Scholar Rock Holding Corporation (SRRK) Earnings Call Transcript & Summary

Hi, everyone. Chris Shibutani, I'm a member of the Equity Research Team at Goldman Sachs. Thanks for joining us. This is our 42nd Annual Healthcare Conference, our second virtual and hopefully, the last one that we'll have. We're super pleased to have Scholar Rock join us for the presentation today. We are joined by CEO, Tony Kingsley; Chief Financial Officer, Ted Myles; and Chief Medical Officer, Dr. Yung Chyung. Gentlemen, thank you for joining us.

Thank you.

So Tony, you and I go way back from a couple of different houses that you've been. You're now at the helm of the new shop here. Congratulations to you. The first year of the journey. I didn't quite catch you early enough to ask you what was the first 100 days of Tony Kingsley, but tell me what it's been like in terms of relative to your expectations, taking the helm, a lot of exciting opportunities. Maybe talk to your own experience and then level set us in terms of where things are at with the company overall.

Sure. Thanks, Chris. Exciting, has exceeded expectations. Look, I was attracted to the company because of the great scientific platform. I joined last summer. We were still 3 or 4 months from first TOPAZ readout in our SMA program. Didn't know what was going to happen, like [indiscernible] but thought it was a well-designed experiment with a good chance of success as SRK-181, which we'll talk about our oncology program, also in human proof-of-concept trials. So the attraction to me was the company with a distinctive technology platform, the ability to create very selective targets to growth factors where the companies apply that as -- in places where the biology is important and well understood, like in oncology like myostatin but other people have struggled to hit those targets. So looked -- dynamic time for the company was another attraction both for the company and for shareholders with lots of value creation, [indiscernible]. The better part of the year and at this point, I would say, it exceed expectation. We obviously had a fantastic readout, both 6-month readout, then 12-month full readout. On TOPAZ, we have a lot of conviction about where we're headed in the SMA space. We continue to make great progress in the oncology trial, our DRAGON trial. Certainly next year, the chance is a pretty efficient path to proof of concept. It might be a very important therapy. The scientific platform, I guess, as I've spent the months here, I've begun even more convinced that there are legs to the scientific platform over time. So an exciting time to be at the company. A little more than 100 days now, I guess I have to admit, but lots of exciting things ahead of us.

That's terrific. And obviously, you have several members of your team here. So I always think it's helpful for people on these to get a little bit of background and context. There are probably a lot of people whom I'm familiar with. Ted, you joined as the CFO. Talk to some of the experiences that you bring to bear, in particular, as you're sitting in the seat as Chief Financial Officer for a biotech company is one of the hot opportunities. It's really important to get the right kind of talent. So what's your secret sauce?

Yes. Thanks, Chris. Pleased to be here. So I actually had an interesting onboarding into Scholar Rock. I was on the board for almost 2 years before joining full-time. And similar to how Tony described, a great scientific platform, got to know the team. I was very happy to be a Board member. And then when the opportunity opened up and when Tony was joining, we decided to jump in together and it's been terrific, exceeded expectations. This is my fifth CFO stint. My prior company was late-stage clinical and commercial stage, had 4 products on the market in a number of iterations. And prior to that, spent time building as CFO and COO for a couple of biotech companies that were pre commercial. So thrilled to be here. This is a really, really exciting opportunity and the platform provides a lot of great things, great opportunities to do good things for patients. So we're really excited about advancing things.

Yes. No, I think some of the key ingredients are folks who have been at different companies, different experiences, wearing slightly different hats, bring to bear all those experiences. And Dr. Chyung, tells us a little bit about what brings you here because there's an interesting kind of 2 pipeline asset story here, neurology side, the oncology. How can you be outstanding at both of them? Tell us about it.

Yes. Yes. So my background, physician scientist by training. My research background is primarily in immunology and microbiology. And then before joining Scholar Rock, was at various companies, biotech companies in the Boston-Cambridge area. Obviously, rare diseases was an area of focus and global drug development. So excited to be here at Scholar Rock. I joined at the beginning of 2016, really excited, impressed by the progress on the scientific front and the true potential of the therapeutic platform to really go after some of those serious diseases in a very novel and exciting way. And it's just been exciting to see the progress over the past few years. So yes, I think it really speaks to the potential and power of our pipeline and platform, the fact that we can go into multiple different therapeutic areas. Because the targets we go after, these are important targets biologically and physiologically with quite a bit of validation behind them, signifying their importance as attractive drug targets to investigate. And I think we have a great team that really goes after on the scientific side to really come up with novel molecules that are aimed at achieving selectivity to really go after these difficult-to-drug targets. And we also have on the development side, a number of folks with a diverse set of experiences, very innovative, very creative, thoughtful folks, diversity of therapeutic area experience. So it's just exciting to see the teams work together and really pleased and proud of the great progress they've made to date, and we're excited to investigate the potential of our platform and our molecules further.

Great. No, I appreciate that commentary. And obviously, this is kind of a next layer of the management team that is still relatively young company. So I think it's always helpful to get an understanding of where everybody has come together. Now because of the work that you're involved with, clearly, obviously, directly involved with neurology. I haven't been doing with this with all the companies, but if we want to talk about excitement. Certainly, this week, the FDA gave everybody something to be very excited about. And I'd be just curious with the show of hands, who expected ADUHELM to get approved?

Hard to predict.

[indiscernible] yourself.

I thought there was a shot that it get approval. Yes, on balance it was more likely. But we'll see.

Ted, what was the reason for you putting your nickel on it?

Look, we were rooting for our neighbors. They're doing -- they're trying to do good things for patients and you got to be an optimist in this business. So I'd certainly. Maybe it was more heart than head, but certainly [indiscernible].

Okay. Okay. So let's get into the meat of what you guys are involved with. I'm going to try to avoid butchering the name of the primarily asset, but maybe we'll just refer to it based upon the TOPAZ trial, which is really where it's been home. But let's set the stage a little bit. SMA. Talk about where we are with the treatment landscape. So much change, very dynamic. Can you just maybe help us -- I'm not sure who is the best for this, but characterize some of the unmet need, particularly with some of the different subgroups. Where do you see the opportunity and where you're trying to position?

Yes. That's a great question. So I'll start, but Yung chime in. Look, there's still is huge unmet need. And SMA, as you know, it's a debilitating disease. The fantastic news is there are 3 SMN upregulators or correctors now approved in the market that have treated, by my count, must be close to 15,000 patients worldwide. We think that's a terrific thing. The SMN upregulators tend to benefit patients early in the treatment cycle. They also -- and sort of flatten out and they also tend to benefit younger patients more than older patients. So there is -- and the patients even after they've been treated with SMN upregulators, they still have very, very significant functional disability. Apitegromab, our asset, was designed specifically to be used in combination in addition to SMN upregulators. It's a muscle-directed therapy. So it's a different approach. And what we're trying to do is to add functionality, meaningful clinical benefit functionality on top of what the SMN upregulators would do. We think our TOPAZ proof-of-concept trial, which we just completed the topline readout on 12 months gave us a lot of conviction in that product profile. We saw what we think is a very compelling efficacy signal in nonambulatory patients with Type 2 and Type 3 SMA. That's about 2/3 of the total population, and it's a huge portion of the market actually that the SMN upregulators treat. So we're excited. We think we have a path forward to a registrational trial and a product profile that could make a big difference for patients. Yung, do you want to add anything to that?

Yes. I mean there continues to be, again, great progress on the SMA therapeutic front with the SMN upregulators, but continued unmet medical needs, severe functional deficits remain. And so there's a lot more work to be done and patients deserve more. And so that's the aspiration and scientific hypothesis that we are investigating, pursuing through our apitegromab program. As Tony outlined, we are aiming to complement through an orthogonal and distinct mechanism to address the muscle side of the equation towards an aim of improving motor function. And we're thrilled with the transformative potential that the TOPAZ trial results demonstrate particularly in the nonambulatory population and the later nonambulatory Type 2 and Type 3 population. And we look forward to investigating this potential further to evaluate this potential through a Phase III trial.

So yours is a myostatin-targeting antibody. Mechanistically, there's some distinctions. It takes a slightly different approach than currently available therapies. Can you talk about what the rationale? And where do you see it being either complementary or competitive with other modes of treatment and standards of care currently?

Go ahead, Yung.

Yes. So the SMN therapies, they are targeted towards primarily on the motor neuron, although there are other cell types that do express SMN. And so the idea is by improving the SMN deficiency by rising the levels, the idea is to stabilize the motor neurons and prevent further deterioration. Now that's great if initiated early in life, because then you can prevent further deterioration. But what do you do given that most patients by the time of diagnosis, they've already experienced quite a bit of motor neuron deterioration. And even with early intervention, there continues to be significant unmet medical need and motor functional impairment. So a new approach is needed. And so our hypothesis and therapeutic aim for the program, apitegromab program, is to complement the disease-stabilizing benefits of SMN upregulators on the motor neuron side to looking towards building motor function by targeting the muscle towards the aim of improving fast-twitch fiber function, and our hope and aspiration in scientific hypothesis is that we can build fast-twitch fiber function to allow patients to now improve their motor function. And so again, that's why we're excited about the potential demonstrated by the proof-of-concept results from TOPAZ and look forward to moving to a Phase III.

Yes. So the Phase II TOPAZ study, the trial. Owing to really the heterogeneity of the patient populations, the structure or the design and the cohorts was fairly complex in its design. Can you remind us sort of why the cohorts were structured the way they were and what the goal of the study was? Well, just maybe just outline the patient groups before we dive into results.

Sure. Look, I think we were trying to test some multiple subsets. The SMA population is heterogenous, and we didn't want to look at different age cohorts and different, frankly, disability level. So that's what the stratification across the different cohorts were, and we can talk about the individual results of those. I think just to echo what Yung said, the clinical endpoint here, as people know, it's a Hammersmith scale. It's a 66-point scale. The patients that we enrolled were the nonambulatory patients in this, which is the bulk of these patients, were patients whose baseline Hammersmith scores were in the low 20s on average despite 2-plus years on average of treatment with nusinersen. So it speaks to that unmet need. What we saw across all the nonambulatory patients is patients achieving 5, 10 and in 1 case, 20 points of Hammersmith improvement despite the fact that they had been on nusinersen treatment over that time frame and at a point where you would not expect them to continue to get benefit. So very exciting -- complicated trial with a very exciting, I think, core message, which is that the nonambulatory population, despite nusinersen treatment, we saw some very significant functional improvement, which we think is very valuable.

Can you comment a little bit more about this Hammersmith endpoint? Help us understand how susceptible it may be to quantitatively -- to things like the design of the trial or the patient population. Just help familiarize ourselves a little bit better.

Sure. Go ahead, Yung.

Yes. So it's -- as Tony outlined, it looks at various motor tasks. It's an endpoint that has both been validated -- designed specifically for SMA, validating a variety of clinically meaningful motor tasks. It's not only validated for SMA, but it's also often used in both clinical practice as well as clinical trials and was the actual primary efficacy measure used in the Phase III trial of nusinersen and later onset SMA in the CHERISH trial. So there's quite a bit of experience with it, and it's quite clinically meaningful and validated, right? So now in terms of the -- what exactly goes on with the Hammersmith scale, right? So it's various different motor tasks, and each task is assigned a score from 0, 1 or 2. 0 means you can't perform task, 2 means you can, 1 means you can partially perform or with adaptation. Now it's really important to note that these gains in the Hammersmith scores can be quite meaningful, right? These are not -- getting a 66-point maximum score on the HFMSE, that's not representative of a score that's an Olympic athlete could achieve, but rather something that a healthy toddler should be able to perform, right? And so when you think about the unmet medical need here, given that the baseline scores that we're seeing in the TOPAZ trial for our nonambulatory population, in the 20s out of 66, it just highlights just how severe the disease is. And this is despite having been on nusinersen therapy for on average approximately 2 years before even enrolling. So, yes, it speaks to the unmet medical need and just how the relevance of the Hammersmith scores in reflecting the motor function.

Got it. Let's go into a little bit on the data here. And so cohort 3, Type 2 less than 5 years of age. How did the data here fit in with your expectation? Were there any surprises? How should we interpret this data considering also that there is no placebo comparator?

Yes. Look, I think we were very pleased with the cohort 3 data. Again, this is -- when we say younger patients, it's patients who had initiated nusinersen therapy before the age of 5. If you look at the CHERISH trial, extension trial from nusinersen, patients who initiated therapy before the age of 5 tend to get bigger gains than patients who initiate therapy after the age of 5, and we can come back and talk about that. But if you look at the curve of improvement, most -- even for the younger patients, most of that improvement as measured in Hammersmith points tends to come in the first year to 15 months. After that time frame, they tend to stabilize. So we specifically enroll patients who on average had been on more than 2 years of nusinersen therapy, which means from a kind of a natural history standpoint, which is the best we could compare to here. Nusinersen natural history is you would expect them to be relatively stable and not have significant gains. The fact that we saw significant gains over a 6- and 12-month time frame, we think was very strong and so apitegromab's effect on these patients and the additive effect on top of nusinersen. So we're not surprised that younger patients do better on various therapies because they're more metabolically active and they're growing. That is true for nusinersen. It was also true for our therapy.

Got it. Yes. And just you made reference to this, but in terms of what we should expect, how SMN treatment alone, what kind of benefit we -- the patients in the different subgroups should be able to achieve? Could you just refresh us on that?

Yes, go ahead, Yung.

Right. So I think this was -- speaks to a big part of why we design it the way it was designed and towards the 3 parallel cohorts, right? So starting with the cohort, which patients were intervened upon earlier in life with background nusinersen therapy, right? This is a population where prior clinical data suggests that they may have an initial improvement and quite meaningful improvement, to be honest, in the first year to 15 months, afterwards, subsequent other clinical trial data for the nusinersen program, this obviously not our data, but from Biogen and Ionis team, what they observed is that after that initial increase, there appears to be a plateauing, so that the primary effect seems to stabilize where there's not much -- maybe slight at best improvement over time. So again, given just again, how much Hammersmith score deficits there are, there continues to be high unmet medical need. So our hypothesis in that chronic maintenance space, right, where there's a plateauing phenomenon that's historically been described, the hypothesis in that context, are we able to drive improvements, not just maintain the stabilization, can we see improvement? And we were very pleased to see in the -- in our cohort of looking at the patients interviewed upon who had been started on nusinersen before age 5, that we were seeing sizable increases in the Hammersmith score of approximately 7 points for the -- of the high-dose arm after 12 months of treatment. So we were thrilled to see that level of effect. And we think it really highlights the potential here to potentially build upon the disease-stabilizing benefits of SMN upregulators, and we look forward to testing this hypothesis further.

Can you comment on -- go ahead.

Yes. Go ahead, Chris. I was going to just talking about another cohort, but just a follow-on what Yung said. We also had a cohort that looked at patients who initiated nusinersen after the age of 5. Again, if you look at the CHERISH trial at 15 months, and you isolate the patients who initiated nusinersen after the age of 5, the result for them appears to be flat to a slight decline on nusinersen. So we tested again in patients who had initiated nusinersen after the age of 5 who had been on nusinersen for an average of 2-plus years to see if we saw an added benefit. We saw the majority of those patients respond. We saw pain change across the cohort from baseline and the majority of patients respond. So we also think that's unexpected result, and we attributed to the additive orthogonal approach of muscle-directed therapy on top of nusinersen. So different answers, but -- based on when people initiated nusinersen background therapy, but I think it fits with what our expectation was.

Got it. So next stage for this cohort would be a regulatory trial. Can you comment upon what you think that trial might look like? What are the endpoints that you think will be key for regulators most likely?

Good. So we'll be cautious about being too specific. At regulatory conversations, we have said we think we'll be in a position to start a registrational trial late this year. We are encouraged by the TOPAZ results that there's a fairly straightforward path there. From an endpoint perspective in SMA HFMSE, the Hammersmith scale is the validated endpoint. That has typically been -- you saw there are precedent trials, again, subject to final regulatory clarity, but it would be our expectation that, that would be the endpoint because there's a lot of precedents there. In terms of time frame, again, subject to clarification with regulators, it seems reasonable based on what precedent trials do to assume something like a 12-month time frame. So we would intend to look at nonambulatory Type 2 and type 3 patients on both risdiplam and nusinersen as background therapy in some sort of a controlled trial, so details will be revealed, but looking at HFMSE change probably over something like a 12-month time frame.

Got it. Let's talk about cohorts 1 and 2. What you're expecting here? What were the key takeaways from the data from these subgroups?

Yes. So both cohort 1 and 2 were older patients. I just actually referenced what use of old cohort, which is the older, nonambulatory patients, where again, expectation was that those patients would tend to be kind of flat to down. And the fact that we saw a majority of patients respond and so a mean change across the cohort was encouraging to us as a signal. Cohort 1 was nonambulatory population. These are people who aren't ambulatory. That's the difference, right? And this is also an older group over the age of 5 in terms of when they started on nusinersen. The science on whether SMN upregulation include nusinersen has a positive impact on these patients is not as well established as it is in the nonambulatory population. We did see majority of patients either stable or respond on this. So we thought there was an interesting signal in there. It will clearly take more exploration on our part. It's certainly a separate regulatory path if we were to pursue that. We would not include it in -- we think, in the initial registrational trial, but we think there's an intriguing efficacy signal there. We may have a solution in time for those patients as well, not the core focus of where we're headed at the outset.

And then, I guess, when should we expect to see data on the breakdown between the Type 3 risk groups, 3A and 3B from cohort 1? Hopefully, I haven't screwed that up.

So our scrutiny versus -- sorry, go ahead.

Yes. So we're in the process of -- obviously, we got a huge amount of data. We have a team that's hard at work to go through all the different more exploratory analyses, cutting the data across all 3 cohorts, and that includes looking at different subgroups and some hypothesis-generating works as well as looking at additional endpoints outside of the Hammersmith score. And so a lot of work ahead and it's ongoing, but pleased with the progress and going through this, and we look forward to presenting results from these various analyses at upcoming medical scientific conferences.

Upcoming medical scientific conferences, somewhere in the background, there's an IR person very pleased with that total piece again? So...

We're coming -- SMA is coming, and we put out a press release this morning where a couple of different [indiscernible] are talking about that.

Okay. Folks, I tried. Okay.

Yes. It's coming soon.

Okay. Got it. Can you -- is there anything else -- I mean, obviously, it's been interesting to watch the stock reaction to the updated data that you have. You've had conversations with investors. Where do you sense that there are some disconnects or the cognitive dissonance? And we talked earlier this week, and so you know some of it is just sort of like The Wall Street aspect. There was the event that happened, et cetera. But in particular, do you notice from the thread of conversations in line of questioning that there are things that you want to make more emphatic or where you feel that people should be -- could be more thoughtful about?

Look, it's a fair question. As I said, from our standpoint, we have a lot more conviction in the product profile. And as I think we said the other day, we'll have to keep working on what we can control. I do think it's important for people to -- and for us to hang around and do messages. The evidence that the benefit -- the additive benefit of apitegromab on top of what would be expected from nusinersen in our mind is very clear. When we talk to investors, I think they see that. But that's the one. Thing two, we just talked about, which is we think there is a pretty clear path to a registrational trial that should have a really improved POS based on what we saw in TOPAZ. So that's what we're after. Right now is to take that 2/3 of the patient population nonambulatory, where we see a signal cross that, translate that into a registrational trial and try to get this to market as quickly as possible.

Got it. Before we leave for apitegromab, can you talk about how you're thinking about potential development and additional indications? Dr. Chyung, what's your wish list?

Yes. So I think, obviously, our initial focus is going to be continuing on SMA, right? That's job 1, the Phase III trial, nonambulatory Type 2 and Type 3 SMA. But even within SMA, we are quite intrigued by the potential that we may have an opportunity to test hypothesis add-on in the context of Type 1 SMA, right? There's huge unmet medical need there. It's actually the largest incident population. And fortunately, with the advent of SMN upregulator therapies, that's improved the ability of patients to live longer and more meaningful life. And so we look forward to investigating potentially in the future, add-on in the context of Type 1 SMA. And we also talked about ambulatory Type 3 SMA and the potential there. But beyond SMA, we think there is a variety of other neuromuscular indications for which the myostatin hypothesis may be relevant, right? There are a number of indications for which fast-twitch fiber deficits play an important role, and we believe and hypothesize that we can have potential benefits there. And so one area of interest for us is actually Becker's muscular dystrophy. And so there, obviously, with DMD, that's been a major area of huge unmet medical need. And we think that with progress in DMD with therapies to address the dystrophin defect that there could be an opportunity potentially to add on top of it with the myostatin-directed therapy to see if there is further motor function gains. Now with that said, we don't think it's quite ready just yet because we think there needs to be strong adequate increase in dystrophin levels, maybe not full, but an important improvement and so -- to be able to add on top of that. And so we think there's more work ahead. Unfortunately, there's a lot of hard work and progress in the field. Now before we get there into Becker's, Becker's in many ways is a less severe form of DMD, where there's actually partial dystrophin restoration. And so it's been brought to our attention by -- in conversations with various thought leaders to consider the hypothesis of exploring -- well, in Becker's you don't have -- it's kind of partial levels of dystrophin, is there a possibility that you have potential add-on benefit in that context? And so our intention is to investigate this hypothesis further in Becker's as well as watching the DMD landscape to see -- with further progress in dystrophin correctors to investigate the potential to add-on benefit in that setting.

Got it. So let's transition to TGFß. It's been an area of interest now for a while in oncology. It's been challenging. And I think some of the progress has been fits and starts. Merck KGaA certainly has run into some issues there. Can you just remind us sort of what you think some of the challenges are that are there? And in particular, how your approach with SRK-181 is maybe trying to thread some of those needles?

Yes. We're very excited about the hypothesis. So look, it is -- obviously, big pictures are backdrop, checkpoint inhibitors are revolution in oncology treatment, $25-plus billion market. They don't work on 80% of the patients, right? And resistance is a big issue. Everybody is trying to solve that puzzle. There's a lot of hot science around TGFß, not just ours, that implicates that as a culprit in checkpoint inhibitor resistance. We think that the way to the evidence suggests that it's the Type 1 isoform that is the culprit in -- the main culprit in checkpoint inhibitor resistance. We know from others prior experience that toxicity and off-target effects with nonselective TGFß inhibitors that hit Type 2 and Type 3 have caused challenges for people in the past that molecules won't make to the clinic, some have to be dosed at suboptimal levels. We are the only program, we believe, that as a Type 1 selective inhibitor in humans in clinical trials in our DRAGON trial. We have a pretty quick way to get the proof of concept on this idea of primary resistance that if you redose patients who have shown primary resistance to a checkpoint inhibitor with SRK-181 plus the checkpoint inhibitor and you see an antitumor response that would be unexpected. So we think our advantage here in our approach is the selectivity because we think it will allow us to dose higher and hit the target hard to really, really give this hypothesis a good test in humans, which we're in the process of doing right now.

Right. And then just to remind us, we are expecting some data later this year, correct? And you kind of partly addressed this, but what should we be expecting? What questions do you think will be answered both for the field and also for 181 specifically?

Yes. So we're in a 2-part Phase I proof of concept trial called our DRAGON trial today. Part A is dose escalation, which includes some monotherapy dose escalation, where, by the way, given the mechanism of action we don't expect to see an efficacy signal and also has some combo dose escalation in combination with checkpoint inhibitors. The real proof of concept in which we will start shortly is Part B of the study, which is 4 parallel tumor cohorts, carefully selected, where, again, we will test patients who've had primary resistance to checkpoint inhibitor, redosed with that plus SRK-181. That's mostly a 2022 event we think and actually potentially a very interesting cascade of data. We have said we will report on Part A, which is dose escalation, late this year. There's a handful of patients in that who are in combination therapy. It's small numbers, but we will have the opportunity to do scans and look for any anti-tumor effect. Again, in small numbers, anti-tumor effect would be interesting. To be clear, we will start Part B before that. We think Part B is real efficacy test and a place we can get relatively quickly.

Great. In the last 5 or 10 minutes or so, let's talk about the company's platform just broadly. The -- what would you characterize as being the real discovery strength? And help us understand why the focus on sort of latent growth factor approach?

Yes. Maybe I'll make an opening statement and then Yung cover that because he's been a lot longer than me. I think there are 2 pieces to the puzzle here. It's the ability -- it's the discovery ability and the ability to engineer antibodies with high selectivity. The second piece is the translational thinking to apply that to diseases where we think the biology is quite important. But that others have struggled to hit that. But Yung, do you want to talk a little bit about the distinctiveness in antibody engineering? And then we can talk a little bit about the translational thinking.

Yes. So Scholar Rock was founded upon the premise that -- with the recognition that there are a number of targets, growth factors, TGFß superfamily members which control some of the powerful biologies and physiologies in the human body, and therefore, represent very attractive drug targets. But the challenge is it's not trivial to drug these targets. In fact, it's very challenging. And the key reason why is many of these growth factors are structurally quite similar to each other. So it's very difficult to hit 1 target, but hitting another target that controls very different biologies. And then you run to the conundrum of do you go with a very robust dosing strategy or a very robust molecule that hits the primary target hard, but then your risk toxicity? Or do you go with a weaker molecule or use a lower dose, which may help mitigate against these off-target effects, but then you're not hitting your primary target hard, right? So what our scientists have done and make great progress on is very creative and thoughtful innovative strategies to handle this conundrum. And a key very promising and fruitful approach has been to going after the latent forms of some of these growth factors. For example, both myostatin as well as TGFß1, they're initially produced by cells and secreted in an inactive latent state that then that's converted into the mature signaling form. And by going after the latent form, one, is able to have a better chance at getting selectivity because the latent forms of these molecules are structurally less similar than the other growth factors out there. And so by doing that, we've been able to get a highly selective inhibitor of the myostatin pathway as well as a highly selective inhibitor of the TGFß1 pathway, and we're excited about testing both of these clinically to evaluate our therapeutic hypothesis. Now the other key element besides the discovery side, which we think is very important is also, as Tony described, is a translational thinking, right? These are validated biologies and physiologies, but requires very thoughtful clinical translational thinking about how we apply like in terms of selecting indications, therapeutic applications as well as designing clinical trials that incorporate the appropriate translational thinking. And I would say that those are 2 very important competencies that we built and are very proud of our teams for having that capability.

Ted, I'll draw you in here. Having 2 assets making such progress and thinking about how source and finance some of these, what the right strategy is in terms of at what point you want to be thinking about maybe a partnership. The company has already done some things with Janssen, with Gilead. Can you talk through some of those decisions that have been made and how that's shaped how you're thinking about some things going forward? I think it might be particularly relevant for 181 because of the whole oncology versus neurology, quite strong, different directions yet.

Sure. So I guess I'll start by commenting just reminding you that because our therapies work with other therapies, as we talked about, with apitegromab working with the SMN upregulators, with 181 helping -- hopefully helping the efficacy of checkpoint inhibitors, there's a lot of parties that are interested in our success and our progress. I'd say a year ago, we were thinking maybe the fork in the road and deciding where to partner was probably -- felt a little closer than it was. We did a very, very significant financing in Q4 on the heels of the interim data back in October, November. That allowed us to really advance our plan independently for a bit longer. So we're going to continue to advance these assets forward. We've got cash into 2023. And continue to advance and turn over these cards and see where we are and then make the best decision possible. We really think -- look at everything from a position of what's best for patients. If at some point down the road, we believe, for example, with the 181 program that we can reach more patients faster with a partner, then we'll do that. Then we'll look at these partnership opportunities as we advance the program. You see patients -- patient interest and shareholder interests are very closely aligned. So those 2 incentive sets really drive a lot of our decision-making.

Right. Orphan disease studies are certainly typically more discretely sized. The oncology and combination trials, things get large, messy, expensive. Maybe I'll phrase it in a certain way. I mean, how long do you carry 181 before you begin to contemplate doing something there, structurally partnering that?

To be determined. But the good news is we've got the funding to get through Part A, get really deep into Part B and probably see -- potentially you have enough time to potentially see a signal. So the partnership discussions, if we go down that road, would be much, much more interesting if we're able to -- if our hypothesis is correct, we should be able to do something really interesting from a partnership standpoint if we choose to do so.

Got it. And then in the last couple of minutes, what's next for the pipeline? This is Wall Street, right? So it's like, what are you going to do from the next kind of thing? A lot of different directions. Maybe Tony or Dr. Chyung can reply, and then I'll watch Ted's face to see if he's got to figure out how to find this answer.

No. Look, it's -- we were really encouraged by the -- what we used call 015, now apitegromab, results. It was the first proof of concept of our platform. It was the first proof concept of I think the latent form of a growth factor. We think -- we're obviously excited about 181. So there's a big body of work ahead of us. So obviously, on apitegromab within SMN fully exploiting that, as Yung spoke, we think there's some opportunities in other neuromuscular diseases. And obviously, 181, we have 1 level of narrow hypothesis we're testing. If you think about the potential in oncology, which as you said is big. So really exciting body work there. Having said that, we're actually investing in discovery and going after new molecules this year. We haven't walked away from that because we think the pipeline can continue to be -- or the platform can continue to be productive. There are 30 plus growth factors in the TGFß superfamily, they control some important biologies. We haven't talked about it a lot, Chris, recently, in part because a lot of the focus has been on the lead programs. I suspect late this year perhaps or into early next year in some form like an R&D Day, we'll probably bring forward some of that stuff and start to give people exposure. But we're quite excited, the Board is quite excited about it, very committed to continuing the research activity.

Yung, get your PowerPoints revved up. Ted, how did you feel about Tony's answer?

Perfectly aligned, perfectly aligned. We have to advance these programs.

Right. Okay. Well, I think it's been very exciting, obviously, for the evolution of the company and to have 2 assets advancing as they are in a platform that has generated so much potential. So thank you so much for joining us. It's a very helpful update. And hopefully, the questions were framed in a way that's useful for the investors who were signed in and are probably much more knowledgeable than I am about all of the aspects of the Scholar Rock story. So we wish you all the best, and thanks much again for joining us.

Pleasure. Thanks, Chris. Well done.

Thanks.

Thank you. Take care.