Good day, ladies and gentlemen, and thank you for standing by. Welcome to the SRK-015 TOPAZ Interim Analyst Results Conference Call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star then one on your telephone keypad. If you require any further assistance, please press star then zero. At this time, I would like to turn the conference over to your host, Miss Catherine Hu. Thank you. Ma'am, please begin.
Good morning, and thank you for joining us on today's call to review the six-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 and Presentation 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 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 three. 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 six-month interim analysis.
Tony will 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'm honored to be kicking off this exciting conference call to discuss the six-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 four and talk about why Scholar Rock is developing 015 as a new treatment for neuromuscular diseases. In SMA, there are now three approved SMN upregulators available to help address the underlying genetic defect that causes SMA. 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 five, 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 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 have 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. Turning to slide six to speak to our proprietary scientific platform.
SRK-015 was discovered by Scholar Rock 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 seven, 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 three 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 three-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, 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 therapist 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 nine, these subpopulations together represent over 85% of the patients living with SMA today. With multiple SMN up regulators, 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 three parallel cohorts, each evaluating a distinct subpopulation of patients with Type II and Type III SMA. More specifically, cohort 1 enrolled 23 patients with ambulatory Type III SMA between the ages of five and 21. These patients are either treated with SRK-015 as a monotherapy or in conjunction with an approved SMN up regulator. Cohort 2 enrolled 15 patients with Type II or non-ambulatory Type III SMA, also between the ages of 5 and 21, and all patients are treated with SRK-015 in conjunction with an approved SMN up regulator. In both cohorts 1 and 2, patients are being treated with 20 mg/kg of IV SRK-015 dosed every four weeks. Cohort 3 enrolled 20 patients with Type II SMA age two and older and who had initiated treatment with an approved SMN up regulator before five years of age.
In this cohort, patients were randomized one to one in a double-blind fashion to receive either a low dose of 2 mg/ kg SRK-015 or a high dose of 20 mg/kg dosed every four 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 five maintenance doses of nusinersen to about two years of treatment before they enrolled into the TOPAZ trial.
Specifically, I want to draw your attention to cohorts 2 and 3. Even after two years on nusinersen, the baseline HFMSE scores continued to be in the low to mid-twenties. Turning to slide 12. The TOPAZ trial was designed and is being conducted in a rigorous manner. The study 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 Hammersmith Functional Motor Scale Expanded, 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.
These efficacy assessments are being conducted in a rigorous fashion. Site underwent extensive training for standardized conduct of Hammersmith Scale assessments. To minimize the 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. 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. Let's move to the six-month interim analysis results on slide 14. We will walk through each of the three cohorts in detail. 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 three cohorts.
A substantial proportion of patients in each cohort also attained the high bar and otherwise uncommon outcome of at least a three-point improvement in the Hammersmith scores over baseline. In cohort 3, the most rigorous part of TOPAZ, 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 six-month interim analysis, the results were consistent in observing Hammersmith score improvements across the three 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 up regulator 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 mean 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 one-point increase in RHS at the interim analysis time point, and about 26% of the patients achieved at least a three-point increase. Results from the two subgroups were comparable. Further analysis and data from 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 five or older. This is also a patient population for which SMN up regulator 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 two years before enrolling in TOPAZ and had a baseline HFMSE score in the mid-twenties. One patient in this cohort missed three doses due to COVID-19-related restrictions to site access, and the six-month interim analysis time point data was not included, and the patient's six-month interim analysis time point data was not included into 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 one-point increase in HFMSE, while 21% of the patients achieved at least a three-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 eight and week 16, This improvement progressively increased over the six-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 into the potential for durability effect and the potential for further motor function gains. 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 five and had been on nusinersen for about two 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 mg/kg and a high dose of 20 mg/kg . 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 three-point improvement, 67% of patients in the high-dose arm achieved this threshold compared to 44% in the low-dose arm. More than half of the patients in the high-dose arm achieved at least a five-point increase from baseline. Now let's examine the time course of the two treatment arms, as shown on Slide 18. The high-dose arm outperformed the low-dose arm numerically at week eight, week 16, and at the six-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 three-point improvement in the HFMSE. In addition, the HFMSE scores progressively increased over time, and a plateau in improvement appears to not yet have been reached, at least as of this six-month interim analysis time point.
12-month 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 six-month treatment period, both in terms of mean change for baseline, as well as proportion of patients achieving at least a three-point improvement. 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 mg/kg yielded higher levels of target engagement. 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 five most frequently reported TEAEs as of the interim analysis were headaches, upper respiratory tract 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 drugs and was assessed by the trial investigator as unrelated to study drug. Now on Slide 21, let's think through these results from an integrative perspective. Based on these interim data, we believe we can make two assertions. Number one, there are multiple lines of evidence supporting the clinical effect of SRK-015. 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 the 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. 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 a 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 three-point improvement in each of the three 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 let's turn our attention to this 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 three 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 six-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. Tony?
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, and 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 analyses including long-term safety, PK/PD, and evaluation of anti-drug antibodies. 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 into 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 and our scientific endeavor on Slide 24. These data demonstrate proof of concept for SRK-015 in SMA, 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.
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 TGF-beta superfamily that mediate diverse biological processes, and we are working hard to generate antibodies against other latent growth factors. Scholar Rock was founded eight 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. 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. Most importantly, we want to thank the patients and their families, recognizing the significant logistical and practical challenges that 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?
Ladies and gentlemen, if you have a question or comment at this time, please press star then one on your telephone keypad. If your question has been answered or you wish to remove yourself from the queue, simply press the pound key. Again, if you have a question or comment at this time, please press star then one on your telephone keypad. Our first question or comment comes from the line of Michael Yee from Jefferies. Your line is open.
Hey, guys. Good morning. Congrats on the 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 one or two 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 during the first six months. Maybe just comment on that. 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. Maybe just comment on what you think is going on there. Thanks so much.
Good. Thanks, Mike. Yung, do you want to take a crack at those? I'm happy to chime in after you go. Yung, you on mute.
Hello, can you hear me? Okay. Sorry. Yeah.
Go ahead. Sorry.
Yes. Sorry.
Placebo effect and monotherapy. Thanks.
Yes. Starting with the first question. Thinking more broadly, we believe that the data across the 3 cohorts are quite compelling in 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. We did indeed observe strong evidence for a dose response based upon these data. The other thing about it is in terms of cohorts 1 and 2, we not only saw mean improvement from baseline, but 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 six-month interim analysis.
It's hard for us to envision that it would be easy for an individual patient to achieve a three-point improvement in the Hammersmith Scale just from a placebo effect alone. We're very excited about the potential of 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. The way we think about it is just thinking about together the two groups. The monotherapy and the dual group, they're generally comparable to each other in terms of the numbers. We think that just broadly for the ambulatory type 3 population, we're encouraged by these results and look forward to investigating the potential further. In terms of the monotherapy results, we're intrigued.
We find it's 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 two years as well, right? They're pretty stable on that, and therefore, seeing these sudden increases, I think, I guess, adds to that.
Yeah. That's another good point, which is that, yes. They've been well into their maintenance regimen, roughly on average about two years. Yeah. It's in that context as well.
Yep. Thank you.
Thanks.
Thank you. Our next question or comment comes from the line of Do Kim from BMO Capital Markets. Your line is open.
Hi. Good morning. Congrats on the great data, thanks for taking my questions. Just to 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 mg/kg 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 two mg/kg dose could reflect what a placebo could be.
Go ahead.
Yeah. I can take this. Based upon when you look at the PD data, given that it is showing target engagement, right, based upon the latent myostatin biomarker. Not at the level of target engagement achieved by the high-dose arm. Now with that said, it's quite plausible that the low dose in cohort 3 might have offered treatment benefit. If so, if that was actually the case, then the effects observed with the high dose would become of even greater magnitude relative to the effects of background nusinersen alone. If one 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 two arms. Again, as a reminder, these are individuals who have been on nusinersen approximately on average for about two years.
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 that their scores are still quite low in terms of thinking about the maximum possible score of 66 points. Together, we find the data quite exciting in terms of potential of SRK-015. The 5.6-point improvement of the high dose is really exciting to us.
Great. That's helpful. 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. As the study's still ongoing, we are blinded to individual patient-level data. When we get to the full 12-month data, there's the opportunity to consider various exploratory analyses along those lines.
Wonderful. Thanks for taking my questions.
Thanks, Do.
Thank you. Our next question and comment comes from the line of Madhu Kumar from Baird. Your line is open.
Yeah. Hey, thanks for taking our question. I guess our first one relates to when we look across cohorts 1, 2, and 3, and you see this kind of numerically higher impact in cohort 3, how does that make you think about to potentially 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?
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. How does it make you think about potentially use myostatin inhibition in type 1 setting on patients who are already on stable SMN modulators?
Yeah. Good question. Not a question that we are testing here, so don't want to speculate too much. I'll let Yung comment on that. It is true that the younger population here saw 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 some of the SMN up regulators. 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. We were happy in cohort 3 to have taken a look at that, and we are very encouraged by what we see in that younger patient population. I think it's probably too early to speculate about type 1.
We have some work to do on these three cohorts right here that all collectively offer a really interesting opportunity. Yung, anything to add?
Yeah. Just to add that we think that there is broad potential for SRK-015 across a wide range of types, age ranges, and that would include the potential in type 1 SMA. As Tony outlined, where the TOPAZ trial is focused on type 2 and type 3 SMA, but we do believe there's broad potential, and we look forward to exploring that broad potential in the future.
Okay, kind of following from that, how many patients among the ones in TOPAZ have not just been on nusinersen, but had done the Hammersmith test before this study?
You want to, Yung, maybe distinguish between the baseline that they did and what might've been prior to the Hammersmith Scale? Because I think that's an important-
Yeah.
Distinction in the trial design.
Oh, yeah. The baseline Hammersmith scores were collected as part of this clinical trial. In terms of scores before collecting, looking back at scores before they entered in trial, we were actually advised against doing this by our trial investigators and physical therapist advisors, as Hammersmith scores collected outside of clinical trials can be quite variable. 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. As you can see from the baseline characteristics, on average, patients had received at least five maintenance doses prior to enrollment, which translates to approximately two years.
Notably, even despite being on nusinersen treatment for an average of two 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 along the lines of, the patients in this trial have had prior experience with the RHS and HFMSE testing kind of matrix. Is that reasonable to say?
It's probably true, but there's little evidence of a kind of training effect in the Hammersmith Scale, if that's what the implication of the question is. It's likely that they would have had experience with Hammersmith Scale. Yeah.
Okay, cool. Last question. You mentioned maybe an expansion beyond SMA into other neuromuscular conditions based upon this result. What kind of neuromuscular conditions do you envision the myostatin could work in? Conversely, what are the ones where you would potentially look to avoid using myostatin blockade because you think that the setup isn't favorable?
Yeah, 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'd announce a second indication by the end of the year. 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 type, on the muscle-directed hypothesis. A little early to talk about what some of those ideas are, but this will encourage us to accelerate thinking about other neuromuscular diseases. We think there's an interesting opportunity set there, and we'll come back in due course and talk about where we think the most promising opportunities are. So long, we're very encouraged.
Okay. Sorry, one last one. In the 12-month data, what would you need to see to really give you encouragement on each of the three cohorts to move forward in a phase III in that specific patient population, based on where you are now?
Well, I think we're recognizing, Madhu, that these data are 15 minutes old. We're pretty encouraged about all three 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. As you, again, I'll go back to where Yung started. As you looked across the cohorts, we saw a majority of patients respond, there's something happening, right? The majority of patients are getting at least one point, which is unlikely to be noise at that broad a level, and a significant portion of patients getting three, four, and five points. We'll see. 12-month data will help us understand exactly which patient population to pursue more specifically in a registrational trial, and is there a sequencing of things that we might do.
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.
Okay, great. Thank you very much, guys.
Thanks.
Thank you. Our next question or comment comes from the line of Marc Frahm from Cowen and Company. Your line is open.
Thanks for taking my questions, and congrats on the data, particularly the pretty robust data in Cohort 3. Maybe following on one of the earlier questions about the impact of age on the treatment effect you're seeing. I recognize it's relatively small numbers, but if you look within Cohort 3 or even adding in the Cohort 2 patients and use age as a continuous variable, do you see a robust effect there, where the earlier you intervene, it looks like it's having a better effect?
I think, we haven't done the individual-level stratification just because the study is still ongoing and remain blinded to individual patient level. We are very encouraged by these data. Again, we think there's broad potential based upon seeing mean improvement across all three cohorts and with a substantial portion of patients achieving at least a three-point improvement in all three cohorts. Now, in theory, in principle, patients with a younger age could have a greater effect or at least a faster effect, given, in theory, the fact that their muscle is in a more dynamic state, is having potentially a more accelerated growth trajectory. With that said, we do think there's broad potential and are quite encouraged. Yeah, but it's not just from Cohort 3, but the data in terms of Cohorts 1 and 2.
We think there's broad potential, not just in the youngest patients, but across a wide range of ages. We'll look forward to and continue to investigate this potential.
Okay. Also, you mentioned 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 longer-term safety data from 12 months before you can have those conversations with regulators?
Yeah. Good question, Marc. Very active topic of conversation within Scholar Rock right now. Obviously, 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. 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. We have to put a little more thought into what that exact tactical plan looks like. Very optimistic.
Okay. 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 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 six months, and we'll be working hard on that in the next handful of months.
Okay, thanks, and congrats again on the data.
Thank you.
Thank you. Our next question or comment comes from the line of David Nierengarten from Wedbush Securities. Your line is open.
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. I was wondering if that was likely due to a shorter time from diagnosis or the patients in the nusinersen combo were already essentially stabilized on nusinersen. Then 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? Thanks.
Yeah. No, go ahead.
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, because it's not like they're that hugely divergent from each other. There's still work that needs to be done. 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 provides an opportunity to explore those interesting questions. The 12-month extension data will allow us to have further insight into the potential of the monotherapy.
Maybe just a quick follow-up. What was the range on prior nusinersen treatments for the combo cohorts? You have the mean, but I didn't see a range on the data.
Oh, in terms of the combo cohorts?
Yeah. How many? Yeah.
Yeah. I think in general, it was generally around roughly average around five or so, a little bit above it. Remember, just in terms of the upper limit, nusinersen has been approved for only a certain amount of time, right. You can imagine what that cap would be, upper cap. We think when you look across the three cohorts, we wanted to make sure, and this was something by design, that we wanted to make sure that patients were well into their maintenance phase and certainly at least the baseline characteristics indicate that they were, on average, well into that baseline range.
Okay. Gotcha. Thank you.
Thank you. Ladies and gentlemen. Our next question or comment comes from the line of Ted Tenthoff from Piper Sandler.
Great. Thank you. 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 increase priority for you in terms of other programs too even beyond SMA and your super cool IO program?
Thanks, Ted. It's Tony. Look, this is huge for us to have this first proof of concept in a clinical setting. What the company has been doing for eight years is blocking the latent form, the precursor of growth factors, using that as a way to do two things. One is to broaden the therapeutic window, and the second is to go after places other people have struggled, right?
We've, I think, gotten very powerful. It's one case, right, but we've gotten very powerful evidence of that. It certainly gives us encouragement as we think about the IO program, our fibrosis stuff that we're doing with Gilead, et cetera. It's the first demonstration that that theory of blocking the latent form, increasing the therapeutic window and going after targets that other people have bounced off the head. I think we're optimistic that we're going to be able to do it again and again. First on deck is really the IO program. As I said, we'll have a progress update. It's really just a dosing progress update late this quarter, but we'll be in Part B of the DRAGON trial pretty early in 2021. That's a good experiment like this designed to get the proof of concept pretty quickly.
Excellent. Great work, guys.
Thank you.
Thank you. Again, ladies and gentlemen, if you have a question or comment at this time, please press star then one on your telephone keypad. 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, I want to especially thank our investors and others who've been supportive of the company over time. It's been an eight-year journey around this theory that I just talked about. This is a pivotal time for the company. Great news for patients who are one step closer in SM A to potentially providing a really new and additive important therapy. As I said, this is a powerful validation of the scientific platform and the great work that Scholar Rock scientists and clinical people have been doing for a long time. 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.