Good morning, and welcome to the Sarepta Therapeutics Conference Call and Webcast for the clinical update for Study SRP-nine thousand and one, 103, 12 weeks expression and safety data using commercially representative material. After the speakers' presentation, there will be a question and answer session. As a reminder, today's program is being recorded. Now I will turn the call over to Mr. Doug Ingram, President and CEO for opening remarks.
Thank you. Good morning and thank you for joining us for the report out from our 11 patient cohort study to characterize our DMD gene therapy 9,001 using our commercial process material. Now before I turn the call to Doctor. Rodino Klapac, let me contextualize these results. I have said before and I will repeat it here, it is difficult to overstate the importance of this data.
Indeed, these results are one of the most significant ones yet in Sarepta's history. And with the benefit of hindsight, I believe, may be among the most seminal moments in the treatment of Duchenne muscular dystrophy. Why do I say this? First, because this is the therapy we will not only take forward into our next clinical trial, but it is also the therapy that we will, if successful, launch commercially, both in the United States and around the world. And this data today will tell us if at commercial scale, we have the differentiated robust expression and safety profile that our earlier preclinical and clinical studies using clinical process material predict.
2nd, because it represents the culmination of an extraordinary and rapid journey from a mere vision to become one of the few genuine world leaders in gene therapy manufacturing to that reality. In early 2018, our aspiration was truly a moonshot. At the time that we began this journey, we needed to not only become experts in this nascent field and build a scalable process and release approach for SRP 1, but to build more capacity than all of the known gene therapy capacity in all of the companies dedicated to gene therapy around the world combined. From that idea, we invested 100 of 1,000,000 of dollars and brought in 100 of experts in technical operations. And these results will tell us if we are achieving that aspiration.
And third, it addresses one of the 2 issues that confounded our primary endpoint in Study 102 Part 1 in January. So that when we get the baseline characteristics correct in the 4 to 5 year old cohort, our therapy acted exactly as all of the preclinical and early clinical evidence would have predicted. It showed strong clinically meaningful and statistically significant results. But the top line results were indeed confounded by 2 issues. 1, an improbable imbalance in the 6 to 7 year old cohort baselines and 2, titerin variability from our clinical supply manufacturers process and assays that resulted in lower than anticipated mean expression.
The first issue is easily resolved in the next study by stratifying for baseline characteristics. As to the second issue, Sarepta developed a much more precise linear titering method that has been applied to Study 103 and the results of this study today will tell us if the second of our two issues has been resolved and if it has any setback from 102 will have been resolved and we will be moving rapidly forward with little delay. Now let me turn the presentation to Doctor. Luis Rodino Klapac. Before Luis begins, I will remind you that we will likely be making forward looking statements today.
Please refer to our public filings for a discussion of the risks associated with making predictions about the future. And with that, Luis?
Thank you, Doug. And if I could have the next slide. Good morning, everyone. I'm very pleased to share the safety and biopsy results from our first 11 patients in our 103 study, utilizing our commercial process material for SRP-nine thousand and one. The need for an urgent treatment for Duchenne could not be more clear.
It's a devastating disease that affects hundreds of thousands of children around the world and it affects skeletal muscle, cardiac muscle and the diaphragm. And we designed SRP-nine thousand and one microdystrophin specifically to treat all aspects of DMD. Next slide please. We've carefully selected and developed every aspect of our 9,001 micro vector and this includes 3 key components. We selected rh74 for its optimal biodistribution to skeletal and cardiac muscle.
Partly, we see low levels of pre existing immunity to rh74 and it's highly differentiated from a safety perspective. We're also using an MHCK7 promoter and this contains a myosin heavy chain enhancer that leads to robust expression in the heart as well as skeletal muscle. And finally, we carefully selected and tested the key components of the dystrophin gene to optimize our micro dystrophin transgene. I'll go into these in more detail in the next slide, but importantly we include spectrum repeats 23, which are critical for membrane stability and corresponding function. Next slide please.
Our optimized micro dystrophin construct is the result of many years of rational design and iteration. The destruction gene is a large gene and encodes for 4 60 kilobelton protein and it acts like a shock absorber in the cell. It connects the inside of the cell with the active cytoskeleton or contractile apparatus of the cell to the sarcolemma or the muscle membrane. And it has anchor points throughout the sarcolemma, which includes spectrum repeats 1, 2 and 3 and then also through the cystine rich domain, which is critical for assembly of the dystrophin associated protein complex or XAPC. Now the impetus for the development of miniature micro dystrophin constructs came from a seminal paper from Doctor.
K. Davy's lab that described a 61 year old ambulatory patient with 50% of his dystrophin sequence. And this work helped to define the domains of dystrophin that were critical for its function. Now his naturally occurring mini dystrophin was too large to fit into AAV. And so then based on these results, we further designed and tested a micro dystrophin that contains all the essential elements, which includes Factor 1 repeats 1, 23, which as you can see, anchor the dystrophin sequence to the membrane and are critical for membrane binding and stability.
And we've recently published additional work in the Journal of Neuromuscular Disorders that shows that inclusion of SPECTRAN REPEAT 3 in particular is critical for the stability. We've also included 3 hinges in our constructs for flexibility of this construct as well as the cysteine rich domain for that important assembly of the dystrophin associated protein complex. Now if I can have the next slide. So now we will turn to our results for Study 103, which is expression and safety data at 12 weeks using our commercial process material. Next slide, please.
To remind you, Study 103 is an ongoing Phase Ib study. It's an open label study using commercially representative material for SRP-nine thousand and one. This is multisite. There are 4 sites included in this trial. Boys with Duchenne are enrolled between the ages of 4 to less than 8, so inclusive of 4 to 7.
In total, 20 patients have been enrolled, but for today, we'll be discussing 11 patients. We previously disclosed that the 1st cohort of patients that were enrolled were favored towards the 6 7 year olds just by tapping chance with 9 patients being 6 and 7 and 2 patients being 4 to 5. Patients were dosed at all at the intended dose of 1.33x1014 secondtograms per kilogram. And again, this is using our Q PCR method with a linear standard. And so we biopsy patients at baseline and at 12 weeks.
So those are the results we'll be sharing today along with safety data and then all patients are then enrolled in Part 2, which is an open label extension study. Next slide please. We've consistently shown our biopsy results sharing each key step of the biological process. So first, how has the vector reached the nucleus efficiently? And this is measured by vector copies per nuclei.
Next is the microdystrophin protein being made of sufficient quantities, and this is measured to measure total protein by western blot. Next, is approximately localized to the muscle membrane and is doing so at meaningful levels. And this is measured by percent positive fibers and intensity. And importantly, what is the safety and tolerability profile? And so first, is 9,001 getting to the nucleus?
And indeed it is at very high quantities. We see a mean of 3.87 copies per nuclei in our first 11 patients. Now is that vector genome copies resulting in high quantities of micro dystrophin protein? And so on the next slide, it certainly is. So by Western blot, we see a mean of 55.4% across our first 11 patients by western blot.
Now this is important that we're generating high quantities of micro dystrophin consistent with what we've seen previously. But next, is this correctly localized? So next slide, please. And we see very robust expression of micro dystrophin correctly localized to the membrane. But first, let me walk you through the images.
So on the top, we see baseline images, representative baseline images. In green on the left, this is meristem staining just to label the membrane. In the middle is microdystrophin staining and on the right is the merge image. So at baseline, you can see there's no microdystrophin present. And then post gene therapy, we see robust expression of microdystrophin correctly localized to the membrane.
And you can see that it's co localization by the yellow images on the right. Now we've measured this 2 different ways. So in terms of the stroke and positive fibers, we see a mean of 70.5% at 12 weeks with a mean intensity of 100 and 11 patients. Now if we turn to the next slide, these results are extremely critical, as Doug mentioned and as I mentioned earlier, that we're showing consistency across our clinical and our commercially representative process material. And so what we've shown here is a comparison of the results of our 102 study.
This is the first 11 patients from the placebo crossover that were all dosed at the intended dose of 1.33x1014. Now we've previously shared these results where we achieved the first 11 patients of Part 2, vetrigene copies per nucleus had 2.62 51.7% on western blot. Now we've also seen 79.2% of serum positive fibers and 100.6% in terms of intensity, call it, 12 weeks. And so if we look at the comparison of the 103 study, you can see there's remarkable consistency between these two studies in terms of our results, with 3.87 copies per nucleus in the 103 study, 55.4 percent in terms of western blot expression, 70.5% is serum positive fibers and 116% intensity compared to normal. This is all at 12 weeks.
So very good consistency with our commercial process material. Now equally important to consistency of expression is safety profile. So if I could have the next slide. With respect to safety, we're very pleased to show that we've consistent safety experience with our previous studies with FRP-nine thousand and one. As you can see, we saw treatment adverse events in 11 patients.
These were most of these were mild. The most common adverse event was vomiting, as we have seen previously, with a typical onset within the 1st week, is mild and treated with normal antiemetics. We also saw transient increases in liver enzymes, which were responsive to steroids. There were 2 SAEs in the study, one patient with increased transaminases who was treated with intravenous steroids and another patient with nausea and vomiting. Importantly, there were no clinically relevant complement activation observed in this study.
The next slide. So to summarize, SRP-nine thousand and one provides a differentiated profile for Duchenne. We've importantly confirmed the characteristics of commercial cost of material for 9,001. We've achieved robust for a mean of 3.87 vector genome copies per nucleus. We've seen robust expression of microdystrophin correctly localized to the sarcolemma membrane, and we've measured this 3 different ways.
We have mean of 55.4% by western blot, 70.5% positive fibers and intensity of 116.9% currently localized to the membrane. We see consistent safety profile with our clinical manufacturing process with no clinical complement manifestations. It can't be understated that Study 103 results provide confirmation of our manufacturing process and our analytics and physician capacity to supply the entire Duchenne population. Next slide, please. Now in terms of next steps, we need to meet with the FDA.
And as we describe, this will occur mid year 2021 this year as well as other regulatory agencies. We need to commence Study 301 following that FDA meeting. In addition, we'll also be expanding Study 103 to include both older ambulance and non ambulant patients. And importantly, we will also have 102 Part II data 48 week results by the end of this year. So to conclude, we are quite pleased with the results from our first eleven patients from our 103 study for FRP-nine thousand and one.
We've confirmed both expression and safety of our commercial process material and importantly, it's consistent with our clinical material at the intended dose of 1.33x1014 vector genomes per kilogram. And finally, I'd like to thank patients and the families who participated in this trial, the trial investigators and their team, and importantly, my Sarepta colleagues and our colleagues at Roche for the relentless dedication to our SRP-nine thousand and one microdystrophin program. And with that, I'll now turn the call back to Doug for Q and A. Thanks.
Thank you. Let's open the call for questions.
And our first question coming from the line of Debjit Chattopadhyay with Guggenheim. Your line is open.
Hi, guys. Good morning. Thanks for taking the questions. This is Aaron on for Debjit. So I just have a question about when making comparisons with studies in Becker's patients from 2016, how different are the methods used to quantify dystrophin compared with current methods that Sarepta uses?
And what would it mean that earlier studies are overestimated or underestimated?
Hey, Aaron. Yes. Sorry, I didn't mean to interrupt you. Thank you for that question, Aaron. I know there's some confusion.
The answer is the methods that we use for Western blot related quantification of dystrophin are completely different than the methods that would have been used some years back. We built this Western blot approach not only to be precise, but we also built it in concert with and at the direction of the FDA and the neuro division of the FDA. So it is very precise. It is, far more precise than what was used from a research purposes some years ago. It's actually relatively conservative in the approach that it's taken as a result of having worked for years with the FDA to get to this precision.
So comparing it to old studies is very difficult. If you look at that 2016 study that you're referring to and then look at what it refers to, that study itself mentions as an example, the problems that they were having with consistent quantification. They referenced a 2014 paper that makes the point. They tried to do laboratory to laboratory comparisons and they got they had very, very poor concordance with those methods across laboratories and they even had pretty low concordance within laboratories. So you can't compare those old studies and those western blots with the much more precise western blots that we use today.
And I would point out western blots that were sufficiently precise to form the basis of the 3 approvals that we received with the neuro division from the FDA. But with that said, Louise, is there anything else that we should comment on with respect to that?
I think you captured the key aspects of it. I would just add that, extremely pleased and impressed with the rigor of our assay and the linear range of the assay, the standards that we employ with our Western protocol. So it's I agree that it's certainly vastly different from the methods that were used back in 2016.
We use a very rigorous reference standard as well, something that was missing historically. In any event, we're extremely excited about these results. There's an enormous level of dystrophin from a western blot perspective and then you look at the dystrophin positive fibers and it's the vast majority of fibers are benefiting from the dystrophin. And then you asked the question, well, that's fine, but are they benefiting significantly and the intensity level here is above 100%. So I think the answer to that would be anybody I think anyone would say that it's very high.
And then if you go back and look at the genome copies per nucleus, we're approaching 4 genome copies per nucleus. So we're getting extraordinarily good transduction. So we feel very excited about it. And we're really excited about this data as we track towards our meeting with the FDA so that we can commence our next study and get going as soon as possible.
Our next question coming from the line of Gena Wang with Barclays. Your line is open. Thank you for taking my questions and also congrats on the data. I have a question regarding the protein level, the Western blot, Slide 11. It seems like standard deviation was pretty high, 40 3%.
Wondering, is there any correlation regarding the disease severity and age of the patients? And also for the remaining 9 patients, would this mostly in the age of 4 to 5 years old range?
So I'll turn this over to Luis. Let me comment briefly on the standard deviation. Look, firstly, you won't always see a certain amount standard deviation. There is at a minimum a sampling bias that's going to occur. Remember what we do, biopsies are extremely invasive.
We take a single biopsy from a single point at a single muscle, in a patient who has the muscle is the largest organ system in the body. And so as Louise has pointed out, I think a 20 14 paper, you'll see a lot of variability just from single biopsies that in this paper from 2014, she notes that primate, you could have gotten 94% or 9%. So the means are in some regards more valuable than the individual points because of that sampling issue. We could improve it, but it would require something that would be unethical. We could do multiple biopsies per patient and I think we would regress to the mean, but that of course is not acceptable from an ethics perspective.
And then the final thing I'll say is on the standard deviation, if you throw out the high and low numbers of these data, you'll see that we're still at 50%. So it's a significantly robust issue. And then the variability that I will note that doesn't exist in these data that existed in Part 1 is the variability that came from different titers. Remember, we had weeded, but our manufacturer was using a different type of, titering method is so called, supercoiled PCR. And with the benefit of hindsight, once we had developed a linear titering method that was much more precise, we could see that in the 3 lots from the prior study was variability in the actual dose versus the target dose and 60% of the kids had lower than the target dose.
You do not get that today because Sarepta's linear qPCR method is very precise. And so we had the target dose for all of the crossover kids and for all of the kids in 103, both just by happenstance or 11 each. And as you can see, we get not only robust expression across all of the measures we see, not only robust expression, robust genome copies per nucleus, but very concordant results between those two as well. I think this has been a really nice confirmation of where we are with this therapy, both from an expression perspective, but also importantly from a safety perspective. But Louise, I know there were parts of that question that I missed.
Yes. No, I think you answered the part of the question quite well. I'd just add for the second part, with respect to the 4 to 5. Certainly, in the second part to fulfill the 20 patients, there will be additional 4 to 5 year olds included and that was the point to make sure that we had representative population across all of 4 to 7.
And it is interesting, we did have a preponderance of 6 to 7 year olds in this 11 patient cohort. 1 will remember that after the Part 1 readout, there was a, I think a concern, it turns out was an unnecessary concern, but a concern by some that maybe there was an issue with expression in older kids because of additional fat and fibrotic tissue or the like. Such was not the case. We didn't see that at all in the part, to crossover patients. And of course, now we actually have an experiment where 9 of the 11 kids are in the older set.
And as you can see, you don't see that. You see really robust expression across the ages. So we feel very good about that as well.
Our next question coming from the line of Brian Abrahams with RBC Capital. Your line is open.
Hi, good morning. This is Steve on for Brian. Congrats on the data and thanks for taking our question. Based on today's data and even the limb girdle data presented earlier in the year, it seems that increases in vector copy number and protein expression don't necessarily correlate 1 to 1. Can you share any thoughts as to why this might be and if there are any implications for maybe durability of expression or eventually redosing if the technology allows it?
Thanks.
Sure. I'll turn this to Louise.
Sure. Yes, in terms of vector genome copies per nucleus and protein expression, we see a general correlation, not always a complete one to one correlation. And I think, based on both these data and our limb girdle data, we're certainly producing robust expression from the vector genome copies that we have. And you also get accumulation of protein over time. So in terms of durability, we're quite pleased with these results.
3.87 is an impressive number that bodes well for sustainment and durability over time. So we're quite pleased with that.
Thanks.
And our next question coming from the line of Alethia Young with Cantor. Your line is open.
Hey, guys. Thanks for taking my question and congrats on the data today. I guess, I just wanted to like kind of think about you dose probably 60 plus patients and you haven't seen the complement activation and some other gene therapies are saying, do you kind of have a deeper understanding as to why AAV9 maybe causing the complement activation versus the R874, which I mean, I guess so far that happened?
Yes. I'm going to turn this to Louise. I will say that we can at least speak empirically. So empirically, we haven't seen at obviously very robust doses, we're at 1.33e14 using our linear process. We haven't seen any clinical manifestations of complement.
And of course, as you know, I think we're up actually probably near or over 60 patients now. So a really big data set that gives us additional confirmation about the stable safety profile that we had. And of course, we know empirically that we have seen in other programs complement not only in DMD gene therapy, but in full body infusions gene therapy using AAP9. So we are very pleased with what we're seeing, which would have also been predicted by our preclinical model. We would have predicted preclinically that we wouldn't see this.
But at least perhaps you have some sort of thoughts on the hypotheses for these.
Sure. Yes. And just to reiterate, we have dosed over 60 patients with 9001 alone, and then we also have our girdle program, which also uses RS-seventy four and we haven't seen complement activation as well. We know that there has been complement activation with other AAV9 trials. And just last week at the ASGCT meeting, there was a poster presented from SOLID.
It was nicely done poster that showed that there are AAV9 capsid, AAV9 antibody complexes that lead to and promote complement activation. They did this study in vitro and they patient serum samples with and without antibodies and this demonstrated, I'd say, conclusively that there was complement activation due to this formation of these complexes for a combination of the casted and the AAV9 antibodies. So that's one piece of evidence that may indicate why other programs might be seeing complement, but we're again displeased that we have not seen that with our programs with rh74.
Our next question coming from the line of Danielle Brill with Raymond James. Your line is open.
Hi, guys. Good morning. Thanks so much for the question and congrats on the results. I guess, I know we only have 2 patients in the 4 to 5 age range, but just curious if there were any noticeable differences in mean expression or any of the other parameters by the different age ranges?
No, we haven't seen any difference. At least I should probably let you answer this since you're closer to the data.
No, that's the short answer, that there wasn't any differences between the 4 to 5 year olds and 6 to 7 year olds. Obviously, there's only 2 patients and 4 to 5, but we do not see any meaningful differences between the two groups.
That's supported as well by the Part 2 crossover as well. Those kids all got the target dose, and we wouldn't have seen any kind of difference between 4 and 5 and 6 and 7. I think that's just that was just concern that filled the empty space, frankly, between Part 1 and then the crossover in 103, it doesn't seem to be an issue.
Our next question coming from the line of Gildan with Needham and Company. Your line is open.
Good morning, everyone, and thanks for taking our questions. And I'd also like to add congratulations on the results. I know it's a little hard to compare, but would you say that the commercial produced results were tighter than those seen in previous studies as in regards to patient to patient variation? Thank you.
Louise, is the question whether there was higher variability, is that the question?
I think it was asking whether they were tighter. I think when we look across the 2, looking at Part 2 crossover and 103, which received the same dose, we generally saw the same spread in 2 processes, consistent results between the 2. Yes.
Now you would have seen more in fairness, the Part 1 results, you would have seen more variability, but that was relating that wasn't sampling, that was relating to the fact that with respect to Part 1, again, our manufacturer used a supercoiled PCR titering method and that titering method when we evolved to the Sarepta titering method, which is this linear qPCR standard and then backward applied it to the lots from Part 1, that, was clear to us that there were, in fact, 2 of the 3 lots didn't hit the target dose and about 60% of the patients then had less than the target dose. And that, of course, created what would look like on its face more variability. But that was all solved. That was solved with the leader titering method and then the confirmation first in the crossover I think our And I think our titering method is really performing very nicely right now as is frankly, the rest of our CMC political work. It's all working very well right now.
Our next question is coming from the line of Salveen Richter with Goldman Sachs. Your line is open. Good morning. Thanks for taking my question. I was just wondering if you
could just remind us, and this just follows up on the last couple of questions about what the standard deviation was for 102 and the clinical research process and how it compares when you look at this number of roughly 40%. And then secondly, as you look to Study 301, if that is still on track to start and maybe help us understand the plans to engage with the FDA to discuss the potency assay data.
Right. I'll just make a few comments and I'll turn to Louise with maybe to quantify some of this. So we're clear, the standard deviation is from Part 1 to 103, the standard deviation is certainly tighter because we're getting the tittering method in the target dose correct. The standard deviation that one would see in the crossover patients at Part 2 of 102 and 103 are very similar because they have we are on the target dose, which is fantastic. Everyone's getting the right dose and then any standard deviation that you see, exist as a result of arguably some biological reaction, but probably more likely than not simply a sampling related issue about one biopsy per one muscle per patient.
So we feel very, very good about where we are. We're getting very consistent results there. We are on track to have our meeting. The biggest issue for us to have our meeting with the FDA are these 103 results. I got to tell you, we're very excited to meet with the FDA with these results in hand and we'll get that process completed.
Our goal is to have a meeting with the agency by the middle of the year. The reason for that, of course, is you've got to get a meeting date, we've got to get a briefing booked, but we're very much on track to have all of that completed and then we'll start our study 301 as soon thereafter as we can and you can imagine we want to move as fast as possible, Louise.
Yes. No, I think you captured it well. I think the only thing to add to data about the comparison between the studies, it's not consistent in terms of standard deviation when we look at the intended dose. And we mentioned it earlier, I think it's important to note that all patients were responded to therapy and that when we did sensitivity analysis removing the highest impression is at the mean, so it's not driven by extremes. So we're pleased with the consistency of the results both within the study, 103 study and in comparison to Part 2 of 102.
And to Luis' point, one should note that with respect to the 103 patients, they all had very robust transduction and very high genome copies per nucleus. As you can see there, nobody was under 1.6 genome copies per nucleus, which would have to be honest, 2 years ago have been a significant aspiration for us as a meeting. We would have been giddy over that number and no patient has had less than that. So we feel really good about where we are right now.
Our next question coming from the line of Anupam Rama with JPMorgan. Your line is open.
Hey, guys.
Thanks so much for taking the question. Last week, the competition showed some expression data looking at kinetics over time, which suggested that there may be some increased expression with time with their gene therapy approach. Is there any thought about maybe getting some maybe an extra one more biopsy in the OLE to better understand expression with time from Study 103? Thanks so much.
I assume you're talking about the solid data. I would say it might be a leap to suggest that that's the data shows exactly that given the scan nature of the data. But with that said, perhaps, Louise, you can touch on this issue.
Yes. I think there's certainly looking at long term expression is something that we've anticipated. As you know, in our girdle study, we've shown expression over 2 years, which importantly, payment of that expression. And in our 102 study, we'll be looking at also biopsies over the course of having a second biopsy in some of our patients from the first study as well from the first part. So certainly, we'll be looking at that.
And we anticipate that we'll see the same. There is the potential to accumulate over time, but that's something we'll be certainly looking at, and the data will speak to that as well.
Our next question coming from the line of Collyn Bristow with UBS. Your line is open.
Hey, good morning and congrats on the data. So I was wondering, could you tell us what the 102 and the other data you collected tells you about the expression threshold for functional improvement? And then as you look at these level commercial patients, just how many of them were above this level? And then just on timing,
you just give us a
bit more granularity when we should expect the Phase 3 start, 1st patient dose, anticipate the enrollment timing, etcetera?
Well, first I'd say, the expression that we're seeing out of 103 is significantly above what we would envision was necessary from a threshold perspective to see a functional benefit. I would note in Part 1, because of the titering issues, we saw lower mean for expression. We were 28.1 60% of the kids had lower than the dose. But with that notwithstanding that, when the baselines were right and in the 4 to 5 year olds they were spot on between the placebo group and the treated group, you will note that those kids hit strongly statistically significant benefit over the placebo and very clinically meaningful benefit as well. So I think the results we're getting and the expression we're getting here ought to be a significant margin for benefit and should correlate with really good durability over time.
That's what we would anticipate. Looking at those genome copies gives us an enormous amount of additional confidence that we're going to see long term durability when you're way over 3 genome copies per nucleus, almost going on 4 genome copies per nucleus, it gives us a ton of confidence. I'd say on the timing for the next study, the short answer is we need to set a meeting with the agency. That meeting will occur by around the middle of the year, won't be longer than that. It's just the timing issue of getting the meeting called for and getting the date.
And then as soon thereafter, as is possible, we have everything in order to start our study and we'll start that study immediately thereafter. People have asked us about recruitment. I think this study is going to be in high demand from everything we've heard from investigators and from families. I think this is going to be a very high demand study. We're going to have over time a significant number of sites up and running in the U.
S. And around the world. And so I do think it will be robustly recruited and we'll get going with that ASAP. Louise, did I miss any part of that question?
No, I think you captured it well.
Our next question coming from the line of vitu Baral with Cowen. Your line is open.
Hi, guys. Thanks for taking the question. What are the current plans for capturing functional data from 103, especially given the significant 248 week tail. And there's nothing on the slides about functional baseline. Could you address sort of where these 11 patients sort of rank in
the spectrum, especially since there
were no inclusion and exclusion criteria on function?
I'll turn that to Louise. Apologies, I'm sorry for cutting you off, Rita. I'll let Louise answer that. Obviously, for those who are wondering about functional results, it's too early to be providing functional results quite yet. This is 12 week biopsies.
But, Louise, perhaps you want to chat about potential plans down the road.
Sure. Yes, as part of the study, we are capturing functional measurements at baseline and then at various post gene therapy measures. I mentioned it's too early to look in detail at 12 weeks, but we're certainly capturing those and open label study, but we will be making sure that we use this information to add to our data package in terms of corresponding function with these patients and certainly similar inclusion criteria to what we anticipate for our next study.
Our next question coming from the line of Difei Yang with Mizuho. Your line is open. Sorry, I put myself on mute. Thanks. Congrats and thanks for taking our question.
So is it the FDA meeting the only gating factor to before starting Phase 3?
Yes. Yes.
Thank you. Our next question coming from the line of Joseph Swartz with SVB Leerink. Your line is open.
Thanks very much. Along the same lines as Ritu's question on functional measures, I was hoping to get your current thoughts on the clinical endpoint or endpoints that you think are best suited to demonstrate functional benefit from microdystrophin gene therapy? How confident are you that NSCA is the best endpoint and that you can control for any confounding that might arise? And what will you be proposing to the FDA
in order to
secure accelerating and or full approval? Thanks for that. So a couple of thoughts. One, we used NSAA with 102. We've gained an enormous amount of insight out of Part 1.
I will say the insight that we have out of Part 1 is unique to us. And we've burrowed into it. As a result of that, it has allowed us to refine the protocol for Study 301. Certainly, NSA will play a role in Study 301, but the approach to the protocol is adapted from the Part 1 study 102 results as a result of which we feel very good about the 301 study and we feel very confident about the probability of success out of that study. As everyone knows, I'm going to beg off giving any detail on that study quite yet because I want to we all want to take that protocol to the FDA, get their blessing and then start the next study and then we can all talk about the parameters and the learnings that we've had from part 1, the Study 102 that has, at least from our perspective, greatly enhance the probability of success of the program in the next study.
And we will certainly look at that once we've had the meeting with the FDA. I think the protocol discussion will go quite well. I would say there's nothing exotic in the protocol, but it is definitely refined. Great. We look forward to hearing more.
Thanks. Thank you.
Our next question coming from the line of Tim Lugo with William Blair. Your line is open.
Hey, this is Lachlan on for Tim. Thanks for taking questions. I was wondering how many validated batches have you now run through the manufacturing process using the FDA agreed process? And what's the rate, if any, that they're sort of failing or having issues on any of those assays?
Oh, my goodness. We've run a significant number of batches through. Even with respect to 103, we pulled from multiple lots for these patients. Again, again, all of them looked great. Do you have any other specific information on numbers of runs?
The short answer is we have a lot, but that's probably not satisfying answer for
it. No, I would just say it's multiple. And I think it's a good question because it is important to highlight that we draw from multiple lots from this study. It wasn't an artifact of 1 lot in particular. It's multiple lots.
And these are released using the potency act data that we agreed upon the FDA back in the fall. And so we're very we're quite pleased with these results and our new titering method as well.
Yes. And that's one other final thing I will say onto that very good point. I mean, we really feel good about where we are from a manufacturing perspective, process development, analytical development and capacity perspective. If one will recall back in 20 19, this was a significant amount of work. And if you read transcripts back 2019, you would hear me repeatedly saying to people, I'm confident we're going to get there, but we're not there yet.
And that had everything to do with yields, process, analytics and then ultimately capacity. And the great news is that we are in a very good place there. We feel very good about our capacity, let's start there, which I think people have gotten now because we get less questions about that, but that's a big, big deal. We'll go back and hearken back to the beginning of this discussion. We talked about the fact that at the beginning of this journey in 2018, we had to become not only opportunity for more capacity than all of the gene therapy manufacturing capacity That existed in the world at the time.
That was no small fee. Then we had to get yields right, then we get analytics right. We then we had that an issue last September with the division where we had what we believe to be a very fit for purpose potency assay the FDA saw it differently. We were able to quickly resolve that issue with them at least for purposes of Study 103. That provided us with an enormous amount of additional insight into the way the FDA looked at potency assays and therefore by extension other assays.
So as we sit here right now preparing ourselves with for a meeting with the agency in the middle of the year, we do feel good about the CMC. We feel good about our manufacturing. We feel good about technical operations perspective. And of course, we feel today very good about the characteristics of our therapy and what it may mean for patients as confirmed by future studies. We're getting robust transduction.
We're getting great expression. And we're seeing a safety profile that puts us in a very it's not a unique place, nearly unique place. We don't see evidence of clinical complement manifestation. We transitioned from clinical supply to a commercial process. And one of the big concerns with that is that you might have been something might have changed in that process.
We might have seen a different level of expression or a different level of transaction and such is clearly not the case. One could have seen some addition of some safety signal that didn't otherwise exist. And in the patients that we've dosed so far, we have seen not that case at all. We've seen a very stable safety profile and consistent. So from a manufacturing perspective and a program perspective, we feel very good about where we are right now.
Our next question coming from the line of Matthew Harrison with Morgan Stanley. Your line is open.
Hi, this is Max Skor on for Matthew Harrison. Thank you for taking our questions and congratulations on the day to day. I was just wondering, is it reasonable to assume you're enrolling older patients to try and treat at peak NSAA scores? Basically, is it easier to evaluate differences between treatment arms when patients are losing motor function compared to ascending MSAA scores? Thanks.
No. If the question is why are there more 6 to 7s and 4 and 5s in the 103 first 11 cohort? The short answer is that's just the patients that were enrolled. We've actually added to the Study 103 with some 4s and 5s as well and we're actually dosed those all those kids have been dosed as well. One of the things you may have seen in Louise's presentation is that we're also going to be dosing non ambulatory patients.
So frankly, the reason we're dosing patients across the spectrum is our ultimate goal clearly is, and when this therapy is confirmed in our trials to have a therapy that's fit for purpose and benefits kids across the entire age spectrum from the very young to the older and non ambulatory child as well. And we don't want to leave any children behind. That's the reason for that. But it was as it was notwithstanding the fact that in the 103, it was simply just the chance of who got enrolled that gave us more 607s. It's a nice little experiment, because there was, I think, some questions that would have been a bit of hindsight where I found it that maybe 67 year olds don't get as much expression as 45 year olds.
And of course, we're not seeing that at all either in the crossover in 103. And it's nice to see even with a predominantly 6 7 year old group in the Study 103, we've got great expression and very, very at least concordant expression with what we were seeing with the clinical supply.
I'm showing no further questions at this time. I would now like to turn the call back over to Mr. Doug Ingram for any closing remarks.
Thank you very much. Thank you all for joining us this morning. If you would indulge me for a second, I would just like to say to my colleague, Doctor. Luis Rubio Klapac, congratulations. I want everyone to Louise Rodino Klapac, even before she joined Sarepta Therapeutics, was the researcher that along with her colleague, Doctor.
Jerry Mendel, was looking into micro dystrophin as a treatment and built the very construct that we now call SIP-nine thousand and one. So I know it's a bit self indulgent, but extemporaneously, I'd like to say Doctor. Luis Rubino Klapac, congratulations for these results. Thank you so much for that. For everyone, let me just say thank you very much.
I would echo again Louise's statement. Thank you to the patients and their families who have been willing to give themselves to these sorts of studies and have allowed us to develop this therapy through their hard work. Thank you very much to our colleagues at Roche for partnership and insight as we track forward, and we really appreciate that. Thank you to the investors for your time today. We're very excited about these results and we're excited about what this means for us going forward.
So keep in mind that we will have a number of important readouts coming. First, we'll have a meeting with the agency. We'll do that by the middle of this year. 2nd, if all goes well, we'll start our next study as soon thereafter as possible, and I promise you, we'll be moving as fast as possible to enroll that study. Next, at some point, I'm sure we'll have an update on 103, but early next year, very early next year, we'll have an update on Part 2 of 102.
Remember, that's 41 children in Study 102, half or approximately half of those children will have been on therapy for 2 years. The other half of those children will have been tracked for a year off of therapy and then we watch them for a year after therapy. So that'll be fascinating data. All of that is blinded today. All of the analysis you'll see early next year from 102 are they are pre specified.
This is not going to be anything like a post hoc analysis. So we're really excited about that. So we've got a lot of work to do, and we'll keep you informed as we do it. So thanks everyone for your time today.