KOL Event

Jun 15, 2021

Morning and thank you for joining us today for our KOL event and panel discussion on epitogromab's therapeutic potential to improve motor function in patients with spinal muscular atrophy or SMA. The webcast slides 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 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 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 future forward looking statements unless required by law. Let me walk you through the agenda for today's event as outlined on slide three. Tony Kingsley, our president and CEO, will provide opening remarks and a brief overview of how we see epitogromab position in the evolving SMA treatment landscape. We are delighted to have Jill Durecki, the chief scientific officer of Cure SMA join us to discuss what they are hearing directly from individuals of SMA and their families on the unmet medical needs. Young Chung, our chief medical officer will then review the TOPAAS phase two trial results along with some additional exploratory analyses since our top line readout in April and will highlight preliminary thoughts on our anticipated phase three trial design. And for the future feature of today's event, we are honored to invite Doctor. Thomas Crawford of Johns Hopkins Medicine and Doctor. Basil Daris of Boston Children's Hospital and Harvard Medical School, both investigators of the TOPADS trial for a panel discussion. Thank you. And I will now turn the call over to Tony. Thank you, Katherine, and thanks to everyone for joining us this morning. We have lined up an exciting agenda to discuss the evolving treatment landscape in SMA and ipitabromab's potential to be the next transformative therapy to help patients address motor function impairments. Starting on slide four, spinal muscular atrophy, or SMA, is a progressive genetic disease that typically manifests in young children. It is characterized by a loss of motor neurons, atrophy of muscles, and progressive muscle weakness, which can impact very basic activities such as breathing, eating, and walking. Despite the utilization of multiple SFN up regulators that address the genetic defect, it remains a devastating and debilitating illness, with individuals continuing to experience significant motor function impairments. A muscle directed approach can further improve motor function and we believe we have shown epitogrelimab's potential to do so through the TOPAZ Phase II trial results. With these positive results in hand, we have been hard at work finalizing the design of a rational, targeted, and efficient Phase III registrational trial, which we anticipate initiating by the 2021. Turning to slide five for an overview of SMA, which is a global disease which we estimate affects approximately thirty thousand to thirty five thousand individuals in The US and Europe alone. There are three main types of SMA. Type one, shown in the orange at the bottom of this chart, represents approximately fourteen percent of the overall prevalence population. Type one is the most severe with symptom onset in the infantile stage, and it is often fatal if left untreated. Individuals with type two, which represent roughly half of the overall population, have severe and progressive disabilities that affect the activities of daily living and they are unable to walk independently. Type three patients, representing about thirty five percent of the overall population, are able to achieve the milestone of walking independently, but many deteriorate rapidly and lose that ability. Through our Topaz Phase II trial, we believe ipilimumab has shown transformative potential in non ambulatory type II and type III patients, which we estimate represents approximately two thirds of the overall patient population. The SFA treatment landscape has advanced and evolved significantly over the past five years. As shown on slide six, there are now three different SMA regulators, or correctors, available to treat the underlying genetic defect that causes SMA. Together, they have helped over fifteen thousand patients worldwide stabilize the degeneration of motor neurons. However, most patients do continue to suffer from significant functional deficits even after treatment with these SNF regulators. And we believe that the stage is set for a new treatment era focused on complementary muscle directed approaches. Which takes us to slide seven. We are developing ipinimumab as a new muscle directed therapy intended to complement the disease stabilizing benefits of SNF regulators and help patients improve motor function. By inhibiting the growth factor myostatin, which is a negative regulator of skeletal muscle growth, we believe vipitigramab can help patients improve muscle function. The TOPAZ Phase II proof of concept study results support our hypothesis that the majority of patients with non ambulatory SMA in the trial observed a clinical improvement in motor function after twelve months of treatment, and some patients achieved big milestones, such as the ability to stand and walk unassisted. Now I'd like to welcome Doctor. Jill Jerrecki, the Chief Scientific Officer of Cure SMA, a premier patient advocacy organization devoted to pursuing a cure for SMA. Through her work at GEAR SMA, Doctor. Gerecki can speak in greater detail on the unmet medical needs of individuals with SMA. Thank you for your time, Doctor. Gerecki. Hi. I'm Jill Durecki, the Chief Scientific Officer at Cure SMA, and I thank you for the opportunity to speak to you today about unmet medical need in SMA. Next slide, please. First, let me tell you a little bit about Cure SMA. Cure SMA is a nonprofit organization dedicated to helping families with SMA and funding groundbreaking research. We have funded about $85,000,000 in research and we have 36 chapters across The United States with 9,000 affected individuals in our membership database and have about 300 newly diagnosed patients contacting us annually. We just completed one of our premier events, our annual conference, and when we're in person we typically have over 2,500 attendees. Now that you know a little bit about Cure SMA, let me comment on the evolving landscape in SMA which we just heard about. Of course, the FDA has approved three new therapies in SMA and they've revolutionized or dramatically changed the natural history of the disease. However, benefits are most striking and dramatic in a pre symptomatically treated context. In the symptomatically treated context there are clear benefits through increases, stabilization and slowing. But much unmet medical need still exists with the complexities of SMA, and unmet need is higher in older patients and compared to younger patients. Next slide, please. For example, currently forty five percent of SMA patients remain untreated. There are still many patients for whom drug treatment options are needed. Next slide, please. Just as an example of our dramatic success, this is data from the Cure SMA Annual Survey which we do each year to collect longitudinal and track trends in our patient population. And you can see that in 2017 in the purple bar, only twelve percent of our Type I patients, which is the most severe form of SMA, were able to sit. This is patient reported data, I should add. But now, in 02/2021, almost forty five percent of our patients can sit. This is a remarkable change in natural history. However, we still need therapeutic options to give those fifty five percent of patients who are still unable to sit further benefits and further gains in SMA. Next slide, please. Among our Type II patients, which is in the intermediate form of the disease, we're now looking at the ability to stand with or without support from data, patient reported data from our annual survey. In 2017, you could see about eleven percent of our patients could stand. Now in 2020, it's increased to eighteen percent. But there's still eighty one percent of our intermediate patients who cannot stand without support and want further gait. Next slide, please. Next slide, please. So how is Cure SMA thinking about that unmet medical need? Well, Cure SMA is not cured. We need more impact for older ages and stages of SMA because we get different results for symptomatic versus newborn screening or presymptomatically treated patients. The results are real in the symptomatic patients, but we would like more for them. The current drugs either slow progression, provide some improvement, or stop or prevent symptoms in the newborn screening context. But we want them and our chronically symptomatic patients to reverse or restore function. And this is a future goal for Cure SMA. Next slide, please. In our community survey, this is data from our community survey again, we asked adults with SMA. We did not ask this question to caregivers of children with SMA, but asked them what benefits they would like from future therapies. And about fifty percent of the patients who took this survey or answered this question were on an SMNA approved therapy. Fifty percent were not, although the data was very similar in both subgroups. The adults with SMA reported last year in our community survey that the top three things that they would like to gain with additional therapies are gaining more muscle strength, achieving new motor functions, and improving activities of daily living. Next slide, please. So at CuraSMA, we have a strategic goal of developing cocktail or combination therapies where we could add on therapies with different mechanism of action to our SMN dependent therapies, our three approved FDA approved drugs. And in this slide you see a motor circuit and you see some of the therapeutic strategies that we are considering to be potentially, beneficial for SMA, although much research, is required to validate that and ensure that that's true. But one of the leading strategies that we believe at CurisMA could have good impact, would be muscle enhancement, with a pitagromab and the Scholar Rock approach. And so we're really happy to see, an SMN independent approach moving forward in the clinic and hopefully and possibly being a viable treatment option for our SMA patients in the future. Next slide, please. So thank you for your time, and I appreciate telling you about unmet medical need in SMA. Thank you. Thank you, Doctor. Gorecki, for a great presentation. It's always wonderful to get an update from you and CRSMA, around your important insights and perspectives. So I know you're very busy and have to jump off the call now, so thank you again for your time. Now let's turn to Scolorox work on developing a potential new treatment option for individuals with SMA. Over the course of the last eight to nine months, we have advanced our understanding of vipigimod in patients with type two and type three SMA through the Topaz phase two trial. These phase two results have further strengthened our enthusiasm and conviction in the transformative potential of epitigramab. As shown on slide 20, initial proof of concept provided by the six month interim analysis results were followed by positive twelve month top line results this April. For this top line readout, we observed the most pronounced increases in motor function, as exemplified by the HFMSE scores, in the non ambulatory type two and type three populations, which were associated with an overall durability effect through twelve months of treatment and continued improvements in a subset of patients. Today, we will review these top line results as well as tell you about findings from additional exploratory analyses from the TOPAZ trial that further our understanding of epitogromaz profile. Turning to slide 21. Top line results from the TOPAZ trial observed meaningful improvements in motor function as measured by the HFMSE following twelve months of treatment with ipitigramab added to background nusinersen in non ambulatory patients with type two and type three SMA. As shown by the green bars in this top chart of individual patients change from baseline, the majority of non ambulatory patients enrolled in TOPAZ experienced improvement, as defined by at least a one point increase in HFMSE, with many individuals attaining sizable HFMSE increases. And we observed meaningful motor function improvements in both the subpopulation of patients who had started their background before the age of five, as well as the subpopulation of patients who had started their background nisinersen after the age of five. Following the top line readout, we have also been conducting additional exploratory analyses to deepen our understanding of epitigramab as outlined on slide 22. These three initial findings further characterize the potential utility of epitigramab. First, HFMSE improvements were observed in the non ambulatory patients across a broad age range with relatively greater effects observed in younger individuals. Second, as we had anticipated, since patients enrolled in Topaz were in the chronic maintenance phase of background nusinersen therapy, we found no apparent correlation between the duration of prior nusinersen treatment and the improvements observed in HFMSE during the Topaz trial. This finding adds support to the interpretation that the observed motor function improvements may be attributable to ipilimumab. Third, we conducted an analysis of a very high bar efficacy endpoint, the World Health Organization Motor Developmental Milestones. This is a very different measure from HFMSE and evaluates six fundamental growth stages of motor development, such as being able to crawl, stand, and walk. Across the two non ambulatory cohorts, we were excited to see that a meaningful number of patients gained new WHO motor milestones. We believe that the TOPAZ trial shows the transformative potential of epitogromab in SMA, and we are advancing towards initiating a phase three trial in non ambulatory patients with type two and type three SMA to further investigate this potential. Now let's take a deeper dive into the CHOPAS trial. First, it is important to understand how patients with type two and type three SMA historically respond to background SMN upregulator therapy and why we believe a muscle directed therapy is needed. As shown by the bar chart on slide 24, even after improvement following fifteen months of treatment with nisinersen in the CHARISH phase three trial, patients continue to experience major functional deficits, which is represented by the significant gap in HFMSE score depicted by the gray shaded region. On slide 25, this age stratification dot plot of the CHERISH results show that the HFMSE increases from nisinersen in the initial phase of treatment primarily appears to be in patients started on therapy before the age of five. Among patients who initiate treatment with nisinersen after the age of five years, as depicted by the yellow box, the majority of individuals did not experience increases in their HFMSE scores. And then, as you can see on slide 26, data from the SHINE study of long term nursing nursing treatment show that HFMSE increases are primarily observed in the first year or so of treatment. Once the duration of treatment goes beyond that initial treatment phase and into a chronic maintenance phase, as shown by this yellow box, a plateau in HFMSE gains seems to occur. Thus, there are two important takeaways here from these Nusinersen CHERISH and SHINE trials. First, based on the presented data available from these trials, nusinersen driven increases in motor function, as measured by the HFMSE, were primarily evident in the initial treatment phase, but then appeared to plateau after this first year or so during the chronic maintenance phase. And second, the majority of patients in the SHINE trial who initiated treatment with nisinersen after the age of five did not seem to, or sorry, the majority of patients in the CHARISH trial who initiated treatment with nisinersen after the age of five did not seem to experience HFMSE increases from baseline even during the initial first year or so of therapy. As a result, it is evident that high unmet medical need persists. We are developing and investigating epitigramab as a muscle directed therapy aimed at increasing motor function to complement the important therapeutic benefits of SMN therapy. Now let's move to slide 28 to briefly review the TOPAZ trial design. 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 SMA. Two of the cohorts enrolled non ambulatory patients who were already on a background of nisinersen therapy in the chronic maintenance phase of treatment. One cohort evaluated patients who had previously initiated nisinersen treatment before five years of age, and another cohort evaluated patients who had previously initiated misnursing treatment at the age of five or older. The third cohort enrolled patients with ambulatory type three SMA. These patients were either treated with epitogromab as a monotherapy or as add on to background misnursing. Slide 29 details the baseline characteristics which reflect the patient populations we hope to enroll in the study. Of note, the age range from two to six years, and eight to 19 years for the two non ambulatory cohorts, and seven to 21 years for the ambulatory cohort. As shown at slide 32 key baseline characteristics are the mean number of nusinersen maintenance doses and the baseline Hammersmith scores. Patients on background nusinersen had received an average of greater than five point zero maintenance doses at the time of enrollment in Topaz, which equates to roughly two years of treatment, putting these patients well into the chronic maintenance phase of nusinersen therapy. In addition, even after an average of approximately two years of nusinersen treatment, the enrolled non ambulatory patients had baseline HFMSE scores in the low to mid-20s out of a total possible score of 66, highlighting their baseline disease severity. Slide 31 shows the efficacy results of patients with nonambulatory type two SMA who had initiated their background misnursing therapy before five years of age, or what we previously referred to as cohort three. Following twelve months of treatment with ipitakimab at twenty milligrams per kilogram on top of background nisinersen, there was a mean change from baseline in HFMSE of 7.1 points. Eighty eight percent of patients had at least a one point increase in HFMSE, sixty three percent of patients had at least a five point increase, and nearly forty percent of the patients attained greater than a 10 increase. To reiterate, these individuals were well into the chronic maintenance phase of nisinersen therapy, and prior historical data from the nisinersen clinical trial program suggests that there could be an apparent plateau in HFMSE gains from nusinersen alone during this chronic maintenance phase. Now as Topaz was not a placebo controlled trial, it is not possible to draw direct conclusions in relation to background nusinersen effects alone or to conduct any cross trial comparisons. Nonetheless, we are thrilled by our Topaz results as we believe they show the therapeutic potential of epitigramab. Let's now consider non ambulatory patients who had initiated their background nisinersen therapy at the age of five or older on slide 32. This cohort had previously been described as cohort two. As a reminder, in the CHARISH trial, the majority of patients who initiated nusinersen therapy after the age of five did not experience an increase in the HFMSE following fifteen months of treatment. And as noted earlier, while Topaz was not a placebo controlled trial, we do intend to initiate a placebo controlled phase three trial by year end. In the Topaz trial, approximately two thirds of the patients who had initiated background nisnirsen at the age of five or older observed an improvement in the HFMSE after twelve months of treatment with, epitogram on top of background nisnirsen. And it is notable that approximately thirty percent of the patients gained at least a three point increase. These results highlight the therapeutic potential of epitogromab in not just aiming for motor function stabilization, but improvement in patients who initiate background nisinersen at a later age. Before we turn to the safety results, we should remind you that the primary intent to treat analyses we reviewed excluded four non ambulatory patients who missed three doses of pidigromab each due to COVID-nineteen related site access restrictions. And as presented and as discussed previously, we also conducted a sensitivity analysis that included all patients which showed similar results to the primary intent to treat analysis results. Now turning to slide 33 to review the safety results, which we had previously described during the twelve month top line readout. The five most frequently reported treatment emergent adverse events, or TEAEs, were headache, pyrexia, upper respiratory tract infection, cough, and nasopharyngitis. The incidence and severity of adverse events were consistent with the underlying patient population and background therapy, and support advancing development to a phase three trial. Slide 34 outlines the serious AEs, grade three AEs, and AE leading to early discontinuation during the trial, which we had previously described. These events were all assessed by the respective trial investigators as unrelated to a epitogroma. Now moving beyond the top line data to go to slide 35. We continue to conduct additional exploratory analyses from the TOPAZ trial to seek further insights. Over the next set of slides, we will walk through three key findings from this additional work thus far. Let's start with slide 36, where we did an exploratory post hoc analysis that pooled data from both non ambulatory cohorts. This dot plot depicts individual patients' HFMSE changes from baseline after twelve months of epigrammatic treatment on top of background dysnursing relative to each of their baseline ages. Improvements in motor function, as exemplified by HFMSE increases from baseline, were observed across a broad spectrum of ages ranging from two years to 19 years old. There also appeared to be an effect of age upon outcomes, as patients started on ipitigramab earlier in life had relatively greater increases in HFMSE. For example, let's consider an exploratory subgroup from the cohort of patients who had previously been initiated on baccarin desinersen at the age of five or older, I. E, the previously described cohort two. If you were to look at individuals up to the age of 12, or in other words, preteenage individuals, fifty percent or four of eight patients had at least a three point increase in the HFMSE following twelve months of ipilogramab treatment on top of background nisinersen. Now let's turn to slide 37. As we previously discussed, we enrolled patients who had passed the first year of nisinersen treatment and were well into the chronic maintenance phase. We did an exploratory post hoc analysis to evaluate whether there was any correlation between the duration of prior nusinersen treatment at baseline and the change in HFMSE at twelve months during the TOPAZ trial. There was no apparent correlation. Patients attained sizable increases in HFMSE regardless of their prior nursing treatment duration at baseline. This observation is consistent with our belief that once patients are in the chronic maintenance phase of nusinersen therapy, where there seems to be a plateauing of nusinersen driven effect, the duration of nusinersen treatment would not influence the HFMSE improvements in Topaz. As you can see from this chart, we had patients who received as few as two maintenance doses, which equates to about ten months of treatment, and had patients who received as many as nine maintenance doses, which equates to over three years of nisinersen treatment by the time they enrolled in the TOPAZ trial. We believe this analysis provides further evidence that the motor function improvements observed in a TOPAZ may be attributed to pipigramab. Now on slide 38, let's direct our attention to the third additional analysis looking at the effects of ipitigramab on WHO motor developmental milestones. First, let's describe and contrast the HFMSE scale with the WHO motor milestones. Looking at the left hand of the slide, the HFMSE is a validated endpoint used in SMA trials, including serving as a primary efficacy endpoint for nisnirsen in the phase three CHERISH study. It encompasses 33 distinct measures of an individual's ability to perform various tasks, including raising a hand to head in a sitting position, rolling to one side, standing for three seconds while supported by one hand, or ascending or descending four steps. Each task 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 could be done either partially or with adaptation. These tasks are important and relevant to individuals living with SMA, which is why we believe a one point gain or even maintenance of the Hammerson score has the potential to make a meaningful difference for an individual with SMA, let alone a three point, five point, or a 10 increase. Now turning attention to the right hand side of the slide. Who motor developmental milestones represent an altogether substantially more challenging bar for motor function gains. This is not about points on a scale like the Hammerson scale, but rather fundamental stages of motor development. In fact, the WHO motor milestones is not an outcome measure specific to SMA. On the contrary, these represent six developmental milestones that healthy young children achieve. And with each milestone gained, such as being able to stand or walk, a child may start experiencing the world in a new way. Now to put things into further perspective for SMA, whether or not one achieves the first WHO motor milestone of sitting unsupported can actually distinguish between whether one has type one or type two SMA. And for the non ambulatory cohorts in the TOPAZ trial, the median baseline number of WHO motor milestones achieved prior to starting epinephrine treatment was one, and that is after having been on nisinersen for approximately two years on average. Let's now move to slide 39 to look at the data. After twelve months of pitigramab treatment, seven non ambulatory patients in the TOPAZ trial achieved at least one new WHO motor milestone. Notably, attainment of at least one new motor milestone occurred in three patients who were in the cohort of individuals who had previously initiated nusinersen treatment later in life, I. E. The cohort previously described as cohort two. In addition, among the non ambulatory individuals overall, one patient gained two new motor milestones as shown by the yellow check marks, and another patient as shown by the red check marks gained three new motor milestones including hands and knees crawling, standing with assistance, and walking with assistance. And another patient gained the ability to walk alone. Seeing results like these inspire us at Scholar Rock and motivate us to work tirelessly in our efforts to develop and investigate epitigramab for patients with SMA. Beyond these three additional analyses that we just outlined, work is still ongoing to further interrogate the data from Topaz. And the Topaz extension trial evaluating the effects of epitigramab beyond twelve months, including safety and efficacy, is ongoing. We look forward to continue to share more data and insights at future medical and scientific conferences. Turning to slide 41. The TOPAZ results further increase our enthusiasm and belief that epitigramab has the potential to have a transformative impact on patients with SMA, and we are advancing towards initiating a Phase III trial by the 2021. The initial development strategy will focus on patients with type two and non ambulatory type three SMA, which we estimate represent approximately two thirds of the overall prevalent population. Many of these patients are already treated with or are eligible to be treated with an SMN and rep regular therapy. Slide 42 details our preliminary thoughts on a potential phase three trial design. Data and insights from the TOPAZ trial, including those we outlined today, have informed our approach, which we believe is rational, appropriately targeted, and efficient. We anticipate it will be a randomized, double blind, placebo controlled trial. Patients will be treated with ipitigramab dosed every four weeks as an add on to baccaronecnirsen or risdiplam. The primary efficacy measure will likely be HFMSE and we anticipate a twelve month treatment duration. The design of this trial is of course subject to regulator interactions and feedback, and we expect to provide an update on the trial plans after we have finalized the design. And the granting of Fast Track designation from the FDA and PRIME designation from EMA for the ipilimumab program in SMA highlight the recognition that regulators have of the persistent unmet medical need. Beyond type two and non ambulatory type three SMA, we see additional opportunities for evaluating epitigramab in SMA as outlined on slide 43, including type one SMA, which has the highest incidence among the various SMA types. Topaz data showed the potential benefits of epitigramab when initiated earlier in childhood, and we look forward to investigating epitigramab in type one SMA through a separate development strategy. In addition, we believe the TOPAZ trial also showed encouraging signals for potential effect in ambulatory type three SMA, and further work is ongoing to better understand this potential. Now let's move on from the prepared remarks and kick off the panel discussion. I am very honored to introduce Doctor. Thomas Crawford and Doctor. Basildaris. Doctor. Crawford is the co director of the MDA Clinic and professor of neurology and pediatrics at Johns Hopkins Medicine. He is the lead Topaz principal investigator. Doctor Daris is the associate neurologist in chief of Boston Children's Hospital, Professor of Neurology at Harvard Medical School, and a Trial Investigator in Topaz. Thank you both for taking time out of your busy schedule to speak with us today, and welcome to the panel discussion. So, yeah, very exciting. We have received a number of questions around various topics of interest in heading up to today's event, and we'll look to cover them. Additional company questions may also come in over the course of the session, and we will try our best to accommodate those as well. So as an opener to start the discussion, can you please each generally describe your SMA clinical practice and how you view the evolution of SMA treatment with the advent of SMA therapies. Let's start with, doctor Crawford. What are your thoughts? So, excellent presentations, by the way. And I'm I'm gonna make one small little addition, which is that the the types, type one, two, three things are historical. They are what people could achieve. In the old days, we used to say if you never sat, you were type one. If you could never walk, you were type two. And if you were able to walk, at some point, you're type three. Going forward, that's not gonna be the case anymore because we're treating people right at the beginning. But there is evidence that the kids that previously would have been type one are even while they're getting better, are not gonna be normal. There's evidence that that they had preexisting disease before we even started it, and so they also will be potential, candidates for this kind of therapy, as we get a little bit further into into that. This is stuff stuff that merge. So, yeah, I've been been, doing SMA stuff since 1987 when I came here to Hopkins. Pretty much the the the major focus of my of my career has been initially on the hospice care of kids with SMA before they die for the first twenty years of my career here. And then, for the last, fifteen years or so, it's been the absolutely extraordinary, opportunity to to to ride this wave of of improving therapy and, learning how to manage, you know, the usual medical complications and things that come along. And and now the, you know, the qualification of the three SMN drugs, enhancing drugs. And, oh my god, we we now this this this this wave of of good fortune that SMA has received is now like another therapy is joining into this. And the idea that we have a muscle based therapy and I was pushing hard to study it on SMA because it seems to me they're the perfect the perfect case for us to be able to show the benefit ipilimumab, in managing muscle, although it may be a therapy that has broader implications than just SMA, of course. Thank you, Doctor. Crawford. Doctor, Doctor. Juris, what are what are your thoughts on involving SMA landscape and your experiences? While you asked me to sort of introduce myself, I'm the, I'm responsible for the neuromuscular program at Boston Children's, since 1986. And, at that time, we're dealing with all different types of, neuromuscular disease, and we'll continue to. But we're not necessarily focused on SMA, at least myself. And, was really in the early two thousands when when I got into the field, of SMA, because I was fortunate to be the cofounder of the pediatric neuromuscular research network, for SMA, with, with with other colleagues from Chopin Philadelphia, Columbia University, University of Rochester, and more recently, Stanford, and St. Jude's Hospital. So we didn't have that many patients, back in, 02/2003, 02/2004, but the our support started in 2004 from the SMA Foundation. And in 02/2006, I I I developed an SMA specific multidisciplinary clinic, with colleagues from other specialties, and the patients started coming. And the numbers went up, to to as high as 120, 140 patients. Some of them international or out of state. And I I was part of the natural history studies who were conducted by the PNCR network, which were instrumental in the execution of the subsequent clinical trials. And it was really in 2011 when, we first started the, nursing trials with single injection and then multiple injections and so on. And then as doctor Crawford said, you know, we had this. We're very lucky to have so much success, not only with the approval of nucineers and SPINRAZA in December 2016, but subsequently, pretty fast, the approval of Zolgensma, which gave therapy for SMA in May 2019. And more recently, in August 2020, we have approval of risdiplam. So we've been very lucky. I mean, there are reasons for that. I don't think we have enough time to get into details of that, but I've been very fortunate to to be in this field at this period of time. And and this is why I continue to be. And I'm very excited to see that we may be moving towards combination therapy we've done with epilepsy and, let's say, with cancer. And everybody has been thinking about this. Doctor Crawford said I'm also supportive of the idea of using, anti mastating, a process for a number of reasons. And I'm glad to see that we're moving forward. Hopefully, we'll have, an on time trial drug approved in the future for the treatment of treatment. Yeah. Thanks for that. And just to build upon that, before we dive into the details around Topaz results, Doctor. Ras, can you just provide your overall view, related to the hopes and aspirations for an anti myasthen approach through apitogram, about apitogram's potential and just a general high level perspective of what your thoughts are about the Topaz trial results? I I think that the study was designed very well. It was necessary to have cohort one, the monotherapy cohort. But then we have cohort two and cohort three, which is combination of nusinersen and and SRK zero one five or epinephrine. I'm sorry. Have a difficulty. Epitegromab. So it's a little difficult to plan. I'm a work about it. Is this is a case zero one five. So and I, I think that, again, women need a combination of of of drugs. We have a condition that has been addressed so far with, primarily with motor neuron directed therapies like lucine nursing and even gene therapy. And we give it systemically, but the vector does get diluted in the periphery and goes into nerves in the nervous system and stays there, hopefully for a while. And then we have risdiplam. And it seems that we do need to have some kind of we have to have a medication like s r k zero one five that is going to work on muscle tissue. And it's really probably the combination of the two that might give us the best possible results. So I'm not surprised to see that we've got very nice results with cohort three, but also good results with cohort two, which seemed to really go beyond what you'd expect to see from nusinersen alone. And I'm not talking just about the clinical trial results. I'm talking about what I have seen by treating 100 patients or more with nursing at our site. And the what I hear from the families is that we've seen improvement in the beginning, and things were wonderful. But now we're in a plateau phase. And they're happy with that. It's not that they're not happy, but they are really asking for something better that's going actually to move the trajectory upwards even after a number of years. And it seems to me that that SRK 015 seems to, provide that and because there's a need there. But we treat these patients. We don't cure them. Stability is desirable. They like it, but they want more than that. It'll be great if we could do more. And it seems to mister Kerr, 015, he that promise to to do better than just nursing or maybe his diploma in in the future. You know what I jump in with? Yeah. One of the things that I find irksome about research, is that, as scientists, we like measurement, obviously, because if you can't measure it, it doesn't exist. But the world is not completely measurable. And an awful lot of the things that are that that that that that are meaningful in the life of humans with, you know, various maladies, and in fact, all of us, are not in the measurable, category. I'm asked oftentimes, you know, what's the significance of three points on the Hammersmith scale? Is enough to be, meaningful to the patient? And I'll just point out that I have many patients who have immeasurable Hammersmith scores who are extraordinarily functional in professional domains doing things that teachers and lawyers and scientists and and professors and and captains of industry who do so with nothing or just the fairest amount of motion. But they're really, really, really skilled, they've been that way for the longest time. The fact that we can improve them just a littlest bit or maybe just maintain what they have is everything between, in some cases, between being, you know, having a full time job with a with a with a, you know, with a healthy salary and being in a nursing home. And I have cases that are just like that. So we need to be mindful of the fact that measurable steps on a Hammersmith scale are important to the to the purpose of regulatory agencies because without that, we can't get approvals. But on the other hand, getting these drugs to people, at at lower levels then that is still extraordinarily important and will make a difference in the actual lives of folks. So that's the wrinkle we have, in the real world. Yeah, that's a great point about, HFMSD and the inevitable, you know, challenge of having clinical trial endpoints to, like as you pointed out, to study, but then also understanding the context of what's meaningful and real contextually the real world experience that patients have and their families. Doctor. Dears, what are your thoughts about, doctor Crawford's comments on HFMSE and what's meaningful and, and the real world experience for what matters for patients with SMA? Yes. I mean, I would repeat a little bit of what doctor Crawford said, and I totally agree with him, that many of the things that seem to make, a difference in the lives of these patients are not measurable, at least with the current scales. And, I had patients who, were treated, and they came in, and they said that, now my voice is stronger. I was never able to sing before, but now I can do it. And I'm really, happy that I I maintain my function, and the function was to just drive the wheelchair. And can you imagine what happens if you lose the bill this patient lose the ability to actually use the stick, move the stick of the of the wheelchair. So so they're very, very happy to be able to to to maintain that. And that's not a lot of change on how to bring the scale. So but we do welcome these changes that have been reported in the topaz study. I think that that's wonderful, but there is also a lot that is not measurable, as doctor Crawford said, which is meaningful to them. And we're talking again about 30 points being clinically meaningful in the Hammersmith, expanded versions of the scale. I I keep saying that, that that stability is still a desirable outcome. And, so so it is, yeah, it it is hard to define, what is meaningful. What's meaningful is what's meaningful to the families and the patients themselves. And if they're happy with that, I think the treatment has been successful. So I'm gonna take it back just a little bit more. The cohort of the older ambulatory with the ambulatory folks, which was the least dramatic in terms of its changes. Also includes people whose, scores are a little bit more locked in. They're the the Hammersmith scale has a little bit less, reactivity, I think, to change in that group. And I wasn't surprised that that that was the group that that was the least enthusiastic about it. It doesn't undermine my enthusiasm for the therapy in that group. I think, the application of more granular kinds of outcome measures, and other ways of looking at it might, in fact, yield much more insight about these these small differences that make a big difference in somebody who's been there for a long time. So, you know, obviously, we go with where the signal is that you can measure because that's what regulatory agencies need. But I am definitely not, giving up on extending this therapy to to the other groups where we haven't yet been able to demonstrate. So there's a I call it the hegemony of measurement. You know, we we we seem to think that that measurement is everything, but in fact, it's meaningfulness to everything. Excellent point. Doctor Harris, what are what are your thoughts, about doctor Crawford's comments on, continuing to explore ambulatory type three, as a potential area before, further exploration for with ipinavirumab? I I think it is it is it is important, because these patients, they do need, to maintain at least what what what they have. But we do know that with SMA, they they they basically, they're be stable for for some time, but eventually, they do decline. So even these older patients, I mean, they've been studies that a full patient fifteen years, and they did notice that muscle strength did go down. It goes down slowly. So even these older patients who seem to be doing okay, eventually, they're gonna they're gonna have some decline. And the there there there is need to to to treat them with with a medication, a drug, or combination of drugs. They're going to maintain to to accomplish that. So it it's just that it's difficult sometimes to measure, as doctor Crawford said, to measure improvement in some of these older patients who are who are stronger. But there is a need a need there to do that, particularly with health medication that could be given once a month and not, you know, intravenously instead of getting a lumbar puncture or something. So so there's more work to be done. You know? And, maybe these older patients, they would be, that they they would benefit from a combination of SRK zero one five and perhaps another SMN regulated medication that can be taken orally or or by lumbar puncture. Notable, by the way, is that, although our outcomes show some people who didn't change much in their Hammersmith or at all, everybody chose to stay on it, which means that they may be experiencing things that they, that we just can't measure. And so switching gears to maybe the other end of the spectrum, in terms of, you know, age at which therapies are started, let's now consider patients who were started, for example, with rest of endemisin therapy earlier in life, such as before the age of five. Now Doctor. Hodaris had made comments earlier about his own clinical experience with over 100 patients, that patients initially experienced initial improvement in the first part of treatment, but then enter seemingly a plateau phase. Doctor. Crawford, are your thoughts, and experience generally consistent with, doc what Doctor. Garis observed? And, obviously, there's the SHINE study data as well. But, what are your thoughts and experience in all this? Yeah. So, I think one of the I I just presented a paper on on, strength measures, dynamometer measurements on on kids and adults with SMA over my thirty four years. And it shows that every in an in an untreated state, everybody declines. Now the rate of decline diminishes the further along you go, but everybody declines at every age. Too soon to know about whether or not, SMN enhancing agents, stabilize that. It's all of our hypotheses and beliefs and limited, data to suggest that they do, but it's gonna take longer to to to to know if that's true or not. I certainly the ones that I have followed, on News Nursing since 02/2017 have stabilized, knowing the the vagaries of measurement and things up and down, of course. But, yeah, so I think that there is potential for benefit across the range. And I don't wanna lose sight of the fact that there is an element of growth and development. For kids who are less than about age 12 or 13, normal development is to get stronger and better and faster and do more things. And so if we stop neurodegeneration with an SMN enhancing agent, we should indeed see some slow improvement. So I don't know that I agree with the idea that it's a plateau phase. I do agree with the idea that it's a slowing of the rate of improvement sort of back to what you would see with normal growth and development. Now the fact is that at least in the two groups we saw rather dramatic improvements on top of what was originally expected is the top line. But I think we can imagine, improving that across the range. And again, I'm going go back to the issues about the type one babies. Almost no one who has two copies of the SMN2 gene, genetic, the genotype that's associated with the more severe phenotype, Almost everybody who has had disease before we ever started nusinersen. I think those people were going to see more and more evidence of the damage that was done before we ever started. And so that group, which was which constitutes about two thirds of patients with SMA, had died because they're they're not seen in the prevalence pictures that that Jill Durecki showed because they're, you know, they're they're departed. But we're expecting to see that group one well, I don't wanna call it type one anymore because they're not type ones. But we were expecting to see them survive. And I think over the years, we're going to expect to see many of them manifesting the difference between what normal is and what they are as a function of the damage that was done before they started. That difference is likely to be, myostatin responsive, anti myostatin responsive. Interesting. And just to talk more about your perspectives, you had mentioned that you would anticipate that there would be some, maybe more gradual improvement on nisiracin alone, when intervening upon earlier in life. So with one of our cohorts, obviously, of Topaz, there were patients who had previously started background nisnirsen, before the age of five and then subsequently treated with pitigramab for twelve months. And with the twenty milligram per kilogram dose level, patients received or observed a mean increase of the HFMSE about seven points. Subset, almost forty percent, got over 10 increases. And so just wanted to get both of your perspectives around these types of results in this type of population. You know, what do you what do you think about those type of results? Any doctor Kraft first and then doctor Daris? Alright. Well, seven points on top is like, oh my god. That's big. Yeah. But it's also you know, the skeptic in me is I don't believe anything. I you know, everything is is gotta be proven before you believe it or not. And this is an unblinded trial. So what I see in this trial is the the the top line results are really impressive. And if we achieve even a fraction of that in a blinded study, we will have accomplished an amazing improvement in the life of people who have SMA. So, I am, extremely bullish on going forward. I think the chances of success are very high with what we've had so far. It's very hard for me to understand how the changes in, Hammersmith outcomes could have been, placebo because this is not really a placebo kind of, of outcome. It isn't a how do you feel about things kind of, the trial. And so the fact it's open label is is is not that damning to the results. And yet it is an unblinded style. So we need to have that blinded study to show that the benefit that we were able to see in the unblinded context is even a portion of what we were able to see this far. Doctor. Dares, your thoughts? Well, we do need to to to remember that the treatment was started with SRK zero five after he had received a number of doses of nucineuridine, about at least five doses. So we're talking about a period of about two years. I mean, we we we do in these younger patients, the truth is that that I have seen some improvement over time. So, again, they have a lot of improvement early on. And but but some of these younger kids, some of them may do improve to to some extent on nursing. I don't think that I have ever seen a young patient after two years of nursing who has improved by by by by five and ten points. So I don't think this can be a nursing effect. It it looks to me as if we have is the effect of the combination of nursing nursing and a case of zero one five. Because that's the the the degree of improvement in the percentage of patients, for example, where sixty percent of the patients had more five or more than five points increase in the Hammersmith Scale, in about more than one third, they have they they they acquired more than 10 points. These are numbers we do not at least myself, have not seen in the younger population on onusineersin after two years of treatment. Thank you both for your perspectives and, sharing your insight. Switching gears a little bit, let's now talk about kind of just starting with just more background, observations, the effects of alone in patients who start their therapy later in childhood. So the CHERISH trial data, seem to suggest that the subset of patients started on nisnirsen after the age of five may have a different, HFMSE response than patients started nisnirsen before the age of five. So, as an example, the majority of patients, the subgroup, it's small, so we have to acknowledge it's a small subset. But with that said, it appears the subset of patients, the majority of patients starting to see later in childhood, did not experience HFMS increases. And, there were, many who actually seem to have declined, in terms of HFMS at least. Is this consistent with your experience and your view, starting with Doctor. Darius? Yeah. The I mean, there are publications on this. We have reported data at the CRSMA meeting in the past and all that. It it does it does seem that the age initiation of treatment makes a big difference. The earlier you start, the better the outcome is is going to be. And in fact, the best outcome was before the age of about three and a half years or something. But there are patients who had an okay outcome up to the age of five years at a time when nucinecerin was initiated. After five years, the results have not been that that good. I mean, we have we we have to be honest. I mean, there there are publications on this and and, presentations at different meetings. So so this is the population who actually needs something better. We need some better results for those older patients over the age of five years. But coming back to your question, it's not just the clinical trial data, but also our experience that the older the patients are, the lower the, efficacy of of nusinersen. And, after the age of five years, you you know, you can you can see some effect that it's not as impressive as it is in kids who have started nusinersen, before the age of five years. Thank you. Doctor Crawford, what are your thoughts, and how how's your experience and have been with it? Well, so we've we've done quite a bit of, work on, on autopsies and, and on the biology of, SMA. And we know that the two copy SMA two folks are having manifest motor neuron degeneration probably before birth and and are and robust losses of motor neurons, you know, in in the first couple months of life so that a substantial amount of their motor neuron tissue is gone by the time they're six months of age. Those that have three and four copies, it's been a little quandary. When the disease start? And the evidence that we're starting to accumulate is that it actually probably starts even in early childhood for the type III people who are not gonna manifest weakness until adult years even. They probably probably the difference between type I, type II, type III, the old designations of those things, is how many motor neurons make it through normal development before degeneration starts happening. So if you have a a a a full complement of motor neurons make it through before your degeneration, then it's gonna take a long time if you lose at 5% per year until you finally pass through that threshold of of, of weakness and start to generate as an adult with with SMA type three or four. Whereas if you have a, you know, a modest, or a moderate amount of loss, then you make it to the point where, the threshold occurs in, you know, at nine months or 18 of age. So the rate of the platform that the development is able to achieve becomes a major determinant of how long it takes until you finally see the degeneration. With SMN enhancement agents, what I think we are doing is we're stopping degeneration and allowing whatever development that normally happens to proceed and to be observed in the form of improvements. If it's done really, really early, you see these incredible improvements. If you wait until they're five and eight years old, the amount of development left is more modest. On top of that, if we can make the muscles that are innervated more efficient and generate more force generating, that they have more contractile protein mass, we can do more with the neurons that have survived and that I hope that we can be able to sustain and stay alive for the rest of their life with these SMN enhancing agents. So there's there's no age beyond which myostatin enhancement is likely to be able to be useful on top of of of that, of of that stability, if if we could work out the biology, if that's the the way the biology, turns. Great. So actually, now that in the context of discussing the hypothesis about the potential of adding on top of ipitigramab in context of patients who may have started their background misunderstood therapy later in life, or SMN, more broadly SMN therapy, later in life, which is our, cohort two. There's actually a question that just came in on that point. Katherine, is that correct? There's a question? Correct. So, we have a question from Anupam Rama from JPMorgan. It's actually very similar to this last question you just asked, Young. And it's for KOLs on the line. You know, for this patient population who started nusinersen age five and older, there are other physician feedback also suggests that these patients are likely far into progression of the disease, so listening effect could be more difficult. Is there a is there a portion of patients who get, you know, three or more points on HRFMSE that would be compelling for you? For example, Topaz showed about thirty percent. What what is kind of the threshold for you? And then a second question is, is there anything with background characteristics, that would be helpful in predicting which patients could benefit better, or more in this patient population. I mean, coming back to the issue of, what is clinically meaningful using the Hammersmith scale, you know, as we discussed, earlier, you know, for years this has been debated at the meetings and the conclusion is that three points is clinically meaningful. But as I said earlier, there are patients who who are happy with only one point increase or in the or they're happy just stability. If you for for them, anything that's going to give them better function would be welcome. And it it seems that, you know, we have hit sometimes you hit the plateau of improvement with with nursing nursing in in many of these, patients, for the reasons that doctor Crawford explained. It has to do with how many motor neurons are are left there and how how how they're functioning. If we if we can, enhance, muscle function, with an anti mastotic medication, like a Circassia zero and five, and, these patients improve even further, they they they will be happy. They they it will be a a welcome, outcome. It's I'm I'm not trying to tell you that that, you know, stabilization is is fine for for everybody. Everybody wants more. And this is why they are asking us to apply for another treatment or apply for combination treatment at this point. So if we have a medication like a schedule on five, which can improve the function even further, that would be absolutely welcomed by by the SMA community. There's there's no doubt. And even if you even if you can go from one point to three points, that would be great. If you go from three points to six point, that would be even better. So that that's what I can tell you. Yeah. Great. Doctor Crawford, your thoughts? Well, I I I a little bit of broken record here, but the issue of, what's meaningful and what's measurable. Of course, regulatory agencies are gonna require something that we can demonstrate to the level of of scientific integrity to show that it's, you know, incontrovertible, of course. And we're using these ordinal scales to do that. I think there's very good reason to believe that there is a broader range of applicability that's milder. But in the case of people who are profoundly weak, milder is not without its merit. And so we will be read forward. If we get an approval, then there'll be an issue of where is the label and also where is the limits at which insurance agencies are likely to approve a drug. And we've been fighting this battle with the SMN enhancing agents all along. I think the agency has been generous in Maine and we have been largely successful getting insurance companies to approve estimate enhancing agents at the margins at the end. So I think we can look forward to that continued beneficence on the part of regulatory agencies and insurance companies. If it makes a difference in the life of the people, if we hear people saying, oh my god, I can now use my wheelchair, Apostol was mentioning, or in case of somebody I know, somebody I can still write a grant with what limited amount of muscle power I've got on my fingers. So I can still write a grant to the scientific agencies. You know, these are extraordinary events that are below measurability. Thank you both for that. So actually, going to the other end of the spectrum in terms of, speaking of, outcome measures and sensitivity, let's go in the opposite direction. Now, away from the HFMSE to something that's considerably more challenging and perhaps not as sensitive, the WHO motor developmental milestones. So, obviously, this was more of an exploratory outcome measure that we evaluated, but, can you help contextualize what gaining a new motor milestone might mean to an individual patient, how challenging it could be, and, your thoughts about, what we observed in Topaz. We had, seven non ambulatory patients who gained at least one new WHO motor milestone. This included also three from the cohort of patients who had started, even their SMN therapy back later in life after the age of five. But, yeah, just would love to hear your thoughts about, going the opposite direction for HF5 to see just something much more challenging and less sensitive, the WHO motor milestones as well as the Topaz results. Doctor Crawford, do wanna go first? Yeah. I I definitely will go with that. So the milestones are are pretty cool because they represent those stages of independence. Each one of those represents you know, when babies are born, moms hold them tight and say no one will ever, ever, ever come between us. And then and the baby sort of has a different attitude about that saying, let me go. I want out. And that's what normal development is. And many of our kids with SMA are intellectually becoming independent but physically require dependence. And so there's this quandary. There's this tension between the fact that they they they wanna be, you know, left alone. They wanna be able to do things on their own. But in fact, they have to have somebody pick up their hand to put it on the controller or the wheelchair in order to go, or they have to be transferred from the wheelchair to the to the pot. And and and so they're being dragged back to their disease over and over and over again even while their their mind is soaring. The idea that we can offer each of these steps, which each one of them represents a stage of independence that is exceptionally meaningful in the life of people who have them is, you know, is is big. And if we can we can and and if we could take people who are on the stable portion of their their SMN enhancing agents and move them up one grade or two grades, that's really it's one of those like, my god. That is that that's touching and meaningful and and big. Doctor Harris? Yes. I mean, I would like to give you a little history because when the Endeer study start started back in 2014 for for nursing nursing, the primary outcome measure was time to death of primary ventilation. And milestones were initiated later on when we started noticing that some of the kids were acquiring milestones. And everybody jumped on that. And the reason is is the reason, certainly, once doctor Crawford mentioned earlier, this is something you can see. This is something can be seen even by people who are not educated. They're seen by the family. You know? And and it it it it's something you cannot doubt. I know that it's not the most sensitive type of developmental of clinic outcome, but but it's the probably the easiest to see. And it has a lot of value. You know? Imagine that having a child who was unable to crawl or stand with assistance. I mean, standing with assistance provides perspective in somebody's life and child's life. Be able to see the world from a different level, not just sitting down or lying down. So this this the the milestone I'm glad you're able to to do this additional topaz analysis. You can discover the factor developmental gains in the area of WHO milestones because this is extremely meaningful. And and you just it's not just in the cineracin trials, but look at the gene therapy trials. They're they've been based on or even rizipram trials, they're based on acquisition milestones, the ability to sit, for example, for ten seconds or five seconds or thirty seconds and all that. So it has huge value. And I'm glad you're able to do this analysis and show that that the some of the enrolled patients actually seven of thirty five were able to acquire milestones even after the age of five years. I mean, that's also very, very important because how often do you see acquisition of milestones after the age of five years? I don't think I've seen it with the with the with the current SMA enhancing drugs. So I I I think it's huge. Thank you. It's important because it's the same thing as, being able to self transfer. If you can self transfer, you can live alone. If you can live alone, the world is your your oyster. You can travel. You can do everything like that. If you if you can't transfer, then you need somebody to help you at home, and it's a tether that holds you back. Yeah. I mean, even rolling over, which is sort of one of the lowest milestones, imagine a child who was not able to roll over in bed during the night. The parents had to get up a number of times every night to to reposition the child. It's not just improving the child or improving the family's life to be they have a child who's now able to roll over to during sleep. And this is not sitting or standing. So I I again, I I I think this is an this is very, very important, and I'm glad you moved into that direction. Alright. Thank you both. So it looks like, Katherine, we have some more questions that came in. Is that right, Katherine? Do you want to go through those questions? Sure, Young. We did receive a few more questions. First from Michael Yee from Jefferies. A couple of questions. First, what data would you like to ultimately see in a phase three trial that you will find clinically relevant? And then second is what is your overall enthusiasm level around epitogromab and thoughts on its use in the clinical practice? Well, as to trial design, I think, we're gonna say that that the specifics of of of which patients to include and how long and what the outcome measures are all a little bit, influx based upon additional evaluation of the pilot trials and obviously what the regulatory agencies are going to want. There's the tension between going to your wheelhouse where the biggest outcomes are and doing broader trials that have the potential for being applicable to a broader audience. And we'll have to sail our way between those the the silliness of those two of those two perils. But I guess the second question was was what is the, enthusiasm level? If you can't tell my enthusiasm level from my my my discussion here, we have some measuring to do with your emotional intelligence because I am really over the top on this one. Doctor. Harris, what are your what are your thoughts? I mean, in terms of clinical trial design, it seems that, you're going to use again the expanded version of the of the Hammersmith scale. I don't know whether you're able to include the revised ACRALI module. Probably, yes. But but I would encourage you to continue to look in the direction also of milestone acquisition. I I think that's that that'll be great. And and not just myself, but many people in the community and the families and and many of the patients would be who are able to to assess the situation, older ones. I'll be very sad if this effort does not move into phase three study. I mean, that does does not seem to be the case, but but the enthusiasm out there does not involve only doctors and physical therapists and nurses. It does involve the families who are looking for something that will enhance what they have accomplished already, with the SMA regulating drugs. So, I think it's a it's a great effort, and, I'm very optimistic about having a positive outcome at the end. I will say that that the the buzz at the Cure SMA meeting was, you know, was, you know, was palpable, even though it was virtual, which where it's hard to feel things buzzing through the, through the computers, but but there was a lot of enthusiasm for this. Great. Thank you both. Catherine, it looks like there's a few more questions that came in. Yes. Next questions are from, are from Cowen. First question is, you know, assuming that the phase three trial will evaluate ipilogrelimab as add on to the correctors, what is the minimum benefit on HFMSE that you will wanna see to use ipilogrelimab broadly in type two and three, patients. Well, I think I've sort of covered that. I I would I we have to have the minimum number to get, regulatory approvals, but I'm I'm going to be advocating, very strongly after we get approvals to not use that threshold for sustaining, the drug and instead flipping over to something that is more meaningful in the life of the patients who who are getting the therapy. They're the ones who are gonna be able to say, yeah. This is worth or not. Fifty seven patients who have gotten so far say, I wanna continue with it, including those that didn't have the three point threshold. They saw something about it that makes it worthwhile to get an IV shot every every month, which is not nothing. And yet they wanted to continue with it. So they see the benefit even beyond beyond that beyond that threshold. Doctor Harris? Yeah. I mean, the the families know. By assessing the things that are not not measurable, and it it is doctor Corfo said there's already a lot of enthusiasm with the families. We have perceived benefit. And I I know there would be numbers that would be thrown out there, let's say, in the phase three study about what what would be the endpoint and all this. But, again, the families do not expect miracles. I mean, they do understand that we cannot cure the disease even combination therapy. But but anything that would push the kids above what they've seen so far within this nursing treatment would be would be, desirable and a good outcome. And I'll do wanna do two corrections. Number one, not just kids. We don't know about the other ones yet, but we're not giving up on the not just, you know, about older ones. And number two, I I may have been, guilty of my enthusiasms. I am wildly enthusiastic, but I'm also a scientist. We have to do this in the most rigorous of fashions. And I've been impressed that the Scholar Rock team is dedicated to that. And, obviously, I'm enthusiastic about doing it the right way. And it looks like we're on that on that on that trajectory. Yeah, thank you for that. Yes, absolutely. Obviously, the safety and efficacy haven't been established yet, for opicaprioMeb as we need to go through a phase three trial and do all the work, go through the appropriate regulatory reviews. A lot of very important work still ahead to further investigate potential of pideogram apps. So thank you for that, Doctor. Crawford. So actually, I think we're wrapping up here. But I just wanted to see if either of you had any final wrap up comments that you wanted to to make before we finish, starting with Doctor. Durst. Yeah. Thank you, Yagvi. I didn't really I don't remember the the last part of of your talk about the the phase three study, but I think you're going to include a cohort of patients who have received ridiplam. Is that correct? Yes. That's correct. Yes, I I I think that's really fantastic because because many patients will be in risdiplam in the near future, and we would like to see what the combination of risdiplam and SRK zero and five k can can do. I mean, I don't wanna get in any we don't even have time to talk about how you know, about the pathophysiology and all and all that. But but in summary, erisinopril seems to upregulate should upregulate SMN protein production in the periphery and, more specifically, in the muscle tissue. And it is possible that in in a case like this where the SMN protein is restored in muscle tissue, adding an antibody like s r k zero one five may even give us a better better result. So I'm glad you have we have we have a third we have a cohort that includes also a. Risdiplam. Doctor Copper, any final wrap up comments to add? I think I pretty much left it all on the table. Although, I I have to say that way back when the myostatin inhibition idea came forward, I had the opportunity to review a lot of the other commercial programs intended to to to try to knock down myostatin signaling. And, I don't remember exactly where I first learned about the the the SclarROC approach to the, pre, latent myostatin. I didn't know if it was really gonna work in terms of of getting into cells and pulling it out otherwise. But it was very clear that it was the most sophisticated and if they were able to pass through those couple biological questions of whether that approach would work at all and and you have, that it was the the program that had the most the most potential. I know that some of the other programs had sort of crashed and burned, and I'm I'm not I'm feeling a little bit smug about the fact that I put my star on this one as the one that I really And wanted to here we are. This has been really quite impressive. Well, thank you very, very much, Doctor. Crawford and Doctor. Darist, for taking time out of your busy schedules to share your important insights and perspectives today. And thank you to the audience for joining this morning's discussion on the unmet medical needs in SMA, the potential of ipilimumab in seeking to address those needs, and the ongoing efforts to investigate that potential. So with that, we will now formally conclude this call, and you may disconnect from the line. Have a wonderful rest of the day, everyone. Thank you. Thank you.