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

Good morning. I'm Rushmie Nofsinger, Vice President of Corporate Affairs and Investor Relations at Scholar Rock. Welcome, and thank you for joining us today for our virtual investor event on apitegromab's potential to advance the standard of care for 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 Scholar Rock website. Before we begin, I want 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 future forward-looking statements unless required by law. Thank you, and I will now turn it over to Jay.

Well, thank you -- thank you, Rushmie, and good morning, and welcome to our investor event focused on the role of apitegromab, our highly selective muscle-targeted therapy in the treatment of spinal muscular atrophy. I'm Jay Backstrom, CEO of Scholar Rock and will be moderating today's session. We're very fortunate to be joined this morning by 4 distinguished experts in the field of SMA, including Dr. Tom Crawford, Professor of Neurology and Pediatrics at John Hopkins Medicine, and lead principal investigator for the Phase II TOPAZ trial and the pivotal Phase III SAPPHIRE trial. Dr. Basil Darras, Professor of Neurology at Harvard Medical School and Associate Neurologist-in-Chief at Boston Children's Hospital. Dr. Darras is a principal investigator of the TOPAZ trial. Dr. Laurent Servais, Professor of Pediatric Neuromuscular diseases at the Oxford University in U.K. Professor Servais is a principal investigator of the SAPPHIRE trial. And Dr. Jackie Glascock, Vice President of Research at Cure SMA, a preeminent organization that represents the voice of the patient and has played a critical role in advancing the care for the SMA community. We have a full agenda today designed to address important aspects of the care and management of SMA, including the potential role for apitegromab. After my opening remarks, Dr. Darras and Professor Servais will provide an overview of the SMA disease and treatment landscape. Dr. Glascock will provide the patient's perspective of unmet medical need, an important voice that plays an essential role in drug development. Dr. Jing Marantz, our Chief Medical Officer, will review the 36-month data from TOPAZ and provide an overview of our pivotal Phase III SAPPHIRE [ spend ]. And finally, Dr. Crawford will close the formal presentation by describing the experience for the patients he's enrolled and treated with apitegromab in the TOPAZ study. We'll have time for questions at the end. In January, at the JPMorgan Healthcare Conference, I described Scholar Rock is having all the elements for success. We have a revolutionary platform, a robust pipeline of promising products that includes our lead candidate apitegromab. As we'll hear today, apitegromab, the first anti-myostatin therapy to demonstrate clinical proof of concept in SMA has the potential to improve muscle function and address ongoing unmet need. Our pivotal SAPPHIRE study is positioned to read out in 2024 and if successful, will be the catalyst for Scholar Rock to become a fully integrated commercial company. We have a second product in clinic SRK-181 being evaluated in combination with pembrolizumab that if successful, could be transformational and 2 additional preclinical pipeline candidates that are not far behind the clinic. Adding to this, we have an experienced leadership team, financing into 2025 and significant strategic optionality to fund continued progression of a growing pipeline. As we enter the second half of 2023, I'm even more convinced that we have all the elements for success. In our industry, success starts with the science. The picture on the left of the slide depicts the scientific insight that's the foundation of our industry-leading platform, targeting TGF-beta superfamily and growth factors with a desired selectivity for both the target, that's the light in their pro forma and disease-specific context. This highly specific approach limits the off-target effects that can lead to toxicity such as bleeding and cardiac effects. We believe our approach having been born out in the clinic to date should lead to a favorable overall benefit risk profile. Targeting the TGF-beta superfamily has broad therapeutic applications given the central role this family of growth factors plays in a wide range of cellular processes, including growth and differentiation, such as myostatin, a negative regulator of muscle growth as well as immune regulation and fibrosis. Selectively targeting the pro and latent form of myostatin is particularly well suited as a potential treatment for SMA, a neuromuscular disorder. The research platform has yielded a robust and growing pipeline of fully humanized novel monoclonal antibodies. In addition to our 2 clinical stage products, apitegromab and SRK-181, which is a selective context independent latent TGF-beta-1 inhibitor in immuno-oncology. We have 2 other preclinical stage products, anti-RGMC, for iron-restricted anemia and a selected context-dependent latent TGF-beta-1 binding protein inhibitor for fibrosis. And we have an experienced leadership team. You'll hear from Jing Marantz, our CMO, who joined Scholar Rock in November of last year and brings over 20 years of development and medical leadership experience with 10 years out of Alexion, Alnylam and Acceleron. Tracey Sacco, our Chief Commercial Officer, joined Scholar Rock in February and brings 20 years of commercial leadership experience, including time at Sanofi Genzyme and Acceleron. Jing and Tracey joined an experienced team that includes Ted Myles, our Chief Operating Officer and CFO, who will be available for the Q&A portion of today's presentation. So in closing my remarks, I'm very pleased with the progress we've made this year toward advancing the apitegromab program in SMA. We have met we're on track to meet all of the 2023 goals for the program that we outlined in January, and that includes reporting the 36-month TOPAZ data in June at Cure SMA, which we'll hear more about today, opening the ONYX long-term extension study, which will serve as a platform for patients from both TOPAZ and SAPPHIRE to continue to receive apitegromab and an opportunity to strengthen the body of evidence on long-term safety and efficacy. Completing enrollment for SAPPHIRE, as we recently announced, we're on track to achieve this goal in Q3 with top line results expected in 2024 and assuming a positive study and regulatory approval, we anticipate commercial launch in 2025. And finally, our team is in the planning stages for additional follow-on SMA studies, including in children under the age of 2 and ambulatory patients. This will allow us to extend the potential benefit of apitegromab to the broadest patient population possible. Overall, I really like our momentum. We have clear focus on driving the successful completion of SAPPHIRE and executing on the promise of apitegromab to advance the standard of care in SMA. Now turning to the main focus of today's presentation, I'd like to invite Dr. Darras to provide an overview of spinal muscular atrophy. Dr. Darras?

Thank you, Jay, for the kind introduction. As you said, I'm going to present an overview of SMA and of the current SMA treatment landscape. I'm a pediatric neurologist and clinical geneticist by training, and I'm responsible for the neuromuscular center, an SMA program at Boston Children's. And I'll start with the definition of SMA as well as muscular atrophy, I refer to it as SMA from now on or chromosome 5q classic SMA is a genetic condition characterized by degeneration and loss of motor neurons in the anterior horns of the spinal cord and brain stem, leading to muscular atrophy and weakness. 5q proximal SMA is an autosomal recessive disorder caused by loss or mutation of the SMN1 gene and retention of the SMN2 gene. SMN1 and SMN2 genes include the survival of motor neuron protein, SMN protein. SMA is caused by decreased levels rather than complete loss of the SMN protein, leading to selective dysfunction of motor neurons in the spinal cord and brain stem, without SMN protein, the [ sitters ] will never make it to the term of the pregnancy. So it's a very -- it's a crucial protein. And here's the time line of SMA. Going back to 1891, when [indiscernible], an Austrian physician [ Johan Hoffman ] described SMA. And it took 100 years till 1991 for the classification of SMA in the 3 known types to be established. So the chronic classification is based primarily on the best motor performance and secondarily on age [indiscernible] symptoms with understanding that we're dealing the continue of severity across a spectrum of our presentation. And also, it's important to know there is a significant overlap between the different types. So here are the 3 main types SMA Type 1, known as also the Werdnig-Hoffmann Disease, the severe form, also known as non-sitters, because they never sit unsupported with [ onset resemblance ] between birth and 6 months of life. And before the development of the disease modified treatments, these babies they -- they will not survive beyond the age of 2 -- treatments without aggressive treatment. And then we have SMA Type 2, an intermediate variety, also known as sitters, because they never stand or walk but they can sit at some time with onset before the age of 18 months, usually between 7 to 18 months. And it can be for the development of the DMTs, disease modifying treatments. About 98% of its children would go up to the age of 5 years. And at the age of 25, 70% were live, meaning that we had some significant mortality there. And then we have SMA Type 3, the mild version known as walkers, because they're able to stand and walk at some time with onset usually after the age of 18 months, so classified in IIIa before the age of 3 years in Type 3b or sitters after the age of 3 years. And this is children they have almost normal life span. We also have SMA Type 0, these are the babies who are born and required ventilation at birth. And we also have SMA Type 4 the adult form more than set after the age of 18 years. So here's babies we had SMA Type 1 Werdnig-Hoffmann disease, the non-sitters you can see the baby on the left that has this typical frog-leg position because significant hypotonia. But also please notice the phase who seem to be very expressive because the muscles around the face seem to be preserved at least early on. So that's typical of SMA. And on the right-hand side, you can see the fact that baby is flappy because when I try to pull this baby up to a sitting position here baby has significant [ head log ]. And we tried to suspend the baby vertically. The baby may fall through your hands, sleeps through your hands if you don't hold -- hold the baby well. And then, here we have on the left, we have a child who has SMA Type 2, the intermediate variety. And on the right-hand side, [ you see Carol ], who is sitting in a wheelchair with SMA Type 2. But even take her off, who is next to her, also has SMA, but she's a walker and therefore, she has SMA Type 3. Coming to the incidence and prevalence of the SMA in the pretreatment era, before the introduction of the disease modifying treatments, you can see that incidence was about 1 in 10,000 or [ 10 in 10,000 ] live births. And most of the babies who are born with SMA, they used to have SMA Type 1, about 58% to 60%, about 27% SMA Type 2, the sitters, and Type 3, about 15% the Walkers. But the prevalence is different because it indicates the number of patients per 100,000 persons in the population and because most type of babies they used to die by the age of 2 years, the percentage in the clinic of Type 1 babies is only about 10%, 12%, compared to Type 2 the sitters, which were the predominant population in the clinic by 52%, and then about 36% were the walkers. But this classification has been shifting because of the introduction of the disease modifying treatments. And we came to 1995 when the SMN genes were identified by Dr. [indiscernible] by the University of Paris and then the molecular era of SMA started with molecular diagnostics and also development of a mouse model of SMA, [ mice develop SMA, naturally ] it had to be engineered. And after that, a number of clinical trials were initiated with small market who most of them failed. So the goal of SMA therapeutics is to try to increase the production of full-length SMN protein from the backup SMN2 gene, which is the second version, a defective version that produce a small amount of SMN protein, trying to increase the production from that or replace the missing SMN1 gene. So in that sense, SMA is unique translational disease because the genetic defect is the same in all patients, and we have clear targets. But in order to conduct clinical trials, you need to have good and sensitive outcome measures, which allow the researchers to measure the efficacy of candidate drugs. So this is why when we established the PNCR network back in 2004, our first goal was to try to develop outcome measures. And one of them is the Hammersmith Functional Motor Scale expanded. This was based on the Hammersmith Scale had only 20 items developed in London. And we added another 13 items with these items quarter was 0, 1 or 2 with a maximum score of 66. So HFMSE is a scale used to investigate the patient's ability to perform various activities and is used in later onset SMA usually Type 2, Type 3, usually after the age of 2 to 2.5 years. As far as what is clinically meaningful, most of us in SMA community accepted a 3-point change is clinically meaningful. But even 1 point improvement on HFMSE is considered meaningful to patients and caregivers. And here a few examples of HFMSE items. You can see, for example, sitting on a chair on the left, if a child unable or needs 2 hands to support and maintain his or her balance who gets 0 compared to child who was able to sit without support for a count of 3 or more, gets it 2. And a child who needs 1 hand support that gets 1. So it is an ordinal scale with 0 being unable to perform a task [ 2, we get a 2 and the task ] can perform without any help. And 1 when the task is performed with modification or adaptation like 1 hand support to maintain balance in a selling position. On the right-hand side, you see items like touching the head above ear level or rolling from supine to prone. And then we have the -- another scale we developed in ear, in fact, [indiscernible], known as motor function measure or MFM 32, which also has been using number of clinical trials, particularly the risdiplam trials. And then we come to the revised operating module, which is designed to assess limb function and has in a wide range of patients with SMA Types 2 and 3. And this scale has 19 items with each item score with a 0, 1 or 2. The maximum score is 37 because one item is scored on a can or cannot score. As far as clinical meaningfulness in revised upper limb module, we consider a 2-point improvement as being clinically meaningful. And here are some examples of RULM items like bringing hands from lap to the table with the lower score 0 when child unable to bring one hand to the table, and it gets a score of 2 and brings 2 hands completed to the table. And then some others like bringing [ a toy hand ] to a cup place vertically, to shoulder height or bringing weight at eye level using 2 hands. So the therapeutic strategies for SMA have been -- have included neuroprotection, amplification of SMN protein production, muscle acting, therapies -- cell therapy and so on. So early on, a number of neuroprotective and SMN protein amplification trials were initiated in most of the field. As you can see, whatever is read, it is a failed study. So either on 2010, 2011, we started using -- moving into the SMN2 Splicing modulation trials to use antisense oligonucleotide Technology to increase the inclusion of exon 7 in SMN2 RNA during splicing. And then around 2014, '15, gene therapy trials using an AAV9 vector were initiated. And a little later, risdiplam, I'm sorry, RG7916 or risdiplam trials were conducted by PTC-Roche. And then more recently, we're focusing more on our muscle acting interventions. The first 3 Albuterol, Carnitine, Creatine are very old. And clearly, we use primarily Albuterol. But the antimyostatin interventions are the most recent. And so coming back to the 3 modifying treatments, I talked to you about a splicing modifiers of the SMN2 gene. Nusinersen is the first one, but it's given every 4 months intrathecally by spinal tap and risdiplam is a small molecule has to be given daily and both increase the production of full-length protein from SMN2. In patients who have SMA, we have -- we call it homozygous deletion of the SMN1, which means that both copies are missing. In gene replacement therapy is -- it tries to replace that missing SMN1 gene. So it's one dose of intravenous on SMN1 gene [indiscernible], commercially known Zolgensma that carries a coding SMN1 gene to produce a full-length protein. So here's a table that has the 3 disease modifying treatments with nusinersen, Spinraza, AVXS-101, [indiscernible], Zolgensma, and Risdiplam, commercially known as Evrysdi. On the top, we have the nature of the compound, the mechanism of action, which is described earlier. In the pivotal clinical trials that led to the approval of these 3 treatments by FDA, EMA and also other regulatory agencies around the world. So 130 years later since the description of SMA in the early 1890s, we have 3 approved treatments, but what determines efficacy? What determines efficacy is really the number or survive the motor neurons in the anterior horns of the spinal cord, this is a normal specimen, you see the motor neurons down here -- and have positive as motor neurons [ who diverse made up 1 ]. And these top motor neurons can really go away, die very fast. And therefore, time is really more turnarounds. We try to intervene as early as possible. But despite these 3 treatments, there is need to -- they still need to improve and sustain maser of action, which remains an unmet need. To give you an example, this summarizes the results of the CHERISH trial of nusinersen a Phase III trial for nonambulatory Type 2, Type 3 patients. And we're able to get a 3.9 point increase in the HFMSE score for nusinersen and 4.9 score for the patients who -- relative to the same control. I mean there are some patients who had a much better increase in their score. So this is the main increase. But when you ask the families and caregivers, what else do they want? They really want us to address the number of unmet needs like increased muscle strength, improved daily activities, stabilize or gain a new motor function and reduce fatigue, which is a problem, a common complaint in SMA. So we're moving from splicing modulation and gene replacement to muscle directed treatments with, for example, muscle activation, the fast skeletal muscle troponin, using a small molecule known as -- by Cytokinetics, which unfortunately hasn't progressed in Phase III trial, but we're likely to have opportunities to inhibit myostatin or promyostatin. And the main example is apitegromab, a monoclonal antibody has been investigated in the TOPAZ study with promised results, and now we're conducting SAPPHIRE with a controlled study, and where we are optimistic about it. So that's what I had to say. And I would like now to turn it over to Professor Servais from Oxford University. Thank you for your attention.

Hello. My name is [ Laurent Servais ] University of Oxford. I'm going to present you the reasonable expectations and unmet need in patients treated with SMN directed to disease modifying treatment. I think that Basil gave an excellent overview of the recent treatments that have been approved. And obviously, it brings a significant benefit to patients. There is no question about it. So to start with, I've got a couple of disclosures. Actually, patients today who are treated with a disease modifying treatment, they present -- they still present with a significant unmet need. And the reason is that they improve certainly when they are given treatment and their quality of life definitely improves, but they reach a plateau. And this is from the extension study for the nusinersen and as you can see, these are actually patients with Type 2, Type 3. If you give them nusinersen, during a period of time, they will improve on the HFMSE up to 3 points and even for those 3 points, and as Basil described, this is clinically significant. But although they are the sooner they will reach a plateau. And they will not improve any more, at least, on the basis of this case. And it's not just a meta scale, because if you change the scale and you go to another scale, Basil has also described the RULM, the same applies. I mean these patients reach a plateau, and this plateau will be reached sooner if the patients are actually older. It is not just nusinersen, the same applies for the other treatment risdiplam. So the oral therapy. These are the 4 years data of Sunfish. And as we can see, these patients, yes, they improved significantly on 3 scales, including the [indiscernible]. But after 1 year, these patients reached a plateau and again, they remain with this significant unmet need. So the concept is that if you want to [indiscernible], if you want these patients to continue to improve, we probably need to change the target. So nowadays, the disease that are -- the drugs that are approved targets that are motor neurons. And now the target is, as Basil described, definitely the muscle. So let me just show you what is the condition of our patients and the condition that we want to improve. This is a patient of mine, [ meta video ] [Technical Difficulty] improvement that she experienced on treatment. And she was very precise and she made a small videos of the improvement. So she says, well, before I was able to bring to my mouth, I'll [Technical Difficulty] cup of tea and nowadays, I'm able to bring the full cup of tea, right? I feel more stable and more straighten my wheelchair. I have [ no joking ] episodes anymore. I'm now able to eat alone in the evening because before I was just able to eat alone in the morning, but because of this fatigue and fatigability that Basil describes as an important unmet need, I could not eat alone in the evenings, but nowadays I'm able. Now, I can write for a longer period of time. That's all minor improvements that are just game-changing for this young women. The problem, as you might see is that we are far off the cure, far off -- there is still a very significant unmet need and she remains certainly with a cloud margin for improvement. Then you could say, well, yes, but it's because she is already 23 years old, that's true. This is another patient of mine. He is a very good responder. Can I have the video please, by the way. He is a very good responder. He was a Type 2. He was not [ indolent ]. He was treated by nusinersen. Can you please play the video? Works but not for a very long period of time. And he is a very good responder. And you can see from the shape of the legs that, he is a very, very significant muscle atrophy, right? Because in spinal muscular atrophy, there is muscular atrophy. Obviously, these 2 patients, we did everything we could for the spinal motor neurons, but we need now to think about these downstream tissues, which is the muscle and for which we still have probably a possibility of action. So, that's why nowadays several drugs are developed and [indiscernible] is developed for the muscle fibers and to counteract a muscle atrophy. In order to help such patients to continue to improve beyond this important but limited improvement that we are nowadays able to offer. And now I'm going to let Dr. Jackie Glascock to explain the patient's perspective and the unmet medical needs in SMA.

Thank you, Dr. Servais. I think you gave a great lead into what I'm about to talk about, which is hopefully bringing to some of the patient perspective and what some of these motor skills kind of look like in activities of daily living for patients with SMA. And so here, what we're looking at is children, and these results are taken from Cure SMA's Community Update Survey, which is an annual survey we do. It's completed by parents or caregivers of children and then also by adults with SMA over the age of 18. And so if we look at a subset here, which is children ages 5 to 7. And so we picked this subset because these are kids who early treatment may have been available as the first FDA approved drug for SMA was approved in 2016. And so if you look here, what we're doing is we're completing a score for the neuromuscular module subset of the PedsQL, which is a proxy reported measures, so caregiver a parent reported measure. And so this is a tabulation of the neuromuscular module subset. And you can see here, generally speaking, for each of these age groups, the scores are going up, indicating improvement in motor function across these various years. So you can see it broken down by children age 5, 6 and 7 here in the table. So overall scores are showing a positive strength and higher scores indicate better health-related quality of life. However, you can see that, as I have said, the maximum score of 100 is not being reached. So there's currently still much room for improvement in motor function here. Again, if we look at that same 5 to 7 age group, and we ask questions like, is it hard for your child to use his or her hands? Are your child's hands weak? We see the vast majority of parents and caregivers are reporting that these are issues for their children. And these would translate into daily activities if they can think about in early childhood education, such as being able to pull the pencil or color with a crayon or open food items at lunch in the cafeteria and those sort of things. So we do have the vast majority reporting that this is sometimes a problem, often a problem, and very few reporting that this is never a problem for their child. So now I want to transition to adults, so moving away from kids, and this is self-reported unmet needs in adults with SMA. And this is a bit of a busy slide, so let me walk you through it. The question here from our Community Update Survey being what are the most significant current unmet needs that you hope new therapies would address? And so these are things like reduction of fatigue where in 2022, we had 83% of participants taking the survey saying that yes, reducing fatigue is an unmet need that I would hope a new therapy would address. Other things include 63% hoping to improve respiratory or breathing function, 48%, so almost half, hoping to improve swallowing, whopping 97%, hoping to gain muscle strength with 89% hoping to achieve new motor function and 91% hoping to stabilize motor function. I think something that's important to realize, especially in the adult population living with SMA is that stabilization of function is really important. The importance of maintenance of skills that allow them to conduct their daily lives, things such as typing to complete test in a job environment being able to self-care routines that they are able to do. It's very important to maintain function. Improving function is great, of course, but that maintenance of function is very important to this population. And then you can see improving activities of daily living, that's 92%. And again, those activities of daily living include things like feeding, dressing, being able to go to the bathroom independently, navigating using a joystick to control a wheelchair combing hair, brushing teeth, those kinds of activities. And so if we look at these remaining unmet needs in adults with SMA, you can see again here, over time, we still see huge numbers of respondents to the survey saying that gaining muscle strength is an unmet need as well as achieving new motor function. And so this is one of the highest ranked categories we see when we ask what current unmet needs that patients hope new therapies would address indicating that really maintenance or gaining of motor function is super important to this population. And so I want to kind of give some context to what we're talking about here. You've heard about the motor skills from others and these kind of data from our Community Update Survey. But I think if you look here from our recently held look back in August of 2022, patient listening -- patient-led listening session with FDA on unmet need, these really kind of come to life. And so we have a team affected by SMA who's explaining that she's in high school, she's on a robotics team, but she often has to choose between something as simple as taking a shower versus doing homework because she doesn't have the energy to do both kind of getting to that aspect of reduction of fatigue that's an unmet need that patients wish to be addressed by future therapeutics. And we have another adult affected by SMA who works in a laboratory setting, and she explains the importance of being able to, to move or lift something that weighs about the equivalent of a half gallon of milk in and out of the fridge and so having to ask for help to do that. And she emphasizes that small tasks are huge successes in her life. So being able to maintain that function to be able to continually do those things are really important to her. And then if we kind of switch from thinking about older individuals living with SMA to parents of younger children, this is even -- unmet need is even really a foresight in the minds of individuals who are treated quite early as well. So we have a mother of [ a infinite ] who was treated prior to symptom onset who says that the development of add-on non-SMN targeted therapies is really top of mind for them because they're thinking to the future and when things arise, they want there to be additional therapeutics to help meet those needs. We have another mother of 3 children, all of whom are affected by SMA saying that each of them could still benefit from another drug or dual drugs to increase their ability and she says compared to typical children. So I want to close with one final kind of anecdotal story by an adult affected by SMA who gives a really elegant illustration on how this kind of -- these small gains on function or maintenance on function translates to his daily living. So I invite you to do this along with me. He says, what seems like minimal gains in strength actually translate to exponential gains and functional ability. So to illustrate this, I invite you to try a little experiment. That is the next time you are eating a bowl of soup, cereal or something of that sort, try this: first, straighten your back and neck, and don't let yourself bend them at all, because you have rods in your back to correct your scoliosis. And then he invites you to keep your elbows on the armrests of your chair and not lift them up, because you don't have the strength in your arms. And so now you have to try spooning food into your mouth, and he's saying, I bet you'll have a difficult time. And so then he gives the thought experiment that once you've gotten used to that, you allow yourself to lift your elbows off the armrests, 2 inches or so and try eating again. And he says that might not sound like much, but you see that those 2 inches are life-changing. And I think that's just a really [ pioneer ] illustration of how these small gains in motor function translate into tangible improvements in activities of daily living for people affected by SMA. And so with that, I will turn it over to Dr. Jing Marantz, who's going to give apitegromab update.

Thank you so much, Jackie. I'm Jing Marantz, its -- Chief Medical Officer at Scholar Rock. It is my pleasure to share the updated 36-month data from TOPAZ. As doctors Darras, Servais and Glascock highlighted earlier, the SMA field has seen significant progress. There are 3 approved therapies, Spinraza, Evrysdi and Zolgensma together has brought about substantial improvement in how SMA patients live their lives. Despite the progress, there is significant room for further improvement as Jackie powerfully highlighted earlier. The reason is illustrated on this slide. These SMN targeted therapies address the motor neuron component of the disease as shown in the middle of the slide. However, they do not address the muscle atrophy that has taken place, the second and important component of the disease pathology for SMA. Myostatin is a negative regulator of muscle growth shown in yellow here on the left. Apitegromab is a fully human monoclonal antibody that selectively binds and inhibits the performance in myostatin in the skeletal muscle, thereby promoting muscle growth and consequently muscle strength and function. The upstream targeting of the performance of myostatin in the skeletal muscle and the highly selective nature of the action has the potential to avoid undesirable off-target effects as pointed out by Jay earlier. This has been borne out in the clinical setting, as I'll show you later. TOPAZ is a proof-of-concept Phase II study designed to evaluate the safety and efficacy of apitegromab in patients with Type 2 and 3 SMA. The TOPAZ study included 3 cohorts. Cohort 1 included 23 patients with Type 3 ambulatory SMA defined as those able to walk without assistance for at least 10 meters at screening. Patients in this cohort was treated with apitegromab at 20 mg per kg dose, either alone or with background nusinersen. Cohort 2 included 15 patients with Type 2 or nonambulatory Type 3 patients treated with 20 mg per kg apitegromab. Cohort 3 included 20 patients with type 2 SMA randomized to 2 doses, either 2 or 20 mg per kg dose of apitegromab. An important distinction between these cohorts was also when these patients received nusinersen prior to enrolling in the study. Patients in Cohort 1 and 2 received nusinersen at or after the age of 5, whereas patients in Cohort 3 all received nusinersen before the age of 5. This is an important distinction because the earlier nusinersen was received, they more on motor neurons, they may be preserved. The greater the potential for these patients to benefit from a muscle-directed therapy, sensing muscle atrophy occurs from denervation of motor neurons. The primary endpoint for the study were main changes from baseline in motor function as measured by revised Hammersmith or RHS for the ambulatory patients in Cohort 1 or Hammersmith Functional Motor Scale Expanded or Hammersmith for short, for the nonambulatory patients in Cohort 2 and 3. I will focus the remainder of the presentation on a nonambulatory patients highlighted in the orange box as this is the main efficacy population in our pivotal Phase III SAPPHIRE study. Results from the TOPAZ trial have been previously reported. Data demonstrated proof of concept for apitegromab in SMA when added on to nusinersen. What is shown here is the motor function data of the nonambulatory patients with Type 2 and 3 SMA ages to the trial, the main efficacy population being studied in our pivotal Phase III SAPPHIRE trial. In a post-hoc analysis, the addition of 20 mg per kg dose of apitegromab resulted in an improved motor function with a mean increase of 4.4 in Hammersmith from baseline. Also note that greater than 80% of the patients have achieved at least 1 point increase in Hammersmith. Importantly, a slight majority of the patients achieved at least 3-point increase in Hammersmith, which is considered clinically meaningful, as Dr. Darras has highlighted earlier. Let's put the TOPAZ trial in context. Here on the left is the long-term data on nusinersen with 4.5 years of follow-up. The mean Hammersmith score increased among the initiation of nusinersen. However, after approximately 15 months, the Hammersmith scores started to plateau as Dr. Servais has highlighted earlier. Specifically, the Hammersmith score between 15 and 4.5 years is within the band of 1 point. This occurs regardless of whether you're young or older, and it is just a matter of time, every patient does plateau. On the right is the long-term data on risdiplam, a similar trend of plateau is also observed. An important point to note that is that TOPAZ patients enrolled in the study with a mean of 2 years of prior exposure to nusinersen already. What this means is that the TOPAZ patients were already in the chronic maintenance phase of nusinersen. This is relevant as we think about the TOPAZ results. The study was designed to make it easier to isolate the effect of apitegromab. The Hammersmith improvement by 4.4 point seen at the 12-month would most likely be attributed to apitegromab based on the natural history of patients already entering the [ baton phase ] on the nusinersen treatment journey. To further strengthen this point, we also analyze the data to understand whether the 12 months Hammersmith change from baseline relates to the duration of prior nusinersen exposure. As is evident from the scatter plot here, there's no clear relationship between these 2. As mentioned earlier, patients entering the TOPAZ trial were already in the chronic maintenance phase of nusinersen treatment, the lack of clear correlation between Hammersmith and the duration of prior nusinersen exposure suggests that the improvement in motor function in the TOPAZ study is likely attributed to apitegromab. Before we show you the updated 36-month data, I wanted to first go over the patient disposition over the course of 36 months. This is a busy slide, but I want to draw your attention to the following points. If you look from the top left, moving towards the right, we start with 58 patients. One of these patients from the ambulatory cohort withdrew early in the study due to fatigue and weight gain. Of the remaining 57 patients, 2 patients dropped out due to COVID, the other 5 who dropped out were all patients on monotherapy. So it's not surprising given the mechanism of how apitegromab works. Importantly, if we look at the nonambulatory population highlighted within the orange box, all these 35 patients who started the trial, only 1 dropped out due to COVID. Therefore, well over 90% of the nonambulatory patients remained on study. With well over 3 years of follow-up, we're pleased about the high rate of patient retention on TOPAZ. For the rest of the presentation, I'll focus on the pooled nonambulatory population. These bar graphs represent the motor function outcome measure by Hammersmith over the course of 36 months. As Dr. Darras explained, Hammersmith is a validated scale that measures motor function, such as the ability to sit independently without hand support or the ability to roll the ability to stand with or without assistance. On the left is the pooled nonambulatory population, age 2 to 21. On the right is the subset population age 2 to 12, that is the main focus of the SAPPHIRE trial. You can see from these graphs that the improvement in Hammersmith seen at 6 and 12 months continued to strengthen over time and was maintained over the course of the 36 months period, both in the combined 2 to 21 Group and in the 2 to 12 subset. Similar trend was observed for upper limb function as measured by RULM, which measures the ability to perform daily activities such as pushing a button, opening a container or a lift in a cup. The improvement in long seen at 12 months continue to strengthen with time was maintained over the entire 36-month period, both in the combined 2 to 21 group and in the 2 to 12 subset. Note that the RULM improvement continues to strengthen with time for patients who are nonambulatory continued improvement in the upper limb function is important to their day-to-day lives, as Jackie highlighted earlier. This slide really highlights the WHO development milestones. These development milestones are designed to capture the gross motor development in the first 2 years of children's lives. However, these key development milestones are often delayed or not achieved in children with SMA. So achieving these major development milestones would therefore, constitute robust outcomes in SMA chronical trials. Looking at the top row, you see that the major development milestones moving from the easier ones on the left to the most difficult ones on the right that is walking alone. Within each of the milestones from left to right is the baseline, 12 months, 24 and 36 months. The green checkbox marks represent each major milestones achieved at a specific time point, as you can see that the new milestones are achieved at various time points throughout the TOPAZ trial. Looking at the panel on the top, patients receiving nusinersen at or after the age of 5 remained mostly stable over time, a few gain milestones temporarily and then lost it. However, if you look at the bottom panel, patients received in nusinersen earlier than the age of 5 improved overall with 6 out of 20 patients gaining new milestones over the course of 36 months. Notably, we see a 2-year-old patient achieved 4 new milestones and 2 of these patients were able to walk independently. These data are striking, taking into account that these patients who are already in the plateau phase of their nusinersen treatment. As I mentioned before, the earlier nusinersen was received, the more motor neurons may be preserved and therefore, the greater the potential for these patients to benefit from the muscle-targeted therapy since muscle atrophy occurs from denervation of motor neurons. Our data are consistent with this concept. In addition to motor function improvement, we also assessed patient-reported outcomes. On the top left, you can see that the PEDI-CAT daily activities measure improved over time. The bottom left shows substantially reduced fatigue as measured by promise fatigue questionnaire completed by caregivers. The improvement in patient-reported outcome measures were consistent with motor function improvement measured in Hammersmith or RULM. Taken together, the consistency and sustainability of the benefit seen over the course of 36 months in patients who are already in a chronic maintenance phase of nusinersen suggests that the improvement not likely associated with apitegromab. With over 3 years of following-up and a total of 198 patient years of exposure, the safety profile at 36 months was consistent with previous reports with no new safety findings. Treatment-emergent adverse events were mostly mild to moderate in severity and generally consistent with underlying patient population and the background therapies they receive. Importantly, there were no death or suspected unexpected serious diverse reactions or hypersensitivity. And no patients had positive titers for [ anti-apitegromab ] antibodies or ADA. Overall, apitegromab was well tolerated, and as I pointed out earlier, over 90% of the nonambulatory patients enrolled in the study remain on therapy. In summary, the consistent and sustained benefit we see, combined with a well-tolerated safety profile provides the proof of concept that apitegromab directly address progressive muscle weakness, a key component of the SMA pathology. In summary, the consistency and sustained benefit -- sorry, moving on to the SAPPHIRE -- Phase III SAPPHIRE trial. Based on the success and the insights we've learned from TOPAZ, the SAPPHIRE study was initiated last year and is on track to complete enrollment by Q3, as Jay pointed out earlier. The key learnings from TOPAZ were integrated into the SAPPHIRE design, as you could see on the right. The SAPPHIRE study is designed, as you can see on this slide, based on the learning gain from TOPAZ and importantly, in close collaboration with both the FDA and the EMA. Patients with nonambulatory Type 2 and 3 SMA are randomized [ 1:1 to 2 ] doses of apitegromab and placebo. Patients were stratified based on age when they initiated the SMN therapy and the type of SMN therapy, whether it's nusinersen or risdiplam. The primary endpoint is Hammersmith at 12 months, the same as TOPAZ. As myostatin regulates muscle growth throughout life, we expect the benefit observed in TOPAZ to be broadly applicable as the SMA field continues to advance, patients are identified and treated earlier, preserving more motor neurons, therefore, potentially with greater potential to benefit from a muscle target therapy. Based on this notion and our exchange with the regulatory authorities, we included a cohort of patients age 13 to 21 as a predefined subgroup for the SAPPHIRE. Patients who complete a 12-month treatment period of the SAPPHIRE study have the opportunity to enroll into the ongoing -- on extension trial, which serves as a mechanism for patients from both TOPAZ and SAPPHIRE study to continue to receive apitegromab. Now, it's my pleasure to introduce Dr. Tom Crawford, who is Professor of Neurology and Pediatrics at Johns Hopkins [ Astro ]. Dr. Crawford is the lead principal investigator for both the TOPAZ and the SAPPHIRE study. He's going to share with you the TOPAZ trial experience at his institution. Dr. Crawford?

Good morning or afternoon or evening, wherever you might be. My title slide says Patient Journey here, but I actually wanted to start off with a little bit of a personal journey because I've been at this for a while. In college, I was desperately ambitious to make a difference in the world and as a philosophy major I wasn't certain how that would work, but got associated or interested in the fledgling hospice movement and decided that it might be worthwhile to take my nerdy science side and become a doctor and become a hospice doc. That sort of fell apart because I was disillusioned by my internal medicine rotation and was left to drift until I did the next rotation in pediatrics. And I encountered a baby with Werdnig-Hoffmann Disease, to get well known with the baby and the mom, and next morning, try to present to the pediatricians on rounds, and I was told by the pediatrician that SMA was the most hopeless disease in all of pediatrics and that we really shouldn't burden mother with our presence. And so that set me off and said, interesting. My journey was that I did a Child Neurology Residency and then came to Hopkins in '87 with the idea that I would be working on the science of motor neuron biology trying to make some contribution that would be useful to the course of SMA. And in the afternoons, I was working on figuring out how to best care or how to best play a losing hand. And so we did that for the better part of 25 years, learning how to measure the disease, how to establish the best care guidelines, all things were necessary to be able to set up good clinical trials. And so I was aware of the value of science that if you can't measure it, then you can't make progress. But there's also the problem of what does it mean. And so that is where we get the patient journeys. I might also add that I was involved in a number of ad boards and advisory things for many of the other companies that were trying to do myostatin inhibition in mostly the muscular dystrophies. And I was a little bit perturbed that I kept saying SMA is a better model to use because SMA's muscles are different than muscles of other muscle diseases like muscular dystrophy. In SMA, the atrophy is half of the muscles are denervated, and the other half are normally innervated. And we know that that myostatin inhibition works well on healthy muscles otherwise. So we have the opportunity to treat muscles that are not otherwise confounded by a disease. And the other thing that was true about SMA and not true of the other myostatin initiatives, was that SMA is, as you've seen, very stable. Their kids are about the same over time. And so that means that clinical trial design was likely to be easier to try to identify if there really was a signal for myostatin inhibition in humans as opposed to other diseases where there are a bunch of other confounders. So with that, I was enthusiastic about trying to push groups into studying SMA, and I had my eye on Scholar Rock and their other approach and not alone, but I was among those that try to encourage them to do SMA. And we designed this pilot study that had 3 different groups that were sort of designed to see where the signal would be in the course. And obviously, we're incredibly pleased that with these small trials, unblinded as they were, but designed in a way to try to prove that the effect is related to apitegromab but not disease. Really pleased to see the extraordinary results. So this is my patient journey slide. Sorry about that. In addition to being the lead for the overall study, we also did a site here with Dr. [ Nas ] being the PI here, and we followed 4 kids that had SMA. And here, we sort of switched to say, okay, what's data for the overall group. But there's information to be had in stories, even though stories aren't truth overall, they do tell something about what's going on underneath it. And so here's the 4 kids that I followed. The top one might be in some ways the most informative. This is an 11-year-old kid who had substantial knee and hip contractures as well as a mild scoliosis. And over the course of the therapy, she clearly gained things in her ability, she told me that she was stronger, she's real puckish young woman, and she was able to identify things that she could do. On the other hand, over 24 or 36 months, her scoliosis went from subtle to worse and worse and worse to the point where she had to have scoliosis surgery. And that means putting a rod in your back, you heard about that this makes it very difficult to be able to do anything when you can't move your trunk and move around to be able to accommodate things. And as a consequence, she took a real hit in especially the lower extremity Hammersmith things, a little bit in the [ RULM ] things as well because again, you can't help with moving your trunk as a consequence. But yet, she is enthusiastic about this therapy and really wants to continue on it, but it's in a different way. The other 3 kids were 4 and 5 when we started with them and going to just talk about one of the next ones. By the way, all 3 of these, the moms, the dads, the kids are enthusiastic about getting this therapy. They each will tell you sometimes too long a story about what they can now do where they couldn't do before. One of them is this 4-year-old boy who is not the best one when you look at the overall function, his Hammersmith and RULM scores were pretty stable over time. But underneath that are stories that don't show up. So he will tell you that before I started this, if I was pushed off, actually mom would tell you, if he was pushed over in the wheelchair, he would have to scream his mom to say, pick me up. And now he can recover himself. In fact, he can now lean over and pick up something that's on his legs or over off the side and use his trunk to be able to get back up. And so it's an extraordinarily meaningful thing for him. And just recently, he's starting to be able to slide his bum on a slide board. We put a real slippery board one place to another, which means he can transfer or beginning to be able to transfer from wheelchair to bed and oh my god, if we can get it from bed back to wheelchair, that may seem subtle, but if you can transfer yourself, you can live alone. If you can't transfer, you can't live alone. And so transferring is akin to independence. And so we're seeing him progress even though it's below the measurability of things on RULM and the Hammersmith outcomes. Another case, probably the most dramatic one I can imagine is a kid, he's 5-year-old when we started. And if you stood him up and set him up just right, everything was great and he would hold on to his walker, he could take a step and then another step and another step for about 4 or 5 steps. And with the advantage of this therapy, his measurable scores just skyrocketed because he now is able to get himself to a standing position. And walk not unlike the video that Dr. Servais showed, he can now walk across the room a little bit weaker than that the way. But that means that he can get out of his chair and potentially walk to the bathroom and back. And he doesn't have to bother mom or dad to help him with that. And so in his case, it's measurable and meaningful. Now I want to sort of pause a little bit and say, what do we get from stories? It's probably, I think, important to realize that words are slippery. And I've long debated the community talks about the meaningful outcome of the RULM is 2 points and the meaningful outcome of the Hammersmith is 3 points. I don't know where that came from. In part, it may reflect the fact that statistically, that amount of the change is likely to be meaningful from the standpoint of statistics. But all these words are fungible, they're slippery, when they're applied to groups, when they're applied to overall groups in data, they mean one thing, when they're applied to individuals, they maybe mean something quite different. Einstein was famous for the statement something along the line of saying not everything that counts can be counted. And I'm impressed at how the word significant sometimes means different things depending upon how you use it. you analyst types are going to know about statistical significance. If you can get a measurable difference, and it's called significant. But if the N for the study is thousands and thousands of people, it may represent a really small effect size in the overall dimension, but nonetheless, it was statistically significant, even though it might not be terribly meaningful. On the other hand, when you shift the word significant to the individual, it means that it is substantial that it makes a difference in the life. The same thing is true about meaningful, group meaningful, measured meaningful thing in groups is not the same thing as a meaningful in the experience. And to highlight that story, that dimension, I'd like to highlight an experience I had with one of my older patients. She was 50 when I first met her, she and I have grown older a little bit since that time. And she is a young woman, she had type 2. So she was able to sit, never able to walk. Her mother emphasized education. By the way, just we hear in today's presentation, I realized how many of the patients are going to school, how many of them are going to the university. That actually is not a matter of cherry picking. People with SMA are as a group, highly functional, highly motivated, and they compete in school so that in the states, the average 25-year-old type 2 person or older is more likely to have a graduate degree than the American population has attended college. So they do things with what they've got. Anyway, this woman was a special ed teacher, she eventually found her way to having a classroom, a locked classroom where she has 8 boys who were expelled from school for disciplinary reasons, many of them in the criminal system. And she's now locked class room by herself. And I say, aren't you afraid, how do you do that? She says, well, how can they threaten me? And she has a point because she's pretty intimidated and she's in this big wheelchair and she has her voice and she has her personality, but she can't do anything to coerce them other than use the strength of our personality, which is substantial. And so over the years, she would control the classroom with a feather. She would hold her hands like this she had this long feather, and she would let the guys go off and do things, but when she wanted to call their attention, she would move her fingers just a little bit and the feather would wave and the guys knew they're supposed to quit what they're doing to come around and discuss what's going on. And so this went on for several years. This is way before the time of nusinersen, by the way. And then she came to see me for her annual health and says, "Dr. Crawford, I'm disabled now." And I'm thinking, what the hell are you talking about? Is it now, you've not been able to move hardly anything at all your life. What's now? She said, "Well, actually, this finger doesn't move anymore. It will probably was one mode or not. That finger doesn't move anymore. So now I can't put the feather in my fingers. Now when I use that feather to control the classroom, I can't control the classroom now. That means I had to give up teaching. That means I lost my job. That means I'm now on disability, which is what she meant by I'm disabled now. And I'm going, "Oh, my god, this is so far below the measurable and so far above the meaningful." This is the experience that almost every patient with SMA tells me about is, they will tell you about stuff that matters even if it's way, way, way below the threshold. And what's remarkable is that all 4 of the cases that I saw that I've had personal experience with tell me about meaningful things that they've accomplished even when we can't measure them. So with that, I am going to turn this over to Jay Backstrom for the Q&A.

All right. Dr. Crawford, thank you, and thank you to all the presenters this morning. I think you really have done a very nice job of providing an overview and really appreciate your time. We're now going to turn this to question and answers. For those that have submitted questions, we're going to go through those now. As you can see, we thought the main focus should be on our guests this morning. So the Scholar Rock team with Ted, Jing and myself are on audio only, and we'll kind of invite our guests to answer the questions. So an important question, and we're going to kind of go around the table here with our experts. An important question we get asked about the TOPAZ data, and you saw Jing had walked through that is whether the gains seen with apitegromab could be attributed to nusinersen, so based on your experience in the clinic and considering that the average patient TOPAZ had been on nusinersen for more than 2 years before receiving apitegromab, how did you interpret the TOPAZ data as the investigators on the study. And maybe I'll start with Dr. Darras first, and then Tom will follow with you. So when you saw the results, Dr. Darras and you know that they were on nusinersen, I mean, how did you interpret the results for the apitegromab gains?

I think the gains are real and for the fine reasons. It's not just the statistics, but in the clinic, when our patients come into the clinic for a follow-up, we ask them how they're doing on nusinersen and are they still improving and so on. I have treated around 100 patients for nusinersen and about 25, 30 with risdiplam. I have to say that we still don't have a huge amount of experience with risdiplam. But with nusinersen, we have a number of years now since it was approved in December 2016. So the vast majority of my patients say that I was improving for a year or 2 and since then being stable. I'm happy with the result, but I haven't seen any more improvements and have put out and this keeps happening on and on every 6 months and a year when I see them back, this is what I hear. So this is very, very consistent with that stabilization curve that was presented by Professor Servais. And I think that given that you ended with stability long term with nusinersen and perhaps risdiplam, while these new increases in this course or some of the things that Professor Crawford describe are real and probably related to the addition of apitegromab.

Very nice. And Dr. Crawford, what was your view?

Well, again, data for groups and stories for individuals. And both of them are compelling. I think it's probably worthwhile, we had such a dramatic response in the 12 and unders who were on the higher dose. The 4 points stands way above the curve that we would have seen previously. But actually, I'm not giving up on that there may be a treatment effect in the other areas. If you look very carefully at some of the slides, one of the ones that Dr. Servais showed, the Hammersmith would decline in the older kids who were treated with nusinersen even though we think they were probably stable. And the reason for that probably is that they're accumulating complications. you start to have a little scoliosis. It's like choppier tree goes [Technical Difficulty] eventually years later, things decline and your scores decline as a consequence, obesity, contractures. There's so many ways that things can go wrong. I guess it's a little bit like a toll story. There's a bunch of stories for how things can go sour. There's only one way you're going to gain something, and that's when you have more power. And so that's the slide that shows improvement in milestones, you can't fake that. There are things that and even though it's an unblinded study, you can't fake the fact that they're doing new things. Now not everybody got new things, but not everybody was at the cusp of the next milestone. And many of those things, those folks were encumbered like my case #1 by internal constraints that would prevent them from being able to take the next step up. So with all the combination of stories and data where we're able to obtain it and design better studies to be able to tease out just the benefit is why I'm really very bullish on this as being meaningful to the experienced people with SMA.

All right. Very nice. And then Professor Servais, there's a related question, and I guess you touched on this when you were presenting the SHINE data. So for children under 2, right, who are being treated, would you expect the plateau from the intervention for example nusinersen? Would you expect that plateau to be within 24 months? You made a comment that everyone plateaus, but that time frame may be different. So for those under 2, what would you expect to see? What's your experience in terms of a plateau effect?

So it's a great question because actually, the data I've shown data from SHINE. And in SHINE, patients that were at the minimum 2 years old when they started nusinersen, right? So the patients were 2 years old when they started nusinersen and reach a plateau during the, let's say, the third year of treatment according to which outcome you contribute. But patients were started before will probably reach that plateau later. And if I want to push the envelope, patients who start the treatment at birth will probably not reach a plateau, right? So it means that the moment at which patients reach the plateau between 0 and 2 years is somewhere between never and 2 or 3 years later. And the closer year of birth, of course, the later will come the plateau. In practice, patients who are actually identified those symptoms with type 2 are best case scenario treated about the age after 10 months, 11 months. And we see these patients progressing very significantly during the 2 or 3 first years of treatment, but they will reach some kind of plateau at the age of 5 or 6, I would say. Again, this is very variable. We don't have hard data and it mostly depends on the exact age. And as you might imagine, there is a huge difference between patients who start at birth or patients who start at 2 years. And then the plateau will come on at very different age according to that treatment age onset.

Okay. Very good. So again, that's kind of putting the TOPAZ data into context, where we already came on 2 years. We reported our 36-month data. We've seen these gains. We've seen it continue. And again, it's basically on the expectation that this would be attributed just to nusinersen versus the apitegromab effect. It sounds like the consensus here is that you would not expect to see that with nusinersen alone. And that, in fact, there's the additive effect or the additional effect from apitegromab. All right. So that's very good. I think the other question that we had, I think, was the reference to risdiplam. And do you expect to see a difference with risdiplam? And I mean maybe Professor Servais you can start, if you've got more experience with that, and then we can turn to then Tom and to Dr. Darras.

Well, we have probably a very different experience of risdiplam because the study that was conducted in risdiplam was conducted in a much broader population from 2 to 25 years old. And [ Roche ] did not present the long-term data the same way in terms of stratifying the patients and showing the, let's say, the 2 to 3, the 3 to 4 and 4 and 5 and so on. So it's slightly different in terms of amount of data that we have. The second point is that from a mechanistic perspective, I think risdiplam is an interesting drug because it can also directly affect muscles with potential, but this is highly theoretical of treating the absence of SMN protein elsewhere than in the motor neurons, which could make even more sense in the context of an anti-myostatin drug. And finally, if you go to our practical experience, we have treated a certain number of patients with type 2 at the age of, let's say, 1 year. We have less years of follow-up because risdiplam came on the market later. But the patients started to treat let's say, 2 years ago and were at that time, let's say, 1 year ago are today 3 years, and they are doing quite well. They progress. But we see the trajectory these patients will reach a plateau soon or late and I would anticipate that it will not be massively different of patients on the [indiscernible].

Okay. Very good. I mean Dr. Darras or Tom, any additional comments on your experience with risdiplam, is that what you would expect as well?

Well, again, I don't have a very huge amount of experience with risdiplam, at least time-wise because it's approved in August 2020. But what I've seen so far is the younger patients, particularly under age of 5 years, they continue to improve for a while. And I cannot say when they plateau. Now with older patients, I can say that universally, again, the numbers are small, but universally, they do seem to report some improvement early on, but most of them report stabilization, not within 2 or 3 years, that happens within a period of time, which less than 1 year. So with older patients I see stabilization for a while. And if these older patients improve after addition of apitegromab, you will think that that gain is related to the inhibition of myostatin.

Okay. Very good. So I mean...

I'd like to jump in on that. I'm fond of saying that if you don't have data, it's just opinion. And I'm not certain I trust my opinion. I trust my opinion for deciding what the experiment to do next, but I don't know that I want to pitch my opinion this meaningful. On the other hand, sort of a snarky rule is if you don't have an answer, change the question. And as a philosophy, is always ask a bigger question. And to me, the bigger question here is for all of the SMN-enhancing therapies. And that basically means the most [ dominant ] one which is ZOLGENSMA for the gene transfer. All of them are leaving a significant unmet need behind. The newborn screen babies that are treated with the gene transfer at or as soon after birth as we can arrange it. still have an unmet need. They are clearly the 2 copy kids. The 3 copy kids seem to be normal. But the 2 copy kids, which were 65% of the population are not achieving milestones at the normal age. And the older they are, the more we realize that the gap between them and normal is evident. And that clearly means that there is a market, if nothing else, for SMN for muscle-directed therapies like apitegromab. And of course, even the larger issue is that what we learn in the best case to be able to identify things in SMA is likely to be true in general for other diseases as well.

Okay. Very good. I mean that's a really nice frame of reference. And actually, that segues very nicely into another question that we've received. right? So we're starting off by, we have the TOPAZ data that informed SAPPHIRE, that whole disentangling, if you will, the nusinersen plateau effect, it's consensus that these changes really are certainly not related to that. And now we're looking at SAPPHIRE and really the question that come into us is let's assume we have a positive SAPPHIRE study, right, which we agreed that the scores are clinically meaningful. I mean how would you see incorporating apitegromab into your care for patients, assuming that we show the success that we expect to in SAPPHIRE. And maybe it's kind of going around the horn. I think Tom, you just said, look, there's still need. Maybe you can start, and then we'll go to Dr. Darras and then circle back to Professor Servais.