it to the rest of the pipeline behind that. Now we've got about 27 gene therapy programs between development and research right now, all of which will benefit from these first discussions.

Okay. Perfect. So maybe just to finish this up. PPMO, just help set reasonable expectations around what people should expect. Obviously, I think you talked about talking about expression, but we're not going to get dystrophin data. So maybe just walk through what the data is we're going to get and why we're going to get that and not dystrophin data?

Sure. A couple of things about it. Just to remind everyone of what we're going to -- what the goal of this multi-ascending dose trial is. So again, I'll just step back for just a second. Apologies, I have to do this. But the PPMO, in many ways, is just an elegant therapy that benefits children with Duchenne muscular dystrophy. It is precise. It does what it's supposed to do when it gets to the right place, creating really something that's really would have been science fiction 7 years ago, editing messenger RNA, putting it back in frame and creating truncated but functional dystrophin. In that regard it's brilliant, and it's got a very laudable safety profile. It has a limitation. There's a reason why our PMOs create phenotypic change, but are limited in how much phenotypic change they can and how transformative they can be. And that, of course, is because they're neutrally charged, so they can then only passively get into the cell. And so it limits the amount of construct that's in the cell and it limits the amount of exon skipping and therefore, ultimately, the amount of dystrophin production. So we are looking for avenues to fix that one issue, to solve that to make the PMOs even more transformative, and that's the PPMO, which is the peptide conjugated PMO, positively charged peptide that, in animal models, works brilliantly. It gets into -- just mechanically drags the PMO across the cell membrane in much greater abundancy. The biggest issue for us, frankly, at this stage, more than dystrophin, et cetera, is can we get to right dosing? Now we tried this before. Some years ago, we tried this with a very different peptide, and it did exactly what it was supposed to do. In the animal models, it significantly increased penetration, it dragged the PMO in, but it did that unsafely. There was a significant renal issue. In fact, it was -- it rapidly ended the study because the animals had enormous renal problems associated with the peptide. So the question then posed was the fundamental question isn't mechanically. It's not the mechanism of action. It's can you dose it. We completely changed the peptide through a whole process of high throughput screening and ripping it apart and testing. I think we've come to the answer on a peptide that can do that without seeing a renal signal. So for us, at least, the biggest issue for us is, can we get to high doses without seeing a significant retinal signal and how high can we go? We -- based on allometric dosing and the like, we had envisioned that we need to get to about 12 mg per kg to really get excited about this therapy. We're already at 20 mg per kg and that's what you're going to see. And it looks like we'll be able to continue to dose through that to 30 mg per kg and perhaps -- perhaps, we don't know yet, even to 40 mg per kg. So what we're going to see later this year is our 20 mg per kg dose. The reason that we're not going to see dystrophin production, but we're going to see exon skipping is dystrophin takes a long time to build. I mean we've seen -- in the PMO, we see it at 1 year, and it actually builds from 1 year to 4 years. So it is through constant tissue exposure, it just builds over a long period of time. This is, I believe, a 12-week data. So it is really too early to be looking for dystrophin production. But we can see exon skipping. So we can at least see the signal of what we would see if the tissue exposure looks good. If the safety looks good, if the dose looks good, we should be able to see a delta in exon skipping, and that's our goal here. So that's the reason between those 2. We're really very excited about this. Now again, we don't have the data, and we'll see the data in the second half of this year. But I think if they're -- if the opportunity to dose at 20 mg per kg and maybe even dose higher than 20 mg per kg up to 30 and 40 exists, we feel very confident about the mechanism of action. And so long as the safety looks good, there is a real possibility this is a transformative therapy over the PMOs. And if that's the case, it could be exciting, not only in DMD, but beyond DMD.

Great. I think we're going to have to leave it there, Doug. But thanks for the time, and thanks for the thoughts. Appreciate it.

Thank you very much, Matthew. Thanks a lot.