Joining us on this next session here at the Jefferies healthcare conference. I'm Michael Yee, a senior biotechnology analyst, and up here on the panel we have the CEO of Scholar Rock, Jay Backstrom. Jay, busy times for you: obesity, oncology, SMA, lots of fields going on, so thank you for being with us.
Yeah, thank you.
Let's talk about those. Yeah. First, I think it would be remiss to maybe just start high level. Tell us about your lead program in myostatin, and your expectations for what you think we could see in this phase lll readout for SMA later this year, and also the status of the obesity program, same drug, and what the status of that would be this year. So let's talk about SMA and obesity.
Yeah, very good. So a very exciting time at Scholar Rock, and we're poised now in this next 12-18 months to really be potentially transformative. To start with our lead program in SMA, SAPPHIRE is our phase lll registration study. We completed enrollment in September of last year. We're on track to report out the results of that trial Q4 this year, so just a few months away of reporting out what will be a major catalyst for the company. In addition, Michael, to your point, we entered into the cardiometabolic space formally in the fall last year, although Scholar Rock has had a long interest in cardiometabolic, and we've advanced kind of on two fronts.
Because apitegromab is in clinic, it gives us an opportunity to do a proof of concept study with apitegromab in the setting of obesity to demonstrate that we can preserve lean muscle mass in combination with either tirzepatide or semaglutide, so it'll be a proof of concept study. Delighted that we actually opened up that trial ahead of schedule, we announced that last week. You know, this is a very hot space, a lot of interest in it, and hopefully will accrue very quickly, but that study's open and running. Concurrently, though, we are advancing a program that we designed specifically to be in the cardiometabolic space, SRK-439, that has properties that would lend itself to low volume subQ administration, and that is advancing toward IND. It'll hopefully be in the IND, opening up that IND next year around this time.
So those are happening very rapidly, and we're doing a lot of things concurrently with 439 generating data. In fact, we'll have the data featured at the American Diabetes Association in a few weeks.
Perfect. Okay. So, there's been a lot already done on SMA, and if you want to delve into all the details of that, you could probably refer to our slide decks. But I do, in the interest of what's most topical, at least with the limited time we have, is to talk about some of the various questions that people have on anti-myostatin for obesity.
Mm.
The first question I have for you is just sort of explaining to people what you think the clinical relevance is of blocking myostatin and how much muscle you can protect in these patients, and why you think your profile is better, because Regeneron is also doing this and put up some data showing myostatin plus activin is even better than myostatin alone. So is your compound gonna be as good as the others who do both? And what is the ramification of what you're doing, and how good is it gonna be?
Yeah, really good questions, 'cause there's a lot of strategies trying to target myostatin, and maybe I'll just take a step back and say that, you know, Scholar Rock was really founded on the idea that selectivity really matters in trying to harness TGF-beta biology. It's complicated biology. There's a lot of signaling and crosstalk, and you can end up hitting a given target, like myostatin, for example, and have unintended consequences 'cause you interfere with other signaling that occurs. So that's just background. I think from the Scholar Rock perspective, as we think about obesity, the problem that we're trying to address is preservation of lean muscle, as it's become apparent that between 20% and 40% of the weight loss is lean muscle mass.
And we believe that, as the field is evolving, and I think we're gonna see this more and more, that it will be important to preserve that for long-term, healthy weight loss management. I think that's emerging more and more, and I think we've entered into that space. But we've entered it because we think benefit risk really matters. Very critical benefit risk matters, and if you think about our approach to targeting myostatin, myostatin plays one role: it regulates muscle. There's knockout models and animal models that suggest that when you block myostatin, the result is more muscle, less fat, but nothing else. So it's a very clean target, and we target it exquisitely, selectively, so we don't have any crosstalk with the other biology. Other strategies to try to affect myostatin through activin signaling, which is another approach, and that's the kind of-
Regeneron and others.
Others are looking at it, and you can either target that through hitting the activin receptor, which myostatin signals through, so that's the bimagrumab program.
And Lilly, yep.
Lilly is... So Lilly is now, bimagrumab is now with the Lilly program. You can do that through ligand trapping, but it's hard to do it with specificity on ligand traps, or you can go after the antibody. So that- those are the strategies. But, but our view is that in the end of the day, why would you introduce additional toxicities if you don't need to? And look at the emerging data that's coming forward, and I think first and foremost, maybe since you posed the question around blocking activin antibody itself, which, through the antibody, which would be the Regeneron approach, I would suggest to you, if you take a look at the data that's already present, hitting activin, it's not just exclusive to muscle.
It's in a lot of different tissue, and blocking activin is already showing that it's having effect on epistaxis and nosebleeds, skin infections, frankly, even the early healthy volunteer data showed mouth ulcerations. You're seeing signals in the emerging data, and this is not long-term, longitudinal, significant amount of data-
Mm-hmm
That I believe is on biology for activin, given-
Yeah
... its distribution across tissues.
Yeah. So let me, let me clarify that. So, yes, activin may play some role in improving, lean muscle gain? however, by doing that, you're introducing various sorts of risks, and you're already seeing that with multiple programs. Both historically, you were seeing all sorts of things, abscesses that had to be drained, I think in some of these other ones. The bimagrumab phase ll publication had some things, like a pancreatitis case, and, the Regeneron phase l data that has been presented, had, in both the high doses of activin, multiple cases of oral mouth ulcers.
Right. So I think, so what's clear is the toxicities are starting to be observed, and it's a view that that's because activin is distributed in a lot of places, and there's a long legacy of blocking the mature growth factor and failing due to toxicities. So I think the activin contribution is then the next question. So I think, quite honestly, I think that's still a question that remains to be seen. From the data that were presented, there was an additive effect on the myostatin, although the myostatin data looked a little bit on the low end of the range, and at the end, the magnitude of benefit was in the 3%-5% range, which seems to be true across.
The one thing that I can say is we've taken a look at it, 'cause, you know, we're making references to cross-trial comparisons, and, you know, there's always limitations in that. We have to be thoughtful about it. What Scholar Rock has done, and we recently presented, is that while we didn't look at the antibody itself, but we took a look at the effect in our non-clinical models, the diet-induced obesity model, where we created an antibody against the activin receptor similar to the bimagrumab program, to see whether or not from that efficacy, we were leaving efficacy on the table, quote, unquote, because we weren't hitting activin signaling.
Mm-hmm. Mm-hmm.
The data that we shared at our investor event last week indicated that we, we have comparable efficacy but at far lower doses. So SRK-439 was designed to be low volume sub-Q administration, high affinity for the target. We see clear effect on preserving lean muscle mass at lower doses than the bimagrumab. And so from the data that we have in hand, we don't believe that we're gonna leave efficacy on the table, quote, unquote, in the setting of preserving lean muscle mass. And we absolutely believe that this strategy is gonna be, I think, the purest way to target with the least amount of toxicity in combination with a drug or drugs that are intended to be chronic use. I, I think benefit risk matters so much in this space.
Okay. Yeah, and I would argue, like, what is the difference between 1%, 2%, 3% overall lean muscle or weight? You know, we're talking about percentages here, a couple%, versus the added risk of one, two, three, four, whatever% of rare effects that could happen in this type of patient population.
Yeah, completely agree. I think at the end, benefit risk really matters. So we'll see. We're running the studies.
Yeah.
The more data that I see from 439, the more... I mean, it's- it looks really quite good. Anxious to share it.
Can I ask a higher level question, which comes when people are learning about this story, which is: okay, maybe you do protect lean muscle loss in combination with GLP-1s, which is what people are trying to do. You want to protect that or treat the issue that GLP-1s is doing. You know, what is the clinical ramification of that? Like, sure, it's not good to lose lean muscle, but one, you know, what does that mean to protect it? Are people who are losing the muscle, are they gonna have more falls or something bad's gonna happen? And number two, there's now all these obesity companies now talking about whether it's amylin or whatever it is, that they are not even having lean muscle losses. So, you know, I think that'd be a question.
Well, Lilly presumably has billions and billions of dollars worth of tirzepatide, so what are you worried about? That's not going away. But, you know, both of those. Now, it's what's the problem that we're trying to actually treat, and does that matter? And then two is, aren't these other drugs coming out that are not gonna have lean muscle problems?
Yeah, it's interesting, right? So we had an expert join us last week-
Mm
on our investor event, Dr. Jastreboff, who's at Yale, and did a review. There's lean muscle mass loss across all means of weight loss, whether it's GLP-1 receptor agonist, bariatric surgery, or even diet and you know, diet-induced weight loss. So there, there's a component to it. I think at the end of the day, I think where, where our view is on this is that given the role that muscle plays in metabolism, in basal metabolic rate, insulin sensitivity, glucose uptake, it plays such a fundamental role, that if you start to look at this over time longitudinally, and not just in three-month, six-month, twelve-month periods, this sustained chronic therapy, preserving that muscle will demonstrate over time how essential that is to do. So metabolic profile is one. You made a, you made a point, it's a really good point.
I think functional improvement is the obvious. We're, we're showing functional improvement with myostatin and SMA. You could do functional measures. It depends on the subset of patients that may be more vulnerable to muscle loss, and maybe that's an older subgroup. So I think there are ways to showcase this across, but at the end, for chronic care, and particularly if you're coming off drug, if you're coming off therapy, and then you're-- the likelihood, I think the prevailing view is that you're gonna gain fat back before you lose muscle, and if you get into this cycle of downward spiral, that doesn't strike us as really a good outcome. So it's back to muscle's role. Preserving that looks to be good. Chronic care is important. And again, we're generating data that would suggest that we have an additive metabolic profile effect 'cause we've showed further reduction in glucose-...
In the setting of our non-diet or diet-induced obesity models, which would play forward as a clinical benefit as we looked at in clinical trials.
So in order to prove this to people, we need to run a clinical trial with these anti-myostatin drugs on top of GLP-1. That is what you're planning to do. Lilly is completing their study. There's different definitions of completing if you look at their definitions, but they may or may not say anything about the result, or they may wait till 2025 for Lilly to put out their anti-myostatin data on top of GLP-1. Therefore, the next, I believe, readout in obesity with anti-myostatin is actually you guys, because you're starting the study, and by mid-2025, you would have data.
Right.
Can you explain the design of your study and what you would expect to see on top of GLP-1? And, like, how many patients, how long of treatment, what would you expect to see?
Yeah, so we just, we just opened up, and I was delighted 'cause the team did this ahead of schedule. We were thinking we were gonna do it later this month. Opened it up. It's actively enrolling, and the trial, to your point, Michael, is exactly that. It's a randomized study with 100 patients, 50 per arm, and where it's the standard of care, so whether it's tirzepatide or semaglutide, and it-- the comparison is that plus or minus apitegromab. So we're using apitegromab because it's our clinical stage asset. This will help inform us as we go forward with four three nine. The primary endpoint, the primary goal of that study, is to demonstrate that our selective approach of targeting myostatin and only myostatin can mitigate the lean muscle mass loss that occurs with the GLP-1.
Over what time period?
We have a 24-week measure. That's our endpoint-
Six months.
6 months, and as you think about it, if you look at the decline of weight loss that occurs with these therapies, it's rather rapid.
It all happens in the first-
Yeah. So it's a really good time to do it. We think we can measure it. Our plan is to start these concurrently. These will be all new patients that have not been on it before.
Okay.
And then we'll proceed lean muscle mass, and we'll then be able to demonstrate that. We'll also be able to show, I believe, in that trial, what... If everything we see in SMA carries forward, no additive toxicities when we add it to the GLP-1 receptor agonist. And in addition, we built in some very interesting exploratory endpoints that will guide our thinking around those measures of clinical benefit, such as hemoglobin A1c and functional A1c and functional measures as we get 439 into clinic. So it'd be quite informative for us.
In terms of the endpoint that you will see, which is trying to protect lean muscle loss, like, if you protect three, four, five, so actually, when you look over 6 months, you might lose 10% weight, of that 3% is muscle, and that's a few kilograms. If you actually protect that, what would you see on 6-minute walk? What would you see on grip strength? So I can quantify how much muscle, but, like, what does that mean functional and 'cause I need to turn muscle into an actual clinical endpoint.
Yeah. Those are, those are really good questions for which I think we're gonna need to generate a little bit more data to demonstrate. What I, what I could say to you, though, is that I think at the end, as you think about 20%-40% weight loss or muscle, lean muscle mass loss, we would like to attenuate that. If we could blunt that and preserve what you have to start with, perfect. If it is, you know, a further prevention and not as much reduction, we'll have to see how that translates into benefit. We will include some of these functional measures that I think will then demonstrate the impact.
Yeah. And just thinking about publishing about this, it's I feel like you're gonna have to pioneer this because I feel like you have to run the study, show the data with your own molecule, prove out myostatin versus everyone else doing myostatin activin, run your study in a randomized study and show it. Because I feel like Lilly is not necessarily gonna say too much, and they probably don't wanna talk about lean muscle loss on their-
You know
crown jewel tirzepatide.
I think that's-
We're talking about side effects.
I think that's absolutely fair, and actually-
Well-
That's our plan. We have a plan that we need to execute. I think we're on the cutting edge of this, and so we do need to generate our data.
So coming up later this year, in the next five or six months, you are gonna report out your Phase III SMA data with the primary drug, apitegromab. If the study is positive and you show a statistically significant benefit on Hammersmith and these SMA patients, one or two points, amazing! You have a new blockbuster drug in SMA, filing, a BLA, potential blockbuster drug on top of standard of care. That's gonna be amazing, great outcome. I don't even need to spend too much time about that 'cause that's gonna be fantastic. However, what is the scenario planning for if the drug does not show the result that we would expect, and certainly the market seems to think that it's high risk? What would you say to that as a read-through to, Oh, that must mean it's not gonna be great in obesity.
See, you protected the muscle in the SMA kids, but they didn't have a benefit. What is the scenario planning for the street if that happens, and what would that read through to obesity if it does not work in SMA?
Yeah, I mean, maybe first to start with the SMA program. I think we feel very good about where we are with the program, the outcome that you'd shared notwithstanding.
Mm.
Given the fact that we were able to design the study, we believe we have the right target for SMA and myostatin.
Yep.
We had a proof of concept study that helped us with the design, and we're seeing with the ongoing therapy in the TOPAZ trial, high retention rate, over 90% still on, very clean safety profile. So we feel really very good about it, and in fact, the SAPPHIRE was designed on the basis of that POC, so that's a really good thing. Now, when it comes to looking at our approach to preservation of lean muscle and the read-through from the SMA program to the cardiometabolic space, you know, I do think, to your point, we have to be thoughtful about how we refer across, because I think we do know that indication matters. There could be some variability that could, unfortunately, give us the outcome, but I wouldn't say that it would block us or our thinking around preservation of lean muscle in the obesity space.
But going back, I mean, I think we're as advantaged—I think about the probability of success in phase lll studies. You're usually better off and get a better outcome if you have a good homogeneous population that was informed by your phase ll. We've done that. We've preserved the same endpoint. We've got a good dose selection in the trial. It's been well run, well conducted, so-
Yeah.
Looking forward to reading it out.
It is a well-designed study, and I'll even preempt the market by saying, Biohaven may have a result as well, a little bit earlier than yours, and they're running a phase 3 SMA study with their product, which is basically an ActRIIB receptor blocker too. So they're sterically blocking, and then they're, therefore, they're blocking myostatin and activin. And so, you know, my point is, they have a different study population than you, and do you believe that therefore we shouldn't have too much read? Then obviously, if it works, great, that's gonna be good for you. If it doesn't work, people might believe that it's a different patient population. You're more narrowly focused and more homogeneous, and you think that that predicts you for better success.
Yeah, I mean-
Explain the differences and why.
Yeah, I mean, I think there are a couple of things. I think first, mechanistically, to your point, the Biohaven program is T-alpha. It's an adnectin.
Yeah.
It's not a monoclonal antibody. It tends to bind to the mature growth factor, myostatin, once it's formed.
Mm-hmm.
And recall that we block and we even prevent the formation, so there may be advantages, obviously, by doing that rather than having it circulate. So it's definitely a different mechanism. It does overlap with GDF-11, and that may or may not have a negative effect on muscle. So it... The mechanisms are different, but I think the point that you raised, which is really important, heterogeneity in patient study populations sometimes is unhelpful. And so I, I think to the point that we try to have more of a homogeneous population informed by TOPAZ, I think advantages us. So I don't think the read-through, if an, if unfortunately they're a negative study, would read through.
To be specific, we're talking about ambulatory. Can you compare the differences?
Yeah, so for the Biohaven program, it was basically an all-comer study. So they're looking at those that were both non-ambulatory, which is the group that we saw the greatest signal in, in the TOPAZ trial. And by definition, non-ambulatory doesn't just mean wheelchair-bound. It means you need to walk with some aid, and you can't walk very far. But they've also included then an ambulatory group, where I do think it's a little bit harder to show that effect size, potentially, given the baseline physical function.
Yeah, so,
So it may-
Yeah
... it may confound the results.
You're focused on non-ambulatory.
Correct.
Ages, remind me again?
The main population is 2-12-
Yeah
... but we've also included 13-21, so we have the full range. Biohaven program, they go to, their lower age is four, so we have younger children in our study.
Which is a good thing.
Yeah.
Yeah.
Yes.
Okay. Because you're focused on non-ambulatory, if you included ambulatory, different baselines, too much things going on, they're healthier, harder to detect the difference there.
It may be.
Yeah.
It may confound or blunt the effect size.
Okay. Good. Okay, so, the other thing I might just point out too, if people try to make read-throughs on SMA to obesity, is you do feel confident on the more potent version of the drug. Now, are there reasons to believe other than just potency leads to smaller dose, so you can fit into a subQ, because uApadacitinib is IV, and this is just for proof of concept, that that would be better? Or again, it's just, look, this is a different patient population, don't read SMA into obesity. But are there other benefits with the second drug that you're filing?
Yeah, I mean, so I think it's important, right? I think upadacitinib is highly selective. We like the program. We like it for SMA. It's IV. If you think about the difference in dosing by body weight, you're getting into obesity, you need a lot... Obviously, you need more drug.
Mm-hmm.
Frankly, the Lilly program is IV, and they're giving quite a bit of that drug, right? So, because you're in a large patient population. So the SRK-439 was designed to be able to move into a larger patient population, like the obesity market or obesity subgroup. So we feel good about it. It's higher affinity. We think it'll work. We will need to optimize the dose for SRK-439. You know, I think upadacitinib will give us some good insight, but SRK-439 stands on its own.
That's actually interesting because the dose in SMA of upadacitinib is, remind me, 10 and 20?
Yes, in the SAPPHIRE trial.
10 and 20 mg, so 20 mg per kg. First of all, that's generally a lot of antibody, and then we're going into obese patients, which are already heavier patients, so it's 20 mg per kg times heavier patients. That's a lot of... We're talking about grams, I think.
Right. And that's, if you look at the amount of drug that's given in the bimagrumab, it's similar, it's large. So, you know, again, that's why we're SRK-439's tailored for that.
Yep.
It's got its own IP, it's its own unique product.
Yep
... and we're gonna move that, continue with that forward-
Okay
... with great speed.
And then as we get to the end of the year, obviously, there's this big SMA readout. We're waiting to hear about what happens with anti-myostatin in obesity with Lilly. Meanwhile, you're running your own, but it is a fairly binary event at the end of the year on SMA. Can you remind us where you are with cash? I think our model has you kind of within a year of cash as we get into 2025. So a lot of time, people like to generate cash before that, raise money ahead of that, because with the binary event, we don't know what the capital markets look like after the election. Just where are you with cash, and how should I think about any opportunistic opportunity to raise money?
Yeah. So we have cash into the second half of 2025. Right now, as we're approaching this major catalyst, we're not inclined to go out and look for additional cash prior to. That's our current strategy. But of course, you know, there's opportunities around business development, other ways-
Mm
... that potentially can bring in some non-dilutive cash. That work has always been underway. You know, we have a platform-
Mm
... and we have potential opportunities-
Mm
... to partner. I'm just saying we're working on those things as well, which, not to say that's gonna happen, but just thinking around how we're considering it.
It's interesting because I would just close by saying, as we get later into this year, you are technically within one year of cash, but then there's this binary event coming up. Binary events, great, easy, big stock price, great. If it's not so great, the stock might change, and then therefore, you'll be still within one year of cash. But you did announce the update at ASCO.
Yes, we did.
That is the cancer program, is a consideration for business development or partnership. That'd be an opportunity to raise money too.
Very much so.
Okay.
If you didn't look at that data, very interesting data.
Okay.
Very interesting data.
Very-
1A, one, overcoming resistance to checkpoint inhibition. Been a tough nut to crack. Data look really compelling. We've got a potential selection strategy. Looking forward to continuing to discuss how that can go forward.
Very good. Thank you very much, Jay. I appreciate it, and continued execution this year.
All right, sir. Thank you.