Welcome back to the 45th Annual TD Cowen Healthcare Conference. Marc Frahm from the Biotech team here at TD Cowen, and really happy to have with us for the next session, Jay Backstrom, CEO of Scholar Rock, where we're going to talk about their programs in SMA with apitegromab, where we have positive Phase 3 data and a filing in front of the FDA now, and then also probably sometime as well on their efforts in obesity and maybe a little bit on broader pipeline, but that'll be most of the time. With that, maybe I'll turn it over to start. Jay, you want to give kind of just a high-level overview, status update of the company to make sure everybody's kind of level set, and then we'll get into some more specific questions? Yeah, first of all, it's great to be here. It's always nice to be at the conference, so thank you for your attention. Great time for Scholar Rock. I think, as you know, the company's been on a journey to get to where we are right now. Outstanding science, that was the foundation of the company. But over the last year, I think we've shown how that science translates into really meaningful outcomes. And we're on a path now with apitegromab to lead the way to potentially be the first muscle-targeted therapy in SMA. It'll be the first innovation in SMA outside of SMN-targeted therapies in a while. And frankly, the first time that anybody's been able to show functional improvement targeting myostatin, which we have deep expertise on. So that in and of itself is exciting. The beauty of it is that the reach that we can have in this community and the opportunity that we have in front of us as we work through the regulatory process to be able to introduce this to the market. We think that with apitegromab, we have an opportunity in SMA alone for a $2 billion opportunity, so substantial for us as a company. Our ambition or vision for the company is that apitegromab will be the basis for a neuromuscular franchise, and we're actively working to build around SMA and into other areas of neuromuscular. It's a really exciting time. Fortunate to have Mo Qatanani here with me and the science that comes from our labs just incredible. That's an amazing time for us, right? I feel the reach that we can have an impact on patients is huge. And then we follow that with our expertise in targeting myostatin and bringing that into the cardiometabolic space, waiting for a Phase II readout on our proof-of-concept study called EMBRACE. So for our portfolio of anti-myostatins performing and executing well, we will see where we go with cardiometabolic next. And then, of course, there is more in the pipeline, but priority number one for us is SMA and getting that drug to market. Great. Thanks for that overview. I should have mentioned also for people in the audience, I have a whole list of questions here, but if you have your own questions, feel free to raise your hand. We'll try to get those answered as well to make this as useful as possible for the investors. But maybe on the BLA submission for apitegromab, just want to update kind of the status of that and what your kind of expectations would be around prior to review and potentially and/or an AdCom. Good question. So when we disclosed the data, top-line data in October, very front-footed on that and said that we were going to be able to get the BLA in Q1 of 2025. So we were able to do that successfully. The BLA was submitted in January, so it's now under active review. In addition to filing in the U.S., we also indicated we would get the MAA in Q1 this year, and we're on track this month to get the MAA in. So the regulatory application work has been done. Now, it's soon to be submitted in Europe and under review in the FDA. So that's priority number one for us to get that in. We're eligible and we meet the condition for priority review. It's a serious unmet need. We definitely think we have meaningful data. So we're in a position to request it. We have sought priority review. We've been very clear on that. And so FDA's under review. We'll learn their decision on that as they complete their initial decisions, but feel very good about our request for that. So that's clear. You know, the advisory committee hearing question is an important one, and we'll learn with greater insight once FDA gets further in their review. But from my experience in the regulatory front, I don't think that FDA needs to go to an advisory committee to make their regulatory decision. There's not a lot of controversy. SMA is well understood. It's an unmet need. Endpoints are clear. Patient population's clear. So I think they can make this action on their own. Of course, that's a, you know, we'll see where FDA gets their review, but I think that there's not a need for it. So we'll see. Okay. On the data itself, I think there's a little bit of debate, I hear at least from investors, of exactly how meaningful the differences in HFMSE you did see in the Phase III. You want to kind of speak to that delta that was observed and what it means for a patient to, you know, what are the things that they can do with apitegromab versus not given that delta? Yeah, I think there's a couple of things to take into consideration when you think about our data. And we try to frame it, I think, in a number of ways. So just take a step back and then I'll get into the meaningfulness of a 1.8 change. If you look at the natural history, and I think we've got insight into that from the nusinersen data that was shared at Cure SMA, where you see an initial increase in the Hammersmith scores when you start therapy, but it doesn't continue. There's about a four-point gain. It tends to level off. But what was sobering is you look at the long-term follow-up, there's actually a decline in function about one point per year once you get to about four to five years on treatment. And what that underscores is that there's an inherent progressive nature to SMA. That's really important to keep in mind. I think the other thing to keep in mind is that when we talk to those living with SMA, they want to be able to do more things. Activity of daily living really matters. The functional points, one to two points means they can do something new, turn over in bed, raise a hand to drink, things that we may think are insignificant from a day-to-day thing. But if you think about it, that's your abilities to be able to do that really matters. And so every point matters for the community. From a registration trial perspective, that's a validated measure that we met clear evidence of a benefit, different treatment effect. We met that condition. But as I think about the total story and the total data packet, we've been able to threefold greater chance of getting a three-point gain or greater than on the best of care. So we're definitely adding additional function. We were able to maintain that function in TOPAZ when you'd expect the decline. And when you take a look at the 52-week data, at the end of that trial, as we saw from nusinersen, those on the best of care lost a point where those on apitegromab gained a point. So as we think about the totality of the data, it's potentially changing the trajectory and the arc of those living with SMA, not just the 1.8 change that we saw in the overall treatment effect. But when you stack it on the beginning of the curve, I think we have an opportunity to change that curve. And then you add to that, we have a safety profile that we have patients now on over going on five years. Benefit-risk on the benefits or the risk side is very, very clean. Safety tolerability is really very, very good. And from a treatment approach of above all, there's no harm, safety's clean, functional benefit is there. And as we engage those who treat with the community, with physical therapists, there's a collective understanding that this is a meaningful advance. And I think we really have a chance to transform care. The other thing is the trial, you met statistical significance on a pooled basis across the two doses that were tested. But then, you know, if you break out the doses, you start losing that significance. You end up in smaller patient populations. One, confirm which dose you're seeking approval of, the 10 or the 20, but then, you know, how do you expect those kind of data cuts to be reflected in the label? Is the pooled data on the label? Is it just the approved dose? Yeah, so first off, you know, as we talked about when we disclosed the data, we predefined the pooled analysis because the primary question we're trying to answer is apitegromab better than placebo in this background setting of SMN therapy. So that was the reason we did the trial in that way. The FDA advised us to include two doses, and it turned out there was really good advice because without that advice, we would have run the 20 mg per kilogram dose alone. And it turned out as when we disclosed our data, the 10 mg per kilogram dose and the 20, the PD effect were superimposable. So effectively, the PD effect are identical, the amount of target engagement. So because of that, we pick the lowest dose that's effective. So we're going forward with the 10 mg per kilogram dose. So that's what we'd anticipate be the labeled dose. And the dossier is built around all the data in there. But at the end of the day, the labeled dose we're requesting or recommending is 10. So in terms of the dose? It's really interesting. For the question if one didn't hear, it's what dose do we choose in cardiometabolic. We started the cardiometabolic study before we knew the SAPPHIRE data, but we have really good understanding of PK/PD effect and exposure from all of the work we've done with apitegromab. We selected 10 mg per kilogram in the cardiometabolic EMBRACE study, in part because that exposure in that weight group was a little higher. It was approaching the 20 mg exposure, but it turned out 10 is effective in saturating the dose. It turned out the dose was actually the same. Just back to my question. So would you expect when you get to, you know, section 14 clinical study, will both doses be in that? Would you anticipate that or just will you only get the delta of the 10 mg? Just how will the label be? Yeah, so it's a review question. So to be clear, I think going forward, we're recommending the 10 mg dose. So we'd anticipate the 10 mg data would be represented because that's the dose we're going to recommend. But also recognize that all safety matters, all safety data will be in the label. So that'll be reflected on the totality of the information. Okay. And the other kind of labeling need to be we hear among investors is obviously the SAPPHIRE trial, you know, enrolls a very specific patient population that is a slice of SMA. But, you know, how broad of a label do you expect or what's the kind of indication statement you're seeking? And And kind of what's the regulatory precedent around that that would support potentially a broader label than just the criteria of SAPPHIRE? So when we put the, you know, the BLA together and we think about labeled indication statements, we look for prior precedent to see how FDA has managed this in the past. And if you take a look at all FDA's labeled like risdiplam or nusinersen, they view SMA as a single disease and their label is broad. It's for the treatment of pediatric and adult patients with SMA. So their labeling convention doesn't parse out type 1, type 2, type 3. They don't talk about ambulatory, non-ambulatory. They just treat it as SMA. So we followed and modeled that indication statement. We will have a caveat behind it because we're eligible to study two and older. So there will be a pediatric age two and above, at least our recommended indication statement. But I think it's from our interaction with them. I think it's pretty safe to expect them to maintain that labeling convention and then look to the clinical trial section, to your point, to then articulate who got into the study, what the inclusion criteria look like. Okay. And maybe for that sliver below two, what are the plans there? So, we have a really good question. We have planned to start this year, Q3, an under-two study for even the youngest, which will give us an opportunity then to be able to guide those treating even the youngest with SMA on dose. And that's really the principal challenge for us. It's weight-based dosing. We've got to be able to model that against what neonates and youngers are going to be able to do. So we'll run that trial. Once we have some PK/PD data that we could then inform, we'll advance that and go to FDA. So that'll give us experience there. Again, from everything that we're seeing in this space, I think the earlier that they treat, the better. We see that with SMN therapies. I think that'll be true for this as well. And so it'll be an opportunity for even the youngest to have a chance to get it. For some of those patient populations that maybe you expect the FDA not to delineate from an indication statement perspective, but, you know, ambulatory patients, you know, or combo with, you know, you have some risdiplam, but not a ton of risdiplam patients in there. Do you think you need to generate some larger data sets, maybe not for labeling purposes, but to help either commercial adoption in the U.S. or particularly, you know, reimbursement levels and criteria outside of the U.S.? I think we have a full evidence generation plan to continue to gather data, real-world experience in different settings. So that plan is underway. I think to your point from a registration perspective in the US, we don't think that data is necessary. We think the trial is rare in orphan disease. We've got reasonable representation across risdiplam, nusinersen, et cetera. I think we're fine. But it's, you know, always gain data. It's always good to have additional experience. We've got ideas that we want to support going further. So more to come on the SMA. Certainly for the under two, that is front and center for us. That's label enabling. We really want to get that in there to guide. And everything else we'll be able to do around the evidence generation. And then on the issue of pricing, just how do you approach pricing in this space? You know, you're going to be asking for essentially at some level two orphan drugs to be administered in a single patient. And, you know, that starts getting to quite high price points on a cumulative basis. Just how are you approaching that issue? First and foremost, I think we're advantaged because SMA is pretty much established now. We've got three available therapies. You look at the range of pricing and reimbursement from gene therapy, it's, you know, $2 million plus. If you look at nusinersen, it's $850 for the first year, $400,000 later. And already a third of covered lives are getting more than one therapy. So there's already a recognition of the need, the value, and the need to treat. So I think that positions us in a very good way. I think as we take a look at the impact we can have over the trajectory, we think we have a good value proposition. So we're going forward, I think, with appropriate value to work within that system. I think we have a good opportunity for payers to recognize and understand that. More to come specifically on pricing as we get closer to launch. That work is underway now. I mean, given that precedent that, you know, maybe as mentioned, a third of patients are getting dual therapy over their lifespan at rare disease type, should we think of this as, you know, in the same ballpark as corrector therapy is today, you know, because they're, I mean, they're doing that without formal evidence. You have a randomized Phase III trial. You know, I think we're, you know, always look at what the current pricing is and use that as some guidance toward it. I think we want to have a balance between access and being able to have the pricing that I think we'd want to anticipate from orphan. So, you know, I would look in that range. I wouldn't say that we would eclipse the current pricing, so to be clear. But I think there's enough room in there for us to really have a meaningful impact. Okay. And maybe as we will hopefully get to a label later this year, you know, the commercial organization that you're going to need to build, what does that look like? And And kind of where are you today and kind of what's that trajectory look like to get to be launch ready at the issuance of a label? Yeah, we've been planning for success and preparing for success since I've joined, right? We did that on the regulatory front. If you take a look, we disclosed data in October and we submitted in January. That's a pretty quick turn for putting a regulatory application together, so we were already planning for that success. Brought on a commercial leader, Tracey Sacco, in October of 2023 to really start to help us frame and think about when we get there. We've been ready, but we've been very careful and we didn't really hire in advance and none really had clear data except for those commercial positions that we thought we had a little bit more long lead time on. Since the data, we've been just on a ramp going forward. We've added pricing reimbursement. We've built up more of our medical affairs team. We're setting together our channel distribution, specialty pharmacy, specialty distribution. All of that piece is coming together very nicely. Had a commercial leader hired. In fact, we had an offer ready for him before we knew the data. So we were really recruiting and getting ready for success. Once we have the PDUFA and we see where we stand, then we'll bring in the field force and kind of get them ready. Usually do that just a few months in advance. You want them to be ready and trained and ready to go, but not too soon and not too late. We've got a very experienced team to know how to time that. And then with respect to the buildout, I mean, again, we're very, very much advantaged for SMA being a well-established market. Payers understand it. We know where the centers are. We know the patients. And so our field-facing force is going to be very efficient. I think we can do that with around 50. So that really allows us to have the reach we need, the impact that we need. But we also want this to really be tailored white glove service. We've got a bunch of dedicated team members joining us. For example, for the administration, we're monthly dosing. We're going to build into home infusion as an option for those patients and families, but that would be an advantage. But at the same time, with enough flexibility to do it in clinic. So we're really thinking very carefully. We've listened carefully to the community, but we're on the on-ramp and we're a magnet for talent. And this is a place where I think everybody wants to be part of the next wave of innovation in SMA. As you get to that launch, what patient population or populations do you view as like the low-hanging fruit and how big are those patients? All on therapy, right? So two-thirds of patients treated right now are on treatment, right? Those are the starting points for us. I think we had some insight into that. You know, we held an investor event in May and we had Diana Castro, who was on the panel with us, and she was posed the question, "Who would you treat?" And she answered it with who she wouldn't treat. And basically it would be those near the end of life that really there was very little opportunity for any additional benefit. You know, unfortunately, even to today's world, there are those that are ventilator dependent because this has really a debilitating disease. But otherwise, I think we've shown that for those that are already on treatment, which is the randomized study, even those that are on four to five years of therapy, we prevented their loss of function. And what you'll see as we show data for those that get it earlier in the treatment, they have a threefold chance of getting additional gains. So I think it's getting there, getting them started, recognizing that now there's another option to really increase function and to really help this very committed community maintain as much independence as they can. Okay. Do you want to turn to cardiometabolic since that is the next data update? One more quickly, you know, any nuances of the EMBRACE trial that you want to make sure people are aware of in terms of, you know, how background therapy is being administered or anything about the dose level? I mean, we did touch on dose a bit, but. Yeah, so that was a dose for apitegromab, right? So 10 mg. That was that we thought carefully about and feel good about that choice now in retrospect, right? It's good to be correct at some point. But the trial itself, to be very clear, we designed this with the apitegromab to really address two very important questions. The question of, is our very specific mechanism targeting myostatin, which we believe advantages us on the benefit-risk side because we do not perturb any of the biology and TGF-beta outside of hitting myostatin. Love that play. I think from benefit-risk, that's a really good play. But can we have an effect on lean mass in the setting of background therapy of, turns out, tirzepatide? That was the question. And so the primary endpoint is DEXA scan change from baseline effect on lean mass. That's the primary question we're answering with our very specific targeted approach. The other question that we wanted to answer, which I believe will be true, is that when we add apitegromab to tirzepatide, we will not add any additional toxicities. So blockbuster therapy, benefit-risk, we don't want to perturb. We want that to be very clean. So those are the principal reasons to do it. We chose to do it with the apitegromab because SRK-439, which is the program we're taking into cardiometabolic, was still pre-IND. We're now moving up to that. That'll be the trial. But it's on the background of tirzepatide. We did design the study to be either semaglutide or tirzepatide. Turned out the team went too fast. They did. We got the trial open in May. It finished in September. We had secured supply for tirzepatide. We had supply coming for semaglutide. You know, that was at the time when there was a little bit of challenge with supply, and boom, trials enrolled, and I'm like, I'm not holding them back, so we did a tirzepatide-only study, so it'll be on the background of tirzepatide, and tirzepatide, because it's an approved drug, the dosing is the product label, so the investigators were advised to just go through the titration scheme and run the play with tirzepatide just as if they were treating commercial patients, and what I can tell you from everything we're seeing is tirzepatide is predictable. I think what we're seeing is what we'd expect to see for tirzepatide, so when you see our data, when we look at it, look at it from that reference. It's always good to see. Did the control perform the way you'd expect? That's why I underscored on this nusinersen data from SAPPHIRE. That control arm performed exactly as we'd expected. Gives you confidence in these data. Take a look at tirzepatide and did it do that? And then we'll take a look and see what effect we have on top of that on lean mass. And, you know, on a recent call we held, I was trying to put sort of what meaningful data looks like, right? I think we want to preserve lean mass, muscle matters. And, you know, we indicated that, you know, if you can preserve the impact of losing one to 1.4 kg of muscle is significant. We saw an effect on losing about 7%-8% of strength. The effect insulin sensitivity by 30% is showing you just that one incremental kilogram, 2.2 lbs of muscle, what that means. And so we're trying to put in the context if we could preserve 20%-40% of the lean mass lost, that'll add about 2 kg. That could really translate anything into a very nice signal for us to go forward. So that's on the primary endpoint, but it's a rich trial. We'll have week 32, which will not be part of the top line. At week 24, everybody stops treatment, both the apitegromab and tirzepatide. Then we have the patients, the subjects come back in eight weeks later and repeat another DEXA scan. As you know, what we'd expect from tirzepatide is there's the likelihood of regain of weight and what tends to come back is fat more than muscle. Our team has done in the diet-induced obesity models shown that when we stop it in those models and apitegromab is still on board, we blunt the weight and fat regain. We blunt that. That'll be an interesting observation because I think it, you think about that downward spiral. You stop, you gain weight, you get more fat. You stop, you gain weight, you get more fat. You're on this downward spiral. We might be able to perturb that, protect that. That's an endpoint that we'll study, but we won't have a top line. And then we build some additional exploratory endpoints into the study. So, you can discuss what you view as meaningful on the lean muscle side. You know, how does that get impacted by what happens on total mass in the dual therapy arm? You know, because I guess at least at first order, if you add, if you add muscle, right, you're going to actually reduce the amount of muscle of total weight loss, right? Yeah, I know. Well, so again, if you look at the magnitude of, so within 24 weeks of treatment, tirzepatide from the SURMOUNT-1 study, they're losing 14% of body weight. 14%. On average, they came into the trial at 100 kgs. Think about it. They're losing 14 kgs of body weight in six months times 2.2. I mean, that's a substantial amount of weight loss. So I think with that magnitude of weight, whatever preservation we have on lean mass and additional muscle, it's going to be a plus or minus. It's not going to be statistically different by any means. I think it'll be comparable. But it's an interesting question because I think 24 weeks will be enough to give us a signal. But, you know, the registration endpoint is 52 weeks, longer therapy. There might be more opportunity to see these influences. But at the end of the day, we posed the question to Dr. Jastreboff. Again, I point to her because she's really a leader in this field who participated in this conference we had in New York. At the end of the day, it is the healthy weight, quality weight, functional benefit, and so to preserve more lean mass, if that meant a difference of one to two pounds on the scale, she'd take the preserved lean mass every time. Body composition trumps it. That's really meaningful. In this trial, at week 24, we're expecting it to be comparable weight loss. Don't think it'll be different. Over time, we might be a different story, but at this mark, we're thinking it's going to be comparable. That's what we're guiding to. Maybe longer term, what is your sense of where the FDA is on lean muscle? Is it of how important they think it is? Is it its own endpoint? Or do you need to translate this into some sort of functional benefit in those kind of 52-week pivotal type of trials? Yes to all those questions, so let me unpack it. I think in FDA's recent guidance, they indicated how important muscle mass is by advising sponsors that they need to assess lean mass in any of their studies, at least a subset of the patients, to be certain that the weight loss isn't disproportionate due to loss of muscle because muscle really does matter, so from an impact, they want to understand that. From a regulatory endpoint today, the regulatory endpoint, as you know, is BMI. It's the amount of weight you're losing, so lean mass in and of itself is not a registration endpoint, but it's an important indicator for us on our approach in a phase two trial. What FDA did signal, which I think is really interesting, is that I think the field is pointing toward body composition as a more important endpoint overall than just BMI. And that will, I think, eventually catch up. That'll eventually be where the field is going to go. And so they do indicate that if you're interested in a body composition claim, come speak to us. So there will be an element to that that I think to be considered. Recognize we would improve body composition by preserving lean mass since it's a ratio of fat mass to lean mass. We should have a positive effect on that. But today, the regulatory strategy would be to demonstrate additional benefit from preserving lean mass. And we see that in two ways. That's either on the play of metabolism, where muscle plays a role in glucose uptake and insulin sensitivity. Myostatin has shown in at least one of our models where we have further reduction in glucose, even on top of semaglutide. In that regard, Hemoglobin A1C could be a registration endpoint in the right setting in the right population. That's one path. The other path, though, is playing off of the role that muscle plays in function. And that's a piece that's really intriguing to me as we think about, first, we've shown functional improvement in Hammersmith scores and SMA, so function should follow. But it's taking a look at the subset of patients where function really matters, right? And so again, if you think about, put this in our discussion points when we had the call last week, if you look at a 60-year-old and older, you're losing 1% of lean mass per year and you're losing 10%-15% of strength per decade. Now, I don't know about you, but I don't want to lose 10%-15% of strength and I'm not inclined to lose additional lean mass. And then if I had to add on top of that, the loss of lean mass that occurs with GLP-1, that's a group to consider where there likely would be a very interesting way to show benefit. But the other piece that's really interesting, again, back to Dr. Jastreboff's comment to us, she had a patient come in to see her who's a 45-year-old construction worker who needed to lose weight, who complained that he didn't have the strength to do his job as he was starting to lose. So you can start to see where there's ways that we can understand better how not only are we showing preserving mass, we're showing increase in strength and function, then we can apply that under the appropriate area and the appropriate setting. I think the older population is probably an obvious one because there's already this decline, but I think you can begin to see that we could carve out some subsets of patients that we could show some really meaningful difference. Are those discussions that you can use the apitegromab data to kind of go to the FDA and have some of them now while you're still waiting for 439 to get into the clinic? Or is it better to wait till you have the 439 data to go to the FDA? Actually, it'd be a bit of both. I think the real opportunity for us to engage FDA will be when we open up the IND for 439 and we begin to have that opportunity to discuss with them the development path. We had very good feedback from them. They were very prompt and giving us really good advice when we opened up the IND for apitegromab. We'll have a chance to do that for 439 and we can begin to take all our thinking into that, how we build that program. So exciting times. That data's coming soon. It's Q2. Q3, we're on track. We'll be a commercial company Q4, getting the MAA in, and we're going to build around it. Mo has data coming at the MDA conference where we had our models. We're looking at DMD on top of an exon skipping, showing how the innovation's catching up. DMD looks interesting. We're doing a lot of work to really double down on thinking about the potential opportunity there. FSHD to build around it, so that neuromuscular franchise, you know, I can see it five years from now. It's a beautiful view from my seat. I want to show you the data so you can walk with me, but I think we're on a cadence to build a multi-billion dollar neuromuscular franchise. Unfortunately, that's all the time we have. So we're going to have to cut it off there. But thanks a lot, Jay. Just getting warmed up. Okay.