All right, let's go ahead and get started. Welcome everyone to the 41st annual J.P. Morgan Healthcare Conference. My name's Anupam Rama. I'm one of the senior biotech analysts here at JP Morgan. I'm joined by Malcolm Kuno and Priyanka Grover from the team. Our next presenting company is Sarepta, and presenting on behalf of the company, we have CEO Doug Ingram. Doug. Thank you, Anupam. Thanks, everyone for joining us today. Thanks for those joining us online as well. I'm gonna go two slides forward. I'll try my best to, for those online to remember to try to reference slide numbers 'cause I know that the slides don't automatically go forward. For the last many years, we've been building, and we've been building frenetically. We gathered together the pipeline and the people. We built a balance sheet. We gained multiple approvals. We've served the Duchenne community. We've been advancing our pipeline. In a very real sense, all of that was in anticipation of this moment, because 2023 will be a bellwether, not merely for Sarepta, but for families with Duchenne muscular dystrophy. I think also in a very real sense for the promise of gene therapy, that's a promise to translate brilliant science to life-altering, life-changing therapies, not at some distant vanishing point in the future, but as close to right now as is possible so that patients can actually benefit from this science now. That bellwether, of course, from our perspective, is our biologics license application for SRP-9001. As you know, last year, we submitted a BLA for 9001 to treat the ambulatory patient population of Duchenne. As you might also know, we did it on the basis of accelerated approval. The standard for accelerated approval is that the 9001 Dystrophin protein is reasonably likely to predict clinical benefit. What I'd like to do with you today if possible, is to sort of walk through the evidence set that we believe makes that conclusion compelling, that the Dystrophin protein is reasonably likely to predict clinical benefit. It has everything to do with the design of this gene cassette, which was done over 10 years of work. It has everything to do with the preclinical animal models and biomarkers and functional data, and then a wealth of patient data, both on biomarkers and functional data. If you'll indulge me, I'm gonna spend some time talking about that evidence. To do that, I need to linger for a moment on what Duchenne muscular dystrophy is, so we can put this all in some context. Duchenne muscular dystrophy, as many of you know, is characterized by a mutation on this gene that codes for this protein called Dystrophin. When we move our muscles and we contract our muscles, Dystrophin protects them and keeps them from getting harmed. Kids with Duchenne muscular dystrophy, as a result of their mutation, don't make this Dystrophin. As a result of that, every time they move their muscles, every time they contract, they damage their muscles. They do irreparable damage to themselves. The consequences of that are as brutal as they are inevitable. That is these kids begin to suffer from this disease very early in life. They will end up in a power wheelchair, usually by their early teens, and then they'll struggle to move their upper limbs. They'll struggle to feed themselves and bathe themselves and maintain any semblance of independence as young men. They'll struggle to breathe, and then they'll die. They'll die usually in their late teens or in their twenties. The goal for us is not to magically go back in time and arrest the very existence of Duchenne. It's a wonderful, comforting idea, but it's not scientifically plausible. The goal, therefore, is to intervene as rapidly as possible to stop the damage that these muscles are having and therefore to arrest or significantly slow the decline of this disease. Let's talk about how a therapy like SRP-9001 can achieve that. This slide here, and I'm on the slide on Dystrophin. This is a schematic of the Dystrophin protein. So it's inside of a muscle. What you'll see is it attaches to this thing called the F-actin-binding site, then it attaches to the muscle membrane itself, and eventually it attaches on the far right to this collection of proteins called the Dystrophin-associated protein complex or DAPC. I'm gonna ask you to remember that 'cause I'm gonna come back to that in a bit. It's gonna become important. Just so we're clear, the lack of this Dystrophin protein in Duchenne kids is the sole and exclusive reason that these kids have Duchenne muscular dystrophy and that they're dying. The obvious goal then is to use a gene therapy that will deliver a gene cassette that codes for Dystrophin. There are a lot of challenges with doing that, one of the challenges is that the gene that codes for Dystrophin is larger than the carrying capacity of any known AAV, which would be a problem. The good news is nature has given us that solution already because natural history is replete with evidence that truncated or shortened versions or edited down versions of Dystrophin remain brilliantly functional so long as they retain the right features. Becker muscular dystrophy, like Duchenne, is a disease characterized by a mutation of the Dystrophin gene itself. Those mutations are in frame, those patients actually make Dystrophin. They make edited versions of Dystrophin. They make smaller versions of Dystrophin, but they often make very functional forms of Dystrophin. Becker muscular dystrophy tends to be much milder than Duchenne, and there are many cases of asymptomatic or nearly asymptomatic Becker patients. As an example, you'll see here on the right side of this slide, I'm on the next slide in the deck from the full Dystrophin protein slide. On the right side here is a schematic of a Becker patient. This patient was 61 years old when he was biopsied. He has B-Becker muscular dystrophy, and he was walking at 61 years old. Okay. That's not a Duchenne patient. I mean, that is brilliant proof that the p-protein that his, that he was making with his gene was brilliantly functional and keeping him protected. You'll look on the slide, and you'll immediately realize that the protein there is significantly smaller than full-length Dystrophin and yet is brilliantly functional, and this person was continuing to walk well into his 60s. That's gonna be our goal, of course. Our goal is gonna be to code for a Becker-like Dystrophin that creates a lot of protection. Just so you know, there is an enormous amount of precedent already at the FDA in being able to do this and using the accelerated approval pathway for the approval of therapies like that. There are today four oligonucleotides that make Becker-like shortened versions of Dystrophin that were concluded to be reasonably likely to predict clinical benefit and got approved. Three of them are ours, EXONDYS, VYONDYS, and AMONDYS, one of the other ones is from another company called VILTEPSO. Let me correct a misunderstanding or potential mythology around this. I think there's some view that those probably aren't like significantly edited Becker proteins that are made. They're probably just one exon, so they're almost full length. Such is not the case. The oligos make very shortened but functional forms of Dystrophin, depending on the particular mutation, those, they can be shortened by as much as 40%. That's exactly the concept that we're dealing with right now with respect to SRP-9001. Now, on the next slide, I'm re-showing you on the left that schematic of that 61-year-old patient. There's a reason for that, and that's because it was his protein that formed the template that Doctors Louise Rodino-Klapac and Jerry Mendell used to begin to develop something that would eventually be called 9001. It took them over 10 years. They did an enormous amount of work. They built constructs. They tested constructs. They figured out over time what areas of the protein were necessary and functional and protective and what could be dispensed with. After all of that long work, they eventually came to the ideal gene cassette, and that ideal gene cassette is ideal for two reasons. One, it retains all of the functional elements that empirically were shown to be protective and would help these children. Number two, it could package comfortably inside an AAV and therefore could be delivered. That's, as I've said, on the right side of this slide, is the schematic for the SRP-9001 protein made by this gene cassette. If you look at the left and you look at the right, you will notice that they are remarkably similar to one another, and that, of course, is by design. From there, Doctors Mendell and Rodino-Klapac packaged that gene cassette in an AAV. They used RH74, which explains why we're getting superior tropism and a differentiated safety profile. They used a very powerful gene promoter, something called MHCK7. All of that work, that decades-long work of experimentation paid off. This is the results of the work on a Duchenne mouse model. You can see on the left side that at the clinical target dose, we get really robust expression across skeletal muscle and diaphragm muscle and cardiac muscle. What does all that mean? If you look on the right side of this slide, you'll see that as a result of that expression and as a result of the Dystrophin protein being functional and protective, you get a significant restoration of function at the clinical target dose. Remember I talked a bit about that DAPC. Well, I'm coming back to it now for this reason. The DAPC is a collection of proteins that the Dystrophin attaches into. The interesting thing about those proteins is they're not associated with any mutations, but in the absence of Dystrophin, they disassemble. They're not there. Duchenne kids essentially don't have a Dystrophin-associated protein complex. You would surmise that if you could actually insert a functioning, protective Dystrophin protein, you might see some upregulation of the DAPC, and that is exactly what you saw in the animal models, and that's on the left side of this case. You see almost a one for one upregulation of the DAPC, the Dystrophin-associated protein complex when you get expression for the SRP-9001 Dystrophin, which I think is very compelling proof that Louise Rodino-Klapac and Dr. Mendell were successful in their effort to make a protective protein and gene cassette. On the right side, that's CK. What you get is, when you get expression of SRP-9001, you get a significant reduction in CK, which is an enzyme associated with muscle damage. Additional proof that the SRP-9001 protein is reasonably likely to predict clinical benefit. From all of that work, we moved to patients. We dosed our first patient in January of 2018. We have by now dosed patients across multiple studies, well over 100 patients. We've dosed more patients in a broader population of patients than all of the other gene therapies focused on Duchenne muscular dystrophy combined together. The results on biomarkers have been really impressive. We get very robust expression of Dystrophin. We get far above what literature would suggest is necessary to be protective of the muscle. Number two, all of it is properly localized at the muscle membrane or sarcolemma, where it can actually do its job and be a shock absorber. We've developed a cell-based potency assay that shows that SRP-9001 is active and functional and protective at the muscle membrane. Just like in animal models, when you get expression of SRP-9001, you get a significant reduction in CK, that enzyme associated with muscle damage. Finally, on the bottom of this slide, yet again. When you get expression of SRP-9001 in patients, you get an upregulation of the Dystrophin-associated protein complex. If we just stop here, I would posit that the data for SRP-9001 being reasonably likely to predict clinical benefit is compelling, to say the least. In fact, as good as the data was for all of those oligos, the amount robustness of this data is even greater. What's interesting and what we're excited about, of course, is that we've gone beyond that. I think this is a bit unusual, perhaps for some accelerated approvals, but we have functional results as well. As I've said, we've dosed across multiple studies, multiple time points, multiple functional endpoints, and we've seen a very significant benefit versus natural history. You can see using NSAA, which is our primary functional endpoint, the North Star Ambulatory Assessment, a 34-point scale. In just 52 weeks, in just the first year, you get somewhere between a two and a three and a half point benefit versus natural history. What's interesting, of course, is that not... If you think about what 9001 is intended to be, it's not a symptomatic therapy. This is not an anti-inflammatory or a steroid. The goal here is to actually deal with the root cause of Duchenne muscular dystrophy by literally reinserting in these patients that missing shock absorber that will protect their muscles. If we're successful in doing that, what we would imagine is that over time, as these kids were on therapy, their benefit would begin to really compound versus the ferocious decline of natural history. That is exactly the signal that we see here. You can look across here, you see it one year versus two years versus four years, you see just that. Let me just focus on the four years. I mentioned that first kid was dosed in January 2018. These are the results from the first cohort of kids out at four years, right? They're 9.4 points different than natural history on the North Star Ambulatory Assessment, which is, you know, frankly, pretty remarkable. Remember what I said earlier, the goal of all this, if at all possible, is to slow or arrest decline in these patients with Duchenne muscular dystrophy. Well, you need to know these kids are over 9 years old, okay? They're over nine years old at the time of their last assessment for this data right here. After 9 years old, you are in the most ferocious decline curve on the Duchenne. You will go from 9 to being in a power wheelchair in a matter of, you know, a 1 or a few years from there. These kids, in addition to being this well off versus natural history, are seven points above their own baselines taken some years previous, and they've been rock solid steady for years. From our perspective, we looked at the data in 2022, and we saw that it's really compelling. Compelling because of the natural history of Becker muscular dystrophy and the way we've designed this therapy with using Dr. Louis Kunkel and Dr. Mendell over a decade to be protective, and all of the animal models that proved that it was working, and then really robust patient data, not just on these biomarkers, but also on function. We decided it was worth a discussion about the potential for accelerated approval. We approached the FDA in 2022 to talk about the possibility of an accelerated approval on the basis that SRP-9001 was reasonably likely to predict clinical benefit. As a result of those discussions, by around the end of September of last year, we submitted our BLA for the ambulatory patient population for accelerated approval. In late November of last year, as you know, the FDA accepted for filing and review that BLA and granted us priority review. The PDUFA date or the target action date for this SRP-9001 is literally May 29 of this year, just a few months from now. That's where we are. Now, you'll notice I don't have an AdCom on this timeline. We don't have official word today that we're having an AdCom. For planning purposes, we're assuming that we do, and we're preparing for an AdCom as if we're gonna get one. If you're here otherwise, you may want to assume the same thing. At the same time, we're doing a ton of work. You know we've already not only started our confirmatory trial to support an accelerated approval, but we've actually fully enrolled and fully dosed that confirmatory trial. Which one would assume would put us in a brilliant position to have a robust, and productive discussion about accelerated approval. At the same time, we're doing the work to expand this label and expand the number and a percentage of the population that can benefit from this therapy. We'll be starting a non-ambulatory study, this year with the goal, if successful, of expanding the label to the non-ambulatory patient population just next year. We're already in a study to limit the excluded mutations in the label, we're exploring opportunities this year in patients with avenues that if successful, would allow us to safely and effectively dose even NAb-positive patients. We're getting all of that work done. At the same time, we're in a very good position from a manufacturing perspective. You should know we have about 400 technical operations employees at Sarepta dedicated to this. Along with our external partners, putting us in a position where we're gonna be able to launch this therapy very, very successfully. In fact, all of our assays for commercial release of this therapy are completed, and we're building launch inventory as we speak right now. At the same time, we've been spending the last few years really looking objectively at the value proposition of SRP-9001. In fact, we'll be publishing later this year our perspective on the way one ought to objectively and holistically think about the value proposition of a transformative one-time therapy like 9001, particularly in rare disease and maybe even more importantly, in diseases of such extraordinary unmet need, like Duchenne. While it would be premature of me today to discuss price, and I'm not gonna do that today, I can at least assure you of this. The cost to the healthcare system of 9001 is gonna be far less than the objective value that 9001 is going to bring to the Duchenne patient population. Which is to say, in addition to great data, we have an enormous amount of work to do in a very short period of time. Before people would worry about that, I would remind you, at least in my opinion, there is no team better prepared to launch a Duchenne therapy and to serve the Duchenne community than Sarepta. Maybe immodestly, I will say I think we know the Duchenne community, we know the Duchenne treating physician, and as it relates to Duchenne, we know the payer community better than anyone. We've been serving this community for years now, and we're very committed to them. If you wanna put numbers to that commitment, for over the last 6 years, with our three approved oligonucleotides, which is EXONDYS, VYONDYS, and AMONDYS, we've been growing sales at about 40% compounded annual growth rate for the last 6 years. I will also remind everybody, this is surprising, perhaps in biopharma, that's with 0 price increase. We've never considered a price increase thus far, even in this inflationary environment. We have that focus. I would also say, you know, our cumulative sales for this, these three oligos are approaching about $3 billion right now. We do know how to make a success of our therapies and to serve the community. 2022 was no different for us. You'll remember at the beginning of 2022, we set guidance for the year. In the middle of 2022, we were overperforming so significantly to that guidance that we had to up our guidance, we significantly increased it. I can now tell you that the fourth quarter stands at about $235.5 million. That means our full year 2022 net product revenue stands at $843.3 million. That number is above the top end of our upwardly revised guidance from 2022. We really started 2023 in a strong position, and 2023 is gonna be a strong year as well. If we just focus on our three approved therapies today, we'll do better than $925 million with respect to our three approved therapies. If and when SRP-9001 is approved this year, if that happens, we'll come back and I'll update the guidance, and we'll include the impact of SRP-9001 on the full year guidance. I spent a lot of time talking about SRP-9001 today. Of course, we have a very significant mission ahead of us, not simply with 9001, which is itself enormous, but also to build what I think can be one of the most significant and meaningful biotechs focused on bringing a better life to rare disease patients with genetic medicine. If our plans come to fruition, if we're successful, if 9001 is approved, given our revenue projections and our cash on hand, we'll be cash positive and profitable just next year in 2024. If 9001 is approved, peak year sales for 9001 based on our forecast would be just about $4 billion. If you want to put a number to the near to midterm opportunity, if you get out to sort of 2026, 2027, our yearly sales will be about $5 billion across our four approved therapies. Of course, we have an enormous pipeline and platforms to drive far beyond 2026, 2027. As you may know, we have 40 programs in some stage of research and development as we speak, across three platforms, RNA gene therapy, gene editing, and currently across three therapeutic areas, neuromuscular, then neurology, and cardiomyopathy. This year alone, we're going to start limb-girdle trials. We're gonna complete our trial for SRP-5051, which is our next generation RNA called the PPMO or peptide-conjugated PMO. If we're successful with that trial, we will commence the process of compiling an NDA for its approval as well. I said at the beginning of this slide that if we're successful, we'll be profitable next year and cash positive next year. I do wanna make the point that profitability and cash positivity does not come through skimping on our investment in our pipeline. We are gonna continue to aggressively focus on this platform. In fact, you'll see on this slide, by the end of this year, we estimate we'll be in approximately 30 clinical trials. Clearly, we are fully committed to this platform. The reason we're committed to this platform is very straightforward. You know, our corporate goals and our corporate ambitions are very important to us, but they are, in a real sense, in service of and subordinate to our broader mission. That's our North Star. Our broader mission can be easily explained. It's to translate brilliant science to life-changing, life-extending therapies for greater and greater patients that need us and to continue to do that fanatically. Thanks. Thanks, Doug. Just a couple reminders that if you wanted to submit a question in the Ask a Question feature, through the digital conference book, that is an option. If you want to get bold and ask a question in person, there are microphones. Please raise your hand and we can make sure you get your question answered. Maybe I'll just start out here. To confirm, you have gotten no indication from the FDA for an AdCom. What are the timelines or periods of between now and PDUFA that we should be thinking about where you could be notified? Well, I mean, there are numbers of check-ins, you know. You got mid-cycle reviews and early cycle reviews, late cycle reviews. I would think until we affirmatively know one way or the other, we ought to all assume that we're gonna get an AdCom. The reason, let me be very clear about the reason we make that assumption. We make that assumption so that we're not caught off guard and have to prepare quickly. We're treating it like we're getting an AdCom. I'm sure the team is working on their AdCom prep today, even as we speak. Go ahead. Could you speak to the technological hurdles and commercial implications of gene therapy redosing Selecta Biosciences Hansa Biopharma and what that might mean for the company? Yeah. I mean, it's a really interesting issue. As it stands today, as you know, the, you know, current thesis is that gene therapy is 1 and done. The good news, before we talk about redosing, the good news is that, you know, muscle is an interesting place to go. The reason it's interesting is it's really hard to get to. If we were sitting here right now at the beginning of our journey and we hadn't dosed patients, I think the number 1 thing people should be worrying about... Well, the 2 things were safety, of course, is always top of mind, and the second would be, come on, can you really dose a gene therapy through a, you know, a full body infusion and get the kind of genome copies to the right place that you imagine? The good news is that that has been fully answered because we can. We get multiple genome copies per nucleus, and we're making, you know, extraordinarily robust expression. The nice thing about muscle, before we move on to redosing, is that muscle is a privileged place to be from a gene therapy perspective, because muscle doesn't turn over like something like the liver or something along those lines. Our animal models have suggested that we get, as long as we've been able to look, very strong durability. I mean, we're not even out at a place where we can start thinking about durability. In the long run, we're very focused on the concept of the ability to redose for hosts of reasons. You know, from our perspective, it is an engineering problem. It's not gonna be a basic science problem. We do have a number of different approaches. We have Imlifidase. There's, you know, plasmapheresis. There are a number of different possibilities, and we're gonna consider all of them. We're confident that that'll eventually be a possibility. If it's a possibility, it may even change the way one goes about dosing gene therapy. You can start at smaller doses and then determine if you wanna top up and the like. We're not there yet. With respect to Imlifidase, we're gonna start a trial with our partner for Imlifidase this year, but it's gonna be for knocking down preexisting neutralizing antibodies. That'll put back into, you know, opportunity to dose probably 13%-15% of kids who would otherwise be screened out right now. We're focusing on that first because it's the. a really significant near term opportunity for these families, but also because it's technically easier than the redosing concept. You know, the amount of titer you get from preexisting neutralizing antibodies is in orders of magnitude less than you'll get after you dose a kid. It's a good, you know, relatively safe place to start this journey. Over here. You want this repeated for me? Yeah. If you do wanna extend EMBARK, is that easy to do if you're not redosing patients hopefully? Or is it a major protocol event? If so what's actually involved in doing that for EMBARK? The qu- Yeah. The question is, can you extend EMBARK or is that a major protocol assessment? Well, the short answer is, what. It's interesting. We're not going to. I suspect the question is essentially, you know, would it make sense if you got an accelerated approval to just extend EMBARK, maybe increase your probability of success? There's a couple different reasons why we're not gonna do that. The first reason is that we don't need to. From our perspective, the powering from EMBARK is well over 90%. It is informed by all of the studies that have come before it. We really understand the study well, and I think it's being executed very rigorously. I'm quite confident that we're gonna get a positive result from EMBARK. Beyond that, you know, we need EMBARK in its readout for ex-U.S. It would be... It would affect a delay, around the rest of the world that would be, you know, not in the best interest of patients, and I don't think we need it. Doug, as a clarification point, on the guidance, if 9001 were to be approved in May, you would revise the guidance and give us some clarity of how you think 9001 should look in the back half of the year? Yeah, we'll do exactly that. Okay. Then another clarification question on the profitability in 2024, what kind of sort of leeway is there if there's an extension- Yeah. a three-month extension or something like that to the PDUFA? CFO. Well, just to go back to your first question around the guidance also. We also do, you know, one of the reasons why we set the guidance at greater than $925 million for the PMO is that we also don't know the impact it's gonna necessarily have, SRP-9001 will have on our PMO franchise. Right? Once a patient gets a start form for SRP-9001, how does that impact the patient who's on a PMO right now? That's something we have to think about too. There are moving parts. We will also obviously have tremendous amount of growth with SRP-9001 if it gets approved, but it's important to understand that there could be some level of impact on our PMO franchise, and so that's why we've given a fairly broad range. The second question? On profitability 2024, what if there's an extension? Is that baked in? We do. Delays. Yeah. 2024, you know, one of the huge advantages to filing for an accelerated approval is that now the book end of when 9001 can theoretically be approved is really at the end of the year, so January of 2024, right? Because even if we got a CRL, obviously not our, necessarily our expectation, but if it were to happen, we wait for the EMBARK data, and then that would read out in the fourth quarter, and then there would likely be a two-month review once we respond as the agency. That puts us at the end of the year for 2023 or January of 2024, and if we're at launching the product in that timeframe, we'd still be profitable in 2024. Questions from the audience. Go ahead. Are you anticipating any kind of supply chain risks, for the AAVs themselves, the AAV manufacturers? No. What was it? The question's on supply chain risks for the AAV. Yeah, no, we should be in great shape from a, from a supply chain perspective. You know, we're working with our partners right now to build launch inventory. I mean, on the basic supply, you know, for plasmid, as an example, we have a very, very strong, positive relationship with Aldevron, which became Thermo Fisher, and we're not concerned about supply chain there at all. The rest of it's just building inventory and releasing inventory, and we're all working on that right now. Additional questions from the audience? Just another quick clarification question. The $4 billion in peak sales that you said in your slide, that's US only? Actually, U.S. only? Okay. Yes, U.S. only. Questions from the audience? One of the questions that we get a lot is related to cost of goods. How do you think about that near and long term? With respect to cost of goods, we've said before this, you know, we haven't given, you know, detailed guidance on cost of goods other than to say that our margins will be in line with other high-value biologics similar to our, to our own. I think there's a real opportunity in the long run to get better and better at the cost of goods, and that's important. It won't be important in the early days, we should be fine, but in the long run, if you really look at gene therapy, and you're committed to the concept of gene therapy in the long run, the problem with the cost of goods and the pricing model for therapies today is that it will leave significant regions of the world behind. You know, you think of, you know, places like India and Africa, which will be more challenging. From our perspective, the goal of getting manufacturing more efficient over the long run isn't simply about getting better COGS, which of course is always great, but it's really about the availability of this therapy to greater and greater patients around the world. Additional questions from the audience? One of the other questions that we've kind of gotten a lot is related to what additional data you'll be submitting to the agency between now and PDUFA, and are there any risks that any of those submissions could be a major amendment and extend timelines? The only thing we anticipate, submitting is just updated safety, information. Okay. Any final questions for Doug or Ian? Dallin. Dallin. Okay. Thanks, everyone. Thank you all. Thanks for joining us today. Thanks, Anand.