Good morning, ladies and gentlemen, and welcome to the Sarepta Therapeutics Clinical Updates Gene Therapy Programs Presentation.
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. And now I'll turn the call over to Doug Ingram, President and CEO for opening remarks. Please go ahead.
Good morning, everybody, and thank you for joining us this morning as we provide some clinical updates for our 2 most advanced gene therapy programs, SRP-nine thousand and one and SRP-nine thousand and three. This is Doug Ingram. I am the CEO of Sarepta. I am going to turn over the call momentarily to Doctor. Louise Rodino Klapac, who will go through updates on both of those programs.
Before I do, I would remind you that we will very likely either in the main presentation or in the Q and A make some forward looking statements or in other words, some potential statements about future events. 1 should review our public filings for a full list of the risks that are attendant whenever one attempts to make statements about the future. And with that, let me turn the call over to Doctor. Rodino Klapac. Louise?
Thank you, Doug. I'm very pleased to be giving an update on our 9,001 program for Duchenne muscular dystrophy. This is our 2 year functional data as well as our 18 month functional data for our LGMD2E program or SRP-nine thousand and three. First starting out, in consideration for development of gene transfer therapy, durability is a key consideration. And so we'd like to take a moment to discuss the durability of transgene delivered via AAV vectors to date.
And this spans across multiple programs in gene therapy. Speaking first in terms of the data to date in hemophilia in both non clinical models and human models, there's data up to 8 years in canine models, up to 10 years in humans in one trial and 3 years in another trial. And this is important in terms of collective data for the durability of change transfer. Additional data in other programs like SMA include a non clinical models for the lifespan of the mouse 250 days or 5 years using AAV9. With respect to our limb girdle and Duchenne programs, which we'll talk about, in limb girdle, we also have data showing durability of the lifespan of the mouse 24 months and in the human for 18 months.
Finally, in our Duchenne program, we have data in humans 2 years, which we'll talk about today. There's also additional data in the canine model for 8 years. So let's go into a little bit more detail about durability. Muscle is really an ideal tissue for durability of gene transfer and there are several reasons why this is. 1, skeletal muscle is post mitotic, meaning it no longer divides.
In adult muscles, so after birth, under normal conditions, there's only very sporadic incorporation of what's called satellite cells or muscle stem cells that compensates for daily wear and tear. There is specific data in muscles called the intercostal muscles, which support the ribs that show an average muscle cell lives for about 15 years in adults. In cardiac muscle, there's even less turnover with less than 50% of cardiomyocytes exchange over the normal lifespan. And this turnover decreases exponentially with age to less than 1% in adults. Now, their ability is affected by multiple factors for gene therapy.
1 is the viral vector transduction and biodistribution, The selection of the AAV serotype for example, we selected rh74, which distributes to both skeletal muscle, cardiac muscle, diaphragm muscle very well in a robust manner. Also the choice of promoter, how much expression you're getting and also in terms of corticosteroid use. So the point being is that the more robust expression that you can achieve in terms of widespread transduction as well as levels that can influence the durability of gene transfer over time. Again, just emphasizing that in the DMD model, we have seen durability for out to 8 years and continuing on as well. We're now turning to our Duchenne muscular dystrophy program FRP-nine thousand and one.
We'll be giving a clinical update on our first study. This is an open label study in 4 patients with Duchenne muscular dystrophy. I'll just remind you quickly that Duchenne is a rare fatal neuromuscular disease. It's inherited in X linked ossessment pattern that affects male newborns. Muscle weakness is noticeable by the agents of 3 to 5, but most patients are dependent on the wheelchair by the time they're 11.
The disease is severe with cardiac and respiratory symptoms leading to significant serious life threatening complications ultimately leading to death. Our open label trial design, we have 4 patients between the ages of 4 to 7 years of age with confirmed DMD mutations. The individuals also have to be negative for antibodies to AZR74. In terms of endpoint, this is an open label safety study as the primary endpoint, but with several key secondary implants, which included micro dystrophin expression, decrease in kinase, the 100 meter time test, Northstar ambulatory assessment, which includes the 10 meter time test and multiple other time tests including Time, Doctor and Go, standing stairs and also cardiac MRI. These are patient demographics at baseline.
They range from 4 to 6 years of age at the age of treatment and their CK levels were significantly elevated as you would expect in Duchenne patients at this age ranging from about 20,000 to about 35,000. Now there are several questions to consider when evaluating gene transfer therapy and I'd like you to keep that in mind as we go through this talk and we'll keep reminding you of that. So first and foremost, was the treatment safe and was recoverable? Next, how efficient was the gene transfer? And we can measure this by measuring the amount of vector genome copies per nucleus.
And does this transduction lead to protein production? We measure the total amount of protein production by western blot followed by localization. So is that correctly localizing at the membrane in the case of micro dystrophin? Then we measure that in terms of number of fibers and the intensity of those fibers at the membrane. And does this membrane staining lead to reconstitution of the dystrophin associated protein complex, which then leads to function, including the NSAA and prime function tests, which we'll go through in detail.
Turning first to safety. I'll remind you, we now have 2 year safety data in these first four patients. There were no SAEs or any AEs that was a discontinuation. There were no abnormalities in hematologic or chemistry panels, which included those with function tux no serious AEs. 3 patients had elevated gamma GP in the 1st 3 months post treatment and that resolved quickly with steroid treatment.
There were no other clinically significant laboratory findings reported. Included that platelets remained in the normal range. The most common treatment related adverse event was vomiting, which consisted of 9 of the 18 treatment related adverse events. Patients had transient vomiting generally within the 1st week post infusion, which did not correlate with liver enzyme elevations or any other abnormality. And all of these occurred within the 1st 90 days.
None of the adverse events are associated with complement activation. So now turning to the biopsies. We took muscle biopsies at baseline and at 12 weeks post gene transfer. We saw a mean of 3.3 copies per nucleus in these first four boys. And this translating into meaningful and robust levels of microdystrophin expression.
Looking at a mean across all four patients, we see 74.3% as compared to normal when not adjusted for fat and fibrosis. When you do adjust for fat and fibrosis, you see 95.8% expression compared to normal by Western blot. Next, we look at microdystrophin expression at the membrane. And again, we quantify this by counting the number of fibers positive for microdystrophin, we see a mean of 81.2 percent and then also quantify the intensity as compared to normal. And here we see 96% intensity.
Next, we looked for restoration of the dystrophin associated protein complex and one of the key members of this complex is beta sarcoglycan. As you can see treatment, we see very low levels of beta sarcoglycan, which post treatment is significantly restored to the membrane and correctly localized the muscle cell membrane in all four patients. We also looked at histology of the muscle and quantified the amount of fibrosis in the muscle biopsy. This is a staining called serious red with stains for collagen, as you can see here in pink. So the healthy muscle fibers are in the bluish green color and fibrosis is in pink.
And what you can see is that we see a significant reduction in the collagen content or the fibrosis content post gene therapy, just at 12 weeks. Now turning to dysfunctional data. Now previously, we've shared our 1 year functional data and now we're updating to 2 years. First, this is the NeuroStar ambulatory assessment. This is an aggregate of 17 measures for a total of 34 points.
And what you can see is that at 2 years, we are still seeing a sustained or improvement in function in the NSAA over that time point. So we see a mean change of 7 points from baseline to 2 years across our 4 patients. At year 1, you can see we had a 5.5 point increase and at year 2, we now see a 7 point increase across these 4 patients. Looking at a summary of the time function test, what you can appreciate is that we see a sustained or improved function across our 4 patients and all these tests as well. So remind you for the time function test including time to rise, forced their climb 100 meter, we're looking for a reduction in the amount of time it takes to do that activity.
And looking across, you can see improvements in our patients for sustained benefit. I'll just have you focus on the 100 meter percent predicted. This is a way of measuring the percent function as compared to a normal age matched individual. And what you can see in all four patients is that we've seen improvement in percent predictive value for 100 meter in our 4 patients. So just to summarize the results from our 1012 year study.
In terms of safety, we saw free felt subjects that elevated gamma GT and that quickly resolved. We had transient vomiting, which did not correlate with enzyme elevation, normal platelet counts and no other clinically significant laboratory findings. In terms of our muscle biopsies, we saw a mean of 3.3 vector copies per nucleus, our western blot, 74.3 percent or 95.8 percent expression compared to normal if you adjust for fat and fibrosis 81.2 percent distrofen positive fibers with 96% intensity. And in terms of function, we saw a mean 7 point improvement on NFAA from baseline to year 2. So now turning to our limb girdle muscular dystrophy Type 2e program for 9,003.
This is a Phase onetwo study, open label study in 16. Just to orient you on lung marrow muscular dystrophy, the LGMDs as a whole have a global prevalence of 1.63 per 100,000. There are over 30 subtypes of LGMD with both genders affected. The LGMDs are genetically heterogeneous, but when you look at an individual subtype, you see more uniform distribution. In LGMD, the muscle weakness begins in the hip and shoulder girdles, as you can see by the image, but then the weakness does eventually extend distally and can also involve the cardiac muscle as is the case in LGMDCE as well as the diaphragm.
So just to summarize our preclinical findings to date here, in terms of safety, we've seen a low prevalence of pre existing antibodies. As far as vector distribution to muscle and preclinical models, we see greater than 10 to the 5 copies in all muscles, including the heart and diaphragm that we've looked at. Expression is greater than 90% in both skeletal muscle and the heart. And we see beta sarcoglycan correctly localized at the sarcolemma by immunofluorescence and restoration of the other DAPC protein. And it's translated into significant improvements in specific force, fatigue, scoliosis and activity and movement in the preclinical animal model for LGMD2E.
Just to show you some of this data, this is our durability data in the LGMD2E knockout mouse model. And what you can appreciate here is that the animals were treated early and then we showed expression as of 6 months, also out to 28 months. And you can see that there was no diminishment of expression over that time frame with greater than 90% of fibers across every single muscle group, including the heart and diaphragm. And on the right, this is just a representative image of expression of both skeletal muscle and in the heart at 27 months. The SRP-nine thousand and thirty three study is an open label trial design with key inclusion criteria confirmed beta sarcoglycan mutations in both alleles, patients have to be negative for R874 antibodies and be greater than 40% of normal on the 100 meter walk test.
Prednisone at 1 mg per kg was started daily one day before study treatment for 30 days in Cohort 1 60 days in Cohort 2 before beginning paper. Multiple biopsies were taken at baseline and 60 days. Primary endpoint is safety with secondary endpoint being beta sarcoglycan expression at week 8. Other secondary endpoints included change in CK and functional endpoints, which included the NorthStar ambulatory assessment, 100 meter walk, 10 meter walk, forced airtime and time to rise. These are the subject demographics at baseline.
In terms of gender distribution, we see an equal number of males and females across our 2 cohorts. Ages range from 4 to 13 years of age. All of the mutations were severe. 5 of 6 patients had mutations in exons 3 or 4. Mutations in these exons lead to complete absence of severely reduced expression of Acycloglycan and that includes cardiomyopathy.
Our 6th patient had a mutation in the very first photon of exon 1 leading also to complete absence of protein. We had a wide weight range between 17 57 kilograms And so this really gave us important safety experience across the large weight range for our programs in muscular dystrophy. We also saw elevated crease in kinase levels in both cohorts as well. There were 2 dosing levels in Cohort 1. The dose is 5 times 1013 vector genomes per kilogram, otherwise stated as 0.5 times 1014 vector genomes per kilogram.
Cohort 2, we saw a 4 fold increase for a dose of 2x1014 vector genomes per kilogram. Again, in terms of what to consider when the bio and gene transfer therapies, we'll go through the same paradigm. We'll first looking at safety, then in muscle biopsy, we're looking at stem section, bivector copies, western blot for total expression, immunofluorescence for localization of that expression and functional outcomes, which include NSAID and time function tests. First, focusing on safety. We'll first focus on Cohort 1.
In this Cohort 2 subjects that elevated liver enzyme, 1 was designated as an SAE as the subject had associated transient increase in bilirubin. One event occurred when the subject was tapered off of oral steroids and the other while the patient was being tapered. These both returned to baseline very quickly and the symptoms resolved within days following supplemental steroid treatment. One patient experienced mild vomiting, which resolved within one day without treatment and there were no other clinically significant laboratory findings or no decreases in platelet counts out of the normal range and no clinical sequelae associated with complement activation. In Cohort 2, the majority of AEs were mild to moderate and resolved easily.
There was one treatment related SAE observed and this was dehydration resulting from vomiting 3 days after infusion, This resolved quickly within 2 days with anti medics and IV fluids. We had one patient with mildly elevated GTC, which returned to normal limits while tapering dose of steroids and the patient did not experience an increase after tapering was concluded. If you remember for our Cohort 2, we increased the steroids for 60 days prior to tapering for this cohort. There were no stopping or discontinuation rules triggered by AEs and no other clinically significant laboratory findings, including no decreases in platelets or complement activation. Now turning to our biopsy data.
Again, we had biopsies at baseline and at 60 days. In our first cohort, we saw a mean of 0.6 copies per nucleus at low dose. At the high dose with a 4 fold increase, we see a mean of 4.2 copies per nucleus. Now turning to expression by western blot for cohort 1, we had a mean of 36.1% as compared to normal. And as expected in our high dose cohort, we saw a mean of 62.1% compared to normal.
So we saw a almost doubling its expression by western blot in our 2nd cohort. In terms of percentage of positive fibers and intensity in our low dose cohort 1, we see 51% of muscle fibers expressing beta sarcoglycan with an intensity of 47% as compared to normal. In our high dose cohort, we saw that increase to 72% beta sarcoglycan positive fibers with an intensity of 73%. This led to an expected reconstitution of the dystrophin associated protein complex. So what we're showing here is staining for beta sarcoglycan in green and alpha sarcoglycan at the same time.
And what you can see in the co localization image is that these are localizing together at the membrane in the appropriate place. We also looked at increasing kinase levels and what we're showing here is both Cohort 1 and Cohort 2. And what we can see at day 90, we see a dramatic decrease increase in kinase levels, which was 83.4% for Cohort 1 and 89.1% for Cohort 2. Now I'll turn to our functional data. And so what we'll be sharing here is our 18 month functional data for Cohort 1 and an early date, our 6 month functional data for our high dose cohort or Cohort 2.
So what we're showing here is a summary data for Cohort 1 for the NSAID over 18 months. And what you can appreciate is that we see a sustained improvement in the NSAD scores across our 3 patients. So we see 4 points, 6 points and 7 points respectively in our first three patients for a mean of 5 point 7 points compared to baseline. So we're consistently seeing a durable effect at 18 months. We previously shared our 1 year data improvement.
Now turning to all of our times function tests. These are functional outcomes for Cohort 1, again, specifically. And what we're showing here is comparison from baseline to month 2018. And what you can see again across every single measure, we see an improvement. And this includes our time test where we see a decrease in time to do these particular activities including time to rise for spares 100 meter and 10 meter.
With consistent improvement in all functional measures. Now turning to our data for Cohort 2, our high dose data shown in the NSAID. We can show here that we're seeing an improvement in just 6 months of 3.7 points on the NSAID across our 3 high dose cohort patients. And when we look at all of the functional measures, again here going from baseline to 6 months, we see an improvement in all of our time tests as well for every single patient across the cohort. Next, what we did was do a summary or a comparison of the mean improvement from baseline to 6 months, just that's for both cohort 1 and cohort 2.
So this is looking at the just 6 months. And what you can see is that as expected with an increase in beta sarcoglycan expression, we see a subtle improvement in at 6 months for Cohort 2 for 3.7 versus 3 in the NSAV at that time point and across all of our time function tests we've seen an improvement as well. So just to conclude, durability is an important consideration for one time treatment such as gene therapies. The durability of transgene delivered with AV vectors has been observed across programs. We've shown it here in our muscular dystrophy program.
Muscle really is an ideal target for durable gene therapy due to the low cell turnover in muscle. And accordingly, higher expression levels protecting more muscle fibers should lead to a more durable functional response. We've shown preclinical data from both our micro dystrophin program and our LGMD2E program that supports restorable functional responses post gene therapy transfer. And clinical data from both our microdystrophin FRP-nine thousand and one, 101 study and the FRP-nine thousand and three program support durable functional outcomes at 2 years for 9,001 18 months for 9,003 respectively. And with that, I will turn it over to Doug to lead the question and answer session.
Thank you, Louise. Let's open the call for questions.
Thank Our first question comes from Ritu Baral with Cowen. Your line is open.
Hi, guys. Thanks for taking the question and congrats on the update. I do have a question on the GGTs across both programs. We usually see ALT, AST elevations with gene therapy programs. I'm wondering what do you think GGT means, were there concurrent alk sauce elevation?
Does that lead to should
we be thinking about cholestatic dysfunction,
the kind that was sort of, sorry, mentioned in the XLMTM posters, that world muscle this morning as well?
Sure. Thank you for that. So one of the reasons we've GVP specifically is because AST and ALT are elevated in Duchenne, also in Limb Girdle. And so GGT is more sensitive to look for changes that are specifically related to liver versus muscle. So that's generally the reason that we use it.
We don't see any specific abnormality in GGT, for example, that would be concerning. I'm just more sensitive in this indication.
Thank you. Our next question comes from Anupam Rama with JPMorgan. Your line is open.
Hey guys, thanks so much for taking the question. Just a quick one from us on if you can provide any more granularity on where the MSAA improvements are coming from for the 4 patients. And as we're thinking about kind of the update early next year for the Phase 2, is that kind of level of detail something we might expect? Thanks so much.
Yes, Elyse, do you want to take that?
Sure. We're seeing improving across all the NSA measures, so there's nothing specific yet. It's something we may parse out later in 102 to look for trends. But we're not seeing certain aspects that are not being improved, for example. So we see consistent improvement across most measures, the components of the NSA.
You could expect that level of detail when we announce 102 will certainly be about 102 when we release it. One of the exciting things about this data is that we're seeing fairly dramatic results, but we're also seeing those results fairly consistent across all of the participants in all of the measures and even in the subcomponents of NSA.
Thank you. Our next
Thank you for taking my questions. Maybe Doug, I wanted to ask one quick picture question. So we did see the complete response letter from Baum Marine and also we saw FDA request another clinical trial for Zolgensma and I believe those are the same division on the CEVA. Just wondering what is your regulatory interaction? Did you see anything changing or FDA become more stringent?
And also any update regarding the pivotal study, the trial initiation?
Yes. So answering the last question first, we don't have an update yet. You can imagine, given that we are serepting, we move with some speed, we are not being dilatory, but we still have work to do and we don't have an update yet on the commencement of our next trial and the resolution of primarily this assay issue that we've discussed before. It is an interesting question as it relates to the agency and whether the agency at some level has changed or increased or become more conservative in its approach to gene therapy over the last 2 years. What I can tell you is that Doctor.
Peter Marks, who is obviously in charge of CBER, who has some years ago, probably in the last 2.5 to 3 years ago, set the stage for the approach the FDA was going to take towards gene therapy. And then of course, spearheaded some guidances that showed an enormous amount of flexibility with respect to gene therapy has repeatedly as recently as late last week reconfirmed that there has not been any change in the FDA's approach to gene therapy, including the willingness to be flexible and to work with companies to advance gene therapies. So at least from our perspective, from the leadership of the agency, presumably that will bleed down to the rest of the division. Doctor. Marks continues to make the same comments about the opportunities to be flexible, the willingness to look at things, which is similar to what was done with respect to AveXis and Zolgensma and the like, and we're confident that he means that.
What is also true, certainly, is that we're in the middle of a pandemic with the division that was already under an enormous amount of pressure given the workload of cell and gene therapy relative to the staff available. So that may be part of what folks are seeing when there are it is difficult at times to have direct or informal conversations with the division. But as far as the broader perspective, we certainly take Doctor. Marks at his word that the division remains completely committed to advancing cell and gene therapy by being flexible and thoughtful and working closely with companies not unlike the approach that they took with Zolgensma and before that with Spark.
Thank you. Our next question comes from Brian Skorney with Baird. Your line is open.
Hey, good morning guys. Thanks for taking the question. The percent predicted analysis that you guys did for the 100 meter measure is really helpful. Great idea of how the patient is improving relative to where kids without DMG would be at that range. Do you have any frame of reference for the North Star Ambulatory Assessment as a percent predicted?
Or maybe you can kind of give us an idea of where on sort of a natural history curve score 30 or more is translating to in terms of age matched trotron, normal dystrophin expression or maybe if there's any data and on small patient population, but any data on the natural history of back orders to compare to that would be really helpful.
Thanks for that question. As we know that the NFAA has a max score of 34, that's maximum and that's certainly normal individuals. There's a range of normal around that. So that's something that we'll certainly look at over time. We don't have the same amount of natural history data represented and present predicted for NFSA like we do for the 100 meter.
But it's certainly a good point to call out that we the 34 is the max scale, but yet not every individual normal individual that's not DMD isn't scoring a 34. So that's something that we'll look at over time.
Thank you. Our next question comes from Chen with Bernstein. Your line is open.
Good morning. Thanks for taking the question. I was wondering if you could comment quickly on the progress you've made in getting approval from the FDA to initiate Study 3. I was wondering, for example, have you received any incremental clarity from regulators on what potency assays will be acceptable? And if not, I guess, what are the next steps in the range of timing as you see it now for when you might get the clarity?
Is there some sort of meeting or discussion that you would need to schedule? Is it just a matter of more informal chats with regulators? Or would this be something where you'll just go ahead and propose a potency assay once you have what you think is likely to be to the answer validated and so forth.
Doug, you're on mute.
Apologies for that, Mike. Everything I just said was brilliant, but I'm going to say not as good now. So thanks for the question. Obviously, I don't, as I said before, I don't have an update right now on the timing or the outcome of those discussions with the agency. You will know certainly if you know Sarepta that we have done a lot to resolve this issue and to get dosing.
There are really probably broadly speaking 3 possibilities in timing. I cannot risk analyze or give you probabilities of success of which these will work. But the longest time, if we had to go down the longest most formal process, it would be a formal dispute resolution process. Our own history would say that's about a 4 month process. Another formal process that doesn't take as long that we would have the right to, of course, is a Type A meeting.
That is on the outside edge about a 60 day process. But there is definitely also the possibility, I can't say what the probability is, but the possibility of coming to an informal resolution short of a Type A meeting. We are working across these various options and working to engage with the agency. And so we will, I promise you, give an update when we have information and better clarity and what the resolution would look like and for instance, where we end up with the assay issue.
Thank you. Our next question comes from Alethia Young with Cantor. Your line is open.
Hey, guys. Thanks for taking my question and congrats on the progress. Can you just talk a little bit about maybe between 2 studies, if you're seeing kind of differential activity based on age? I know it's a relatively small sample size, but just wondering if you think that this is suggestive of broad activity or does it kind of does it work a little bit different if you're a little older? And then just also how does this impact your confidence into the first pivotal study?
Before Louis speaks, I will say broadly and then Louis can give more insight. I mean, we are excited about the fact that if you look across these two relatively similar disease states and treatments that are very similar, rh74, same promoter, and then of course, gene that codes for a missing structural protein. There's a lot to be excited about in here. The age range is broad in small data set. So we do see benefit across a large group of children.
Some of the other children in the LGMD trial are in their, if not teens, almost teens and we're talking about children who are over 50 kilograms. We're very excited about the fact, of course, in addition to the functional benefits that we're seeing, significant genome copies per nucleus across both groups. But with that said, I'll turn it over to Louise to provide a more nuanced perspective on this.
Thank you. So So, Glenn, actually, I'll just add that this really gives us a lot of confidence in our platform for the use of RS74 and the MHCK7 promoter. I think the limb brittle study makes us very pleased because we're seeing a large age range and a large weight range similar effects, and we're not seeing differences in terms of expression or in function with age or weight. And so that is a lot of research to both programs and something that we're quite pleased about. Obviously, these are in a small study, but it gives us a lot of continued confidence in this platform moving forward.
Our next question comes from Tyler Van Buren with Piper Sandler.
I guess just had a follow-up on the 2 year DMD NSAA data. Was there anything, I guess, specific with patient 1 that caused the decline in the functional score from year 1 to 2? And I guess conversely, anything unique about patients 2, 34 that caused them to see that nice increase in year 2? And you talked about durability of transgene expression going out to 8 years. Would you expect to see another jump up in year 3?
Or when do you expect functional improvements to ultimately top out?
Louise?
Sure. So for the MSA, what we see in Patient 1 is really just some small variability. We've seen in some other patients where at one time point and they've gone down one point and then they've gone right back up. So we're not concerned about that at all. And when you look at the SITALIA data, specifically Patient 1, we're continuing to improve on all of the other measures as well.
So, we're continuing to be pleased about the sustained benefits across for all patients across all of the measures. And the second part of the question, I think, was on an improvement right above the year. So we're certainly continuing to look for sustained benefit and potentially additional going into milestones over time.
Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.
Good morning. Is it possible to give us any data since baseline for the CK levels for 9,001? Yes. What we can say is they're consistent with what we've seen previously. We focus on CK early on to show the correlation between expression and function.
So right now, we know that CK can be variable, but what we've seen is the sustained benefit, and it's right in line with what we've shown recently for the 1 year data.
It's interesting. CK is an interesting biomarker. It's more binary really is. It's more of a signal about muscle health as opposed to some sort of analog version where you can test it. And we found that out.
We found that directly when we would see that as these kids became more active, they would have these moments of decay spike associated with activity. But it's a really interesting biomarker that we're still looking at. There are other interesting biomarkers to look at as well. And I would say that there is some information, it's not our own, so we can't present it ourselves. But if one is interested in biomarkers and our program in DMD, there will be, I believe, at 2 p.
M. Eastern Time today from Doctor. Kristen Vandenberg, I believe at the University of Florida, you correct me if I'm wrong, Louise, some really interesting data on these kids in the SRP-nine thousand and one Cohort 1 group, Study 101, where she's done muscle MRI studies to look at post treatment MRI and muscle health data versus what one should see in DMD unaffected by the therapy. And so if one's interested in addition to the functional data that we've seen, in addition on the genome copies, in addition on the immunofluorescence that we've shown and Western blot we've shown and CK that we've shown, what it might also look like directly looking at the muscle using MRI, I would suggest that folks should really get interested in watching that presentation by Doctor. Vandenberg.
Hopefully, I didn't get any of the particulars wrong, Louise, if I did, please correct me.
No, you're correct. And there's a poster as well.
Our next question comes from Brian Abrahams with RBC Capital Markets.
This is Steve Mallow on for Brian Abrahams. Do the data on the 4 year old Zimgiril patient imply the ability to fully restore function if patients are dosed early enough? And as a quick follow-up, if more mild patients can easily reach the top of the NSID scale, any concern for using that test as an endpoint in a trial of, say, heterogeneous patients on heterogeneous on age or function.
Elyse?
Yes. Thank you for calling that out. So in our low dose cohort, the 2nd patient, 4 year old, did max out the scale. So the NSAD, the highest measure is 54. Certainly, he achieved that and sustained that as well.
And so this is where we continue to look at the totality of evidence. And then I would also point out that we know from natural history in LGMD2E that patients start to decline around the age of 10. So there the NSAID would certainly still be helpful because you will be looking for the same benefit of the NSAD over time, whereas controls might be declining, but then together with collective other measures as well. That's how we're approaching it.
Thank you. Our next question comes from Danielle Brill with Raymond James. Your line is now open.
Hi guys, good morning. Thanks for the question. I was just wondering if you could clarify a little bit on some of these functional endpoints, particularly time to raise, how much variability you would normally see in the course of disease? I noticed that the patient 3 and time to raise specifically bounced around quite a bit by a second or more at various time points. Just wondering if you could give some color on how to interpret that?
Thanks. There's obviously some variability in some of these measures. And again, that's why we look at all measures across multiple time points. If you think about it, just even you and I getting up from the floor, we might see a one second variability in the way that we do that. So again, just looking at multiple measures over multiple time points, We don't see anything significant in terms of the variability for a specific individual versus another.
Also, it's important to put this in the context. So, of course, there is going to be some variability time point to time point across the kids. One interesting thing, by the way, another interesting data is that Doctor. Montoni, one of the world leaders in Duchenne muscular dystrophy neuromuscular just published a paper on essentially over time the lack of a significant or any real placebo effect in kids with Duchenne muscular dystrophy. But beyond that, when you look at these data sets, while there may be some variability across time point to time point, it's really looking at the totality of the data and the fact across every kid in almost every single time point and in aggregate and in the components, everything improved.
So it would be a really interesting one if there was one kid driving it or one time, one measure driving it or this time test drove it. When you look across all the time test, you look across the NSAAs, you look across each component of the NSAAs, you put that in the context of the robustness of the dystrophin that's being produced, that it's properly localized to the sarcolemma, that it's associated with up regulation of the dystrophin associated protein complex, that is all associated with a fairly dramatic reduction in CK as a measure of muscle health. And then you put all of that in the context of, well, what you'll see this afternoon, which is what MRIs might show us, and I would suggest people might want to tune into this, what MRI data might show on muscle health in children who have been treated with SRP-nine thousand and one, it becomes pretty clear that the occasional variability is completely swamped by the overall positive nature of all of these and positive in a way that can't be explained by natural history. Yes. And Danielle,
this is Ian. Just to clarify, patient 3a is our oldest patient. And
if you look across all
the measures, there actually isn't variability for his time to rise. He's improving across all measures, which again is really supportive because he's the oldest patient. But at baseline, it was 3.9 seconds for time to rise, 3.9 seconds at a year and then 2.8 seconds at 2 years. That's consistent with the improvement that you're seeing with this 100 meter, 100 meter percent predicted. And obviously, for the oldest patient going from a baseline of NSAA at 26 and then going up to 31, this really supports that this patient is doing better when he would be predicted to decline on NFAA 2 to 4 points in his age, if not even more, to actually see a 5 point improvement is certainly not what we would expect for natural history.
So there really isn't variability across this patient at all.
Our next question comes from Joel Beatty with Citi.
Are you able to share an update on your commercial manufacturing capacity for the DMD gene therapy?
Well, we're in good shape from a manufacturing perspective. As I think anyone who lived with us through 2019 knows we spent an enormous amount of time and energy and resources on manufacturing across 2019. The biggest issue was for us was not only getting capacity in place and getting iCELLis units in suites, but also getting the process development to a place that our yields were acceptable for the launch of the therapy. As we stand here right now, we're in a good place. We've hit our targets.
In fact, we have exceeded our internally set targets on yield. So we are in a good place. If we can get this therapy confirmed and we can get this therapy approved, we will be able to fully serve the community with the capacity that we would have available to us based on all the work that we're doing. The issue for us now, of course, is to start the next trial using that commercial process, and we're working with the agency right now to resolve any questions that they might have, get their blessing and maybe start that trial as soon as is possible. You can only imagine if you see the data that we're seeing today across these children, both in the cohort, the first cohort of 9,001 and the 2 cohorts we had in 9,003, you can imagine how much sense of urgency Sarepta has to get that resolved with the agency and get that next study started.
This is truly and I am not being hyperbolic when I say in a very real sense, at least from our perspective, a matter of life and death. We have to get this trial started. Kids are waiting for this therapy, but we are working hard on it. And I will provide an update on that as soon as I have an update to share with everyone.
Thank you. Our next question comes from Joseph Schwartz with SVB Leerink. Your line is open.
Thanks a lot. What have you learned from collecting and analyzing the data for the 1 100 and and one study that you can apply to the 102 study in order to maximize your probability of success. Can you talk about your approach to adjudicating observations in the 102 study in order to give this trial the best chance of working?
I'll say a couple of things and Luis can probably either correct me or say even more. First, know that we already had access to information from Study 101 when we did not only the design for Study 102, but the powering of 102. So we've already benefited from that. We also had some experience. So one of the things that you will see in Study 101 is that we had elevated liver enzymes.
We responded to that. We had elevated liver enzymes that could be treated fairly rapidly and back to baseline with no significant ongoing issues by increasing steroids. But we use that information to help us think about what the steroid regimen should be for Study 102 and we changed the steroid regimen for Study 102. Now we won't know until we unblind that was we were able not only to have been able to deal with less elevated liver enzymes if it happens, but to avoid elevated liver enzymes by a longer course of steroid treatment. But what you will have seen in the 9,003 studies is that in the high dose version of 9,003, we had implemented that same change in protocol where we extended the steroid use.
And at least in 9,003, small data set, but in older kids, it appeared to have worked and we didn't get elevated liver enzymes. So there is no doubt that Study 102 has already been informed by Study 101. And what we see in Study 101 gives us continuing confidence in the powering, in not only the protocol that we designed for Study 102, but in the powering that we and analysis that we did with respect to 102 that got us to a 41 patient study. But with that, Louise, I'm sure I probably missed something.
No, actually, I don't think I can add anything else. I think you covered it very well.
Thank you. Our next question comes from Tim Lugo with William Blair. Your line is open.
Thanks for taking the question and congratulations on the durability. For the DMD boys, I know it's only 2 patients, but it does seem like patient 42 are seeing the greatest North Star improvements. They're both 4 years of age. I mean, does this impact your thoughts at all around the age of patients you'll be enrolling in the pivotal program? And also can you just remind me the strategy for studying the therapy in older, more severe patients?
2 things and then Luis can comment. So we already took into account, even though we have a fairly tight age range in both Study 102, which was the same as Study 101, which is 4 to 7. We've balanced patients out between the 4 to 5 year olds and the to 7 year olds between the placebo and the active arm in Study 102. And we did that because we do know that even in that small age range, there are subtle differences between those two groups. So that's already informed.
And we will the short answer is we will have and I'll announce this more of this as we track forward. We have a strategy to start as soon as possible a non ambulatory study as well to confirm the continuing safety of this therapy in older and non ambulant children as well as the younger children, it's certainly our goal to have that started as soon as possible. The first thing we've got to do, of course, is resolve the assay issue and get started with the main study, and we'll give you an update on that as soon as we can. I don't know if I've missed anything, Elyse.
No, I think you captured it.
Thank you. Our next question comes from Martin Auster with Credit Suisse. Your line is open.
Hi, everyone. This is Matt Torrevont for Marty. Thanks for taking the question. Would you be able to provide any perspective on whether there are plans for longer term biopsies for the Phase 1 patients? And also if you could discuss the biopsy plan for Study 102?
Thanks.
So we don't hey, thanks for the question. First of all, we don't have a plan to buy off these kids again. Frankly, we'd have to re consent them and I suspect that they would object to that given where they are. In fact, we've been consistent with what we would have imagined, we've actually been counseled by the agency to be careful not to over biopsy kids. And one of the reasons we biopsied kids early, but we don't do longer biopsies is that there really is within the timeframe that we're talking there really is no credible reason to imagine that you would have any durability related issues.
If you look across restricted microdystrophin generally in gene therapy and you look in muscle, you look across the mouse model as you've seen, the non human primate model, the dystrophic golden retriever model, you see continuing functional benefit and durability for as long as we've been able to look so far, which can get out into the 8 to 9 year range. So frankly, in the context of that, trying to consent a child to do a to engage in yet another biopsy at like 1 or 2 years would be challenging to say the least given that you probably wouldn't get meaningful information that you didn't get in the first biopsy. And so for Study 102, the biopsy is a 3 month biopsy. Did I miss anything there, Louise?
No.
Thank you. And I'm currently showing no further questions at this time. I'd like to turn the call back over to Doug Ingram for closing remarks.
Thank you very much. I'll just repeat what I said during the Q and A. We are obviously, as you can imagine, very excited about these results and the continuing functional benefits that we see across these cohorts in addition to all of the exciting expression, safety, tolerability data that we've had and all of the biomarkers as well. One thing I will say so two things on that. 1, of course, it speaks to the need to move fast.
So while I'm not yet able to understand better the to understand better the agency's views, to adapt to their views, to address that issue and to get that next trial started as soon as possible. I think, all of us who see this data ought to feel compelled to move as quickly as possible for these children. 1st with 9,001, then with 2E, because this is really an exciting set of data. We are in both of these cases, we're restoring the structural protein to nearly normal. So we need to get that moving as well.
And then once we get that moving, we need to get all of the limb girdles moving as well. There are a lot of patients waiting for us right now. So we are moving with a sense of urgency and we'll give up things about that along the way. One final thing I will say, I said it now twice, I'll say yet again, I'm very excited about I think we all are very excited about the study that was done by Doctor. Kristin Vandenberg on muscle health in these DMD boys and Study 101 using MRI.
There is a presentation later today on that. I am told now that the poster for that is already up. So for those who are curious of seeing that in advance of the presentation, the poster is available to review and I would suggest that could be interesting data as well. We cannot present it ourselves because that was a study done entirely independent of Sarepta. But with that said, thank you all for your participation today.
Obviously, thank you, Doctor. Luisa Klapac for going through this and answering questions today. And thanks to the broader team, and we look forward to providing additional updates as we continue to move these and our other programs forward. With that, have a wonderful day, everybody.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.