Investor Update

Apr 6, 2021

Good day and thank you for standing by. Welcome to the twelve month top line results of Topaz Phase two trial. At this time all participants are in a listen only mode. After the speaker presentation, there will be a question and answer session. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Kathryn 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 twelve month top line results from our ipilimumab topaz Phase two clinical trial of patients with Type two and Type three 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 discussed in the section entitled Risk Factors in our annual report on Form 10 ks as well as other important factors in Scala 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 three. Tony Kingsley, our President and CEO will provide opening remarks. Young Chung, our Chief Medical Officer will review the trial design and baseline characteristics followed by the twelve 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 pitobromab program. We will take questions at the end of the call. Thank you and I will now turn the call over to Tony. Thanks Kathryn and thanks to everyone for joining this morning. We are very pleased to share the top line results from the twelve month Topaz Phase II trial evaluating upitigrovab in patients with type two and type three SMA. These results which we believe show positive momentum following on our exciting six month interim analysis from October increase our enthusiasm and belief that epitigramab could potentially have a meaningful impact on patients with spinal muscular atrophy. Starting on slide four, let me remind you of the proprietary ScholarRock scientific platform that led to epitogromab'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. Epigrammab is a selective inhibitor of the latent form of the growth factor myostatin. Scholar Rock believes the inhibition of latent myostatin with epigrammab may 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 epitogromab's therapeutic benefits in patients with spinal muscular atrophy or SMA. Turning to slide five, SMA is a rare and often fatal genetic disorder that typically manifests in young children. It is characterized by the loss of motor neurons, atrophy of 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 SNN up regulators or correctors that address the underlying SNN deficiency to prevent further motor neuron deterioration. However, for many patients, treatment with SNN upregulators may only stabilize disease progression and they continue to suffer from significant motor function deficits. We are developing epitogromab as a new muscle directed therapy intended to complement the disease stabilizing benefits of SMN upregulators. Now on slide six, let me briefly summarize how the twelve month data builds on the six month interim analysis we shared in October, starting with cohort one, which evaluated patients with ambulatory type three SMA. As a reminder, at the six month interim analysis, this cohort observed the mean increase in RHS score from base line, and the majority of patients maintained or improved their RHS scores. At twelve months, while the mean RHS score for the cohort overall saw a modest decline, a majority of patients continued to maintain or increase their RHS scores from baseline. Cohort two evaluated patients with nonambulatory type two or type three SFA who had initiated treatment with nusinersen at five years or older. At the six month analysis, the mean HFMSE score increased from baseline, and the majority of patients improved. The data at twelve months were consistent. The mean HFMSE score improved from baseline and the majority of patients had a one point or greater improvement, suggesting potential durability of effect. Notably, we observed a sizable percentage of patients achieving at least a three point increase from baseline. Now on cohort three, which evaluated patients with type two SMA who had initiated treatment with nusimersen before the age of five, at the prior six month interim analysis, we observed mean increases in HF MSE scores from baseline with a majority of patients achieving at least a three point increase. At six months, we also observed a dose response between the high and low dose arms. At twelve 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 continued evidence of dose response. Adverse events 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 Young will take you through the details, overall compared to the six 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 registrational trial, which we anticipate initiating by year end. Now I will turn it over to Young Chung, our Chief Medical Officer, to review the study design and baseline characteristics and the details of the Topaz top line results. Young? Thanks, Tony. We are excited to present the twelve month top line results of the Topaz phase two trial. Before we start, I want to thank the ScholarRock 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-nineteen pandemic. Let's now start with a review of the TOPAZ trial design as outlined on slide eight. This phase two proof of concept trial consists of three parallel cohorts, each evaluating a distinct subpopulation of patients with type two and type three SMAs. More specifically, cohort one enrolled 23 patients with ambulatory type three SMA between the ages of five and 21. These patients were treated with ipilimumab either as a monotherapy or in conjunction with an approved SMA upregulator. This is a nursing. 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 were treated with ipitigramab in conjunction with an approved SMN upregulator, nusinersen. In both cohorts one and two, patients were treated with twenty milligrams per kilogram of IV ipitigramab 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 and parallel arm fashion to receive either a low dose of two milligrams per kilogram of epitogram or a high dose of twenty milligrams per kilogram dosed every four weeks in conjunction with background nusinersen treatment. Turning to slide nine. 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 epitogromab on top of background SMN upregulator therapy. While the protocol allowed the use of any approved SMN upregulator, the FMN upregulator with which patients were treated was nisinersen, as it was the only therapy with widespread approved use over the course of the study enrollment. We also explored the potential for ipiticimab as a monotherapy in a subgroup of patients in cohort one. Topaz was purposely designed with three 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 our understanding of the results, as we continue to investigate the potential of pitigramab in SMA. We also conducted dose exploration in the Topaz trial. More specifically, we evaluated two different doses in cohort three, the selection of which were informed by the phase one dose escalation trial results and PKPD modeling. Through the twenty milligram per kilogram dose, we wanted to test a dose which we felt confident would maximize and sustain target saturation. At the same time, we recognized that complete target saturation may not be necessary to achieve therapeutic effect. So we also selected the two milligram per kilogram dose aimed at achieving a high level of target engagement, but relatively lower than the twenty 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 nisinersen. 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 nisinersen, which translates to roughly two years of treatment before they enrolled into the TOPAZ trial. Of note, the baseline HSMSE scores for Cohort two and Cohort three were in the low to mid-20s, even after approximately two years of treatment with These patients had been treated with nisinersen for an average of about three years at the twelve month analysis time point. Turning to slide 11 to review the safety results from the twelve month top line analysis, which supports the continued evaluation of vipigramab in a phase three registrational trial. The incidence and severity of adverse events were consistent with the underlying patient population and background therapy, with the five most frequently reported treatment emergent adverse events, or TEAEs, being headache, hyrexia, upper respiratory tract infection, cough, and nasopharyngitis. Antidrug antibodies were present at low titers in three out of the fifty eight enrolled patients and had no apparent impact on drug exposure and were not associated with any hypersensitivity reaction. No safety signals for opitigramab were identified as of this twelve month top line analysis. Turning to the next slide on serious and severe TEAEs in the study, as well as one TEAE leading study discontinuation, all of which were assessed by the investigators as unrelated to opitibromat. There were five serious TEAEs, of which two were grade three and three were grade two. Another grade three nonserious TEAE occurred in a patient in cohort one. As a reminder, one patient discontinued following two months in the trial due to preexisting leg muscle fatigue that persisted. Now let's move to the efficacy data. Slide 13 provides a high level summary of the twelve month top line efficacy results across all three cohorts. We believe we met the main goals of the TOPAT trial and showed that epitigramab offers therapeutic potential of improving motor function for patients with later onset SMA, and that the observed safety profile of epitigramab as of this twelve 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 one. Slide 15 offers some background insights into the ambulatory type three population. Based on a natural history study conducted by a third party, motor function decline, as measured by the Hammerson 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 one. The epitogromab monotherapy subgroup had a mean 0.4 decline from baseline in RHS, while the epitogromab plus nursing subgroup had a mean 0.3 decline after twelve months of treatment. While we did observe a wide variance of responses, fifty seven percent 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, thirty nine percent of patients experienced at least a one point increase in RHS, and twenty two percent had at least a three 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 epitogromat potential in this patient population. Now let's consider Cohort two. Slide 18 offers background insights into the non ambulatory later onset population, particularly patients of age five years and older. Based on the NRSA Nurse and CHERISH trial, in patients who have been starting on treatment at the age of five years or older, as highlighted by the orange box, the mean HFMSE score declined over fifteen 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 three point or greater increase in the HFMSE. In a separate study, natural history data showed that for patients with non ambulatory later onset SMA who are of age five years or older, there is a mean decline in the HFMSE over the course of twelve months. And less than five percent of patients achieve a three point or greater increase in the HFMSE. Against that backdrop, let's move to slide 19. Here are the efficacy results of cohort two, which enrolled patients with non ambulatory layer onset SMA, who started on nusinersen at the age of five years or older. Recall that on average, this patient population had been treated with nisinersen for roughly two years before enrolling in Topaz, and had a baseline HFMSE score in the low 20s. One patient in this cohort did miss three doses due to COVID nineteen related site access restrictions and was not included in the primary intent to treat analysis. At the twelve month top line time point, the mean change from baseline in HFMSE score was a 0.6 improvement. Sixty four percent of the patients achieved at least a one point increase in HFMSE, and twenty nine percent achieved at least a three point increase. Of note, as shown on the waterfall plot on the left side of the slide, there was one patient who had an outlier result of a seven point decline in HFMSE score. Before and during 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 three consecutive doses of ipitigramab due to COVID-nineteen site access restrictions. For the per protocol analysis, the mean change in HFMSE from baseline, or COR2, was a 1.2 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 remained positive at all assessed time points beyond week eight. Together, these findings highlight the therapeutic potential of epitogromab 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 twelve month top line time point, with the majority of patients, or more specifically, sixty four percent experiencing at least a one point increase from baseline. We are also encouraged by the observation of a sizable proportion of patients, specifically twenty nine percent, who attained the otherwise rare outcome of at least a three point increase in the Hammersmith score after twelve months treatment. Turning our attention to Cohort three. Slide 21 shows a third party trial that offers background insights into the non ambulatory later onset SMA population, including patients who initiated treatment with nusinersen at a young age. As a reminder, most nusinersen treated patients in the CHARISH trial had started therapy before the age of five years. As you can see in the blue curve with diamond shaped dots, patients who received nusinersen in CHARISH experienced a mean HFMSE improvement from baseline of almost four points in the first fifteen 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 to primarily have motor function stabilization, or only modest and gradual improvement over the subsequent long term phase of nisinersen treatment. As a reminder, patients in cohort three of the TOPADS trial had on average been treated with nisinersen for roughly two years at the time of enrollment, and three years at the 12 analysis time point. Now against this backdrop, let us advance to slide 22. Here are the Cohort three efficacy results. This cohort evaluated patients with type two SMA who had initiated treatment with nisinersen before the age of five. Patients were randomized in double blind fashion to epitogimab treatment at either a high dose of twenty milligrams per kilogram or a low dose of two milligrams per kilogram. A total of three patients, one in the low dose and two in the high dose arm, each missed three doses due to COVID nineteen related restrictions to site access and were excluded from the primary intent 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 twenty milligram per kilogram dose of ipitibramat for twelve months was a 7.1 improvement. The mean change for baseline in HFMSE in patients treated with a two milligram per kilogram dose for twelve months was a 5.3 improvement. Although cohort three was not placebo controlled, we believe that these observed improvements in motor function for both the high and low dose arms are substantially greater than what one might hypothesize would be observed from nusinersen alone. We believe these results demonstrate the therapeutic potential of epitogimab 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, at not only the twelve month top line analysis time point, but also at each of the assessed time points throughout the twelve month treatment period, as shown by the time course plot 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 three point or greater increase in HFMSE, but at least a five point gain. Now as outlined by the blue box, what was particularly notable to us was that six out of seventeen patients, or about thirty five percent of patients, experienced a greater than 10 improvement in HFMSE. Amongst these six patients, one patient experienced a 20 gain, and another patient an 18 gain. Of note, at the six month interim analysis, only one patient had greater than a 10 improvement from baseline in HFMSE score. This suggests that at least a subset of patients' improvements continued over the course of the twelve 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 epitogimab had dose proportional and sustained drug exposure over the course of the twelve month trial. Importantly, as you can see in the PD date PD data in the graph on the right, both two milligrams per kilogram and twenty milligram per kilogram yielded greater than 100 fold mean increases in the latent myosin concentrations relative to baseline, thus signifying that both doses do indeed offer high levels of target engagement. In addition, twenty milligrams per kilogram did achieve a relatively higher absolute level of target engagement than two milligram per kilogram dose. These target engagement results are consistent with the observed clinical efficacy results that we observed for the two dose arms. We are encouraged by the efficacy results for the two milligram per kilogram arm in itself. But given the relatively greater numerical improvements observed by the twenty milligram per kilogram dose, our belief is that there may be potentially greater benefit in pursuing a higher dose than the two milligram per kilogram dose. Now it is possible that an intermediate dose between two and twenty milligrams per kilogram may offer efficacy similar to that provided by the twenty 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 ipitigramab program. To summarize on Slide 24, we believe these top line results provide further evidence of the therapeutic potential of epitigramab in improving motor function for patients with type two and type three SMA. Each of the three cohorts represents an important subpopulation of patients with SMA, and we believe the data supports advancing development of ipitigramab as the potential first muscle directed therapy for SMA. We also have an ongoing extension study. Of the fifty seven patients who completed the twelve 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 TOPADS clinical trial results, and speak to what motor functions are evaluated as part of the Hammerson scale, and what an improvement or decline might mean for individuals living with SMA and their families. Listed on slide 25 are the 33 individual motor task items making up the HSMSE scale. Each item is scored a zero, one, or two points, in which zero means you cannot perform the task, two means you can, and one means that it can be done either partially or with adaptation. As you can see, these motor tasks are not what 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 one hand to head in a sitting position, or ascending and descending four steps. By the way, that's four steps, not four flights of stairs. Improved performance of the basic motor tasks have the potential for for profound impact upon one's daily living. 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 bedstorm formation, or having an uninterrupted night of sleep. The Hammersmith Scale measures tasks that are important and relevant to individuals living with SMA. This is why we believe a one point gain, or even maintenance of the Hammerson score, has the potential to make a meaningful difference for individuals with SMA, let alone a three point, five point, or a 10 increase. With that, Tony will now speak to the next steps for the pitigraft program. Tony? Yes, thanks, Young. 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 ipilimumab going forward. As shown on slide 28, we see broad potential for ipilimumab in SMA and intend to develop the drug to explore its full potential to help patients. SMA is global disease, and we estimate that there are thirty thousand to thirty five thousand 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 three broad categories to pursue further development. First, patients with nonambulatory type two and type three 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 SMNF regulator or are eligible to be treated with an SMNF regulator. And our Topaz data demonstrates that epitogromab could have additive therapeutic benefit in this population. Next, ambulatory patients. While these individuals can walk, there remains high unmet need as this patient population is typically expected to experience declines in motor function. We do not believe that the benefit of FMN upregulation is well established with this population, and our TOPADS data suggests that epitigramab could potentially offer a clinical benefit in a meaningful subset of these patients. Based on TOPADS data, we see an opportunity for additional exploration of epitogromab both as a monotherapy and in conjunction with SNN upregulators. Finally, Type I SMA. This is the most severe form of SMA and is usually diagnosed during the first six months of life. This represents the highest incidence patient population and the prevalence is growing as these infants are now being treated with SNF regulators. The promising results we saw from cohort three reinforce the potential benefit of treating at an early age and encourage us to evaluate ipadigromab in this population, including patients treated with gene therapy. We will leverage the findings from our TOPAAS 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 Miles, our CFO and Head of Business Operations, who will describe where we see the additional opportunities for ipilimumab 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 Young 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 epitogimab beyond SMA. Over time, we believe various muscular dystrophies represent attractive potential for a 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 epitogimab 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 TOPAAS 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 develop 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 epitigramab 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. Are the muscles structurally intact? Relative to DMD, patients with Becker's tend to have less severe dystrophin deficiency and 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 twenty thousand individuals in The US 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 epitigramab 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, and epitigramab specifically, into the late 2030s. Just in the last couple of months, we have added two new patents, one that is broadly directed to the use of epitigramab 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 a neurocorrectal therapy. Epitomav 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 the unmet medical need in SMA. Scholar ROC has a rich set of opportunities driven from proprietary platform, as presented on slide 32. In addition to advancing epitigramab, we continue to advance our DRAGON Phase I proof of concept trial evaluating SRK-one hundred eighty one in immuno oncology. We are the first company to selectively target the latent TGF beta-one growth factor, and we are evaluating SRK-one hundred eighty one'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 a goal of selecting a dose by mid year, 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 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 site 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 and A. Operator? Thank you. Our first question comes from Michael Yee with Jefferies. Your line is open. Hi, good morning guys. Congrats on the great data. I just wanted to ask two related questions. On my first question, if I understand your points correctly, the reason why you're excited, I think, is because in Cohort three, you show that there's about a five point stable improvement on background use in nursing after many years. But you're showing, I think, five to seven points above and beyond the five points you would already be getting on use in nursing. Can you just clarify that? And is that the same sort of idea in Cohort one and two? It's just a little bit more muted and hard to interpret. And if that's the case, my second question is for Phase three, is it most obvious that Cohort three is some sort of randomized controlled trial, and would you think about doing a second Phase three study? Thank you. Thanks, Michael. It's Tony. 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 characterized that our belief is relative to the for all three cohorts, what one would expect from background or a treatment on nusinersen. There appears a benefit in addition to that. You're correct. Consistent with the six month data, it's most pronounced in cohort three. Cohort three 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 two and cohort one. Cohort two, again, if you look at what you would hypothesize the expectation is based on the CHARISH trial, the improvements that we're seeing there, we attribute to something obviously in addition to that. Cohort one, 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 massive enough regulated 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 until we have full clarity with the agency. But as we said a couple pages back, we think all three of those areas, non ambulatory, ambulatory and Type I 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. Okay. Thanks, John. Thanks. Thank you. Our next question comes from Anupam Rama with Your line is open. Hey, guys. Thanks so much for taking the question. In Cohort three, I realize it's small patient numbers, but were there anything in the baseline characteristics that could predict which patients, are getting, you know, five, ten point benefits here? Just thinking about if there could be an inclusionexclusion criteria scenario for a Phase III in this type of population. Thanks so much. Yeah, good question. Probably relevant across all three 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. Baseline characteristics that you see in one of the early slides shows that on a mean basis and 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 along those lines. Thanks so much for taking our question. Thank you. Our next question comes from Mark Fram with Cowen and Company. Your line is open. Hi, thanks for taking my questions and congrats on the update today. Let me just first, all this or the vast majority of the patients in this trial were treated in combination with SPINRAZA. Can you just 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, to discussions with regulators. Our hypothesis has always been that vipetigromab could be used across all the SMNUP regulators. 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 three different SNF regulators. 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 Young, within Cohort one, 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 history shows slightly different outcomes for those subtypes. Yeah. So I think hi, Mark. So I think, you know, as we show in the baseline characteristics, you know, the patients were, by the time they enrolled in our study, well into the second decade, right, they were mean age in around the 12 years of age range. And so I think that's one consideration. And I think the other consideration is just in terms of their mean Hammersmith scores were 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 three. So against that backdrop, we are encouraged to see potential signals of efficacy as reflected by a majority of patients, approximately fifty seven percent, experiencing either, you know, maintenance or improvement of their IHS scores over the twelve 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 at a future scientific forum. But overall, we are encouraged by the current result and we believe there's potential here to work further investigating. Okay. And then just following up on the, dosing comments that you made during your prepared remarks. Yeah, I think in the slides all the significant AEs that are being reported within the trial seem to be enrolled not related to pidegroomab. So why explore intermediate doses at all? Mean, you think that a lower dose is absolutely necessary to ultimately translate into subcutaneous administration? Or could you pull that off with a twenty milligram dose? Yeah, fair question, Mark. 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 twenty milligram dose was picked very carefully based on healthy volunteer work, based on preclinical modeling, understanding PKPD, etcetera. We think it's an interesting opportunity that, you know, we'd like to look into. So I would view it as a potential positive. We'll explore it further. Okay. Thank you. Thank you. Our next question comes from Do Kim with BMO Capital. Your line is open. Hi. This is Jameson on for Doe. Thanks for taking our questions, and congrats on the great data. First one on the antidrug antibodies. There was no apparent impact on drugs exposure, but any additional color on any impact on motor function compared to other patients on study? Go ahead. Yeah, go ahead. Yeah. So, you know, we haven't done the individual patient level data. But with that said, I think just given, you know, first principles, if there's no apparent impact on drug exposure, one 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 on all the more exploratory type of looks at the data. Great. Another on the second indication in bacteremuscular dystrophy. Given there's no approved up regulators, what gives you confidence from the Topaz data in taking this approach or or, versus your approach in SMA? Sure. Yeah. You wanna comment on that? Yeah. So so I think, in terms of just thinking about MCOT1 or ambulatory type three, yeah, I mean, obviously, we're encouraged by the potential of fitogram ambulatory type three. With that said, since Becker's and ambulatory type three SMA are different diseases, we feel it's important to think about the therapeutic hypothesis for each indication on its own merits. And, yes, we are indeed intrigued by the prospect of investigating the potential of sacrogrammat and Becker's. And patients with Becker's are younger in age. The dystrophin deficiency and muscle disease progression are less severe, relative DMD, fast rich fibers are affected, and there are endpoints available that involve fast rich fiber function. So, know, Becker's, as an indication, aligns with the four criteria that we use to think about where a myosin inhibitor potentially could potentially offer therapeutic benefits. So, we're excited about the potential of big round Becker's and look forward to, exploring the potential further. Yeah, yeah. 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, we've tested this hypothesis with a bunch of KOLs, and I think gotten a lot of encouragement. Great. Thanks, and congrats again on the great data. Thank you. Thank you. Our next question comes from David Nierengarten with Wedbush. Your line is open. Hi, thanks for taking the question. Just a quick one from me. Were there any patients who started out with the six month data, you know, with a three point or, you know, increase in scores, for example, that then decreased after that? Or was the general improvement longitudinally experienced by the patients who were improving at the six month and continued to improve at the twelve month data? Yeah. Yeah. Go ahead. Yeah. So so we don't have the individual, patient level, analyses done just yet. So that's something that we'll explore further. But I think one thing in aggregate, I think that we find encouraging overall is, like, for example, Cohort three, remember that, less than, we didn't have, you know, we only had, like, say, one patient who achieved greater than 10 increase, at the six month time point for cohort three. And now at the twelve month time point, now we're seeing, you know, six out of 17 with at least a 10 a greater than 10 increase. So it's suggesting at least in a subset of patients, there's continued improvement. And then for cohort two, for example, the majority of patients, nine out of 14, experienced at least a one point improvement as of the twelve month time point. And so that, you know, further supports, in our view, the potential that at least, you know, that roughly about twothree are experiencing evidence of, at least a one point gain. So we find these all encouraging in aggregate. Obviously, we'll have more work ahead of us in terms of the individual patient level, analyses and work. Got it. Thank you. 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, etcetera. But consistent with our six 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've helped 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.