Great. Looks like we can go ahead and get started. Thanks everyone for being here. My name is Ally Bratzel, one of the biotech analysts here at Piper. And it is my pleasure to introduce Scholar Rock. So joining us this afternoon, we have CEO and President, Jay Backstrom. So thanks all for joining us. This is meant to be informal, so if anyone here in the audience has questions, feel free, go ahead, raise your hand, and we'll get to it. But I will go ahead and start out with some questions for you, Jay. You know, coming off the successful Sapphire readout in SMA, you know, just walk us through the data. What does this mean for patients, and what could it mean on the commercial front?
Yeah. So first of all, Ally, thank you. It's nice to be here. You know, I've said before, as we were leading into the data, this is an exciting time for Scholar Rock, really transformational. We were thrilled, of course, when we saw the results of our phase III study. I'll tell you, importantly, to your point, is not only what it means for the company, what it means for the community of SMA, right? We got into this space, we've had very deep connection with the patient advocacy group. And before we ran this trial, as we listened to the community, they want to gain function, maintain function, because this is an inherently progressive disease. And so what we saw in the Sapphire data really, I think, really addressed all those concerns. We obviously met the primary endpoint.
For those who are not familiar, we studied it on the background of standard of care therapies, so either nusinersen or risdiplam, randomized to apitegromab. We had the primary endpoint was Hammersmith, so it's the gold standard validated measure. We showed there for the first time for anybody studying targeting myostatin, a successful phase III study with functional improvement. That was significant in and of itself. The magnitude of benefit that we saw in the primary endpoint, and this is looking across all the data, was a 1.8 change on the scale, which is clearly significant and clinically meaningful. I'm gonna give you a little bit more color around that.
But I think important is that if you take a look at the totality of the data, and the thing that really struck us is when you looked at the curve for the standard of care, best of care, what's existing today. It's really high, tremendous innovation. Individuals randomized without apitegromab lost function. They lost the point, which is exactly what we've seen in the nusinersen data. And adding apitegromab, they gained function. So they're gaining functions instead of losing. We saw that nice change across the entire cohort. And on top of that, 30% of patients achieved a three-point or greater increase. So the richness of the data, I think, were really striking. The robustness of the data, very consistent across all of the subgroups that we took a look at.
And then, final comment, the whole concept for Scholar Rock is to be highly selective in targeting TGF-β biology because it really matters when it comes to toxicity and benefit risk. What we showed in Sapphire is what we'd seen before, is this extraordinarily well tolerated, safety is very clean, lending itself to chronic care. So summarizing all that together, I do think we are on the verge of having a new standard of care as we move through the regulatory front. And I think it's exciting, not only for the community, but for us, and then I think what it means commercially.
Excellent, so maybe digging into a couple of those points. This is a question I've been getting a lot since the Sapphire readout, just on the, you know, putting into context the magnitude of that 1.8 point benefit on HFMSE. You know, I guess we try to do some analysis, and it turns out that's like 3x the benefit that risdiplam showed in their trial. But can you maybe just describe to us, you know, the clinical meaningfulness of that and what gives you confidence that that is gonna put patients on therapy?
Yeah, I think it's really important to just take a look at your comment about what is happening with the current standard of care. Nusinersen, for example, showed a four-point gain. That was against no background therapy at all.
Mm-hmm.
And risdiplam had a similar, more attenuated effect. For the community, any of these points, functional improvement really matter. And I think this is the piece that we kind of lose sight of. An example, to operate a motorized wheelchair allows an individual to maintain functional independence. That's a very, very tiny point on a scale. And so really it's around maintaining activities of daily living, functional improvement, and to not look at it so much as is a point enough, it's what does it allow and enable a patient to do? How can they do more things for themselves? And I think what we've seen is adding on top of this care, we're giving them even a greater boost.
And I'd point, you know, the audience, if you haven't taken a look at it, the data that were presented at Cure SMA of the long-term follow-up for nusinersen, which shows initial increase, a plateau, and then a decline. And we're envisioning from our data, we've already shown that in a decline phase, we're adding function, so we're preventing that, and we're adding additional points on top. I think we can change the trajectory of the curve for these patients with added apitegromab to it. So all that together, I think we should give early and often, give them the best boost and maintain it. But I think at the end of the day, it's really addressing the community's needs for more function, maintain function, gain function. That's what our data are telling us.
Yeah, no, that makes sense, and I know something I'm looking forward to is full Sapphire data. You know, there's some other efficacy endpoints that I think will be particularly interesting, like RULM, looking at upper limb function. I guess, can you discuss just your sense of kind of what will be most important to patients and docs when we get that full data, and just, you know, when can we expect that?
Yeah. So first, when do we expect it? So we reported out the top line. You know, these data, this is like a very significant randomized phase III study in an area. So it deserves to be the opportunity to be presented at a scientific and medical conference, which is why we didn't go through the full data on our call. That will happen. You can envision an idea of when neuromuscular conferences are held over the course of the year. So we'll have an opportunity next year to really get a full disclosure and discussion around these data. So that, that's on the endpoint. I think from the consistency of effect and what the community is needing, you know, I've always, the Hammersmith, again, is a validated scale. It measures a number of different things from can you sit, stand.
There's elements in there that really are functional assessments. The other validated measure, to your point, is this Revised Upper Limb Module, which really assesses upper extremity strength. If you look at our Topaz data, we had a really nice effect on that. That effect was seen at the beginning, but continued to increase over time. And for those that are wheelchair-bound or really need the upper extremity to maintain and function, I think that will be an important point to see. But I think the Hammersmith in and of itself, I think, is significant and meaningful. But we'll, we'll share those data. I think what you'll find is that there, what I was struck by is the consistency of effect that we've seen across. And we'll have an opportunity to share that.
Excellent. Can you talk to just, you know, among the SMA community, you know, it's been a couple of weeks since Sapphire has been out. Just how has the community reacted? Kind of, what's the level of awareness, excitement among patients and families, for the therapy?
Yeah. So that's such an important question, right? We have really had a very nice relationship with the patient advocacy group, the Cure SMA, and also the group in Europe. I've done this 30 years. I've never seen an advocacy group as just so effective.
Mm-hmm.
Really such a sense of community. So they're very excited. I think they've been anticipating our therapies. We've been kind of working with them over the course of time. I had the good fortune, before we disclosed the data, you know, under confidentiality, to reach out to the president of Cure SMA and inform him of the trial results. I mean, I can't imagine the enthusiasm that he greeted with. And the very next morning, once the data were publicly disclosed, it was throughout his entire network. So the community is really looking forward to this. When we've engaged, just put yourself into the context of these are parents or grandparents with children that they wanna be able to give as much function and preserve their independence. They are just looking for any opportunity. And I think we've really shown that we have that. So they're waiting for it.
That's why we're, you know, doing with a sense of urgency getting the application in and get this ready for commercial. And then equally, we've had an opportunity now with the data being out there to then not only share with our investigators who we've worked with and who know us well and know the data, but, you know, part of the community that is hearing more and more about it. And you immediately the reaction is beginning to see how this could be adopted into practice. So I think we're in a really good place. We've got a lot of momentum going into 2025.
Great. So this is a question I got a lot, particularly before the T-alfa data came out. But, you know, the route of administration is once monthly IV. You know, is that viewed as a barrier for patients? You know, I know there should be the opportunity for home infusions for many patients. And you, I think you've got a sub-Q in the works. Yeah, just, just discuss the dynamics there.
Yeah. So I think what's clear is the community's looking for effective therapies. They're looking for functional gains. And you think about it right now, there's intrathecal administration for nusinersen. There's other forms for risdiplam. Both are establishing themselves equally and nicely in the market because they're effective. What we've seen from our Topaz data is that monthly infusion is not a barrier. They're seeing effect. They're not stopping. We've got over 90% on now going into five years of ongoing therapy. So that monthly dosing is really managing because they're seeing the benefit from it.
I think as we come into the commercial setting, you know, we really are trying to be very attuned to how to make this as easy and as seamless as possible for those getting treated, which means that we are gonna have the option for home infusion, assuming that meets the needs of those needing treatment or in clinic, so we can do either, and I think that'll allow it to be seamless. Monthly treatment is an advantage, and I think that's something we've seen and back to the point about maintaining, so when we finished the Sapphire study, 98% of the patients completed it, and they rolled into the Onyx therapy and to our long-term extension, so we're maintaining because of the benefit that's being perceived.
So on the market opportunity and commercial front, you know, I think since we've last spoken, we've seen data, you know, unsuccessful data from a competitor. So the competitive setup looks a little bit different than it did before. So I guess, you know, given that and now with Sapphire data in hand, how are you thinking about the market opportunity, you know, the TAM here? And then also, how well equipped do you feel going to payers ahead of launch?
Yeah, good questions, right? I think so we were anticipating even in advance of, of one of our, you know, the competitors reporting on it that they were not successful, that we'd be in a competitive space. And at that point, we were indicating, given what we understand about the current market, we thought this was, you know, a billion-plus market opportunity, considering it's a $4.5 billion market across three programs. We're not competing with the established SMN therapies. We're, we're adding to, we're enhancing. So we thought we had a really good opportunity to really take full advantage of that. I mean, looking now with us as being the first and the only for a window of time, obviously feel that that gives us more momentum to really be established.
Again, the vision that we have for the program in light of these data is that this should be part of the new standard of care and should be considered in addition to the existing therapies. And the current, you know, two-thirds of the current patients with SMA are already on treatment. So we think we have a really, really good opportunity here to kind of meaningfully advance care, but at the same time, commercially turn this into, you know, truthfully, multi-billion-dollar opportunity, not just in SMA, but adjacencies to it.
Right.
This is gonna be, I think, a very important medicine for us and for the community.
Mm-hmm. So, you know, this time next year, you could be commercial stage. So walk us through some of that, you know, some of the prep work you're doing now, and launch readiness activities. And then, you know, how we should be thinking about this launch. Is Spinraza, the risdiplam launches, those good analogs? You know, why or why not? Just.
Yeah. So let's start with the preparation because I think we've been planning for success truthfully since I've joined, right? So I think for the regulatory application, the regulatory team was putting this application together, waiting for data, dropping it in. That's why I could be stating that we're on track for a Q1 submission 'cause we've been preparing. Similarly, with Ted and the team's guidance, we've been putting together sort of strategic hires on the commercial front for long lead time, things that we need to do with payer access, et cetera, but poised to then really ramp up on commercial. And as an example, you know, we have the head of our commercial sales that was hired almost within the day or a week after we had the announcement because we were screening and planning and interviewing, really running in.
So there's a really nice ramp up on the commercial front, getting supply chain in, thinking about how we interact with payers. On the medical side, our medical teams have been out there, fully engaged. Market access team is engaged, payer community. So we're, we're really teeing this up, Ali, to really be, I think, with great, great momentum. I wish I could kind of give you that sense that's happening within the Scholar Rock organization, but to a person, we're just really, really, really running fast.
Excellent. So yeah, 2025 is gonna be a big year for apitegromab and SMA, but also proof of concept data coming for obesity. So I wanna spend some time on that. I guess kind of before we get too much into the specifics, so can you just help us understand your overall, you know, strategy here, and selectively targeting myostatin in addition to GLP-1 therapies? Are you aiming to provide incremental weight loss over GLP-1 alone or preserve lean muscle, maybe at the expense of overall weight loss? You're looking to improve the AE profile. Like what is the ultimate goal of this combination strategy?
So we entered into the cardiometabolic space formally a year ago, October. But that was because we've spent a lot of time taking a look at myostatin and muscle as a kind of metabolic approach because muscle plays such a critical role in metabolism, glucose uptake, insulin sensitivity. You know, and Mo, Scientific Officer and team really have shown to the opportunity that we could have to really make a difference in the setting of cardiometabolic disease. We entered into obesity. The problem that we were trying to solve wasn't additional weight loss. I mean, personally, I don't think there's a need for another drug for additional weight loss. The innovation's incredible. What seems clear is that we could enhance the profile of these really highly effective weight loss therapies by preserving what is essential, which is muscle.
Mm-hmm.
I mean, so we come into it. So that's the view. Muscle matters. We can preserve it. And then the next piece, think about cardiometabolic and weight loss. Benefit risk matters in every indication that we think about therapies. You can tolerate more risk in areas like cancer, but in weight loss, the risk tolerance is extraordinarily low. There is not a more elegant way to preserve lean muscle mass than through the highly selective approach that we're taking by hitting the precursor forms of myostatin. We do not perturb any of the other biology of the TGF-β pathway. And if you look at the strategies, it's littered with toxicity. We block myostatin. You get more muscle and less fat. That's it. So there is not a more elegant, selective solution to this problem.
And when you start to think about other strategies, if you're targeting ligand trapping or if you're selecting the receptor, by definition, you're gonna perturb any of the biology that signals through that. And hitting the activin receptor brings with it additional toxicities, which we don't believe are gonna bring. So that's the thinking. We don't think we're gonna disadvantage the weight loss, but we do think we'll advantage the preserving lean mass. And then we think with that, we'll have a better sustainable health outcome. The work we've done in the nonclinical setting suggests that in fact, when we do head-to-head nonclinical trial against bimagrumab, which is kind of the lead, we are equally effective at far lower doses. We are more potent. We've got a much more elegant antibody, to be honest. And I think it really lends itself to sub-Q getting into clinic.
We've shown that when you stop these therapies, we can attenuate the fat mass rebound in the background of our continued treatment. So I think we can really have a nice opportunity to really, really enhance the profile of these existing treatments.
For EMBRAZE, your phase II proof of concept trial looking at apitegromab plus GLP-1, can you talk about just what's the bar for success there? You know, like what do you need to see on efficacy on the primary endpoint, change from baseline and lean mass, you know, to be confident taking that forward that you've got the right clinical profile?
Yeah. So to start, I think for those that aren't familiar with EMBRAZE, it's a randomized phase II study, on the background, new starts of either semaglutide or tirzepatide, randomized to apitegromab or placebo. We opted to do apitegromab in this study because it's a clinical asset. And we are looking for the question we're trying to answer is, can we preserve lean mass? You take a look at the data that Mo and team have generated. What we've shown is that we can, we can preserve it. So if I think about what good would look like at the end of the trial, you start with your lean mass, and on the apitegromab arm, you maintain that. And if you're randomized to the other, you lose it. And we show that differentiated effect, you know, if we attenuate, that's great.
But if we can preserve it, that would be, that would be really good. And our nonclinical data would suggest we could do that. So that, that's the first question. Can we preserve it? And I think it also addresses some of the, you know, the uncertainty that's been around is, do you need to hit the activin pathway to really maximize your effect on lean muscle? And I think we're gonna answer that unequivocally from Sapphire. It's pretty clear we show functional improvement by our selective strategy. I think we're gonna be able to show that here, that we can preserve it without the need for adding the toxicities of hitting the activin pathway. So that's, that's principally there. We'll be able to show side-by-side safety data. And then in addition, we built in some additional exploratory endpoints. 24-week is the primary.
And then we stop therapy for both semaglutide, or tirzepatide, and apitegromab. And then we'll repeat a DEXA scan eight weeks later to see whether or not we can actually blunt the rebound effect of fat mass. So we'll have that data too. Won't be in the top line, but it'll follow.
Excellent. So, I think this is also a question that comes up a lot with investors. It's just, you know, in terms of approval endpoints in obesity. And it seems like some of those, you know, other exploratory endpoints you're looking at, A1C, body composition, you know, function, things like that could, you know, be useful, perhaps not on a regulatory endpoint framework. Just how are you thinking about that? And does FDA need to evolve their thinking?
Yeah, it's interesting. I think so the changing regulatory endpoints is a journey. I've been involved in getting new things set, and it takes a while. So there's no anticipation that that's gonna happen in the near term. But I think as the field evolves, what I would say is both EMA and FDA are open to understanding how to more appropriately represent endpoints that translate into meaningful clinical benefits. So I think that's to come. Current endpoint right now today is weight loss. Having said that, I think what FDA is clear, some of the uncertainty is 'cause this is the first time we're doing this in a weight loss setting. But if you look at other regulatory approaches, combination therapy, adding an additional therapy, you just need to show that you have what's the additional clinical benefit?
And that, do you feel better with that additional therapy? Do you function better? Or, you know, you're influencing survival. I think so. For our view, there's a subset of patients today that I think are not getting access to GLP-1 receptor therapy because of the concern of loss of lean mass, maybe an older group that's a little bit of concern. That would be a good group to study to show functional improvement, for example. We've also shown what's a very well-established regulatory endpoint is Hemoglobin A1C. And from our nonclinical data, again, because muscle plays such a role in metabolism and glucose uptake and insulin sensitivity, we've seen additional effect on glucose on top of. So if you can imagine now a subset of patients where you can show added benefit to Hemoglobin A1C, those are very clear regulatory paths going forward.
And so, you know, I think about, as we think about going forward, first and foremost, EMBRAZE will show we can preserve lean mass. We believe that's the essential building block. That's what we're trying to answer. And then we'll have an opportunity from this to think about subgroups of patients that we can study when 439 gets into clinic. What I can tell you is that one thing we should be able to do when we get 439 into clinic, so it's our cardiometabolic anti-myostatin, even during the healthy volunteer study, we'll be on biology. We'll show we have an effect on lean mass. So I think it's a, it's a journey that we can really showcase as we go forward, feeling very good about it. Again, I feel extraordinarily fortunate to lead an organization that is just so committed to everything we do.
To this point, we've met or exceeded all our timelines. I think we did catch people a little bit by surprise in our Q4 readout for Sapphire. I think folks were thinking a little bit later in the course of the year. You just can't hold these guys back, right? They were driving. I feel good that EMBRAZE is coming and looking forward to sharing that data.
So maybe, and I think we've got time for, oh, question from the audience. Go ahead.
There was a difference. That's similar in.
Well, it's interesting, right? I think kinda what we were saying, the foundation of the company is we think selectively hitting the precursor form avoids interfering with any other growth factors within the family. And, for example, T-alfa does block GDF-11, so it is hitting another growth factor, right? So there's some issues where that would be nice to avoid. If you think about it scientifically, we're not even letting the mature growth factor even be activated. So we're blocking it before it's even activated. It doesn't even have a chance to engage with the receptor to even do any of that signaling. That should have a theoretical advantage on efficacy, right? So I think it does matter. I think the approach matters.
Now, whether that'll be discernible as we look at lean mass and we'll see that effect over time, we'll need more clinical data on that. But that's where I was feeling really, really good about our approach. I mean, this highly selective, really well-engineered monoclonal antibodies, fully human, well-behaved. And now we're showing that we've starting to demonstrate myostatin is a target worthy of consideration when you have the right approach to it, right? And I think that's what Sapphire's telling us. Looking forward to our work continuing in the cardiometabolic space. But in addition, just to kinda go back to where we are with SMA, we're really excited about getting that forward. This is transformational for us as a company. But we're not done in the neuromuscular area either.
There are adjacencies that we'll be talking more about as we get into next year where I think we can expand even beyond what I think is a really significant opportunity for us in SMA.
Great. And with that, it looks like we're kinda running up on time. So Jay, thanks so much for joining us. Great to hear about all the progress and what's to come.
Yeah. Thank you, Ally.
Thank you.
Thank you for your attention.