Just to level set for investors, can you give us just an overview of Scholar Rock, you know, the story, how it's evolved since you started a little over a year ago, and the setup into 2024?
Yeah, thank you. First, it's great to be here, and it's a really exciting time for the company. So I joined a year ago. We made a lot of progress in the last, in the last year. So for those new to the story, we're a clinical stage company. We have two programs in clinic, apitegromab, which is our lead in SMA. We're going to hear a lot about today. Very excited about that program. We reported out some data for SRK-181, which is a program we had in immuno-oncology, so we've got some nice data there. But I think about what we did to try to set up the year. It was really important for us to advance SAPPHIRE, which is our Phase 3 registration study, which we've done, on track with that, which is beautiful, get to some decisions around the 181.
But importantly, we had a really nice opportunity to announce our entry into the cardiometabolic space, given our long history with, with anti-myostatin. So I think we really had a nice setup for the year, but great momentum going into 2024 and really looking... It should be a very exciting, pivotal year for us.
Excellent. So let's kick things off. Yeah, lots to talk about, but let's start with some SMA, and go right into the ongoing phase III trial, SAPPHIRE. So a question I get a lot from investors, I'm sure you do, too, is about how the distribution of patient ages in the phase III SAPPHIRE trial can impact, you know, the outcome of that readout. Could you just kind of talk to that and remind us of the stratification factors and other learnings that you implemented based on TOPAZ that give you confidence, you know, in a positive SAPPHIRE readout?
Yes. Maybe to start with, with sort of the whole idea of apitegromab and SMA, because SMA, as you know, is a neuromuscular disease. Current therapies really to be celebrated because they're all addressing the SMN protein, which is the fundamental issue, right? But it's really addressing only the neuro portion of the neuromuscular disorder. And I think what I really celebrated about Scholar Rock was going into SMA with a muscle-targeted therapy, really has an opportunity to really enhance, which is what TOPAZ showed us. We showed that when we added to the SMN upregulator, which at that time was Spinraza, we had an additional 4-point gain on the Hammersmith scale. That's a significant, significant increase on top of background therapy, and we celebrated 36-month data.
Because we had that phase II study, that was the first, to my knowledge, where targeting anti-myostatin with the strategy, which is very selective for Scholar Rock, translated into improvement on a functional measure. So it really vAllydated, I think, the idea. Because we had a phase II, then to answer your question directly, we had an opportunity to interrogate that data and really try to enrich the phase III study with those we thought would have the most likely to demonstrate the benefit. What we saw in that trial is for, particularly for those non-ambulatory type 2-3, and we focused on 2-21, principally the 2-12 age group, that showed the greatest effect, to really power and sample our trial around it. But we're studying the full range of 2-21 in SAPPHIRE.
So I think we had the opportunity to vAllydate the endpoint, pick the dose, find the right patient population. All those are really good things for successful Phase 3. And then we did stratify, to your point, around two variables. What we saw in the TOPAZ data, which really proved to be true over time, is that the time between birth and getting an upregulator really matters because it's a degenerative disease. The motor neurons are being lost with time. And so we thought it was important to be sure that those who got into the trial had received that under the age of five. That did seem like there was an effect there that really translated into potential loss that might be difficult to recover or over five. So we stratified by the age of onset, and then we also stratified it by the two SMN upregulators.
So, Spinraza, which we had the TOPAZ data was based on, and risdiplam, because we're agnostic to that, we think we should have an effect. And so those are the two factors that went into Phase 3.
Excellent. So just thinking about, you know, when Q4 2024 rolls around, and we're getting the SAPPHIRE top-line, you know, I know you're also enrolling an exploratory population with those older patients, aged 13 to 21. Is that something we should expect in the, you know, in Q4 2024 readout? And just how does that data impact, you know, how you think about, you know, a potential label and what's included in that?
Yeah, very important questions. I think two things, right? So when we report our top line, it'll be the entire data set. So it'll be the 2 to 21 and the 13 to... or 2 to 12 and 13 to 21. So the entire trial will be reported out. You know, I have you think about the exploratory group as a predefined subgroup, so that if in fact, the point estimate, the effect size is similar, then I think that would give us an opportunity to see that full age range within the FDA label. So that'll, of course, be a label discussion, but the trial should be designed to be able to show us that. So we see that as the potential opportunity is the full age, from 2 to 12 to- or 2 to 21.
There's practically no difference in biology between a 12- and a 13-year-old. We should expect the effect to be the same.
Excellent. And then just thinking about, you know, assuming success in SAPPHIRE, what can we expect in terms of additional trials for apitegromab and other SMA populations, like under two, you know, ambulatory patients? And then also just in terms of life cycle plans, you know, I think you've articulated the potential for a subQ dose format. Just any color there, or is that something we really need to kind of just sit tight and wait till SAPPHIRE reads out to get some visibility?
Well, you know, it's interesting. I mentioned, you know, earlier last year. We're executing on SAPPHIRE, which is critical, right? And we're delighted that we're done with enrollment, and we're planning to lock data as we speak and getting ready for that readout. But this is also, for just a planning opportunity, to think about lifecycle plans. So the team has been working on it. You know, we've been able to enroll patients age 2. You know, what I was commenting on now is practice is such that really almost at birth, newborn screening and initiation of therapy. So we're very interested in an under 2 population. We've been working on the planning of that protocol and study and working through a regulatory agency. So we'll have more color when we complete all that work, but definitely have a plan to do that.
And then, you know, I made a comment when I looked at the TOPAZ data. You know, I think that we will have an opportunity to show improvement even in an ambulatory setting. We just focus more on the non-ambulatory, so more to come on additional lifecycle play. And then finally, yes, I think we certainly have intention to bring a subQ formulation forward. Although right now, I like that we have monthly dosing, and we think we really can enhance the patient experience with our current program, but we certainly have plans for lifecycle play.
Okay. And maybe just one last one on SMA. Just, just on the competitive setup, you know, there's other companies out there advancing myostatin inhibitors in late-stage development. Do you think there's, like, room for three myostatin-targeting drugs in the SMA market? You know, assuming... It's a big assumption, assuming all, you know, succeed in, in phase III and, and hit the market. Or just kind of frame for us how you see the potential, you know, competitive setup shaping up in a, in a world where there are multiple approved in, in SMA.
Yeah, well, I think two things, right? I think, as I think about the treatment of SMA, I do believe we've said this before, that the next real standard of care therapy coming forward is gonna be muscle-targeted therapy. I think we're gonna show that with our trial, hopefully, and I think that really set the stage. I think the patient community is hungry for additional therapies, and so I think we're really teed up nicely. I think right now, today, if I look at the market, there's 3 SMN upregulators all being used. We're seeing that there's crossing and switching across those, again, underscoring the demand. And I think, you know, at the end, as we think about it, I think there will be, you know... Hopefully, we'll report out early and maybe first.
But nonetheless, I think there's opportunities for us to really have a successful opportunity in the commercial space. Maybe I'll let Ted comment on that. Because I think frankly, the data will probably dictate sort of uptake and dictate the color and shape and usage. A couple of things that I really like about it. You know, we chose an endpoint that was the Hammersmith endpoint. That arguably is gold standard in the standard of care of using these measures. Spinraza used it, and I think reporting out against that, I think, will carry some weight, and so we'll see at the end. I don't know if you want to add some color to that.
Yeah, I mean, as Jay mentioned, we learned a lot from TOPAZ. We designed SAPPHIRE with the intention. With everything that we learned, we think that's de-risked. We think that'll serve us well, and if the data turn out the way we expect, we do think that'll be a real boost to our commercial success. We plan on commerciAllyzing in the U.S. and Europe on our own. We think this is a market and an opportunity, a therapeutic area that serves, you know, a small biotech can commerciAllyze on its own. U.S., Europe, rest of world to be determined, likely distributors and partners. But it's really a great opportunity, and we're committed to the space.
We see the big de-risking event, as we talked about, when the data read out, and we're doing some commercial prep now and then a whole bunch of planning. And once that de-risking event happens, the SAPPHIRE data, we'll really be ready to go.
Excellent. I'm gonna shift now to cardiometabolic. So I think we all know you, you know, unveiled your cardiometabolic strategy earlier, earlier this year, introducing SRK-439, plans for the proof of concept obesity trial with tirzepatide plus GLP-1 next year. So obviously, lots of questions there. But first, can you just kinda explain the origin of all, of all this, this program? You know, I don't think this was just kind of a rash decision to go into cardiometabolic. You know, it's my understanding this has been in the works for a long time, kind of a natural extension of those kind of foundational principles of Scholar Rock and your expertise. So just kinda discuss how that came about and then the strategy there.
Yeah, a really good point. You know, it's like overnight success, and suddenly we come out and, like, all of a sudden, right? It's like nothing happened before. Really, really fascinating, right? Again, looking at the history of the company, you know, targeting myostatin was really one of the early targets. TGFβ1, as you know, is another one. And I think when you start to look at the potential effects that enhancing muscle has in a cardiometabolic play, where it enhances insulin sensitivity and glucose metabolism, there's like a logical extension of thinking about taking a myostatin program there. You know, and so there was a lot of nice non-clinical work and a whole campaign around finding, you know, apitegromab and a family of programs. So that was going on for a while. As I think about what Ted said beautifully, right?
So for Scholar Rock to be in its first indication in a commercial setting, SMA makes perfect sense, right? Rare disease, established market, capital investment show that. So the apitegromab program going into SMA made sense, but behind the curtain was all of this additional work with cardiometabolic. And when I joined the company last year, the team did a portfolio review, and I'm telling you, the data that I saw coming out of 439, we just said: This is some- this is very interesting. Put this in the pipeline, let's move. And we've been moving 439 through the year, revisiting all the discussions we had with cardiometabolic and thinking, great advisory input, all of this work, and then it turned out timing was quite good for us as we came off a very successful financing....
So I feel very good about seeing that window of opportunity. But I, more importantly, I think that we really have a very thoughtful strategy, given that we are so selective in hitting myostatin. We don't bring any additional off-target effects. I think this is a new target to hear more and more about, and I really like our strategy of selectivity.
So on that point, I think, you know, there's some other players in the space exploring myostatin approaches and obesity, a lot of which also target Activin signAllyng with the rationale that if you only hit myostatin, you know, you're giving up a lot on efficacy. So I guess, Ken, what are your thoughts there? You know, what gives you confidence targeting myostatin alone gives you the best clinical profile for 439?
Yeah, again, I think it's like we have to ask, what, what problem are we trying to solve? You know, what is the need there, right? And so I would go back, and I would say, what we do know from targeting myostatin is that we can increase muscle mass. We, we know that. And so the current challenge, I think, with the GLP-1 receptor agonist therapy is weight loss is accompanied by loss of lean muscle. We know we can address the lean muscle, so I think that's really important. I think the second thing, as I think about, is in an area where everything is tied around benefit risk, why bring anything additional to bear if you don't need it? And to hit myostatin and increase lean muscle, we don't think we need to have the Activin portion.
Mm-hmm.
It certainly plays a role in some other effects, but there's already significant and substantial weight loss. The challenge is the lean muscle mass loss. Hit that, preserve that, and I think benefit risk really matters. It matters in just about every indication. You think about it in oncology, we tolerate more risk because it's such a severe disease. We know from weight loss markets that the tolerance for risk is not there, right? We had effective weight loss drugs that were pulled because of toxicities. It's a big market, large market, lots of exposure. I have the principle that just do what you need to do and nothing more. And I think what we're doing is really substantial because muscle plays such a significant role. It is a, you know, consumes energy, glucose metabolism, crosstalk with the adipose.
I think doing that is really a good idea, and I think from our non-clinical data, what we've shown is that we can actually have a very nice effect, the GLP-1s, potentially additive. Really sets the stage for really interesting opportunity to think about how we can really, if you will, create this weight loss that is maybe healthier, quote, unquote, sustainable, and yet not bring any additional off-target toxicities that are really not necessary. So I like where we are with this.
Excellent. So turning to the proof of concept trial that should be kicking off next year. So apitegromab plus GLP-1. You know, I think you've been pretty clearly articulated this isn't gonna be like a dose-ranging study. This is just purely a proof of concept trial with an approved or a dose of apitegromab where you're looking at SMA. I guess, can you frame any more for us on the kind of scope of that trial? I think a lot of this might be dependent on your pre-IND meetings with FDA, so maybe we'll have to kind of wait and see on that.
Yeah, a bit more to come, but I'll give some color behind it because I think some of those things I know I've said before, and I'm really happy to restate. You know, again, I think we're advantaged because apitegromab is a clinical stage asset, right? So we can then get some clinical data through, you know, a new IND, of course, so we have to do the regulatory work. But we're able then to go right into a proof of concept study, which we're anticipating will be a randomized design of add-on to a GLP-1 receptor agonist. So that, I think, will really be good.
The size and scope of that, we'll kind of talk about, but if you look at what we've shared, you know, we plan to get the study started 2024, and we have data readout in 2025. So we don't need a 500-patient trial to show proof of concept, so we can do a really nice, efficient study. We're also advantaged because we are in clinic. We don't need to do dose ranging. We have two very effective doses that we believe will show to be true in SAPPHIRE, 10 mg/kg and 20 mg/kg, and it'll be one of those two doses that we'll take forward. And again, as we think about the program, what it will... should demonstrate for us is it'll remove the question, can we preserve lean muscle mass? Because we'll be able to show that in the study.
So that'll be tick the box. We've done that. As a randomized trial, we will begin to see what I believe will be true, is that the safety profile that we're seeing for apitegromab in the SMA program, which has proven to be really, really well tolerated in TOPAZ, will bear out in a randomized study. And then we'll- I don't believe we're going to be adding any additional safety issues, and so we'll be able to show that. And that'll be demonstrated and reported out if everything goes according to plan, right as we're opening up an IND for 439. And so that'll be a nice de-risking lean in to get the 439 program, because to be clear, 439 will be the program that we're going to advance in the cardiometabolic.
We're just taking full advantage that apitegromab is available to us to study, and that'll be our proof of concept, but it will be clearly the SMA program.
So then, you know, timing-wise, when 439 kind of gets, is clear to go into the clinic, I guess, you know, how does that, having that proof of concept trial with apitegromab, like, how does that jumpstart the 439 program?
Yeah, I think two things. I think we'll, first of all, we'll have demonstrated that our strategy for targeting anti-myostatin will do what we expect it to do.
Mm-hmm.
And so you think about follow-on programs that already have established, that should be clear. Everybody should buy into that because we'll have shown that. I think the second thing is just from drug development. You know, we haven't run a cardiometabolic study before. We'll be running one this year. We'll know the centers, the studies. We'll have the operational efficiencies. We'll kind of be in the game, if you will. And I think that'll afford us then to go very quickly into the dose range of healthy volunteer, right into whatever we need to do for 439. So there's definitely learnings that happen just by being in the space.
But I think just having reporting out this data and really the energy and excitement that we think 439 will bring, I think really will afford us to really be able to run quickly into those, that program.
Okay. And then a question that I get a lot, and I'm sure you also get this, is, you know, read through from some competitor programs. You know, I think we should be getting some phase 2b data from the BELIEVE trial, looking at semaglutide plus GLP-1 next year. Plus, you know, potentially other clinical readouts from some other players looking at myostatin approaches. So can you kind of frame for us how we should be thinking about read-through from those approaches, and specifically, you know, the BELIEVE trial? You know, or the read-through to SRK-439 and to apitegromab.
Yeah, I mean, I think, again, from our non-clinical work, we feel very good about a combination strategy. And I think from the readout, we'll see sort of variation of a combination strategy from another target on the anti-myostatin side, which does include the Activin A. So I think my anticipation would be that there should be preservation of lean muscle in that setting, which to me would vAllydate targeting myostatin. Beyond that, I'm not sure, right? It depends on the tolerability of the dosing, right? We'll see whether or not there's any potential issues with tolerability. I can't tell. But I do think it will be kind of further vAllydation of an opportunity to go there. Again, I think our strategy lends itself to combination 'cause we're not bringing additional toxicities.
For example, I think there are some GI toxicities and some other events that we don't think we'll bring. But I think it positions this as a, an idea that I think will kinda come to fruition.
Mm-hmm. On that tolerability side, I guess, how do you think about, you know, the potential for SRK-439 to act to improve the, you know, AE profile of GLP-1s? I mean, I know it's, it's pretty benign, but we all hear about some of the, you know, GI side effects and not, you know, besides the lean muscle loss. Is that another potential kind of area of differentiation, improving the tolerability of assisting?
Yeah, it's interesting, right? I mean, as we think about it, and again, this is all things we'll have to show over time. We believe if you look at our non-clinical data, it's possible that we can get to goal target weight loss and preserve lean muscle, maybe at a lower dose of the GLP-1s. And if you look at the whole strategy now, I think, you know, step dosing, there's ways to manage that, and patients can stay on. But if you can actually stay at a lower dose, then that actually might improve the tolerability. And so if you're... Again, it's what's the end game and what's the goal in weight loss and weight management? And frankly, our belief is that it really should be sustainable.
We shouldn't be at risk of losing lean muscle, and I do believe there's gonna be advantages either with sparing dosing on one or maintaining the effect over time-
Mm-hmm.
or even seeing some enhanced metabolic profile with the preservation of lean muscle. So it's just really, it's, it's very exciting, to be honest. Fun to be in this space at this time, and I really like the... I mean, I give the research team enormous credit, and Ted keeps finding ways to keep the company financed, which is really quite good, right? 'Cause ideas can't happen without the financing. We feel very good about coming off of that. And I think, you know, honestly, Ally, it's just terrific to think about where we were, you know, when I stepped on a podium in January last year, talking about the year we were gonna have, and then kind of what we've seen in the pull-through right now. This has been really a very good year for the company.
And frankly, next year is gonna be transformational for us, I think, to be honest. We turn over the card on SAPPHIRE, and if that data proves out to be positive, we'll have done something just extraordinary, from great science to clinical application to commercial. I mean, that's-
Yeah, no. Definitely been a good year.
Right.
Definitely say that again.
Thank you, Ted. Right?
Maybe just, you know, last sort of question or series of questions. We're kinda coming up on time. You know, on the, just on the pipeline, you, you have a number of earlier-stage assets in the pipeline, an intriguing fibrosis program. You also mentioned 181, and where it seems like, you're positioning that for, you know, strategic optionAllyty, potentially with a partner. I guess, what, what should we be looking for in terms of, 181 in the earlier stage pipeline, and, and how that's prioritized, with respect to obesity and, and SMA?
Yeah. You wanna start?
Yeah. So I mean, SRK-181 is really important. I guess across the pipeline, the common thread, as we talked about earlier, is targeting the latent form, having exquisite selectivity, and with that, we expect safety and tolerability. That applies to everything we're doing. And we think SRK-181 showed that. Obviously, a different patient population, but the DRAGON study was really productive. We've guided that the spend next year relative to this year is gonna be dramatically lower. We're gonna finish, you know, complete enrollment in DRAGON in 2023, continue to treat patients, obviously, who are on study. That'll be a bit of a tail cost. But we think ultimately that this program should probably go forward in someone else's hands.
Someone with a global oncology infrastructure would make a lot of sense for that program, and it's the best service for shareholders and for patients. To your point about prioritization, it allows us to focus. The theme here now is very heavily weighted toward anti-myostatin.
Yeah.
We're really good at it, and there's a lot, a lot of work to do there. Other programs in the pipeline, you mentioned the fibrosis program, the RGMC program. We're excited about these. We can move them forward without a significant amount of capital and move closer to inflection points. There's strategic interest now. We're continuing to move those forward, and we'll figure out what's best for each of those programs.
Okay.
Yeah, so it's good to have a pipeline. That's some optionAllyty, right?
Rule of thumb, yeah.
Yes. Yeah.
All right, I think we're up on time, but thanks, thanks for joining us.
Thank you.
Thanks for spending time.