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 Presentation 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 a 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, 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, will be moderating today's session. We're very fortunate to be joined this morning by four distinguished experts in the field of SMA, including Dr. Tom Crawford, professor of Neurology and Pediatrics at Johns Hopkins Medicine and Lead Principal Investigator for the Phase 2 TOPAZ trial and the pivotal Phase 3 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 University of Oxford in the U.K. Professor Servais is a Principal Investigator of the SAPPHIRE trial. 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 3 SAPPHIRE study. 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 JP Morgan Healthcare Conference, I described Scholar Rock as 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 two 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-β superfamily of growth factors with the desired selectivity for both the target, that's the latent or pro form, 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 borne out in the clinic to date, should lead to a favorable overall benefit risk profile. Targeting the TGF-β 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 two clinical stage products, apitegromab and SRK-181, which is a selective context-independent latent TGFβ1 inhibitor in immuno-oncology, we have two other preclinical stage products: anti-RGMc for iron-restricted anemia and a selective context-dependent latent TGFβ1 binding protein inhibitor-... for fibrosis. 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 at 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 join 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. 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 or are on track to meet all of the 2023 goals for the program that we outlined in January. 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, 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. Assuming a positive study and regulatory approval, we anticipate commercial launch in 2025. Finally, our team is in the planning stages for additional follow-on SMA studies, including in children under the age of two 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. Turning to the main focus of today's presentation, I'd like to invite Dr. Darras to provide an overview of spinal muscular atrophy. 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 and SMA program at Boston Children's. I'll start with the definition of SMA, spinal muscular atrophy. I will 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 brainstem, 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 encode the survival 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 brainstem. Without SMN protein, a fetus will never make it to the term of the pregnancy. It's a very crucial protein. Here's the timeline of SMA, going back to 1891 when Werdnig, an Austrian physician, and Johann Hoffmann described SMA, and it took 100 years to, till 1991, for the classification of SMA in the 3 known types to be established. The current classification is based primarily on the best motor performance and secondarily on age at onset of the symptoms, with understanding that we're dealing with a continuum of severity across a spectrum of presentation. Also, it's important to know there's significant overlap between the different types. Here are the three 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 of the symptoms between birth and six months of life. Before the development of the disease-modifying treatments, these babies, they will not survive beyond the age of two treatments without aggressive treatment. 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 seven and 18 months. Again, before the development of the DMTs, disease-modifying treatments, about 98% of these children would go up to the age of five years. At the age of 25, 70% were alive, meaning we had some significant mortality there. 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. are subclassified in 3A before the age of 3 years, and a type 3B or when the onset is after the age of 3 years. These children, they have almost normal lifespan. We also have SMA type 0. These are the babies who are born and require ventilation at birth. We also have SMA type 4, the adult form, with onset after the age of 18 years. Here's babies who have who had SMA type 1, the Werdnig-Hoffmann disease, the non-sitters. You can see the baby on the left, he has this typical frog-leg position because significant hypotonia. Also, please notice the face, which seem to be very expressive, because the muscles around the face seem to be preserved, at least early on. That's typical of SMA. On the right-hand side, you can see the fact this baby is floppy because when I try to move this baby up to a sitting position, baby has significant head lag. We try to suspend the baby vertically, the baby may fall through your hands, slips through your hands if you don't hold it, hold the baby well. Here we have on the left, we have a child who has SMA type 2, the intermediate variety. On the right-hand side, you see a girl who is sitting in a wheelchair with SMA type 2. Even the girl 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 SMA in the pretreatment era, before the introduction of the disease modifying treatments, you can see that the incidence was about 1 in 10,000 or 10 in 10,000 live births. Most of the babies who were born with SMA, they used to have SMA type 1, about 58%-60%, about 27% SMA type 2, the sitters, and type 3, about 15%, the walkers. The prevalence is different because it indicates the number of patients per 100,000 persons in the population. Because most Type 1 babies, they used to die by the age of two years, the presence in the clinic of Type 1 babies was only about 10%, 12%, compared to Type 2, the sitters, who were the predominant population in the clinic, about 52%, and then about 36% were the walkers. This classification has been shifting because of the introduction of the disease modifying treatments. We came to 1995, when the SMN genes were identified by Dr. Melki's group at 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 do not develop SMA naturally, it had to be engineered. After that, a number of clinical trials were initiated with small molecules, but most of them failed. The goal of SMA therapeutics is to try to increase the production of full-length SMN protein from the backup SMN2 gene. There's a second version, a defective version, that produces a small amount of SMN protein, try to increase the production from that or replace the missing SMN1 gene. In that sense, SMA is a unique translational disease because the genetic defect is the same in all patients, and we have clear targets. 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. This is why, when we established the PNCR Network back in 2004, our first goal was to try to develop outcome measures. One of them is the Hammersmith Functional Motor Scale Expanded. This was based on the Hammersmith scale, it had only 20 items, developed in London, and we added another 13 items, with each item scored with 0, 1, or 2, with a maximum score of 66. 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 or type 3, usually after the age of 2 to 2 and a half years. As far as what is clinically meaningful, most of us in the SMA community accept that a three-point change is clinically meaningful. Even a one-point improvement on HFMSC is considered meaningful to patients and caregivers. Here we have a few examples of HFMSC items. You can see, for example, the sitting on a chair on the left, if a child is unable or needs two hands to support and maintain his or her balance, he gets a zero compared to a child who's able to sit without support for a count of three or more, gets a two, and a child who needs one hand support, he gets one. It is an ordinal scale with zero being unable. To perform a task, two, you get a two when the task can perform without any help, and a one when the task is performed with modification or adaptation, like one hand support, to maintain balance in a sitting position. On the right-hand side, you see items like touching the head above ear level or rolling from supine to prone. Then we have another scale was developed in Europe, in fact, in France, known as Motor Function Measure or MFM32, which also has been used in a number of clinical trials, particularly the risdiplam trials. Then we come to the Revised Upper Limb Module, which is designed to assess limb function. and it has in a wide range of patients with SMA, types 2 and 3. This scale has 19 items, with each item scored with a zero, one, or two. 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 2-point improvement as being clinically meaningful. Here are some examples of room items, like bringing hands from lap to the table, with the lowest score, zero, when someone is unable to bring one hand to the table, and it gets a score of two and brings two hands completely to the table. Some others, like bringing and talking to a cup placed vertically at the shoulder height for bringing weight at eye level, using two hands. The therapy strategies for SMA have been included neuroprotection, amplification of SMN protein production, muscle acting therapies, cell therapy, and so on. Early on, a number of neuroprotective and SMN protein amplification trials were initiated, and most of them failed. As you can see, whatever is red is a failed study. At around 2010, 2011, we started using moving into the SMN2 splicing modulation trials to use the antisense oligonucleotide technology to increase the inclusion of exon 7 in SMN2 RNA during splicing. Around 2014, 2015, gene therapy trials using an AAV9 vector were initiated. A little later, RG7916 or risdiplam trials were conducted by PTC Therapeutics. And then, more recently, we're focusing more on muscle acting interventions. The first three, albuterol, carnitine, creatine are very old, and in clinic, we use primarily albuterol. The anti-myostatin interventions, they are the most recent. Coming back to the three modifying treatments I talked to you about, splicing modifiers of the SMN2 gene. Nusinersen is the first one, but it's given every 4 months intrathecally. branaplam and risdiplam is a small molecule that has to be given daily, and both increase the production of full-length protein from SMN2. In patients who have SMA, we call it homozygous deletion of SMN1, which means that both copies of SMN1 are missing. Gene replacement therapy, it tries to replace that missing SMN1 gene. It's one dose of intravenous onasemnogene abeparvovec-xioi, commercially known as Zolgensma, that carries a coded DNA of SMN1 gene to produce a full-length protein. Here's a table that has the three disease-modifying treatments: nusinersen, Spinraza, AVXS-101 or onasemnogene abeparovec, Zolgensma, and risdiplam, now commercially known as Evrysdi. On the top, we have the nature of the compound, the mechanism of action, which I described to you earlier, and the pivotal clinical trials that led to the approval of these 3 treatments by FDA, EMA, and also other regulatory agencies around the world. 130 years later, since the description of SMA in the early 1890s, we have 3 approved treatments. What determines efficacy? What determines efficacy is really the number of surviving motor neurons in the anterior horns of the spinal cord. This is a normal specimen. You can see the motor neurons down here. You know, and here, positive is motor neurons in a child who died with SMA type 1. These top motor neurons can really go away, die very fast, and therefore, time is really motor neurons. We try to intervene as early as possible. Despite these three treatments, they still need to improve and sustain muscle function, which remains an unmet need. To give you an example, this summarizes the results of the CHERISH trial of nusinersen in a phase 3 trial for non-ambulatory type 2 to 3 patients, and they were able to get a 3.9 point increase in the SFMSC score for nusinersen in 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. This is the main increase. 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 new motor function, and reduce fatigue, which is a problem, a common complaint in SMA. We're moving from splicing modulation and gene replacement to muscle directed to treatments with, for example, muscle activation of the fast skeletal muscle troponin, using a small molecule known as by Soligenix, which unfortunately hasn't progressed to a phase III trial. We're likely to have opportunities to inhibit myostatin or follistatin. The main example is apitegromab, a monoclonal antibody, has been investigated in the TOPAZ with promising results. Now we're conducting SAPPHIRE, which is a control study. We're very optimistic about it. That's what I had to say. I would like now to turn it over to Professor Servais from University of Oxford. Thank you for your attention. Hello. My name is Laurent Servais. I'm professor at the University of Oxford, and I'm going to present you the reasonable expectations and unmet need in patients treated with SMA directed disease-modifying treatment. I think that Basil gave an excellent overview of the recent treatments that have been approved. Obviously, it brings a significant benefit to patients. There is no question about it. To start with, I've got a couple of disclosures. Actually, patients today who are treated with a disease-modifying treatment, they still present with a significant unmet need. The reason is that they improve, certainly, when they are given treatment, and their quality of life definitely improves, but they reach a plateau. This is from the extension study for the nusinersen. 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 HFMSC up to 3 points and even far above 3 points. As Basil described, this is clinically significant, but the older they are, the sooner they will reach a plateau, and they will not improve anymore, at least on the basis of the scales. It's not just a matter of scale, because if you change the scale and you go to another scale, as he 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. As we can see, these patients, yes, they improve significantly on three scales, including the French MFM. After one year, these patients reach a plateau, and again, they remain with this significant unmet need. The concept is that, if you want to push the envelope and if we want these patients to continue to improve, we probably need to change the target. Nowadays, the disease that are the drugs that are approved targets the motor neurons. Another target is, as Basil described, definitely the muscles. Let me just show you what is the condition of our patients and the condition that we want to improve. This is a patients of mine, made a video. She was very precise, and she made a small videos of the improvement. She says, "Well, before I was able to bring to my mouth half of a cup of tea, and nowadays I'm able to bring the full cup of tea," right? "I feel more stable and more straight in my wheelchair. I've no choking episodes anymore. I'm now able to eat alone in the evening," because before I was just able to eat alone in the morning. Because of this fatigue and fatiguability that Basil described as an important unmet need, "I could not eat alone in the evenings. Now, nowadays I'm able, and I can write for a longer period of time." That's all minor improvements, but that are just game-changing for this young woman. The problem, as you might see, is that we are far off a cure, far off a, there is still a very significant unmet need. She remains certainly with a clear margin for improvement. 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's a very good responder. Can I have the video, please, by the way? He's a very good responder. He was a Type 2. He was not ambivalent. He was treated by nusinersen. Can you please play the video? Walks but not for a very long period of time, and he's a very good responders. You can see from the shape of the legs that he has a very, very significant muscle atrophy, right? Because in spinal muscular atrophy, there is muscular atrophy. Obviously, these two 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. That's why nowadays several drugs are developed, and drug of Scholar Rock is developed for the muscle fibers and to counteract 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. 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-in to what I'm about to talk about, which is hopefully bringing to light 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. 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. If we look at a subset here, which is children ages 5 to 7, and so we picked this subset because these are kids whom early treatment may have been available as the first FDA approved drug for SMA was approved in 2016. 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 measure, so caregiver or parent-reported measure. 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 improvements in motor function across these various years. You can see it broken down by children aged 5, 6, and 7 here in the table. Overall scores are showing a positive trend, and higher scores indicate better health-related quality of life. However, you can see that, as I've said, the maximum score of 100 is not being reached, so there's currently still much room for improvement in motor function here. If we look at that same five to seven age group, and we ask questions like: Is it hard for your child to use his or her hands? Or, Are your child's hands weak? We see the vast majority of parents and caregivers reporting that these are issues for their children. These translate into daily activities that you can think about in early childhood education, such as being able to hold a pencil or color with a crayon, or open food items at lunch in the cafeteria, and those sort of things. 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. Now I want to transition to adults, so moving away from kids, and this is self-reported unmet needs in adults with SMA. 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? 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. A 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 tasks in a job environment. The 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. Then you can see improving activities of daily living, that's 92%. 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. 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. 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. 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. I think if you look here from our recently held, well, back in August of 22, patient-led listening session with FDA on unmet need, these really kind of come to life. We have a teen 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. We have another adult affected by SMA who works in a laboratory setting, and she explains the importance of being able to move or lift something that weighs about the equivalent of a half gallon of milk in and out of the fridge, instead of having to ask for help to do that. She emphasizes that small tasks are huge successes in her life. Being able to maintain that function, to be able to continually do those things are really important to her. 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 forethought in the minds of individuals who are treated quite early as well. We have a mother of an infant who was treated prior to symptom onset, who's 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. 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 in function or maintenance in function translates to his daily living. I invite you to do this along with me. He says, "What seems like minimal gains in strength actually translate to exponential gains in functional ability." To illustrate this, I invite you to try a little experiment, and 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 at all because you have rods in your back to correct your scoliosis. Then he invites you to keep your elbows on the armrest of your chair and not lift them up because you don't have the strength in your arms. Now you have to try spooning food into your mouth. He's saying, "I bet you'll have a difficult time." He gives the thought experiment that once you've gotten used to that, you allow yourself to lift your elbows off the armrest 2 inches or so and try eating again. He says, "That might not sound like much, but you see that those 2 inches are life-changing." I think that's just a really poignant illustration of how these small gains in motor function translate into tangible improvements in activities of daily living for people affected by SMA. With that, I will turn it over to Dr. Jing Marantz, who's going to give an epidemiological update. Thank you so much, Jackie. I'm Jing Marantz. It's Chief Medical Officer at Scholar Rock. It is my pleasure to share the updated 36 months data from TOPAZ. As Doctors Darras Servais in Jackie Glascock highlighted earlier, the SMA field has seen significant progress. The three 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. 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 proform of myostatin in the skeletal muscle, thereby promoting muscle growth and consequently muscle strength and function. The upstream targeting of the proform 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 a clinical setting as I'll show you later. TOPAZ is a proof of concept phase 2 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 non-ambulatory 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, the more motor neurons they may be preserved, the greater the potential for these patients to benefit from a muscle-directed therapy, since muscle atrophy occurs from denervation of motor neurons. The primary endpoint for the study were mean changes from baseline in motor function, as measured by Revised Hammersmith or RHS, for the ambulatory patients in cohort one, or Hammersmith Functional Motor Scale Expanded, or Hammersmith for short, for the non-ambulatory patients in cohort two and three. I will focus the remainder of the presentation on the non-ambulatory patients highlighted in the orange box, as this is the main efficacy population in our pivotal phase three 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 non-ambulatory patients with type 2 and 3 SMA, ages 2 to 12, the main efficacy population being studied in our pivotal Phase 3 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. Note that greater than 80% of the patients have achieved at least one 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. After approximately 15 months, the Hammersmith score started to plateau, as Dr. Servais has highlighted earlier. Specifically, the Hammersmith score between 15 months and 4.5 years is within a band of one 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 plateauing is also observed. An important point to note is that TOPAZ patients enrolled in the study with a mean of two 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 seen at the 12 months, would most likely be attributed to apitegromab, based on the natural history of patients already entering the plateauing phase on the nusinersen treatment journey. To further strengthen this point, we also analyzed 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 two. 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, two patients dropped out due to COVID. The other five 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 non-ambulatory population highlighted within the orange box, of the 35 patients who started the trial, only one dropped out due to COVID. Therefore, well over 90% of the non-ambulatory 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 non-ambulatory 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 non-ambulatory population, age 2 to 21. On the right is the subset population, age 2-12, 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 2-21 group and in the 2-12 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 lifting a cup. The improvement in RULM, seen at 12 months, continued to strengthen with time, was maintained over the entire 36 month period, both in the combined 2-21 group and in the 2-12 subset. Note that the RULM improvement continues to strengthen with time. For patients who are non-ambulatory, continued improvement in 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 two years of children's lives. These key development milestones are often delayed or not achieved in children with SMA. Achieving these major development milestones would therefore constitute robust outcomes in SMA Concorde 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 months, and 36 months. The green checkmark 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 gained milestones temporarily and then lost it. However, if you look at the bottom panel, patients receiving 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 patients achieved 4 new milestones, and two of these patients were able to walk independently. These data are striking, taking into account that these patients were 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 a 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 assess 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 PROMIS 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, suggest that the improvement are not likely associated with apitegromab. With over 3 years of follow-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-emerging adverse events were mostly mild to moderate in severity, and generally consistent with underlying patient population and the background therapies they received. Importantly, there were no deaths or suspected unexpected serious adverse 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 non-ambulatory 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 phase 3 SAPPHIRE trial. Based on the success and insights we learned from TOPAZ, the SAPPHIRE study was initiated last year and is on track to complete enrollment by Q3, as Jay Backstrom pointed out earlier. The key learnings from TOPAZ were integrated into the SAPPHIRE design, as you can see on the right. The SAPPHIRE study is designed, as you can see on this slide, based on the learning gained from TOPAZ, and importantly, in close collaboration with both the FDA and the EMA. Patients with non-ambulatory Type 2 and 3 SMA are randomized 1 to 1 to 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-targeted therapy. Based on this notion and our exchange with the regulatory authorities, we included a cohort of patients aged 13 to 21 as a predefined subgroup for the SAPPHIRE. Patients who complete the 12-month treatment period of the SAPPHIRE study have the opportunity to enroll into the ongoing ONYX 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 Medicine. 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, 'cause 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, 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 aside 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 adrift until I did the next rotation in pediatrics. I encountered a baby with Werdnig-Hoffmann disease. Sit up all night with the baby and the mom. Next morning, tried to present to the pediatricians on rounds. 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. That set me off and said, "Interesting." My journey was that I did a child neurology residency, 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. In the afternoon, afternoons, was working on figuring out how to best care or how to best play a losing hand. We did that for the better part of 20-25 years, learning how to measure the disease, how to establish the best care guidelines. All the things that were necessary to be able to set up a good clinical trials. You know, I was aware of the value of science, that if you can't measure it, then you can't make progress. There's also the problem of what does it mean? This 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. I was a little bit perturbed that I kept saying, you know, 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 muscle are denervated, and the other half are normally innervated. We know that myostatin inhibition works well on healthy muscles otherwise. We have the opportunity to treat muscles that are not otherwise confounded by a disease. 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. 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 were a bunch of other confounders. 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. Not alone, but I was among those that tried to encourage them to do SMA. We designed this pilot study that had three different groups that were sort of designed to see where the signal would be in the course. Obviously, we were incredibly pleased that with these small trials, unblinded as it 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. This is my patient journey slide. Sorry about that. I, in addition to being the lead for the overall study, we also did a site here with Dr. Nance being the PI here, and we followed four kids that had SMA. Here we sort of switched to say, "Okay, what's data for the overall group?" There's, there's information to be had in stories, even though stories aren't truth overall, they do tell something about what's going on, it underneath it. Here's the four 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. Over the course of the therapy, she clearly gained things in her ability. She tells me that, you know, was stronger. She's a real pluckish young woman, and she was able to identify things that she could do. On the other hand, over 24 to 36 months, her scoliosis went from, you know, subtle to, I have to point at it like this, subtle to worse and worse and worse, to the point where she had to have a scoliosis surgery. That means putting a rod in your back. You heard about that. It makes it very difficult to be able to do anything when you can't move your, your trunk and move around to be able to accommodate things. As a consequence, she took a real hit in the especially the lower extremity, the Hammersmith things, a little bit in the RULM things as well, because it's again, you can't help with moving your trunk as a consequence. Yet she is enthusiastic about this therapy and really wants to be continue on it, but it's in a different way. The other 3 kids were 4 and 5 when we started with them, 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 a 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. Underneath that are stories that don't show up. He will tell you that, "Before I started this, if I was pushed over..." Actually, his mom would tell you. If he was pushed over in the wheelchair, he would have to scream at his mom to say, "Pick me up." Now, he can recover himself. In fact, he can now lean over and pick up something that's, you know, on his legs or off the side, and use his trunk to be able to get back up. It's an extraordinarily meaningful thing for him. Just recently, he's starting to be able to slide his bum on a, on a slidey board. We put a real slippery board from 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 him 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. Transferring is akin to independence. We're seeing him progress, even though it's below the measurability of things on these the RULM and the Hammersmith outcomes. You know, another case, probably the most dramatic one I can imagine, is a kid. He was five years 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 then another step for about four or five steps. With the advantage of this therapy, you know, 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 RULM, a little bit weaker than that way. That means that he can, you know, 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. You know, in his case, it's measurable and meaningful. Now, you know, I want to sort of pause a little bit and say: Well, what did we get from stories? It's probably, I think, important to realize that words are slippery and I've long debated, you know, 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 a change is likely to be meaningful from the standpoint of statistics. You know, all these words are fungible. They're slippery. When they're applied to groups, when they're applied to overall groups and data, they mean one thing. When they're applied to individuals, they maybe mean something quite different. Einstein was famous for stating something along the lines of saying, "Not everything that counts can be counted." I'm impressed at how the word significant sometimes means different things depending upon how you use it. You analyst types are gonna know about, you know, statistical significance. If you can get a measurable difference, then it's called significant. 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, a measured meaningful thing in groups is not the same thing as a meaningful in the experience. To highlight that story, I... 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 are growing older a little bit since that time. 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, one of the, I just hearing today's presentation, I realized how many of the patients are going to school, how many of them are going to 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 the average 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. They do things with what they've got. Anyway, this woman was a special ed teacher. She eventually found her way to a having a classroom, a locked classroom, where she has eight boys who were expelled from school for disciplinary reasons, many of them in the criminal system. She's in a locked classroom by herself. You know, I say, "You know, aren't you afraid? How do you do that?" She says, "Well, how can they threaten me?" She has a point because she's pretty intimidating. 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 her personality, which is substantial. 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 and come around and discuss what's going on. This went on for several years. This is way before the time of nusinersen, by the way. Then she came to see me for her annual follow-up and says, "Dr. Crawford, I'm disabled now." I'm thinking: What the hey are you talking about? Just now? You haven't been able to move hardly anything at all all your life. What's now? She said, "Well, actually, this finger doesn't move anymore." Well, probably has one motor neuron. "That finger doesn't move anymore. So now I can't put the feather in my fingers. Now, when I have the feather 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." 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 below the threshold. What's remarkable is that all four 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. 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 gonna turn this to question and answers. For those that have submitted questions, we're gonna go through those now. As you can see, we thought the main focus should be on our guests this morning. 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. An important question, and we're gonna kinda go around the table here with our experts. An important question we get asked about the TOPAZ data, you saw Jing had walked through that, is whether the gains seen with apitegromab could be attributed to nusinersen. Right, based on your experience in the clinic and considering that the average patient in TOPAZ had been on nusinersen for more than two years before receiving apitegromab, you know, how did you interpret the TOPAZ data as the investigators on the study? Maybe I'll start with Dr. Darras first, then, Tom, we'll follow with you. 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 following reasons: It's not just the statistics, but in the clinic, when our patients come into the clinic for a follow-up, you know, we ask them how they're doing and, you know, on nusinersen and you know, are they still improving and so on. I have treated around 100 patients with 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. The vast majority of our, of my patients say that, "I was improving for a year or two and since then, being stable. I'm happy with the result, but I haven't seen any more improvements. I have plateaued." This keeps happening on and on. Every 6 months, a year, when I see them back, this is what I hear. This is very, very consistent with that stabilization curve that was presented by Professor Servais. I think that given that you end up with stability long term with nusinersen and perhaps risdiplam, you know, all these new increases in this course or some of the things that Dr. Professor Crawford described are real and probably related to the addition of apitegromab. Yeah, very nice. Dr. Crawford, what was your view? Again, you have data for groups and stories for individuals, and both of them are compelling. I think it's probably worthwhile. You know, we had such a dramatic result, response in the the 12 and unders who were on the higher dose. The 4 points stands way above the the curve that we would have seen previously. Actually, I'm not giving up on that there may be a treatment effect in the other areas. If, if you look very carefully at some of the slides, one of the ones that Dr. Servais showed, you know, the Hammersmith would decline in the older kids who were treated with nusinersen, even though we think they were probably stable. The reason for that probably is that they're accumulating complications. You know, once you start to have a little scoliosis, it's like chopping a tree. It goes, timber, and eventually, you know, 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 Tolstoy. There's a bunch of stories for how things can go sour. There's only one way you can gain something, and that's when you have more power. That's the slide that shows improvement in milestones, you can't fake that. That's the things that... Even though it's an unblinded study, you can't fake the fact that they're doing new things. Now, you know, it was not everybody got new things, but not everybody was at the cusp of the next milestone. Many of those things, those folks were encumbered, like my case number one, by internal constraints that would prevent them from being able to take the next step up. With all the, you know, 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. Thank you. Professor Servais, there's a related question. You touched on this when you were presenting the SHINE data. For children under two, 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 timeframe may be different. For those under two, what would you expect to see? What's your experience in terms of a plateau effect? It's a great question because actually the data I've shown were, data from SHINE, and in SHINE, patients, were at the minimum two years old when they started nusinersen, right? The patients were two years old when they started nusinersen and reached a plateau, during the 3rd year of treatment, according to which outcome you contribute. Patients who started, before, will probably reach that plateau later. If I want to push the envelope, patients who start the treatment at birth will probably not reach a plateau, right? It means that the moment at which patients reach the plateau, between zero and two years is somewhere, between never and, two or three years later. The closer you are of birth, of course, the later will come the plateau. In practically, in practice, patients who are actually identified those symptoms with type 2 are best case scenario, treated about the age of 10 months, 11 months. We see these patients progressing very significantly during the two or three first years of treatment, 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, it mostly depends on the exact age. As you might imagine, there is a huge difference between patients who start at birth or patients who start at the age of two years. The plateau will come on at very different age, according to that treatment age onset. Okay, very good. Again, that's kind of putting the TOPAZ data into context where everybody came on two years. You know, we reported our 36-month data. We've seen these gains, we've seen it continue. Again, it's basically on, you know, 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, 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? I mean, maybe Professor Servais, you can start if you've had 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. Roche, did not present the long-term data the same way in terms of stratifying the patients and showing the, let's say, the two to thee, the three to four, and so forth and so on. 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 a, an interesting drug because it can also directly affect muscles, and with potential, but this is highly theoretical, of treating the absence of a SMN protein elsewhere than in the motor neurons, which could make even more sense in the context of an anti-myostatin drug. 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, one year. We have less years of follow-up because risdiplam came on the market later. The patients I started to treat, let's say, two years ago and were at that time, let's say, one year ago, are today three years, and they are doing quite well, they progress. We see the trajectory. These patients will reach a plateau sooner or later. I would anticipate that it will not be massively different of patients on nusinersen, to be honest. Mm-hmm. 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, a huge amount of experience with risdiplam, at least, the time-wise, because it was approved in August 2020. What I've seen so far is the younger patients, particularly under the age of five 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 two or three years. That happens within a period of time, which is less than one year. With older patients, I see stabilization for a while. If these older patients improve after apitegromab, you would think that that gain is related to the inhibition of myostatin. Okay. Very, very good. So- I mean- I'd like to jump in on that. I'm fond of saying that, you know, if you don't have data, it's just opinion. I'm not certain I trust my opinion. I trust my opinion for deciding what experiment to do next, but I don't know that I wanna pitch my opinion as meaningful. On the other hand, sort of a snarky rule is, if you don't have an answer, change the question. As a philosophy, it's always ask the bigger question. 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 two copycats. The three copycats seem to be normal, but the two copycats, which are 65% of the population, are not achieving milestones at the normal age. The older they are, the more we realize that the gap between them and normal is evident. That clearly means that there's a market, if nothing else, for SMN, for, muscle-directed therapies like apitegromab. Of course, the larger, 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. Yeah. Very, very good. I mean, that's a really nice frame of reference, and actually, that segues very nicely into another question we've received. All right, so we're, you know, starting off by we have the TOPAZ data that informed SAPPHIRE, you know, that whole disentangling, if you will, the nusinersen plateau effect consensus that these changes really were certainly not related to that. Now we're looking at SAPPHIRE, and really, the question that came in to us is, you know, 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, you know, apitegromab into your care for patients, right? Assuming that we show the success that we expect to in SAPPHIRE. You know, maybe we can... You know, just kinda going around the horn. You know, I think, Tom, you just said, "Look, there's still need." You know, maybe you can start, and then we'll go to Dr. Darras, and then circle back to Professor Servais. I was hoping to let those guys talk first because I haven't figured out what I would say. Yeah. Um- I can talk first. Go for it. That's why we have a roundtable discussion. You're allowed to defer. It's okay. Yeah. Go ahead, Dr. Darras. Yeah. I think that if the SAPPHIRE study shows positive results and gets approved, many of our families will be asking for the treatment. The reason is that when you're talking about the symptomatic population, all three treatments are not a cure. We have a huge unmet need in that area. Even after, let's say, they go from nusinersen to risdiplam, you still have a lot of deficits like the ones that were described by the families in my presentation, which need, which require or they need to be addressed. I think apitegromab will probably be the obvious choice in those cases. We have the population of newborns who are diagnosed by SMA, as you know, about 98% of the babies with SMA are now detected at birth because of widespread newborn screening. As Dr. Crawford said, many of these babies can be symptomatic. Talking about the vast majority have two copies of SMN2, as many as 40%-50% of those babies may have symptoms. They're symptomatic at birth. They're not presymptomatic. When you treat them, let's say with gene therapy, which seems to be the most commonly used intervention in this population of patients, that many of these babies end up with deficits. We don't prevent SMA in the population, and the families come back and say, "My child continues to have symptoms. He has developmental delays, he's not progressing well." I think in that population, apitegromab, I think, would be a very good option. It wouldn't be very different from what do we do in conditions like epilepsy and cancer, we have polytherapy. At the end, I think we're probably using not just one, maybe not two, perhaps three interventions to treat our patients with SMA. Very good. Professor Servais? Well, I would say that they, for me, there are two populations today. The first one, which I call the prevalent population, which are the population that is born after newborn screening or in countries where newborn screening is not yet widespread, who are born nowadays, and the new patients. In the prevalent population, we have only patients with unmet need. I think they, at the bare minimum, I would give a try in every patient I'm allowed to try, and probably under the control of a very clear predefined objective with my patients. As Tom rightly mentioned, it's very difficult to define a responder on the basis of a, of a figure, on the Hammersmith on any scale. The most important is for the person that you treat to achieve the objective that you and this person feel reasonable and achievable in a certain time frame. That would be my position for the prevalent populations and for patients who are identified by newborn screening. I would, of course, treat them at first with a disease-modifying therapies acting on the SMN2, and then just follow them carefully and as soon as these patients diverge of the normal developing newborn, I will probably start the treatment with anti-myostatin. This could mean never for patients with 3 copies treated soon. It could be very soon for patients with two copies, especially those who present already mild sign, at birth, because we know that these patients, very none of them will, for instance, walk at the age of 18 months. Yeah, very interesting. Very good. Tom? I got a chance to think about what I could say at this point, and I'm not gonna speculate about what is truth because, you know, we have science to be able to decide that. I do think there may be some purpose to speculate about how humans, and particularly regulators, deal with the data that we have. You know, the unblinded trial we have so far has this dramatic response in the youngest, weakest, and it tails off when you're older and ambulatory. I'm not giving up on those folks at all because looking under the cover, we realized that part of the trial was really burdened by complications, by the scoliosis, by the fact that the monotherapy patients couldn't get onto a disease-modifying therapy and stay in the trial. It would make sense that they would want to drop out, so the ends would drop off. There are a whole series of reasons why we may not have seen a biological effect in the older ones. What will the regulatory agencies do with that data is something you guys are probably more expert at than I am. I do know that the drug has been safe across the range. There doesn't appear to be any safety signal, which is just dramatic because the previous, more, messy myostatin inhibitions had toxicities. By targeting here, it seems that we're able to clear it out. On the balance of safety versus benefit, might suggest a broader label. Again, it would be. We'll see what we're allowed to do in after the data come in. Yeah, well, that's interesting. Everybody will want it. Yeah, come back to me. Let me make a couple comments because I think there's some really, really salient points that were just made. You know, as I mentioned at the beginning, we are in the planning stages for doing some additional follow-on studies, one of which is the under two population. Professor Servais, your point about getting experience into that and maybe the timing of when we can introduce an anti-myostatin therapy relative to the need for those under 2, for those listening, we're in the planning stages for that. I think for the ambulatory, Dr. Crawford, I completely agree with you. I don't think that we have more opportunity there, we're certainly working into that. I think there are ways for us to demonstrate that, we'll continue. If we go back to the question, which is around Sapphire. Sapphire, we have 2 to 12 as our main efficacy population. We've also included the 13 to 21, and we've called it an exploratory group, and I would describe it more as a predefined subgroup within the entire data that we're generating. I think as we're looking about what FDA and others would say, it's gonna be a function of the consistency of the data across those groups. I think in the end, you know, we're studying the non-ambulatory, and that would make sense to me from a regulatory perspective of that would be type of the clinical trial data that support the indication, but also to have it across the age range from 2 to 21. Frankly, I had a question that came to me is: If someone's now 20 and they're turning 21, and they're getting benefit from an anti-myos like from apitegromab, would you continue to treat them into 22, 23, and beyond, right? I think you would continue the therapy if, in fact, they're gaining benefit independent of the age. Right? That's a bit of the kind of the real-world use. We have a question on the scales, right? This has been, you know, I think, really nice review of this. And Dr. Darras, thank you for describing the extended or expanded Hammersmith. You know, what we saw in our data, and this is a question that has come to us. We saw that on the extended Hammersmith that we are certainly maintaining that effect, right? We heard from Dr. Glascock that that's really important to patients. Where it, there's a suggestion that on the Revised Upper Limb Module, that we're seeing some continued benefit, including, you know, for those, particularly those that were in that 2 to 12 range. How do you see these scales and the concordance and the ability to maybe see some additional improvement on one versus the other? Maybe I'll start with Dr. Darras to introduce the scales, and then we can kind of go around and see what you think about those different scales. Yeah, I mean, I will start by saying that the scales are not perfect. I think we tried to eliminate the floor and ceiling effects of the original Hammersmith scale to be able to include weaker and stronger patients. Despite that, neither HFMSE or MFM32 are perfect scales because they do not necessarily capture the whole range of improvements, like the ones that Dr. Crawford described in his presentation. The other thing is that the Revised Upper Limb Module scale is more suitable for patients who have, for example, SMA type 2. I think it's quite sensitive, and this is why it has been used widely. These scales have been very useful during the execution of this, of clinical trials. When it comes to everyday life in the clinic, these scales do not necessarily capture everything the patients report, the improvements that they have. I similarly had a patient who told me that, "If I lose the ability to use my index finger and thumb to drive my wheelchair, I'll be destroyed because I won't be able to go around and have the life that I have now." Something like this is not captured, and this is why there is value into using the patient-reported outcome measures that are used during the TOPAZ are using it during the SAPPHIRE trial, or the trial, like PROMIS, that measures fatigue, another major complaint of our SMA patients. Okay, very good. I think we can go on then to another question that we have coming in, I think it really relates to... Well, we had a question about, is there biomarkers that we've included in our disease assessment? I think, you know, we had talked about, Jing had reviewed beautifully. You know, we went straight to the clinical measures in the TOPAZ trial. I think there is obviously some interest in biomarker work, and we'll certainly incorporate that into some subsequent studies. Just to answer that question, I think I'll take that one myself. There was a question, though, which is interesting, and again, this goes back to the scores. You know, if your baseline expanded Hammersmith, right, where you have come in, and how that potentially affects the ability to discern a difference with intervention, right? The sort of baseline Hammersmith. I think, you know, we talk about we have some minimum expectations for the Hammersmith in terms of what you can expect to see, but from your experience, you know, the kind of effect size that we could see, how is that affected by the baseline Hammersmith scores? Well, I can take on that a little bit. You know, these ordinal scales, where, you know, 1 to 40 or 1 to 66, is our best attempt to try to come up with milestones or markers that represent the disease across its range. In the pre-DMT therapy years, we spent a lot of time trying to modify the various Hammersmith suite outcomes to see if we can get these numbers to be relatively even spaced across the range. Who's to say that the difference between a, you know, a 5 and an 8 is the same thing as the difference between a 15 and an 18, or between a, you know, a 25 and a 28? From a biology standpoint, I'm thinking: Okay, how many motor neurons, how much contractile protein mass does that represent? It may be a completely different thing. Obviously, which of those things would be amenable to a change in contractile protein mass as a way to influence function? I can't emphasize enough how once you develop certain complications, it puts a ceiling on what you can accomplish. If your back is rigid, as been mentioned, that means you can't do a whole lot of things, like roll over without having a big power folder roll the whole thing. You can't do it bit in sort of an inching way of one after another. If your, if your legs are contracted at the hips and knees, there's no way you're gonna be able to stand, because the amount of power necessary to keep a knee or a hip straight, it requires much more if you have even subtle contractures. These are things that are gonna be dragging people down, especially in the Hammersmith. Older people with Hammersmiths have more confounders that prevent them to do it, where the RULM probably is less confounded by the usual things that people with SMA encounter, although not completely. I do like the fact that the RULM seems to be showing benefit over a longer period of time. I'm not surprised that the Hammersmith is sort of tailing off because of the group difficulties with confounders. All right, very good. It's really important. 'Cause, you know, I've said this to others. I mean, I'm always intrigued by the Revised Upper Limb Module. I think it does isolate. I think for non-ambulatory patients, this strikes me as something that would be important to continue to see. I think what you just described is, you know, help us understand a little bit why one measure shows that and another doesn't, which is really good. We have another question. I think, you know, we set the stage today, I thought, very nicely by looking at what has been achieved with the SMN-targeted therapies, whether gene therapy or the up regulators. We talked a little bit about what we can potentially expect for now those that are newly diagnosed. To tie into what looks like a very thoughtful strategy of targeting myostatin therapies as well, right? Can we lift and move beyond the SMN upr egulators? It's really looking at what are you anticipating? You know, are we achieving a threshold? Can we expand even further with targeting the muscle, like with an anti-myostatin? You know, it's almost looking to the future, but it's also tying to mechanistically what we potentially could expect. You know, maybe I'll start with Professor Servais. As you think about sort of that combination therapy, you showed that really poignant video of the young man who was treated fairly early, that still looked like he had significant muscle atrophy. You know, if we're thinking about our ability to move that, can we move him beyond? That's what we're hoping for. Obviously, we'll need to measure that in clinical trials. It's really a question around that strategy and maybe your views on that. Well, I think that any strategy to fight spinal muscular atrophy has to start with newborn screening. I mean, that's the very first thing, right? Not forgetting the current prevalent population, but the future is a population mostly issues from newborn screening. As Tom Crawford said in Basel also, some of these patients are normal, but not all. We know that about 40% of patients with two copies of SMN2 have symptoms at birth. These patients will not be normal even if you treat them immediately with gene therapy. The same also applies for some patients who appear to be normal with two copies of SMN2. Which means that's certainly the place in the future of anti-myostatin trial. When we look at these patients, when they are three, four years old, they have muscle atrophy. We also know that the myostatin level is much higher in the younger age. Probably it's at this age that we have the best chance to be efficient. These patients actually complain of often than not. They are happy, of course, to be able to walk, but they see their limitations. They've never experienced being in a situation that is worse, so they are not, you know, in this human experience of improving. They just see the difference with their pair. That's, I think, the best indication in the future. Again, I mean, the anti-myostatin for me is, has, needs to be understood in the context of treated patients with another treatment and in context and in the future in patients identified by newborn screening. very good. Dr. Darras. I'd like to go to a different place on that one. We haven't talked at all about, you know, what I spent my mornings doing, which is the science of motor units and motor neurons and how you move things around. What's characteristic of kids with SMA is that they do get larger type 2 muscles. They hypertrophy the innervated muscle fibers, where the denervated ones atrophy and melt away. But not all of the type 2 high strength, early fatigue muscle fibers increase. In fact, more, vastly more don't respond to that kind of strength, strain by hypertrophy. In a, the chief effect of myostatin is to increase the contractile protein mass within innervated fibers of a type 2 or high, high strength, early fatigue characteristics. That's where people with SMA are, you know, most impaired, where they have the greatest need. It does appear as though even in the, in the conditions of some early work by electrophysiologic work by Michelle Farrar in Australia, demonstrates that there still is a substantial population of muscle fibers that are that are small. It looks to me from a, from a pure biology, here's the speculation thing, that there's a potential to be able to affect folks even after a DMT is well established. Mm-hmm. Very good. Very good. I mean, that really is right on point to the question that came to us mechanistically. Thank you for that, Dr. Crawford. Dr. Darras, I'll give you last opportunity here. I think we're coming up with the- Yeah. close of the Q&A, but any additional thoughts or comments, Dr. Darras? Yeah. I really. Sure. Please. Sure, Jay. I would like to amplify on what Laurent said. At least the United States and pretty soon in Europe and other parts of the world, we're gonna have a diagnosis made at birth, so by newborn screening. What we've seen so far, and, I mean, newborn screening was initiated in Massachusetts in January 2018. So we have, you know, a number of years of experience. When we have these symptomatic newborns who do not respond, well to SMN-directed therapies, and I would say most frequently now is gene therapy. It doesn't take two, three years to see it. Within a number of months, 6 months, 7 months, the family will come in and say, "My child is not progressing well as I was hoping." At that point, they ask for another SMN-directed treatment. If the child receives gene therapy, we add nusinersen or risdiplam. Even with those treatments, the results are not spectacular, I have to say. There continues to be unmet need. There will continue to be unmet need, even with combination therapy early on. If on time our study, a drug like apitegromab is found to be effective, it would be the obvious choice to try. Most probably in combination with an SMN-directed treatment. It's just a matter of proving that it works. I think if it works and gets approved, it's gonna be used widely. Well, I think we can close on that final comment there, Dr. Darras. What I would say for those listening, first, my sincere thanks to Dr. Darras, Professor Servais, Tom Crawford, and Dr. Glascock. I mean, honestly, we really wanted to kind of put everything into context today as a refreshing reminder of the disease. I mean, I'm left with clear understanding that there is continued need. I think we need to keep pushing hard on apitegromab. Hopefully, that'll be an option for you to consider once we get through the trial and get the regulatory results. Honestly, thank you for the review. For those that dialed in, really appreciate your interest, and I think, again, we're gonna use this as a close. Thank you all again this morning for being part of this presentation. We'll close the call.