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

Good morning, ladies and gentlemen, and welcome to the Sarepta Therapeutics' Clinical Update SRP-9003 for Limb-Girdle Muscular Dystrophy Type 2E. [Operator Instructions] As a reminder, today's program is being recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today, Ian Estepan, Senior Vice President, Chief of Staff and Corporate Affairs. Please go ahead.

Good morning all. Thank you and thank you all for joining today's call. Joining me today are Doug Ingram, Dr. Louise Rodino-Klapac, Dr. Gilmore O'Neill, Sandy Mahatme and Bo Cumbo. After our formal presentation, we'll open up the call for Q&A. I'd like to note that during this call, we will be making a number of forward-looking statements. Please take a moment to review our slide on the webcast, which contains our forward-looking statements. These forward-looking statements involve risks and uncertainties, many of which are beyond Sarepta's control. Actual results could materially differ from these forward-looking statements, and any such risks can materially and adversely affect the business, the results of operations and the price -- trading prices of Sarepta's common stock. For a detailed description of applicable risks and uncertainty, we encourage you to review the company's most recent annual report on Form 10-K and the most recent quarterly report on Form 10-Q filed with the Securities and Exchange Commission as well as the company's other SEC filings. The company does not undertake any obligation to publicly update its forward-looking statements. With that, let me turn the call over to our CEO, Doug Ingram, for opening remarks. Doug?

Thank you, Ian, and thank you all for joining us today as we provide an update on our limb-girdle muscular dystrophy 2E program. In a moment, Dr. Luis Rodino-Klapac will present the data on Cohort 2, our 3-patient higher dose cohort with SRP-9003, which is our gene therapy designed to treat LGMD 2E by transducing skeletal and cardiac muscle with a gene that codes for native full-length beta-sarcoglycan, the protein missing in limb-girdle Type 2E patients and the absence of which causes the progressive muscle degeneration and shortened lifespan that is characterized by this disease. This is a profoundly meaningful readout for a number of reasons. First, it will tell us if we can safely obtain a dose-dependent increase in expression and will inform our dose selection for limb-girdle 2E. Second, it will inform our dose decisions and development pathway for our broader limb-girdle platform, and in particular, the rest of our sarcoglycan portfolio. And third, it provides additional safety transduction and other evidence and read-through for our entire rh74 platform, and in particular, our separate gene therapy program for Duchenne muscular dystrophy, which is SRP-9001. To remind you, while our limb-girdle 2D -- 2E therapy, SRP-9003, codes for a different but related protein in the dystrophin-associated protein complex, it shares much in common with SRP-9001 for BMD. They both employ the same vector, rh74; they both employ the same promoter, MHCK7; and with Cohort 2, they employ the same dose. Albeit for this cohort, we are treating older and heavier patients. And with that, I will turn the presentation over to Dr. Louise Rodino-Klapac. Louise?

Thank you, Doug. Thank you, and good morning, everyone. And today, for the purposes of this call, I'd like to do an update on Cohort 1. I'll remind you we've previously shown data from our low-dose cohort, so we'll be reminding you of that data along with the updated 1-year functional data. We'll also be showing you the biopsy data from our high-dose cohort or our Cohort 2. Now as a reminder, limb-girdles are devastating muscular dystrophy. These are all monogenic rare neuromuscular diseases, and they affect hundreds of thousands globally. Monogenic, meaning that there's an individual gene that's missing or nonfunctional in each of these related disorders. Limb-girdles affect males and females equally. They affect skeletal muscle, and in many cases, cardiac muscle as well. They're characterized by elevated creatine kinase levels, which is an enzyme that leaks into the serum [ before ] muscle damage. Symptoms often developed in many of the forms of limb-girdle before the agents [ contend ], in particular, limb-girdle muscular dystrophy Type 2E, which we're talking about today, is one of the more severe forms and often -- and mimics DMD in that individuals are usually diagnosed before the age of 5. There are no approved therapies for limb-girdle muscular dystrophy, and thus there's an urgent need for treatment. There's a relatively consistent disease progression within each of the LGMD subtypes, although there's some heterogeneity when you look at LGMDs as a whole. Each of these 30 -- approximately 30 subtypes is a rare disease in and of itself. Now turning to our limb-girdle portfolio. We have 5 internal limb-girdle assets as well as 1 partner program with Dr. Zarife Sahenk at Nationwide. Then looking at the function of some of the limb-girdle proteins, in particular, we're focusing on the sarcoglycans out of the case of LGMD2E. Beta-sarcoglycanopathy is characterized by mutation of sarcoglycan gene, which sits in a complex at the membrane called the sarcoglycan complex. This is important for functions and preventing muscle damage during contraction. What happens is that this complex sits at the membrane as part of the greater dystrophin-associated protein complex. And there's a reciprocal relationship between dystrophin and the sarcoglycan. And that's when you lose -- have a defective sarcoglycan protein, you lose or have reduced expression of the other sarcoglycans as well as other proteins in the complex such as dystrophin. And so thus by restoring the missing proteins, such as beta-sarcoglycan, you're restoring that functional complex at the membrane to restore function to the muscle. The 3 programs are characterized by sarcoglycan proteins. We have an additional 2 programs, Dysferlin and Anoctamin-5. And these 2 proteins are involved in muscle membrane repair. A failed repair to lead to chronic muscle degeneration, much like we see within the other limb-girdle dystrophies. And so thus, some of the incidence of the protein damage at the -- within the muscle may be slightly different in terms of function. Downstream consequences are the same, but chronic muscle wasting disorder leading to chronic muscular dystrophy. Now just to remind you of our design for our limb-girdle muscular dystrophy Type 2E trial. This is an open-label trial design. It's comprised of 2 cohorts. The first cohort was 3 subjects at a low dose of 5x10^13 vector genomes per kilogram, and our high-dose cohort is 2x10^14 vector genomes per kilogram, so fourfold higher. This is systemic delivery with AAVrh74, MHCK7 beta-sarcoglycan. MHCK7 promoter, as Doug mentioned, is important for transduction and expression of the protein specifically in skeletal and cardiac muscle. And we are using the full-length beta-sarcoglycan genes in this program. Inclusion criteria for this study are: Subjects had to be between the ages of 4 to 15 and have beta-sarcoglycan gene mutations at both alleles; also has to be negative for rh74 antibodies; and patients need to be ambulatory as characterized by being greater than 40% normal on the 100-meter walk test. All subjects were on prednisone. This is 1 day prior to gene transfer, maintained for 60 days at 1 mg per kg before being tapered. The primary endpoint for this study is in the Phase I safety study with evidence of beta-sarcoglycan gene expression at week 8. Other endpoints included the decrease in CK as well as various functional endpoints, including NSAD and the 100-meter walk time. Now to set the stage for this study, there was robust preclinical data generated. And one of the studies that was completed showed that 20% expression led to an increased functional improvement in preclinical models. And this set the stage for the threshold for success for this trial, which was already met within the first low-dose cohort in terms of expression. Just to review the Cohort 1 or low-dose cohort. These are the demographics for these first 3 subjects at baseline. The 3 subjects were between the ages of 4 and 13. They had mutations in exon 3 or 4. Exons 3 through 6 are -- encode the extracellular domain of beta-sarcoglycan and mutations in these exons are known to be more severe and lead to a complete absence or severely reduced expression of beta-sarcoglycan. The weights in this low dose were between 18 and 57 kilograms. And CK levels at baseline were elevated between 10,000 and 12,000 for these patients. And we looked at biopsies at baseline and at 60 days. And what you can see in the low-dose cohort, we had a mean -- a 51% beta-sarcoglycan positive fibers with an intensity of 47% as compared to normal. So as you can notice that even in this low-dose cohort, we saw robust expression that was correctly localized to the muscle membrane and with a mean intensity of 47% as compared to normal biopsies. If we look at a patient-by-patient level data, we see similar ranges of expression between our 3 patients between 42% and 63% of positive fibers with intensity between 38% and 57%. Now as I mentioned previously, beta-sarcoglycan sits in this sarcoglycan complex at the membrane and restoring a complex is critical to its function. And as we looked at alpha sarcoglycan as one of those components in our biopsies, both pre and post, and what you can notice in the low-dose cohort, we see significant upregulation of alpha sarcoglycan that's correctly localized to the membrane. We look further and did colocalization staining -- stain for both beta-sarcoglycan and alpha sarcoglycan at the same. time. And what you can see by the colocalization images that these 2 proteins are sitting in the complex together as membrane, really ensuring that this complex is correctly being formed. Now we also looked at the total amount of beta-sarcoglycan that was expressed by Western blot. And we can see here that we saw mean of 36.1% across this low-dose cohort with a range from 34% to 39%. Just a reminder that this gene transfer does deliver the full beta-sarcoglycan gene. And so our next slide is just a summary of the expression data that I've just showed you for the low-dose cohort. And for vector genome copy number for this cohort, we saw a copy number of 0.6. And so even with this lower copy number, we saw a significant increase in beta-sarcoglycan expression. And so thus we hypothesized in our high-dose cohort that we would see a larger or higher copy number, which would result in higher expression. And just to review our safety data from the first cohort, which we've previously disclosed, we had 2 subjects that had elevated liver enzymes. One of those was designated as an SAE. This subject also had transient increases in bilirubin. Both of these events occurred when the subjects were tapered off of oral steroids. And they -- as soon as oral steroids were re-administered, the liver enzymes returned to baseline. Because of this, we modified our protocol to extend prednisone to 60 days versus the previous 30 days for the high-dose cohort to prevent the liver enzyme elevation in the high-dose cohort. We also had 2 patients that had transient mild nausea within the first week. This did not correlate with liver enzyme elevations or any other abnormalities. There were no other clinically significant laboratory findings. No decreases in platelet counts outside of normal range and no signs of complement activation were observed. So now I'd like to update the 1-year functional results for the low-dose cohort. And what you can see, this is a busy slide, but we'll walk you through it. So this is the summary of the data we're showing both as baseline, 9 months and 1 year. And what you can you appreciate is that all 3 subjects at every single time points has improved in our functional cohort. Looking first at NFAD. This is a functional score that ranges from 0-54 points. It's a variety outcomes that are relevant to limb-girdle muscular dystrophy. And what you can see is that all 3 subjects improved their score from baseline. In particular, if you look at patient 2, this subject achieved a perfect score at 9 months and that continued for 1 year. All of the patients improved in their time test, which includes time to rise, time to go upstairs and 100-meter. And just a reminder for all the time test, you're actually looking for a decrease in the amount of time it takes to do that activity. Looking at the 100 meter, we see significant improvement across our -- all 3 patients. In particular, looking at patient 3, you see almost a 9-second improvement on 100-meter walk time. And also all 3 patients improved on the 10-meter as well. So all in all, very consistent results that are extending out for 1 year in this low-dose cohort. Now looking at NSAD in particular. What we're showing here is the NSAD scores, the mean NSAD scores for all 3 patients over the course of the year. And what you can see is consistent improvement over the course of the year, almost a 6-point improvement from baseline of mean across the 3 patients. Now previously, we've compared to natural history. For NSAD, muscular dystrophy Type 2E, and in this age range, we would expect almost a 4-point change during this time point. Actually, when we disclosed the 9-month data, there was close to a 4-point change in the natural history control. Okay. So now I'll turn to our high-dose results. These are our demographics for our 3 patients in the high-dose cohort. They range between the ages of 8 to 11. They also have severe mutations in either exons 3 or 4. Our sixth patient was -- had a mutation in exon 1. In particular, this mutation was a dilution in the start site. And so this particular mutation is expected to be a null mutation because of the start site mutation. The weights of these patients are between 26 and almost 40 kilograms. And the CK levels at baseline were also elevated. It's important to note that, in particular, these patients in this age range and this weight gives us added safety data, safety exposure across our platform and that these patients receive the highest amount of total vector given their larger weight range that applies to cross-platform programs as well. Now turning to expression on our muscle biopsies. What we're showing here is beta-sarcoglycan expression at baseline as compared to post treatment. And what you can appreciate is that we see very robust and widespread expression post treatment. When we quantify this, we see 72% of muscle fibers expressed beta-sarcoglycan. In terms of intensity, we see there 73% mean as compared to normal. I think what's striking about this is the beta-sarcoglycan protein is expressed at the membrane. And you can appreciate the architecture of the muscle fibers. You see a uniformity amongst the muscle fibers in this high-dose cohort. When we look at the patient level data, we see consistent results between the 3 patients ranging from 65% to 77% and mean intensity ranging from 55% to 97% in the 3 patients. Now we also looked at the up-regulation of alpha-sarcoglycan in this high-dose cohort as we did previously in the low-dose. And again, here, you can appreciate there's a significant upregulation in alpha-sarcoglycan that's correctly localized to the membrane. So again, here, we're showing that alpha-sarcoglycan is colocalizing with beta-sarcoglycan as a membrane, reforming that functional complex to restore function to the muscle. Now turning to Western blot to look at total amount of protein expressed. And what you can see is we have a mean of 62.1% beta-sarcoglycan expression as compared to normal. You can see the range is from 53% to 70.3% across the 3 patients. And again, this is the full entity of sarcoglycan gene that's being expressed. And so just to summarize, the muscle biopsies results so far. We saw a mean of 72.3% positive fibers, 73.1% intensity, 62.1% by Western blot. And looking at vector genome copy number, we see 4.2 copies per nucleus in this high-dose cohort, a mean across the 3 patients. We also look at creatine kinase as a biomarker in the high-dose cohort. And what you can see here at day 90, we see a mean 89.1% reduction in CK out to day 90. Now we've also been following CK in our low-dose cohort. And out to 1 year, we still see a sustained 72% reduction in CK over the course of 1 year. So this is a nice comparison of expression results from Cohort 1 and Cohort 2. And so what's nice here is that you can see that there is an increase across all measures in the muscle biopsy. So for immunofluorescence-positive fibers, we see a 72-point increase in the high dose compared to 51% at low dose; intensity, 73% as compared to 47% at low dose; Western blot, we see 62.1% compared to 36.1% in low dose; and copies per nucleus, we're at 4.2 as compared to 0.6. So across all of these measures, we're seeing a consistent up-regulation of beta-sarcoglycan in the high-dose cohort as compared to the low-dose cohort. Now turning to safety. In Cohort 2, the majority of patients had mild to moderate AEs which resolved. We had 1 serious adverse event. This was in 1 patient that was -- the dehydration, which resulted from vomiting that occurred 3 days after the infusion, it resolved rapidly within 2 days with antiemetics and IV fluids. This patient, in particular, had a history of gastrointestinal reflex, but regardless, this resolved very quickly with the antiemetic therapy. There were no stopping or discontinuation rules triggered by AEs, and there were no other clinically significant laboratory findings, so there was no decreases in platelets outside of the normal range and no signs of complement activation. It's important to note that we did not see the liver enzyme elevations as we did in the first cohort, and this can be attributed to the fact that we continued the steroids for 60 days prior to tapering versus 30 in the first cohort. So now just to summarize, really, this data reflects the optimized LGMD2E construct design. We've known from this program and others that rh74 efficiently transduces all muscle types. The selection of the MHCK7 promoter allows for efficient expression in cardiac and skeletal transgene muscle expression, and we have low preexisting immunity for rh74. And so in terms of this program across our platform, the rh74 serotypes as well as MHCK7 promoter is really yielding robust results in programs. We've shown that increased beta-sarcoglycan expression across all patients has a systemic dose of 2x10^14 vector genomes per kilogram as compared to 5x10^13 in our low dose. We saw a substantial reduction in CK in both cohorts and sustained improvement in all functional measures in all patients in Cohort 1. And importantly, we see a similar safety and tolerability profile observed in both Cohorts 1 and 2. And so next steps for this program. The official final dose for the registration trial will be selected by Q3. But I think based on the safety and expression data that we just showed you, I think it's clear that we will be focusing on the high dose. We will be engaging global regulatory agencies to discuss our pivotal trial designs. We've commenced commercial manufacturing runs to support clinical development, and we look forward in early 2021 to initiating our registrational study and perhaps discussing our path forward for all of the sarcoglycan. So just to remind you, we have 5 programs in our clinical pipeline for LGMD, internal programs and 1 partner program for LGMD2E with Dr. Zarife Zahenk. And what's important to note is that we are really utilizing rh74 platform with promoters that are similar, whether they're being MHCK7 OR tMCK. And what we've shown is the favorable profile for rh74 across programs as well as the robust nature of MHCK7 in terms of expression. And we look forward to moving all of these programs in our pipeline forward. And so with that, I'm going to turn it back to Doug to lead the Q&A.

Thank you very much, Louise. And also, congratulations to Dr. Rodino-Klapac. I should remind everyone that the construct for limb-girdle Type 2E as well as all of the other 5 limb-girdle constructs that we obtained from Myonexus were designed, tested and optimized by Dr. Rodino-Klapac. So really fantastic, and thank you for that. And with that, let's open the line for questions.

[Operator Instructions] Our first question comes from the line of Debjit Chattopadhyay with H.C. Wainwright.

So just a quick one on the enrollment of -- at enrollment, the patients needed to have 40% of predicted 100-meter walk distance. So just curious if the baselines were closer to [Audio Gap] or 80%? And do you think there's a threshold for full-end protein expression, after which, there's a plateau in surrogates like CK?

Sure. Louise?

Sure. We had a range of functional -- sorry, a range of -- on the 100-meter walk time at baseline. So they definitely weren't all at the upper end of the range. You can see looking at the functional data, there was some -- a breadth of baseline characteristics for the NSAD as well as the 100-meter between our patients. So they definitely weren't all in one range or the other. In terms of the amount of threshold expression, I think based on our preclinical data, when you get to doses higher than what we're currently looking at, you might start to see a threshold. We saw diminishing returns in terms of improvements in functions beyond a certain amount.

Our next question comes from the line of Christopher Marai with Nomura.

I was wondering if you could comment further on the NSAD data that you updated. It was pretty clear that you saw some improvement in patients expected to decline, but this can be a variable in terms of an endpoint. So number one, what you expect would represent a clinically meaningful benefit here? And then how much natural history is really available for this endpoint for this patient population? Or do you expect you might have to look at placebo controls in the next trial? And I have a follow-up.

Sure. Yes. Christopher, I'll make 2 comments, and I'm going to hand it to Louise who can answer it in depth. First, on the development pathway, we are working right now with the agencies on the development of regulatory pathway. And we'll update on the pathway in the first quarter of next year after we get through that. We have the time to go through that process because we're also going to spend the bulk of this year manufacturing the GMP material as well. But we're looking at creative ideas for the development in and regulatory pathway. And with respect to the North Star, the NSAD, in this case, one should note, and I think Louise did note it in the presentation, not only are these kids doing very well on NSAD and in fact have all improved over the course of the 1 year, but we actually have a child that is -- actually maxed out that score cannot do better. No one can do better than the score they got. They topped the score. And with that, Louise, can you comment on Christopher's questions?

Sure. Just to further elaborate on the natural history data. Based on the natural history data we have in this age range for LGMD2E, we saw a 4-point decline during this time course. And so if you take the 6-point gain that we saw across our 3 patients, that would be a delta of a 10-point change on the NSAD. So based on the data that we have in hand, we feel quite confident that there's so much -- the improvement we're seeing is much diverged from natural history, and we're certainly seeing meaningful gains across the low-dose cohort and expect to see the same with high-dose as well.

Okay. And then just in terms of potential cardiomyopathy benefit. Have these patients had any indication of cardiomyopathy? And then could you maybe comment on some of the interest you received in this program for both patients and physicians relative to your DMD program?

Louise?

Sure. So we're certainly monitoring cardiac as part of this trial, and we'll continue to monitor that as the patients continue on. This is a 3-year study. And -- all right, the second question was related to -- sorry. Interest in regards to HCP is in comparison to DMD. We're certainly seeing much interest in this program for patients that are caregivers that are -- have LGMD to patients, and they're certainly watching the data closely. Much -- many of our investigators that see DMD patients also see limb-girdle patients and vice versa. So certainly, the read-through from the programs is important to them, and we're in close communication. There's a high degree of excitement around these programs.

And one added note, just to follow-up to Louise. One should note that with respect to all of the limb-girdles, particular subtypes of limb-girdle that we're pursuing, these are patients not only that are suffering from very serious muscle wasting and degenerative diseases that very often shorten one's life significantly so in connection with limb-girdle Type 2E. But there are no current therapies of note for any of these diseases, and there really are no other therapies in development at any advanced stage beyond the programs that we're pursuing. So one can envision both families and their -- and patients as well as those who treat this disease are watching this very closely. And I'm quite confident cheering this from the sidelines as we have the data that we have today.

Our next question comes from the line of Brian Abrahams with RBC Capital Markets.

Congratulations on the data. So as you look across the data and think about dose selection, what are some of the considerations that you're thinking about and that we should focus on with respect to differences among the 2 dosing arms? So it looked like there were slightly different mutations as you mentioned. Baseline CK was not quite as high in the high-dose group. I'm curious how low beta-sarcoglycan expression was at baseline for the high-dose patients before starting therapy? And would any of these differences as well as the differences in steroid regimen and baseline function have any expected impact on the rate of improvement in function in CK or expressions as we compare the high versus low-dose arms?

Yes. I'm going to turn this over to Louise, but before I do, let me say 2 things. One, as Louise said at the end, we're efficiently making our dose selection, as we said, in the third quarter. But let's be honest with one another. When one looks across the expression that we're seeing, the other correlates and biomarkers we're seeing and the safety profile that we're seeing at the high-dose relative to the lower dose, I think it's pretty obvious where we're heading. The high-dose appears to be the right dose for us. And the second thing I'll note, and Louise can give more detail on is all of these children, both the low-dose and the high-dose were bereft of essentially any real beta-sarcoglycan in advance of this therapy. I think they were all below the level of quantification. But Louise, can you correct me on that? Louise, with that, do you want to provide some more nuance?

Yes. No, absolutely. Correct in terms of there was no differences between the cohorts in terms of baseline. And there's certainly no meaningful way in terms of segregating the patients into high and low dose. We saw similar mutations and expression levels at baseline in terms of functions. There was no large differences. I think, the slightly lower CK levels from high dose was just based on those particular patients at that time. There was no intention to -- [ lack ] patients for the different cohorts in any way. And I think what I'll note between both the low-dose and the high-dose cohort is that we saw consistent results amongst the 3 patients in each cohort, and that really speaks to the fact that we're delivering a full line gene. We're focusing on high levels of expression of this protein to protect the muscle. And I think the results that you're seeing are consistent between -- in the low dose as they are in the high dose. And really, that speaks to the robustness of the cassette and moving forward. And so likely, in terms of dose selection, we're very focused on both safety and efficacy and giving the favorable safety profile. I think we would favor the high-dose expression that we're seeing.

Our next question comes from the line of Vincent Chen with Bernstein.

Congrats on the strong data. Just wondering, just given what looks to be a very clean safety profile with the 2E 14-dose in larger patients in your LGMD2E program, does this give you incremental confidence in moving your DMD gene therapy program more rapidly into older and larger patients? What might we expect to see studies started in older DMD patients? And is there an opportunity to move more expediently to larger patients in order to potentially broaden a potential label for DMD gene therapy, assuming that the ongoing DMD study reads out positively?

Yes. Thank you for that question. So first of all, certainly, this data provides us with even more confidence, and we had already built in confidence over time in our SRP-9001 construct and utility across the entire age range of patients with Duchenne muscular dystrophy. We had a study, 102 (sic) [ 101 ], that I won't get into detail on here, but everyone will recall that data and that safety profile and expression level and then functional results. And by now, we have treated between that and a study -- I think I said 102. I meant 101. And then with 102 and 101 together, we have dosed probably around 35 patients so far. So we were already getting a significant confidence in the approach that we're taking. But here we have with SRP-9003 the same construct, the same vector, the same promoter, the same dose now in older children, so it does provide us with additional confirmatory data and additional confidence as we proceed. It is our every goal to move as fast as possible with respect to not only the younger children but older and nonambulatory patients as well. So I cannot say that this is going to speed us -- speed our thinking up because we're already moving as fast as we can. We feel an enormous obligation to move these therapies both limb-girdle and SRP-9001 for Duchenne as fast forward as is possible and confirm the results that we're seeing in these early days and get this therapy to patients across the entire age range. So we will as fast as we can be in a place where we can dose patients in the 4 to 7-year-old range, but also in the older ranges as well, including the nonambulatory patients. So we're working hard on that. And just to give you -- apology, I'll veer a bit off of SRP-9003. For a second I just give everyone an update, which is that things are proceeding as we had anticipated they would. We still with respect to Duchenne muscular dystrophy and SRP-9001, anticipate GMP material in July. So that is on track, thankfully. We had already mentioned that process development was complete at the earnings call at the end of Q1. We had said that the 24 -- all 24 of the assays for SRP-9001 are built and that 22 of 21 have either been qualified or validated as required, and that we had 2 remaining to validate or qualify. Those are done now. So all of the assays are done. All of the process development is done. We're in multiple GMP runs, and we're tracking to get that done, so we can sit with the agency, get their confirmation and start a trial in the second half of this year. So everything with respect to our DMD program is on track. I will also note, and I give our technical operations team an enormous amount of credit for this, even in the midst of this pandemic, with respect to limb-girdle Type 2E, we are already in GMP runs for that material. So we want to be in a position once we've confirmed the development pathway to as rapidly as possible with respect to limb-girdle Type 2E, and then the other limb-girdles start pivotal trials for those therapies as well. So the team is doing a good job of moving things forward as fast as reasonably possible given the importance of these therapies to patients that are waiting for them. Louise, is there anything about any of that, that I've missed or misstated?

No. I think you characterized it well. Thanks.

Our next question comes from the line of Gena Wang with Barclays.

I also wanted to add my congratulations on the great data. I have 2 questions regarding the data. First is, one, NSAD, the vomiting 3 days after dosing and dehydration, would that deem to be drug-related or drug unrelated? My second question is for patient #4 and 5 since those are the severe mutation absence of the protein. Did you see any antibody gradually build up against the beta-sarcoglycan? And then lastly, I have a 1 question regarding the Phase III of the pivotal trial design. Is it possible that biomarker could be a -- or let's say a beta-sarcoglycan protein level as a primary endpoint while the North Star is a secondary endpoint?

Yes. So I will answer the last question, then I'll turn the technical questions over to Louise. The short answer on the development and regulatory pathway is that we have to work with the agency, take their input and advice, and then we'll come back with the protocol early next year. But certainly, one should know with the disease that's not only severe as this but as rare as limb-girdle Type 2E, we have to look at ways to speed the development up and be realistic about the kind of trial we can do. And the idea of looking at biomarkers as surrogate endpoints is something that we certainly are going to discuss with the agency. But I'd say that process of discussion, education, in both directions, and then coming to a development and regulatory approach is going to take us to better part of 2020, and we'll have an update on that in the first quarter. And with that, I'll turn over the questions to Louise for the first 2.

Sure. With regards to the SAE, that was determined that was likely related to the therapy and then the second question about the antibodies, we did not see any anti beta-sarcoglycan antibodies form following treatment in any of the patients.

Our next question comes from the line of Tazeen Ahmad with Bank of America.

As it relates to natural history, Doug and Louise, can you talk about if there's any similarity from a limb-girdle to Duchenne and that there's a marked acceleration in ability for kids at a certain point in time in age? And if there is, how is that going to impact the age range that you would potentially see as ideal for enrollment since your pivotal study? And then as it relates to Type 2E, can you just remind us how many patients there are in the U.S.? And are they as well diagnosed as, let's say, DMD patients are?

Louise, do you want to take those questions?

Sure. With regards to the natural history of the disease, we do see a consistent decline. I would say, in LGMD3, specifically, we see patients typically lose ambulation in early to mid-teens, and we're certainly looking at natural history to inform our pivotal trial design in order to achieve the broadest label. So we'll come back with the specifics of the design in future conversations.

Next question our next question comes from the line of Tyler Van Buren with Piper Sandler.

Great to see the clean results. You mentioned the other limb-girdle programs. I just wanted to ask specifically about the other sarcoglycan programs, 9004 in process. How confident are you in these programs following the results? And from a mechanistic perspective, they appear highly transferable. But are there any important differences in the approach of the patient population that we could think of? And just in terms of the programs moving forward, can you just provide any detail on timing of data from those 2 programs as well?

So we'll come back in the first quarter of next year and provide an update on the development pathway across the limb-girdles, including 2E. But certainly, there is a lot of insight that we're getting on all of the sarcoglycans that come out of the data that we have with limb-girdle Type 2E. They're very -- they share a lot in common. They share very similar phenotypes. They are all part of the dystrophin-associated protein complex, and so the insight that we're getting from this program will allow us to move faster with respect to the other sarcoglycans as well. Now we'll come back next year and provide you the flight path -- development regulatory flight path for the limb-girdles, but we're trying to move the sarcs as fast as possible with 2E as well. Louise, is there anything that I missed?

No. You characterized it well. I think it's just -- important to know as we developed these 3 programs, we used learnings from [indiscernible] to apply to the other with preclinical data and then translate to clinical. So we certainly expect that there's significant read-through and learnings that we can apply to the other programs.

[Operator Instructions] Our next question comes from the line of Ritu Baral with Cowen.

Do you guys have any concerns that you might be overshooting on steroids now given the vomiting signal and the flat lining of livers? This dose over 2 months is pretty high. And any desire to sort of tweak this down maybe in the Phase III? And then can you just very quickly go over when we might get high-dose functional data released, what those time lines might be? And is it fair to expect that the functional data will be better than the low-dose functional data, if there's any ceiling effect we should be worried about?

Well, on the first one, I'll let Louise answer both in more detail. But I mean, obviously, we're -- I'm happy to see that -- a child had dehydration and vomiting, but I will say mild nausea has been something associated with full-body infusions. We were very pleased in this cohort to see that the amendment to the steroid protocol, at least in this cohort, eliminated the elevated liver enzymes that we had seen in other -- in the other prior cohorts. So actually, on whole, we're very, very pleased with the steroid protocol that we've chosen for the high-dose cohort. And I suspect it will significantly inform our pivotal trial. But with that, Louise, do you want to touch on that and the functional question?

Sure. No, I would agree with that in terms of steroids and certainly as -- we weigh the pros and cons of adding additional steroids, and this is an overall short duration of these high-dose steroids that there's certainly a benefit to not having the liver [indiscernible]. So we feel quite good about the decision we made in this program in terms of increasing the steroids for that short period of time. With regards to function for low dose, we previously showed functional data at 9 months. We're certainly looking to, at the appropriate time, to disclose the high-dose data. But we'd be looking in a similar time frame, but we haven't decided that yet.

And then before I move to the next question, I do want to real briefly touch on the question that was asked earlier, and I think we may not have answered it. But it was the broad question about the prevalence in the United States, the limb-girdle Type 2E. So first, the data on the exact prevalence is limited on 2E. You should know that with respect to limb-girdle 2E it's very rare as a result of which we're thinking of thoughtful innovative development and regulatory pathways that would speed the therapy to the patients. But you should know, if you look across our limb-girdle portfolio, that is -- we have about a 70% or more of all limb-girdles diseases captured in the therapies we're working on right now and limb-girdle on whole approach about the same prevalence as Duchenne muscular dystrophy. So while limb-girdle 2E is itself quite rare, there is a real opportunity to do a lot of good across this portfolio informed by the results that we're seeing in the limb-girdle Type 2Es. For that reason, we're going to move fast, not just with 2E, but across the limb-girdle platform that we have.

Our next question comes from the line of Alethia Young with Cantor.

Congrats on the data. It's very good. And I just want to talk a little bit about some of these functional endpoints that you studied. Do you think there are any ones that are particularly very well correlated? And then just as we kind of think about, I know you're not going to opine on this exactly, but obviously, kind of how -- what might resound more with the regulators on the functional endpoint of sorts?

Yes. Thank you for anticipating. I'm going to beg off the second part of your question, only because I really want to spend time with regulatory agencies and the experts in the FDA and elsewhere and then come back early next year with an update on that. But with respect to the first question, Louise?

Sure. I think based on the functional endpoints that we selected, the NSAD, the 100-meter as well as rh10, these have all been highly correlated in the limb-girdle population and led to the reason why we selected those. There's additional natural history data being collected on these endpoints and specificity for that. So NSAD scale, in particular, was developed for this population. And so we feel good about the correlation that we're seeing with these particular endpoints that are selected. They -- the NSAD incorporates activities that are especially relevant to the limb-girdle population with regards to getting up from a seating position, for example, or squatting from the floor. And so they're very relevant to activities that this population needs improvement in particular.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

I mean as we think about scaling on commercial manufacturing, I guess, just what sort of learnings have you gleaned from the DMD process that you're now attributing to the LGMD process, and just thinking about where you currently stand in scaling up to GMP and what needs to be completed at this time to hit your 1Q benchmark.

Great. So the good news is while we have to do the work for every program, of course, one needs to know that the process is very similar for 2E and the other limb-girdles compared to our SRP-9001 for Duchenne muscular dystrophy. To recall, we started over Nationwide Children's Hospital with DMD using hyperstacks. But otherwise, mammalian adherence process, we've moved to iCELLis units to be able to scale up without taking undue additional risk and moving too far away from the process that has worked with hyperstacks, and that's iCELLis, which is while it's in a 3-dimensional structure so you can essentially make more product in a smaller space, it's still adherent. It's still mammalian. All of that is equally true for the rest of the limb-girdles and certainly for 2E. And as a result of that, that all of the work we did, as everyone knows, as they sort of lived this with us over the last year plus, we spent an enormous amount of time with respect to SRP-9001 defining, working, optimizing process, getting to the yield that we found acceptable, dealing with assay development and the like, and all of that will yield to the benefit of limb-girdle Type 2E and the other limb-girdles. And it is for that reason, in part, without oversimplifying it, that we are now in GMP runs for limb-girdle Type 2E. So we still have a lot of work to do, and we'll be working on it over the course of this entire year, but we're in great shape right now. We're already in GMP runs for 2E, and so I feel very confident right now that when we are in a place to define the development pathway and regulatory pathway early next year that we will have the material first to do that pivotal trial and then to fully serve the community in the United States and around the world, families who have loved ones with muscular -- limb-girdle muscular dystrophy 2E.

Our next question comes from the line of Difei Yang with Mizuho.

Just a quick one for pre-acting kinase levels. For the low dose, we saw over time an increase of the CK level. And for this title, should we be expecting phenomenon that's similar?

Louise, do you want to take that?

Yes. I think I heard the whole question. We'll certainly be monitoring CK. CK is a nice biomarker. There's some fluidity within CK as we've seen as interestingly as patients get more active. We may see some noise in the CK, but I think overall, we're seeing even a low dose. Over the course of the year, we're still seeing a reduction in 72%. So we'll continue to monitor it, obviously, looking at collectively, holistically with expression and function as we continue to monitor that.

Our next question comes from the line of Joseph Schwartz with SVB Leerink.

Congratulations. I was wondering if you could talk about the NSAD data in some more detail. And in particular, are there any noteworthy patterns that you can see across the many different domains that are evaluated? And how do the NSAD improvements seen for the patients in this program compare to the NSAA improvements that you've observed after SRP-9001 treatment?

Yes. So I'm going to turn this over to Louise. I will note 2 things. But first is that these patients -- every child at every functional endpoint and every subpart of every functional endpoint improved over the course of the therapy. That also was the case with respect even to the low-dose cohort. And that also was the case with respect to our 4-patient cohort in Duchenne muscular dystrophy. So obviously, we're very excited about the performance of all of these constructs. The ability to deliver the robust expression using rh74, the ability to get robust expression with MHCK7, and obviously, the early data on functional benefits that we're seeing from the NSAD. I apologize, I think I said the high-dose cohort. We don't have the functional data on the high-dose cohort. I misspoke. But with respect to the low-dose cohort at 1 year and 9001, 9 months, and then, of course, we'll get the update this -- hopefully, this month on the 1-year data there. And then the one thing I will note, and then I'll turn it over to Louise for the patterns, I will note that at least one of the children at the high-dose cohort has literally maxed the test out. So certainly, it's difficult to be more pleased than that with the result on this important composite functional score. But with that, Louise, do you want to provide any additional color on that?

Yes. Just a few things to add. So the NSAA that's used in Duchenne as a 34-point scale, this is a 54-point scale for NSAD. It includes additional measures relevant for limb-girdle. We'll certainly be looking at the individual components of the NSAD over time. It's a small end at this point of -- end of 3. And so as we look at the low-dose and high-dose cohort together, we'll certainly look for any important trends within the scale. But what's nice about a composite scale is by adding up all the components, you're really driving towards functions that are important to the daily living of patients. And so the overall scale and the fact that we're seeing improvement is significant in and of itself. We certainly want -- be expecting patients in this age range to be improving like we've seen. So overall, very encouraged by the data. And across every single measure, it's improving. So we have a lot of confidence moving forward just based on these low-dose cohorts so far.

Our next question comes from the line of Joel Beatty with Citi.

Congrats on the data. The question is for the functional assessments. Could you discuss how many times each subject is tested for each test at each time point? And then are we seeing best scores or average scores?

Sure. Louise?

Right. Each of these is being done once at the individual appointments.

Our next question comes from the line of Anupam Rama with JPMorgan.

Congrats on the update. Kind of based on the functional data that you've seen to date, what are your thoughts on any age range modifications you may make for the next study?

Well, yes, on limb-girdle Type 2E, we're going to work on the development pathway. And we'll come back in the first quarter of next year and provide an update on what we see as the development pathway and the regulatory pathway. Obviously, our goal is to treat all patients who have limb-girdle Type 2E across the entire age range. So anything we come up with from a development pathway has to consider that concept. One of the nice things about what we've seen right now is that we are looking at a fairly broad range from 4 years -- if you take the low-dose cohort and the high-dose cohort together, we're talking about an age range that goes from as low as 4 years old to as high as 13 years old. So we're already looking at a significant age range. But we'll come back. I just don't want to speak right now. We'll come back after a more detailed discussions with the agencies and provide an update on the regulatory pathway. But please know that our goals are a couple-fold. We -- it is our every goal to ensure that this therapy is available for all patients who have limb-girdle Type 2E, not a particular age range, and certainly, our goal is to be as creative and thoughtful as possible with the agency so that we can move these -- this therapy along as fast as is reasonably possible, to get this therapy to patients that are waiting for. And that's the answer across our gene therapy programs and a similar answer for SRP-9001 for Duchenne muscular dystrophy.

Our next question comes from the line of Hartaj Singh with Oppenheimer & Co.

Great. I just want to be clear. I think on Slide 19 where you have the safety review for the 1-year follow-up for the low-dose cohort, is this -- encapsulates all of the 1 year's work of AE? So -- and are there any AEs related to study drug that happened after initial dosings of patients? So -- and then secondly, most of your colleagues in the DMD space with different modalities, I believe even Myonexus 2 years ago in a public presentation indicated that you require Phase III with long-term follow-up, why your colleagues in other companies state the same thing. What -- is there anything specific that in your interaction with regulators that you need you to believe that you could go faster than that?

We'll -- I'll answer the second question first, and then Louise can comment on the first one if she likes. So with respect to the -- again, the development pathway, we're going to work with the regulatory agencies and the FDA to define the regulatory and development pathway. I think this is a very rare disease. A couple of things to remember when you think about limb-girdle Type 2E. This is a very rare disease, number one. And number two, this is a monogenic disease that results in the lack of a structural protein, the absence of which is the sole reason that these children are suffering from degenerative muscle wasting and general degeneration and an early demise. And these children gene construct codes for the native full-length protein, which we have seen both in the low-dose cohort and the high-dose cohort, is correlate -- is probably localized to the sarcolemma where it would need to be functional and is correlated with an up-regulation of the other proteins associated with the dystrophin-associated protein complex. So one would envision with those things together that we might be able to come to a more creative solution to bring this therapy forward to patients who are degenerating without hope but for a therapy like this. So with that said, I'm going to decline the request to sort of describe what that might be, but we're going to work with the agencies certainly over the course of the next -- rest of this year and then come back with a view on that, informed by the agency perspective in the first quarter of next year.

The next question comes from the line of Tim Lugo with William Blair.

Congratulations on the data. There are some recent comments coming out of the agency suggesting that because of COVID, the agency is going to be bringing therapies to market even faster now. They've obviously taken down a lot of barriers in development for the pandemic, but that might be broader applied and maybe some of those changes are kept and taken to other areas in the agency and other therapies. Sarepta has obviously always been aggressive in bringing therapies to patients. Can you just maybe talk about how the tone of the -- how your interactions have changed over the past year or so? And this obviously looks like great data. What we should expect when you approach the agency next?

Yes. I think -- look, I think the tone of the agency has been positive for some time actually. We've got great leadership at the FDA right now to a very good point. There's been -- one wonders if there's great leadership in response to COVID. You see the leadership at the FDA immediately realize that we have to be thoughtful to ensure that in addition to dealing with all of the other issues that are happening in society as a result of COVID-19 that we don't find ourselves getting off-track with respect to therapies and gene therapies that are going to, if they work, are going to extend and save the lives of the numerable patients. So the agency, I think, has been quite positive and thoughtful and rigorous at the same time. So it's been more significant what we've seen in the statements and signals that we see out of the agency as respect to SRP-9001 has been very positive. I mean this in a broad sense, not specific to our DMD program. But the fact that they've issued guidance, making clear that they're going to be thoughtful about things like out-of-window, functional measures and the like, I think it's all positive. With respect to SRP-9003 in limb-girdle Type 2E, we're going to just have to engage in discussions with the agency. We work through those issues with the agency and take their insight and educate one another. And then we'll come back in the first quarter. We'll have a better understanding of what the development and regulatory pathway is, but I will say, without making any statements about what that development pathway may look like, it's going to require a lot of interaction with the agency. I'm quite confident that we're going to get a thoughtful perspective from the FDA on these issues.

Our next question comes from the line of Whitney Ijem with Guggenheim.

Just a quick one on manufacturing. Can you remind us in terms of process here, is this inherent iCELLis kind of similar to 9001? And I guess broadly speaking to this program and the platform in general, any plans to move towards suspension?

Yes. Thanks. So yes, the answer to that first question is yes. Limb-girdle Type 2E is mammalian adherent iCELLis exactly as is SRP-9001 for Duchenne muscular dystrophy. And I would anticipate that being the same answer across the sarcoglycans at least with respect to the limb-girdle programs and perhaps all the limb-girdle programs. As it relates to these lead programs, both 2E and DMD and the sarcoglycans, it is not our intention to move to a suspension. We're getting good yields out of iCELLis. We are becoming the world experts in iCELLis. We have built an enormous amount of capacity across both our relationship with Thermo Fisher Brammer where we have a stand-alone site for -- with iCELLis units for Duchenne muscular dystrophy as well as Catalent Paragon where we have even more significant capacity both for micro dystrophin SRP-9001 and our limb-girdle program. So we are very pleased with the progress we've made with respect to manufacturing capacity, process development, analytical development, all using iCELLis units. And that is what we're going to continue to do to bring certainly Duchenne muscular dystrophy 9001 and limb-girdle Type 2E and very likely the bulk of the rest of the limb-girdles to the waiting patient community.

This concludes today's question-and-answer session. I would now like to turn the call back to Doug Ingram for closing remarks.

Well, thank you very much, and thank you for joining us today. As you might imagine, we are very excited by the data that we have presented today. But more -- we're even more passionate and more excited by the fact that behind this data, behind these numbers are patients, right? So patients with rare genetic diseases whose lives may be better and longer and more fulfilled because of these data. We're fueled by this knowledge. We're going to keep driving to build our GMP manufacturing material for our pivotal trial and to define our development and regulatory protocol and pathway and will come back early next year and discuss all of that. And with that, I hope you all have a nice day. Thank you for joining us.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.