Good morning and welcome to the Sarepta Therapeutics conference call and webcast for the clinical update results from the 30 mg/kg cohort of the MOMENTUM study of SRP-5051 for Duchenne muscular dystrophy. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you either press star one on your telephone. If you require any further assistance, please press star then zero. As a reminder, today's program is being recorded. At this time, I will turn the call over to Doug Ingram, President and CEO, for opening remarks. Thank you all for joining us today for our review of what is a very important program to Sarepta, and more important still, to the Duchenne patients that we serve. What you will hear today from our head of R&D, Dr. Gilmore O'Neill, is that we have seen a very significant dose response with our 30 mg/kg cohort for SRP-5051, that we believe we have found the optimal dose to discuss with the agency moving to what we hope to be a pivotal trial for our program, and that if successful, SRP-5051 could offer a step order improvement in the treatment of Duchenne muscular dystrophy in terms of both efficacy and convenience. We will be making some forward-looking statements today. Of course, please refer to our public filings for the various cautions and risks that are attendant when one makes predictions about the future. With no more delay, let me turn the presentation over to Dr. O'Neill, who will present the results. Gilmore. Thank you, Doug. Good morning, everyone. It's a pleasure to be here with everyone today to share the results from the 30 mg/kg arm of MOMENTUM, our multi-ascending dose study of our lead PPMO program, SRP-5051. Today's results suggest that we are far along in our objective of advancing a next generation PMO that demonstrates significantly higher potency with more convenient once per month dosing. As you are well aware, Duchenne muscular dystrophy is a rare, X-linked, recessive, degenerative neuromuscular disease which almost always affects young boys. It is caused by the absence of dystrophin protein and causes patients to die in their mid to late 20s. Sarepta's PMO platform uses a phosphorodiamidate morpholino backbone chemistry that precisely targets a specific sequence of a pre-messenger RNA that enables the translation of an internally truncated, yet functional dystrophin protein. Sarepta is currently serving the Duchenne community with three approved products born of our PMO platform. EXONDYS 51 for patients amenable to skipping exon 51, VYONDYS 53 for patients amenable to skipping exon 53, and the recently approved AMONDYS 45 for patients amenable to skipping exon 45. All three of these drugs have consistently shown increased exon skipping and dystrophin production in patients. Now, our approved PMO therapies have been among the most significant advancements to date in the treatment of DMD and are the current standard of care for the Duchenne mutations they address. In addition to the data on which we obtained the approval of PMOs, subsequently generated evidence has continued to bolster the importance and impact of our PMO technology, including the work of independent investigators looking into the correlations of dystrophin production and functional benefits. Indeed, a paper published just two months ago using the French human UMD-DMD database to correlate genotype, muscle biopsy dystrophin expression, and clinical phenotype confirmed that even very small amounts of truncated dystrophin, under 1% of normal, is correlated with a delay in loss of ambulation, a delay in decline in pulmonary function, and reduction in necessary spinal surgery. This is additional support for our current PMO platform. That study, I emphasize, also found that at 5% and above, the benefits become profoundly greater still, with significant delays in loss of critical functional milestones for Duchenne patients. Now, despite the success of our PMO platform, we have identified that if we can improve tissue targeting, we could enhance the potency, exon skipping, and dystrophin production of our platform, perhaps even achieving or exceeding the 5% or greater standard I just referenced. If so, we would have an immensely more beneficial next generation PMO to treat the DMD population. The goal of our PPMO program has been to engineer a next generation PMO that will greatly enhance dystrophin production and do so with far more convenient dosing. To do this, we have conjugated to our PMO a positively charged cell-penetrating peptide. The addition of the peptide should increase cellular uptake, and if we can safely drive more drug into the cell, we will see greater exon skipping and greater dystrophin production, which is exactly what we've already observed in the results from the 20 mg/kg once per month cohort of the MOMENTUM study that were shared in December of last year. Increase of levels of tissue exposure, increased exon skipping, and increased dystrophin in half the time with fewer doses and 10 times less cumulative drug exposure than with the PMO. This is no small feat, as we and many others have tried approaches to increase cellular penetration that have been hampered by dose-limiting toxicity. Now, the results I will now share demonstrate that our PPMO is extremely potent, induces dystrophin production much more rapidly, much more robustly, and at much lower exposures than our PMO platform, and that it does this with significantly greater dosing convenience than our PMOs. By way of reminder, there are two parts to the MOMENTUM study. Part A is a multi-ascending dose study to evaluate the safety and tolerability of SRP-5051 in patients with Duchenne. SRP-5051 is administered by intravenous infusion once per month. The goal of the study was to safely increase dose levels with each dose cohort enrolling three to six patients until we determined that we identified the appropriate dose to bring forward to pivotal trial. MOMENTUM recruited both ambulatory and non-ambulatory patients between seven and 21 years of age with a confirmed DMD mutation amenable to exon 51 skipping. Muscle biopsies were specified to occur up to 10 days after the week 12 dose of SRP-5051. Once the appropriate dose has been identified in part A, part B of MOMENTUM is designed to evaluate SRP-5051 in what we hope to be the pivotal trial and would include patients who complete part A and an additional cohort of patients. Today, we will report on the 30 mg/kg dose cohort from the MOMENTUM study, sharing the primary outcome measures of safety, plus measurements and change from baseline at week 12 for exon skipping, as measured by digital droplet polymerase chain reaction or ddPCR, and dystrophin expression as measured by Western blot. What you will hear from me later is that with the 30 mg/kg data, we have now determined our target dose to bring forward to our pivotal trial. To help contextualize the data, we will compare our results with the PPMO with a control group of Duchenne patients selected from the PROMOVI study, who each received eteplirsen at a dose of 30 mg/kg once per week for 25 doses prior to muscle biopsy at 24 weeks. To that end, we have re-assayed all of the eteplirsen sample materials using the same methodology for ddPCR and dystrophin measurements as for our PPMO. Recall that we are looking at PPMO 30 mg/kg cohort results at the earliest possible opportunity after only three doses and at 12 weeks. There were four patients in the 30 mg/kg cohort in MOMENTUM for whom we have muscle biopsies at the week 12 follow-up time point. Here you can see the baseline characteristics. Three of the patients were in their late teens and non-ambulatory, and one patient was seven years old at the time of treatment. It is important to note that due to COVID-imposed delays, patient one actually received five doses of SRP-5051 before he was biopsied, while the others received their biopsy after three doses. I will comment on patient one later in this presentation, as he has provided us with very interesting confirmation of our hypothesis about time-dependent accumulation of dystrophin. Now to the data. The 30 mg/kg cohort showed a significant dose-dependent increase in exon skipping. SRP-5051 dosed monthly at 30 mg/kg, represented by the purple bars on the right of the graph, achieved approximately 11% mean exon skipping at week 12. Compared to the PPMO 20 mg/kg dose, we observed a greater than four-fold dose-dependent increase in exon skipping at only a 50% increase in dose, indicating that we have hit the predicted steep part of the dose response curve. Versus the current standard of care, eteplirsen, revealed in gold on the left, we observed an 18 times increase, so 18-fold increase in exon skipping. Was this increase in exon skipping result associated with a commensurate increase in dystrophin protein? The answer is yes, it was. After 12 weeks and after a median of only three doses, the 30 mg/kg dose of SRP-5051, represented by the purple bars at the right again, resulted in over 6.5% mean dystrophin protein expression as measured by Western blot. Dystrophin builds over time, but even at the early 12-week time frame, this represents a greater than 100% increase in expression versus the 20 mg/kg cohort, represented by the purple bars in the middle. This represents a greater than 800% increase in dystrophin expression compared to our currently approved therapy, eteplirsen, represented by the gold bars on the left. The results with SRP-5051 at a monthly dose of 30 mg/kg suggest we are resoundingly successful in achieving our goal of developing a far more potent next generation PMO with the ability to significantly increase dystrophin production with a much more convenient dosing schedule. As we have said, in part A of MOMENTUM, we look for dystrophin at an unprecedentedly early time point. The evidence is clear that dystrophin accumulates over time, so that we will see accumulating and greater dystrophin as we extend chronic dosing. This slide shows the supporting evidence from our 96-week PROMOVI study of eteplirsen. There is a time-dependent increase in exon skipping, shown on the left, and a time-dependent increase in dystrophin expression seen on the right. This next slide provides the predictive model for dystrophin production over time. Our model for dystrophin accumulation uses several assumptions, including a known coverage turnover of dystrophin in the muscle. Based on our modeling, SRP-5051 at 30 mg/kg should comfortably achieve greater than 10% dystrophin with once per month dosing. We already have a strong signal supporting this production on this model. As I mentioned earlier, patient one received five doses over 19 weeks due to COVID-imposed delays connected to his biopsy timing. Consistent with our modeling, patient one has the highest level of accumulation of dystrophin at over 12% dystrophin after only five doses. One might ask whether patient one is just a super responder. This does not appear to be the case. First, three of the four patients share a similar exon mutation, and patient one is one of those three, so his mutation is not dissimilar to the other patients. Second, very interestingly, remember that exon skipping occurs more rapidly than dystrophin accumulation, and the exon skipping for patient one is equivalent to the exon skipping of the rest of the cohort. Thus, from a tissue concentration and exon skipping perspective, this patient is not an outlier. The one variable that is different is that unlike the other three patients, he was on the therapy longer, received two additional doses, and had more time to accumulate dystrophin. Now let's move to safety. Here, you can see the safety experience across all study doses of MOMENTUM. You will appreciate that we saw treatment emergent adverse events in all patients in the 30 mg/kg cohort. We observed three serious treatment emergent adverse events in the highest dose cohort of 30 mg/kg. These are described in more detail in the next slide, where you will see that there were three events in two patients classified as serious treatment-related adverse events. Two cases of reduced magnesium or hypomagnesemia, and one case of reduced potassium or hypokalemia. The events were not symptomatic and all resolved with supplementation. Review of the non-clinical kidney biomarker data, serum and urine, indicates that the hypomagnesemia appears transient, reversible, not correlated with changes in renal function, and is manageable by magnesium supplementation. The cases all rapidly improved with magnesium supplementation. Our primary working hypothesis is that as infusion, the PMO may interfere with the magnesium transporter, causing a decrease in magnesium after infusion. Markers of kidney function have generally been normal and have not shown any consistent relationship to the hypomagnesemia. In addition to our analysis, we have consulted with external expertise and believe that serum monitoring of magnesium and oral supplementation with magnesium is a feasible approach to enable early detection and management going forward. In summary, SRP-5051 dosed once per month at 30 mg/kg delivers profound and clinically meaningful levels of dystrophin that represent a significant improvement in potency over our marketed first generation PMO medicine, and with a positive benefit-risk profile. SRP-5051 achieved that increased potency with more convenient and less burdensome once per month dosing. Our modeling predicts that dystrophin production of greater than 10% expression will be achieved with monthly chronic dosing of SRP-5051. Finally, 5% is a typically stated bar for profound improvement. At over 10%, we are confident the expression driven by SRP-5051 will deliver clinically better changes in patient outcome. What are the next steps for this program? The purpose of Part A was to optimize efficacy, evaluate dose-limiting toxicity, and determine the dose to bring forward into a pivotal trial. After an enormous amount of work, we have identified our dose to take forward into Part B of MOMENTUM. Our next step is to meet with the FDA Division of Neurology to discuss the results of Part A and discuss the commencement of Part B of MOMENTUM. Subject to discussions with the FDA, our goal will be that Part B is a pivotal trial supporting an accelerated approval in the U.S. Having engaged with international regulatory agencies on Duchenne several times in the last two years, we are equally confident that these data will serve as the foundation for our global registration package in target regions outside of the U.S. as well. As always, learning from the clinical studies of SRP-5051 will help inform the development of future PMOs for other exons in Duchenne and in other indications. In closing, the results today bolster our confidence that SRP-5051 has the potential to profoundly affect the course of disease progression in Duchenne. On behalf of everyone at Sarepta, I want to thank all the patients, their families, and clinicians who participate in these trials and continue to participate in all of our studies. With that, I would turn the call back over to Doug for Q&A. Doug? Yes. Thank you, Dr. O'Neill. Operator, let's open the line for questions. Ladies and gentlemen, if you have a question or a comment at this time, please press the star, then the one key on your touchtone telephone. If your question has been answered and you wish to remove yourself from the queue, please press the pound key. We also ask that you limit yourself to one question. Our first question comes from Alethia Young with Cantor Fitzgerald. Hey, guys. Thanks for taking my question and congrats on all the progress. I guess I just wanted to talk a little bit about your confidence interval and finding that the 30 mg is the best dose based on the risk-benefit profile that you're seeing here as well. Thanks. Yeah, sure. Basically to not dose higher, basically. Yeah, that's a great question. I guess the question is, why are we so excited about 30 mg? The short answer is because the results are so profound right now. Let's think about it. There's three things to think about with respect to where we are. We have spent a lot of time. There's no doubt that a single ascending dose that moved to a multi-ascending dose trial, it's been a lengthy trial to find the right dose that we can bring forward. What we've seen right now, let's start, there's sort of three things. There's benefit, risk, and time. On the benefit side of things, we now have a therapy that, at least in this cohort of patients, leads us to the following conclusions. Versus the standard of care today, we see 18 times better exon skipping. We see over a 400% increase in dystrophin production. We're doing that in an unprecedentedly short period of time, 12 weeks. I think there would have been a time when people would have thought we were crazy to be even looking for dystrophin this early. We see that with only 12% of the dose exposure, on median, only one kid was five doses, but for most of the kids, it was only after three doses at once per month. From a benefit perspective, if confirmed in our next trial, suggests we have a profoundly improved therapy over our current RNA therapy, which was exactly the goal. Let's think about what would happen if we continued to dose up. If we decided we wanted to move further up, and maybe the next one we could potentially go to would be 40 mg/kg. We've shown this in prior slides, so it's not here, but you can look at our prior presentations to see that at least the non-human primate data predicted the following. It predicted, and thankfully it's borne out here, that when you move from 20 mg to 30 mg, you see the steep part of the dose response curve. Lo and behold, when we moved to 30 mg/kg, we saw that here with an 18 times increase in exon skipping between as we move up and a significantly greater exon skipping than we saw with the 20 mg/kg. If you kept going up, if we tried to push the dose up to 40 mg/kg, our current data suggests that you wouldn't get much more from a benefit perspective. From 30 to 40 mg/kg, it actually starts to flatten out. If you kept pushing up and up and up, and you got up to, let's say, 60 mg/kg, you doubled where we are today. Theoretically, you could get a significant increase in dystrophin production yet again. The problem with that is the next two issues. One, of course, we have risk, which is the goal here is constantly to find the right risk-benefit along the way, and there is no obvious reason to be extremely confident that you could keep pushing and pushing and pushing till you double yet again the dose. Then, of course, the second big thing in all that is it would take a very long time. As we sit here today, don't imagine for a moment that it doesn't mean that later we might consider as yet another line extension or additional work looking at dosing yet again. For purposes of this program right now and trying to get going for these patients, we're very confident that the 30 mg/kg, if confirmed in the next trial to get the kind of efficacy and to be safe as we have seen it here, the 30 mg/kg will be a significant improvement over our current RNA technology. We're confident we have the right dose. We want to get in front of the FDA. We want to talk about the FDA, about starting Part B. Part B of that trial, if the FDA concurs with us, would be built so that it could be the pivotal trial. In the United States, it could be the basis for an accelerated approval. At least that has been the pathway for dystrophin-producing therapy like EXONDYS and AMONDYS and VYONDYS. We are at least confident we will have a very good discussion with the FDA around that. Separately, I should note, we're going to take the results from our 30 mg/kg. We're going to start talking to ministries of health around the world, outside of the United States, about the development pathway to bring the PPMO, if successful, to other parts of the world as well. As everyone will know, the PMO was approved in the United States with this accelerated approval pathway, which makes it difficult to get additional approvals outside of the United States in advance of the confirmation of our post-marketing commitments on those PMOs. With the profound effect that we're seeing in the therapy right now and the speed with which dystrophin is produced with the PPMO, at least in the cohorts that we've looked at, I think we have a real shot at talking to regulatory agencies outside of the United States about hopefully a very speedy pathway from a development perspective to get approvals outside the U.S. as well if the therapy is successful. Awesome. Thank you. Congrats on the progress. Thank you. The next question comes from Difei Yang with Mizuho Securities. Hi, good morning, and thanks for taking my question. Just a quick one with regards to the magnesium supplements. Would you let us know what's the dose used there, and as well as should we be expecting additional biopsy data on the 30 mg at a later time? I'll briefly answer, then I'll turn it to Dr. O'Neill. The grade 4 hypomagnesemia that we saw was at the 30 mg/kg. I think as Dr. O'Neill suggested, our working hypothesis relates to the transport, the magnesium transport. It appears to be transient. It appears to be resolvable with the intervention of magnesium supplementation, and doesn't appear to correlate with any kind of change in kidney function. We will see, of course, we'll see additional biopsies, but that'll be in Part B. If we're successful with our discussions with the FDA, we'll commence a Part B of the trial, which would be these children plus additional children, and then we build that out in the hope of seeing, just discuss a number of things with the agency, obviously. Do you agree with our approach to Part B? What are the number of patients that we would need? What's the length of time we should follow them? What would be the appropriate biopsy time? Could this be a pivotal trial that would, if successful, lead to an accelerated approval? As part of that, of course, we would see biopsy data because that is an accelerated approval. That's what it would be founded upon. Dr. O'Neill, have I missed anything there? Any additional color on that? No, I think the only other part of the question was that the usual supplementation is about 300-600 mg per day. There are a number of formulations, slow-release tablets, chewables, and liquids, such as Milk of Magnesia. There are a variety of ways of doing it orally, and that is the dose, 300-600 mg per day. Apologies, I misunderstood the question. Thank you. Thank you. Our next question comes from Ritu Baral with Cowen. Hey, guys. Thanks for taking my question. Doug, can you, Doug and Gilmore, can you go through, I guess, what the dosing paradigm was such that we know that this transporter issue on the magnesium is reversible? At any point, did any of these patients skip a weekly dose? Have you been able to go back into non-human primates and just confirm that the transporter dysfunction is reversible in absence of drug? Do you think this is something that you'll have to go back and do in non-human primates concurrent with. Yeah Part B? Let me give a little color on it, then I'll turn it over to Dr. O'Neill to add additional color. First of all, I want to be very clear. I want to be fair. The magnesium transporter is our lead hypothesis right now. We need to do additional work on that. What we do know is that beyond and this here is the issue, like effect on function and the lack. Let me answer on the accumulation of hypomagnesemia after intervening with magnesium. In In addition, it does go back down rapidly in a patient on hypomagnesemia. But Dr. O'Neill, though perhaps you have some additional color on that. Sorry, Doug, you broke up on my line. I'm not sure if you broke up on others' lines. Okay just to add to that, the disruption of the transporter is our leading hypothesis. We are initiating a number of evaluations and experiments of that. I'm not sure if Doug already said this. Forgive me if I couldn't hear what he said. We did look at our non-clinical tox species, and the non-human primates in particular, and found hypomagnesemia there. Very importantly, this was not associated with the exposures that we are using here with any adverse pathological findings on the histology of the kidneys. I think Doug already said supplementation rapidly solves this for the subjects with hypomagnesemia. Oh, goodness gracious. Okay. Let me just now I understand I completely broke up, I will now bore everybody by repeating what I think Dr. O'Neill just said to make sure we're on the same page. To read it through the explicit question, the hypomagnesemia does not build over time, number one. Number two, it resolves with the intervention of magnesium supplementation. It does that very rapidly back to either baseline or grade one. I think that answers all of the questions, and I think Dr. O'Neill provided additional color on the non-human primate. One of the things I want to clarify, it's once-a-month dosing, not once-weekly dosing. I just want to make sure everybody understands that. I think I heard, Ritu, I'm not sure if you actually said once a week. It's once-a-month dosing. Forgive me for being picky this early in the morning. All right. Thank you. Your next question comes from Brian Skorney with Baird. Hey, good morning, everyone. Thanks for taking the questions and congrats on some good expression data. I guess I'm just wondering from a regulatory perspective, we've all sort of followed the controversy around the eteplirsen approval, and I think we can all say this looks like a much, much more potent, better expressor than eteplirsen. It sort of begs the question in terms of a regulatory and pivotal study, why not just do a head-to-head against eteplirsen? I mean, it is standard of care in exon 51 amenable patients. You could do a rapidly enrolling one-year study based on six-minute walk and it sort of, if it turns up positive, sort of resolves any of the outstanding concerns around PPMO and trial design here. Thanks. Yeah, we don't have the trial design obviously locked for the simple reason that we have to meet with the division and talk to the division. I will say, I mean, the neuro division has been a very responsive group. I think we are confident that we'll have a good, robust discussion with them about things like protocol. The idea of a head-to-head is an interesting one. It's certainly one the team's talked about. I don't know if we'll end up landing on that or not. We have two goals. I mean, our goal in the United States is to divine for ourselves and with the support of the division and the concurrence of the division, a pathway that is robust but as rapid as possible to confirm the benefits of this therapy and get it approved in the United States. If the division agrees with us to do that on an accelerated approval pathway. At the same time build a program that gives us the greatest opportunity also of getting approvals outside of the United States, either full approvals or conditional approvals, for instance, at EMA. We'll consider all of those issues. There are a lot of interesting elements to that that we'll need to discuss with the division. As an example, what is the timing of this trial. It's very interestingly, it is clear from the data, it would have been a fool's errand for us to look at eteplirsen at 12 weeks and imagine that we would see something meaningful. Dystrophin has to build over a fairly significant period of time. For those who may recall, eteplirsen built literally over one year and then built more from one year to four years. Dystrophin builds slowly over time. Here we can actually see robust dystrophin expression at only 12 weeks. On the other hand, we also have to have safety data, and of course, we have to talk to the agency about what's the right time to look for dystrophin, what's the right safety follow-up for the therapy, and what are the number of patients that the agency would be comfortable with, both from an efficacy perspective and a safety perspective. Some of the nuances about that protocol that you've raised are things that we're going to ponder and then discuss with the division. All of which is to say, the very important next step for us is to meet with the neuro division and discuss the data, discuss the plans for part B, and get their concurrence. In that regard, I will say, this division has been very responsive. I feel like we have a good shot at having a very good discussion with them and one of a timely one as well. Thank you. Our next question comes from Brian Abrahams with RBC Capital Markets. Hi, this is Steve on for Brian. Thanks for taking our questions and congrats on the progress. Data from the 10-mg and 20-mg groups presented at the last cut showed better exposure in the muscle compared to the eteplirsen. I'm curious, did you collect any data or do you plan to collect data on exposure at the higher dose? Can you comment on anything you may have learned about exposure at this stage? Yeah. Without going into a lot of detail, because I don't have the detail in front of me, we saw great exposure with the 20 mg/kg. There's no doubt that the PK/PD and exposure is the mechanism of action that explains why the peptide conjugated PMO performs so much better from an efficacy perspective. We're really starting to dial in what that exposure is and its correlate. Yes, we've seen a significant benefit on exposure. That explains the exon skipping, explains why we've seen such robust increase in dystrophin production, and it will play a significant role in the next study. Sort of thinking about exposure across the patient population is going to be an important part of the next study. I'm sure at a future medical meeting, we'll probably provide more data, including perhaps some of the exposure-related data. The short answer is the PPMO is working as it was designed and as our hypothesis would have suggested, which is a positively charged peptide conjugated to the PMO will drive better exposure by driving the PMO into the cell and getting to the right place. If that happens, the PMO will do its job at that place and will create far more exon skipping as it did, and significantly more dystrophin as it did. I would say, sitting here at 6.55% after on median, only three doses is pretty remarkable, but our modeling suggests we should comfortably get to over 10%. I think if one looks at the literature and talks to people, I think that there are a few that wouldn't say 5% and above, and certainly 10% and above is a remarkable improvement and a remarkable potential for benefit to patients with Duchenne muscular dystrophy. Great. Thanks. Our next question comes from Debjit Chattopadhyay with Guggenheim Securities. Hi, guys. Good morning. Thank you for the data presentation and congrats on all the progress. This is Aaron on for Debjit. Could you just comment on how low the potassium dropped in the patient with hypokalemia, and also is there a supplementation or monitoring plan in place for potassium as well? I will turn this over to Dr. O'Neill. Just comment briefly that we don't have the exact numbers, but it was a grade 4 hypomagnesemia. With that, Dr. O'Neill, do you have an answer to his second part of his question? I think the key thing is that monitoring for potassium is very simple. With blood tests like that of magnesium, and it's actually part of the routine electrolyte panel that all of you have when you go to see your primary doctor [audio distortion], easily supplemented where necessary. Thank you. Our next question comes from Tazeen Ahmad with Bank of America. Hi. Good morning, guys. Thanks for taking my questions. Just as you think about your general commercial offering, as you try to integrate with the PMO programs that you are currently marketing, how would you say this would fit in, the PPMO program would fit in with your currently marketed programs? Obviously, you are touting a much better dystrophin production for PPMO relative to PMO, so should we make the assumption that PMO would be cannibalized should PPMO reach the market? Secondly, as we look forward to gene therapy, would you see PPMO as being used in combination? Thank you. That's a great question. Everybody must understand that at this point, I'm going to be speculating, of course, because the commercialization of our PPMO will only come after the next trial and the approval of the therapy. With that said, I think everybody who knows this knows that we're a very mission-driven organization. Our goal is to improve and extend the lives of patients with Duchenne. First and foremost, if the PPMO is approved and the PPMO as a platform is an improvement over the PMO, then I certainly hope that it cannibalizes the PMO in the U.S. I also know it will expand the use of our RNA technology. It will expand it very likely in the U.S., but it will expand it beyond the U.S. as well. It's not simply cannibalization, remember. Right now, we're doing very well from an RNA perspective and a PMO perspective. We have three therapies. We've been growing very significantly, serving the community, but it's been very U.S.-centric. We have some managed access distribution outside the United States, but primarily, this is a U.S.-related launch because that's where we have our approvals. Because of the vagaries of the accelerated approval pathway, when you take that pathway and you attempt to bring it overseas to other countries, it doesn't exist, and therefore, we are locked out from an approval perspective in a number of places, including but not limited to Europe. This, I will posit, would change with this profound improvement of a therapy that can create significantly more dystrophin in a short period of time. Do I think that it will, in the long run, cannibalize the current PMO? Yeah, I hope so. I certainly hope so in the long run. Do I think it will expand in Duchenne muscular dystrophy, the number of patients that can benefit and the benefit that those patients get? I certainly do, if this therapy is proven borne out in Part B and gets approved. I think there's a lot of excitement there. I also would linger on one other thing before we move on to gene therapy for a second, and its interaction with gene therapy. That is that with this mechanism bearing out, this idea of getting greater tissue exposure, driving more therapy to the right place, getting more steric blocking from our morpholino technology, then the opportunity to take the RNA technology into other areas where steric blocking could benefit those who have rare diseases really becomes more possible and more practical. I think there is a real chance as we build this out that there are going to be other diseases that might benefit from this PPMO technology. Let's move to gene therapy. There's a lot of very interesting aspects to the PPMO. It's very valuable in connection with the RNA franchise itself and with treating Duchenne muscular dystrophy and beyond. As it relates to gene therapy, it's a number of things. In the short run, of course, it's de-risking and all of the concepts of diversity, but also with a very profound chronic therapy. Let us all assume that you're successful with Part B, so it doesn't look like I'm presuming the success of Part B. Let us assume for a moment that we are successful with Part B and we see this profound benefit that we're seeing in Part A with this significant increase in dystrophin. I think we really do have a much greater potential of providing benefit to patients with Duchenne muscular dystrophy through both a profoundly successful gene therapy with SRP-9001 when that is confirmed and approved, plus a profound PPMO. There's a lot of different ways that can occur, and we're doing a bunch of work on that behind the scenes right now. Obviously, pre-treating with the PPMO in advance of gene therapy, there's some early data that suggests that that combination would be a significant benefit to patients. I think we're doing some work to consider the concept of a one-time profound gene therapy followed by a very significant chronic therapy thereafter, and if that combination would be a significant benefit to children with Duchenne muscular dystrophy across the entire journey of DMD. That's something we're looking at right now. Of course, there will always be places in the world where, for instance, chronic therapy may be available where a gene therapy isn't, and vice versa. I think having both two powerful tools to treat this deadly disease in our armamentarium is going to benefit these kids and benefit Sarepta. I think there is going to potentially be a place for both of these therapies down the road, assuming that we can confirm them both in our clinical trials. Thank you. Our next question comes from Anupam Rama with JPMorgan. Hi, guys. Thanks so much for taking the question. I also had perhaps a broader strategic question, and it really relates to the competitive landscape here with a range of companies, both public and private, looking at various oligo approaches, specifically in DMD as well, that may be entering the clinic later this year or early next year. How do you think about this space and what wins out based on what you've seen with your own data and what you know competitively? Thanks so much. Yeah. Thank you for that. First of all, I would say there's a lot of work being done in Duchenne muscular dystrophy, and I think that there's one compound that deserves all of the credit for that, and that's eteplirsen. If you look back in time, I think eteplirsen really proved out the value that is driven from being able to induce the production reliably of dystrophin. Frankly, it makes me proud to think on behalf of those who invented the eteplirsen, that it's really spawned a lot of interest in creating dystrophin and helping these kids. Then, of course, the recent companies that are looking at other ways for targeting is part of that. I would also say that as it stands today, the only approved therapies for DMD that actually produce dystrophin and have been able to show it are our three therapies, which is EXONDYS, VYONDYS, and AMONDYS. Even though many have tried, no criticism to people for trying. I think that is the way research and development works. Many have tried to induce dystrophin. It is not an easy thing for people to do, and so there is a graveyard of failed programs that looked, to some people, promising early on. I would only say as well, without being overly snarky, that it is easy, at least it's much easier, to show something interesting in a cell line in a Petri dish or to show something in an mdx mouse. It is much more challenging to show reliable dystrophin production in a child with Duchenne muscular dystrophy. We stand alone right now as an organization, having shown in three different therapies the reliable production of dystrophin to help these kids. As it stands now, we're the only company that I'm aware of anywhere in the world that in a Duchenne muscular dystrophy patient, has been able to show the kinds of results we're seeing here, where with the additional of a targeting, positively charged peptide, we're able to drive more PMO at the right place, oligo in the right place, and induce significant amounts of dystrophin, literally modeled to be over 10%. I think there's a lot of interesting things that are going on in the research community. Research is one thing. Research in mice is one thing. Research in a Petri dish is one thing. Showing the results like this in a patient is a very different thing, and this has come after a lot of years of hard work. I'd say, I certainly think we are in the lead with the results that we have. I think that would be probably an understatement. Thank you. Our next question comes from Gena Wang with Barclays. Thank you for taking my questions. Doug and Dr. O'Neill, just have two quick questions. We look at slide 13 and 14, first maybe if you can define what is baseline. It seems like baseline for 30 mg seems a little bit higher than 20 mg for both exon skipping and also for the protein level. That was the first question. The second question is regarding the slide 20, the onset date. I'm just wondering when did the hypomagnesemia happen? Is that happen after first dose, or did that happen after every single dose? How frequent that happen? I'll let Dr. O'Neill answer the second one. The first one, just to be very quick about it. If you look at the baselines, you'll see the 30 mg looks modestly higher than the 20 mg, but in the same hunt. This is very likely just an artifact of small numbers. Even if you go back and look at the eteplirsen data, there are more kids in that data, and I think when you average them out, you see a lower baseline. In fact, there were kids in the same hunt of baseline dystrophin in the eteplirsen. One of the things we did do, just so we're clear about this, is we did a sensitivity analysis, and the starting baseline of dystrophin does not in any way correlate to the on-therapy benefit that you get. In fact, quite the opposite. This is probably just an artifact, but actually the two kids with the lowest baseline dystrophin had the greatest post-treatment dystrophin. There's no correlate to that. It's just, I think, just a sampling artifact. With that, perhaps, Dr. O'Neill, you want to touch on the onset issue that was raised. Yes. Thanks very much. In fact, the onset is calculated based off the most recent dose. The index case of hypomagnesemia was identified by an investigator at one of the sites who was very perceptive, and it was when he identified that we actually went back and looked at other patients and looked at our banked samples and then identified. The timing you're seeing at the onset is after the most recent dose. I will tell you that based on our analyses of the clinical and non-clinical data set, we're seeing onset after the first dose. This is actually a retrospective analysis. However, what we have also noticed is that it does not accumulate or increase over time. I think that's an important point. Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Good morning. Thanks for taking my question. Could you talk about your thoughts on the correlation between this program and functional data, and when we might see that for the 20 mg/kg and 30 mg/kg cohorts? One of the reasons we obtain an accelerated approval, of course, for our dystrophin producing PMOs is that it takes much longer than the making of the dystrophin to start teasing out the functional benefits in the population, given the fact this is a degenerative disease. These are small cohorts of kids. I think we're going to see the functional results that we would see would likely come out of part B of the study at the target dose of 30 mg/kg, is my working assumption. Dr. O'Neill, if I'm incorrect in that, you can certainly correct me. No, you're correct. Part A was designed as a safety and PK/PD study. There are also, as you know, small numbers of patients, no placebo controls within the study. More importantly, we actually allowed for and have recruited both ambulatory and non-ambulatory boys at various stages of disease because of the original objective of Part A, Part B, where we could actually start really, in a meaningful way, collect functional data. Thank you. Our next question comes from Gil Blum with Needham & Company. Good morning, everyone, and thanks for taking our question. Maybe on the other potential exon skipping drugs, considering this is a more generalistic strategy, how will these findings with the 51 skipping be translatable to skipping of the other two targets? Thank you. That's great. Great question. First of all, let's be clear. This is a platform issue, and it is not merely the next two. We have, just to remind people, apologies for repeating myself, we have EXONDYS and VYONDYS and AMONDYS, and together that treats primarily in the U.S., about 29% of kids with Duchenne muscular dystrophy. The fact is that the exon skipping approach that our PMOs take can at least theoretically, treat over 80% of kids with Duchenne muscular dystrophy. Our view is, in the long run, if the PPMO bears out, we can start treating a significant number of patients with this, literally up to 80% or more over time. That will be our approach. We have to take the results that we have right now. We have to meet with the Division around Part B to this study for 5051. Informed by that, at the risk of predicting too much, that will all inure to the benefit of the platform in its treatment of the other sequences and other mutations that make up Duchenne up to, again, as much as 80%. We'll start rolling that out across them with that data in hand. We'll come back later, probably it'll probably be after our meeting with the Agency, talk about the flight path for 5051, hopefully what would be an accelerated approval pathway if the Division agrees with us there. We'll talk about what that means for the other mutations in the other kids that have Duchenne muscular dystrophy but have other than exon 51 amenable mutations. This is definitely, once you look at this and see this as a platform issue, and I think what we are seeing today, if it's all confirmed and we're able to safely dose at these levels and we get these kinds of results, this is a significant advancement in the platform from a PMO to a PPMO. Thank you. Our next question comes from Danielle Brill with Raymond James. Hi, guys. Good morning. Thanks so much for the question. A follow-up to the earlier baseline levels of dystrophin and exon skipping. It appears that the fold change was the same between 20 mg/kg and 30. In fact, it actually looks like the increase in dystrophin versus baseline was higher with 20 mg/kg. I'm wondering how we should think about that. Then just to confirm, was the western blot data adjusted for muscle content? Thanks. Yes, on muscle content. Going to the first question, again, the starting baseline doesn't correlate with the on-therapy treatment, so you should look at the aggregate number on dystrophin. You should also, one person's view, recognize the mechanism of action and that dystrophin accumulates slower than exon skipping. If you want to predict where these kids are going to be at versus the various milligrams, look at the exon skipping as the lead indicator, because exon skipping happens much faster. Dystrophin builds over time, and even in a short period of 12 weeks, we're seeing 100% increase in the amount of dystrophin made at 30 mg/kg versus 20 mg/kg, and that's only with a 50% increase. Of course, the exon skipping is going to predict what ultimately is going to happen. What we see is that the 30 mg/kg has much better tissue concentration, much better PK/PD, and we see the steep part of the curve relative to what we thought with [audio distortion] in primates, and indeed, we're seeing it here. We're confident that 30 mg/kg is the steep part of the curve relative to 20 mg/kg. Thank you. Our next question comes from Colin Bristow with UBS. Hey, good morning, congrats on the data. Just to expand on what a couple of people have asked already, can you talk about the cadence of the adverse events and just how this has factored into your thoughts about dosing higher? I mean, if they're more front-end loaded, could you not titrate the dose higher over time? Obviously more dystrophin is better. Just a housekeeping one on patient numbers. I think this is a six-patient cohort, when will we get the next two patients' worth of data? Thanks. The other patients had an interruption. They didn't have weekly three months, so they didn't have a biopsy, and that's why you see the number of patients that you see on. The issue is the onset occurred rapidly after the first infusion and then was transient and responded to magnesium supplementation. The answer of the reason to not go higher, it is a combination of a lot of things. It is all three issues. It's the first efficacy. We're seeing a very profound improvement. I mean, I jokingly said to someone yesterday, when I joined Sarepta in June of 2017, if I had told our senior leadership that I thought we could see 6.5% growing to 10% dystrophin in 12 weeks if we use this PPMO, they would've really questioned whether they had hired the right CEO. This is a really profound improvement, versus what you're normally seeing with respect to a dystrophin-inducing therapy like our PMO. I would point out our PMOs are the only therapies that have ever, in humans, been able to induce dystrophin production. When we look at what we're going to do, we look at all three issues, and the first issue is benefit. We're seeing an enormous benefit. If we kept trying to dose up to 40 mg and beyond, the non-human primate data says that it would take a lot to start seeing any incremental benefit that's meaningful off of where we are today, given what we're seeing today. The second one, of course, is risk. You always take risk as you dose escalate. That is the very goal of dose escalating, so we would take risks along that way. There's no guarantee we'd even get up to 60 mg/kg, which is what you'd really have to get to to get something that would be even more meaningful than what we have. Of course, we have time. The big issue is now we're at a therapy that would remind you is nearly an order of magnitude. At 12 weeks, almost an order of magnitude better than the current standard of care for Duchenne muscular dystrophy. From our perspective, we could spend the next couple of years going more dose exploration. The candle is not worth the game. We need to get this therapy confirmed. We need to start bringing this therapy, if approved, to kids in the U.S. and around the world who have Duchenne muscular dystrophy, exon 51 amenable and beyond that. Now, you raise a really good question, which is, okay, that's fine. There are going to be other things you can explore down the road. The answer to that is there are. We don't imagine that this means you never look back at things like dose. We will look at that separately and later. If there are ways to get to even higher doses and higher doses benefit these kids, we'll look at that. This is chronic therapy. This is not like a one-time therapy where we can explore chronic dosing and different dosing regimens down the road. With the results we have in hand today, we don't think it's advisable or in the best interest of the patients that we serve, that we continue to do that for the next couple of years before we land on a dose. We really think we need to get to the agency, show them the results, talk to them about Part B, and with the agency's concurrence, start Part B with the hope of getting this therapy confirmed into kids as soon as reasonably possible. Thank you. Our next question comes from Tim Lugo with William Blair. Tim, your line is open. You can ask your question. Thanks. Sorry about that. I was muted. How many of the patients in the 30 mg/kg dose were non-ambulatory? It seems like the patients were maybe older outside of the seven-year-old. I know the PPMO backbone is thought to have maybe penetrating the cardiac muscle. Is there anything suggesting that this is occurring outside of obvious functional data, which won't come for some time? Yeah. On the latter question there is, obviously, we don't have confirmed data in the patients themselves, because one can't easily do a cardiac biopsy. The non-human primate data would suggest that with the cell-penetrating peptide, you would see benefit in the cardiac muscle that is difficult to find with the PMO, given the fact that it's neutrally charged. Dr. O'Neill, you're going to confirm this just to make sure I'm not crazy. I think three of the four were non-ambulatory in this, and that's really important because I think there was a question about the ability to dose older and non-ambulatory kids, and what kind of dystrophin that you would see in older non-ambulatory kids as well as ambulatory kids. Given the fact that we have such a broad age range and weight range with respect to this therapy, that really is good confirmation for us. Dr. O'Neill, confirm if I've misstated anything there. Thank you. Our next question comes from Joseph Schwartz with SVB Leerink. Great. Thanks very much. When you speak with the FDA about Part B, will you seek to gain clarity on how much dystrophin expression they want to see for approval of a PPMO, or will you assume at this point that they share the same views as some of the recent literature that you cited and just leave those discussions for the ultimate review decision that they make down the road? Yeah. We'll obviously have a far-ranging discussion with the division. I think one of the things that we've seen over the last few years with the neuro division is that they're very expert in DMD, having dealt with DMD therapies for a long time. They've been very open and willing to have discussions and debates and dialogue with us. With that said, I think we know where the division is right now. We've seen that with eteplirsen, EXONDYS, VYONDYS, and AMONDYS, and there is a dystrophinopathy guidance that helps guide our views. That guidance would align well with what we're seeing, for instance, in the [audio distortion] paper that Dr. O'Neill referenced in the slide deck, where even very small amounts of dystrophin correlate to a phenotypic benefit and predict clinical benefit over time. I think we're going to go into those discussions with all of that background that already exists with a group that is very sophisticated about these issues, and I think that we'll have a good discussion then when we see the results that we're seeing now. I would note, I don't even have to think it. I know it. No one's ever seen these kinds of dystrophin production results in Duchenne muscular dystrophy children like these PPMOs. I think we will have a good discussion around those issues. Thank you. Our next question comes from Matthew Harrison with Morgan Stanley. Great. Good morning. Thanks for taking the question. I guess two clarifications and then one question. One, can you just clarify the difference? It looks like the safety database with seven patients, but you reported on four. Can you just tell us what happened with the other patients? A second question on, I can't remember if everybody has discontinued from this study at lower doses or if there's an opportunity for those on lower doses to be given the higher dose and what might happen there. I guess a third question, just on Part B, and this would obviously be for you to speculate, but do you have any sense for what size of safety database you ultimately will need here and what would qualify? That's the reason I'm asking if you can move some of the patients on the other doses up to 30 mg/kg. Thanks. Yeah, I'll go through them quickly. Dr. O'Neill, if I've missed anything, you tell me. Number one, you see seven patients in safety, but the four patients, that's simply because a number of the patients had interruption of dosing. We required three consistent dosing before a biopsy. We've got data for them from a safety perspective. We don't have biopsies for them, so there's no biopsies there to look at. Yeah, our goal would be, if we started Part B, our goal would be to offer the therapy at the dose that, hopefully, at the 30 mg/kg dose, to all of the participants in the study. That would be the goal of the next study. The goal of the next study would be to roll all of the kids in the current study that are willing to go into Part B into that study and then augment that with the naive patients as well for the basis of an approval. How many patients that will be is unclear right now. I think historically, with respect to EXONDYS and VYONDYS and AMONDYS, we've been more in the kind of, I think, 25 or so total patients from a safety perspective, if I'm not misremembering. Of course, we've got to talk to the agency. The PPMO is a different, it's a conjugated peptide to a PMO, and we need to talk to them about how much safety data they would need. Historically, I believe it's been sort of 25 or so patients has been the number of patients, at least for the PMOs, and we'll have those discussions. Dr. O'Neill, have I misstated any of that? No, we have actually enabled people. We will be using target dose in 30 mg/kg. I'm not showing any further questions at this time. I turn the call back over to Doug. All right. Well, thank you all for joining us today for these results. We're very excited about the next steps for the PPMO. We will schedule a meeting with the agency as soon as reasonably possible to discuss these results and talk about the next steps in this trial, including a commencement, hopefully, of a Part B of this trial that could form the basis of a pivotal trial and in the United States, hopefully, even become an accelerated approval trial. Then we will build out the strategy we have to get this PPMO successful to other kids with Duchenne muscular dystrophy and beyond. This is a very meaningful moment for us and hopefully for, over time, for the patient community as well. I will also note, this will be one of two readouts we'll have this quarter. Later this quarter, we will eventually have a readout on a different therapy, which is our gene therapy. Just so you know, we don't have that data yet in hand, but we'll have the data this quarter. We will schedule a presentation on that. That's another extraordinarily important moment for Sarepta. The 103 data will be the data using our commercially representative material, and there's a lot of importance to that as well as the PPMO because that data will form the characterization of the therapy using the process that will be not only our next trials, but commercial [audio distortion] and I think it will speak volumes if we are successful in Sarepta's journey going from the vision of being a gene therapy manufacturing leader to being one of the most significant process development and analytical development and capacity leaders. But, of course, that is all depending upon that data. We'll have that data this quarter, and then we'll have a number of additional milestones over the course of this year. So we'll have a lot of opportunities to talk over the course of 2021 into 2023. So thank you all for joining us today, and we'll give you updates as we move along. Ladies and gentlemen, this concludes today's presentation. You may now disconnect and have a wonderful day.