Good afternoon, ladies and gentlemen, and welcome to the Sarepta Therapeutics microdystrophin SRP-9001/102 Top Line Clinical Data Part 1 conference call and webcast. At this time, I'll turn the call over to Doug Ingram, President and CEO, for opening remarks. Please go ahead. Thank you very much. Before I begin, let's move to the next slide, please. I would just remind everyone that we will be, of course, very likely making forward-looking statements today. I would ask folks to look to our public filings and SEC filings for the various risks and uncertainties that are attendant when one makes forward-looking statements about the potential issues that will occur in the future. With that, let's go to the next slide. Good afternoon. Thank you for joining all of us today for our investor conference call to review the top line results from our part one interim analysis of Study 102, evaluating our gene therapy SRP-9001 in patients with Duchenne muscular dystrophy. By now, you will have seen our press release announcing the results. In a moment, I will turn the call over to our Chief Scientific Officer, Dr. Louise Rodino-Klapac, to review those results. Let me start by making a few introductory comments. You will hear today that Study 102 has largely confirmed our hypotheses on the performance of SRP-9001. We strongly hit statistical significance in all biological measures, including expression, genome copies, localization, and CK levels. We continue to see a favorable safety profile with no new safety signals, and it is clear that the therapy is providing a substantial benefit to patients. With that said, it is an understatement to say that I was initially not only surprised but deeply disappointed that while we saw separation between active and placebo, at every time point, we missed statistical significance on our primary functional analysis for SRP-9001. Upon review, the likely reason for this became immediately apparent. While you should view these analyses as tentative until we conduct a deeper review, it seems evident that our miss on statistical significance was not a problem with the overall design of the study. Neither the study size, nor the endpoint, nor the timeline, nor our assumptions in how the DMD patients performed in the chosen four to five and six to seven age groups. Importantly, we do not believe it relates to therapy performance. On its face, the lack of statistical significance appears to relate to improbable bad luck in the randomization process for the six to seven-year-old cohorts. Let me explain. As we've talked about often, as an organization that understands the disease course of Duchenne, we identified that there would be a difference in the predicted trajectory of the four to five age group and the six to seven age group. We took many steps to ensure we accounted for this. Indeed, age was the stratification variable we used for randomization. We stratified for four to fives and six to seven age groups, and we set up separate pre-specified statistical analyses for the separate groups, and we further worked to reduce variability by placing a ceiling and a floor on the entrance criteria. With respect to the four to five age range, our plan worked. In the randomization process, the active and the placebo groups had nearly identical baseline characteristics. Thus, you will also see that the active therapy cohort did exceptionally well versus the placebo cohort, and we robustly hit statistical significance, a P value of 0.017. Some have voiced concerns that the end of our study might have been too modest, I would point out that we achieved robust statistical significance with only 16 participants achieving NSAA numbers that are very similar to what was predicted by our prior proof of concept Study 101. As impressive as the statistical significance was for the performance of the four to five-year-olds on therapy, unfortunately, there was an even more impressive statistically significant between group difference in this trial. Through the vagaries of the randomization process, the baseline characteristics for the six to seven-year-old placebo cohort on NSAA were very substantially different, and importantly, far milder than the baseline characteristics of the six to seven-year-old active cohort, which were more severe. Indeed, the difference has a P value of 0.004, meaning that random chance of this occurring was about 1/ 250. As Dr. Rodino-Klapac will show you in her presentation, this imbalance occurred in favor of the placebo group in each and every baseline functional characteristic. This means that for the six to seven-year-olds, we had two very different and non-comparable treatment populations. The active group, by random chance at the bottom of the entrance criteria, would be predicted to be moving into the potentially significant decline phase of the disease, while the placebo group, at the ceiling of the entrance criteria, would be predicted to be in a much milder phase of the disease. Where the baseline characteristics were well-matched in the four to five-year-olds, the therapy performed as predicted, and we robustly hit statistical significance and a clinically meaningful benefit over placebo. Where the baseline characteristics between the active and placebo six and seven-year-olds resulted in materially non-comparable treatment populations, we could not show a between-group difference on function. This is the reason we missed the overall statistical significance on the primary functional measure. We are very frustrated by this randomization issue. Having now treated over 50 patients, the fact remains that the results of this study further bolster our confidence in the transformative potential of SRP-9001, and we owe it to the patients that we serve not to be taken off track by a random error, but instead to take the wealth of information and insight that we have from Study 102, inform our program going forward, refine our protocol for the next trial, and continue to advance SRP-9001 with a sense of urgency, which is exactly what we will do. We will learn from this trial. We will keep moving forward to gather the evidence necessary to bring these therapies to patients that are waiting around the world. With that, let me turn this call over to Dr. Louise Rodino-Klapac. Dr. Klapac? Thank you, Doug. I'd like to start out by reminding you of our study design for our SRP-9001/ 102 Study. It's important to note that we're reporting results from Part 1 of the study. The study is ongoing and remains blinded. Because of that, we will be providing top-line data and will not be sharing individual patient-level data. There's additional data that we cannot share today, but we will in the future. Regarding the study design, it's a 41-patient, double-blind, randomized, controlled trial. As Doug previously mentioned, the randomization was based on the age stratification between four and five-year-olds and six to seven-year-olds, and that was later used as a pre-specified subgroup analysis. In Part 1 of the study, subjects were randomized 1:1, and half of the subjects received SRP-9001, whereas the other half received placebo. Following Part 1 at 48 weeks, subjects will cross over to either placebo or SRP-9001. Today, we'll be presenting 12-week biopsy data from Part 1, as well as 48-week functional data. Now, it's important to note that we'll be receiving additional data in the near future, which will include biopsy data from Part 2, which will be 12 weeks post crossover. The study will remain monitoring safety and functional outcomes for an additional 48 weeks. Following Part 2, subjects will cross over into an open-label extension study where we'll be gathering additional safety data. In terms of the primary endpoints, primary endpoint for expression was at 12 weeks, as measured by Western blot, and then change in NSAA total score from baseline to week 48. There are secondary endpoints, which included microdystrophin expression by immunofluorescence and percent positive fibers and other timed function tests. Now turning to expression. We met the primary endpoint showing significant microdystrophin expression at week 12 by Western blot with a mean of 28.1%. In terms of looking at immunofluorescence labeling, a mean intensity, this is the amount of microdystrophin localized at the membrane for a mean of 63.7% and also a mean of 33% dystrophin-positive fibers. In terms of vector genome copy number, we had a mean of 1.56. We did see a range of expression. As you will recall, we used clinical material from Nationwide Children's Hospital for this trial. At the start of the study, we used Nationwide's method for titering, and this is our qPCR assay with a supercoil plasmid standard. We developed a robust titering method at Sarepta that is more accurate, precise, and well-controlled using a linear standard. When we went back and we retrospectively titered the clinical lots used, there was some lot-to-lot variability due to the previous method used at Nationwide. Preclinical studies did not predict this variability would lead to differences. The dose used in Study 101 was 1.33 × 10¹⁴ vg/kg using the linear standard, and all lots are now titered using this method, and the dose will be consistent for this for the remainder of the 102 Study. Thus, we will not see variability in part two or other studies moving forward, and we will predict to see an overall higher mean for expression, but this will have to be confirmed. On the next slide, we're showing representative image of our microdystrophin expression is labeled by immunofluorescence. What you're seeing at the top, this is a baseline biopsy. We co-labeled all of our biopsies using merosin, which is a marker for the membrane, and then stained for dystrophin. At the top you see a biopsy labeled the membrane with merosin, but for microdystrophin, we see nothing. There's no expression at baseline. On the bottom panel, we see, again, membrane labeling and then robust microdystrophin labeling, as you can see in red. As I mentioned, it's correctly localized to the membrane. As you can see, that merged image clearly co-localizing with the membrane marker as well. Now turning to function. Next slide, please. NSAA, or the North Star Ambulatory Assessment, was the primary functional outcome measure. To remind you, this is a 34-point scale including 17 different primary motor function measures. Here what you'll see is the NSAA plotted from baseline to 48 weeks comparing SRP-9001 treatment, as you can see by the red dotted line, compared to placebo in the blue solid line. What you'll note is that at every time point post baseline, there was an improvement in NSAA in the SRP-9001 treated group versus placebo. However, it did not reach statistical significance at 48 weeks. If you look just at the 9001 treated group from baseline to 48 weeks, we did see a statistically significant improvement. The treatment group showed a 1.7-point increase compared to baseline for a P value of 0.009. When you look at the placebo group, we saw a 0.9 increase compared to baseline, and that was not significant. Now if we turn to the next slide for the pre-specified subgroup analysis in four to five-year-olds, you will see a clearer picture. You'll see that comparing baseline to 48 weeks, there's separation between the 9001 treated patients and placebo patients at every single time point, including 48 weeks where we see statistical significance. Just to orient you on the graph, the placebo is shown on the bottom line, SRP is the gold dash line on the top. What's important is that there was a 4.3-point improvement in NSAA in the SRP-9001 group from baseline and a 1.9 change in placebo, and that resulted in a delta of a 2.5-point difference between the groups. This was significant, where P= 0.0172. We did not, as Doug mentioned, see the same result in the six to seven-year-old subgroup. The next two slides I'll go through will address why. Next slide. Here we're looking at the baseline functional characteristics of the four to five-year-old group. You will note that the two groups were very well matched at baseline and with all measures, there were no significance between the groups. Let me just take a minute to orient you on these measures. For NSAA, again, this is a 34-point scale, so the higher the number, the better the individual is doing. Whereas all the time tests that you're seeing, 100-m, four stairs, timed rise in 10-m, you're looking for a reduction in the amount of time. Patients that have a lower number are doing better because they're taking less time to do an activity. In this case, in the four to five-year-old group, you're seeing that these patients are all very well matched between the 9001 group and the placebo group. You see no significant difference between the groups. When we look in the six to seven-year-old group on the next slide, we see a much different picture. In this case, at baseline, we are highly favoring placebo in all measures. As Doug mentioned, there's a significant imbalance between the two groups at baseline except for one. The difference between the two groups is significant. Let's take a little bit of time to walk through this in detail. Focusing on NSAA, you'll see that the SRP-9001 group has a mean baseline of 19.6, whereas the placebo has a mean of 24. That's a 4.4 difference between those two groups. For all of the time tests, you see the placebos have a significant reduction in the amount of time it takes to do that activity. They're doing much better at baseline compared to the 9001 group. These are all significant with the exception of the four stair climb. In summary, these baseline characteristics were highly imbalanced between the two groups and very likely contributed to the lack of statistical significance that we saw in the six to seven-year-old group. If we just focus on six to seven, in particular, the microdystrophin treated group, we know from natural history that the six to seven-year-old age group, as Doug mentioned, are generally declining, and those with a low baseline function, specifically in the 9001 group, would be significantly declining over a year. Yet we only saw a very small 0.4 decline. It's difficult to demonstrate a treatment effect with the significant imbalance between these two groups. As we're looking at this in greater detail, at this point, the imbalance between these two groups was quite clear. Now on the next slide, we're going to turn to safety. We continue to see a very favorable safety profile with no new safety signals identified. The most common adverse event was vomiting, and the majority of AEs were mild to moderate. There were four patients with a total of five SAEs. Three patients were in the treated group and one in the placebo group. There were three cases of rhabdomyolysis, in which case two were in the treated group and one in placebo, and two cases of transaminase elevation. There were no adverse event-related discontinuations and no deaths in the study. Importantly, no clinical complement activation was observed. The next slide, I'd like to take you through next steps. We're going to continue to advance the Part 2 crossover phase. As I mentioned, we'll be collecting biopsy data at 12 weeks to assess expression and other biological markers. We'll be assessing longer-term assessments of functional measures, including the NSAA for the Part 1 patients that received SRP-9001, as well as the placebo crossovers. Importantly, in our 103 Study, this is our open-label commercial process material study, we've enrolled and dosed 11 patients, and we're expected to have biomarker and safety results from that study in Q2 of this year, 2021. We'll be leveraging the learnings from both Study 102 and Study 103 to inform our future clinical development plan, including a phase III. Next slide. In conclusion, we've identified, importantly, that there's no new safety signals that have been observed. We're pleased that we met the primary biological endpoint of microdystrophin expression at 12 weeks. Our total NSAA score treated patients versus placebo demonstrated a positive increase at every single time point, but yet did not reach statistical significance versus placebo at 48 weeks. Importantly, we had a pre-specified analysis in the four to five-year-old age group that showed a significant improvement in NSAA versus placebo at 48 weeks. The imbalance in baseline functional characteristics in the six to seven-year-olds group contributed to the lack of statistical significance on the functional endpoint. We've collected a wealth of data in this study, and that will continue to support future clinical development plans. We still have data to come in this study, and this will guide our development as we move forward with our 9001 program. With that, I'm going to turn it back to Doug for questions. Thank you, operator. Let's open the line for Q&A. Ladies and gentlemen, if you'd like to ask a question at this time, please press the star and the number one key on your touch-tone telephone. To withdraw your question, press the pound key. In the interest of time, we ask that you limit yourself to one question. Our first question comes from Brian Abrahams with RBC Capital Markets. Your line is now open. Hey, guys. Thank you so much for taking my question. Just wanted to expand a little bit more on this idea of the imbalance in baseline function. I guess, how much do we know from historical natural history data about the degree to which baseline function should predict the trajectory of one-year progression? If you were to adjust or match the baseline NSAA within the six to seven-year-old cohort, would there have been a clearer delta favoring drug? Thanks. Louise? Sure. We do know from natural history that in the six to seven-year-old age group, we would typically see a decline in this group from zero to four points, and also the particular baseline does predict the trajectory to some extent. In this case, it was clear that the significant imbalance made it virtually impossible to see a treatment difference in this group. Gilmore, would you like to add to that? Yeah. No. Thanks very much, Louise. Thanks, Brian, for your question. I think Louise has summarized what we would predict. I think your second part of your question was around sensitivity analyses, and we're obviously doing further analyses. These are the top-line data that we're getting to you fresh. We have a lot of other pre-specified and obviously post hoc analyses that are ongoing. Next. Our next question comes from the line of Tyler Van Buren with Piper Sandler. Your line is now open. Hey, guys. Thanks for taking the question. I guess my question is there any chance that you go to the regulators and see if there's some sort of filing that could occur based upon the pre-specified four to five-year age group? Without a doubt, based upon this data, do you think you need to generate more data in Study 103, and what type of data do you think you need to generate to eventually file? Yeah. Thank you for that question. First, of course, we have had no additional discussions with any of the regulators about this. I think as it stands right now, we are going to focus on the completion of Study 102. Remember, this is in fact an interim analysis. This trial remains blinded. One of the reasons we're not going into the depth that you might otherwise expect at the end of a trial on patient-level data is that we have an ongoing trial. We'll have a readout on that, and it'll be interesting because that readout of the study, which will occur when all of the kids have had 48 weeks, including the crossover participants, will be a different sort of analysis than this concept of looking at the therapy on active versus placebo at 48 weeks. We'll do trajectory analysis and a number of other analytics that are pre-specified there. We're also focusing on Study 103 and getting the expression level information out of Study 103 to see the performance of our commercial material. That will be coming up in the not-too-distant future, which will tell us a lot about the therapy. Of course, very importantly right now, what we are focusing on right now is to take the learnings out of Study 102. We've seen a lot out of this study. Again, I'm not going to ignore the fact that I'm extraordinarily disappointed that this imbalance caused us to miss that sig. Inside of this study, not only are we more confident than ever in the performance of this therapy and the ability for this therapy to have a transformative impact on the lives of patients, but we have a wealth of information out of Study 102 that no one has ever received in a trial such as this with Duchenne muscular dystrophy. We have dosed over 50 patients already. We're going to take all of that learning and all of that information at a granular level and ensure that the Study 301 that we're going to launch this year is going to maximally have the best chance of not only resolving this issue, but having the strongest probability of success. That's really what we're focused on right now. Our next question comes from the line of Alethia Young with Cantor. Your line is now open. Thanks for taking my question. I hope you guys can work through something for at least the kids. I looked quickly at that NSAA picture you put up by time point. Between 12 and 24 weeks, it seemed like in the placebo, there was a huge jump up with wide error bars. After that, it seems like you might have hit if it had been 12 weeks. I just wanted to get your perspective on that, thanks. Yeah. I'll just say real briefly on that 24-week time point, you'll see this strange increase or momentary increase for the placebo group. We can't say a ton about it yet because we haven't done all the analysis and analytics. What one can point out there is that was in the middle of the most difficult period of the pandemic. If you look at the numbers below the graph, you will immediately see that there were more out-of-window and missing time points. That may very well just be an artifact of the pandemic. We don't believe it actually affected the 48-week time point itself, but it might have been an aberrant reading on the 24-week scale. Louise, did I miss anything with respect to that? No, I think you captured it. All right. Thank you. Our next question comes from Gena Wang with Barclays. Your line is now open. Thank you for taking my questions. Just two quick ones. The first one, just wanted to ask if did you see higher protein level at the age four to five, compared to six to seven? Also, Doug, based on the current data or different data subgroup, is it fair to say, likely you will have to run a Study 301 in order to get approval? Based on the data we're seeing so far, what could be the study trial design you will have in mind? I remember in the past we discussed, we tried to minimize the North Star. I'm a little bit surprised to see even in the placebo arm, we saw 24- Yeah six to seven. Going forward for the Study 301, what could be the best design enrollment criteria to minimize the mistake or unfortunate the events we've seen so far? A couple of things on that. First, we got a lot more analytics to do, but on the face of it, there's nothing about protein levels that explains this. This result is explained entirely, at least based on what we know today, entirely by what you see in the six to seven-year-old baseline characteristics. The difference between those two groups impacted the active versus placebo for the six and seven-year-olds. When you add that to the entire group, you miss statistical significance. As it relates to the design of the next study, we're going to learn from this study and address it. There may be a number of ways in which we can address the next study to increase the probability of success even further. One of the things. Look, you're exactly right. The NSAA number for the placebo arm on the six to seven-year-olds, to use the colloquialism, is ridiculously high. It is in fact, at the very top of the ceiling for the entrance criterion. I will also say that ironically, when you look at the P value, we're struck by lightning. It is a 1/ 250 or 4/ 1,000 probability that that would have occurred. Indeed, it did. We are going to address that issue, and frankly, notwithstanding the fact that it is an extraordinarily improbable thing that might occur, we will ensure and find ways in the entrance criteria and the design of the next study that we address this issue so that we don't have that issue for the next study. Beyond that, I think on the face of it, that alone would drastically increase the probability of hitting statistical significance. We have other learnings inside of our Study 102 that's going to help us inform the next trial. Our next question comes from Anupam Rama with JPMorgan. Your line is now open. Hey, guys. Thanks so much for taking the question. Doug, just following up on your comments right now. I don't think you've ever disclosed the floor or ceiling on NSAA for this trial. You just said that it was basically at the ceiling for the six and seven-year-olds in the placebo. How close to that ceiling and in your next study, is it likely that you're going to decline that ceiling to maybe elicit a better treatment outcome? Well, it's ironic. Let me be defensive for a second and say that I don't think on the face of it was an issue with too wide a ceiling and floors. The reason I'll say that is because if you look at the four to five-year-olds, it worked brilliantly. In fact, those children had strikingly similar baseline characteristics, and they were, of course, subject to the same ceiling and floors as the six to sevens. It really was this crazy, improbable, best we know, we don't think there was any kind of inherent flaw in the randomization. There was just this very improbable randomization that occurred with one group at the very top of the ceiling and one at the floor. While we haven't, and I still will not provide the exact details of the floor and the ceiling for this call, I will tell you that you can backward engineer this because the placebo group in the six to sevens were right near the top of that ceiling. The active group was right at the floor of that NSAA floor for the criteria. With all that said, we're not going to simply say that was improbable, and we're not going to make changes, and we're just going to continue to forge forward. We will find a way through different kinds of stratification to ensure that we do not replicate this problem as frankly on the face of it, as improbable as it was. We are going to address these issues, though, that we are very, very confident in our next trial, the baseline characteristics will end up very similar between the treatment arms and the placebo arm. Our next question comes from Joel Beatty with Citi. Your line is now open. Hi, thanks for taking the question. It seems that there was lower dystrophin expression in this study compared to the previous study. Do you think that that's a real difference between studies or a difference in measurement techniques? Are you considering any differences in dosing in DMD or limb-girdle going forward? Thanks. A couple broad strokes on this. One, there were some changes in the way the measurements occurred, but we don't think on the face of it that played a material impact. One of the things that Dr. Rodino-Klapac did mention in her remarks was that the Nationwide Children's Hospital in their manufacturing process used a form of titering called qPCR. That titering does result in more lot-to-lot variability than what we currently use. We've come to a different titering process, much tighter, a linear titering process that has been applied not merely to our commercial process material, Study 103, but also to all of the children at crossover. We use linear titering. While, again, I will hearken back to my forward-looking statements and say it's dangerous to make predictions about the future, we do anticipate that we will likely see higher mean expression levels with the tighter titering range. Our next question comes from Ritu Baral with Cowen. Your line is now open. Hey, guys. Thanks for taking the question. When might we have the functional data from the crossover patients? Given that at least half of those placebo patients started off with really, really high baselines, what could you potentially show? I'm interested in any statistical analysis from baseline that might be robust enough to help you design 301. Do you need that before you start 301? Well, we don't need it before we start 301. I want to start with that. We don't need the crossover done before we start 301, and that wouldn't be our plan. We would have an analysis of all of the 41 patients, including all of the crossovers at the 48-week time point, which would really be essentially at the very end of this year, would be the analysis. While I don't want to predict in advance, and we've got a lot of work and thinking to do, we do have pre-specified analyses on all of the patients. That will be, in many regards, different than the approach that we took to the part one analysis because, of course, we're moving into a phase where all of these patients will now be on therapy, and so we have to use other measures. Some of those measures include the fact that many of these patients had significant run-in periods, and then we have trajectories. We will see, as opposed to simply looking at baseline characteristics versus post-therapy or placebo characteristics, we'll be looking at a trajectory analysis as well as natural history analysis, and there are a number of other analytics. I don't want to predict in advance that it will make a significantly meaningful difference, but there is a real possibility that this analysis may wholly or partially address the fundamental flaw that occurred in the randomization of the six to seven year olds. There is that possibility. That analysis will not occur until the 48-week time point for the last patient, so that'll be really at the end of this year. We're very clear about that. We are going to take a deep dive into Study 102. We're going to inform Study 301. We are not going to wait for that secondary analysis before we commence Study 301. Our next question comes from Vincent Chen with Bernstein. Your line is now open. Thanks for taking the question. I'm wondering, have you had the opportunity to assess what the expected change in the natural history would've been for the six to seven year olds in the placebo group? I guess, what the expected change in the natural history would've been for the six and seven year olds in the gene therapy group? If you have, I'm curious, what's it look like, and what's your best guess for what the effect size achieved would have looked like in the six to seven year old cohorts if you had been able to adjust for this? We're just in the beginnings of that analysis now, so I think everything that we could say right now would be fairly speculative. We do know on whole that six to seven-year-olds would have been beginning to be in some decline right now, some serious decline. In fact, given that these children on the active group were on the very severe end of what one would have expected for a six and seven-year-old, we're going to do a lot of patient-level looking at natural history. Our presumption is you'd see a significant decline in these patients. On the active therapy, you didn't see that among these patients. Again, we had that versus a comparator in very mild patients that didn't act consistent with the severe six and seven-year-olds. We're going to do all of that work. We would have expected, broadly speaking, even on the mean, we would have expected six and seven-year-olds to be in decline right now. Of course, the kids on therapy were not in any steep decline right now at all. They were very stable and, in fact, these kids were on the more severe end. Very likely, although we're going to look at the patient-level data on natural history to confirm this, we very likely have seen an even more significant decline in this group. Our next question comes from Matthew Harrison with Morgan Stanley. Your line is now open. Great. Good afternoon. Thanks for taking the question. I want to go back to the comment you guys made about the titering process. 30% dystrophin expression is a lot different than, I think it was 73% or 74% in the earlier studies. Can you just talk about your confidence that the material really is the same and that some of the issues might not have been material related? Thank you. Yeah. Well, first of all, I don't think that it was material related. Just so we're clear, this material was the same type of material from the same manufacturing process at Nationwide Children's Hospital. 101 and 102 that you've seen so far all came from the same process. As Louise will note, there's variability in the titering that Nationwide historically used, this qPCR process. We identified early that we needed to move to a very significantly tighter process, which we did, which we use for the commercial process material that we use, as well as even for the Nationwide material at the crossover patients, number one. Number two, I would remind us that, actually on the first four patients, and Louise, you're going to correct me when I get some of these numbers wrong, but I'll give them directionally. If you omit the fourth patient, which was a very high responder, you were sort of in the low 50%s for Western blot, I believe. We're sitting here, what is lower than those 50%s? We do believe that when we tighten up the titer, what we'll see out of Study 103 is something that's getting closer to what we saw before. Of course, we're going to wait and see that in the next couple of months. With all of that said, I do want to be clear, if you're looking for this as an explanation, really the explanation here is the differences in, the obvious one, is the differences in baseline characteristics. Unfortunately, we took in the six to seven-year-olds, just through randomization process, we took a very severe group of six to seven-year-olds that ought to have been in steep decline, and they got on active therapy, and we compare them to a very mild. These are just different populations. Every single solitary functional measure at baseline is significantly different and milder for the placebos than for the actives. Even the four stair climb, Louise noted that the four stair climb didn't hit statistical significance. If I'm not mistaken, it was 0.09, and it was nearly statistically significant, even in the four stair climb. Those kids in the severe group that were on active in the six to sevens, given that four stair climb, one of the things we already know is that the slowness of that stair climb is correlated with a significant loss in the six-minute walk test and then in ambulation. I think that you can look at this statistically and say that six and seven-year-old imbalance appears on its face to explain why we wouldn't hit overall statistical significance. That imbalance is unbelievably surprising. I do want to linger for a moment on the fact that in the four to five-year-olds, which was only 16 children, they were well-matched, very well-matched. I mean, very pleased to see that the randomization process worked there. We saw a very significant delta across all of the time points between the placebo children and the active children. Even at 16 participants, we saw very robust statistical significance, 0.017, below 0.02 on statistical significance and a very significant difference. I think it was about 4.3 NSAA points versus baseline. We're going to do a lot more thinking on this. We've got a lot more analysis to do. We're going to do everything we can to greatly increase the probability that this therapy that we're very confident about shows itself in the next study statistically. We're very pleased to see that in the four to five-year-olds and do believe that if we get the balance right, that we're going to see a very positive next study. Our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is now open. Hi, guys. Good afternoon. Thanks for taking my question. I don't know if this is best for Doug or maybe for Louise, understanding everything that you've said about natural history progression, I'm just wondering, just based on the data that you've seen so far, your thoughts about whether the use of microdystrophin might just end up being better for younger cohorts, that the older you go in the age group, it's more important to have a full-length dystrophin presence. I'd like to hear your thoughts on that. Thanks. Yeah, I'll touch on it briefly, and then Dr. Rodino-Klapac can provide some comment on that. When you first looked at the data, you might wonder about that because you see the four to five-year-olds that look like they're performing very well versus the placebo versus the six and seven-year-olds, even though on the face of it really makes no mechanism of action-related sense that a four to five-year-old would benefit from this truncated dystrophin that a six to seven-year-old would not. At least from our perspective, this puzzle is resolved almost immediately as soon as you look at the baseline characteristics. I think Occam's razor would say, more likely than not, if you want to understand why these two groups act differently than one another versus their respective placebo arms, you look at the baseline characteristics and realize that you literally with the six and the six to seven-year-olds literally compared different patient populations. To use a metaphor, it would be like we had looked at a five-year-old versus a nine-year-old with Duchenne. Nobody would imagine that that would have been a successful approach. That, in a sense, through random bad luck, really, that's what we did. We took kids that had more than four points, almost five points or so in delta between them on NSAA, on mean, and compared them to one another. Unfortunately, not surprisingly, we didn't see a statistically significant difference between those groups. I think more likely than anything else, that explains why we're seeing such a stark difference in the performance of kids that are four to five and six to seven. Louise, perhaps you can provide additional color on this, or if you disagree with me, certainly do that. No, all I'll add is that the mechanism of action of microdystrophin, there's nothing that's specific about four to five-year-olds versus six to seven in terms of the way microdystrophin would act. It's what you predicted on its function. The sevens, we have more data coming, and I think this is something that obviously, the baseline characteristics influence it significantly, but we may see over time play out in six to sevens well as the crossover. The data that we'll be collecting will be important to inform this group. As far as mechanisms, there's no difference in terms of age. Our next question comes from Colin Bristow with UBS. Your line is now open. Hey, thanks for taking the questions. To piggyback off a couple that have already been asked, for patients that were dosed early in the trial, is there anything you can share about the NSAA trends you're seeing beyond the 48 weeks? I think this was asked, I didn't hear a response. The difference in expression, if any, between the four and five-year-olds and the six to seven-year-old groups. I just wondered, as you look to phase III or maybe even reconsenting current patients, is there any value at looking at the biopsies at a later time point just to get sort of greater insight into expression turnover, like at how ultimately this correlates with efficacy? Would you consider this in phase III? That's it. Thanks. On the last point, I will note that with respect to our current trial, we don't have to reconsent the patients, thankfully, because the study remains blinded, and we will have additional biopsies in that study. With that, Louise, do you have any comments on some of those questions? I think to your point, we do not have any functional measurements beyond 48 weeks at this time. We're certainly looking, but we're doing additional analysis. At this time, there's no indication that protein impact is the results or differences that we saw between the age groups. Our next question comes from Debjit Chattopadhyay with Guggenheim. Your line is now open. Hi. Thanks for taking my questions. This is Aaron Welch on for Debjit. Maybe I missed this earlier, was the change in NSAA scores from baseline in the six to seven-year-old patients, was that reported? Is it possible to only enroll four to five-year-olds in Study 301? Thanks. I'll let Louise answer the first question. The second question is, we certainly could create a study that was narrowly focused only on four to five-year-olds. We are still doing more work on this. I suspect that will not be the conclusion that we come to, and that, in fact, if we are correct in our analysis that the imbalance in the six to seven-year-olds explains why they were able to hit stat sig, then we can address that issue directly and still enroll that patient population. They should. If the results we've seen so far, both in the four to fives and the preclinical and the 101 all bear out, they should certainly benefit in the same way that the four and five-year-olds do from this therapy. We frankly think they are today. They're all benefiting from it. Louise? Yeah. In the six to seven-year-old group, they're essentially stable with only a 0.4-point decline. As we mentioned, we would expect in this age group, especially with the severe or low baseline scores to see a significant decline. Our next question comes from Brian Skorney with Baird. Hey, good afternoon. Thanks for taking the questions. Maybe just trying to contextualize a little bit, in terms of the differences and tying that to any differences you're seeing in the safety profile. When I look at the percent positive fibers, that almost looks even more disparate. I think it was 81% in the phase I versus 33% here. It's only a third of the muscle fibers are actually showing dystrophin expression and similar big differences in vector copy number. Just a straightforward question is, what are sort of the immunological markers that you're monitoring? I mean, the two cases of rhabdo, is there any association with complement activation at all? Is there anything in terms of immunological markers that would indicate that you're seeing lower expression because the immune systems are responding to this more aggressively? No, as we've said, Brian, we have seen no clinical complement continuing. One of the things, again, I would say is, we do a different, I'll let Dr. Rodino-Klapac explain it. We did do a different, more automated approach to PDPF, she can talk to that a bit. I'd say with respect to the Western blots, we're seeing, excluding the patient in 101, 28%-53% or so. We do expect that when we evaluate the 103 data with a much more predictable and tighter titer, that we will see something that's going to start looking more like the data that we saw out of 101. Dr. Rodino-Klapac, do you want to comment on this? Just on the PDPF assay, we're using an automated method, but we did do studies and the two methods are concordant in terms of expression. Like Doug said, we would expect on all measures, not just the Western blot, that in future studies that we would expect to see higher numbers with the tighter titering method in the future studies. We did see very high intensity as well. I would note we saw, I think about 60% on intensity. Our next question comes from Danielle Brill with Raymond James. Your line is now open. Hi, guys. Thanks for the question. I guess, Doug, I'm curious if there was a specific reason why you didn't stratify by NSAA scores at baseline, and then I might have missed this, but did you see any correlation with mean dystrophin expression and NSAA scores? Thanks. Yeah. To the best of our knowledge right now, no to the second question. On the first question, we did a lot to keep this study tight, frankly. We had a ceiling and a floor. We had frankly done a number of things in advance that we got right. I mean, we had identified what I think so many people hadn't in the literature, hadn't fully identified before, which is that four to five-year-olds and six to seven-year-olds act differently, and we stratified on that basis. We did try to tighten up NSAAs between putting a ceiling and a floor in. I do, again, I'm getting very close to being defensive about this, and I apologize. Let me say that it works. With respect to the four to five-year-olds, it works, and that's why I think you see a nice balance. It didn't work in the six to seven. I wish we had done something different. I will note that the probability that what we got would happen randomly was 4/ 1,000. I mean, it should not have occurred. It was, in a very real sense, very bad luck. Very significant bad luck. With that said, we're not going to allow it to occur again, and we're going to address this issue and find a way to ensure that this doesn't occur, even though frankly, statistically it ought not to occur another time. Doug, could I just add, just with regards to the question about multiple strata, we actually considered a number of stratification approaches. We even considered using two strata. Owing to the size of the study, realized that that was just not feasible, going to the patient numbers, and would actually make running the study extraordinarily challenging. We actually then also looked at age versus NSAA as the stratum, and for the reasons that Doug and Louise have outlined in their previous answers and Louise's presentation, determined that age as an overall surrogate, it was the better stratum at where we had to choose a single stratum for randomization. Our next question comes from the line of Hartaj Singh with Oppenheimer. Your line is now open. Great. Thank you for the questions. I echo Alethia's comment, it's tough day at the DMD patients today. I just wanted to ask a question on safety. You've mentioned that you got four SAEs in the treatment group, one in the placebo. Can you please let us know which ones are related to study drug, if any were, and whether they're probable or likely related to study drug of those four? Why did you get so much vomiting? I mean, it's almost three times as much in the treatment group versus the placebo. Thank you. Dr. Rodino-Klapac? I'm going to answer the question about vomiting. We saw this in 101 as well as our limb-girdle trial. This is not atypical of gene therapy trials. I've seen in others. This is not unexpected as far as finding. I did miss you broke up in the first question. I don't know if, Doug, did you hear more if you heard the first part of the question? I wonder if we have a view on Hy's law with respect to the SAE. Well, I think I actually asked if there was a relatedness to treatment. Were the SAEs related to treatment? Okay. Sorry. I don't know. Yeah, I apologize. Just if the SAEs were related to a study drug, of those fours, which one were related, and how likely were they related? Thank you. These were as related. The rhabdo is obviously a potential side effect from muscle indication for DMD, so it was not unexpected. There were two in the treated and one in the placebo arm. The transaminase elevations, again, were expected from previous trials, and so those were designated as related. Our next question comes from the line of Difei Yang with Mizuho Securities. Your line is now open. Hi, good afternoon, thanks for taking our questions. Just two quick ones. Number one is that is there an option left to use the new method to analyze those four patients, Study 101 patient sample, so that we can compare the expression data apple to apple? Number two is that would you have an opportunity to talk to the FDA before starting Studies 301? Two things. One, there's no reason to believe that the methods between the two approaches are substantially different and that there's no reanalysis of Study 101 that would render a different result. Study 101 remains very accurate in its expression. We certainly will be talking to the division before we commence Study 301. We'll do a couple of things with respect to Study 301. We're going to take all of the learning from 102. We're going to think about the results from 102 to enhance the probability for Study 301. We can get that done very rapidly. That'll all go into our thinking for Study 301. Of course, we will meet with the division and talk to the division before we commence Study 301. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open. Good afternoon. Thanks for taking my question. Just following up on Anupam's question here. Could you narrow the target NSAA range for the older group versus the younger group, just given the slope of decline? The older group and the younger group had the same ceiling and floor entrance criteria for NSAA. We will do additional work on looking at the natural history to get a better view on how aggressively, for instance, we would expect the patient populations in the six to sevens would've trajected both on the placebo with the much higher NSAA scores and the active group with a much lower and more severe NSAA scores. Our next question comes from the line of Joseph Schwartz with SVB Leerink. Your line is now open. Hi, thanks. I was wondering, have you looked to see whether the less severe six to seven-year-old patients within the SRP-9001 arm performed better on NSAA than those who were more severe, or that the more severe six to seven-year-old patients treated within the placebo arm performed worse than those who were less severe, just to confirm your hypothesis that the baseline NSAA levels are so predictive? Are there any analyses like this that you can do to substantiate the hypothesis that an imbalance in disease severity amongst the older patients caused this aberration? Dr. Rodino-Klapac? Yeah, we'll certainly be doing additional sensitivity analyses. I will mention that we're going to have a low end when you start to look at these things. We'll have to be very careful about the conclusions that we draw from that. Certainly, we are looking at the data from every angle possible. The additional data that we get from Part 2 will also be informative as well. Our next question comes from the line of Tim Lugo with William Blair. Your line is now open. Thanks for taking the question. Could you include another biopsy at the end of Part 2 for some more expression data which may be informative? You also showed time course data for NSAA, but was there anything positive to glean out of the time course data from the four steps to stand or time to rise or 10-m secondary endpoints? Dr. Rodino-Klapac, do you have a view on any of that? On the biopsy, we are taking a biopsy in Part 2 of the study. I don't know if you were asking for an additional biopsy, right now there's a biopsy at 12 weeks post Part 2. As far as the other secondary measures, we're not providing additional data at that time point. We're still going through that, the study is still blinded, we'll continue to look at all of those endpoints and follow up in the future at a medical meeting. Our next question comes from the line of Gil Blum with Needham. Your line is now open. Hello. Thank you for taking our question. Maybe a bit of a naive question. It seems like the patients on the placebo trended upwards on NSAA over time. Is this normal in either age group? Yeah, it would be normal in the four to five-year-olds. You see just about what we saw in this trial in the four to five-year-olds. You could see a modest increase in NSAA over that course. One of the things we had often talked about as we designed the trial, so if you look at the literature, you will often see four to seven-year-olds treated very similar. One of the things that we noted and made a point of discussing was that actually, there's a difference. The four to five-year-olds can benefit about a point or so, and that's about what we saw over the course of this trial. The six to sevens will start declining. What we saw in this trial was the four to five-year-olds acted as we would have anticipated. The six to sevens in the placebo group were very mild relative to what we would have expected. We didn't see that decline, of course. Unfortunately, the actives were very aggressive. What we would have thought we would see in natural history is that they would aggressively decline. We didn't see that either, of course, and we think that's because they're on therapy, and they're benefiting from the therapy just like the four to five-year-olds are. We're going to have to do, obviously, more work on that and help inform Study 301. That concludes today's question and answer session. I'd like to turn the call back to Doug Ingram for closing remarks. Thank you all very much for joining us today. I want to thank as well our participants in Study 102 and their families for their willingness to play a significant role in advancing this therapy. I'm not going to hide from the fact that I'm disappointed that we did not hit statistical significance in our primary efficacy endpoint. I am nevertheless both frustrated but also pleased, ironically, that it does appear, at least on the face of it, that an imbalance in the six to seven-year-olds explains this, and that when we adjust for that as the four to five-year-olds did, because they naturally had a better balance between the two, we see in this therapy what we would have anticipated, a therapy that brings a transformative benefit to patients with Duchenne muscular dystrophy. We're also very pleased that we not only saw good expression, and we actually think we'll see even better expression with the better titering that we have and the tighter titering. We saw good expression. We've got obviously good genome copies per nucleus, and we saw a statistically significant benefit on CK as well. We're going to take all of this data and all of these learnings, and we're going to prepare our next study, Study 301, on that basis to enhance the probability of success of that study and continue to move with a sense of urgency to bringing this therapy to patients waiting around the world, as we are convinced that SRP-9001 will play a transformative role in the treatment of Duchenne muscular dystrophy. As we track across this year, there will be a number of moments with additional readouts. We'll have a readout on Study 103, which will provide data both on expression as well as other biomarkers and safety. Of course, in the back half of this year or into early next year, we'll have actually the part two readout of Study 102, and we'll commence Study 301 this year. Thank you all very much for this. Thanks for spending time with us this evening, and we'll continue to update as we progress throughout 2021. Ladies and gentlemen, this concludes today's conference call. 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