Investor Update

Oct 27, 2020

Good day, ladies and gentlemen, and thank you for standing by. Welcome to the SRK-fifteen 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. At this time I would like to turn the conference over to your host, Ms. Kathryn 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 SRK015 TOPAD Phase II clinical trial patients with type II and type III spinal muscular atrophy or SMA. The webcast slides for this call can be accessed on the Events and Presentations section of the Investor Relations page on the ScholarRock website. I wanted to note that we'll be making various statements about ScholarRock'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 ScholarRock'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. Young Chung, 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 then offer summary remarks and next steps for the SRP-fifteen clinical program. We will take questions at the end of the call during which Tony and Young will be joined by Ted Miles, our CFO and head of business operations. Thank you, and I will now turn the call over to Tony. Thank you, Katherine, and thank you, everyone, for joining us this morning. I am honored to be kicking off this exciting conference call to discuss the six month interim results from the SRK-fifteen TOPAZ Phase II trial in patients with type two and type three SMA. Let's start on slide four and talk about why Scala Rock is developing 15 as a new treatment for neuromuscular diseases. In SMA there are now three approved SNN up regulators available to help address the underlying genetic defect that causes SMA. But patients may still have significant impairments in motor function. SRK-fifteen is a muscle directed therapy intended to complement the disease stabilizing benefits of SNN upregulators. By blocking latent myostatin, we believe treatment with 15 has the potential to drive additional functional improvements. Turning to slide five. SRT-fifteen 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 a one five, the rare pediatric disease designation, an 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-fifteen 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 15, 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 six to speak to our proprietary scientific platform. SRK015 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. Young 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-fifteen 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 Youngblow explained, 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 Chung, 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. Young? 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 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-nineteen pandemic. The initial focus of the SRK15 program is on Type two and Type three 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 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 as 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-fifteen has the potential to achieve those aims. Let's review the design of our Topaz trial as outlined on slide 10. This Phase two study consists of three parallel cohorts, each evaluating a distinct subpopulation of patients with type two and type three SMA. More specifically, cohort one enrolled 23 patients with ambulatory type three SMA between the ages of five and 21. These patients are either treated with SRK015 as a monotherapy or in conjunction with an approved SMN upregulator. Cohort two enrolled 15 patients with Type two or non ambulatory Type three SMA, also between the ages of five and 21, and all patients are treated with SRK015 in conjunction with an approved SMN upregulator. In both Cohorts one and two, patients are being treated with twenty milligrams per kilogram of IV SRK015 dosed every four weeks. Cohort three enrolled 20 patients with Type two SMA age two and older and who had initiated treatment with an approved SMN upregulator 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 two milligrams per kilogram SRK15 or a high dose of twenty milligrams per kilogram 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 passed the loading phase of treatment. And importantly, as you can see here, these patients had received an average of about five maintenance doses of nisnursen to about two years of treatment before they enrolled into the Topaz trial. Specifically, I want to draw your attention to cohorts two and three. Even after two 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 is for patients 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 nisinersen. Furthermore, these efficacy assessments are being conducted in a rigorous fashion. Underwent extensive training for standardized conduct of Hammersfield Scale assessments. In addition, 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. 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 SRK015. Now let's move to the six month interim analysis results on slide 14. We will walk through each of the three 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 three cohorts. A substantial proportion of patients in each cohort also attained a high bar and otherwise uncommon outcome of at least a three point improvement in the Hammersmith scores over baseline. In Cohort three, 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 improvement as compared to a 2.4 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. And the results were consistent in observing Hammersmith score improvements across the three parallel cohorts. Together, the dataset offers multiple lines of evidence that demonstrate the potential to improve motor function through SRK015. Let's walk through the interim analysis results in detail, starting with Cohort one on Slide 15, which evaluated patients with ambulatory type three SMA, both in terms of SRK015 as a monotherapy, as shown in orange, and with background nucinersen treatment, which is shown in green. As a reminder, this is a patient population for which SMN of regular therapy alone historic historically appears to primarily offer motor function stabilization rather than improvement. In the SRK015 as add ons in this nursing 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 improvement. Fifty two percent 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 twenty six percent of the patients achieved at least a three point increase. Results from the two subgroups were comparable. Further analysis and data from the full twelve month treatment period can provide additional insights on SRK015's potential in this patient population. Now moving to cohort two on slide 16. As a reminder, cohort two enrolled patients with type two and non ambulatory type three SMA started on nisinersen 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-20s. One patient in this cohort missed three doses due to COVID-nineteen related restrictions to site access, and the six month interim analysis time point data was not included the patient's six 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 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. Seventy one percent of the patients in the cohort achieved at least a one point increase in HFMSE while twenty one percent 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 sixteen. And this improvement progressively increased over the six month treatment period. A plateau in improvement appears to not yet have been reached. Data from the twelve month and extension period can provide insights into the potential for durability effect and the potential for further motor function gains. Now let us advance to Cohort three on slide 17, which evaluates patients with type two SMA. These patients initiated treatment with nisinersen before the age of five and had been on nisinersen for about two years. Even with chronic nisinersen 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 two milligrams per kilogram and a high dose of twenty milligrams per kilogram. Two patients, one in the low dose and one in the high dose arm, each missed three doses due to COVID-nineteen related restrictions to site access, and the six 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, one hundred percent of patients attained at least a one point improvement as compared to sixty seven percent with low dose. Looking at the high bar of three point improvement, sixty seven percent of patients in the high dose arm achieved this threshold compared to forty four percent in the low dose arm. And 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 sixteen, 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 increase 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. Twelve 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 dataset as the high dose arm numerically outperforms 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. And the PK and PD results are logically consistent with the observed dose response as shown on Slide 19. SRK015 exhibited a PK profile consistent with that of a well behaved antibody and showed dose proportionality. Based upon the latent myasthen biomarker data, treatment with the high dose of twenty 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 twelve month treatment period will provide additional insights on SRK015 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 three 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 o one five. This patient had a had a prior history of upper respiratory infections and developed a grade two 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 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 SRK15. And number two, SRK15 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 three 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 two, a population where patients typically experience motor function stabilization on nucinersen treatment, we observed a mean improvement in the HFMSE from baseline upon treatment with SRK015. 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-fifteen. Now let's 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 SRK015 for patients with type two and type three SMA. In each of the three cohorts, mean improvements from baseline in the Hammerslip scores were indeed observed, and most patients across 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 twelve month study and that the results we have presented today are from a six month look. In cohorts two and three, the mean improvement progressively increased over time and a plateau in improvement appears to not yet have been reached. The twelve 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-fifteen 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, Young. Thanks, Young. Well done. Let me talk about where we go from here as outlined on slide 23. First, we will complete the ETOPAZ trial as planned. You should expect top line data from the full twelve month treatment period in the 2021. As Young said, these twelve 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, PKPDE, and evaluation of antidrug antibodies. Next, we will also continue our ongoing extension study. As of last Friday, thirty nine of thirty nine patients who have completed the twelve 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 15 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-fifteen and SMA. Now let's talk about the implications for SCALID ROCK overall and our scientific endeavor on slide 24. These data demonstrate proof of concept for SRK-fifteen and 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 and 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-one 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. Stolar 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-fifteen and across our other programs. This includes SRK-one 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 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 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 and A. Operator? Our first question or comment comes from the line of Michael Yee from Jefferies. Your line is open. Hey guys, good morning. Congrats on very promising data. This is great. Two part question. In Cohorts one and two 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 rolling out any sort of open label for placebo impact? When you look at some of the earlier studies from new generation there is some modest placebo positive improvement during the first six 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. Thanks so much. Good. Thanks, Mike. Young, do you want to take a crack at those? I'm happy to chat after you go. Young, you're on mute. Hello? Can you hear me? Okay. Sorry. Yeah. Go Yes. Yes. Sorry. The effected monotherapy. Thanks. Yes. So yes, so starting with the first question, you know, thinking more broadly, we believe that the data across the three cohorts are quite compelling and demonstrating the potential of STK15. In particular the Cohort three 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 a dose response based upon these data. Now the other thing about it is in terms of cohorts one and two, 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 three point improvement in their Hammersmith scores at least through this six month interim analysis. And 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. So we're very excited about the potential of SRK1-five based upon these data. And we look forward to the twelve month data extension period to evaluate what the longer term results are over time. In terms of the second question about the monotherapy, so the way we think about it is just thinking about, you know, together the two 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 three population we're encouraged by these results and look forward to investigating 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 twelve month data offers an opportunity to characterize this potential further. You also said people have been on news to nursing for I think an average of two 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 two years. So yes so it's in that context as well. Yes 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 and thanks for taking my questions. Just a follow-up on Jung's comments. On Cohort three, when you look at the PKPD data, would you expect those levels to predict benefit the two 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 two milligram per kilogram dose could reflect what a placebo could be. So yes, so I could take this. So 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 mystatin biomarker, but 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 three might have offered treatment benefit. And 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. And 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. And again, as a reminder, these are individuals who started who have been on nusinersen approximately on average for about two years. And despite this, you know, their HAMRST 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 SRK15 And the 5.6 improvement of 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 twelve month data there's the opportunity to consider various exploratory analyses along those lines. Wonderful. Thanks for taking my questions. Thanks, Al. Thank you. Our next question or comment comes from the line of Madhu Kumar from Baird. Your line is open. Yes. Hey, thanks for taking our question. So I guess our first one relates to when we look across Cohorts one, two and three, you see this kind of numerically higher impact in Cohort three. How does that make you think that it potentially uses drug in SMA Type one patients who are stably on some kind of SMN modulator under this notion that younger patients might achieve greater benefit from myasthen inhibition than relatively older patients? Sorry, you're asking, Matto, about Type one? Basically, based on the data you see so far, it seems like in Cohort three, which is the youngest population in the trial, you seem to have a numerically bigger impact on these Hammersmith scores. How does it begin to about the potential to use MYOS10 inhibition in Type one setting on 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 Young comment on that. You know, 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, etcetera. And that's consistent with even what's happened with some of the SFM regulators. 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 three 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 one. We have some work to do on these three cohorts right here that all collectively offer a really interesting opportunity. Jon, anything to add? Yes, yes. Just to add that we think that there is broad potential for SRK15 across a wide range of types age ranges. And that would include the potential in Type I SMA. And as Tony outlined, the TOPAT trial is focused on Type II and Type III SMA. But we do believe there's broad potential, 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 have not just been on nusinersen but had done the Hammersmith test before this study? Yeah. You wanna, yeah, 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 assumption in the trial design. Oh, yeah. Yeah. Yeah. So so the the baseline, the Hammersmith scores were collected as part of this clinical trial. And, you know, in terms of scores before collecting you know, 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. 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, you know, 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. And notably, even despite being on new centers in treatment for an average of two years or so, the patients, for example, in cohorts two and three had, baseline HFMSV scores in the low to mid twenties. I guess I'm asking a much more practical question on the lines of, like, the 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 that that's what the implication of the question is. It's likely that they would have had experience with Amherst Smithfield. Yeah. Okay. Cool. And then, last question. So you mentioned that you have expansion beyond SMA to other neuromuscular conditions based upon this result. Like, what kind of neuromuscular conditions do you envision the myasthen could work in? And then conversely, what are the ones where you would potentially look to avoid using myasthen 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, they have guided that we'd announce 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 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 neuromuscular 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 so long. We're very encouraged. Okay. And then sorry. One last one. In the twelve month data, what would you need to see to kind of really give you encouragement on on each of the three cohorts to kinda move forward in a phase phase three in that specific patient population based on where you are now? Well, I think recognizing, Mona, that these data are kind of 15 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. But, you know, as you again, I'll go back to where Young started. As you looked 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 broad a level. And a significant portion of patients getting, you know, three, four, and five points. So we'll see. A twelve 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. 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 in the twelve 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 Mark Fromm 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 three. 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 recognize it's relatively small numbers, but if you look within Cohort three or even kind of adding in the Cohort two patients and use kind of age as like a continuous variable, do you see kind of a robust effect there where, you know, the earlier you intervene, it looks like it's having a better effect? So I think, you know, we haven't done the individual level stratification just because, you know, the study is still ongoing and 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 three cohorts and with a substantial portion of patients achieving at least a three point improvement in all three cohorts. Now in theory, you know, in principle, younger age could have patients with a younger age could have a greater effect or at least a faster effect given, in theory, the fact that, you know, their muscle is in a more dynamic state, is having, potentially a more accelerated growth trajectory. 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 three, but the data in terms of Cohorts I and II. And so we think there's broad potential not just in the youngest patients but across a wide range of ages. And we'll look forward to continuing 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 twelve months before you can kind of have those conversations with regulators? Yeah. Good question, Mark. Very active topic of conversation within ScholarRec right now. Obviously we 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 what 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, yeah, in the broader estimate space, you know, 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? TBD, 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, you know, and and combination. For cohort one, you have a couple more patients with a three point increase, you know, monotherapy versus in combination. And, you know, I was wondering if that was, likely due to a shorter time from diagnosis or, you know, the patient was or the patients in the nusinersen combo, you know, were already, you know, essentially stabilized on nusinersen. And then drawing going forward with that on Cohorts two and three, are those patients who have a greater than three point increase more likely or skewed to having fewer nusinersen treatments or any other, you know, differences or, you know, outliers in those, groups? Thanks. Yes, go ahead. Yes. So, you know, 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've to because it's not like they're that 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, you know, we want to maintain the blind, right? The study is still ongoing. But certainly as we get to the twelve month data, you know, it provides an opportunity to explore those interesting questions. And the twelve month 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 nuciners and 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? Yeah, how many? Yeah. So yes, so I think in general, it was generally around, you know, roughly average around, five or so, a little bit above it. But remember, it's, you know, just in terms of the upper limit, nusinersen, it's been approved for only certain amount of time, right? And so that you can kind of imagine what that cap would be, upper cap. But, you know, we think the when you look across the three cohorts, you know, 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, you know, at least the baseline characteristics indicate that they were on average well into that baseline range. Okay, got you. Thank you. Thank you. Our next question or comment comes from the line of Ted Tittenhoff from Piper Sandler. Your line is open. Great, thank you. And 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 to even be on SMA and your super cool IO program? Thanks, Ted, it's Tony. So 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 the Gilead, etcetera. 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. And I think we're optimistic that we're gonna 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, and we'll we'll have that's a good experiment like this designed to get the proof of concept pretty quickly. Excellent. Great work, guys. Thank you. Thank you. I'm showing no additional questions in the queue at this time. I would like to turn the call back over to for any closing remarks. Okay. Thanks. This is Tony. I'll wrap this up. Thank you all for joining us this morning. Again, I to especially thank our investors and others who have been supportive of the company over time. It's been an eight year journey around this theory that I 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 the great work that ScholarRock 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.