Morning, thank you for joining us today for our KOL event and panel discussion on apitegromab'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 Presentation section of the Investor Relations page on the Scholar Rock website. I wanted to note that we'll be making various statements about Scholar Rock's 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 titled "Risk Factors" in our quarterly report on Form 10-Q, as well as other important factors in Scholar Rock's future filings with the Securities and Exchange Commission.
Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any future date. We disclaim any obligation to update any forward-looking statements unless required by law. Let me walk you through the agenda for today's event, as outlined on slide three. Tony Kingsley, our President and Chief Executive Officer, will provide opening remarks and a brief overview of how we see apitegromab positioned in the evolving SMA treatment landscape. We are delighted to have Jill Jarecki, the Chief Scientific Officer of Cure SMA, join us to discuss what they are hearing directly from individuals with SMA and their families on their unmet medical needs.
Yung Chyung, our Chief Medical Officer, will review the TOPAZ phase II trial results, along with some additional exploratory analyses since our top-line readout in April, and will highlight preliminary thoughts on our anticipated phase III trial design. For the feature of today's event, we're honored to invite Dr. Thomas Crawford of Johns Hopkins Medicine and Dr. Basil Darras of Boston Children's Hospital and Harvard Medical School, both investigators of the TOPAZ trial, for a panel discussion. Thank you, and I will now turn the call over to Tony.
Thank you, Catherine, 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 apitegromab'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 SMN upregulators 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 apitegromab'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 end of 2021. Turning to slide five for an overview of SMA, which is a global disease which we estimate affects approximately 30,000-35,000 individuals in the U.S. and Europe alone. There are three main Types of SMA. Type 1, shown in the orange at the bottom of this chart, represents approximately 14% of the overall prevalence population. Type 1 is the most severe, with symptom onset in the infantile stage, and it is often fatal if left untreated. Individuals with Type 2, 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 3 patients, representing about 35% 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 apitegromab has shown transformative potential in non-ambulatory Type 2 and Type 3 patients, which we estimate represents approximately 2/3 of the overall patient population. The SMA treatment landscape has advanced and evolved significantly over the past five years. As shown on slide six, there are now three different SMN upregulators or correctors available to treat the underlying genetic defect that causes SMA. Together, they have helped over 15,000 patients worldwide stabilize the degeneration of motor neurons. However, most patients do continue to suffer from significant functional deficits even after treatment with these SMN upregulators, 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 apitegromab as a new muscle-directed therapy intended to complement the disease-stabilizing benefits of SMN upregulators and help patients improve motor function. By inhibiting the growth factor myostatin, which is a negative regulator of skeletal muscle growth, we believe apitegromab 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 12 months of treatment, and some patients achieved big milestones, such as the ability to stand and walk unassisted. I'd like to welcome Dr. Jill Jarecki, the Chief Scientific Officer of Cure SMA, a premier patient advocacy organization devoted to pursuing a cure for SMA.
Through her work at Cure SMA, Dr. Jarecki can speak in greater detail on the unmet medical needs of individuals with SMA. Thank you for your time, Dr. Jarecki.
Hi, I'm Jill Jarecki, the Chief Scientific Officer at Cure SMA, and I thank you for the opportunity to speak to you today about unmet medical needs 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 million in research, and we have 36 chapters across the U.S. 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 and dramatically changed the natural history of the disease. However, benefits are most striking and dramatic in the pre-symptomatically treated context. In the symptomatic treated context, there are clear benefits through increases, stabilization, and slowing. Much unmet medical need still exists with the complexities of SMA and unmet need is higher in older patients when compared to younger patients. Next slide, please. For example, currently, 45% 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.
You can see that in 2017, in the purple bar, only 12% of our Type 1 patients, which is the most severe form of SMA, were able to sit. This is patient-reported data, I should add. Now in 2021, almost 45% of our patients can sit. This is a remarkable change in natural history. However, we still need therapeutic options to give those 55% of patients who are still unable to sit further benefits and further gains in SMA. Next slide, please. With among our Type 2 patients, which is in the intermediate form of the disease, we're now looking at the ability to stand with or without support from patient-reported data from our annual survey. In 2017, you can see about 11% of our patients could stand.
In 2020, it's increased to 18%, there's still 81% of our intermediate patients who cannot stand without support and want further gains. Next slide, please. How is Cure SMA thinking about that unmet medical need? 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 pre-symptomatically treated patients. The results are real in the symptomatic patients, 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. We want them in 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. About 50% of the patients who took this survey or answered this question were on an SMA-approved therapy. 50% 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. At Cure SMA, 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 FDA-approved drugs.
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. One of the leading strategies that we believe at Cure SMA could have good impact would be muscle enhancement with apitegromab and the Scholar Rock approach. 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. Thank you for your time, and I appreciate telling you about unmet medical need in SMA.
Thank you, Dr. Jarecki, for a great presentation. It's always wonderful to get an update from you and Cure SMA around your important insights and perspectives. 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 Scholar Rock's 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 apitegromab in patients with Type 2 and Type 3 SMA through the TOPAZ phase II trial. These phase II results have further strengthened our enthusiasm and conviction in the transformative potential of apitegromab. As shown in slide 20, initial proof of concept provided by the six month interim analysis results were followed by + 12-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 2 and Type 3 populations, which were associated with an overall durability effect through 12 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 apitegromab's profile. Turning to slide 21. Top line results from the TOPAZ trial observed meaningful improvements in motor function as measured by the HFMSE following 12 months of treatment with apitegromab added to background nusinersen in non-ambulatory patients with Type 2 and Type 3 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 1- point increase in HFMSE, with many individuals attaining sizable HFMSE increases. We observed meaningful motor function improvements in both the subpopulation of patients who had started their background nusinersen before the age of five, as well as the subpopulation of patients who had started their background nusinersen after the age of five. Following the top line readout, we have also been conducting additional exploratory analyses to deepen our understanding of apitegromab as outlined on slide 22. These three initial findings further characterize the potential utility of apitegromab. 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 apitegromab. 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 apitegromab in SMA. We are advancing towards initiating a phase III trial in non-ambulatory patients with Type 2 and Type 3 SMA to further investigate this potential. Let's take a deeper dive into the TOPAZ trial. It is important to understand how patients with Type 2 and Type 3 SMA historically respond to background SMN up regulator therapy and why we believe a muscle-directed therapy is needed. As shown by the bar chart on slide 24, even after improvement following 15 months of treatment with nusinersen in the CHERISH phase III trial, patients continued 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 nusinersen 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 nusinersen after the age of five years, as depicted by the yellow box, the majority of individuals did not experience increases in their HFMSE scores. As you can see on slide 26, data from the SHINE study of long-term nusinersen 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. Second, the majority of patients in the SHINE trial who initiated treatment with nusinersen 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 apitegromab 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 II proof of concept trial consists of three parallel Cohorts, each evaluating a distinct subpopulation of patients with Type 2 and Type 3 SMA. Two of the Cohorts enrolled non-ambulatory patients who were already on a background of nusinersen therapy in the chronic maintenance phase of treatment.One Cohort evaluated patients who had previously initiated nusinersen treatment before five years of age, and another Cohort evaluated patients who had previously initiated nusinersen treatment at the age of five or older. The third Cohort enrolled patients with ambulatory Type 3 SMA. These patients were either treated with apitegromab as a monotherapy or as add-on to background nusinersen. Slide 29 details the baseline characteristics which reflect the patient populations we hope to enroll in the study.
Of note, the age ranged from two to six years and 8-19 years for the two non-ambulatory Cohorts, and 7-21 years for the ambulatory Cohort. As shown on slide 30, two 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 5.0 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 non-ambulatory Type 2 SMA who had initiated their background nusinersen therapy before five years of age, or what we previously referred to as Cohort 3. Following 12 months of treatment with apitegromab at 20 milligrams per kilogram on top of background nusinersen, there was a mean change from baseline in HFMSE of 7.1 points. 88% of patients had at least a 1-point increase in HFMSE, 63% of patients had at least a 5-point increase, and nearly 40% of the patients attained greater than a 10-point increase. To reiterate, these individuals were well into the chronic maintenance phase of nusinersen therapy, and prior historical data from the nusinersen 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 apitegromab. Let's now consider non-ambulatory patients who had initiated their background nusinersen therapy at the age of five or older on slide 32. This Cohort had previously been described as Cohort 2. As a reminder, in the CHERISH trial, the majority of patients who initiated nusinersen therapy after the age of five did not experience an increase in the HFMSE following 15 months of treatment. As noted earlier, while TOPAZ was not a placebo-controlled trial, we do intend to initiate a placebo-controlled phase III trial by year end.
In the TOPAZ trial, approximately 2/3 of the patients who had initiated background nusinersen at the age of five or older observed an improvement in the HFMSE after 12 months of treatment with apitegromab on top of background nusinersen. It is notable that approximately 30% of the patients gained at least a 3-point increase. These results highlight the therapeutic potential of apitegromab in not just aiming for motor function stabilization, but improvement in patients who initiate background nusinersen 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 apitegromab each due to COVID-19 related site access restrictions. 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 12-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 III trial. Slide 34 outlines the serious AEs, Grade 3 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 apitegromab. 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 12 months of apitegromab treatment on top of background nusinersen 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 starting on apitegromab 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 background nusinersen at the age of five or older, i.e., the previously described Cohort 2.
If you were to look at individuals up to the age of 12, or in other words, pre-teenage individuals, 50%, or four of eight patients, had at least a 3-point increase in the HFMSE following 12 months of apitegromab treatment on top of background nusinersen. Now let's turn to slide 37. As we previously discussed, we enrolled patients who had passed the first year of nusinersen 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 12 months during the TOPAZ trial. There was no apparent correlation. Patients attained sizable increases in HFMSE regardless of their prior nusinersen 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 10 months of treatment, and had patients who received as many as nine maintenance doses, which equates to over three years of nusinersen treatment by the time they enrolled in the TOPAZ trial. We believe this analysis provides further evidence that the motor function improvements observed in TOPAZ may be attributed to apitegromab. On slide 38, let's direct our attention to the third additional analysis looking at the effects of apitegromab on WHO motor developmental milestones.
First, let's describe and contrast the HFMSE scale with the WHO motor developmental 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 nusinersen in the phase III 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 as 0, 1, or 2 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 1-point gain, or even maintenance of the Hammersmith Score, has the potential to make a meaningful difference for an individual with SMA, let alone a 3-point, 5-point, or a 10-point increase. 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 Hammersmith Scale, 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 6 developmental milestones that healthy young children achieve. 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 1 or Type 2 SMA. For the non-ambulatory Cohorts in the TOPAZ trial, the median baseline number of WHO motor milestones achieved prior to starting apitegromab treatment was one, and that is after having been on nusinersen for approximately two years on average. Let's now move to slide 39 to look at the data. After 12 months of apitegromab 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 2.
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. 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 apitegromab for patients with SMA. Beyond these three additional analyses that we just outlined, work is still ongoing to further interrogate the data from TOPAZ. The TOPAZ extension trial evaluating the effects of apitegromab beyond 12 months, including safety and efficacy, is ongoing. We look forward to continuing 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 apitegromab has the potential to have a transformative impact on patients with SMA. We are advancing towards initiating a phase III trial by the end of 2021. The initial development strategy will focus on patients with Type 2 and non-ambulatory Type 3 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 SMA-approved upregulator therapy . Slide 42 details our preliminary thoughts on a potential phase III 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 apitegromab dosed every four weeks as an add-on to background nusinersen or risdiplam.
The primary efficacy measure will likely be HFMSE, we anticipate a 12-month treatment duration. The design of this trial is, of course, subject to regulator interactions and feedback, we expect to provide an update on the trial plans after we have finalized the design. The granting of Fast Track designation from the FDA and PRIME designation from the EMA for the apitegromab program in SMA highlight the recognition that regulators have of the persistent unmet medical need. Beyond Type 2 and non-ambulatory Type 3 SMA, we see additional opportunities for evaluating apitegromab in SMA as outlined on Slide 43, including Type 1 SMA, which has the highest incidence among the various SMA Types. TOPAZ data showed the potential benefits of apitegromab when initiated earlier in childhood, we look forward to investigating apitegromab in Type 1 SMA through a separate development strategy.
In addition, we believe the TOPAZ trial also showed encouraging signals for potential effect in ambulatory Type 3 SMA. 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 Dr. Thomas Crawford and Dr. Basil Darras. Dr. 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. Dr. Darras 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. Yeah, very exciting. We have received a number of questions from various topics of interest in heading up to today's event, and we'll look to cover them. Additional questions may also come in over the course of the session, and we will try our best to accommodate those as well. As an opener to start the discussion, can you please each generally describe your SMA practice and how you view the evolution of SMA treatment with the advent of SMA therapies? Let's start with Dr. Crawford. What are your thoughts?
Excellent presentations, by the way. I'm going to make one small little addition, which is that the Types, Type 1, 2, 3 things are historical. They are what people could achieve. In the old days, we used to say, if you never sat, you were Type 1. If you could never walk, you were Type 2, and if you were able to walk at some point, you're Type 3. Going forward, that's not going to be the case anymore because we're treating people right at the beginning. There is evidence that the kids that previously would've been Type 1, even while they're getting better, are not going to be normal. There's evidence that they had pre-existing disease before we even started it, they also will be potential candidates for this kind of therapy as we get a little bit further into that.
This is stuff to emerge. Yeah, I've been doing SMA stuff since 1987 when I came here to Hopkins. Pretty much the major focus of my career has been initially on the hospice care of kids with SMA before they die for the first 20 years of my career here. Then for the last 15 years or so, it's been the absolutely extraordinary opportunity to ride this wave of improving therapy and learning how to manage the usual medical complications and things that come along. Now, the qualification of the three SMA drugs, enhancing drugs. Oh my God, this wave of good fortune that SMA has received is now like another therapy is joining into this.
The idea that we have a muscle-based therapy, and I was pushing hard to study it on SMA because it seems to be the perfect case for us to be able to show the benefit of apitegromab in managing muscle. Although it may be a therapy that has broader implications than just SMA, of course.
Thank you, Dr. Crawford. Dr. Darras, what are your thoughts on involving the SMA landscape in your experiences?
Well, you asked me to sort of introduce myself. I'm responsible for the neuromuscular program at Boston Children's since 1986. At that time, we were dealing with all different Types of neuromuscular disease, and we continue to, but we're not necessarily focused on SMA, at least myself. It was really in the early 2000s when I got into the field of SMA because I was fortunate to be the Co-Founder of the Pediatric Neuromuscular Clinical Research Network for SMA with other colleagues from CHOP in Philadelphia, Columbia, University of Rochester, and more recently, Stanford and St. Jude's Hospital. We didn't have that many patients back in 2003, 2004. Our support started in 2004 from the SMA Foundation.
In 2006, I developed an SMA-specific multidisciplinary clinic with colleagues from other specialties, and the patients started coming, and the numbers went up to as high as 120-140 patients, some of them international or out of state. I was part of the natural history studies that were conducted by the PNCR network, which were instrumental in the execution of the subsequent clinical trials. It was really in 2011 when we first started the nusinersen trials with single injection and then multiple injections and so on. As Dr. Crawford said, we're very lucky to have so much success, not only with the approval of nusinersen SPINRAZA in December 2016, but subsequently, pretty fast, the approval of ZOLGENSMA, the gene therapy for SMA in May 2019. More recently in August 2020, we have approval of risdiplam. We've been very lucky.
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 be in this field at this period of time. 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. Dr. Thomas Crawford said I'm also supportive of the idea of using anti-myostatin for a number of reasons. I'm glad to see that. We're moving forward. Hopefully, we'll have an anti-myostatin drug approved in the future for Duchenne.
Yeah. Thanks for that. Just to build upon that, before we dive into the details on TOPAZ results, Dr. Darras, can you just provide your overall view related to the hopes and aspirations for anti-myostatin approach through apitegromab, about apitegromab's potential, and just a general high-level perspective of what your thoughts are about the TOPAZ trial results?
I think that the study was designed very well. It was necessary to have Cohort 1, the monotherapy Cohort. We have Cohort 2 and Cohort 3, which is a combination of nusinersen and apitegromab or pimobendan. I'm sorry, I have difficulty. Pimobendan. It's a little difficult to pronounce.
No worry about that.
This is apitegromab. I think that, again, when we get a combination of drugs, we have a condition that has been addressed so far primarily with motor neuron-directed therapies like nusinersen and gene therapy. We give it systemically, but the vector does get diluted in the periphery and goes into the nervous system and stays there, hopefully for a while. We have risdiplam. It seems that we do need to have some kind of a medication like apitegromab that is going to work on muscle tissue. It's really probably the combination of the 2 that might give us the best possible results. I'm not surprised to see that we've got very nice results with Cohort 3, but also the results with Cohort 2, which seem to really go beyond what you'd expect to see from nusinersen alone.
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 nusinersen at our site. 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. 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. It seems to me that apitegromab seems to provide that because there's a need there. We treat these patients, we don't cure them. Stability is desirable. They like it, but they want more than that.
It would be great if we could do more, and it seems to me apitegromab has that promise to do better than just nusinersen or maybe risdiplam in the future.
You know what, 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 doesn't exist. The world is not completely measurable, and an awful lot of the things that are meaningful in the life of humans with various maladies, and in fact, all of us, are not in the measurable category. I'm asked oftentimes, "What's the significance of 3- points on the Hammersmith Scale? Is that enough to be meaningful to the patient?" 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 professors and captains of industry who do so with nothing or just the fairest amount of motion.
They're really, really skilled, and they've been that way for the longest time. The fact that we can improve them just a little bit or maybe just maintain what they have is everything between, in some cases, between having a full-time job with a healthy salary and being in a nursing home. I have cases that are just like that. We need to be mindful of the fact that measurable steps on a Hammersmith Scale are important to the purpose of regulatory agencies, because without that, we can't get approvals. On the other hand, getting these drugs to people at lower levels than that is still extraordinarily important and will make a difference in the actual lives of folks. That's the wrinkle we have in the real world. Yeah.
That's a great big point about HFMS being the inevitable challenge of having clinical trial endpoints to, like as you point out, to study, but then also understanding the context of what's meaningful and contextual in the real-world experience that patients have and their families. Dr. Darras, what are your thoughts about Dr. Crawford's comments on HFMS and what's meaningful and in the real-world experience for what matters for patients with SMA?
Yes. I would repeat a little bit of what Dr. Thomas Crawford said. 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. 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 maintain my function." The function was to just drive the wheelchair. You can imagine what happens if this patient loses the ability to actually move the stick of the wheelchair. They are very happy to be able to maintain that. That's not a lot of change on the scale. We do welcome these changes that have been reported in the TOPAZ study.
I think that's wonderful, but there is also a lot that is not measurable, as Dr. Crawford said, which is meaningful to them. We're talking again about 3- points being clinically meaningful in the Hammersmith expanded versions of the scale. I keep saying that stability is still a desirable outcome. It is hard to define what is meaningful. What's meaningful is what's meaningful to the families and the patients themselves. If they're happy with that, I think the treatment has been successful.
I'm going to take it back just a little bit more. The Cohort of the older, 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. The Hammersmith Scale has a little bit less reactivity, I think, to change in that group. I wasn't surprised that that was the group 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 small differences that make a big difference in somebody who's been there for a long time. Obviously, we go with where the signal is that you can measure because that's what regulatory agencies need.
I am definitely not giving up on extending this therapy to the other groups where we haven't yet been able to demonstrate. There's a I call it the hegemony of measurement. We seem to think that measurement is everything, but in fact, it's meaningfulness is everything.
Excellent point. Dr. Darras, what are your thoughts about Dr. Crawford's comments on continuing to explore ambulatory Type 3 as a potential area for exploration with the apitegromab?
I think it is important because these patients, they do need to maintain at least what they have. We do know that with SMA, they basically can be stable for some time, but eventually they do decline. Even these older patients, there've been studies done of four patients for 15 years, and they did notice that muscle strength did go down. It goes down slowly. Even these older patients who seem to be doing okay, eventually they're going to have some decline, and there's need to treat them with a medication, with drug or combination of drugs, they're going to accomplish that. It's just that it's difficult sometimes, as Dr. Crawford said, to measure improvement in some of these older patients who are stronger.
There is a need there to do that, particularly with medication that could be given once a month and not intravenously instead of getting a lumbar puncture or something. There's more work to be done. Maybe these older patients, they would benefit from a combination of apitegromab and perhaps another SMA-regulating medication that can be taken orally 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 we just can't measure.
Switching gears to maybe the other end of the spectrum in terms of age at which therapies are started. Let's now consider patients who are started, for example, with SMA [uncertain] therapy earlier in life, such as before the age five. Dr. Darras 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, interestingly, a plateau phase. Dr. Crawford, are your thoughts and experience generally consistent with that what Dr. Darras observed? Obviously, there's the SHINE study data as well. What are your thoughts and experience in all this?
Yeah. I just presented a paper on strength measurements, dynamometer measurements on kids and adults with SMA over my 34 years. It shows that in an untreated state, everybody declines. The rate of decline diminishes the further along you go, but everybody declines at every age. Too soon to know about whether or not SMA-enhancing agents stabilize that. It's all of our hypotheses and beliefs and limited data to suggest that they do, but it's going to take longer to know if that's true or not. Certainly, the ones that I followed on nusinersen since early 2017 have stabilized. Knowing the vagaries of measurement and things up and down, of course. Yeah. I think that there's potential for benefit across the range, and I don't want to 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. If we stop neurodegeneration with an SMA-enhancing agent, we should indeed see some slow improvement. I don't know that I agree with the idea there'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 already expected is the top line. I think we can imagine improving that across the range. Again, I'm going to go back to the issue about the Type 1 babies.
Almost no one who has two copies of the SMN2 gene, the genotype that's associated with a more severe phenotype, almost everybody who has it has had disease before we ever started nusinersen. I think those people, we're going to see more and more evidence of the damage that was done before we ever started. That group, which constitutes about 2/3 of patients with SMA and died because they're not seen in the prevalence pictures that Jill Jarecki showed because they're departed. We're expecting to see that group. Well, I don't want to call it Type 1 anymore because they're not Type 1s.
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. Just to talk more about your perspectives, you mentioned that you would anticipate that there would be some maybe more gradual improvement on nusinersen alone when intervened upon earlier in life. In one of our Cohorts, obviously, the TOPAZ, there were patients who had previously started background nusinersen before the age of five and then subsequently treated with apitegromab for 12 months. With the 20 milligram per kilogram dose level, patients received or observed mean increases in HFMSE at about 7- points. Subset almost 40% got over 10-point increases. Just wanted to get both of your perspectives around these Types of results and this Type of population. What do you think about those Type of results? Dr. Thomas Crawford first and then Dr. Basil Darras.
All right. Well, 7- points on top is like, "Oh my god, that's big.
Yeah.
It's also the skeptic in me is I don't believe anything. Everything has got to be proven before you believe it or not. This is an unblinded trial. What I see in this trial is the top-line results are really impressive. If we achieve even a fraction of that in a blinded study, we will have accomplished an amazing improvement in the lives of people who have SMA. 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 outcome. It isn't a how do you feel about things kind of a trial. The fact it's open label is not that damning to the results.
Yet it is an unblinded style. 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.
Dr. Darras, your thoughts?
Well, we do need to remember that the treatment was started with SRK-015 after he had received a number of doses of nusinersen, about at least 5 doses. We're talking about a period of about two years. In these younger patients, the truth is that I have seen some improvement over time. Again, they have a lot of improvement early on. But some of these younger kids, some of them may do improve to some extent on nusinersen. I don't think that I have ever seen a young patient after two years of nusinersen who has improved by 5-points or 2- points. I don't think this can be a nusinersen effect. It looks to me as if we have is the effect of the combination of nusinersen, so SRK-015.
That's the degree of improvement in the percentage of patients, for example, where 60% of the patients had 5-points or more than 5- points increase in the Hammersmith Scale, in about more than one-third, they acquired more than 10- points. These are numbers that at least myself, I have not seen in the younger population on nusinersen 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 just starting with more background observations, the effects of nusinersen alone in patients who start their therapy later in childhood. The CHERISH trial data seem to suggest that the subset of patients starting nusinersen after the age of five may have a different HFMS response to patients starting nusinersen before the age of five. As an example, the majority of patients, the subgroup is small, so we have to acknowledge it's a small subset. With that said, it appears the subset of patients, the majority of patients starting nusinersen later in childhood did not experience HFMS increases, and many who actually seem to have declined in terms of HFMS, at least. Is this consistent with your experience and your view? Starting with Dr. Darras.
Yeah. There are publications on this. We have reported data at the SMA meeting in the past and all that. It does seem that the age initiation of treatment makes a big difference. The earlier you start, the better the outcome is going to be. In fact, the best outcome was before the age of about three and a half years or something. There are patients who had an okay outcome up to the age of five years at the time when nusinersen was initiated. After five years, the results have not been that good. We have to be honest, there are publications on this and presentations at different meetings. This is the population who actually needs something better. We need some better results for those older patients over the age of five years.
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 nusinersen. After the age of five years, 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. Dr. Crawford, what are your thoughts and how's your experience been with this?
Well, we've done quite a bit of work on autopsies and on the biology of SMA. We know that the two copy SMN2 folks are having manifest motor neuron degeneration probably before birth, and robust losses of motor neurons 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 a real quandary. When does the disease start? The evidence that we're starting to accumulate is that it actually probably starts even in early childhood for the Type 3 people who are not going to manifest weakness until adult years even. Probably the difference between Type 1, Type 2, Type 3, the old designations of those things, is how many motor neurons make it through normal development before degeneration starts happening.
If you have a full complement of motor neurons make it through before your degeneration, then it's going to take a long time if you lose it 5% per year until you finally pass through that threshold of weakness and start to degenerate as an adult with SMA Type 3 or 4. If you have a modest or a moderate amount of loss, then you make it to the point where the threshold occurs at nine months or 18 months of age. The rate of the platform that development is able to achieve becomes a major determinant of how long it takes until you finally see the degeneration. With SMA 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, generate 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 SMA enhancing agents. There's no age beyond which myostatin enhancement is likely to be able to be useful on top of that stability if we can work out the biology, if that's the way the biology turns.
Great. Actually, now that in the context of discussing the hypothesis about the potential of adding on top [uncertain] in context patients who may have started their background therapy later in life, or SMN, more broadly SMN therapy later in life, which is our Cohort 2. There's actually a question that just came in on that point. Catherine, is that correct? There's a question?
Correct. We have a question from Anupam Rama from JPMorgan. It's actually very similar to this last question you just asked, Yung. It's for the KOLs on the line. For this patient population who started nusinersen age five and older, their other physician feedback also suggests that these patients are likely far into progression of the disease, so eliciting effect could be more difficult. Is there a portion of patients who get 3 or more points on HFMSE that would be compelling for you? For example, TOPAZ showed about 30%. What is kind of a threshold for you? 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?
Coming back to the issue of what is clinically meaningful using the Hammersmith Scale, as we discussed earlier, for years this has been debated at the meetings. The conclusion is that 3- points is clinically meaningful. As I said earlier, there are patients who are happy with only 1- point increase, or they're happy just stability. For them, anything that's going to give them better function would be welcome. It seems that sometimes you hit a plateau of improvement with nusinersen in many of these patients. For the reasons that Dr. Crawford explained, it has to do with how many motor neurons are left there and how they're functioning. If we can enhance muscle function with an anti-muscular medication like SRK-015, and these patients improve even further, they will be happy. It will be a welcome outcome.
I'm not trying to tell you that stabilization is fine for everybody. Everybody wants more. This is why they are asking us to apply for another treatment or apply for combination treatment at this point. If we had a medication like SRK-015, which can improve the function even further, that would be absolutely welcome by the SMA community. There's no doubt. Even if you could go from 1- point to 3- points, that would be great. If you go from 3- points to 6- points, that would be even better. That's what I can tell you. Yeah.
Great. Dr. Crawford, your thoughts?
A little bit of broken record here, but the issue of what's meaningful and what's measurable. Of course, regulatory agencies are going to require something that we can demonstrate to the level of scientific integrity to show that it's incontrovertible. Of course. 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. In the case of people who are profoundly weak, milder is not without its merit. We will be read forward. If we get approval, there'll be an issue of where's the label and also where is the limits at which insurance agencies are likely to approve a drug. We've been fighting this battle with the SMN enhancing agents all along.
I think the agency has been generous in the main, and we have been largely successful getting insurance companies to approve SMN enhancing agents at the margins at the end. 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," as Dr. Darras mentioned, or in case somebody I know, "I can still write a grant with what limited amount of muscle power I've got on my fingers. I can still write a grant to the scientific agencies." These are extraordinary events that are below measurability.
Thank you both for that. 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. Obviously, this was a more exploratory outcome measure that we evaluated. Can you help contextualize what gaining a new WHO 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 milestone. This included also three from the Cohort of patients who had started even their SMA therapy back later in life after the age of five.
Yeah, just would love to hear your thoughts about going the opposite direction for age, something much more challenging and less sensitive, the WHO motor developmental milestones, as well as the TOPAZ results. Dr. Crawford, do you want to go first?
Yeah, I definitely would go with that. The milestones are pretty cool because they represent those stages of independence. Each one of those represents, when babies are born, moms hold them tight and say, "No one will ever, ever come between us." The baby sort of has a different attitude about that, saying, "Let me go. I want out." That's what normal development is. Many of our kids with SMA are intellectually becoming independent, but physically require dependence. There's this quandary, there's this tension between the fact that they want to be left alone. They want to be able to do things on their own. In fact, they have to have somebody pick up their hand and put it on the controller of the wheelchair in order to go, or they have to be transferred from the wheelchair to the pot.
They're being dragged back to their disease over and over and over again, even while 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 extraordinarily meaningful in the life of people who have them is big. If we can take people who are on the stable portion of their SMA enhancing agents and move them up 1 grade or 2 grades, that really is one of those, like, oh, my God, that's touching and meaningful and big.
Dr. Darras.
Yes. I would like to give you a little history because when the ENDEAR study started back in 2014 for nusinersen, the primary outcome measure was time to death or ventilation. Milestones were initiated later on when we started noticing that some of the kids were acquiring milestones. Everybody jumped on that. The reason is the reasons are the ones Dr. Crawford mentioned earlier. This is something you can see. This is something that can be seen even by people who are not educated. They're seen by the family. It's something you cannot doubt. I know that it's not the most sensitive Type of developmental of clinical outcome, but it's probably the easiest to see, and it has a lot of value. Imagine that having a child who was unable to crawl or stand with assistance.
Standing with assistance provides a new perspective in somebody's life, in a child's life. Be able to see the world from a different level, not just sitting down or lying down. The milestone, I'm glad you were able to do this additional TOPAZ analysis and discover that in fact, there are developmental gains in the area of WHO milestones, because this is extremely meaningful. It's not just in the nusinersen trials, but look at the gene therapy trials. Or even risdiplam trials, they're based on acquisition of milestones, the ability to sit, for example, for 10 seconds or five seconds or 30 seconds and all that. It has huge value. I'm glad you're able to do this analysis and show that some of the enrolled patients, actually 7 of 35, were able to acquire milestones even after the age of five years.
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 current SMA enhancing drugs. 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 oyster. You can travel. You can do everything like that. If you can't transfer, then you need somebody to help you at home, and it's a tether that holds you back.
Yeah. 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 reposition the child. It's not just improving the child, it's improving the family's life to be able to have a child who's now able to roll over during sleep. This is not sitting or standing. Again, I think this is very, very important, and I'm glad you moved in that direction.
All right. Thank you both. It looks like, Catherine, we have some more questions that came in. Is that right, Catherine? Do you want to go through those questions?
Sure, Yung. 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 III trial that you would find clinically relevant? Second is what is your overall enthusiasm level around apitegromab and thoughts on its use in a clinical practice?
Well, as to trial design, I think we're going to say that the specifics of which patients to include and how long and what the outcome measures are all a little bit in flux 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. We'll have to sail our way between the Scylla and Charybdis of those two perils. I guess the second question was what is the enthusiasm level? If you can't tell my enthusiasm level from my discussion here, we have some measuring to do of your emotional intelligence because I am really over the top on this one.
Dr. Darras, what are your thoughts?
In terms of clinical trial design, it seems that you're going to use, again, the expanded version of the Hammersmith Scale. I don't know whether you're able to include the Revised Upper Limb Module, probably yes. I would encourage you to continue to look in the direction also of muscle acquisition. I think that'll be great. Not just myself, but many people in the SMA community and the families and many of the patients who are able to assess the situation, older ones, will be very sad if this effort does not move into a phase III study. That does not seem to be the case. 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 SMN upregulating drugs.
I think it's a great effort, and I'm very optimistic about having a positive outcome at the end.
I will say that the buzz at the Cure SMA meeting was palpable. Even though it was virtual, where it is hard to feel things buzzing through the computers, 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 Callan. First question is, assuming that the phase III trial will evaluate apitegromab as add-on to the correctors, what is the minimum benefit on HFMSE that you'll want to see to use apitegromab broadly in Type 2 and Type 3 patients?
I think I've sort of covered that. We have to have the minimum number to get regulatory approvals. 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 are getting the therapy. They're the ones who are going to be able to say, "Yeah, this is worth it or not." 57 patients who have gotten so far say, "I want to continue with it," including those that didn't have the 3-point threshold. They saw something about it that makes it worthwhile to get an IV shot every month, which is not nothing. Yet they want to continue with it. They see the benefit even beyond that threshold.
Dr. Darras?
Yeah. The families know by assessing the things that are not measurable. It is, Dr. Crawford said there's already a lot of enthusiasm with the families who have perceived benefit. I know there would be numbers that would be thrown out there, let's say, in the phase III study about what will be the endpoint and all this. Again, the families do not expect miracles. They do understand that we cannot cure the disease, even in combination therapy. Anything that would push the kids above what they've seen so far with the nusinersen treatment would be desirable and a good outcome.
And-
I'll give 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 about older ones. Number two, 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, I've been impressed that the Scholar Rock team is dedicated to that. Obviously, I'm enthusiastic about doing it the right way. It looks like we're on that trajectory.
Yeah, thank you for that. Yes, absolutely. Obviously, the safety and efficacy haven't been established yet for apitegromab as that we need to go through a phase III trial and do all the work, go through the appropriate regulatory reviews. A lot of very important work still ahead to further investigate the potential of apitegromab. Thank you for that, Dr. Crawford. 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 make before we finish, starting with Dr. Darras.
Yeah. Thank you, Yung. I don't remember the last part of your talk about the phase III study, but I think you're going to include a Cohort of patients who have received risdiplam. Is that correct?
Yeah, that's correct.
I think that's really fantastic because many patients will be on risdiplam in the near future, and would like to see what the combination of risdiplam and SRK-015 can do. We don't have enough time to talk about the pathophysiology and all that, but in summary, risdiplam seems to up-regulate SMN protein production in the periphery, and more specifically in the muscle tissue. It is possible that in a case like this where the SMN protein is restored in muscle tissue, adding an antibody like SRK-015 may even give us a better result. I'm glad we have a Cohort that includes also risdiplam.
Dr. Crawford, any final wrap-up comments to add?
I think I pretty much left it all on the table, although 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 try to knock down myostatin signaling. I did not remember exactly where I first learned about the Scholar Rock approach to the pro-latent myostatin. I didn't know if it was really going to work in terms 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 you have, that it was the program that had the most potential.
I know that some of the other programs had sort of crashed and burned, and I'm feeling a little bit smug about the fact that I put my star on this one as the one that I really wanted to watch. Here we are. This has been really quite impressive.
Well, thank you very much, Dr. Crawford and Dr. Darras, for taking time out of your busy schedules to share your important insights and perspectives today. Thank you to the audience for joining this morning's discussion on the unmet medical needs in SMA, the potential of apitegromab in seeking to address those needs, and the ongoing efforts to investigate that potential. 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.