Good day, and welcome to the Sarepta Therapeutics Conference Call and webcast for the SRP-9001 Microdystrophin R&D Day. At this time all participants are in listen only mode. After the speaker's presentation they'll be a question and answer session. To ask a question during the session, you need to press star one on your telephone. As a reminder this today's program is being recorded. Now, I'd like to turn the call over to Douglas Ingram, President and CEO, for opening remarks. Thank you, Catherine. Good morning, everyone. Thank you for joining us today for what we are calling Sarepta's Microdystrophin Day. First, remember, we will make a number of forward-looking statements today. Please refer to our various public filings for a list and discussion of the risks and uncertainties that come with making predictions about what may occur in the future. In a moment, Dr. Louise Rodino-Klapac will walk us through recent updates from our three ongoing studies: Study 101, Study 102, and Study 103, and then we'll provide information on the protocol for our pivotal trial, Study 301, a study that we call EMBARK. SRP-9001 represents the most advanced and significant opportunity in gene therapy to date. The goal of this meeting is to share additional data from what is indisputably the most comprehensive evidence set for any Duchenne gene therapy to convey to you the basis for our deep conviction in the transformative potential of SRP-9001 for those living with Duchenne muscular dystrophy and to detail the thoughtful design of EMBARK, our phase III trial, which we recently announced has already initiated. We are indeed proud of how far we have come with SRP-9001. With 77 patients dosed thus far, we have the largest database to inform us on the performance of SRP-9001 and to inform our program and enhance its probability of success. We have become leaders in the manufacture and release of gene therapy. We are the first Duchenne gene therapy sponsor to have been green-lighted in the U.S. to commence a genuinely global pivotal trial with sites eventually in the United States, Europe, and Asia. With the wealth of patient data so far, some of it stretching beyond three years, it is beyond genuine debate that as of now, we have a highly differentiated gene therapy construct in terms of safety, in terms of tropism, in terms of expression, and in terms of functional signals. Yet we advance forward with the humility of a patient-driven team that never forgets that the patients we serve, and for whom we exist, are in a daily fight against a brutally degenerative disease where time is of the essence. While SRP-9001 may stand alone today, nevertheless, we know that we are indeed in a race. We are in a race against a disease that daily robs children of their muscle and their function, and invariably their lives. Hopefully, by the end of our discussion, you will agree that we have kept that race in mind and have built a program with the greatest probability of rapidly advancing to the community a potentially life-altering therapy. With that, let me turn the presentation over to Dr. Louise Rodino-Klapac. Louise? Thank you, Doug, and good morning, everyone. It's a pleasure to be here today to really describe the breadth and depth of our data with SRP-9001. Just to quickly review the agenda for today, as Doug mentioned, we'll be reviewing data from our three trials, 101, 102, and 103. In terms of new analyses for the Study 101, we'll be showing you three-year functional data in comparison to natural history. We'll also be sharing additional analysis for part one, where we've also compared to natural history as well. Finally, in our Study 103, using our commercial process material, we'll be sharing functional results from the cohort one first 11 patients. This is all leading up to the study design for our 301 EMBARK study. If we go to the next slide. This slide really needs no introduction. As Doug mentioned, DMD is a devastating disease, and children need urgent treatment. SRP-9001 was designed specifically to target all aspects of DMD, which includes skeletal muscle weakness, cardiac manifestations, and respiratory manifestations. It is truly a race to be able to get to these patients. On the next slide, just to review the three components of gene therapy that are essential, really, and that just includes the vector, the promoter, and the transgene. The vector, which really derives how you get to your target, in this case, skeletal muscle and cardiac tissue, and then really defines the safety or immunogenicity profile of your construct. Next, the promoter, which turns it on and off in the tissues that you like or desire, and then also the transgene. The next slide is to talk specifically about the components of SRP-9001. As you know, we have selected the AAVrh74 vector. We selected it specifically for several reasons. One, in comparison to all other vectors, we saw the transfection profile, specifically in muscle, which had a broad distribution across all the muscle cells, also in cardiac tissue. It also has a low level of preexisting immunity. We see approximately 15% of patients with antibodies to rh74. Next is the promoter. We are using the MHCK7 promoter, which expresses nicely in skeletal muscle and cardiac tissue, which is critically important to any therapy for Duchenne. Lastly, our transgene, which I'll talk about in a few slides, which was designed specifically to maintain all of the critical components of the dystrophin gene and protein. On the next slide. To highlight rh74. As I mentioned, it has broad uniform distribution. We currently have it in gene transfer trials for both Duchenne and limb-girdle muscular dystrophy. It remains to have a differentiated safety profile. We've now dosed over 80 patients in both DMD and LGMD trials combined. Specifically just the MHCK7 promoter to specifically target cardiac muscle as well as high levels of skeletal muscle transfection. Next slide. Microdystrophin is a shortened functional form of dystrophin. If you look at the left, in normal muscle, dystrophin is a shock absorber that has critical links inside the cell to outside the cell. When the muscle contracts, dystrophin absorbs that shock. It's too large, as you know, to fit into adeno-associated virus or AAV. About 30 years ago, a patient was identified by Dr. Kay Davies, who was a 61-year-old ambulatory Becker muscular dystrophy patient. Becker muscular dystrophy is a form of dystrophinopathy, in which patients have shortened versions of dystrophin. It's a much milder course of disease than Duchenne. This particular patient retained critical components of dystrophin and was still ambulating until an older age of 61. When we designed our microdystrophin construct, we took lessons from that patient and made sure that we were maintaining these critical regions. Specifically, if you'll note, spectrin repeats one, two, and three directly bind to the muscle membrane and really are important for maintaining force and resistance to contraction. Also, we've retained the critical components to restore the dystrophin-associated protein complex. All of this design and iteration over many years has led to the development of SRP-9001, and it shouldn't be forgotten in terms of the differentiation of our construct. Now turning to NSAA. Apologies. Just wanted to highlight the key considerations for evaluating gene transfer therapy. First and foremost, we always highlight safety. It's critically important, and for each of the trials, we'll go through the safety profile. Next, in terms of biopsies, it's important to know if the transgene getting into the cell, we do this by measuring vector genome copies per nucleus. Is it making protein? This is measured by Western blot, measuring the total amount of protein. Is it getting to the right place in order to do its function? Is it getting to the muscle membrane? We measure this by percent positive fibers and intensity. Finally is all of this leading to functional improvement. Our primary functional outcome across these studies is NSAA, which I'll talk more about, and then various time function tests as secondary outcomes. Now, specifically, we'd like to highlight the understanding of the NSAA. This is such a critical outcome. It's a 34-point scale of 17 different activities, these represent daily life. Each patient could have zero, one, or two for each of these activities. Zero, you're unable to do the function. One, you can do it with assistance. Two, you can perform it without any difficulty. Each of these measures is, as you can see on the left, goes from most difficult, these are lost early on in the course of disease, to least difficult or lost late. Some of the more difficult activities are things like hopping on one leg and rising from the floor. It's important to note that these tasks are administered by professionals, this whole scale was developed by investigators to really mimic clinically meaningfulness. Now thinking about one of the more difficult activities, rising from the floor, what we'd like to do on the next slide is really show you what this means, because I think seeing it in action really makes the point in how different 1 point can mean on this scale. If we're going to see the first video, if you'll direct your attention to the video screen on the first video on the left, the boy rising from the floor. This is a 2 point on the scale. Are you able to play it? Is it playing? Sorry, I'm going to see. Okay. He's able to get up from the floor without any difficulty at all. Next is 1 point on the scale, you can see that this child has significant difficulty getting off the floor. He needs to use his arms to be able to push himself off the floor and has significant difficulty. Now a zero on the right. This is a hard video to watch, this boy is unable to get off the floor. This really speaks to the impact of the disease and how it impacts not only a child having difficulty getting off the floor, needing assistance to get to a sitting position, also the family, because he becomes completely dependent. This just speaks to the significant impact of a 1-point change on the scale. As we go through the NSAA data for each of the components, please keep this in mind on the impact of these changes. Okay. Now turning to Study 101, just to remind you on the next slide of the study design. This was a single-center study of four boys, open label with baseline biopsy at 12 weeks, and then the boys would be followed for a total of five years. Patients had to have confirmed DMD mutations between 18 and 58 and be negative for AAV antibodies. We'll review the results that we've previously shown. On the next slide, I'd just like to point out the baseline characteristics for the first four patients. As you can see at treatment, there was a mean age of 4.8 and the baseline NSAA, you see a mean of 20.5. First, just to review the biopsy data. This is their expression at 12 weeks. You can see all four boys post-gene therapy had robust expression with a mean intensity of 96% and percentage of dystrophin-positive fibers of 81.2%. On the next slide, it was also important to show that this microdystrophin expression led to the restoration of the dystrophin-associated protein complex. As you can see on the right, this is beta-sarcoglycan, one of the components of the DAPC, was upregulated correctly localized to the sarcolemma post-treatment. Next, just to summarize the expression results. We see by Western blot we had 74.3%. When it was adjusted for fat and fibrosis, it was 95.8%. Intensity, 96%, 81.2% of positive fibers. When we looked at vector genome copies per nucleus, there were 3.3 copies. Next, now turning to the functional time test results. What we want to point out is that NSAA will show you that data has consistently improved over time, the planned function tests have also been supportive and improved over the course of three years. You can see on all time function tests, each of the patients has improved. For time function tests, you're looking for a reduction in the amount of time that it takes to do the activity. Those negatives that you see are actually a positive response, with the exception of the 100 m percent predicted, where you are looking for a positive response. This is where you want to see a rise in the amount of prediction that it takes to do the activity. Next, turning to the NSAA. Here, this is each of the four boys individually showing their NSAA scores over time from one to three years. On the right, you see we saw a mean of 7.5 point improvement from baseline in the four boys. What's important to note is I showed you previously that the boys were four to six at treatment, but now at three years, they're at seven to nine in terms of age. At this point, we would be expecting a downward trajectory for these patients. Yet they're stable or improving. What we did in the next slide is did a comparison to natural history. We used a model to predict where these boys would be over the course of three years. We developed a trajectory model from approximately 300 patients across three data sets, then modeled the trajectory over the course of three years using an MMRM model to fit. As you can see, we see a highly significant difference between the treated patients and natural history comparator arm with a highly significant P value less than 0.0001. What's really important about this, and as you can see from the graph, is that the treated boys continued to improve over the course of three years, whereas the natural history comparison are declining over that. You really see an increased separation over time. This leads to about an 8.6 difference in treated compared to natural history. Really strong. This just speaks to the point that the effects will grow over time. We're really looking for a difference from natural history over the course of time, and this will become apparent in our next trials as well. If we now turn to Study 102. For safety summary. In terms of safety on 101, we now have three years of follow-up and no additional safety signals. We had treatment-related SAEs that were mild to moderate, that all resolved, and these all occurred within the first 90 days of treatment. We had no additional safety within the second or third years of follow-up. The three patients where we did see safety signals were elevated gamma GT in the first three months. They all resolved with steroid treatment. The most common treatment-related AE was vomiting. We had no AEs that were associated with clinical complement activation. To summarize, we've seen no additional safety signals since our last report. It was all within the first 90 days. All right, now turning to Study 102. To remind you of the study design. The study was designed with one stratification factor, and that was age. This was a study of 41 boys, stratified by age, where half were four to five, generally half, and the others were six to seven. This was a randomization factor. The part one of the study, half of the children received SRP-9001, the other half received placebo. The primary endpoint was NSAA at one year, and then the boys crossed over to the other treatment. We did have a weight-based dosing at 1.33x 10 to the 14th metric units per kilogram. That's using our linear qPCR standard. As you recall, we started off Study 102 with a different titrating method using supercoiled qPCR. It was later identified when we developed our validated qPCR method with the linear standard that 60% of those patients did not receive the target dose. We'll talk about that later on. We did convert to 1.33 x 10^14th, so linear qPCR, and that all children received that dose moving forward. Next slide. These are the baseline demographics. As you can see, half received placebo, half received 9001. Approximately eight children per group were in the four to five-year-old group. The rest, majority, were six to seven-year-old. Next slide. These are the baseline demographics in the intent-to-treat group. What we'd like to highlight here is that in all cases, this is looking at all patients. The placebo group is better in all parameters relative to the SRP-9001 group. All of the time function tests, in addition to the NSAA, the placebo group was better at baseline. This is all patients. When you look at just the six to seven-year-olds, it's even more profound. Next slide. These are the microdystrophin biopsy endpoints. This is just a summary slide. At 12 weeks, we saw a mean of 28.1% by Western blot. As far as immunofluorescence, with 63.7% intensity, 32.9% dystrophin-positive fibers, and a mean of 1.6 copies per nucleus. This is part one of the study. Now translating into function. As we mentioned, the primary endpoint was NSAA. This is looking at all patients in the study. As you can see, we saw an improvement at every single time point in the treated group. The change from baseline of 1.7 points compared to 0.9 points in the placebo group. This is not statistically significant. The reason for this becomes crystal clear on the next few slides. If we go to the next slide. As you recall, we had a pre-specified analysis with the four to five-year-old. We did see a statistically significant improvement in NSAA versus the placebo group at week 48. As you can see, the baselines were very well-balanced with 20.1 and 20.4, and in just eight children per group, we did see a significant difference at 48 weeks. If we look in the next slide of the six to seven-year-old, we see a much different picture, where the baseline NSAA scores for the two groups, placebo versus treated, were significantly different from one another, 19.6 versus 24. It was highly significant, actually, with a P of 0.0046. What's important to note is that when we looked at the placebo group here as a validation for our natural history model, we used that prediction model to model out where the placebo patients would be in the six to seven-year-old group. In fact, it was highly concordant with only a 0.3-point difference between what was observed at 48 weeks versus what our model would have predicted, where P was equal to 0.0013. This really validates our natural history model that we've used for the additional studies. Now, on the previous slide, what we noted was that the treated patients Let me go back. Sorry, one slide. Yeah. What I'd like to highlight here is on the bottom, the purple graph. The treated patients, although they were significantly affected, and in fact, many of these patients had a rise time of greater than five seconds, they remained stable over the course of the 48 weeks. When we compare those on the next slide to the natural history arm, where we've matched for both baseline age and NSAA, we do see a significant difference from what natural history would predict, with a 0.3 change in SRP-9001 group versus 3.2 change in the natural history comparison. An approximately 3-point difference in treated versus natural history. Now turning to safety. In terms of safety for Study 102, we've seen no additional safety signals. Let me just summarize. Approximately 85% of the patients had treatment-related SAEs. These were primarily mild, with the most common being vomiting. There was no clinically relevant complement activation observed. There was a total of four patients with five treatment-related SAEs. Four of those were in the treated group and 1 in the placebo group. Three were rhabdomyolysis, two in the treatment group, one in placebo. These resolved. We had increased transaminases in another patient that resolved with increased steroids. No other clinically significant laboratory findings. No clinically relevant complement activation. In terms of safety, no new safety signals since the last report. Now turning to Study 103. Again, this is our commercially representative processed material, and we'll be looking at six-month functional data. We previously showed expression data for the first 11 patients. We go to the next slide and talk through the study design. Again, this is a multi-center, open-label study looking to evaluate the commercial processed material. In total, 32 boys have been treated, 20 in Cohort one. This is between the ages of four to seven. Six in Cohort two. This is older ambulatory between the ages of 8 to 17. Cohort three, this is six patients who are non-ambulatory. In this study, we did expand the patient population to study all mutations. As I mentioned in the previous studies, we studied 18 to 58. This is, again, a linear qPCR dose of 1.33x 10 to the 14th. We will be showing results for the first 11 of 20 ambulatory boys in Cohort one. On the next slide, this is the first 11 patients of Cohort one. We just wanted to point out that the majority of these patients, nine of the 11, are age six to seven. The other are age four to five. As you can see, the various demographics here. The next slide, I'll just remind you of the expression profile that we saw. We saw robust expression correctly localized to the membrane, again, with our commercial processed material at 12 weeks. We saw a mean expression of 55.4% by Western blot, 70.5% by dystrophin-positive fibers, and 117% in terms of mean intensity. Now on the next slide, we'll show the six-month functional data for the NSAA. What you can see is that we saw a 3-point improvement on NSAA at six months in the first 11 patients. If you look at just the 67-year-olds, who are nine of those patients, we saw an improvement of approximately 2.9 points from baseline. Virtually identical to the total cohort. We're very pleased to see this improvement across six months. When we look at natural history, we would predict an approximately 0.5-point decline in natural history if we were to look at this age group, so that would be adults of approximately 3.5 over the course of six months. Now turning to safety. In general, safety was similar to what we've seen in our previous studies, with the most common AE being vomiting. We also saw increases in serum enzymes that were responsive to steroids as we've seen previously, and no clinically relevant complement activation was observed. We did have one new SAE in cohort two, which was immune-mediated myositis. This patient experienced muscle weakness post-infusion. He did have a cellular immune response that was detected to his mutation, and I'll talk more about that. There was no associated myocarditis. He did receive plasmapheresis and at discharge, tacrolimus, and he has now returned to his pre-event function and is doing well. As you recall, an immune response to the transgene was a theoretical risk that Dr. Mendell and I had previously identified. As you remember, in our first two trials, we excluded certain mutations for this reason. In Study 103, based on the safety profile, we had expanded mutations in 103. In total, we had dosed a total of nine of the 32 patients with mutations in the N-terminus. Only one of those patients had difficulty, and that was the SAE I just described. This patient had a particular mutation in the N-terminus that was large and different from the others. We've taken the conservative approach to exclude these mutations in the 301 study, but we'll be studying this group separately. In addition to the eight additional patients that we've already treated in this area of the gene, we'll be studying to understand exactly what patients or what mutations are at risk. Based on the data in hand, we believe that the number of mutations at risk is quite small, and we'll do this in collaboration with external consultants to determine the final number, but it would be well below 3% in terms of the final number that would potentially be affected. We'll confirm that over time with data and in consultation with experts. Now turning to the recap. Just to summarize so far what we've described across SRP-9001. What I hope you can appreciate is now we have a wealth of data across 77 patients with SRP-9001 in three ongoing studies. 45 have been dosed with the clinical process material, and 32 have been dosed with commercially represented material. 59 were ambulatory boys between the ages of four to eight, 12 ambulatory boys greater than eight, and six are non-ambulatory boys. We have a wide age range of 4-19. Also, a very wide weight range between 13.7 kg and 80 kg. We've successfully dosed older and non-ambulatory boys up to 80.1 kg, which speaks to the breadth of our data. We see durable clinical activity with sustained functional improvements compared to natural history, now having data out to three years in Study 101 with consistent positive expression results. All patients are at least six weeks post follow-up. As I mentioned, the first 101 boys are now in year four follow-up. We also have a consistent safety profile. Now turning to the 301 design. As you know, we've taken in all the learnings from our Study 101 and 102 study and applied them to the Study 301. I've highlighted the key features here of Study 301. We have an N of 120 patients, and we've now included two stratification factors, which include age and baseline NSAA. In addition, to ensure a homogeneous trajectory, we will also have an exclusion criteria for time to rise with patients having a rise time of less than five seconds. We'll have a balance between the age cohorts, with at least 50% of the patients four to five. This is a one to one randomization between the two groups. In terms of the study design, it's similar to the Study 102, where you have after patients receiving treatment, while the other two receive placebo. The primary endpoint is at 52 weeks for NSAA. Patients are then crossed over to the other treatment and then followed in a long-term extension study. This is a global study with 43 sites in approximately 10 countries. In terms of the dose, it's again the 1.33x 10 to the 14th using linear qPCR. As I mentioned, the inclusion criteria include the rise time, less than five seconds, stable dose of corticosteroids. This is the same regimen we used previously in 102, and the antibody titer is less than 1 to 400. We are excluding mutations between the exons 1 to 17, as I mentioned previously, and also mutations within exon 45 because of the mild course of disease. The primary endpoints are NSAA at 52 weeks, but with various secondary endpoints of expression and primed function tests. This study is very well powered to seek the benefit as in the NSAA at one year. All right. Next slide. Just to summarize, 9001 is the only candidate in development with results from a randomized placebo-controlled trial. This construct has been very carefully designed and studied over time. We've developed a robust and reproducible manufacturing process and an improved assay matrix acceptable to FDA and other regulatory agencies for release. We've now demonstrated robust microdystrophin in Duchenne patients with this commercially representative processed material. The totality of the clinical data that was demonstrated and showed you today shows you that the microdystrophin construct confers clinically meaningful benefits to Duchenne patients. This benefit is sustained and is now shown out to three years of follow-up in terms of function. Our broad 80+ patient experience, including those with limb-girdle and including patients over 70 kg, has to date observed a safety profile that's consistent and manageable. We continue to use only a single drug corticosteroid regimen. Now, where are we going next? We have several upcoming milestones, which include announcing expression of functional data for SRP-9001-102 part two. That will be in early 2022. As far as our Study 103, our commercially representative material, we'll have cohort one full expression and function coming up, as well as cohort two expression function, and as well as cohort three. This will show you the breadth of data in both our younger patients, four to seven, older ambulatory patients, and older non-ambulatory patients, really addressing the full spectrum of this disease in Duchenne. With that, I'm going to turn it back to Douglas for question and answers. Thank you, Louise. Catherine, let's open the line for questions. Thank you. As a reminder, to ask a question, press star one on your telephone. To withdraw your question, press the pound key. We ask that you please limit yourself to one question. Our first question comes from Tazeen Ahmad with Bank of America. Your line is open. Hi. Good morning. Can you hear me? Yep. Okay, great. Thanks, guys. How are you? Just wanted to get a sense about Study 103. Based on the data that you've presented today, and based on your understanding with FDA about what needed to be shown and by when, Doug, can you give us an update on where you stand today? With just what? The path forward? Whether or not you had to agree to show a certain level of efficacy or equivalence between the commercial grade supply and your previous data, and how today's data would potentially address that. Okay. Yeah. Just so we're clear, that is not an issue at all today. Just to remind us, there was a period of time when we were considering some bridging issues between the clinical supply and the commercial supply. As we stand here today, just so we're absolutely clear, we've had very productive discussions with OCAT and FDA. OCAT, as everyone hopefully knows, is the division within CBER and FDA that is responsible for cell and gene therapy. They have blessed the commencement of our next trial, which is Study 301, and all of the assays associated with that trial. We are in good shape. We don't have any additional work to do or bridging to do as well. As we announced very recently, within the last two weeks, we have already initiated Study 301 with the blessing of the FDA and obviously with regulatory authorities around the world, and we're getting going as fast as we can with Study 301. Thank you. Our next question comes from Gena Wang with Barclays. Your line is open. Thank you for taking my questions. Doug, maybe wanted to ask you now with the new evolving data, the Study 103 data you showed today, and then beginning of next year, you will also show Study 102 two-year data. What kind of a data package will make you reconsider the potential accelerated approval path? Very quickly, just on Study 301, is the study powered to detect significant differences in group 4 to 5, and also six to seven? Yeah. Let me ask the second question first. Yes. You'll notice we have at an N of 120, this is a robustly powered study. I think going to the point that I made at the inception of the meeting, we have prioritized probability of success. It is, from our perspective, the wisest way to ensure that children around the world will get this therapy. That's why we didn't cut any corners. We've been very specific with respect to the protocol. We've got floors, we've got ceilings, we're eliminating or limiting kids to being under five seconds in rise time, not because obviously the therapy is going to limit that. Just so that we reduce any heterogeneity and we see it. Of course, the N of 120 answered that same question. We did that not only for the pooled analysis, but for the separate pre-specified analyses as well. Just to remind everybody, so there is no misunderstanding, we are stratifying on the basis of not only age, but baseline characteristics, that we will not have the issue that we had in part one of Study 102, nor will we have any of the titering issues that we had in part one of Study 102 because we use a linear approach. Let's go to the first part of your question, the question about the path forward. I want to be very clear about the discussions that we've had with the Agency to date. Our goal this summer was to get our pivotal trial Study 301 going, get them to bless all of the assays, get them to bless the protocol, we've done all of that to the satisfaction of the FDA. Obviously we're doing the same thing with regulatory bodies around the world. I will repeat what I've said many times, which is the base assumption that everyone should have is that Study 301 EMBARK, we should probably start using the name of the study now, EMBARK. That is the pathway to our approval in the United States and around the world. It is also true, Gena, that the data that has evolved is becoming significant in the breadth of the data and in the signals. I mean, in almost every single way you look at this, the potential for a profound effect comes off, not just the expression levels, the safety profile, the functional signals, the restoration of the dystrophin-associated protein complex. We're not showing some of this stuff today, but we have the independent study of muscle MRI, it's clear. We will see what happens early next year. As everyone knows, we're going to have very informative information early next year. Part two of Study 102, we'll have that completed right at around the end of this year, and we'll see that and have that data available in the first quarter of 2022. There's going to be a wealth of information. That's 41 patients. Approximately half of those kids will have been on that therapy for two years against a pre-specified, not post hoc, because remember, this is still blinded, a pre-specified natural history cohort, and then the other group will have been tracked for one year off therapy and tracked for one year on therapy, again, against the natural history cohort. We can look at their trajectories. If that data is additionally compelling with everything else we're seeing, then we will, of course, consider whether, given the wealth of the information that we have and the data set that we have, whether the totality of evidence justifies us beginning to have conversations with divisions, agencies around the world about a more accelerated approach to bringing this therapy to patients who do not have the benefit of time. I want to be very clear, from my perspective, the base case assumption, and I would argue for investors, the investing assumption ought to be that Study 301, as it stands today, will be the pathway for approval for SRP-9001 in the United States and around the world. Thank you. Our next question comes from Brian Abrahams with RBC Capital Markets. Your line is open. Hey, good morning. Thanks so much for taking my question. Really appreciate the comprehensive overview and contextualization of the data. I was wondering if you could maybe expand a little bit more on the immune SAE that you observed, in terms of which mutation, whether there was any overlap with what any other companies have observed with their transgene, or might you expect some differences there, and any kind of monitoring that you'll incorporate into the ongoing studies. I'm also just curious on that front, the natural history data that you showed as a comparison for Study 101, Study 102, and Study 103, to what degree does that represent all the different mutations matched by age and NSAA versus just the ones that are being included in these studies? Thanks. Yeah. I'll turn those two questions over to Dr. Rodino-Klapac. In terms of the SAE, this was the mutation in the N-terminus, and it was large, significantly larger than the others. We do note that other sponsors have seen cases of immune-mediated myositis, and we do think it's related to this class effect for certain mutations. Certainly not related to anything with the capsid. In terms of monitoring this is something we're already monitoring for and that we will continue to be monitoring for closely. We're being conservative by excluding all of these mutations, as I mentioned, in the next trial. We'll be sure to identify the exact mutations at risk, because ultimately we believe that it's a very small number that would be at risk specifically. The size of the mutation does appear to matter, but ultimately over time, between the data and in consultation with expert, we'll determine the exact amount. It is specific to each program in terms of constructs. You may see different exclusions in other trials, much as based on what's included in individual constructs. The second question was around the natural history. This is a comprehensive data set that was derived from 300 patients, so it does represent our population. We develop a model and then in certain cases where we can, these are then matched for both age and NSAA, so it does take into account the considerations or the characteristics of our patients in comparison. One final thing, just to bring us back a bit on this mutation-related issue. We note, for instance, that Pfizer has had three of these. I think two of them actually were associated with a myocarditis. Ours was not. I want to be clear that we feel pretty confident that this is a mutation-related issue that just may very well be the case that Pfizer just got unlucky with their three. If you look back, actually, the data that we've developed has been very informative for our ability to bring this therapy to the greatest number of patients possible. In Study 101 and Study 102, because of this theoretical risk that if you have a mutation in these ranges, you might have an immune response to the gene itself, we were very conservative. In 103, the ranges were expanded. In fact, those issues were eliminated. While we wish we had had none, it was actually quite informative. In that one through 17 range of exons, we dosed nine children with mutations in that range that historically we would've worried about theoretically. In fact, eight of the nine had no issue. The ninth that had an issue, it isn't just random. That mutation is qualitatively different than the others in a very significant way. There's two issues there. There's this enormously large mutation deletion, and it's in one through 17. Now, we're taking a conservative approach for Study 301, of course. While we have limited the exclusions from Study 101 and Study 102, we are going to maintain this idea of excluding exons one through 17 during Study 301. We are separately, and frankly we're going to do it as rapidly as possible, we're going to start other development and studies so that we can really frame out what is this combination of where the mutation exists and the enormity of the deletion that would be at genuine risk. That we're pretty confident, given all the data we have right now and given what we've done in 103, that by the time that SRP-9001 is approved, it will be a fleetingly small group of children who would have to be excluded. That's, of course, extremely important work, because if we remain with this conservative approach that we're taking for 301, eight of the nine kids that are today have been treated and are doing very well wouldn't have been treated, and that's not right for the community. We are going to do the work so that when we launch this therapy, we're going to be in a place where a fleetingly small number, we suspect, of children would be at any risk of this issue. Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open. Good morning. Thanks for taking my question. Could you just comment on your confidence level here that when you've gone back and looked at the previous studies, that these two stratification methodologies and the titrating aspect are really the only trial design changes that need to be made here? Well, we've tweaked a number of things in the protocols, but there is no doubt that in Study 102, the therapy performed brilliantly. The study did not for the top line because of the issues that we've mentioned. The first is, of course, as we went back and used our linear qPCR method and retested the lots that were released through this supercoiled method from Nationwide Children's Hospital, concluded that 60% of the kids were dosed at substantially less than the 1.3E14, which was our target dose. That is 100% solved. Just so we're very clear, it was solved at the crossover for 102, and of course, it's solved in 103, and it'll be solved in EMBARK, of course, because we're using this linear method going forward. It is also clear, you see it jump off the page for us, that the problem with the six and seven-year-olds is that the baseline characteristics were so wildly different that it was comparing the wrong groups. There was just no way to intelligently compare it. If you actually use this very sophisticated natural history modeling that we use, we would have seen a strong statistical significance if we had had the right group against the six and seven. That is also fully solved in Study 301. We are stratifying on the basis both of baseline characteristics as well as age, so we will not have a repeat of that issue. Of course, if you look at Study 102, part one, and you look at the four and five, even with the titrating methods, when you get the baselines right, in a short 48-week period, you see a strong statistically significant benefit of this therapy in the four to five. That's in 16 patients, and yet our Study 301 is 120 patients across those age ranges with those tight entrance criteria. We have an enormous amount of conviction in the design of the study and frankly, in the probability of success of this study. Thank you. Our next question comes from Alethia Young with Cantor. Your line is open. Hey, guys. Thanks for taking my question. Maybe just two. One, can you talk about how you're thinking about enrollment timelines for the next commercial study in light of everything going on in the space? The next one is just a big picture question. There's a lot of, obviously, some concerns, not exactly in gene therapy, but around safety. I wanted to get your perspective on how you're thinking about the safety and the FDA's thinking about safety overall with cell and gene therapy space. On the first one with enrollment, we're going to take, obviously, if we had started much earlier in the year, I think I had talked before about giving certain timelines. We're now obviously initiating this trial, and we'll have kids enrolled and dosed this month. First things first, it will enroll robustly. As sites come online, we'll have eventually over 40 sites up and running. We'll be starting in the U.S., which I'm very excited about. We'll be moving to Europe and Asia and the like. The study will robustly enroll. Just to give you anecdote, one of the reasons we are being a little circumspect about exactly which sites exist is because we have heard stories anecdotally of patients trying to move countries just to get the chance of being in a study, and we would not recommend that, and so we are being careful about that. The study will robustly enroll. I am going to say that conservatively, we will have this enrollment complete and dosed by the end of the first half or in the first half of next year. It will enroll very robustly. There is an extraordinary demand for potentially transformative therapies such as this one. On the safety side of things, the FDA has reviewed, let me focus specifically on our therapy. I don't want to be overly competitive, so I won't talk to others. We have, and you saw it in the advisory board that occurred in September, there have been issues that have been discussed with respect to other AAVs, things like effects on the dorsal root ganglion, neurological effects, integration-related issues, and then, of course, this concern that people have regarding complement-mediated aHUS, and kidney failures, and the need to use Soliris, and the need to use dialysis on kidney failures. We see none of that. We have had none of that in our program. The FDA has looked across all of our safety database, including obviously all of the information that we provided today, and on that basis, has blessed our ability to move to our pivotal trial. That's why we've been able to initiate it. We feel very good about where we are as an organization from a safety perspective, an expression perspective, a functional signal perspective, in a performance perspective. Thank you. As a reminder, we ask that you please limit yourself to one question. Our next question comes from Anupam Rama with JP Morgan. Your line is open. Hey, guys. Thanks so much for taking the question. On Study 301, just thinking about your inclusion/exclusion criteria based on time to rise, what portion of four and five-year-old and six and seven-year-old would be excluded from this? Logistically, how many attempts do the kids get to meet the criteria? Thanks so much. You present, Louise? Yeah. In terms of the four to five-year-old, it would be a low percentage that would screen out for that, very small. Six to seven, I can't give a specific number. Obviously the goal of doing this is to create a study that has a high probability of success and we have successfully treated patients with rise time above five seconds and we've proven that within Study 102. I think that's an important thing to keep in mind. Sorry, was there a second part to the question? Oh, how many times did I think the question that Anupam asked was how many attempts does a child get to rise before you decide that they are definitively over five seconds? The physiotherapist will do the test once, officially. One final thing we should say. Look, the exclusion criteria, just so we're very clear, and I'm sure everyone understands this, the goal of the majority of these exclusions for purpose of the trial is to simply reduce heterogeneity so we see an effect. Obviously, I think I'm telling people what they don't need to know, but one should not imagine that commercially this therapy wouldn't be available to children who had rise times over five seconds. That's not the goal. In a controlled experiment, you have to reduce this. Now, there is one significant exclusion criteria that is meaningful commercially, and so ensuring that that exclusion percentage is low is unbelievably important, and that is exclusion for preexisting binding or neutralizing antibodies. We're not excluding that for heterogeneity issues. We're excluding that because, as it currently stands in gene therapy, if one has a previous experience with something that looks like the capsid and then therefore has neutralizing or binding antibodies related to that capsid, it isn't currently safe to dose those children. The good news about our construct right now, and it's stayed very stable over a long period of time, is that we're in the mid-teens, around 15% or so excluded. We don't like 15%. We'd like it to be zero. Louise and team are doing an enormous amount of work to eventually someday have a pathway through the use of other therapies or other treatment paradigms to knock down preexisting neutralizing antibodies to bring these children back into frame. The good news is the vast percentage of children will not have a preexisting neutralizing antibody. The second good thing, at least so far, remember, is that we're a little different than other companies. We're not simply working with RH74 for Duchenne. We also use RH74, which is our capsid, for limb-girdles, and limb-girdles affect adults as well as children. We've had an opportunity to look at screen-out rates over ages, and interestingly enough, it does not get significantly different as one gets older. Even looking up at full adults with limb-girdles, the screen-out rates we're seeing from an RH74 perspective and the seroprevalence looks about 15% stably. That is a really important issue to ensure that we can reach the maximum number of patients possible. Thank you. Our next question comes from Colin Bristow with UBS. Your line is open. Good morning, thanks for your helpful presentation. Just a little bit more on the controlling for baseline characteristics and specifically trajectory. I think if you look at the Muntoni data, certainly at the younger ages, like around four, five, the different classes can have very similar baseline NSAA scores. How well does the time to rise control for this? Did you at any point consider just doing serial NSAA to just try and at least plot trajectory on a shorter term basis? Just second quick question, what's the longest duration data you have for expression? Any commentary you could give on just what you are seeing in terms of trends over time would be helpful. Thanks. I'm going to turn the first part of the question over to Louise. On the latter part of the question, obviously, we have three-year data from the children from a functional perspective. From an animal model perspective, one of the things we've often said is that. In one sense, muscle is a very difficult place to go for gene therapy because getting the tropism and getting the gene to the right place can be very challenging. Obviously, we've solved for that. We're now seeing, with respect to our expression in our commercially representative material, some 3.8 genome copies per nucleus. The good thing about muscle is that once you get there, you don't get significant turnover, so you see very good long-term durability. We've seen solids, consistent durability, for as long as we've been able to look across models for icrodystrophin and generally mouse models, non-human primate models with our partner golden retriever models. We will see, we predict very good long-term durability with this therapy, and we're certainly seeing it functionally, of course, in the first four kids. With that, I would turn over the first part of the question to Louise. Sure. Characterizing the baseline characteristics by both age and baseline NSAA is highly predictive. In terms of the rise time, it's been shown that a rise time less than five seconds is predictive of loss of ambulation within one year, and that's been demonstrated by experts in the field. I would just add that as far as the predictability of that, you can just look to the model work that we did. Using the model that we generated, we then applied that to the 102 placebo patients. Using those baseline characteristics, we were able to see very highly concordant data between what was predicted and what we actually observed. There's about 0.3 points difference between the two. In terms of the predictability of applying the NSAA and age criteria using our model, it's highly predictive of what we would expect. That would lead to our overall confidence in the Study 301 that it is very well adequately powered based on those criteria. I would just add finally, just to keep reminding us, I mean, this is an N of 120, so we have robustly powered this study so that we should be in good shape. Thank you. Our next question comes from Brian Skorney with Baird. Your line is open. Hey, good morning, everyone. Thank you for taking the question. I was hoping you can maybe help us sort of understand the key differences between part one and part two of Study 102. It seems like the part two analysis that we'll see early next year is becoming increasingly important. When we sort of look at that part two data, what should we really be looking for as the proper comp here to determine the effect size here? Are we looking at something like the 2.9 point benefit, which I think is what you're saying you saw in the six to seven-year-olds in the 103 cohort at six months? Just help us think through what would really be the expected difference here between sort of the better baseline controlled part two 102 and the part one. Sure. Well, the first thing to know, Brian, is that this will all be pre-specified. There'll be nothing post-talk about it. We'll have a pre-specified natural history cohort, both against the kids that have been on therapy for two years, as well as the kids that have been on therapy for one year, plus a trajectory analysis, plus a pooled analysis, I believe, as well. At the broadest strokes, our goal is to see a significant difference between the natural history, what a kid would do with these trajectories versus what they're doing on therapy. Beyond that, I will turn it over to Louise to comment. Yeah, I would just point out, it would be several pieces of data from 102 in comparison. We'll have the two-year data of the treated patients that were treated in the first part one. We'll have the comparison of the patients treated in part two compared to natural history as well as the initial placebo. There'll be several pieces of data coming from that that will be critically important. Also the trajectory data from the patients that were placebo and crossover. Taken together, those three pieces of data will be highly supportive. As Doug mentioned, it's all pre-specified. Remember, the two confounding issues in part one of Study 102 was the titering method that was previously used, as well as a mismatch in the baseline characteristics of the six and seven-year-olds. I think the use of a natural history set, because we won't be able to use the placebos, no kid will be on placebo by then. The use of a pre-specified, rigorous matched natural history set can correct for that issue, of course, in part two. Then, as you know, in the part two crossover kids, half of the kids that were crossed over, that titering issue was resolved. We used the linear titering method. We should be in a good shape to get very informative information out of part two of Study 102 early next year. We're very excited to share it with everybody in early 2022. Thank you. Our next question comes from Joseph Schwartz with SVB Leerink. Your line is open. Hi. Thanks very much. I was wondering how many sites will you use to enroll the 120 patients in EMBARK, how will you ensure that you don't sacrifice any rigor when you go from, I think there were just one or two sites for Study 102 and Study 103, you don't try to power up the trial, but potentially dilute it by having more variability across many different clinicians evaluating patients with NSAA. Yeah. We'll ultimately have about 41 sites or so around the world. The second point is a really good one. It's something we obsess over. I would say the way we're going to ensure that we don't increase standard deviation as we move to sites around the world is through sort of our quintessential obsessive detail-oriented worldview. We are going to stay very close. We've got great monitoring. We've got a great clinical operations team. We've got the insight of people like Dr. Mendell, who knows how to do this, who's helping inform all of the other sites in precisely how to do this. We are going to obsessively focus on the rigor of the exclusion and inclusion criteria, the performance of the functional tests, the way the infusions are performed, to ensure that we don't increase standard deviation across sites as we move across the world. That second one is a real straightforward issue. It's just obsessive operational excellence and execution, and I would hope people would see, particularly with the work that we've done this year, that we're an organization across tech ops, commercial medical affairs, development, clinical operations. We're an obsessively detail-oriented executing organization. That's the best way. Finally, of course, keep saying it over and over again, we've got an N of 120. We're taking a conservative approach even with respect to that. We are not cutting corners with respect to Study 301. Thank you. Our next question comes from [Yanan Zhu] with BTIG. Your line is open. Hi. Thanks very much for taking the question. Just a follow-up on the enrollment criteria. I wonder, are there any external natural history data besides what you have seen from the subgroup analysis from the Study 102 that suggest that in addition to making sure that the baseline condition is similar, you have to look at the four to five years old, that's a pretty narrow range to make sure? I understand that it increases data homogeneity, just wondering if any additional evidence? Dr. Louise Rodino-Klapac? Yeah, the short answer is that we certainly took into account all natural history data sets in designing this trial and informing our model. There are external data sets which support our model in terms of the prediction of our natural history. If I were to say, certainly we took into account all the available data, that would inform our model and consistent with our model in terms of the probability of success and powering our study. I should also say, I won't name them because it's premature, but there is an independent modeling approach that is unrelated to us that have applied this to our data. It is almost identical. This is the three-year data, so really the long-term data, almost identical to the information that we have. We're not at liberty to share it yet. That'll be published early next year, and then we'll see the additional confirmation of the validity of our model. We feel very good about where we are. I will just finally say this, and I don't think this comes as a surprise to anyone, no one, at least in the sponsor world, has more access and more patient-level data to inform their programs than Sarepta does, given the amount of work we've done with Duchenne muscular dystrophy. Thank you. Our next question comes from Tim Lugo with William Blair. Your line is open. Hey, this is Lachlan, not Tim. Thanks for taking the questions. I just wanted to clarify, Doug, when you were talking about the regulatory path forward in your base case, are you assuming that you could file after the first cohort of EMBARK, or would you be expecting to wait for the second cohort and have a cohort with one year and a cohort with two years' worth of data before you went to the agency? Yeah. Thank you. Thanks for asking that question so I can make sure that people know this. It's the first cohort. Unquestionably, the first cohort. That is our goal. That is our primary. Yeah. Thank you for that. Thank you. Our next question comes from Ritu Baral with Cowen. Your line is open. Hi, this is from the Cowen for Ritu. Just a quick question from us, please. First, in Study 101, do you think there's a slight roll-off of effect in patient one at year three? Any thoughts on why that might be? In Study 103, how many 12 to 19-year-olds have you dosed, and how many would you say were heavier weight across the cohort? Thank you. I think I missed the first part of the question. If I'm not mistaken, you were asking about whether there was a dip in the first patient and whether that was meaningful. If I'm right about that, the answer is no, it's not meaningful. It's just within the variability. That child has done, if you look across the study, look across the three years, he's done just brilliantly and far better than natural history would've assumed. Of course, you're going to get moment-to-moment variability. These are function tests. Sometimes kids can be tired, et cetera, and it would create some variability. Our kids are all doing brilliantly. I'm trying to remember, what was the second question? Louise, did you capture it? Hold on one second. Apologies for that. Apologies for the second question. Thank you. Our next question comes from Shanshan Xu with Berenberg. Your line is open. Great. Thank you. Good morning. Thanks for taking my questions. I'm wondering if you can comment on how many patients in your phase III EMBARK trial would be eligible for your three approved drugs. I guess, do you think you will run into a situation where patients might receive those drugs in the trial and potentially confound your results? Thank you. Yeah. Louise, you correct me if I'm wrong, but they would not be permitted to take another Duchenne-related therapy while they're in the trial. Am I correct about that, Louise? Yeah. Correct. Yeah. There are no other questions in the queue. I'd like to turn the call back to Douglas Ingram for closing remarks. All right. Well, thank you, everybody, for spending time with us this morning. As you can well imagine, we're very excited about where we're going with SRP-9001. I think the organization's done a brilliant job moving this therapy forward as fast as possible. I want to thank everybody involved, our technical operations folks, our process development analytical folks have just done a brilliant job with respect to our commercial process materials so that we're in a place where we are starting our phase III trial in the U.S. and in Europe and Asia. I want to thank our development team for the great work they did in developing what is a very sophisticated protocol, and of course, our research and translational group as well. The entire regulatory group did just a wonderful job of representing us with regulatory bodies around the world. Everyone has just done a fantastic job getting us to where we are. I also want to thank our investigators, of course, who have been enormously valuable, and Dr. Mendell, who deserves just more credit than one could give a single human being for what he's done for Duchenne and SMA and gene therapy generally. Obviously, I want to thank Louise, who was one of the co-designers of SRP-9001. We stand in a wonderful place right now. We're very excited about where we've come. We have an enormous amount of conviction to the transformative potential of SRP-9001, but I will end with what I said at the beginning, which is it is always dangerous with success to get complacent or arrogant. We stand alone. SRP-9001 is a unique construct with unique qualities, and it is undoubtedly, to anyone who's objective, qualitatively safety tropism function, a therapy that stands alone. We have an enormous mission in front of us every single day. Patients and their families are not simply suffering from Duchenne muscular dystrophy, but are degenerating and having their muscles stolen from them. We are going to execute aggressively to enroll Study 301, to get 301 moving as fast as possible, and to be fully enrolled. We are then, as we look forward to the rest of the year and into early next year, we're very excited to come back and talk to you early next year about the results of Study 102, part two, which we'll have. Along with our just wonderful partner, Roche, who's just been a fabulous partner with us as we develop this therapy. We're really excited about moving this program forward as fast as possible, exploring the art of the possible once Study 102, part two comes out, and getting this therapy, once confirmed, to patients living with Duchenne muscular dystrophy around the world. I look forward to updating everyone on this call and the community as we do that. With that, please have a great rest of the week. This concludes today's conference call. Thank you for participating. You may now disconnect.