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

Good afternoon. I'm Salveen Richter, biotechnology analyst at Goldman Sachs, and we're pleased to have Sarepta with us this afternoon. We have Doug Ingram, President and CEO; as well as Sandy Mahatme, CFO of the company.

With that, Doug, we've seen a rapid evolution of the company over the past few years with Sarepta now positioned as a leader with multiple platforms to address neuromuscular diseases. Can you just walk us through what you see on the horizon when you look out 5 years from today?

Sure. Thank you very much for having us, Salveen. And I've been asked to remind everyone, I will, no doubt, and thank you for the first question, anticipated, I'll be talking about things that may happen in the future. Of course, we -- there are risks and uncertainties associated with that. So I would ask everyone to go to our public filing to get the full list of all of the risks and uncertainties that are attendant with attempts to predict the future. So with that said, let's sort of set it up by thinking about where we were when we entered 2020. So we knew entering into 2020, that sort of 20 -- 2020 into 2021, with the monumentally important period of time for this organization, with a lot of execution that had to occur this year and some significant milestones across 2020 into 2021. Then COVID-19 hit. The good thing, and I said this at the last earnings call, is that notwithstanding the distractions, enormous distractions that occur as a result of this unfortunate horrible pandemic, we've stayed on mission. So we've largely stayed on mission, and we're executing, and really through great work of both the Sarepta workers but also of our partners out there, people like Dr. Jerry Mendell and others, we've been able to continue to execute. So let's think about where we are and where we're going. We're launching VYONDYS this year. Certainly, there will be some impact on that launch and a delay in some of the uptake of that launch as a result of COVID-19, but the good news across both VYONDYS and EXONDYS is that, that impact is not going to be very significant, and it won't be long-lived. It will be short and moderate. Beyond that, we're executing against our plans. So let's start with 9001, and I think it's a lead-in to where we're going to be in 5 years. 9001, which is our gene therapy associated with Duchenne muscular dystrophy, our placebo-controlled trial, had thankfully all been dosed for the main analysis before COVID-19 really distracted everybody. And so we're on track there. It'll be last patient out in December, and we'll have a readout on function and safety, is going to be enormously important early next year. We have manufacturing. We've made an enormous amount of progress in the last 12 to 15 months, thankfully so that when COVID-19 hit, we weren't distracted by that. We'll still have GMP material available in July, then we'll meet with the agency to show the agency what we have from a manufacturing perspective, analytical process development, et cetera. We talked to them about protocol. We'll get started on our next trial, which is our commercial process trial in the second half of this year. So things are going well, and we're executing against 9001. On the RNA side, we've got -- not only do we have the therapies that we're bringing to the DMD community right now will be complete this month with our submission for our third therapy, which is casimersen. And if all goes well, by the first quarter of next year, we'll be one of those rare biotech companies that have 3 internally developed and approved therapies in the United States in biotech. So we're very proud of this. And we've got the PPMO, which is our next-generation version of our RNA technology, and we'll have a readout on that in the second half of this year. And then just yesterday, thinking about our gene therapy platform as a whole, yesterday, we announced the results from our high-dose cohort for limb-girdle type 2E, which will inform the dose selection for 2E. It will inform the rest of our limb-girdle platform. We have 6 total programs in limb-girdle, including the one with Nationwide and Zarife Sahenk. And it's been very validating in giving us additional confidence around what we're seeing in Duchenne muscular dystrophy with SRP-9001 as it is indeed the same capsid, rh74, it's the same promoter, MHCK7. And it's the same dose at 2x10^14. So seeing the expression and genome copies for nucleus and safety has been an additional confidence across the entire approach we're taking. So then when we look out into the future, and we look out 5 years from now, it is undoubtedly our goal to be one of the most meaningful, and I use the word meaningful as opposed to big, because what we're doing is so important from a mission perspective. So meaning the -- one of the most meaningful genetic medicine companies focused on gene therapy and RNA treating rare disease and bringing a better life. And if we do it right, by 5 years from now, tens of thousands, hopefully, of patients who are otherwise consigned to much shorter lives and daily degeneration will be profoundly improved because of the work of the Sarepta workers and the partners that we are engaged with. So that's kind of the broad goals for it.

And then, Doug, you have 40 programs in your pipeline, 27 of which are gene therapy and some are actually gene editing and other modalities. How are you thinking about portfolio management and how you manage -- how you move these programs forward and how you pick? And then also, what are you doing with gene editing, I guess, as -- I know you're focused on gene therapy now, but what are next steps there?

Yes. So let's think about portfolio management in the first instance. We have 42 programs or so that we talked about or we have talked about. And one might look at that and think, well, my goodness, how on earth can you execute 42 programs all at one time, even though we have an enormous amount of resource, our balance sheet, we had $2.2 billion on our balance sheet as of the end of the first quarter. How does that happen? Well, the answer is we have a very clever approach to multiply our effect without distracting ourselves. So a significant number of the programs that we talk about are actually partnered programs, where we allow our partners who many of which are the experts in their areas, to do the preclinical work and the advancement of the therapies up to the point of clinical development. And then we'll evaluate them. So we really look at that as a portfolio and ability to essentially increase the sort of shots on goal and multiply the effect that the organization has. So we have got this sort of alliance management portfolio approach to the early stage, efforts outside of the organization. They feed in to our development approach. And then, likewise, we have both an RNA research group, and we have a gene therapy center of excellence in gene therapy research group. And they also bring forward construct. So we have a significant portfolio today. It will remain significant and probably become even more significant over time because we have these feeders into this development approach creating what we call our genetic medicine engine, or a gene therapy and RNA engine. And then you raised the interesting issue. We're focusing from a development perspective today on gene therapy and RNA, but we have an interest in gene editing. We see gene editing today as a research. We don't think, at least with respect to neuromuscular diseases, it's at a place right now where it is ready to go into demand. But it's a really fascinating approach to genetic medicine. And so we've got -- we've had a significant relationship with Dr. Charlie Gersbach at Duke University around the research associated with gene editing. And we have started this year building out a gene editing innovation center. So we actually have a facility already in place and notwithstanding all of the distractions with COVID. We're hiring there now, and our entire genetic -- our gene editing center of excellence will report in to Dr. Charlie Gersbach who, in turn, will report to Louise Rodino-Klapac, our Head of gene therapy broadly. So we see -- in the future, we've got this development path for RNA and gene therapy, and we've got a lot of tools for advancing genetic medicine in the future. One of those tools is gene editing. And we think that's a very interesting concept down the road. But we've got other tools as well. We've got a relationship with StrideBio. StrideBio is the next-generation approach to capsids with rationally designed capsids. And we've got this new relationship with Dyno, one of Dr. Church's companies, to focus on artificial intelligence and build new capsids. We're looking at a number of other innovative approaches to delivering genetic medicine, gene therapy and gene constructs as well, even beyond AAV, which we'll talk about in the future. So we've got a lot to focus on now. We've got a great pipeline for the future, and we're building the tools to play a significant role in advancing the science when we look out 5, 10, 15 years into the future as well.

And then should we expect you to kind of stick to the current portfolio of assets? Or should we expect additional BD? And are you adjusting your muscular focus company at this point?

So we're already -- we've already evolved beyond just neuromuscular, we're today, neuromuscular and neurology as well -- and one of the things we've said over time is we're going to let the science drive us, and we're going to be driven forward primarily through adjacencies so that we can move into new areas, but move into new areas where we have enough base of understanding that we don't allow, for instance, the Dunning-Kruger effect to take it over, that we don't get to places where we're so bereft of expertise and knowledge that we make missteps. So we'll move through adjacencies as we move out. But from a business development perspective, business development has been a big part, essentially, of the fuel for our development and in research pipeline. And one ought to assume that we'll continue to do that in the future. Now we're disciplined about it. So we're very thoughtful about the deals that we do. But you can envision more business development similar to the business development we've done, both from a construct perspective but also from a tool perspective as well. You've seen a couple of those tool alliances that we've done over the last 12 months or so.

And then what are your thoughts with regard to building in-house manufacturing at some point?

So as it stands, it is something that we are looking at, and we will continue to look at. What we have right now, and I'm very pleased with the approach that we've taken. I think it is bearing an enormous amount of fruit. And it started as a concept, and it has become a reality. One of the things we said early on when we thought we had something very exciting to bring a better life to children with neuromuscular diseases like the LGMD limb-girdles is that we needed to move fast by building expertise on manufacturing. And the way we decided to do it was through this concept of a hybrid manufacturing model where we would take -- essentially, we would borrow some of the expertise of others by aligning ourselves with the best and brightest in gene therapy manufacturing. We would end up in a place where sort of the brick-and-mortar of gene therapy might be -- there might be landlords for that, but that all the intellectual aspects of gene therapy we build in-house. So our concept was build a bunch of capacity. Build -- get facilities going. Build capacity. Get suites. Get iCELLis units in those places, et cetera. Build expertise inside the organization from a process development and an analytical development. And that's what we've done along the way. We've got a facility up in Burlington, Massachusetts, dedicated to process development and analytical development. We have analytical development expertise in our gene therapy center of excellence in Columbus, Ohio. So as we sit here today, we're in a really privileged place. We've got a significant amount of manufacturing capacity, probably one of the most significant manufacturing capacities that exists in all of biotech today, and that includes big pharma as well. And we've got the expertise on process development and analytical development. And I can tell you, the greater the strides that we made from an AD and PD perspective in the last 6 to 9 months came out of our own work. So we essentially are the intellectually differentiating aspects of manufacturing. We already [ are ]. And then the question is, would it be a benefit to us to have some part of our manufacturing as well in-house from just a brick-and-mortar perspective as well, and we're looking at that. And there may be a value to that, simply the ability to move faster at times and the like, having some direct manufacturing. But just so we know, it would -- we would always still want this federated approach as well where we've got relationships and essentially landlords with Thermo Fisher and Brammer and Paragon, Catalent and the like.

And then, Sandy, I mean it looks like you have a pretty significant balance of cash reserves here. Is that -- I guess how are you thinking about using that cash with regard to the type of BD deals you might be doing? And are you comfortable with being able to use that as you look to the trajectory in the future of what you need to execute across with this portfolio?

Yes. As Doug pointed out, our cash balance was, at the end of last quarter, was about $2.2 billion. We have 2 approved drugs, hopefully, a third approved drug next year. We have cost-sharing from -- coming in from Roche. So we feel we are in a very strong cash position. In terms of capital allocation, the focus is obviously manufacturing, as Doug pointed out, specifically commercial manufacturing and shoring of our inventories as we go into launch. As far as BD is concerned, we continue to add adjacencies, technologies that can help us and future generation technologies, whether it's redosing or exosomes or what have you. But in terms of transformative technology, our transformative deals, that's not something we are thinking about right now. There'll be bite-sized deals that just flesh out the company, add future indications. As we get more visibility next year with our DMD data Study 2 and as we saw, as of yesterday, with the limb-girdle data, as we feel more and more comfortable, we look at other kinds of deals. But for now, we don't think BD is going to be something that's going to be transformative from a financial perspective.

And Doug, moving to the pipeline here. So with the DMD gene therapy program, you're currently in the process, as you mentioned, of scaling to commercial supply and having the GMP material ready. What more needs to be done? And what are those 2 remaining assays, I think you've mentioned before out of the 24 that need to be developed here?

Yes. So good news on the -- let me answer the last question first. At my earnings call, I said that we had 24 assays that needed to be built and then either validated or qualified. Some we validated. Some we qualified. 22 of 24 -- 24 had been built. 22 of 24 had already been validated or qualified. Today, all of them are done. So all of our assay work is complete. All of our process development work is complete. We have multiple GMP runs going right now. We'll have GMP material by July. The significant things and the broadest of strokes that need to occur is, first and foremost, we need to meet with the agency. So after we have the material in hand, we need to sit with the agency and go over a number of things, the CMC, the manufacturing approach, comparability, all of those related issues, of course, and then also look at the protocol for Study 3. And then after that, of course, we need to start study, what we broadly call it, Study 3 or Study 301. And we'll do that in the second half of this year. We have delayed it a little bit, purposefully sort of thoughtfully, because we're in the middle of a pandemic. And we want to make sure that we don't rush so fast that we -- we want to make sure that every site that we engage is ready to be engaged, is going to stay open, that it's going to be able to keep these kids safe at the same time. We want to make sure that we can get in. There's a lot we can do virtually, but we also want to make sure that we can get into these sites and do live training, do live site initiation as well, to make sure that we have strong concordance across the sites and a rigorous approach to the study. So we'll start the Study 301 in the second half of this year. We'll certainly have first patient in this year. So we're in good shape there. Then in the future, what else do we have to do? The last patient, last visit of our placebo-controlled trial with Nationwide will happen at the end of this year. So that means we'll QC that data in the first quarter of next year. We'll have data. And what we'll have, if all goes well and if we're successful, we'll have 3 things if we're successful. Number one, we'll have shown that our therapy is efficacious, that our therapy is benefiting and transforming children with Duchenne muscular dystrophy, and we can get that out of Study 102. We'll have safety data. We'll have a -- we already have, by now, across the 101 and 102 and the crossovers in 102, we were upwards of about 35 or more patients who have already been dosed with active therapy. So we're going to have a very substantial safety database in the first quarter of next year. And then we'll have, if all goes well, an interim cut from Study 301 on expression, showing the comparability, not only from a CMC perspective, but from a biopsy perspective, between Study 301 and 102. And on that basis, we'll have a dialogue with the agency about the pathway forward. But of course, it will be our view that we should move to file for the therapy and to get the therapy to kids that are waiting, assuming that we're successful.

And I know you haven't started 301 yet, but has COVID, in any way, impacted how you've been thinking about trial design?

It doesn't affect trial design. I mean there are certain things we're doing. We are trying to find ways -- one of the things that Dr. Gilmore O'Neill, our Head of R&D, talks often about is this idea of bringing the trial to the patient as much as possible. So there will be elements. There'll be elements from COVID-19. We're taking some of the learnings out of COVID-19 and finding ways to make the studies less burdensome among patients, okay? From a broad strokes protocol perspective, Study 301 isn't significantly different than what it would have been pre-COVID. And what we just need to make sure now is that we get into -- that we can get into the sites, that we can have live meetings in the sites now, that we can train properly, so that everyone is clearly aligned on infusion protocols, functional assessment protocols and that we can assess that, given the macro issues in the particular regions around the world as well as the particular institution protocols, that those sites are going to stay up and running and admitting patients and the like once we initiate the study. So that's one of the reasons we're taking a couple of extra months to put ourselves in a good position for Study 301.

Okay. So at the recent ASGCT conference, we saw updated DMD gene therapy data from competitor, Pfizer. And what are your views here on the current competitive landscape in DMD? And what do you see is the biggest differentiator between your programs and the other -- your program and the others pursuing micro or mini-dystrophin gene therapy?

Yes. I'm going to try my very best to not be overly competitive and just put -- just talk about the facts. These programs are different from one another in the current structure that they're using. They're all forms of microdystrophin, both Solid and Pfizer and Sarepta. But Solid and Pfizer are different than Sarepta. Solid and Pfizer use AAV9, and Sarepta alone uses rh74. Solid and Pfizer use a miniaturized CK promoter. And at the guidance of Dr. Louise Rodino-Klapac, we use MHCK7. And in the gene cassettes themselves are very -- have significant differences between the respective repeats that are used, where the hinges are placed. So not just talking about our rh74 and our program specifically and what we're excited about. First thing to know when we see the results that we're seeing right now is that that's not mere serendipity, that Dr. Louise Rodino-Klapac spent many years, and well over a decade, testing -- designing and testing empirically, then amending, retesting, optimizing that construct. And then the limb-girdle constructs, before we ever moved to patients that started dosing patients. And I think that explains why we're seeing what we're seeing perhaps. And what do we see with rh74 and MHCK7 and these gene cassettes? We're seeing, in our first group of patients since 101 at 2x10^14, we're seeing really impressive expression, right? We're talking about in the 80% to 95% expression, depending on the particular measure that you use. Really significant genome copies per nucleus, 3.3 genome copies per nucleus over -- on Study 101 and DMD. And that's really important. Think about genome copies per nucleus. That is going to correlate with a lot of confidence around durability when you have that kind of level of genome copies per nucleus. And then, of course, from a safety perspective, we -- in 101, we did not see complement activation. We did not see platelet counts that were dropping below the normal range. We did not see the kidney issues that have plagued other programs and the like. So we're really excited about that. And then we look over at limb-girdle, and what we announced yesterday is exciting for limb-girdle 2E, and it's exciting for the rest of the limb-girdle program. But it's also exciting for DMD because it's additional confirmatory evidence around what we saw in 101, what we believe we're seeing in 102, which is we dose at 2x10^14. So we're talking same vector, rh74; same promoter, MHCK7; same kind of therapy, which is the replacement of a structural protein in the dystrophin-associated protein complex, same dose, 2x10^14. And when we did that, what did we see? We saw very laudable tolerability. We had 1 kid that had an SAE, but that SAE was dehydration associated with vomiting. You do get some nausea with these full-body infusions. But it resolved very quickly. But otherwise, we didn't even see the elevated liver enzymes that we saw in the first instance, which was great news because we changed the protocol, and they have solved that. But more important than that, we didn't see complement. We didn't see platelet count drops below the normal range. We didn't see kidney issues, and then we saw just enormous expression. If you walk over to the limb-girdle type 2E and we're getting 4.2 genome copies per nucleus. I mean I remember back in early -- or mid '17, 2017 and fall of '17, when I was meeting with experts around this issue of full-body infusions in gene therapy, the biggest question was, really, could you really do a full-body infusion and get genome copies to the right place in any amount that's sufficient to be meaningful in creating expression? And here we are, 3.3 to 4.2 genome copies per nucleus in muscle cell. That's enormous. And then of course, with expression, we're nearly 75% or so expression across immunofluorescence and protein-positive fibers and intensity and western blot with that safety profile. So I think broadly speaking, it's really just focusing on our own program. We are very excited about the building of evidence around the entire approach that we're taking to gene therapy. And with respect to these neuromuscular diseases, the use of rh74, the use of this MHCK7 promoter, what it might mean, and the intelligent approach, the thoughtful approach to the design and optimization of the gene cassette itself, it probably plays some significant role in the expression that we're seeing both in DMD and limb-girdle. So we're very excited. I have to say, just kudos to Dr. Louise Rodino-Klapac and her team who, even before she was at Sarepta, is the person responsible for the design and optimization of all these constructs and the use of rh74.

And then what are your thoughts on western blot versus liquid chromatography, mass spectrometry protein detection methods, as it relates to measuring microdystrophin? And can you also just comment on the natural history databases? Are these validated at this point?

Well, so first of all, we're using western blot, as everyone is, by the way, I just want to be very clear. Let's not fudge this up. Everybody is using western blot. Whether we're talking about western blot, whether we're giving -- we're revealing data regarding western blot that may be a different industry. Everyone is using western blot. And there's a reason why everyone's using western blot. It is the gold standard. It is the only thing, so far, the FDA has ever accepted as the quantification for the production of dystrophin. It's the way that our last 2 therapies were approved. It's the way this therapy will be approved, casimersen, if it's approved. With western blot, and we're quite expert now in the ability to quantify and conservatively quantify dystrophin reproduction using western blot, so that's why we're looking at it. Using alternative measurements like mass-spec is interesting. It just hasn't been used before. And certainly, if we had mass-spec data, we would provide it, just as I think anybody should provide the data they have with respect to quantifications. So we're very pleased with the western blot approach because it's the approach that's been accepted. It has been the gold standard for a long time. And then with respect to the -- there's -- on DMD, in particular, if you're asking about sort of the natural history, there is a significant amount of data and literature on natural history with respect to Duchenne muscular dystrophy. So it is approaching well-characterized as a natural history set. And we have probably more natural history on a patient-level basis than anybody, given that we've been doing it -- we've been in this area, working on this mission for over 10 years. We've got placebo-controlled data. We got placebo-controlled data we've gotten from others. We have our own patient-level data. We have access to patient-level data from significant registries as well. And so we have a very good view on what you should be seeing from the case of DMD. Limb-girdle is different. Limb-girdle, in some ways, is different. Limb-girdle is a very rare disease. And so the amount of natural history associated with limb-girdle is less robust than you would see with DMD, certainly with 2E, which is extremely rare. But the good news with what we're seeing so far is if we were seeing sort of moderating the decline right now in 2E, it might be difficult to compare that against a fairly thin natural history set and ask ourselves if that's meaningful. But at least as it relates to our low-dose cohort, we didn't see that. We were seeing across every measure, every patient, significant improvements, not even stabilization but improvements on functional end points, with 1 child, as an example, actually masking out the composite score NSAD. So that literally -- none of us on this web could do better than that patient, which gives us a lot of confidence in what the limb-girdle 2E may mean for these children.

Maybe just a last question here on the gene therapy program for DMD. But when you look to -- if this drug is to get onto the market, how are you thinking about supply here with how much you can manufacture over a set period of time?

So there's a lot of nuance that we haven't revealed only for competitive reasons, but so we're very clear about our goal. We have -- we started some time ago, like we were investing significantly in manufacturing 2 years ago when this was just an idea at risk and amounts of money that might have scared people at the time, hundreds of millions of dollars in manufacturing. And we did it all to put us to the place now that when we launch this therapy, if we are so fortunate as to have a successful therapy and get approved in our serving the community, then we can fully serve the community. Even if we're [ alone ], we can fully serve the community, at least in the U.S. and Europe, which is kind of the broad stroke initially. And then what's interesting now the next level that we have to think about, and this is where we don't yet have answers, but we have to work with them, is we've entered into an alliance with Roche. And the goal of our alliance with Roche, in addition to some things that were great for us during this pandemic like bolstering our balance sheet, we got -- just about $1.2 billion upfront. So we had $2.2 billion at the end of Q1. But more important than that in other economics, and the economics are significant milestones and back end royalties and the like, is we can get this therapy to just an enormously greater number of patients much faster than we could ever have done in our own way. Example, China. China's got 60,000 DMD children there. And it would be foolhardy for Sarepta to imagine that it was going to make, on its own, any real headwind in China. Now Roche can deal do with. That's going to create its own interesting issues that are associated with manufacturing, and that's work that we need to work on over the course of the next year or so, how do we actually build out that level of capacity for the rest of the world. But we'll work on that. But from a launch perspective, both in the U.S. and then in some other places around the world, like Europe, early days, our goal is to fully serve the community without being on back order. And that's the way we're building our capacity.

Great. And then limb-girdle, so you did announce data yesterday. Could you just recap it for us high level? And then what -- I guess what do you have to analyze to finalize the dosing in third quarter? And then what are next steps for this program?

Well, I would just say on that last part, it's hard for me to answer that second half. And I'm not sure what else we need to analyze. The truth is when you look at the data, while we are officially making a dose selection in the third quarter when we said that, there -- it is really difficult to envision that we're not going to move forward with the high dose. So I want to be direct about that. What we saw -- so let's think about what we saw on the low dose cohort, the first cohort, which using our titering method is 5x10^13. And at that dose, we saw great -- we had great results. We had protein positive fibers of 41%. We had intensity levels of 47%. We had a western blot of 36%. We had great reductions in creatine kinase, and we had genome copies of about 0.6 per nucleus. And then you look at the functional data there, and it just looks fantastic. We updated the 1-year functional data yesterday. As I said before, every child, every functional measure is improving significantly. Some of those kids are now 14 years old. And they should be -- under the natural history that we have, they should be in fairly steep decline, and they're not, and they're not stable. They're actually improving pretty significantly, as I've said. So Cohort 2. So we said, okay, we already -- so we have a therapy, right? One would say, we have a therapy. But let's see if we can get even better expressions. We definitely have a mantra with these structural proteins, which is more is always better. We're trying to not just save the life of a kid and improve the life of a kid for 5 years or 7 years or 10 years, but we're trying to get durability that we'll be out longer than we can predict right now, right? 10, 15, 20, 30 years out into the future, that's got to be at least our aspirational role. And the best chance of that is to get the greatest expression, to get the greatest number of genome copies per nucleus and to get the most robust results if we could do that safely. So we went to one higher dose, 2x10^14, which is the same dose that we did with DMD. So we had some confidence about what we would see, at least from a safety perspective. And what we saw across the Cohort 2 is significant improvements on every measure and still remained tolerable. I mentioned the one SAE, which was associated with dehydration from vomiting that resolved rapidly with antiemetics, but other than that, it was quite tolerable. And we saw protein positive fibers went from about 50% to well over 70%, I think 72%. We had intensity levels went up to literally almost 3/4. So almost 75%. I think it was 73% for intensity. And if one wonders what that means, just look at the images, look at the immunofluorescence images, look at the normal control, then look at the kid's predosing. Well, you'll see the inky blackness, these kids had no beta sarcoglycan. And you look at what they had afterwards, and it was lit up, which is exciting. Western blot went from about 36% to almost double that to 62%. And the genome copies per nucleus was 4.2. So just great genome copies per nucleus. CK dropped almost 90% in the first 90 days. So -- and then there's a lot of other things. The protein was probably localized to the sarcolemma, where it needs to be to act like a functional structural protein and benefit these children. And it was associated with almost a 1:1 upregulation of alpha sarcoglycan which says that it's reconstituting the dystrophin associated protein complex, again, acting like a functional protein. So we're really excited about the results we saw. Obviously, in the high dose cohort, really exciting for what it means for 2E and what it means for limb-girdle. And of course, we're very pleased at what it confirms that we saw some time ago with our Study-101 in the first 4 patients with respect to DMD and SRP-9001.

And the thought [ into ] that you would have the GMP material ready for early 2021?

Correct. Correct.

And then how are you thinking about read-through from this study to 2B and 2C? Just -- and is there an opportunity to expedite development of those programs as well?

So we hope so. And we think there's an enormous amount of read through. Those -- all those therapies together, the sarcoglycans, they're all associated with the dystrophin-associated protein complex. The phenotypes are very similar across those 3 diseases. They are separate diseases, but they are very similar. And the therapy that we have does the same thing in all 3. It delivers a gene that codes for the native protein itself. And they're all monogenic well-characterized diseases. So we do believe that the insight that we're seeing, both for safety and dosing with respect to 2E, will linear completely to the benefit of the other sarcoglycans. Now the exact development pathway is going to require discussions with the agency. We're already in those discussions. That's going to take the rest of this year. We're going to take the time available to us because we have this time, because we got to get the manufacturing in order in any event, to work with the agency, to define the -- from our perspective, but equally important, of course, from our regulator's perspective, the most expeditious but appropriate development and regulatory pathway, for not only 2E, but for the other sarcoglycans as well. And once we have that in hand and our manufacturing, we'll come back, hopefully, in the first quarter of next year, talk about the development pathway, the regulatory pathway for all the limb-girdles, and then we'll get started on our pivotal trial next year.

Got it. Thank you. And then when you look to the PPMO platform, so we're going to see initial data here from 12-week Phase II data, the multi-ascending dose data. Can you -- could you just frame expectations about what -- how we should be thinking about the level of dystrophin expression that you're looking to achieve? I think you've mentioned maybe an 8 to 12x improvement in the past over the PMO platform. And then what were you trying to optimize on the safety side?

So I don't know what we're going to see. Our biggest goal is just to -- do we see a profound improvement in betterment of the PMO? So to remind us of what we have with the PMO. So PMO is, in many regards, just a brilliant platform for Duchenne muscular dystrophy in particular. It is precise. It always creates exon skipping and that creates dystrophin production. And think about how clever that is, a therapy that actually edits pre-messenger to messenger RNA. I mean it would have been science fiction some years ago. And safe, we can dose at very high levels with the PMO as well. So really a fantastic platform. There is a limitation to the PMO, a significant limitation. It's a neutrally charged molecule. It clears the body in about 4 hours, so it has a limited opportunity to get into cells, and that's why we get a limited amount of it in the cells. And while it creates phenotypic change in children, it doesn't create the amount of dystrophin that would be massively long-term transformative that changes the phenotype and gives it a better life, and it keeps them out of a wheelchair and all of those things. But our goal is to do even more than that over time. That's the goal of the PPMO. PPMO is called PPMO because it's a peptide conjugated PMO. The peptide is a positively charged peptide. And so in animal models it very reliably, very reliably, pulls in far more PMO into the stell, just mechanistically. And the PMO creates significantly more exon skipping and significantly more dystrophin production. And you can envision multiples higher in the PMO. I don't know what precisely it would be, but that's what you would see in an animal model. Now the big issue is, remember, I said the first 2 was precision. We'll still get precision because it's still the PMO. And safety. So the big issue for the PPMO is safety. Can we dose it? We know if we dose it at the higher -- at the right levels, we get this mechanistic approach and we get more PMO and we can get more exon skipping and dystrophin production. And the big question for us is, can we do that? We tried it once before in the past, and it caused kidney issues. It caused renal issues, significant renal issues in animal models, and that made that particular peptide not possible. We redesigned the peptide. We did -- we ripped it apart, did a bunch of high throughput screening, put it back together again and thought we solved it and in non-human primates and other animal models, we have. So then we get to very high levels before we started getting the renal signals, which we would eventually get no matter what with this. But that we got -- we could get to high levels before we had that. And that was the presumption that we were using what went into this PPMO single-ascending to multi-ascending dose trial. What we had hoped for to see something significant, at least based on animal models, and I do want to say there's a limitation to what animal models could predict, was to be able to get to something in the sort of bottom of 6 mgs per kgs, to maybe as high as 12 mgs per kg. But we're right now at 20 mgs per kg, and we're dosing multiple children at multiple doses at 20 mgs per kg without the risks that we are worried about coming into fruition. So I don't know what we're going to see in the data yet, and we'll have to see that data together when it's revealed. But we are certainly very encouraged by the fact that we've been able to dose through the doses we thought might be limiting, and get to 20 mgs per kg already, and actually, now we're designing to go higher. So we're trying to go higher even to 30 and maybe been up to 40 mgs per kg by the end of this year. But the data that we'll look at in the second half of this year will be 20 mgs per kg, and we'll look at safety. We'll look at dose. Those are the 2 big ones. We'll look at PK/PD, and we'll almost certainly look at exon skipping as well, which will correlate to dystrophin production. It's probably too early to start looking at dystrophin production for an RNA therapy. But from an exon skipping, it'll give us that correlate because it's the exon skipping that results in the dystrophin production itself. And then we'll be able to correlate what that might mean for the therapy at 20 mgs per kg.

Great. And then one last question here, Doug. What's playing out with the Charcot-Marie-Tooth program.

Well, the Charcot-Marie-Tooth program, we're very excited about the Charcot-Marie-Tooth program, and it's just the program that's run by Nationwide Children's Hospital at Nationwide's Children's Hospital with Zarife Sahenk. That program is waiting for manufacturing material. And we were supposed to have it last year. We're still waiting for it right now. So the delay that we have in CMT, which we're frustrated with, but I can guarantee you, so was Dr. Zarife Sahenk at Nationwide, comes from the fact that we just don't yet have the manufacturing material for it. So our goal is to see if we can get that material this year, and if we can, we'll start that trial. But that's the big rate limiter for CMT is manufacturing.

Great. With that, thank you so much for joining us. Thank you, Doug. Thank you, Sandy.

Thank you so much. Thanks for having us.

Take care.

Thanks, Salveen. Bye.

Thank you.