Hi, I'm Marc Frahm from the biotech team here at TD Cowen. Welcome back to the 44th annual TD Cowen Healthcare Conference. Our next session, we're really happy to have with us Jay Backstrom, CEO of Scholar Rock, where we'll talk a little bit about both their programs in SMA as well as the emerging programs in obesity in combination with GLP-1s. But so maybe just to start off with, Jay, you want to give a kind of brief status update of the company and maybe what you view as kind of the key catalyst over the next 12 or so months, and then we will dive into some of the specific programs.
All right. Sounds good. First, good morning. Good morning, everyone. It's a pleasure to be here. Exciting time for Scholar Rock, right? For those new to us, we're a late-stage development company, but we're on the threshold of becoming a commercial company based on the readout that we have coming up later this year. The company was founded on the science and the insight of how to very selectively target TGF-beta superfamily growth factors, something for which we built a very nice, robust pipeline for. And our lead program, apitegromab, which is targeting myostatin, will read out later this year in SMA. So very big deal for us. I think the other thing that's been exciting is that, given the role that myostatin plays in cardiometabolic disease, that we've also then advanced into a proof of concept study.
We're setting up for apitegromab and obesity and moving another one of our pipeline assets forward to IND SRK-439. Really kind of exciting time for us. In addition, we also have a program in immuno-oncology. Very nice pipeline. I think where I said we're on the threshold, depending on our key milestones this year, will be the phase III readout for SAPPHIRE. We'll talk later today about the basis for that and the confidence that we have leading into the trial. But upon success for that, that will afford us the opportunity then to commercialize the product. I do believe that SMA is a really good place for us to open up our introductory commercial opportunity. That'll make us a neuromuscular franchise. It's a $4 billion opportunity. And I think we've got a highly motivated, committed team.
And I think we can do a really nice job of helping patients upon success. So really excited about that. And I'd just say, over the last year, I've been really, really pleased. I think we've been laser-focused on execution as a company. We've delivered flawlessly against completing enrollment on our studies, which has really been nicely followed in IND for the cardiometabolic program. So the execution has been first rate. We've been able to attract really talented individuals into the company. Again, highly motivated workforce, which is fabulous. Great science. We revised our strategy. We took full advantage of our understanding of cardiometabolic and myostatin. I think we have a really nice solution to address a need that we believe is emerging and real, and the muscle mass loss. And then finally, we had a nice financing in October.
And so we're really in a good position, cash position, to run through our really next key milestone. So exciting time with the company.
Great. Thanks for that overview. Maybe we'll start on SMA, and then we'll keep going through the programs from there. But for us, maybe just review for people kind of the rationale for targeting myostatin here in SMA and why this is really. Myostatin has been around for a while in a handful of other settings, but why is this really the key setting?
Yeah. First of all, I mean, targeting myostatin is really an elegant solution to Spinal Muscular Atrophy, which is a neuromuscular disorder, right? So just a brief background. It's a genetic defect. There's a lack of SMN protein, which is necessary to preserve the motor neuron, which helps control muscle. The absence of that protein, you get motor neuron loss, and that leads to muscle loss. And so the hallmark of the disease is weakness, atrophy, paralysis, right? So it's a devastating disease for those that have it. And the current therapies all direct the neuron portion of the neuromuscular disorder. There's no direct therapies, at least on the market today, targeting the muscle. And that was the insight from the Scholar Rock scientists. I think this is a really nice place for a muscle-directed therapy. Blocking myostatin results in increased muscle mass and function.
We've shown that in the non-clinical setting. We've also shown it in the TOPAZ phase II study. And so now you have a strategy where you're hitting two elements of the disease, the motor neuron portion and the muscle, and really lends itself, I think, to meaningfully advance care for those living with SMA.
I want to review the phase II data that you have shown before. And kind of what is the meaningfulness of the improvements that you think you're seeing when you add this in?
Yeah. The current kind of approval measures for SMA are validated scales. The Hammersmith Functional Motor Scale Expanded is one. There's another one called Revised Upper Limb Module. We included both of those in the TOPAZ proof-of-concept study. And just for those that are just following new, Scholar Rock was the first to demonstrate functional improvement by targeting myostatin in any setting where myostatin was used as a target. And you mentioned that earlier. I think partly that's because of our ability to select very thoughtfully and block myostatin. So we avoid a lot of the off-target effects of toxicity, which had plagued the field. And I think partly it's because there's a potential better efficacy tying to the latent form. And then the SMA space lends itself to that because the muscle is not the fundamental disease. The problem is really with the motor neuron.
But we demonstrated in the proof of concept study the Hammersmith scale. We had a measure we saw of a four-point increase. That four-point increase is meaningful, significant for patients. They can do more things when they achieve a four-point scale. And recall that that was the magnitude of benefit that was seen with nusinersen for its approval. And it's the first to be approved in this space. So we have a similar magnitude of effect. This is on top of nusinersen. So we've added that to patients so they can do even more together. And what we showed over the reported out last year, we've been following patients over a 36-month period and now into four years. And that substantial increase that we saw, that four-point gain, was sustained and maintained over the entire time. That really matters. SMA is an inherently progressive disease.
If you listen to those in the community, they want to be able to improve function. That functional scales, that's definitely addressing the need. They don't want to lose the function that they've maintained and gained because of that inherent nature of progression. Sustaining that endemic status is really profound. We're in that really meaningful change of 3-4 points.
And do you think that Hammersmith scale, is that accurately capturing all the benefits of the apitegromab, or are there kind of meaning because that was really developed for people who had no therapy. And now we've already put nusinersen in there or other correctors. Or are there other aspects of disease that are really not being captured?
Yeah. It's really interesting, right? I think from, like we talked about, from a clinical trial perspective and/or regulatory perspective, these are validated instruments. So they're used routinely. Again, I don't know that they reflect in fact, we've demonstrated, they don't capture all of the benefit. They're a meaningful measure of benefit. What we also demonstrated in the TOPAZ study is we included patient-reported outcome measures that measured activity of daily living, for example. Now, those are really meaningful measures that are not necessarily completely captured. And we showed improvement in that. And then what plagues those with the underlying disease is fatigue. And just imagine, these are individuals that don't have enough muscle, right, because of this progressive degeneration. And so any activity is a major event. And so to sustain things, to maintain them, fatigue dominates it.
We've shown in our study that we reduced the fatigue as well. Kind of taking a step back, targeting the muscle addresses so many fundamental issues with the disease: strength, function, fatigue, improving activity of daily living. I think we really have a nice opportunity to improve patients when we get this commercial.
You want to walk through the design of maybe the phase III SAPPHIRE trial that has been read this year, just and maybe some of the important nuances of patient selection and relative to how things were done in the phase II?
Yeah. I feel very fortunate because the SAPPHIRE design was based on the phase II proof of concept. Again, in my experience in drug development, you tend to have higher probability of success if you've got a phase II study that informs your decisions around the phase III. We were fortunate to do that. The learnings that we took from the TOPAZ study that we embedded into the SAPPHIRE trial are several. First and foremost, we definitely saw a dose response. There was definitely a difference between the 2 and the 20 milligram dose. As a result, we moved the 20 milligram dose into the clinic. So that was an important measure. We also understood the endpoint, right? So the initial data from TOPAZ, we read out at six months on the Hammersmith score. We saw that at 12 months, we even had a greater effect.
So the endpoint is the same, but we did it at a 12-month mark. So that was built into the study. TOPAZ was based on the background of nusinersen only. Our non-clinical data and our belief is that we should be equally effective, agnostic to the SMN upregulator. So we did include in the SAPPHIRE study risdiplam. So patients can come in on the background of nusinersen or risdiplam. And then they're randomized to that background alone versus 20 milligrams and 10 milligrams in the SAPPHIRE study. So we're testing two doses based on feedback we have from the regulatory agencies. We believe, from our understanding of the target engagement, that those two dose arms should be comparable. But it's a three-arm randomized study. Primary endpoint Hammersmith, again, what we did in TOPAZ. We'll read out in 12 months.
We stratified by background therapy, so nusinersen and risdiplam, just to control for that, as well as the time of onset of initiation of those. Key endpoints are Hammersmith, Revised Upper Limb Module, WHO milestones, measures that we included in TOPAZ. We also included in SAPPHIRE.
Okay. You mentioned in phase II, you're showing that maybe 3-4-point benefit. Obviously, it'd be great if you showed that again in phase III. But what's kind of, in your mind, the minimum threshold there that's actually significant?
Yeah. It's really interesting, right? I think that if you talk to those living with SMA, any measure of improvement that maintains independence matters. So that's a, "Can I still operate a motorized wheelchair?" So that's the level of that's really different in the patient's life. From the scale, three is considered that clinically important measure of benefit. But quite honestly, one and two-point changes also matter. So I think it's going to be a spectrum. I think if we're in the range of the two to three points, I think that will be important. We've certainly run the study to allow us to capture that measure. And again, what we saw in the 36-month data, very, very encouraging, is that what we gained, we sustained and maintained. That, I think, is really, really an important matter. It's the durability.
The final piece that I should have commented on earlier is that from the TOPAZ study, I'm calling out what we saw in the efficacy. But by design, we did expect this to be a very clean safety profile. Because when you target myostatin as selectively as we do, the only thing you get is more muscle and potentially less fat, which lends itself to the cardiometabolic discussion. But we don't catch any of the other sort of biologic effects of interfering with the other ligands and this growth factor. So it's very selective. And what we're seeing is the tolerability has been really excellent. We've got over 90% of patients continuing through into our four-year follow-up. Just a very, very clean profile, which should lend itself to a very nice benefit risk and long-term treatment.
You started to mention a couple a minute ago, some of the secondary endpoints. Are any of those, in your view, particularly important that you need to show an effect on? Or is it really just make sure you check the box on the primary and?
Well, clearly, it's important to hit the primary endpoint in the registration study. I really like the secondary endpoint of the Revised Upper Limb Module. We're principally exploring this in patients that are of non-ambulatory status, which means that they need to either walk with some level of assistance or wheelchair-bound. And if you think about the significance of upper extremity strength in that setting, that's a really meaningful endpoint. Now, if you look at our data from TOPAZ, we saw an effect on that. We saw an effect on Hammersmith. So both were there. The Revised Upper Limb Module read out a little bit later. It continued to increase over time. But we think those are both really important endpoints, which is why we included the study. But clearly, they're supportive.
We have an opportunity to continue to follow patients once they leave SAPPHIRE into ONYX to show that benefit that could continue for other endpoints as we go forward.
Okay. There's also, I believe, an exploratory cohort in older patients. Can you maybe explain that cohort and kind of what you're hoping to learn?
Yeah. So again, from the TOPAZ study, the greatest treatment effect size that we saw was in the younger 2-12 group. And so that was the reason for the main efficacy group to be focused on 2-12. It allows us to run a really tight study. However, we also have effect in the 13-21. And so that's included in the trial. I would ask you to consider that as a predefined subgroup, a subgroup of 13-21. In our view, there should be no biologic difference for us to be able to achieve benefit in that group. And we're envisioning that consistency of effect from the main efficacy 2-12 and the same magnitude of effect in the 13-21, that'll allow us to then see the full breadth of that patient population in our label. So it's an important group.
Biologically, we believe we should be effective. So that's why it's included in the study.
Okay. And just, I know we're a little bit away from data, but just your thoughts on kind of the disclosure strategy around there. Should we just expect the primary endpoint and everything else is going to be held for medical meetings? Should we expect some of these secondaries, the exploratory cohort, to be kind of disclosed at the same time? Just how are you approaching that?
Yeah. So we're on track. We announced we completed enrollment in September of last year. So we're absolutely on track to report out Q4 this year. So that's a big event for us. And we anticipate reporting our top-line results, which would include the key primary and secondary endpoints. And we'll also anticipate including the exploratory group in that data. So something to look forward to.
I believe there's also some competitor data coming similar time frame from Biohaven. They're phase III, but also potentially phase II for Roche with this kind of similar type of combination. Just important differences in trials or the design of the molecules that you'd want to highlight as?
Yeah. I think starting with perhaps with the Biohaven approach, I mean, it's certainly a different strategy to targeting myostatin. Again, Scholar Rock has been the innovator in targeting the latent form. We think there's clear advantages to that. We're highly selective. The Biohaven program is an Adnectin and has a different approach. It targets the active. There's a lot of overlap with GDF11 in that targeting. But it's certainly different. I would say probably so fundamentally, there's a different strategy targeting myostatin. I would say from a trial design, again, I spent time emphasizing, which I think is important, that we had a phase II trial that informed our decisions for the phase III design. We are a pretty tight, very homogeneous group that we put in that trial, not a lot of heterogeneity. The Biohaven study is a bit more of an all-comers study.
So there's quite a bit of heterogeneity into that. My experience over time is heterogeneity is not your friend necessarily in clinical trials. It may have a potential to dilute the effect. So that's a key point. I think from the Roche strategy, they've been very much leaning in on the ambulatory and older population. I think it's a very nice strategy for them relative to their risdiplam drug. And so they're going to be, from what I saw most recently, probably 2026 and beyond for their potential registration, although their informing phase II will be interesting. But I think from the time to get to regulatory approval, we have a nice head start.
Okay. Maybe we'll move to the cardiometabolic programs that are starting up. Just to start off, if you want to walk through the rationale for targeting myostatin and maybe layering in there, there's a little bit of debate of the receptor versus myostatin itself. Just your viewpoints there.
Yeah. So I think there's this start. I think muscle matters. That's a really important point. I mean, that matters in SMA, but it also matters in cardiometabolic disease. And if you think about the role that muscle plays in metabolism, glucose uptake, insulin sensitivity, basal metabolic rate, I mean, it is the engine. So it's really an important organ, if you will. There's a lot of crosstalk between muscle and fat. And so that whole strategy of getting to kind of a healthy weight loss management, muscle plays an important role. The Scholar Rock team has been interested in the cardiometabolic effects of targeting myostatin, given that, for years. We took the opportunity over this last year to step into the cardiometabolic space because we believe that we can enhance, if you will, the receptor readiness.
The loss of lean muscle mass that's seen with these highly effective weight loss drugs, we believe over time will prove not to be helpful and that we think that it's really important to sustain and maintain lean muscle mass. We think we have a very, very thoughtful solution to that because we target myostatin exquisitely, selectively, and specifically. And again, what I said earlier, we block out the knockout models. There's human and animal genetic evidence that if you don't have myostatin, you get more muscle and less fat. You don't bring any additional toxicities to bear. And as we think about weight loss, just think about weight loss drugs that have been available. They've been effective, but they've been toxic. The benefit risk is very, very narrow in weight loss management. And so we think that benefit risk matters.
We think that our strategy where we don't bring any additional potential off-target toxicities, we just hit the muscle, is a really nice solution to combine with agents such as this. And so there's been a lot of interest in this area now. There's a lot of different strategies to trying to target myostatin. This is a 30-year-old field. It's been littered also with failures because of toxicities. And the strategies of blocking the receptor will introduce the blocking of activin signaling. And that has its potential downside effects. Blocking GDF11 has its potential downside effects. So you're introducing potential uncertainties of toxicity when you hit other signaling pathways because of the complexity. But if you hit myostatin only, I think that's the.
Can you review how those would manifest in trials?
Well, I think as an example, I think probably what we can point to is the phase II data that exists right now for the bimagrumab, which is the one that's being studied now in combination. It targets the activin receptor, so it hits across the signaling. And if you look at the profile out there, first of all, there's a significant report of muscle spasms. There's significant GI effects. There's a potential liver signal and a potential signal in the pancreas. And I'll tell you, activin signaling is in a lot of different organs. And so you wonder if there's a value in doing that. So I think that's one example. There's clear effects on FSH because of the way it works in reproductive biology. There's a number of fetal toxins.
So a host of things that probably you go, "Is it needed?" And if it's not needed, why bring it to bear? And our view is that we have the effect on muscle. We're going to show that in our proof of concept that we can preserve lean muscle. That's the goal. I think showing that, then I think we'll address the questions of why bring any additional potential risks or toxicities. So I think it's a very nice, very exquisite, very selective solution to what we think is an important problem.
You're starting to touch on this, but just, we are expecting Lilly to have data for that combination probably late summer, sometime in there, maybe. How are you going to interpret that data? What are you going to be looking for?
Well, I think it's interesting, right? I mean, I do think that the credit to the Versanis team. I think that running that study and showing that preservation of lean muscle really was kind of the rallying cry to say, "Okay, there's opportunities here." And so I think first and foremost is that it'll be very interesting to see to the extent that they can preserve and blunt that lean muscle mass loss from an efficacy perspective. I think that'll be interesting. I think the other thing that'll be of interest in turning to us is to see to what extent the safety profile is influenced or not by the combination strategies for the things that I just said. As I think about the proof of concept trial that we're going to design, it'll be a randomized study with GLP-1 receptor agonists plus or minus an apitegromab.
Randomized, we'll be able to see it. I think it'll answer two really important questions for us. Can we preserve the lean muscle mass? Do we maintain the efficacy that we need? That'll be unambiguous because we'll do that with DEXA scans. Then we'll be able to show side by side a safety profile. From what I see in the SMA data and what I understand about our target, I don't think we're going to be adding any additional toxicity. Those are elements that'll be interesting.
What do you think is a meaningful preservation of lean muscle mass or even a gain of?
Yeah. It's interesting. If you look now, I mean, it's reported between 20% and 40% of the weight loss is lean mass, lean muscle mass loss, right? So that's a significant amount. I think if you can blunt that and reduce that, flatten that, I think that would be optimal. If you can enhance it, probably even better. But I think the goal is to blunt or set that loss. And the reason this really matters, right? You just think about the end of the day, the goal is sustainable weight loss and healthy weight loss management. I mean, that's the ultimate goal, right? What we do know is that we have profound weight loss. We need to see more longitudinal data over time.
But muscle plays such an important role in metabolic health, function, et cetera, that preserving that, we believe, is an enormous opportunity to really get to that really good, healthy weight loss management. And frankly, it affords opportunities to potentially maintain the effect and blunt the rebound effect that occurs. There's so many ways that muscle can play a role that I think you're going to see this evolve over time. We certainly have plans to measure that in our studies.
Okay. And I know you haven't even started your study, but just thinking through approval endpoints, right? The current weight loss approval is just pure weight loss, right? It doesn't care where it's coming from for the approval endpoint. And if you preserve muscle mass, at first, it's going to be loss. So what's the approval endpoint? Is the FDA there on kind of differentiating between muscle mass and non-muscle mass, or do you need to show some sort of functional endpoint?
Yeah. I think to be clear to your point, today, the current regulatory approval endpoint is 5% weight loss over a sustained period of time. It is also not just efficacy. It's clear benefit risk. So benefit risk will matter. And if you're combining anything that looks like it's perturbing that benefit risk, which is why I'm really interested in seeing these combination strategies, that will, I believe, affect the regulatory decision for approval. But the primary endpoint is weight loss. We believe that we can enhance that profile, not add toxicities, but we will need to demonstrate the benefit of preserving lean muscle that will be expected of us. And there are a couple of ways to do that. We could show that through improvement or maintaining function, which, depending on the patient population, could be easier perhaps to show.
We can also demonstrate that through an improved metabolic profile. We just released an abstract and presented it at the Keystone Conference where we showed we had an additive effect on reducing glucose in the setting of GLP-1 receptor agonists. Hemoglobin A1c is a regulatory endpoint. There are really some nice opportunities for us to really, I think, build out over time. We'll see more as this field goes. I think anybody that's targeting myostatin that doesn't have the potential to have that additive weight loss effect will need to do the same thing. I think if you listen to those speaking about it, I think there's an acknowledgment to that. That's expected. That's not a hurdle that's insurmountable by any means.
I think what we're going to demonstrate, again, for our proof of concept is the primary endpoint will be lean muscle mass because that's really our mechanistic basis and then the safety. But we'll build into that trial some exploratory endpoints that will help inform the SRK-439 program, which is our cardiometabolic program going forward, such that we'll have a better feel for what measures we want to include to show those functional metabolic improvements.
Can you walk through the design of the trial? I mean, you started to touch on some of the endpoints, but just kind of size and.
Yeah. So we're going to go into a lot more granularity of the trial design in about 2 months as we get closer to getting it open. We're absolutely on track for everything we've said, getting it open in the summer. But I've given a bit of color to it. So it will be a randomized study. We don't think it needs to be a large trial. So we're probably thinking around 100 patients. So that'll be sufficient for us to be able to open, close, and report out within a 12-month window. If you look at the magnitude of decline in the weight loss, it's a pretty steep curve early on for the GLP-1 receptor agonist. You probably get to near maximum loss within a six-month window. So we think the endpoint can be a six-month endpoint, and it'll be a DEXA scan.
It'll be people who are naïve, not waiting for them to plateau and then.
Yeah. That's correct. That's correct. I think that's the greatest opportunity for us, I think, to show that in such a trial.
Okay. And then you talked about the differences between 439 and apitegromab and why those are potentially important here.
Yeah. It's really interesting, right? I think as you look I look back over the history of Scholar Rock, and apitegromab was that first program moving forward. The decision to go into SMA was brilliant. It's an IV formulation. So certainly, IV doesn't lend itself into the cardiometabolic space. For those listening, we definitely have plans to have a sub-Q formulation available. So that's part of our lifecycle plan. But moving that forward, the team didn't stop looking in the cardiometabolic space. And we've got a family of compounds we've been looking at. And so really, we're selecting a program that would lend itself to a population that would require milligram-per-kilogram dosing that needed something better. And we wanted something that was a sub-Q formulation. So what was preserved was the exquisite selectivity of targeting the latent. Our strategy to do that, that was inherent in this.
So that had to be a criteria. It has higher affinity, and it lends itself to low-volume sub-Q formulation. So that's what we're looking for. It'll be a sub-Q presentation. We believe we'll be able to do that at the opening of the IND.
Is that difference so important that 439 is kind of the long-term molecule no matter what? Or if, unfortunately, the SMA trial is negative, does that kind of change the calculus where maybe apitegromab, because it's so much further in the clinic, so much more clinical experience, you are doing some work towards a sub-Q for it, it kind of changes the calculus, and maybe that's the one that you put forward with?
Yeah. I mean, I think our lean-in position is we are absolutely committed to the SMA space. I mean, we made that very clear. I mean, you should walk the halls of Scholar Rock. We are absolutely committed to the SMA space. So we didn't want to in any way leave the impression that we were leaving SMA behind as we ran into cardiometabolic. So we are very clear on the apitegromab plan, right? But that's the plan, right? Things change when circumstances change. At this point, we obviously do scenario planning. But right now, today, I'm telling you, we feel pretty good about where we are with the apitegromab program. So I'm not sure we're going to have to face that question. I do like the fact that we have SRK-439. It has its own IP. It has a longer IP runway. It's its own unique compound.
It lends itself beautifully to go in. That's the play forward plan. But we certainly, again, I think the proof of concept will be interesting for us for apitegromab, and there may prove to be opportunities there as well. But right now, our position is that's our SMA drug.
Okay. And just ED strategy here, do you think ultimately, do you need to partner with somebody who does have a GLP-1? Can you do this yourselves? Do you need to kind of hand this off to be developed?
Yeah. To be clear, and I think we've been pretty straightforward from the beginning. While I believe and I feel very good about, frankly, bullish about our opportunity to become a commercial stage company in a rare disease like SMA, given our time in there and the current market, we definitely need to, we would not take our cardiometabolic program all the way through registration and commercialization. That's, at this point, not our ambition. So we definitely would be interested in strategic partnering. What I feel my responsibility is is to drive value for the company. And I know what we can do, and we can do well. We can run proof of concept studies. We prove that we can run randomized phase III studies in sort of rare and orphan disease. So we would be obviously looking for a strategic partner at some point along the journey.
But we're ready to run the apitegromab study and drive SRK-439 to IND. As you know, there's a lot of strategic interest in this space now. I'm really delighted that we're in it.
There's a number of other kind of incretin family member approaches also working their way through the clinic related to GLP-1. Any of those that you would point out as particularly good or opposite, poor combos for a myostatin, or does it really just not matter what happens on the incretin side in your mind?
Yeah. Our view, much like an SMA, we're kind of agnostic. I think our effect on muscle should work independent of whatever the mechanism is for weight loss because lean muscle mass tends to accompany it. So we believe we could work with that. And our preclinical work has been principally in the GLP-1 receptor space is the data that we've shared. But I think going forward, I don't believe that it would I think we would have an opportunity there as well.
Okay. Unfortunately, that's all the time we have. So we'll have to cut it off there. But thanks a lot, Jay. Thanks, everybody, for.
All right. Exciting time for the company, right? Stay tuned. Big year for us.