Good morning, ladies and gentlemen, and welcome to the Sarepta Therapeutics Clinical Update SRP-nine thousand and three for Limb Girdle Muscular Dystrophy Type 2E. At this time, all participant lines are in a listen only mode. After the speakers' presentation, there will be a question and answer session. As a reminder, today's program is being recorded. I would now like to hand the conference over to your speaker today, Ian Estipan, 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, Doctor. Luis Rodino Klapac, Doctor. Gilmore O'Neill, Sandy Mahatme and Bo Cumbo.
After our formal presentation, we'll open up the call for Q and 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 Surupta'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 of 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 ks 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 IIe program. In a moment, Doctor. Luis Rodino Klapac will present the data on Cohort 2, our 3 patient higher dose cohort with SRP 9,003, which is our gene therapy designed to treat LGMD2E 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.
2nd, 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-nine thousand and one. To remind you, while our limb girdle 2D 2E therapy SRP-nine thousand and three codes for a different but related protein in the dystrophin associated protein complex, it shares much in common with SRP-nine thousand and one for DMD. 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 Doctor. 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 100 of 1000 globally. Monogenic meaning that there's an individual gene that's missing or done functional 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 leads into the serum before muscle damage. Symptoms often develop 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 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 one partner program with Doctor. Theresa Henk at Nationwide. Now looking at the function of some of the limb girdle proteins, In particular, we're focusing on the sarcoglycans in the case of LGMD2E. Beta sarcoglycanopathy is characterized by mutation of the sarcoglycan gene, which fits in a complex at the membrane called the sarcoglycan complex.
This is important for function 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, however, 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 that's by restoring the missing proteins such as beta sarcoglycan, you're restoring that functional complex at the membrane to restore function to the muscle. So 3 of our programs are characterized by sarcoglycan proteins.
We have an additional 2 programs, diferalin and Enoctin-five, and these two proteins are involved in muscle membrane repair. Failed repair can lead to chronic muscle degeneration, much like we see within the other limb girdle dystrophies. And so that's some of the incidence of the protein damage at the within the muscle may be slightly different in terms of their function. The downstream consequences are the same. You have a 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 5x1013 vector genomes per kilogram, and our high dose cohort is 2x1014 vector genomes per kilogram, so it's 4 fold higher. This is systemic delivery with AAVrh 74 MHCK7 beta sarcoglycan.
MHCK7 promoter, as Doug mentioned, is important for transduction expression of the protein specifically in skeletal and cardiac muscle, and we are using the full length beta type of glycan genes in this program. Included in 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% of normal on the 100 meter WAF test. Subjects were on prednisone. This is one 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 1 safety study with evidence of beta cycloglycan gene expression at week 8. Other endpoints included the decrease in CK as well as various functional endpoints, including NSAD 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 shows that 20% expression led to an increased functional improvement in preclinical models. And this sets 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 a low dose cohort, these are the demographics for these first three subjects at baseline.
The 3 subjects were between the ages of 4 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 the slow dose were between 18 57 kilograms and CK levels at baseline were elevated between 10,012,000 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 of 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% 57%. Now as I mentioned previously, beta sarcoglycan sits in this sarcoglycan complex at the membrane and restoring that complex is critical to its function. And thus 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 looked further and did co localization staining, stain for both beta sarcoglycan and alpha sarcoglycan at the same time. And what you can see by the co localization image is that these two proteins are sitting in the complex together at the 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 a 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 length 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 copy number of 0.6. So even with this lower copy number, we saw a significant increase in beta sarcoglycan expression. And so that's what hypothesize 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 previously disclosed, we had 2 subjects that had elevated liver enzymes.
1 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 readministered, 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 myel nausea within the 1st 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 the 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 baseline, 9 months and 1 year. And what you can appreciate is that all three subjects at every single time point have improved in their functional scores. Looking first at NSAD, this is a functional score that ranges from 0 to 54 points. It's a variety of outcomes that are relevant to limb brittle muscular dystrophy. And what you can see is that all three 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 tests, which includes time to rise, time to go upstairs and 100 meter. And just a reminder, for all the time tests, 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 all three patients. In particular, looking at patient 3, you see almost a 9 second improvement on a 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, NSAID in particular, what we're showing here is the NSAID scores, the mean NSAID scores for all three 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 for Lymphoma Oral Material Distributed Type 2E.
And in these AIMs 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 month 4 point change in the natural history control. Okay. So now I'll turn to our high dose results. These are demographics for our 3 patients in a high dose cohort.
They range between the ages of 8 to 11. They also have severe mutations in either exons 3 or 4. Our 6th patient had a mutation in exon 1. In particular, this mutation was a deletion in the start site. And so this particular mutation is expected to be a null mutation because of the start site mutation.
The weight 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 exposures 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 in 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 via 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, you 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 upregulation of althasarcoglycan 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 co localizing with beta sarcoglycan at the membrane, reforming that functional complex to restore function to the muscle. Now turning to western blot to look at total amount of protein expressed. Now you can see 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 length beta sarcoglycan gene that's being expressed. And so just to summarize the muscle lapse 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, I mean across the 3 patients. We also looked at creatine kinase as a biomarker in the high dose cohort.
And we can see here at day 90, we see a mean 89.1 percent 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 blop, we see 62.1% compared to 36.1% in low dose and copies per nucleus were at 4.2 as compared to 0.6.
So across all of these measures, we're seeing a consistent upregulation of beta sarcoglycin 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 one serious adverse event. This was in one patient that was 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 reflux, 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 continue 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 pre existing immunity for rh74. So in terms of this program across our platform, the rh74 serotype as well as MHCK7 promoter is really yielding robust results in these programs. We've shown that increased beta sarcoglycan expression across all patients at a systemic dose of 2x1014 vector genomes per kilogram as compared to 5x1013 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 12. 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 one partner program for LGMD2A with Doctor. Theresa Henkes. And what's important to note is that we are really utilizing rh74 platform with promoters that are similar, whether they're being MHTK7 or TMCK.
And what we've shown is the favorable profile for rh74 across programs as well as the robust nature of the MHCK7 in terms of expression. And we look forward to moving all of these programs in our pipeline forward. So with that, I'm going to turn it back to Doug to lead the Q and A.
Thank you very much, Louise. And also congratulations to Doctor. Rodino Klapac. I should remind everyone that the construct for Limb Girdle Type 2 as well as all of the other five Limb Girdle constructs that we obtained for Myonexus were designed, tested and optimized by Doctor. Louis Bienkleibut.
So really fantastic and thank you for that. And with that, let's open the line for questions.
Thank
Our first question comes from the line of Debjit Pekopadhyay with H. C. Wainwright. Your line is now open.
Hey, good morning and thanks for taking my question. 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 close to the 4th or 80%? And do you think there is a threshold for full length protein expression after which there is a plateau in surrogates like CK? Thank you and congrats.
Shailesh?
Sure. We had a range of functional sorry, a range of on the 400 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 breadth of baseline characteristics for the MSAD 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 3 year threshold. We saw diminishing returns in terms of improvements in functions beyond a certain
amount. All right, next.
Thank you. Our next question comes from the line of Christopher Marchese with Nomura. Your line is now open.
Good morning and thank you for taking the questions. I was wondering if you could comment further on the NSAID data that you updated. I was pretty clear that you saw some improvement in patients expected to decline, but this can be variable in terms of an endpoint. So number 1, 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?
Would 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 Luis who can answer it in-depth. First on the development pathway, we are working right now with agencies on the development of regulatory pathway and we'll update on the pathway in the Q1 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 and regulatory pathway. And as respect to the North Star, the NSAD in this case, one should note and I think we still noted in the presentation, not only are these kids doing very well on, NSAID and have all improved over the course of the 1 year, but we actually have a child that is actually maxed out that score, cannot be better. No one can do better than the score they got. They topped the score.
But with that, Louise, can you comment on Christopher's questions?
Sure. Just to further elaborate on the natural history data. So 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 NSAID. So based on the data that we have in hand, we feel quite confident that there's a much that the improvement we're seeing is much diverged from natural history and we're certainly seeing meaningful gains across the slow dose cohort and expect to see the same with high dose as well.
Okay. And then just in terms of potential cardiomyopathy benefit, had these patients had any indication of cardiomyopathy? And then could you maybe comment on some of the interest you receive in this program for both patients and physicians relative to your DMD program? Thank you.
Sure. Certainly monitoring cardiac as part of this trial and we'll continue to monitoring that as the patients continue on. This is a 3 year study. And sorry, the second question was related to oh, sorry, interest in regards to HDPs in comparison to DMD. We're certainly seeing much interest in this program for patients that are for caregivers that are have LGMD patients and they're certainly watching the data closely.
Many of our investigators that see DMD patients also see Limb girdle patients and vice versa. So certainly the read through from their programs is important to them and we're in close communication. There's a high degree of excitement around these programs.
And one audit note, just as a follow-up for 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 patients as well as those who treat this disease are watching this very closely and I'm quite confident cheering us from the sidelines as we have the data that we have today.
Next question?
Thank you. Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is now open.
Hey, guys. Thanks for taking the question and 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 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 CK or expression as we compare the high versus low dose arms?
Thanks.
Yes. I'm going to turn this over to Louise. But before I do, I'm going to say 2 things. 1, as Louise said at the end, we're efficiently making our dose selection, as we said in the Q3. 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 that the high dose appears to be the right dose for us. And the second thing I'll note, and then we can give more detail on it 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 correct me on that. Louise, with that, do you want to provide some more nuance?
Yes. No, absolutely correct in terms of that 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 reshow similar mutations and expression levels at baseline. In terms of functions, there was no large differences. I think slightly lower CK levels than the high dose was just based on those particular patients at that time. So there was no intention to select 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 on 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.
Next question?
Thank you. Our next question comes from the line of Vincent Chen with Bernstein. Your line is now open.
Congrats on the strong data and thanks for taking
the question. Just one given what looks to be a very clean safety profile with the 2e14 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? When might we expect to see a study 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 building confidence over time in our SRP-nine thousand and one construct in futility across the entire age range of patients with Duchenne muscular dystrophy. We had Study 102 that I won't go 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've treated between that and Study 1 I think I said 101.
And then with 102 and 101 together, we have dosed probably around 35 patients so far. So we are already getting a significant confidence in the approach that we're taking. But here we have with SRP-nine thousand and three, 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 non ambulatory 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-nine thousand and one through 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 range as well, including the non ambulatory patients. So we're working hard on that. And just to give you apology, you're a bit off of SRP-nine 1,003 for a second and just give us 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-nine thousand and one, 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 24 all 24 of the assays for SRP-nine thousand and one 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 the pivotal trials for those therapies as well. So the team is doing a good job of moving things forward as fast as is 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, you characterized it well. Thanks.
Next question.
Thank you. Our next question comes from the line of Gena Wang with Barclays. Your line is now open.
Thank you for taking my questions. I also wanted to add my congratulations on the great data. I have two questions regarding the data. First is, 1 SAE, the vomiting 3 days after dosing and then dehydration, was that deemed to be drug related or drug unrelated? My second question is for patient number 45, since those are the severe mutation absence of the protein, did you see any antibody gradually build up against the beta cycloglycan?
And then lastly, I have one question regarding the Phase III of the pivotal trial design. Is it possible that biomarker could be, say, a beta cycloglycan protein level as a primary endpoint, while the Northstar 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 of regulatory pathway is that we have to work with the agency, take their input and advice, and then we'll come back with a protocol early next year. But certainly, one should know with the disease is 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 endpoint is something that we certainly are going to discuss with the agency.
But I'd say that, that process of discussion, education in both directions and then coming to a development and regulatory approach is going to take us the better part of 2020, and we'll have an update on that in the Q1. And with that, I'll turn over the questions to Louise for the first two.
Sure. With regards to the SAE that was determined that it 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.
Next question?
Thank you. Our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is now open.
Hi, guys. Good morning. Thanks for taking my questions. As it relates to natural history, Doug and Louise, can you talk about if there is any similarity for limb girdle to Duchenne and that there is a marked acceleration in abilities 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 essentially see as ideal for enrollments into 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 lessee DMD patients are? Thank you.
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 the 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.
Thank you. Our next question comes from the line of Tyler Van Buren with Piper Sandler. Your line is now open.
Hey, guys. Good morning. Great to see the clean growth and results. You mentioned the other limb girdle programs. I just want to specifically about the other sarcoglycan programs, 9,004 and Fox.
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 two programs as well?
So we'll come back in the Q1 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 TUI as well. Louise, is there anything that I missed?
No, I characterized it well. I think it's important to know as we develop these 3 programs, we use learnings from one to apply to the other preclinical data and then translate into clinical. So we certainly expect that there's significant read through and learnings that we can apply to the other programs.
Great. Thank you. All
right. Next question?
Thank you. In the interest of time, we please ask that everyone please limit yourself Our next question comes from the line of Ritu Baral with Cowen. Your line is now open.
Hi, guys. Thanks for taking the question.
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 3? And then can you just very quickly go over when we might get high dose functional data released? What those timelines 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 of them 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 the other prior cohorts. So actually on hold, we're 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 overall short duration of these high dose steroids that certainly a benefit to not having a liver enzyme. 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 that we'd be looking in a similar timeframe, but we haven't decided that yet.
And then before we move to the next question, I do want to just real briefly touch on the question that was asked earlier. I think we may not have answered it, but with the broad question about the prevalence in the United States of the Limb girdle type 2b. So first is 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 patients. But you should know if you look across our limb girdle portfolio, that is we have about 70% or more of all limb girdles diseases captured in the therapies we're working on right now and limb girdles 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 2E. And for that reason, we're going to move fast not just with 2E, but across the limb girdle platform that we have. And then with that, next question?
Thank you. Our next question comes from the line of Alethia Young with Cantor. Your line is now open.
Hey, guys. Thanks for taking my question. Congrats on the data. It's very good. And I just want to talk a little bit about some of these functional endpoints 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? Thanks.
Yes. Thank you for anticipating that. 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 the 100 meter as well as RYSTEN, 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.
The NSID incorporates activities that are especially relevant to the low 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, in particular.
Next question?
Thank you. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open.
Hi, thanks for taking the question. 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.
Thank you. 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-nine thousand and one for Duchenne muscular dystrophy. To recall, we started over at Nationwide Children's Hospital with DMD using HyperStax, but otherwise in the 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 Hyperstax. And that's iCELLis, which is while it's in the three-dimensional structure, so you can fit 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 QE. And it is a result of that, that all of the work we did, as everyone knows, is they should live this with us over the last year plus. We spent an enormous amount of time with respect to SRP-nine thousand and one defining, working, optimizing process, getting to the yield that we found acceptable, dealing with assay development and the like. And all of that will endure 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 QE. 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 limb girdle muscular dystrophy 2E. And with that, next question?
Thank you. Our next question comes from the line of Difei Yang with Mizuho. Your line is now open.
Hi. Good morning and thanks for taking my question. Just a quick one for creating kinase levels. For the low dose, we saw fluctuations of the CK level. And for this high dose, should we be expecting a 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 because 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, what 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. Thank you.
Thank you. Our next question comes from the line of Joseph Schwartz with SVB Leerink. Your line is now open.
Hi, 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 NSAID improvement seen for the patients in this program compared to the NSA improvements that you've observed after SRP-nine thousand and one treatment?
Yes. So I'm going to turn this over to Louise. I will note 2 things. The 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 to 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 NHCK7 and obviously the early data on functional benefits that we're seeing from the NSAID. 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 9,001, 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 patterns. I will note that, at least one of the children in the high dose cohort has literally matched the test out. So, certainly, it's difficult to be more pleased than that with the results 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 NFPA that's used in Duchenne is a 34 point scale. This is a 54 point scale for NSID. 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 n at this point of n 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.
And we certainly wouldn't 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.
Thank you.
Thank you. Our next question comes from the line of Joel Beatty with Citi. Your line is now open.
Hi, congrats on the data. The question is for the functional assessments. Could you discuss how many times each subject is tested for the 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.
Great. Thank you.
Thank you. Our next question comes from the line of Anup Pan Rama with JPMorgan. Your line is now open.
Hey, guys. Thanks so much for taking the question and 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? Thanks so much.
Well, again, on Limb girdle type 2E, we're going to work on the development pathway and we'll come back in the Q1 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 well 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 him to speak right now. We'll come back after 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 and it is our every goal to ensure that this therapy is available for all patients who have a ngrinal 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 this therapy along as fast as is reasonably possible and get this therapy to patients that are waiting for it. And that's the answer across our gene therapy programs and it's a similar answer for SRP-nine thousand and one for Duchenne muscular dystrophy. Next question?
Thank you. Our next question comes from the line of Hartaj Singh with Oppenheimer and Co. Your line is now open.
Great. Thank you for the question. 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 that initial dosing of the patients?
And then secondly, most of your colleagues in the DMD space with different modalities, I believe even my own access 2 years ago in a public presentation indicated that you require a Phase 3 with long term follow-up, while your colleagues are in other companies state the same thing. What is there anything specific that in your interaction with regulators that lead you to believe that you could go faster than that? Thank you.
I'll answer the second question first and then Luis can comment on the first one if you're not. 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 path way. 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 1.
And number 2, 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 this 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 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 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 Q1 of next year. Next question?
Thank you. The next question comes from the line of Tim Lugo with William Blair. Your line is now open.
Thanks for taking my question and 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's obviously always been aggressive in bringing therapies to patients. Can you just maybe talk about how the tone at the how your interactions have changed over the past year or so?
And this obviously looks like great data and 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 your very good point, if one wonders if there's great leadership in response to COVID, you see the leadership of 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-nineteen 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 new normal 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-nine thousand and one has been very positive. I mean this in a broad sense, not specific to our DMD program, but the fact that they 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 SRT-nine thousand and three and Limb girdle type 2E, we're going to just have to engage in discussions with the agency and work through those issues with the agency and take their insight and educate one another. And then we'll come back in the Q1, 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.
Thank you. Our next question comes from the line of Whitney Ijem with Guggenheim. Your line is now open. Hey, guys. Thanks for taking the question.
Just a quick one on manufacturing. Can you remind us, in terms of process here, is this adherent iCELLis kind of similar to 9,001? And I guess broadly speaking for this program, but the platform in general, any plans to move towards suspension?
Yes, thanks. So yes, the answer to the first question is yes. Limb girdle type 2E is mammalian adherent iCELLis exactly as is SRP-nine thousand and one 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 of
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 Icellus. We are becoming the world experts in Icellus. We have built an enormous amount of capacity across both our relationship with Thermo Fisher Brammer, where we have a standalone 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-nine thousand and one 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 9,001 and Limb Girdle Type 2E and very likely, the bulk of the rest of the limb girdles to the awaiting patient community.
Next question. Thank you.
This concludes today's question and answer session. I would now like to turn the call back to Doug Anmall 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 and 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. And fueled by this knowledge, we are 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 we'll 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.