Good morning, ladies and gentlemen, 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 speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one on your telephone. As a reminder, today's program is being recorded. 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 two most advanced gene therapy programs, SRP-9001 and SRP-9003. This is Doug Ingram. I am the CEO of Sarepta. I am going to turn over the call momentarily to Dr. 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&A, make some forward-looking statements or, in other words, some potential statements about future events. One should review our public filings for a full list of the risks that are attendant whenever one attempts to make statements about the future. With that, let me turn the call over to Dr. Louise Rodino-Klapac. Louise?
Thank you, Doug. I'm very pleased to be giving an update on our SRP-9001 program for Duchenne muscular dystrophy. This is our two-year functional data, as well as our 18-month functional data for our LGMD2E program, or SRP-9003. First starting out, in consideration for development of gene transfer therapy, durability is a key consideration. We'd like to take a moment to discuss the durability of transgenes 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 eight years in canine models, up to 10 years in humans in one trial, and three years in another trial. This is important in terms of collective data for the durability of gene transfer.
Additional data in other programs like SMA, including non-clinical models for the lifespan of the mouse, 250 days, or five 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 humans for 18 months. In our Duchenne program, we have data in humans, two years, which we'll talk about today. There's also additional data in the canine model for eight years. 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. One, skeletal muscle is postmitotic, meaning it no longer divides.
In adult muscle, 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's 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. This turnover decreases exponentially with age to less than 1% in adults. Now, durability is affected by multiple factors for gene therapy. One is the viral vector transduction and biodistribution. The selection of the AAV serotype, for example. We've 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.
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 up to eight years and continuing on as well. Now turning to our Duchenne muscular dystrophy program, SRP-9001. We'll be giving a clinical update on our first study. This is an open-label study in four 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 recessive pattern that affects male newborns. Muscle weakness is noticeable by the ages of three to five, but most patients are dependent on a 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. For open-label trial design, we had four patients between the ages of four to seven years of age with confirmed DMD mutations. The individuals also had to be negative for antibodies to AAV-rh74. In terms of endpoints, this is an open-label safety study as the primary endpoint, but with several key secondary endpoints, which included microdystrophin expression, decrease in creatine kinase, the 100-meter time test, North Star Ambulatory Assessment, which includes the 10-meter time test and multiple other time tests, including timed up and go, ascending stairs, and also cardiac MRI. These are patient demographics at baseline.
They range from four to six 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. 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. First and foremost, was the treatment safe, and was it tolerable? Next, how efficient was the gene transfer? We can measure this by measuring the amount of vector genome copies per nucleus. Does this transduction lead to protein production? We measure the total amount of protein production by Western blot, followed by localization. Is that correctly localizing at the membrane in the case of microdystrophin?
We measure that in terms of number of fibers and the intensity of those fibers at the membrane. Does this membrane staining lead to reconstitution of the dystrophin-associated protein complex, which then leads to function, including the NSAA and timed function tests, which we'll go through in detail. Turning first to safety. I'll remind you, we now have two-year safety data in these first four patients. There were no SAEs or any AEs that led to a discontinuation. There were no abnormalities in hematologic or chemistry panels, which included liver function tests, no serious AEs. Three patients had elevated gamma GT in the first three months post-treatment, and that resolved quickly with steroid treatment. There were no other clinically significant laboratory findings reported. Concluded that platelets remained in the normal range.
The most common treatment-related adverse event was vomiting, which consisted of nine of the 18 treatment-related adverse events. Patients had transient vomiting generally within the first week post-infusion, which did not correlate with liver enzyme elevations or any other abnormalities. All of these occurred within the first 90 days. None of the adverse events were associated with complement activation. 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, we see 95.8% expression compared to normal by Western blot. Next, we look at microdystrophin expression at the membrane. Again, we quantify this by counting the number of fibers positive for microdystrophin, which we see a mean of 81.2%, and then also quantify the intensity as compared to normal. Here we see 96% intensity. Next, we looked for restoration of the dystrophin-associated protein complex. One of the key members of this complex is beta-sarcoglycan. As you can see pre-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 biopsies.
This is a staining called Sirius red, which stains for collagen, as you can see here in pink. The healthy muscle fibers are in the bluish-green color and fibrosis is in pink. What you can see is that we see a significant reduction in the collagen content or the fibrosis content post gene therapy at 12 weeks. Now I'll turn to this functional data. Now, previously we've shared our one-year functional data, and now we're updating to two years. First, this is the North Star Ambulatory Assessment. This is an aggregate of 17 measures for a total of 34 points. What you can see is that at two years, we are still seeing a sustained or improvement in function in the NSAA over that time point. We see a mean change of seven points from baseline to two years across our four patients.
At year one, as you can see, we had a 5.5 points increase, and at year two, we now see a 7-point increase across these four patients. Looking at a summary of the timed function tests, what you can appreciate is that we see a sustained or improved function across our four patients in all of these tests as well. I'll remind you for the timed function tests, including time to rise, wheelchair climb, and 100 meter, we're looking for a reduction in the amount of time it takes to do that activity. Looking across, you can see improvements in our patients for sustained benefits. I'll just have you focus on the 100 meter % predicted. This is a way of measuring the % function as compared to a normal age-matched individual.
What you can see in all four patients is that we've seen improvement in the percent predicted value for 100 meter in our four patients. Just to summarize the results from our Study 101 two- year study. In terms of safety, we saw three subjects had 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% or 95.8% expression compared to normal if you adjust for fat and fibrosis. 81.2% dystrophin-positive fibers with 96% intensity. In terms of function, we saw a mean seven-point improvement on NSAA from baseline to year two. Now turning to our limb-girdle muscular dystrophy Type 2E program, or SRP-9003.
This is a phase I/II study, open-label study in six patients. Just to orient you on limb-girdle muscular dystrophy, the LGMD 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, when you look in 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 LGMD2E, as well as the diaphragm. Just to summarize our preclinical findings to date here. In terms of safety, we've seen a low prevalence of preexisting antibodies.
As far as vector distribution to muscle and preclinical models, we see greater than 10^ 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. We see beta-sarcoglycan correctly localized at the sarcolemma by immunofluorescence and restoration of the other DAPC proteins, and it's translated into significant improvements in systolic force, fatigue, scoliosis, and activity and movement in the preclinical animal models for LGMD2E. Just to show you some of this data, this is our durability data in the LGMD2E knockout mouse model. What you can appreciate here is that the animals were treated early, then we showed expression at about six months, also out to 28 months.
You can see that there was no diminishment of expression over that time point, with greater than 90% of fibers across every single muscle group, including the heart and diaphragm. On the right, this is just a representative image of expression of both skeletal muscle and in the heart at 27 months. The SRP-9003 study is an open-label trial design with key inclusion criteria of confirmed beta-sarcoglycan mutations in both alleles. Patients had to be negative for rh74 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 and 60 days in cohort 2 before beginning taper. Muscle biopsies were taken at baseline and 60 days. Primary endpoint is safety, with secondary endpoint being beta-sarcoglycan expression at week eight.
Other secondary endpoints included changes to PK and functional endpoints, which included the North Star Ambulatory Assessment, 100-meter walk, 10-meter walk, four-stair climb, and time to rise. These are the subject demographics at baseline. In terms of gender distribution, we've seen equal number of males and females across our two cohorts. Ages ranged from 4- 13 years of age. All of the mutations were severe. Five of six patients had mutations in exons three or four. Mutations in these exons lead to complete absence of severely reduced expression of beta-sarcoglycan, and that includes cardiomyopathy. Our sixth patient had a mutation in the very first codon of exon one, leading also to complete absence of protein. We had a wide weight range between 17 kg and 57 kg, and so this really gave us important safety experience across a large weight range for our programs in muscular dystrophy.
We also saw elevated creatine kinase levels in both cohorts as well. There were two dosing levels in cohort 1. The dose was 5x 10^ 13 vector genomes per kg otherwise stated as 0.5x 10 ^ 14 vector genomes per kg. Cohort 2, we saw a four-fold increase for a dose of 2x 10^ 14 vector genomes per kg. In terms of what to consider when evaluating gene transfer therapies, we'll go through the same paradigm. We'll first look at safety, then in muscle biopsies, looking at some sections by vector copies, Western blot for total expression, immunofluorescence for localization of that expression, and functional outcomes, which include NSAA and timed function tests. First, focusing on safety. We'll first focus on cohort 1. In this cohort, two subjects had elevated liver enzymes.
One was designated as an SAE, as this 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. No decreases in platelet counts out of the normal range and no clinical sick biology 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 three days after infusion. This resolved quickly within two days with antiemetics and IV fluids.
We had one patient with mildly elevated GGT, which returned to normal when the slow tapering off 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. Turning to our biopsy data. We had biopsies at baseline and at 60 days. In our first cohort, we saw a mean of 0.6 copies per nucleus at the low dose. At the high dose with a four-fold increase, we see a mean of 4.2 copies per nucleus. Turning to expression by Western blot. For cohort 1, we had a mean of 36.1% as compared to normal.
As expected in our high-dose cohort, we saw a mean of 62.1% compared to normal. We saw almost doubling of expression by Western blot in our second 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. What we're showing here is staining for beta-sarcoglycan in green and alpha-sarcoglycan at the same time. What you can see in the colocalization image is that these are localized together at the membrane in the appropriate place.
We also looked at creatine kinase levels. What we're showing here is both cohort 1 and cohort 2. 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. What we'll be sharing here is our 18-month functional data for cohort 1 and an early read, our six-month functional data for our high-dose cohort, or cohort 2. What we're showing here is the summary data for cohort 1 for the NSAD over 18 months. What you can appreciate is that we see a sustained improvement in the NSAD scores across our three patients. We see four points, six points, and seven points respectively in our first three patients for a mean of 5.7 points compared to baseline.
We're consistently seeing a durable effect at 18 months. We previously shared our one-year data improvement. Turning to all of our timed function tests. These are functional outcomes for cohort 1, again, specifically. What we're showing here is comparison from baseline to month 18. What you can see, again, across every single measure, we see an improvement. This includes our timed tests where we see a decrease in time to do these particular activities, including time to rise, four stairs, 100 meter, and 10 meter with consistent improvement in all functional measures. Turning to our data for cohort 2, or our high-dose data showing the NSAD. What we can show here is that we're seeing an improvement, which is six months of 3.7 points on the NSAD across our three high-dose cohort patients.
When we look at all of the functional measures, again here going from baseline to six months, we see an improvement in all of our timed 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 six months just for both cohort 1 and cohort 2. This is looking at just six months. What you can see is that, as expected with an increase in beta-sarcoglycan expression, we see a subtle improvement at six months for cohort 2 for 3.7 versus three in the NSAD at that time point. Across all of our timed function tests, we're seeing an improvement as well. Just to conclude, durability is an important consideration for one-time treatments such as gene therapy.
The durability of transgene delivered with AAV vectors has been observed across programs. We've shown it here in our muscular dystrophy programs. Muscle really is an ideal target for durable gene therapy due to the low cell turnover in muscle. Accordingly, higher expression levels protecting more muscle fibers should lead to a more durable functional response. We've shown pre-clinical data from both our microdystrophin program and our LGMD2E programs that supports this durable functional responses post gene therapy transfer. Clinical data from both our microdystrophin SRP-9001101 study and the SRP-9003 program support durable functional outcomes at two years for 9001 and 18 months for 9003, respectively. 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 you. As a reminder, to ask a question, you will need to press star one on your telephone keypad. To withdraw your question, press the pound key. We ask that you please limit yourself to one question. Please stand by while we compile the Q&A roster. Our first question comes from Ritu Baral with Cowen. Your line is open.
Hi, guys. Thanks for taking the question, 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 phos elevations? Should we be thinking about cholestatic dysfunction, the kind that was sort of mentioned in the XLMT posters at World Muscle this morning as well?
Go ahead, Louise.
Sure. Thank you for that. The reason we use GGT specifically is because AST and ALT are elevated in Duchenne, also in limb-girdle. GGT is more sensitive to look for changes that are specifically related to liver versus muscle. That's generally the reason that we use it. We don't see any specific abnormality in GGT, for example, that would be concerning. It's just more sensitive in this indication.
Thank you. Our next question comes from Anupam Rama with JPMorgan . Your line is open.
Hi, 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 NSAA improvements are coming from for the four patients. As we're thinking about the update early next year for the phase II, is that level of detail something we might expect? Thanks so much.
Yeah. Louise, do you want to take that?
Sure. Yeah, we're seeing improvement across all the NSAA measures. There's nothing specific yet. This is something we may parse out later in 102 to look for trends. We're not seeing certain aspects that are not being improved, for example. We see consistent improvement across those measures for components of the NSAA.
You could expect that level of detail when we announce 102. We'll certainly be transparent 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 consistently across all of the participants in all of the measures and even in the subcomponents of NSAA.
Thank you. Our next question comes from Gena Wang with Barclays. Your line is open.
Thank you for taking my questions. Maybe, Doug, I wanted to ask one big picture question. We did see the complete response letter from BioMarin, also we saw FDA request another clinical trial for Zolgensma, and I believe those are the same division under CBER. Just wondering with your regulatory interaction, did you see anything changing or FDA become more stringent? Also any update regarding the pivotal study, the trial initiation?
Yeah. Answering the last question first, we don't have an update yet. You can imagine, given that we are Sarepta and 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 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 two years.
What I can tell you is that Dr. Peter Marks, who is obviously in charge of CBER, who had some years ago, probably in the last two and a half to three 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. At least from our perspective, from the leadership of the agency, presumably that will bleed down to the rest of the division.
Dr. Marks continues to make the same comments about the opportunities to be flexible, the willingness to look at things 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 a division that was already under an enormous amount of pressure given the workload of cell and gene therapy relative to the staff available. That may be part of what folks are seeing when it is difficult at times to have direct or informal conversations with the division.
As far as the broader perspective, we certainly take Dr. 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 was 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 to give us a great idea of how the patient's improving relative to where kids without DMD would be at their age. Do you have any frame of reference for the North Star Ambulatory Assessment as a percentage predicted? Maybe you can kind of give us an idea of where on sort of a natural history curve a score of 30 or more is translating to in terms of age-matched children, normal distribution or expression, or maybe if there's any data, I know this is a small patient population, but any data on the natural history background just to compare it to that'd be really helpful.
Thanks for that question. As you know, that the NSAA, the max score of 34, that's maximum and there's certainly normal individuals, there's a range of normal around that. That's something that we'll certainly look at over time. We don't have the same amount of natural history data represented in present predicted for NSAA like we do for the 100-meter. It's certainly a good point to call out that the 34 is the max scale, but yet not every normal individual that's not DMD isn't scoring a 34. That's something that we'll look at over time.
Thank you. Our next question comes from Vincent 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 would be acceptable? If not, I guess, what are the next steps and 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 the regulators? This is something where you'll just go ahead and propose a potency assay once you have what you think is likely to be the answer validated and so forth?
Doug, you're on mute.
Apologies for that. Everything I just said was brilliant, but I'm going to say it not as good now. 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, three possibilities in timing. I cannot risk analyze or give you probabilities of success of which these will work. 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 four-month process.
Another formal process that doesn't take as long that we would have a right to, of course, is a Type A meeting. That is on the outside edge, about a 60-day process. 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, we will, I promise you, give an update when we have information and better clarity in 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.
Hey, guys. Thanks for taking my question and congrats on the progress. Can you just talk a little bit about maybe between two 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 suggests the broad activity or does it work a little bit different if you're a little older? Then just also, how does this impact your confidence into the first pivotal study?
Before Louise speaks, I will say broadly, and then Louise can give more insight. 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, the gene that codes for a missing structural protein. There's a lot to be excited about in here. The age range is broad in a small data set. We do see benefit across a large group of children. Some of the children in the LGMD trial are in their, if not teens, almost teens. 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.
With that said, I'll turn it over to Louise to provide a more nuanced perspective on this.
Thank you. Good structure. Well, I'll just add that this really gives us a lot of confidence in our platform for the use of rh74 and the MHCK7 promoter. I think the limb-girdle study makes us very pleased because we're seeing in 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. To that is a lot of recruit to both programs and it's something that we're quite pleased about. Obviously, these are a small study, but it gives us a lot of continued confidence in this platform moving forward.
Thank you. Our next question comes from Tyler Van Buren with Piper Sandler. Your line is open.
Hey, guys. Good morning. Thanks for taking the question. I guess just had a follow-up on the two-year DMD NSAA data. Was there anything, I guess, specific with patient 1 that caused the decline in the functional score from year one to two? I guess conversely, anything unique about patients 2, 3, and 4 that caused them to see that nice increase in year two? You talked about durability of transgene expression going out to eight years. Would you expect to see another jump up in year three, or when do you expect functional improvements to ultimately top out?
Louise?
Sure. For the NSAA, what we see in patient 1 is really just some small variability. This is we've seen in some other patients where at one time point they may go down one point and then they've gone right back up. We're not concerned about that at all. When you look at the totality of data, specifically patient 1, he's continuing to improve on all of the other measures as well. We're continuing to be pleased about the sustained benefits for all patients across all of the measures. The second part of the question, I think, was on improvement, right? Above two years. We're certainly continuing to look for sustained benefit and potentially additional attainment of 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 SRP-9001?
Yeah. What we can say is they're consistent with what we've seen previously. We focused on CK early on to show the correlation between expression and function. 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 one-year data.
It's interesting. CK is an interesting biomarker. It's more binary, really. It's more of a signal about muscle health as opposed to some sort of analog version where you can test. We found that out directly when we would see that as these kids became more active, they would have these moments of CK spike associated with activity. 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 that's not our own, so we can't present it ourselves.
If one is interested in biomarkers and our program in DMD, there will be, I believe at 2:00 P.M. Eastern time today from Dr. Krista Vandenborne, I believe at the University of Florida, you correct me if I am wrong, Louise, some really interesting data on these kids in the SRP-9001 cohort 1 group from 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.
If one's interested, in addition to the functional data that we've seen, in addition to the genome copies, in addition to the immunofluorescence that we've shown, 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 Dr. Vandenborne. Hopefully, I didn't get any of the particulars wrong, Louise. If I did, please correct me.
No, you're correct. There's a poster as well.
Thank you. Our next question comes from Brian Abrahams with RBC Capital Markets. Your line is open.
Hi, this is [Steve Malin] for Brian Abrahams. Thanks for taking my questions. Do the data on the four-year-old DMD girl patient imply the ability to fully restore function if patients are dosed early enough? As a quick follow-up, if more mild patients can easily reach the top of the NSAD scale, any concern for using that test as an endpoint in a trial of, say, heterogeneous patients on major function?
Louise?
Yeah. Thank you for calling that out. In our low-dose cohort, the second patient, four-year-old, did max out the scale. The NSAD, the highest measure is 54. Certainly he achieved that and sustained that as well. This is where we continue to look at the totality of evidence. I would also point out that we know from natural history and in LGMD2E that patients start to decline around the age of 10. There, the NSAD would certainly still be helpful because you would be looking for sustained benefit of the NSAD over time, whereas controls might be declining. Together with the 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 open.
Hi, guys. Good morning. Thanks for the questions. 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 patient 3 in 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, again, that's why we look at measures across multiple time points. If you can 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. 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.
It's important to put this into context. 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 Dr. Muntoni, one of the world leaders, obviously, in Duchenne muscular dystrophy, in 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. 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, every kid improved.
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 tests, 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 upregulation of the dystrophin-associated protein complex, that it's all associated with a fairly dramatic reduction in CK as a measure of muscle health.
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-9001. 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.
Danielle, this is Ian. Just to clarify, patient 3A is our oldest patient. 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. At baseline, he was 3.9 seconds for time to rise, 3.9 seconds at a year, and then 2.8 seconds at two years. That's consistent with the improvement that you're seeing with his 100 meter, 100 meter percent predicted.
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 NSAA two to four points at his age, if not even more. To actually see a five-point improvement is certainly not what we would expect from natural history. There really isn't variability across this patient at all.
Thank you. Our next question comes from Joel Beatty with Citi. Your line is open.
Hi. Thanks for the question. 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 for us was not only getting the capacity in place and getting isolate 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. 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 of 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 then to 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 first cohort of 9001 and the two cohorts we had in 9003.
You can imagine how much a 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 S.V.B Leerink Partners. Your line is open.
Thanks a lot. What have you learned from collecting and analyzing the data for the Study 101 that you can apply to the Study 102 in order to maximize your probability of success? Can you talk about your approach to adjudicating observations in the Study 102 in order to give this trial the best chance of working?
Yeah. I'll say a couple things, and Louise 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. We've already benefited from that. We also had some experience. 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. We used 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.
We won't know until we unblind if we were able not only to have been able to deal with elevated liver enzymes if it happens, but to avoid elevated liver enzymes by a longer course of steroid treatment. What you will have seen in the 9003 studies is that in the high-dose version of 9003, we had implemented that same change in protocol, where we extended the steroid use. At least in 9003, small data set, but in older kids, it appeared to have worked, and we didn't get elevated liver enzymes. There is no doubt that Study 102 has already been informed by Study 101.
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 and the analysis that we did with respect to 102 that got us to a 41-patient study. 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 my question, and congratulations on the durability. For the DMD boys, I know it's only two patients, but it does seem like patient 4 and 2 are seeing the greatest North Star improvements. They're both four years of age. Also, can you just remind me of the strategy for studying the therapy in older, more severe patients?
Two things. Louise can comment. 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 four to seven. We've balanced patients out between the four to five-year-olds and the six to seven-year-olds between the placebo and the active arm in Study 102. We did that because we do know that even in that small age range, there are subtle differences between those two groups. That's already informed. The short answer is we will have, and we'll announce 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, Louise.
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 [inaudible] from 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 I patients? Also if you could discuss the biopsy plan for Study 102. Thanks.
Hey, thanks for the question. First of all, we don't have a plan to biopsy 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, consistent with what we would have imagined, we've actually been counseled by the agency to be careful not to over-biopsy kids. One of the reasons we biopsy these kids early, but we don't do longer biopsies, is that there really is, within the timeframe that we're talking about, no credible reason to imagine you would have any durability-related issues.
If you look across the restricted microdystrophins and generally in gene therapy, 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 eight to nine-year range. Frankly, in the context of that, trying to consent a child to engage in yet another biopsy at one or two 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. For Study 102, the biopsy is a three-month biopsy. Did I miss anything there, Louise?
No.
Thank you. 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.
Well, thank you very much. I'll just repeat what I said during the Q&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. One, of course, it speaks to the need to move fast. While I'm not yet able to provide you with an update on resolving the issue that can get our next trial started, please know that this team is as motivated as it has ever been 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. First with 9001 , then with 2E, because this is really an exciting set of data. In both of these cases, we're restoring the structural protein to nearly normal, and so we need to get that moving as well. 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 updates on that along the way.
One final thing I will say, I've 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 Dr. Kristen Vandenborne on muscle health in these DMD boys in Study 101 using MRI. There is a presentation later today on that. I am told now that the poster for that is already up. 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. With that said, thank you all for your participation today. Obviously, thank you, Dr. Louise Rodino-Klapac, for going through this and answering questions today.
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.