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

Good day, and thank you for standing by. Welcome to the 12-month top-line results of TOPAZ Phase II trial. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today, Catherine Hu, Vice President of Investor Relations and Communications. Please go ahead.

Good morning, and thank you for joining us on today's call to review the 12-month top-line results from our apitegromab TOPAZ Phase II clinical trial of 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 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 Litigation Securities -- 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 discussed in the section entitled Risk Factors in our annual report on Form 10-K. 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 today's agenda, as outlined on Slide 3. Tony Kingsley, our President and CEO, will provide opening remarks. Yung Chyung, our Chief Medical Officer, will review the trial design and baseline characteristics, followed by the 12-month top-line efficacy and safety results. Tony will be joined by Ted, our Chief Financial Officer and Head of Business Operations, to walk you through the next steps for the apitegromab program. We will take questions at the end of the call. Thank you, and I will now turn the call over to Tony.

Thanks, Catherine, and thanks to everyone for joining this morning. We are very pleased to share the top-line results from the 12-month TOPAZ Phase II trial evaluating apitegromab in patients with Type 2 and Type 3 SMA. These results, which we believe show positive momentum following on our exciting 6-month interim analysis from October increase our enthusiasm and belief that apitegromab could potentially have a meaningful impact on patients with spinal muscular atrophy. Starting on Slide 4, let me remind you of the proprietary Scholar Rock scientific platform that led to a apitegromab's discovery, we have a revolutionary approach to targeting the latent forms of growth factors. We leverage deep structural insights to engineer antibodies with exquisite selectivity and we apply that against targets where the biology is well validated, but the targets have historically been challenging to drug. Myostatin inhibition fits this profile. Apitegromab is a selective inhibitor of the latent form of the growth factor of myostatin Scholar Rock believes, the inhibition of latent myostatin with apitegromab, they help patients who suffer from muscle weakness, and functional impairments to improve their motor function. The TOPAZ Phase II study is our first proof-of-concept trial, assessing apitegromab's therapeutic benefits in patients with spinal muscular atrophy or SMA. Turning to Slide 5. SMA is a rare and often fatal genetic disorder that typically manifests at young children. It is characterized by the loss of motor neurons, atrophy and muscles, and progressive muscle weaknesses, which can impact very basic activities such as breathing, eating, and walking. There has been significant progress with the development and availability of SMN upregulators or correctors that address the underlying SMN deficiency to prevent further motor neuron deterioration. However, for many patients, treatment with SMN upregulators may only stabilize disease progression, and they continue to suffer from significant motor function deficits. We are developing apitegromab as a new muscle directed therapy intended to complement the disease stabilizing benefits of SMN upgrade layers. Now on Slide 6, let me briefly summarize how the 12-month data builds on a 6-month interim analysis we shared in October. Starting with Cohort 1, which evaluated patients with ambulatory Type 3 SMA. As a reminder at the 6-month interim analysis, this cohort observed a dean increase in RHS score from baseline as the majority of patients maintained or improved their RHS scores at 12 months, while the dean RHS score for the cohort overall saw a modest decline a majority of patients continue to maintain or increase their RHS scores from baseline. Cohort 2 evaluated patients with non-ambulatory Type 2 or Type 3 SMA with an initiated treatment with nusinersen at 5 years or older. At the 6-month analysis to be HFMSE score increased from baseline at the majority of patients improved. The data at 12 months were consistent and the HFMSE score improved from baseline and the majority of patients had a 1-point or greater improvement, suggesting potential durability of effects. Notably, we observed a sizable percentage of patients achieving at least a 3-point increase from baseline. Now on Cohort 3, which evaluated patients with Type 2 SMA who had initiated treatment with nusinersen before the age of 5, at the prior 6-month interim analysis, we observed the increases in HFMSE scores from baseline with a majority of patients achieving at least a 3-point increase. At 6 months, we also observed a dose response between the high and low-dose arms. At 12 months, we saw further increases in the mean change in HFMSE scores from baseline and an increase in the number of patients seeing substantial improvement. We also saw a continued evidence of dose response. Adverse events were observed in the study were consistent with the underlying patient population and background therapy. We believe these are very exciting results. While the results differ by cohort as expected, and Yung will take you through the details, overall, compared to the 6-month interim analysis, we see both potential durability of effect as well as substantial improvements in HFMSE scores among certain subgroups. These results increase our excitement about moving to a Phase III registrational trial, which we anticipate initiating by year-end. Now I will turn it over to Yung Chyung, our Chief Medical Officer, to review the study design and baseline characteristics and the details of the TOPAZ top-line results. Yung?

Thanks, Tony. We are excited to present the 12-month top-line results of the TOPAZ Phase II trial. Before we start, I want to thank the Scholar Rock team for their dedication and commitment. We are also very appreciative of the high level of engagement from our clinical trial investigators, physical therapists, study coordinators, study site staff and our CRO colleagues. Most importantly, thank you to the patients and their families for their dedication to the trial despite the challenges of the ongoing COVID-19 pandemic. Let's now start with a review of the TOPAZ trial design as outlined on Slide 8. The Phase II proof-of-concept trial 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 were treated with apitegromab, either as a monotherapy or in conjunction with an approved SMN upregulator, nusinersen. 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 were treated with apitegromab in conjunction with an approved SMN upregulator, nusinersen. In both Cohorts 1 and 2, patients were treated with 20 milligrams per kilogram of IV apitegromab dosed every 4 weeks. Cohort 3 enrolled 20 patients with Type 2 SMA, age 2 and older, and who had initiated treatment with an approved SMN upregulator is 4 or 5 years of age. In this cohort, patients were randomized 1:1 in a double-blind and parallel arm fashion, to receive either a low dose of 2 milligrams per kilogram of apitegromab or a high dose of 20 milligrams per kilogram, dosed every 4 weeks in conjunction with background nusinersen treatment. Turning to Slide 9. Let's take a moment to walk through some key considerations in the design and conduct of the TOPAZ trial. The main focus was to assess the potential additive therapeutic benefit of apitegromab on top of background, SMN upregulator therapy. While the protocol allows the use of any approved SMN upregulator, the SMN upregulator with which patients were treated was nusinersen as it was the only therapy with widespread approved use over the course of the study enrollment. We also explored the potential for apitegromab as a monotherapy in a subgroup of patients in Cohort 1. TOPAZ was purposely designed with 3 distinct cohorts to allow an evaluation across patient populations with varying disease severity and different background expectations for the disease course. Clinical data for nusinersen as well as natural history data help inform our background expectations for disease course, absent additional intervention and further are understanding the results as we continue to investigate the potential of apitegromab in SMA. We also conducted dose exploration in the TOPAZ trial. More specifically, we evaluated 2 different doses in Cohort 3. The selection of which were informed by the Phase I dose escalation trial results and PK/PD modeling. Through the 20-milligram per kilogram dose, we wanted to test the dose, which we felt confident with maximized and sustained target saturation. At the same time, we recognize that complete target saturation may not be necessary to achieve therapeutic effect. So we also selected the 2-milligram per kilogram dose aimed at achieving a high level of target engagement but relatively lower than the 20-milligram per kilogram dose. With that backdrop, let's start with reviewing the baseline characteristics on Slide 10. These characteristics reflect the patient population we hope to enroll in the study. As previously noted, with the exception of the monotherapy patients, all patients were receiving background nusinersen. Such patients were required to be past the loading phase of treatment. And importantly, as you can see here, these patients have received an average of about 5 maintenance doses of nusinersen, which translates to roughly 2 years of treatment before they enrolled into the TOPAZ trial. Of note, the baseline HFMSE scores for Cohort 2 and Cohort 3 were in the low to mid-20s, even after 2 rough -- even after approximately 2 years of treatment with nusinersen. These patients have been treated with nusinersen for an average of about 3 years at the 12-month analysis time point. Turning to Slide 11 to review the safety results from the 12-month top-line analysis which support the continued evaluation of apitegromab in a Phase III registrational trial. The incidence and severity of adverse events were consistent with the underlying patient population and background therapy. With the 5 most frequently reported treatment-emergent adverse events or TEAE, being headache, pyrexia, upper respiratory tract infection, cough, and nasopharyngitis. Anti-drug antibodies were present at low titers and 3 out of the 58 enrolled patients and had no apparent impact on drug exposure and were not associated with any hypersensitivity reaction. No safety signals for apitegromab were identified as of this 12-month top-line analysis. Turning to the next slide. On serious and severe TEAEs in the study as well as 1 TEAE, leading study discontinuation, all of which were assessed by the investigators as unrelated to apitegromab. There are 5 serious TEAEs, of which 2 were Grade 3 and 3 were Grade 2. Another Grade 3 nonserious TEAE occurred in a patient in Cohort 1. As a reminder, 1 patient discontinued following 2 months in the trial due to pre-existing leg muscle fatigue that persisted. Now let's move to the efficacy data. Slide 13 provides a high-level summary of the 12-month top-line efficacy results across all 3 cohorts. We believe we met the main goal of the TOPAZ trial and showed that apitegromab offers therapeutic potential of improving motor function for patients with later onset SMA and at the observed safety profile of apitegromab, as of this 12-month top-line readout, supports the potential for chronic dosing, including in a pediatric population. Let's now walk through each cohort in detail, starting with Cohort 1. Slide 15 offers some background insights into the ambulatory Type 3 population based on a natural history study conducted by a third party, motor function decline as measured by the Hammersmith scale occurs on average and can be severe in a subset of patients, such as the loss of ambulation. And as a reminder, the clinical efficacy of SMN upregulator therapy alone in this population has not been as well-established or characterized. Against that backdrop, let's move to Slide 16 on Cohort 1. The apitegromab monotherapy subgroup had a mean 0.4-point decline from baseline in RHS, while the apitegromab plus nusinersen subgroup had a mean 0.3-point decline after 12 months of treatment. While we did observe a wide variance of responses, 57% of patients in the cohort overall did maintain or improve their RHS score from baseline and as highlighted by the blue box on the bottom left. In addition, in the cohort overall, 39% of patients experienced at least a 1-point increase in RHS and 22% had at least a 3-point increase in their RHS score. We are encouraged by these results. And we'll look to explore the data further to gain additional insights on apitegromab's potential in this patient population. Now let's consider Cohort 2. Slide 18 offers background insights into the nonambulatory later onset population, particularly patients of age 5 years and older. Based on the nusinersen CHERISH trial, in patients who have been starting on treatment bought at the age of 5 years or older, as highlighted by the orange box, the mean HFMSE score declined over 15 months of treatment. In this third-party trial, the majority of patients did not experience an improvement in their HFMSE, and it was rare to observe patients with a 3-point or greater increase in the HFMSE. In a separate study, natural history data shows that for patients with nonambulatory later onset SMA were of age 5 years or older, there is a mean decline in the HFMSE over the course of 12 months. And less than 5% of patients achieved a 3-point or greater increase in the HFMSE. Against that backdrop, let's move to Slide 19. Here are the efficacy results of Cohort 2, which enrolled patients with nonambulatory layer onset SMA. We started on nusinersen at the age of 5 years or older. Recall that on average, this patient population had been treated with nusinersen for roughly 2 years before enrolling in TOPAZ and had a baseline HFMSE score in the low 20s. 1 patient in this cohort did miss 3 doses due to COVID-19 related site access restrictions and was not included in the primary intent-to-treat analysis. At the 12-month top-line time point. The mean change from baseline in HFMSE score was a 0.6-point improvement. 64% of the patients achieved at least a 1-point increase in HFMSE and 29% achieved at least a 3-point increase. Of note, as shown on the waterfall plot on the left side of the slide, there was 1 patient who had an outlier result of a 7-point decline in HFMSE score. Before enduring the study, this patient happened to receive concomitant treatment with an acetylcholinesterase inhibitor, which is not permitted for the trial protocol and has the potential to impact neuromuscular function. In accordance with the prespecified approach, this patient's data were not included in the per protocol analysis, along with the patient who had missed 3 consecutive doses of apitegromab due to COVID-19 site access restrictions. For the per protocol analysis, the mean change in HFMSE from baseline for Cohort 2 was a 1.2-point improvement. The time course for the change in mean HFMSE scores is shown on the right-hand side of the slide. The mean change from baseline in HFMSE score remain positive at all assessed time points beyond week 8. Together, these findings highlight the therapeutic potential of apitegromab for improving motor function in a patient population that otherwise could be hypothesized to not improve on average. There was mean improvement in HFMSE from baseline at the 12-month top-line time point with the majority of patients or more specifically, 64%, experiencing at least a 1-point increase from baseline. We are also encouraged by the observation of a sizable proportion of patients specifically 29% retained the otherwise rare outcome of at least a 3-point increase in the Hammersmith score after 12 months of treatment. Turning our attention to Cohort 3. Slide 21 shows a third-party trial that offers background insights into the nonambulatory later onset SMA population, including patients who initiated treatment with nusinersen at a young age. As a reminder, most nusinersen treated patients in the CHERISH trial has started therapies before the age of 5 years. As you can see in the blue curve with diamond shaped dots, patients who received nusinersen and CHERISH experienced a mean HFMSE improvement from baseline almost 4 points in the first 15 months of treatment. But beyond this initial phase, as highlighted by the yellow box, when individuals rolled over into the shine extension study, these patients appear who primarily have motor function stabilization, or only modest and gradual improvement over the subsequent long-term phase of nusinersen treatment. As a reminder, patients in Cohort 3 of the TOPAZ trial had, on average, been treated with nusinersen for roughly 2 years at the time of enrollment and 3 years at the 12-month analysis time point. Now against this backdrop, let us advance to Slide 22. Here are the Cohort 3 efficacy results. This cohort evaluated patients with Type 2 SMA who had initiated treatment with nusinersen before the age of 5. Patients were randomized in double-blind fashion to apitegromab treatment at either a high dose of 20 milligrams per kilogram or a low dose of 2 milligrams per kilogram. A total of 3 patients, 1 in the low dose and 2 in the high dose arm, each missed 3 doses due to COVID-19 related restrictions to site access and were excluded from the primary intense-to-treat analysis. Turning your attention to the orange column in the table. The mean change from baseline in HFMSE in patients treated with a 20-milligram per kilogram dose of apitegromab for 12 months was a 7.1-point improvement. The mean change for baseline in HFMSE in patients treated with the 2-milligram per kilogram dose for 12 months, was a 5.3-point improvement. Although Cohort 3 was not placebo-controlled, we believe that these observed improvements in motor function were both the high and low-dose arms are substantially greater than what 1 might hypothesize would be observed from nusinersen alone. We believe these results demonstrate the therapeutic potential of apitegromab in SMA. In addition, a dose response continues to be apparent. The high dose arm consistently had numerically greater improvements in HFMSE than the low dose arm and not only the 12-month top-line analysis time point but also at each of the set time point throughout the 12-month treatment period, as shown by the time core slot on the bottom right. Moving to the waterfall plot on the bottom left. The majority of patients in each dosing arm experienced not only a 3-point or greater increase in HFMSE but at least a 5-point gain. Now as outlined by the blue box, what was particularly notable to us was that 6 out of 17 patients or about 35% of patients experienced a greater than 10-point improvement in HFMSE. Amongst these 6 patients, 1 patient experienced a 20-point gain and another patient an 18-point gain. Of note, at the 6-month interim analysis, only 1 patient had greater than a 10-point improvement from baseline in HFMSE score. This suggests that at least a subset of patients, improvements continued over the course of the 12-month treatment period. Now let us turn our attention to the PK and PD results as shown on Slide 23. The PK data in the graph on the left side show that apitegromab had dose proportional and sustained drug exposure over the course of the 12-month trial. Importantly, as you can see in the PD data in the graph on the right, both 2 milligrams per kilogram and 20-milligram per kilogram yielded greater than 100-fold mean increases in the latent myostatin concentrations relative to baseline. Thus, signifying that both doses do indeed offer high levels of target engagement. In addition, 20 milligrams per kilogram did achieve a relatively higher absolute level of target engagement than the 20 -- than the 2-milligram per kilogram dose. These target engagement results are consistent with the observed clinical efficacy results that we observed for the 2 dose arms. We are encouraged by the efficacy results for the 2-milligram per kilogram arm in itself. But given the relatively greater numerical improvement observed by the 20-milligram per kilogram dose, our belief is that there may be potentially greater benefits in pursuing a higher dose than the 2-milligram per kilogram dose. Now it is possible that a intermediate dose between 2 and 20 milligrams per kilogram may offer efficacy similar to that provided by the 20-milligram per kilogram dose. We are, therefore, looking into potential further dose exploration, perhaps in the context of the pivotal Phase III trial to investigate this question further. Potential flexibility with the dose level could allow for potential future exploration of subcutaneous dosing in the apitegromab program. To summarize on Slide 24, we believe these top-line results provide further evidence of the therapeutic potential of apitegromab, an improving motor function for patients with Type 2 and Type 3 SMA. Each of the 3 cohorts represents an important subpopulation of patients with SMA, and we believe that data supports advancing development of apitegromab as the potential first muscle directed therapy for SMA. We also have an ongoing extension study. Of the 57 patients who completed the 12-month period of the TOPAZ trial, all elected to opt into the extension period for further treatment and follow-up. Now I want to step away from the TOPAZ clinical trial results and speak to what motor functions are evaluated as part of the Hammersmith scales and when an improvement or decline might mean for individuals living with SMA and their family. Listed on Slide 25 are the 33 individual motor test items making up the HFMSE scale. Each item is scored as 0, 1, or 2 points in which 0 means you cannot perform the test, 2 means you can, and 1 means that it could be done either partially or with adaptation. As you can see, these motor tasks are not when an athlete might perform, but rather basic actions that a healthy young child can easily perform, such as moving from a sitting to lying position, standing unsupported, raising 1 hand to head in a sitting position or ascending and descending 4 steps. By the way, that's 4 steps, not 4 flight upstairs. Improved performance of the basic motor task has the potential for profound impact upon 1 daily list. For example, the ability to bring your hands to your head might mean the difference between whether or not you can comb or wash your hair. The ability to turn to your side while lying down, might mean the difference between a caregiver having to go and turn a child multiple times a night to prevent potential bedsore formation or having an uninterrupted night of sleep. The Hammersmith scale measures that are important and relevant to individuals living with SMA. This is why we believe a 1-point gain or even maintenance of the Hammersmith score has the potential to make a meaningful difference for individual with SMA, let alone a 3-point, 5-point, or a 10-point increase. With that, Tony will now speak to the next steps for the apitegromab program. Tony?

Yes. Thanks, Yung. Exciting results. For the next steps, as shown on Slide 27, we do expect to receive and analyze additional data from the TOPAZ trial in the coming months. These will include exploratory analyses using patient level data, additional outcomes measures and additional safety data. We plan to present the top-line results as well as additional analyses at upcoming medical congresses. Now let's take a step back and talk broadly about where we see the potential for apitegromab going forward. As shown on Slide 28, we see broad potential for apitegromab in SMA and intend to develop the drug to explore its full potential to help patients. SMA is a global disease and we estimate that there are 30,000 to 35,000 individuals affected by SMA in the U.S. and Europe alone. With the caveat that all of this is, of course, subject to dialogue with regulatory authorities, we see 3 broad categories to pursue further development. First, patients with nonambulatory Type 2 and Type 3 SMA. This represents the most prevalent patient population as well as the majority of patients studied in TOPAZ. Many of these patients are already treated with an SMN upregulator or are eligible to be treated with an SMN upregulator. And our TOPAZ data demonstrates that apitegromab could add additive therapeutic benefit in this population. Next, ambulatory patients. Well, these individuals can walk. They remain high unmet need. As this patient population is typically expected to experience decline in motor function. We do not believe that the benefit of SMN upregulation is well-established with this population and/or TOPAZ data suggests that apitegromab could potentially offer a clinical benefit in a meaningful subset of these patients. Based on TOPAZ data, we see an opportunity for additional exploration of apitegromab, both as a monotherapy and in conjunction with SMN upregulators. Finally, Type 1 SMA. This is the most severe form of SMA, and it is usually diagnosed during the first 6 months of life. This represents the highest incidence patient population and the prevalence is growing as these invents are now being treated with SMN upregulators. The promising results we saw from Cohort 3 reinforced the potential benefit of treating at an early age and encourage us to evaluate apitegromab in this population, including patients treated with gene therapy. We will leverage the findings of our TOPAZ trial to conduct further exploration across all these patient populations again, we will be engaging in dialogue with regulatory authorities, and we expect to initiate a pivotal trial by year-end. As we turn to the next slide, I'll hand it over to Ted Myles, our CFO, and Head of Business Operations, who will describe where we see the additional opportunities for apitegromab beyond SMA. Ted?

Thanks, Tony. On Slide 29, while addressing SMA, as shown in the left column, remains our highest priority, our investigations and discussions with KOL, along with the exciting TOPAZ trial results that Yung just discussed, encourage us to expand the evaluation of this myostatin inhibition approach to other neuromuscular disorders. Here is how we currently see what we believe is the landscape of interesting additional opportunities for apitegromab beyond SMA. Over time, we believe various muscular dystrophies represent attractive potential for myostatin based muscle directed therapy. Duchenne is the largest prevalent population with high unmet need as patients suffer from severe symptoms and motor impairments. As progress is made in the development of next-generation disease stabilizing therapies, we believe apitegromab could have potential as an add-on to help improve motor function, and we remain committed to exploring this potential. In the near-term, we believe that Becker muscular dystrophy is an attractive place to start. In contrast to DMD, Becker patients have less severe dystrophin deficiencies and slower progressing muscle damage. For these reasons, we believe Becker could be a strong fit for investigating a selective inhibitor of myostatin as a monotherapy. Input from multiple KOLs and learnings from the TOPAZ study have informed our hypothesis. It is also worth noting that there are more than 20 other dystrophies, some of which may also have less severe phenotypes addressable with muscle directed monotherapy or become tractable as better correctors are developed. Finally, the right-hand column offers examples of additional indications we have identified through research and discussions with KOLs where muscle pathologies may be addressable with a myostatin inhibition approach. These include late-onset Pompe disease, where enzyme replacement therapy may address underlying pathology, but muscle strength remains an ongoing challenge. Muscle recovery for subsets of pediatric cancer patients who developed severe muscle wasting as a result of chemotherapy and Glucocorticoid induced myopathy. We have more work to do to flesh out these hypotheses, but based on preliminary analysis, believe they represent interesting additional avenues to investigate the use of apitegromab to help overcome or help improve muscle function. Diving a bit deeper on Becker muscular dystrophy on Slide 30, we used the same guiding principles that were used to select SMA as our first indication. First is the patient population young. Yes, Becker is a genetic disorder, and the majority of patients are diagnosed at a young age. Although muscle's structurally intact relative to DMD patients with Becker's tend to have less severe dystrophin deficiency in muscle disease and have slower progression of the disease. Does the disease impact fast-twitch fibers? Yes, it causes substantial deficits in fast-twitch muscle fibers. And lastly, there are clinically relevant endpoints that have been used in previous studies of muscular dystrophy therapies that are dependent on fast-twitch fibers, such as the North Star Ambulatory Assessment. For these reasons, we believe Becker muscular dystrophy, which we estimate affects approximately 20,000 individuals in the U.S. and Europe is a natural next indication for us to pursue. In the coming months, we intend to do additional work with KOLs and clinicians to design a proof-of-concept trial to evaluate apitegromab in Becker's. We anticipate initiating a proof-of-concept trial in 2022, and we look forward to updating you all with more details in the coming months. It is worth noting as highlighted on Slide 31, that we have pursued a comprehensive patent strategy and continue to build a broad patent portfolio that provides protection of our scientific approach in apitegromab specifically into the late 2030s. Just in the last couple of months, we have added 2 new patents, 1 that is broadly directed to the use of apitegromab to achieve certain therapeutic effects, such as increasing muscle function and preventing muscle atrophy. And the second covers both add-on and combination therapy with myostatin inhibitor and the neuronal corrector therapy. Apitegromab has been granted multiple designations by the FDA and EMA as both agencies recognize the unmet medical needs of patients with SMA. Just last week, the EMA granted prime designation a recognition of high of the unmet medical need in SMA. Scholar Rock has a rich set of opportunities driven from our proprietary platform, as presented on Slide 32. In addition to advancing apitegromab, we continue to advance our DRAGON Phase I proof-of-concept trial evaluating SRK-181 in immuno-oncology. We are the first company to selectively target the latent TGFß1 growth factor, and we are evaluating SRK-181's potential to overcome immune exclusion and potentially expand the power of checkpoint inhibitors. We continue to advance Part A of the DRAGON trial, dose exploration, with the goal of selecting a dose by midyear, which would allow us to initiate Part B, a multi-cohort proof-of-concept study across multiple solid tumor types. We anticipate initial clinical responses and safety data from Part A at the end of 2021. In addition, we continue to progress our preclinical and discovery work generating and evaluating antibodies against other latent growth factors and beyond. To close, we want to thank our colleagues for their diligence and persistence towards our mission of helping patients. We want to thank our clinical trial investigators and sites, partners and shareholders for their guidance and support. And most importantly, we want to thank the patients and their families for helping us advance this important program. We can now turn to Q&A. Operator?

[Operator Instructions] Our first question comes from Michael Yee with Jefferies.

Congrats on the great data. I just wanted to ask 2 related questions. On my first question, if I understand your points correctly, the reason why you're excited, I think, is because in Cohort 3, you show that there's about a 5-point stable improvement on background nusinersen after many years, but you're showing, I think, 5 to 7 points above and beyond the 5 points you would already be getting on nusinersen. Can you just clarify that? And is that the same sort of idea in Cohort 1 and 2, it's just a little bit more muted and hard to interpret. And if that's the case, my second question is for Phase III, is the most obvious that Cohort 3 is some sort of randomized controlled trial? And would you think about doing a second Phase III study?

Thanks, Michael. So, I think that's basically correct again. We are using third-party studies to characterize what we think the expectation for these patient groups would be. And I think you've characterized that. Our belief is relative to the -- for all 3 cohorts, what 1 would expect from background or a treatment on nusinersen. There appears if a benefit in addition at -- you're correct. Consistent with the 6-month data, it's most pronounced in Cohort 3. Cohort 3 is a younger cohort and there's more dynamic muscle growth, we've always expected that you'd see better performance in that group. Having said that, the second question, we're very encouraged by the results in Cohort 2 and Cohort 1. Cohort 2, again, if you look at what you would hypothesize, the expectation is based on the CHERISH trial. The improvements that we're seeing there. We attribute to something, obviously, in addition to that. Cohort 1 is, as we've often said, tough population. It's a population that is expected to decline on average. We don't think the benefit of SMN upregulator therapy is well characterized. So as it relates to registrational trial. Again, we'll be pretty quiet on exactly what we think that looks like. We have full clarity with the agency. But as we said in page -- a couple of pages back. We think all 3 of those areas nonambulatory in Type 1 are areas that we'd like to explore. We'll get back to you with the details on what we think the first registrational trial looks like. We do continue to expect that we will do a registrational trial. That it's likely a placebo-controlled trial, and it's something that would start late this year.

Our next question comes from Anupam Rama with JPMorgan.

In Cohort 3, I realized its small patient numbers, but were there anything in the baseline characteristics that could predict which patients are getting 5, 10-point benefits here? Just thinking about if there could be an inclusion/exclusion criteria scenario for a Phase III in this type of population?

Yes. Good question, probably relevant across all 3 cohorts. Again, Anupam, we will have the ability to interrogate individual patient data and do some exploratory analyses. That's not been done yet as of the time of this top-line analysis of the baseline characteristics that you see in 1 of the early slides shows that on a mean basis in the ranges. In the coming months, we expect to interrogate that further. We think there's a lot that we could potentially learn and a lot of hypotheses, we could generate a lot in those lines.

Our next question comes from Marc Frahm with Cowen & Company.

Congrats on the update today. Maybe just first, all this -- or the vast majority of the patients in this trial were treated in combination with Spinraza. Can you just kind of speak to the plans for combinations with risdiplam. And do you think the initial kind of combo patients for that would be within the Phase III trials that you're working with regulators to design currently? Or do you need to run a small cohort kind of like TOPAZ with those patients?

Good question, again, subject to discussions with regulators. Our hypothesis has always been that the apitegromab could be used across all the SMN upregulators. We look to the SUNFISH trial for risdiplam which is very different and obviously not comparable, but we think largely delivers the same kind of baseline expectation in a lot of ways that nusinersen does. How that manifests itself. And so that's certainly our intention of how we would like to develop the drug across the 3 different asset and upregulators exactly how that manifests itself in the registrational trial. Again, we'll be pretty quiet on that until we get clarity with the FDA, but that's clearly our intention.

Okay. And then maybe for Yung, can -- within Cohort 1, can you maybe speak to the kind of age at which these patients were first diagnosed and seeing symptoms and maybe the breakdown between Type 3a versus 3b since I believe the natural industry shows slightly different outcomes for those subtypes.

Yes. So I think -- so I think as we've shown the baseline characteristics, the patients were -- by the time they enrolled in our study, well into the second decade, right? Their mean age in around the 12 years of age range. And so I think that's 1 consideration. And I think the other consideration is just in terms of their mean Hammersmith scores or in the -- for RHS was roughly in the high 40s, low 50s. So it's right in ballpark of where you would -- a lot of the natural history studies are done for ambulatory Type 3. So against that backdrop, we are encouraged to see potential signals of efficacy as reflected by a majority of patients, approximately 57%, experiencing either maintenance or improvement of their RHS scores over the 12-month period. Now with that said, in terms of getting to your questions about, is there any potential effect of individual baseline characteristics. We're going to look into that. As Tony said, we don't have -- we're not right now at the stage of doing the deep dives into individual patient level data, but certainly, our intention is to do that work and provide an update on a future scientific forum. But overall, we are encouraged by the current result. And particularly there's potential here to more further investing.

Okay. And then just following up on the dosing comments that you made during your prepared remarks. Yes. I think in the slides, all the significant AEs that are being reported within the trial seem to be being rolled not related to apitegromab. So kind of why explore intermediate doses at all. I mean, do you think that a lower dose is absolutely necessary to ultimately translation to subcutaneous administration? Or could you pull that off with the 20-milligram dose?

Yes. Fair question, Marc. Look, we think it's an interesting opportunity. From our standpoint, this is a positive that we may consider exploring a lower dose. We were very -- the 20-milligram dose was picked very carefully based on healthy volunteer work based on preclinical modeling, understanding, PK/PD, et cetera. We think it's an interesting opportunity that we'd like to look into. So I would view it as a potential positive, we'll explore it further.

[Operator Instructions] Next question comes from do Do Kim With BMO Capital.

This is Jameson on for Do. Congrats on the great data. First 1 on the antidrug antibodies. There was no apparent impact on drug's exposure, but any additional color on any impact on motor function compared to other patients on study.

Got it. Yung, go ahead.

So we haven't done the individual patient level data. But with that said, I think just given first principles, if there's no apparent impact on drug exposure, 1 would hypothesize, it'd be hard to make any type of link per se. Obviously, though, we still have to do the individual patient level work that will be coming in the near future for -- as we work in all to explore more exploratory type of what's the data.

Great. Another on the second indication in Becker muscular dystrophy. Given there's no proved upregulators, what gives you confidence from the TOPAZ data and taking this approach or versus your approach in SMA?

Sure. Yung, you want to comment on that.

Yes. So I think in terms of just thinking about Cohort 1 or ambulatory texture, yes, I mean, obviously, we're encouraged by the potential of apitegromab ambulatory Type 3. With that said, since Becker's ambulatory type 3 SMA are different diseases. We feel important to think about the therapeutic hypothesis for each potential indication on its own merits. And yes, we are indeed intrigued by the prospect of investing in potential of apitegromab at Backers. Manage the patients with Becker's are younger in age, the dystrophin deficiency, and muscle disease progression are less severe, relative to DMD, fast-twitch fibers are affected. There are endpoints available then evolve fast-twitch fiber function. So Becker's, as an indication, aligns with the 4 criteria that we use to think about where a myostatin inhibitor potentially could potentially offer therapeutic benefits. So we're excited about the potential of apitegromab at Becker's and look forward to exploring the potential further.

Yes. I just -- we've had pretty significant interaction with KOLs who treat Becker's testing these hypotheses, again, work to do on exactly what that proof-of-concept trial looks like, and we'll come back to you. But we've tested this hypothesis with a bunch of KOLs and I think a lot of encouragement.

Our next question comes from David Nierengarten with Wedbush.

Just a quick 1 from me. Were there any patients who started out with the 6-month data with a 3-point or increase in scores, for example, that then decreased after that? Or was the general improvement longitudinally experience that are patients who are improving at the 6 months and continue to improve at the 12-month data?

Yes. Yung, go ahead.

Yes. So we don't have the individual patient level analyses done just yet. So that's something that works for further. But I think 1 thing in aggregate, I think that we find encouraging overall is like for example, Cohort 3, remember that less than -- we didn't have -- we only have, like, say, 1 patient who achieved greater than 10-point increase at the 6-month time point for Cohort 3. And now at the 12-month type now we're seeing 6 out of 17 with at least 10-point increase. So suggesting at least in a subset of patients, there's continued improvement. And then for Cohort 2, for example, the majority of patients, 9 out of 14 experienced at least a 1-point improvement as of the 12-month time point. And so that further supports, in our view, the potential at least that roughly about 2/3 are experiencing evidence of at least a 1-point gain. So we find these all encouraging in aggregate. Obviously, we'll have to do more work ahead of us in terms of the individual patient level analyses at work.

Thank you. And there are no other questions in the queue. I'd like to turn the call back to Tony Kingsley for any closing remarks.

Thanks, operator. Thanks all for joining today. Thank you for your questions. We're obviously very, very excited about this. We think we have the potential here to make a big difference for patients in an area with a tremendous unmet need. We have lots of work to do, but lots of excitement on our side to move forward with next steps. We'll look forward to sharing more data with you, as we said, as it emerges from TOPAZ in terms of interesting exploratory analyses, et cetera, but consistent with our 6-month presentation to you, this really gives you a very rich and complete set of the data, at least at a top-line level at this point. So congratulations to the team. And thanks, as everyone said, to all the people who help make this happen, and we'll get back to work. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.