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

Good day, ladies and gentlemen, and thank you for standing by. Welcome to the SRK-015 TOPAZ Interim Analyst Results Conference Call. [Operator Instructions] After the speakers' presentation, there will be a question-and-answer session. [Operator Instructions] At this time, I would like to turn the conference over to your host, Ms. Catherine Hu. Thank you. Ma'am, please begin.

Good morning, and thank you for joining us on today's call to review the 6-month interim analysis results from our SRK-015 TOPAZ Phase II clinical trial patients with Type 2 and Type 3 spinal muscular atrophy or SMA. The webcast slides for this call can be accessed on the Events & Presentations section of the Investor Relations page on the Scholar Rock website. I wanted to note that we'll be making various statements about Scholar Rock's future expectations, plans and prospects that constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by any forward-looking statements as various -- as a result of various important factors more fully disclosed in the section entitled Risk Factors in our quarterly report on Form 10-Q as well as other important factors in Scholar Rock's future filings with the Securities and Exchange Commission. Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any future date. We disclaim any obligation to update any forward-looking statements unless required by law. Let me walk you through the agenda for today's call, as outlined on Slide 3. Tony Kingsley, our President and CEO, will provide some opening remarks. Yung Chyung, our Chief Medical Officer, will review the trial design and baseline characteristics, followed by efficacy and safety results from the 6-month interim analysis. Tony will then offer summary remarks and next steps for the SRK-015 clinical program. We will take questions at the end of the call, during which Tony and Yung will be joined by Ted Myles, our CFO and Head of Business Operations. Thank you, and I will now turn the call over to Tony.

Thank you, Catherine, and thank you, everyone, for joining us this morning. I am honored to be kicking off this exciting conference call to discuss the 6-month interim results from the SRK-015 TOPAZ Phase II trial in patients with Type 2 and Type 3 SMA. Let's start on Slide 4 and talk about why Scholar Rock is developing 015 as a new treatment for neuromuscular diseases. In SMA, there are now 3 approved SMN upregulators available to help address the underlying genetic defect that causes SMA. But patients may still have significant impairments in motor function. SRK-015 is a muscle-directed therapy intended to complement the disease-stabilizing benefits of SMN upregulators. By blocking latent myostatin, we believe treatment with 015 has the potential to drive additional functional improvements. Turning to Slide 5. SRK-015 is a fully human monoclonal antibody and a highly selective inhibitor of the activation of latent myostatin. By targeting the latent form of the growth factor, we are able to avoid closely related growth factors that play varying roles outside of muscle biology. In August, the FDA granted at 015 the rare pediatric disease designation in SMA. This highlights the significant unmet need and underscores the potential benefit that it could provide to the community. We continue to build a strong patent portfolio protecting SRK-015 well into the 2030s. This is not an exhaustive list, but to highlight a few notable ones, we had a composition of matter patent for 015, a broad patent that covers monoclonal antibodies that inhibit the activation of the myostatin precursor and a patent that covers treatment methods for various myostatin-related conditions. Now turning to Slide 6 to speak to our proprietary scientific platform. SRK-015 was discovered by Scholar Rock's scientists and stems from our platform that discovers and develops monoclonal antibodies that target the latent forms of growth factors. We leverage deep insights into structure and function to engineer antibodies with exquisite selectivity. By doing so, we aim to limit the off-target effects and increase the therapeutic window. We apply that against targets where the underlying biology is well validated and understood, but they've proven difficult to drug. The historical challenges with pursuing the myostatin target are well known. These TOPAZ interim results provide the first clinical data showing the therapeutic potential of inhibiting latent myostatin. This is also the first compelling demonstration of our revolutionary approach of targeting the latent form of a growth factor, which could offer read-throughs to our other preclinical and clinical programs. Yung will take you through the details, but let me summarize that we believe the evidence of proof-of-concept in TOPAZ is very powerful. As shown on Slide 7, we have met our main goals of this interim analysis. Based on the primary efficacy endpoints of Hammersmith scales, motor function improvements were observed with SRK-015 treatment in all 3 cohorts. The majority of patients achieved at least a one-point gain, which is meaningful on an individual level. A substantial portion of patients in each cohort also achieved at least a 3-point gain. This is highly clinically meaningful and otherwise an uncommon occurrence in any given patient. As Yung will explain, there is very strong evidence of dose effect in the cohort of the study that had a double-blind high dose versus low dose comparison. And we did not observe a safety signal from this interim analysis. We are delighted with this data. I will now turn it over to Yung Chyung, our Chief Medical Officer, who will review the study design and baseline characteristics and then walk you through the details of the TOPAZ interim analysis. Yung?

Thanks, Tony, and thanks to everyone for joining us on today's call. We are thrilled to be presenting the interim analysis results of the TOPAZ Phase II trial. Before we begin, we want to thank the physical therapists and physician thought leaders, the SMA Foundation and Cure SMA, who each provided us with highly insightful guidance and advice in the design and conduct of the TOPAZ trial. I also want to say how proud I am of the team's dedication and commitment to advancing our clinical programs, including the TOPAZ trial, and how appreciative we are of the high level of engagement from our clinical trial investigators, physical therapists, study coordinators, study site staff, our CRO colleagues and the dedication of the patients and families despite the challenges of the ongoing COVID-19 pandemic. The initial focus of the SRK-015 program is on Type 2 and Type 3 SMA. And as you can see from the pie chart on Slide 9, these subpopulations together represent over 85% of the patients living with SMA today. With multiple SMN upregulators, also known as SMN correctors, now available to help stabilize one's disease course, we envision a new and complementary era of muscle-directed therapy aimed at driving improvements in motor function. In addition to improving motor function, such a therapy would need a safety profile that enables chronic dosing, including in a pediatric population, have a low drug administration burden and may be applicable broadly across the SMA population. We believe SRK-015 has the potential to achieve those aims. Let's review the design of our TOPAZ trial, as outlined on Slide 10. This Phase II study consists of 3 parallel cohorts, each evaluating a distinct subpopulation of patients with Type 2 and Type 3 SMA. More specifically, Cohort 1 enrolled 23 patients with ambulatory Type 3 SMA between the ages of 5 and 21. These patients are either treated with SRK-015 as a monotherapy or in conjunction with an approved SMN upregulator. Cohort 2 enrolled 15 patients with Type 2 or non-ambulatory Type 3 SMA, also between the ages of 5 and 21, and all patients are treated with SRK-015 in conjunction with an approved SMN upregulator. In both Cohorts 1 and 2, patients are being treated with 20 milligrams per kilogram of IV SRK-015 dose every 4 weeks. Cohort 3 enrolled 20 patients with Type 2 SMA aged 2 and older,and who had initiated treatment with an approved SMN upregulator before 5 years of age. In this cohort, patients were randomized 1:1 in a double-blind fashion to receive either a low dose of 2 milligrams per kilogram SRK-015 or a high dose of 20 milligrams per kilogram dose every 4 weeks in conjunction with background nusinersen treatment. The baseline characteristics of the TOPAZ trial are shown on Slide 11. Overall, these characteristics appropriately reflect the patient populations we hope to enroll in the study. With the exception of the monotherapy patients, all patients are receiving background nusinersen as it was the only approved therapy for most of the TOPAZ enrollment period. Such patients were required to be past the loading phase of treatment. And importantly, as you can see here, these patients had received an average of about 5 maintenance doses of nusinersen. It's about 2 years of treatment before they enrolled into the TOPAZ trial. Specifically, I want to draw your attention to Cohorts 2 and 3. Even after 2 years on nusinersen, the baseline HFMSE scores continue to be in the low to mid-20s. Turning to Slide 12. The TOPAZ trial was designed and is being conducted in a rigorous manner. The study [ include ] patients from a large and diverse group of study sites across the U.S. and Europe, and enrollment was not skewed to any one site for any given cohort or across the study. The primary efficacy endpoints, the Expanded Hammersmith Functional Motor Scale, or HFMSE in short, and the Revised Hammersmith Scale, or RHS in short, for non-ambulatory SMA and ambulatory SMA, respectively, are well-validated outcome measures. The HFMSE was specifically designed for SMA and is often used in clinical practice and clinical research and served as the primary efficacy endpoint used in the Phase III CHERISH trial of nusinersen. Furthermore, these efficacy assessments are being conducted in a rigorous fashion. [ All trial sites ] underwent extensive training for a standardized conduct of Hammersmith scale assessments. In addition, to minimize potential for bias, the physical therapists conducting the assessments are blinded to the baseline and prior-visit scores for each individual patient. In this way, scoring is done objectively in isolation without knowledge of how a patient's scores are trending. And finally, within this Phase II trial, we embedded a randomized, double-blind, parallel arm cohort to evaluate for dose response between high and low doses of SRK-015. Now let's move to the 6-month interim analysis results on Slide 14. We will walk through each of the 3 cohorts in detail, but first, a summary of the interim analysis results. There were mean improvements from baseline in the primary efficacy endpoints of Hammersmith scale scores in each of the 3 cohorts. A substantial proportion of patients in each cohort also attained the high bar and otherwise uncommon outcome of at least a 3-point improvement in the Hammersmith scores over baseline. In Cohort 3, the most rigorous part of TOPAZ and which had a randomized, double-blind, parallel arm design, there was a dose response observed in which the high dose had a mean change from baseline of 5.6 point improvement as compared to a 2.4 point improvement in the Hammersmith scores in the low-dose arm. This observed dose response was supported by PK and PD data. As Tony indicated before, we met the main goals of the 6-month interim analysis, and the results were consistent in observing Hammersmith score improvements across the 3 parallel cohorts. Together, the data set offers multiple lines of evidence that demonstrate the potential to improve motor function through SRK-015. Let's walk through the interim analysis results in detail, starting with Cohort 1 on Slide 15, which evaluated patients with ambulatory Type 3 SMA both in terms of SRK-015 as a monotherapy, as shown in orange; and with background nusinersen treatment, which is shown in green. As a reminder, this is a patient population for which SMN upregulator therapy alone historically appears to primarily offer motor function stabilization rather than improvement. In the SRK-015 as add-on to nusinersen group, one patient withdrew consent and discontinued early from the study for reasons unrelated to study drug. The patient was included in the intent-to-treat analysis. The main change from baseline in RHS for all 23 patients was a 0.5-point improvement. 52% of the patients saw an improvement as measured by at least a 1-point increase in RHS at the internal analysis time point, and about 26% of the patients achieved at least a 3-point increase. Results from the 2 subgroups were comparable. Further analysis and data for the full 12-months treatment period can provide additional insights on SRK-015's potential in this patient population. Now moving to Cohort 2 on Slide 16. As a reminder, Cohort 2 enrolled patients with Type 2 and non-ambulatory Type 3 SMA started on nusinersen at the age of 5 or older. This is also a patient population for which SMN upregulator therapy alone historically appears to primarily offer motor function stabilization rather than improvement. As a reminder, this patient population had been treated with nusinersen for about 2 years before enrolling in TOPAZ and had a baseline HFMSE score in the mid-20s. One patient in this cohort missed 3 doses due to COVID-19-related restrictions to site access, and the 6-month interim analysis time point data was not included -- and the patient's 6-month interim analysis time point data was not included in the interim analysis. Mean change from baseline in the HFMSE score was a 1.4-point improvement. This mean increase was not driven by outliers as improvement was widely seen across this cohort, as shown on the plot on the left side of this slide. 71% of the patients in the cohort achieved at least a 1-point increase in HFMSE, while 21% of the patients achieved at least a 3-point increase. The time course for the change in mean HFMSE scores is shown on the right side of the slide. Patients started to demonstrate an improvement between week 8 and week 16, and this improvement progressively increased over the 6-month treatment period. A plateau in improvement appears to not yet have been reached. Data from the 12-month and extension period can provide insights in the potential -- into the potential for durability effect and the potential for further motor function gains. Now let us advance to Cohort 3 on Slide 17, which evaluates patients with Type 2 SMA. These patients initiated treatment with nusinersen before the age of 5 and have been on nusinersen for about 2 years. Even with chronic nusinersen therapy, the baseline mean HFMSE score was in the low 20s. This cohort had a randomized, double-blind, parallel arm design and evaluated a low dose of 2 milligrams per kilogram and a high dose of 20 milligrams per kilogram. Two patients, one in the low dose and one in the high-dose arm, each missed 3 doses due to COVID-19-related restrictions to site access, and the 6-month interim analysis time point from these patients was not included in the interim analysis. The high-dose arm, as shown in orange, demonstrated a substantially greater improvement in the mean change from baseline in the HFMSE score than the low-dose arm, which is shown in green. Improvement in the high-dose arm was 5.6 points as compared with 2.4 points for the low-dose arm. In the high-dose arm, 100% of patients attained at least a 1-point improvement as compared to 67% with low dose. Looking at the high bar of 3-point improvement, 67% of patients in the high-dose arm achieved this threshold compared to 44% in the low-dose arm. And more than half of the patients in the high-dose arm achieved at least a 5-point increase from baseline. Now let's examine the time course of the 2 treatment arms, as shown on Slide 18. The high-dose arm outperformed the low-dose arm numerically at week 8, week 16 and at the 6-month interim analysis time point. This was shown both in terms of a greater mean change from baseline in the HFMSE as well as in the proportion of patients with at least 3-point improvement in the HFMSE. In addition, the HFMSE scores progressively increased over time, and a plateau in improvement appears to not have been -- yet have been reached at least as of this 6-month interim analysis time point. 12-months and extension data can offer insights into the potential for durability and the potential for further motor function gains. Although not powered for formal statistical testing, the numerical differences between the high-dose and low-dose arms in the primary efficacy endpoint are large. Our confidence in the observed dose response is further strengthened by the internal consistency of this data set as the high-dose arm numerically outperformed the low-dose arm across every time point in the 6-month treatment period, both in terms of mean changer baseline as well as proportion of patients achieving at least a 3-point improvement. And the PK and PD results are logically consistent with the observed dose response, as shown on Slide 19. SRK-015 exhibited a PK profile consistent with that of a well-behaved antibody and showed dose proportionality. Based upon the latent myostatin biomarker data, treatment with the high dose of 20 milligrams per kilogram yielded higher levels of target engagement. And in fact, the low dose did not appear to achieve full target saturation. Turning to Slide 20 on safety. We did not identify any safety signals from the interim analysis, and results from the 12-month treatment period will provide additional insights on SRK-015 safety and tolerability profile. The incidence and severity of adverse events were consistent with the underlying patient population and background therapy. There were no apparent dose-related safety signals, and there were no Grade 3 or higher treatment-emergent adverse events. The 5 most frequently reported TEAEs as of the interim analysis were headaches, upper respiratory track infections, pyrexia, nasopharyngitis and cough. There was one serious TEAE that was assessed by the trial investigator as unrelated to SRK-015. This patient had a prior history of upper respiratory infections and developed a Grade 2 viral upper respiratory tract infection that led to hospitalization. The event resolved without sequelae. In addition, one patient discontinued from treatment and study early due to muscle fatigue that had started prior to initiation of treatment with study drug and was assessed by the trial investigator as unrelated to study drug. Now on Slide 21, let's take through these results from an integrative perspective. Based on these interim data, we believe we can make 2 assertions: number one, there are multiple lines of evidence supporting the clinical effect of SRK-015; and number two, SRK-015 has broad and meaningful therapeutic potential for SMA. Starting with the first assertion on the left-hand panel of the slide. First of all, Cohort 3 provides most direct line of evidence. It is the most rigorous part of the trial and embodies a randomized, double-blind, parallel arm study embedded within TOPAZ. And indeed, dose response was observed, and PK and PD results further support this observed dose response. Second, in Cohort 2, a population where patients typically experience motor function stabilization on nusinersen treatment, we observed mean improvement in the HFMSE from baseline upon treatment with SRK-015. Third, we observed substantial proportions of patients meeting the high bar of at least 3-point improvement in each of the 3 cohorts. Remember, attaining this level of improvement in any given patient is a high bar outcome and is rare to observe. These multiple lines of evidence together support the therapeutic hypothesis that the observed improvements in efficacy are due to SRK-015. Now I'll turn our attention to the second assertion on the right-hand panel of this slide. We believe that the interim analysis results demonstrate the broad and meaningful therapeutic potential of SRK-015 for patients with Type 2 and Type 3 SMA. In each of the 3 cohorts, mean improvements from baseline in the Hammersmith scores were indeed observed, and most patients across the study experienced an improvement. Gaining improvements in the ability to perform motor tasks is quite important for patients living with SMA. Finally, please note that this is a 12-month study and that the results we have presented today are from a 6-month look. In Cohorts 2 and 3, the mean improvement progressively increased over time and a plateau in improvement appears to not yet have been reached. The 12-month and extension data will offer additional insights on the potential for durability of clinical effect and on the potential for further motor function improvements. To summarize, with the body of evidence emerging from this TOPAZ interim analysis, we believe that proof-of-concept for SRK-015 in SMA has been achieved and look forward to further investigating the potential of this therapeutic approach. With that, I will now hand it over to Tony for closing remarks.

Thanks, Yung. Thanks, Yung. Well done. Let me talk about where we go from here, as outlined on Slide 23. First, we will complete the TOPAZ trial as planned. You should expect top line data from the full 12-month treatment period in the second quarter of 2021. As Yung said, these 12-month results will allow us to learn more about the longer-term efficacy and durability of the clinical effect, and they will also include additional analysis, including long-term safety, PK, PD and evaluation of anti-drug antibodies. Next, we will also continue our ongoing extension study. As of last Friday, 39 of 39 patients who have completed the 12-month study have decided to opt the extension period for further treatment and follow-up. We have been planning to initiate a registrational trial for 015 in 2021, and these results encourage us to accelerate that work. We look forward to engaging with regulatory authorities to discuss the best regulatory path for SRK-015 in SMA. Now let's talk about the implications for Scholar Rock overall in our scientific endeavor on Slide 24. These data demonstrate proof-of-concept for SRK-015 in SMA, validate -- validating the potential of inhibiting latent myostatin for therapeutic benefit. Furthermore, it validates the therapeutic potential of targeting the latent forms of growth factors. This is a pivotal accomplishment for the company. And it positions us to continue to pursue a wide range of R&D efforts. In addition to broader exploration within SMA, we have the potential to translate this myostatin approach to other neuromuscular disorders. We can explore addressing diseases where we believe myostatin biology is important. And of course, this validation gives us further confidence in the other work we are already progressing, including our very exciting immuno-oncology program, SRK-181, which is currently being evaluated in our DRAGON Phase I proof-of-concept trial. There are more than 30 related growth factors in the TGFß superfamily that mediate diverse biological processes, and we are working hard to generate antibodies against other latent growth factors. Scholar Rock was founded 8 years ago on revolutionary science. Today, we believe our first clinical proof-of-concept positions us to accelerate and expand our mission. Look at the upper left-hand corner of the pipeline chart on Slide 25. You are here at the TOPAZ interim analysis. There is a rich cascade of data events ahead of us with SRK-015 and across our other programs. This includes SRK-181, where we intend to share a progress update on dose escalation in Part A of the DRAGON trial this quarter as we prepare for the start of Part B in the first quarter of 2021. So to close, I want to thank my colleagues for the hard work that got us here. We want to thank our clinical trial investigators and sites. And most importantly, we want to thank the patients and their families, recognizing the significant logistical and practical challenges that are -- the ongoing pandemic has caused. I know I'm speaking for every employee at Scholar Rock when I say that we are grateful for your dedication and your sacrifice. I think we can now turn to Q&A. Operator?

[Operator Instructions] Our first question or comment comes from the line of Michael Yee from Jefferies.

Congrats on very promising data. This is great. Two-part question. In Cohorts 1 and 2, where you do see some mean improvement, which I think is great, what are the 1 or 2 strongest data points to give you confidence against ruling out any sort of open-label or placebo impact? When you look at some of the earlier studies from nusinersen, there is some modest placebo positive improvement in the first 6 months, so maybe just comment on that. And then the second question actually was more scientific. In the monotherapy arm versus on top of nusinersen, I would have maybe hoped actually for more improvements with nusinersen as a background just because of synergy of the mechanism. So maybe just comment on what you think is going on there.

Good. Thanks, Mike. Yung, do you want to take a crack at those? I'm happy to turn after you go. Yung, are you on mute?

Hello? Can you hear me? Okay. Sorry.

Yes, go ahead.

Yes. Yes. Sorry.

So placebo effect and monotherapy. Thanks.

Yes. So yes, so starting with the first question, speaking more broadly, we believe that the data across the 3 cohorts are quite compelling and demonstrating the potential of SRK-015. In particular, the Cohort 3 data are compelling to us because it was data showing dose response in the context of a randomized, double-blind, parallel arm study, and we did indeed observe strong evidence for our dose response based upon these data. Now the other thing about it is in terms of Cohorts 1 and 2, we not only saw mean improvement from baseline. The other thing that was encouraging to us was that we saw a substantial subset of patients achieve at least a 3-point improvement in their Hammersmith scores at least through this 6-month interim analysis. And it's hard for us to envision that it would be easy for an individual patient to achieve a 3-point improvement in the Hammersmith scale just from a placebo effect alone. So we're very excited about the potential SRK-015 based upon these data, and we look forward to the 12-month data extension period to evaluate what the longer-term results are over time. Now in terms of the second question about the monotherapy, so the way we think about it is just thinking about together, the 2 groups, the monotherapy and the dual group, they're generally comparable to each other in terms of the numbers. And so we think that just broadly for the ambulatory Type 3 population, we're encouraged by these results and look forward to investing the potential further. And in terms of the monotherapy results, we're intrigued, we find it clearly intriguing, but it needs further exploration to really understand this further. And we think that the 12-month data offers an opportunity to characterize this potential further.

You also said people have been on nusinersen for, I think, an average of 2 years as well, right? So they're pretty stable on that and therefore seeing these sudden increases, I think, I guess, adds to that.

Yes. That's another good point, which is that -- yes, they've been well into their maintenance regimen roughly on average about 2 years. So yes, so it's in that context as well.

Our next question or comment comes from the line of Do Kim from BMO Capital Markets.

Congrats on the great data. Just a follow-up on Yung's comments, on Cohort 3, when you look at the PK/PD data, would you expect those levels to predict benefit in the 2 milligram per kilogram dose? In other words, do you think that low dose is an active dose? Just trying to gauge on the question of a potential placebo response and how close the 2 milligram per kilogram dose could reflect what a placebo could be.

Go ahead, Yung.

So yes. Yes, so I could take this. So it's based upon -- when you look at the PD data, given that it is showing some -- it is showing target engagement, right, based upon the latent myostatin biomarker but not at the level of target engagement achieved by the high-dose arm. Now with that said, it's quite possible that the low dose in Cohort 3 might have offered treatment benefit. And if so, that -- if that was actually the case, then the effects observed with the high dose would become an even greater magnitude relative to the effects of background nusinersen alone. And if we were to assume that the low-dose arm did not offer any benefit, it's still exciting to us because of the large difference observed between the 2 arms. And again, as a reminder, these are individuals who started -- who have been on nusinersen approximately on average for about 2 years. And despite this, their Hammersmith scores are still in the low to mid-20s, again, highlighting that there's a lot of unmet need there and a lot of -- that their scores are still quite low in terms of thinking about the maximum possible score of 66 points. So together, we find the data quite exciting in terms of potential of SRK-015. And the 5.6-point improvement in high dose is really exciting to us.

Great. That's helpful. And when you look across the individual responses and outcome, I know it's pretty early days in the data analysis, but did you observe any relationship with the baseline characteristics and how the patients performed?

Yes. So as the study is still ongoing, we are blinded to individual patient-level data. But when we get to the full 12-month data, there's the opportunity to consider various explorative analysis along those lines.

Our next question or comment comes from the line of Madhu Kumar from Baird.

So I guess my first one relates to, when we look across Cohorts 1, 2 and 3, you see this kind of numerically higher impact in Cohort 3. How does that make you think about the potential to use this drug in SMA Type 1 patients who are stably on some kind of SMN modulator under this notion that younger patients might achieve greater benefit from myostatin inhibition than relatively older patients?

So you're asking, Madhu, about Type 1?

Basically, based on the data you've seen so far, it seems like in Cohort 3, which is the youngest population in the trial, you seem to have a numerically bigger impact on these Hammersmith scores. So how does it make you think about the potential to use myostatin inhibition in Type 1 SMA patients who are already on stable SMN modulators?

Yes. So good question, not a question that we are testing here, so I don't want to speculate too much. I'll let Yung comment on that. It is true that in the younger population there's more benefit. That's in some ways not surprising based on the fact that they're growing and they're developing muscle, et cetera, and that's consistent with even what's happened with the SMN upregulators. So that's kind of where the market is moving if you think about it over time very slowly toward more people who are getting treated early, so we were happy in Cohort 3 to have taken a look at that. And we are very encouraged by what we see in younger patients in this. I think it's probably too early to speculate about Type 1. We have some work to do on these 3 cohorts right here that all collectively offer a really interesting opportunity. Yung, anything to add?

Yes. Yes. Just to add that we think that there is broad potential for SRK-015 across a wide range of types and age in patients, and that would include the potential in Type 1 SMA. And as Tony outlined, we're -- the TOPAZ trial's focused on Type 2 and Type 3 SMA. But we do believe there is broad potential, and we look forward to exploring that broad potential in the future.

Okay. And then kind of following from that, how many patients among the ones in TOPAZ had not just been on nusinersen but had done the Hammersmith test before this study?

Yes. You want to, Yung, maybe distinguish between the baseline that they did and what might have been prior to the Hammersmith test because I think that's an important function in the trial.

Yes. Oh, yes. Yes. So the baseline Hammersmith scores were collected as part of this clinical trial. And in terms of scores before -- looking back at scores before they entered in trial, we were actually advised against doing this by our trial investigators and physical therapist advisers as Hammersmith scores collected outside of clinical trials can be quite variable. And so instead, it's important to have the assessments done in a standardized and rigorous fashion. And so that's how we approached it in TOPAZ. Now the other point here is, to enroll in TOPAZ, patients had to be beyond the loading dose phase and had to be well into the maintenance period. And as you can see from the baseline characteristics, on average, patients had received at least 5 maintenance doses prior to enrollment, which translates approximately 2 years. And notably, even despite being on nusinersen treatment for an average of 2 years or so, the patients, for example, in Cohorts 2 and 3 had baseline HFMSE scores in the low to mid-20s.

I guess I'm asking a much more practical question on the lines of like the patients in this trial have had prior experience with the RHS and HFMSE testing kind of matrix. Is that reasonable to say?

Probably true, but there's little evidence of a kind of training effect in the Hammersmith, if that's what the implication of the question is. It's likely that they would have had experience with Hammersmith scale, yes.

Okay. Cool. And then last question. So you mentioned that you have expansion beyond SMA into other neuromuscular conditions based upon this result. Like what kind of neuromuscular conditions do you envision the myostatin could work in? And then conversely, what are ones where you would potentially look to avoid using myostatin blockade because you think that the setup isn't favorable?

Yes, thanks. That's a really good question. We've obviously been thinking about this question pretty hard. I know that the company, earlier in the year before I joined, may have guided that we've announced a second indication by the end of the year. Frankly, when I came in, I said let's not rush to do that. We want to see the TOPAZ data first. This is hugely encouraging on the myostatin -- on the muscle-directed hypothesis. Probably a little early to talk about what some of those ideas are, but this will encourage us to accelerate thinking about other muscular diseases. We think there's an interesting opportunity set there. We'll come back in due course and talk about where we think the most promising opportunities are, but we're very encouraged.

Okay. And sorry, one last one. In the 12-month data, what would you need to see to kind of really give you encouragement on each of the 3 cohorts to kind of move forward in a Phase III in that specific patient population, at least on where you are now?

Well, I think we're recognizing, Madhu, that these data are kind of 15 minutes old. We're pretty encouraged about all 3 cohorts right now. Look, we're going to be looking for durability of effect. We're obviously going to be looking at long-term safety. But as -- again, I'll go back to where Yung started. As you look across the cohorts, we saw a majority of patients respond, so there's something happening, right? The majority of patients are getting at least one point, which is unlikely to be noise at that broader level. And a significant portion of patients getting 3, 4 and 5 points, so we'll see. 12-month data will help us understand exactly which patient population to pursue more specifically in a registrational trial and as there are sequencing of things that we might do. But I think it's a little early to either write any of these off or say one would be the sole focus. I think we've got a really interesting opportunity set here, and the 12-month data with durability and other things will help us think a lot more clearly about that.

Our next question or comment comes from the line of Marc Frahm from Cowen and Company.

Congrats on the data, particularly the pretty robust data in Cohort 3. Maybe following on one of the earlier questions about kind of the impact of age on the treatment effect you're seeing, if you look -- I recognize it's relatively small numbers. But if you look within Cohort 3 or even kind of adding in the Cohort 2 patients and use kind of age as like a continuous variable, do you see kind of a robust effect there where the earlier you intervene, it looks like it's having a better effect?

So I think we haven't done the individual level stratification just because the study is still ongoing, and we remain blinded to individual patient level. But we are very encouraged by these data. And again, we think there's broad potential based upon seeing mean improvements across all 3 cohorts and with a substantial portion of patients achieving at least a 3-point improvement in all 3 cohorts. Now in theory, in principle, younger age could have -- patients with a younger age could have greater effect or at least a faster effect given, in theory, the fact that their muscle is in a more dynamic stage, is having potentially a more accelerated growth structure. But in that -- with that said, we do think there's broad potential and are quite encouraged by the -- yes, but it's not just from Cohort 3 but the data in terms of Cohorts 1 and 2. And so we think there's broad potential not just in the youngest patients but in -- across a wide range of ages, and we'll look forward to and continue to investigate this potential.

Okay. And then also, you mentioned kind of the intention to go to pivotal trials. Do you have enough here to start having your conversations with regulators on the designs of those trials? Or do you think you need that durability and kind of longer-term safety data from 12 months before you can kind of have those conversations with regulators?

Yes. Good question, Marc. Very active topic of conversation within Scholar Rock right now. Obviously, we are -- we think these data are terrific. We want to engage with the regulators as quickly as possible. We'll have to do a little more thinking about the exact sequencing of when we do that. But we're very encouraged. And to the extent we would be in a position to engage with regulators on this data, that's obviously something we'd be interested to do with it, put a little more thought into what that exact tactical plan looks like, but very optimistic.

Okay. And then in this -- in the broader SMA space, there's been a mix of approvals using single-arm data versus randomized data. Is your assumption you're going to need a randomized trial? Or do you think the kind of longer-term follow-up of the correctors is getting robust enough that you can just use a single-arm approach?

Probably too soon to get specific on that kind of level of detail on trial design, but those things are definitely part of the consideration set that we've been hypothesizing about in the absence of data, doing scenario planning, obviously, for the last 6 months, and we'll be working hard on that in next handful of months.

Okay. Congrats again on the data.

Thank you.

Our next question or comment comes from the line of David Nierengarten from Wedbush Securities.

Nice data. I just wanted to dig in a little bit on the monotherapy and combination for Cohort 1. You have a couple more patients with a 3-point increase, monotherapy versus in combination. And I was wondering if that was likely due to a shorter time from diagnosis or the patient was -- or the patients in the nusinersen combo were already essentially stabilized on nusinersen. And then drawing -- going forward with that on Cohorts 2 and 3, are those patients who have a greater than 3-point increase more likely or skewed to having fewer nusinersen treatments or any other potential differences or outliers in those groups?

Yung, go ahead.

Yes. So the monotherapy data are intriguing. We do have much to learn. But I think we want to be cautious about over-interpreting the data sets just yet. I mean we got to -- because it's not like they're -- that's hugely divergent from each other. So there's still work that needs to be done. And as of now, we don't have the individual patient-level data because we want to maintain the blind, right? The study is still ongoing. But certainly, as we get to the 12-month data, it's an opportunity to explore those interesting questions, and the 12-month and extension data will allow us to have further insight into the potential of the monotherapy.

And maybe just a quick follow-up. What was the range on prior nusinersen treatments for the combo cohorts? You have the mean, but I don't see a range on the data.

Oh, in terms of the combo cohorts?

Yes. How many? Yes.

So yes, so I think in general, it was generally around -- roughly average around 5 or so, a little bit above it. But remember, just in terms of the upper-limit nusinersen, it's been approved for only a certain amount of time, right? And so that -- you can kind of imagine what that cap would be upper cap. But we think the -- when you look across the 3 cohorts, we wanted to make sure and we just do something by design that we wanted to make sure that patients were well into their maintenance space and certainly the -- at least the baseline characteristics indicate that they were on average well into that baseline range.

[Operator Instructions] Our next question or comment comes from the line of Ted Tenthoff from Piper Sandler.

My congratulations, too. Actually, most of my questions have been answered. But I guess, maybe looking back to the pipeline and really sort of the validation of the approach more broadly, what does this sort of increased priority for you in terms of other programs to even beyond SMA and your super cool I-O program?

Ted, it's Tony. So what -- this is huge for us to have this first proof-of-concept in a clinical setting. What the company has been doing for 8 years is blocking the latent form, the precursor of growth factors, using that as a way to do 2 things: one is to broaden the therapeutic window; and the second is to go after places other people have struggled, right? We, I think, got very powerful -- it's one case, right, but we've got very powerful evidence of that. It certainly gives us encouragement as we think about the I-O program or fibrosis stuff that we're doing with Gilead, et cetera. It's the first demonstration that, that area of blocking the latent form, increasing the therapeutic window and going after targets that other people advanced have to hit. And I think we're optimistic that we're going to be able to do it again and again. The first on deck is really the I-O program. As I said, we'll have a progress update. It's really just a dosing progress update late this quarter but will be in Part B of the DRAGON trial pretty early in 2021. And we'll have -- there's a good experiment like this designed to get the proof-of-concept pretty quickly.

[Operator Instructions] I'm showing no additional questions in the queue at this time. I would like to turn the call back over to management for any closing remarks.

Okay. Thanks. It's Tony. I'll wrap us up. Thank you all for joining this morning. Again, we especially thank our investors and others who have been supportive of the company over time. It's been an 8-year journey around this theory that we just thought about. This is a pivotal time for the company. Great news for patients who are one step closer in SMA to potentially providing a really new and additive important therapy. And as I said, this is a powerful validation of the scientific platform and a great work that Scholar Rock scientists and clinical people have been doing for a long time. So thank you to the team. Thanks all for listening this morning. We look forward to talking more about this as we get more data. Thank you.

Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day.