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

All right. We'll get started. Good morning, and welcome to Investor Day. I'm Rushmie Nofsinger, Vice President of Corporate Affairs and Investor Relations at Scholar Rock. On behalf of our team, I'd like to thank you all for coming. We appreciate those of you calling in, and those of you who took the time to spend your Wednesday morning here with us. And we're thrilled to be here today to highlight our exciting myostatin inhibition programs in SMA and obesity. Before we begin, I'd like to point out that we will 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. 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. I encourage you to go to the Investors and Media section of our website to find the most up-to-date SEC statements and filings. A recording of today's event will also be available on our website should you want to rewatch at a later date. It is my pleasure to introduce the members of the Scholar Rock team who will be presenting during today's event. I am joined by Dr. Jay Backstrom, President and Chief Executive Officer of Scholar Rock; Dr. Jing Marantz, our Chief Medical Officer; Tracey Sacco, our Chief Commercial Officer; and Mo Qatanani, our Chief Scientific Officer. We are also very grateful to have 2 accomplished guest speakers with us today. Dr. Diana Castro is the Founder of the Neurology and Neuromuscular Care Center and the Neurology Rare Disease Center. She is a board-certified neurologists and neuromuscular physician and a pioneer in the research and management of patients with spinal muscular atrophy and other neurologic diseases. We are also joined by Ania Jastreboff, who is an associate professor at the Yale School of Medicine. She serves as Director of Yale Obesity Research Center and Co-Director of the Yale Center for Weight Management. Dr. Jastreboff is trained in both adult and pediatric endocrinology is an obesity medicine physician scientist and an international leader in the research and clinical application of anti-obesity pharmacotherapeutics. She also serves as a member of the Board of Directors for the American Board of Obesity Medicine. Thank you so much for being here and sharing your knowledge and experience with us this morning. Moving on to our agenda. After some opening remarks from Jay on Scholar Rock's vision and strategic overview, we will move to Part 1 of today's event, in which we will discuss our progress to date and future plans for apitegromab in SMA. To begin, Dr. Castro will speak to the patient journey for those living with SMA. Then Jing will present on our development program for apitegromab. To close out the first half of our event, Tracey will discuss our commercial readiness activities, and then we will turn to a question-and-answer period. Following a brief 10-minute break, the second half of our event will resume around 10:15 and focus on our cardiometabolic program. Dr. Jastreboff will first provide an overview of the treatment landscape and the importance of preserving lean muscle mass and obesity. Then Mo will speak to our differentiated approach with SRK-439. Finally, Jing will present on our cardiometabolic development program. We will then take any remaining Q&A. The day will conclude with closing remarks, and we look forward to spending more time with those of you who will be joining us for lunch afterwards. As you can tell, we're very excited to share Scholar Rock's accomplishments and future opportunities with you. I will now turn it over to Jay Backstrom, our Chief Executive Officer, to kick things off. Jay?

All right. Well, thank you, Rushmie. And let me extend my welcome and good morning to you. We've got a very full agenda. We're very excited about our programs, and we're delighted that you're here with us today. At Scholar Rock, we're a global leader in harnessing the life-changing potential of TGFß1 biology with a mission to bring new possibilities for people living with serious diseases and we're on the threshold of doing that with people living with SMA. What you'll hear from us today is how we're advancing on our journey towards commercialization of apitegromab. And our excitement around SRK-439, our highly differentiated, very selective anti-myostatin program for obesity. But of all the information you hear today are 3 things I'd like you to leave with. Selectivity is the key, it's the hallmark of a differentiated platform that we've taken our strategy and areas of large unmet need with both SMA and obesity representing significant potential revenue opportunities. And we're positioned for success. We have an experienced team who has been executing on our strategy and our goals. And the next 12 to 24 months of execution is expected to be transformative for us as a company. For my portion of the presentation, I'd like to review the pipeline and how we see creating value from that pipeline, then focusing on our muscle-targeted franchises road map for value creation. And then finally, a glimpse or our view of the road ahead. But it starts with selectivity. Selectivity is the key to safely harnessing the therapeutic potential TGFß1 superfamily of growth factors. Traditional approaches of targeting the mature growth factor have been challenging due to the structure similarities of the growth factors and led to unwanted toxicities such as bleeding. At Scholar Rock we're [indiscernible] on a way to overcome that challenge. And as a result, we identified the right target which is the pro or latent form of the growth factor represented by the cage where we can target it with exquisite selectivity and we hit it at the right time prior to the activation of the mature growth factor. When applying that strategy to myostatin, which you're going to hear from Mo and Jing, we hit myostatin and only myostatin, and as a result, as demonstrated in our TOPAZ data, we have unparalleled safety with now over 4 years of patient experience. And in addition, and importantly, we're the first to demonstrate functional improvement by targeting myostatin. So we've succeeded where others have failed. We've that selective approach to our pipeline, and we've created a portfolio of pipeline and high-value therapeutic areas with validated targets such as myostatin, but also TGFß1, which plays a significant role in immunosuppression as well as in fibrosis. But in addition to that pipeline, we've expanded the pipeline over the last 12 months, bringing in SRK-439 into the cardiometabolic space. But in addition, the research teams are focusing on a new muscular program, driving that to development candidacy as it can add them to our portfolio of products as we're on the threshold of building out a neuromuscular franchise. So very, very proud and excited by the work that the research teams are doing. So we've built the pipeline. We've expanded the pipeline. But importantly, in our business, we've executed and advanced the pipeline. We have brought across our projects, driving them toward very important developmental milestones. We look forward to the readout of our Phase III study in SAPPHIRE later this year, and I was very pleased with the team to announce that we've opened the enrollment for the EMBRAZE study in obesity. So very good execution. And while not the subject of today's discussion, I've been very pleased with the progress and the promise that we're seeing in our immuno-oncology program with SRK-181. It will be featured at ASCO for an oral presentation, and I look forward to a separate call to review and discuss those data. So now turning to our muscle-targeted franchise as an idea or a road map to how we see creating value with our diverse pipeline. Well, first and foremost, I think we're world-class at myostatin inhibition. We have an industry-leading portfolio, and we've applied that portfolio with apitegromab SMA, and SRK-439 into 2 distinct high value opportunities. The current market size for the SMA is $4.5 billion, so represents significant opportunity. And for obesity, it's estimated at $20 billion. But as you know, that number changes and rises constantly projected to be $100 billion by 2030. So 2 distinct areas, 2 high-value areas. But importantly, we believe we have differentiated products that can really make a meaningful difference. And you're going to hear from Dr. Castro later today, there is significant unmet need yet in those living with SMA. And we believe that we have an opportunity to meaningfully help them. So SMA is clearly a place that we want to be in. But if I think -- we think about the market and the opportunity, you're going to hear from Tracey why we believe that commercializing apitegromab on our own in the U.S. in selected markets in Europe makes sense. If you meet the team that's working on this, there's nobody with greater passion and this program couldn't be in better hands than in the Scholar Rock team. So we believe that we can advance that meaningfully to really make a difference for patients on our own. You compare that SRK-439, highly differentiated I think you're going to hear later today. We believe we have a potential best-in-class product here to preserve lean muscle. But given the size, scale and scope of the market, this is clearly a program that would be ideal for partnership. So our strategy from a diverse pipeline is commercial where we believe we can do it on our own really well, highly effective with passionate teams that are driving to success and to improve outcomes or to benefit from the power of partnership and other indications. So where are we? We've got powerful building blocks today from the foundation of the company from the platform, from the experienced team, from markets we believe we can immediately contribute in global rights across the portfolio. And those building blocks, we're going to leverage what will be a transformative period of time for the company as we become upon significant value inflection points. So what's next? We've got great momentum today, and the teams have executed on time or ahead of schedule for every program since I've joined the company. They are delivering and executing. And as a result of that execution, we are positioned to have some very meaningful and significant milestones coming up in the near term, starting with SRK-181 data at ASCO with an oral presentation. 3 weeks later, an oral presentation of the American Diabetes Association featuring SRK-439. The EMBRAZE study opened and enrolled ahead of schedule with SAPPHIRE data reading out Q4 this year, with potential launch Q4 in 2025. So great cadence of meaningful events. And in addition, we've delivered on things we said we were going to deliver. I said from the podium at the JPMorgan Healthcare Conference that we would spend time building out and developing flanking studies on the studies that can run as soon as we have SAPPHIRE data. The team have delivered on that. We've got an under 2 protocol and we look forward to starting in 2025. So really terrific momentum today, and that momentum will carry us forward. As I look at the next 5 years, the promise and the opportunity is extraordinarily bright for the company. 5 years, I see us a multibillion-dollar neuromuscular franchise built around apitegromab on a SMA and adjacencies. And what that means to me is that we will be making such an impact on patients. We'll get that to as many patients as possible because that's the mission. That's the mission. To create new possibilities for those living with serious disease. So that's what I see for us as a company. But the pipeline is going to continue to move. I see 5 programs in clinic, One of those is a neuromuscular asset that will build out our neuromuscular franchise, at least 1 partnered program in that 5 clinical programs and continued mining of our research team, there's more value that we can create. Our scientists can do more with TGFß1 biology. But considering we're world-class and antibody engineering, we can target things that are adjacent to our franchises. So enormous promise for the company. And so with that, from a world-class scientific platform, our vision for the company is a world-class biopharmaceutical company. We've got unparalleled selectivity, pay attention to selectivity in this space of TGFß1 biology, it matters. This is complicated biology. You interfere with signaling. There's a lot of things that can happen that you don't want to happen. Selectivity matters. We've got enormous opportunity where we stand with our leading anti-myostatin portfolio, a seasoned research team who is on a roll, we're a company on the move. And with that, I thank you for your attention. I'm going to invite Dr. Castro to the podium. We look forward to you reminding us of how much more there is to do for those living with SMA. So thank you. Dr. Castro?

Thank you. Good morning, everybody. I'm Diana Castro. I have been treating patients with a spinal muscular atrophy for more than a decade neuromascular specialist. And I want to give you today a little overview about SMA and about really the needs that we still have in this condition. So let me start with an SMA overview. I really like when I talk about SMA people to understand where is exactly the problem? Or do you have the issue in this condition. The brain communicates with the spinal cord and in the spinal cord, we have these cells called anterior horn= cells. They are nerve cells that really are the ones from that point, take information through the nerve, through the muscle. For them to work for these anterior horn cells to work, they require something called survival motor neuron. In patients with SMA with spinal muscular astrophy, survival motoneuron is affected. In this case, not only the anterior horn cell gets affected, but you can see in this graphic, where the nerve gets affected. And finally, the muscle will progress to get astrophy to get a weakness. So that's what happened in this condition. So again, not only the anterior horns cell is affected, but everything from that point on, it's affected. Humans, we have SMN1 and SMN2 genes. This is humans. For us, for most of us in this room, we have -- we really depend on when we call SMN1. Why? Because SMN1 produce this functional protein. It's 100% of functional protein that allows that cell to be alive and that nerve and muscle to work. And we have humans, we have SMN2 which most of the protein that produces is not functional. So again, most of us in this room, we don't really care about SMN2. But what happened with the patient with spinal muscular astrophy. They don't have SMN1. So they do depend on the backup. They do depend on this SMN2. This is the only thing they have left in their body. So because of that, because of the SMN2 copies the patients have, that is one of the determines of how strong the patient is going to be. So we have a, let's say, an all classification because now we have therapies that have changed the disease. So we have to call it in a different way sometimes. But what we have in the past is a classification from 1 to 4. Type 1. One was a patient usually with 2 copies of SMN2, so you are going to see the less copies of SMN2, the weaker the patient is, right? So a patient with 2 copies of the SMN2 will be a patient that is what they'll never able to see, never able to stand on walk. And a patient that will develop respiratory dysfunction and difficulties hearing. At Type 2, it's a patient with 3 copies of SMN2 usually, and they will call it the [ ceders ]. They will never be able to walk. A Type 3 is a walker, patients that were able to walk with 3 to 4 copies of SMN2, and Type 4 usually happens in patients that are around 20 years of age. What happened with this that is important to understand. If we don't treat them, they are going to progress so even if you're able to walk, you're going to the ability to walk, even if you were able to see, you're going to lose the ability to see. That's why it's so important to treat these patients. And there are all other modifiers. And I'd like to always mention the fact that we have siblings where one of them has a Type 3 and the other one has a Type 2 in the same family with the same genetics. So let me show you some videos to illustrate that. So like I say, SMA Type 1, this was a typical patient that I had to take care of in the past. So these patients will develop severe weakness from head to toe. Patients will be [ traded ] then [ G2 ] dependent. They could not move at all. And they develop these contractures everywhere because when you get a week, you get contract. Then you have a Type 2 who is -- it's a little girl who can -- is been able to see it, but you have -- you see already some of the difficulties she has with her arms. And the promise as she gets older, she doesn't get better. She gets worse. And then before I play this video, these brothers have been taking care of them since they were very little. And in this family, I can show you what I was telling you what this kid has SMA Type 2, so he was never able to walk. He's still not able to walk and then his brother has Type 3 who was able to walk. So you see it's an abnormal gate. And again, it's a patient that we tag if we don't treat, they are going to lose that capacity of walking. So let me tell you about the current treatment landscape and the unmet needs. So since we start treatment, I have been working on the research. I did pretty much all the research that was -- that took us to the place we are, where we have 3 therapies that are approved. And we have seen tremendous improvement. When I was telling you about classification has changed is because now we treat patients early, and they go from being what they were going to look as a Type 1. Now they look like at that Type 3. So now they can walk. So we have tremendous, tremendous progress. But what we see clearly is that patients respond better if they get treated early in life. As early as we can. So newborn screening has helped us tremendously because now we can diagnose the patients and treat them early. But what happened that is not perfect? And that's a point I want to make today that it's not a perfect, it's not perfect medicine. And what I tell all the families is I have to set the expectations is very clear. These are not cures. These are not perfect, and we still have to keep an eye on this patient as they go because they have difficulty. So what difficulties we still have, we have patients that have mobility difficulties. Patients that even though we treat early, they're still never able to stand up and walk. They were only able to get to be seating and use in their arms. They will get fatigue. So we have patients that tell me, I go through the day, I'm able to work, but then I get home and destroyed. I cannot do anything else. I cannot enjoy my wife, I cannot enjoy my children because my energy is completely going. Emotional difficulties, obviously, an educational and work difficulties because of other motor function. This graphic, the reason I included is because it's an easy way to see what I'm trying to show you. So we have a as core call, Hammersmith, the Hammersmith is core shows you -- we use it before we treat the patient, and then we're going to continue having this core through life. And what I want to see -- what I want to show you is that even in patients that were treated with nusinersen, the max point they get is around their 20s. So look at all of this space. We look at all the gap we still have. So the patient gets treated, the patient gets to a functional state, but there is still a huge gap of function that we're not reaching out. And the same is in these graphics. These were patients treated with nusinersen where you see the improvement, and this was patients treated with risdiplam where you see the improvement, but there is a plateau. There is a point where the patient says, I wish I could. I wish I was able to. I wish I was able to get through the day, I wish I was able -- I wish my son didn't come home. I had a temper tantrum because they cannot do absolutely anything else because they are exhausted. So this is where we have the opportunity. And when I say I am not satisfied, I'm not satisfied as a physician because I want my patients to get to their best because they still have a whole life in front of them. These are patients that are smart. These are patients that can have -- patients that are lawyers, patients that are bankers, patients -- all kind of professionals. So they actually quite productive people. But the treatments we have right now are targeting these area only, the [indiscernible] cell. The 3 treatments we have, the treatments are not targeting the muscle. And I think this is where we have the opportunity. Targeting the muscle will give us an extra point, an extra area that we can improve the patient's outcomes. Now let me show you specific cases where you're going to understand a little bit of what I'm trying to say. This is one of my patients who initially he developed completely normal until he was 8 months, but he was never able to stand up and walk. So we call it a [indiscernible]. So this is a type 2 patient with 3 cups. He was diagnosed, we started him on nusinersen 3 years of age. But unfortunately, when he was 3.5 years of age, he lose the ability to crawl. He was crawling already. But like I say, if you don't treat the patients are going to lose a function even sometimes of treatment, they are still losing function. So you see the difficulties is trying -- is getting to try to get to a rolling position, and he actually cannot do it. I had the opportunity to enroll them. I had the opportunity to enroll 3 of my patients in this study, in the TOPAZ study. It was very exciting because I had something else that hopefully, was going to be able to help them. And 6 months into the trial in the TOPAZ trial, when he was 5.5 years of age, he regained the ability to crawl. And I remember when I got this video from the mom, this was one of the most exciting days for me because, again, I get a goosebumps every time I think about that video because the mom said he regained -- he regained the ability to move around by himself, he regain independence. And I think that's where we have to go through. It's thinking about how can we push these patients to take the next step to be able to have a better life. And then a year later into the trial, he was also able to use a gate trainer. Again, this is huge because he has to go to school. He can live in school independently. He doesn't need to depend on anybody pushing him around and doing everything for him. He regained better trunk control. He had more energy. He has less fatigue. This is another one of my patients that I was able to include. This beautiful girl, she was 8 months when the parents start noticing again, she could not walk. So a diagnosed seriousness in 2 years of age. And what I want you to see and you see there are beautiful kids, all of them. I swear. Every patient is just -- they're gorgeous kids. But I want I want you to pay attention to is whenever she tries to bring this board up with her arm, you're going to see that she turns a little bit to the side, and she has to do this, right? She has sense other kind of muscles to be able to get to that movement. When he was -- I was able to get her into the TOPAZ trial. So she continued nusinersen, but then she got into the trial and at 5.7 years of age. This is really quick, but look where her arms are. Look what she does. So she's [indiscernible] So not only we're improving the function, but the quality of the movement. And now we're going to spend -- she's going to spend less energy trying to do this because actually, this takes more energy than doing this. So this is extremely, extremely important for a patient like this. I have a third patient that I was not able to include here because I'm on -- [indiscernible] share the videos, but I just saw him actually in the clinic last week. One of the biggest things for him was the fact that when he's laying on his belly, he's able to pick up his head. He's able to hold his head up, which is you will take that as -- we all take it as we're able to do these things. We don't think about picking up our head on doing this stuff. But for them, it's a big, big deal. So the last case I want to show you, it's a newborn because when I talk to the payers, when I talk to patients, when we talk to everybody, I want them to understand that now because we're treating them are, we're getting perfection. We're not, unfortunately. I hope one day we will, but we're still not there. In Texas, the newborn screening got approved in 2021 or it was included finally in 2021. I have this girl who came to my clinic at 6 days of life. Her physical examination was completely normal, but you will test it positive for SMA. I start her on treatment, she got on [indiscernible] on day of life 22. And on day on life 31, at a month of age, she start coughing and sounding gargling whenever she was getting fed. I sent her to the hospital. They did a video SOL study, and she did have difficulties swallowing. So it was clear that she could not take anything by mouth because you would choke and obviously die. So we put a tube on her. And then after that, she actually require a gastric tube. So again, she was treated extremely early. So it's not a once and done. It is one and let's see what happened. So right here, you see her where she is holding her head at 3 months of age. You see her with her little tube in there. So this is a normal time for this milestone holding head around 3 months. That's perfect. She was able to get her leg [indiscernible]. So you see her she gets definitely stronger. And unfortunately, the last one is not a video, but I want you to see is the hand of the caregiver right here. Because by 8 months, she was able to sit, but you were sitting just for a few seconds. So they always had to have somebody behind her because she will flop. By 6 months of age, you should be able to sit independently without any help. So it happened. I'm seeing her. She still has a lot of low muscle tone. She's in seating, but sitting for a few seconds. She's unable to roll. She's still eating only through the G2. She could not eat anything by mouth so I decided to address the pump at 9.5 months of age. And what did I get? I got, obviously, amazing milestones coming. So rolling over by 11 months of age. Then cruising, what cruising is just holding and walking, holding to something. And then finally, walk in by 23 months of age, but pay attention to the way she walks. Is this a perfect walk? No. Is this a perfect gate? No, it's not, right? So we got to an amazing point, but do we have a lot that we can work on? Yes. She still has faults every day. She gets tired. She cannot stand up from the floor without assistance, she cannot run. So what's going to happen? She's going to get to school. And that's where the point for me is a big milestone for children because you may have your child at home, you're not comparing to anybody. You get to school and then you see the difference between your child and the other kids, right? So how -- I'm happy? Yes. But I am not satisfied. I still want more. And I think the opportunity we have with this type of medication, which type of technology is huge. And this is just my summary. Again, advances, amazing therapies. We have amazing improvements. We have newborn screening, but the limitations are there, mobility activities of daily living, fatigue, and we have the opportunity to using another therapy like a therapy that can target the muscle. And I think that was my lesson and I will let Jing come in.

Thank you, Dr. Castro for a great overview and for the powerful patient stories. My name is Jing Marantz. I'm the Chief Medical Officer of Scholar Rock. I'm delighted to have the opportunity to give you an update about the apitegromab development program. 6 years ago, in 2018, apitegromab entered the clinic. Thanks to the patients, the caregivers and the study team, we're poised to really excited to take advantage of the years of hard work. And looking up at the upcoming milestones, we have 2 of them, very exciting. One is the top line readout in Q4 and then the upcoming launch in 2025. So what I'd like to cover about the development program is our 3 aspects. First is why we are confident that the pivotal SAPPHIRE study will deliver. And then I'll take you through the clinical evidence to date that speaks to the potential for apitegromab in SMA. And then lastly, what we have planned to further expand on the opportunities we see. There are 4 key elements that really underline our confidence. Top on the left, the differentiated approach of selective muscular astrophy, as Jay alluded to earlier, that has the potential to minimize undesirable side effect, translating that to the clinic where we saw in TOPAZ, substantial and sustained clinical benefit across broad SMA patients. And then leveraging that learning, we designed SAPPHIRE for success with the upcoming milestone we're all excited about. And then lastly, with 4 years of treatment, the safety profile remains favorable. Dr. Castro has articulated earlier, there has been a tremendous amount of progress in SMA. However, despite that, there is a lot of room for further improvement, and that is illustrated here. The 3 approved therapies, they target survival motor neuron, so we call it SMN targeted therapies. They address the motor neuron component of the disease pathology. What they do not do is to address the muscle atrophy that has taken place. This is where we come in. Apitegromab is designed specifically to bind myostatin and inhabits the activation of myostatin which is a negative muscle regulator. The upstream targeting combined with the high selectivity has the potential to minimize side effect. We've demonstrated this in a nonclinical setting in disease translational disease models. We now have also shown you that in a clinical segment. So here, we show you the Phase II TOPAZ data, these bar graphs represent motor function measures measured by Hammersmith on the left and [indiscernible] on the right. Hammersmith is a validated scale that measures motor function specifically designed for SMA. They really measure the ability of these children to either sit with one hand or move from one side to the other or standing with one hand. And each point on the Hammersmith increase means the child is able to do, go from like not be able to do something to be able to do something but help or to be able to do something with ease or with less difficulty as Dr. Castro illustrated earlier. And the [ ROM ] function really measures primarily the upper limb function. As you can see here, both outcome measures improved from baseline, what you see at 6 months and 12 months are sustained over the course of 36 months. So the third reason for our confidence is really the way that we design our study. We're the only company that has clinical data in hand when this occurred. And I want to point out 2 main aspects. First is the efficacy population that we -- that's part of the SAPPHIRE study reflects the population in TOPAZ with transformative potential. And the primary endpoint, which is Hammersmith at 12 months is the same as TOPAZ. The 20 milligram per kg dose was chosen based on sustained target engagement and a clinical benefit seen in the study. So in summary, the SAPPHIRE study is really optimized for clinical success, while at the same time, we're striving to be broadly representative of the SMA population that we're trying to serve. So here's the schematic. You can see that the Type 2 and 3 patients are randomized 1:1:1 to 2 dose levels of apitegromab and to placebo. And the patients are stratified based on the age at which they initiated the SMN targeted therapies or the type of SMN therapies, either nusinersen or risdiplam. The primary endpoint is the Hammersmith at 12 months. We included a population ages 13 to 21, just to be more representative of the patient population. And importantly, we're also measuring additional endpoints such as caregiver reported outcomes, clinical benefit that matters to patients. So the objective for this study are outlined here. The primary goal for us is to demonstrate improved motor function, both Hammersmith and RAM across broad SMA patients. In addition, caregiver reported outcomes such as those we included in TOPAZ were also included here, including promised fatigue and [ PDCAT ]. These will give us the ability to demonstrate clinical benefit that matters most to patients. And lastly, we also expect to confirm the safety and tolerability profile in the SAPPHIRE remains favorable. And lastly, an important element underlying our confidence is really the safety and tolerability profile. As Jay pointed out earlier, we now have 4 years of experience on study, and over 90% of the patients remain on study. No new safety findings. There's no serious adverse events that's attributed to apitegromab nor hypersensitivity nor antidrug antibodies. The high retention rate really speaks to the benefit perceived by patients. So now I want to take you through the clinical evidence that underlines the potential. So this is the list that I want to go through. What I'd like to do is first take you through the natural trajectory of those patients that are treated with SMN. So you can get a good idea of the type of patients that enrolled in TOPAZ and what you can expect from them. And then the next 4 points really speak to the specific aspects of the TOPAZ results. So now I'll take you through each of these points. So you saw this graph before. On the left is the long-term follow-up of nusinersen and the vertical access shows the Hammersmith. You can see the initial increase of the Hammersmith score within the first 15 months, shaded in light blue. However, pay attention to the line graph between the 15 months and 4.5 years. You can see that the changes started to plateau and the actual change of Hammerman score within that time band from 50 months to 4.5 years is staying within the band of 1 point. And the same trend is seen on the right. That's the long-term data on risdiplam, where the same trend is seen and Hammersmith is a secondary end point. And what I want to point out is that all of the patients enrolled to TOPAZ had a minimum prior exposure to nusinersen. On average, they've received 2 years of nusinersen prior to entering the study. So well into the interval where you would expect the motor function to plateau. Now here's the data. The Hammersmith at 12 months, the increase from baseline 3 point increase, and that's well above what you would expect from these patients that I just showed you in the previous slide. And that benefit is durable, as you can see, the increase is sustained over the course of 3 to 6 months. So the third element of the study is outlined here. On the left is the data coming out of the Cohort 3 of the TOPAZ study where patients are randomized in a double-blind fashion to 2 different dose levels, 20 mg dose and a 2 mg dose. You can see that the Hammersmith motor function increase from baseline quickly after initiation of therapy with both doses. However, clear separation was seen between those 2 dose levels. And that on the right-hand side, what you can see on the horizontal arm is the duration of previous nusinersen exposure. On the vertical access is the Hammersmith score. We're trying to look at the correlation between those 2 parameters. As you can see, the lack of correlation is shown on this graph. So both the dose response on the left and the lack of correlation with the prior duration of nusinersen speaks to the fact that the primary benefit that we see in TOPAZ is attributed to apitegromab. So the fourth element of the data is really the consistency of results across different parameters. What you see on the left on top is the PD CAT, which measures the daily activities of the patients. What's on the bottom is promised fatigue, which measures the perceived fatigue by the patients. You can see both outcome measures improved and were sustained over the course of 36 months. What I'd like to really point out is what's on the right. It's really powerful images, you can see on the right, you can read it on your own. Dr. Castro has spoken about this earlier. These are really patients voice. They are interviews and representative quotes from caregivers. They speak about the ability of these patients that can now take up the market and draw that can cross from one side of the room to the other, that can stand on their own. These may not mean much to us, but they are extraordinarily powerful in the context of these patients. They give them greater access to the world and give them freedom to move. And so that's really powerful when we see these things. So lastly, we spoke about this. With over 4 years of treatment, over 90% of patients remain on therapy. In fact, 94% of the patients of the nonambulatory combined cohort remain on therapy. This is a powerful statement about the motivation of these patients that also perceive the benefit that they see. Now I'm going to take you through briefly about what we have planned in the near future. We're in the home stretch. Very excited about the upcoming milestones, the top line readout in Q4. And the team is already very excited that 2025, as you can see, is no less transformative for us as a company. We have BLA and MAA filing in 2025. And Tracey is going to take us throughout the commercial strategy in anticipation of the regulatory approval. And lastly, we have additional studies planned, as Jay mentioned. And first on that list is the under 2 years of age population, which are primarily treated with [ zulgintumab ]. And we have a clinical study design that's endorsed by the pediatric committee of the EMA. We're anxious to get started. The plan is to initiate the study in 2025. So to conclude, built on the strength of the TOPAZ result. We have confidence that the SAPPHIRE study is designed for success. We look forward to the upcoming data readout. We're committed to continue to expand our [ concodevelopment ] program into broader patient setting as we wanted to make sure we maximize the benefit to patients. So with that, I'd like to invite Tracey to the podium to talk about the commercial strategy.

Thank you, Jing. We already heard very clearly from Dr. Castro that there have been tremendous advancements in SMA over the last 7 years. But we also heard clearly that more is still needed. And we're really excited to be on the forefront of what is next in SMA. Today, I'm first going to talk about some of the insights we've gathered on SMA, where the market has evolved to and the remaining unmet need. And then I'll turn to how we're thinking about commercialization planning at Scholar Rock. But first, I'd like to start with our purpose. Our purpose is to create possibilities for those living with SMA. This is Liza. Liza is a 22-year-old [ dynamo ] living with SMA who's on SMN targeted treatment. And although she has accomplished more in her life than pretty much any 22-year-old I've ever met, she is also reliant on a caregiver for daily activities that we all take for granted. And she told us a story upon hiring a new caregiver that, that individual fell asleep while Liza was in the shower and left her there for 2 hours. She did not have the strength to reach out and shut off the water. She didn't have the strength to yell loud enough to wake the individual. So when we ask Liza, what would it mean to have more muscle strength and function? She told us muscle is everything. It is the difference between knowing I could take care of myself if left alone. We stay focused on that purpose of creating possibilities by listening. By listening to individuals like Liza and others who have SMA and their caregivers, but also listening to the physicians who treat SMA and the payers who are covering in this space, in the U.S. and Europe to understand the space. And we've built deep insights to understand where SMA has gone and where it needs to go. And it has evolved. We heard today that more patients are diagnosed, treated and living longer than ever. Newborn screening, which is now 100% of states in the United States as of last year and improving across Europe is leading to earlier diagnosis and treatment. Access is broad and expanding globally. In the United States, we have well over 90% coverage amongst commercial and government payers. And in Europe, Axis is good and continuing to improve. Care is concentrated at expert centers, tertiary centers in the U.S. and the United States. We believe there are about 2,000 prescribers in SMA in the U.S., but patient care is highly concentrated in the top to 10% to 15%. And a lot of this is due to the fact that there is a highly engaged and organized patient advocacy community that have led to these successes. So today, patients are diagnosed, they're treated and they're treated by experts. But we also heard that more is needed, and we've heard it from all of our stake holders, the patients, the physicians and the payers. In a Cure SMA survey of SMA patients, 97% identified that improvement in muscle strength is what they sought most from a new therapy in SMA. When we conducted research with physicians who treat SMA in the U.S. and Europe, they indicated that they would prescribe a muscle-targeted therapy to over 70% of their SMA patients today. And as we look to the U.S. market, we see that over 1/3 of lives covered by commercial plans today already have coverage, which we heard today, of treatment with an SMN targeted therapy and the gene therapy. Before that clinical data is even available. All of this tells us that more is still needed. That more is to address progressive muscle weakness. We hear from Liza and so many others that addressing this can mean the difference of being able to function basic activities that we take for granted like hygiene, like getting in and out of bed, creating independence. We hear from treating physicians that improving muscle weakness and improving function on the Hammersmith scale is important, is measurable and it's meaningful. And we hear from payers that improving and restoring motor function to enable practical improvements of daily lives and independence is needed. So as we look to commercialize our first product, SMA is the right opportunity for Scholar Rock and apitegromab. There is a clear unmet need, and there's alignment across stakeholders on the need. There is concentrated in proactive care. Patients are treated and they're treated by experts. There's a highly engaged and organized patient advocacy community that has lended to the successes today but who are also not satisfied and agree it more as needed and they're aligned on the need for muscle targeted therapy. And amongst the payers with 3 approved therapies, there's an understanding of the space and established value frameworks for improving motor function. As we think about planning for commercialization, success starts with a meaningful medicine. We're confident in the potential success of opitigrimab. We are demonstrating efficacy in a gold standard measure in SMA. The Hammersmith is an SMA specific and validated functional scale that is used with daily practice today with physicians and payers. We're the only muscle targeted therapy with 4 years of clinical experience in SMA patients and we heard from Jing that we remain with a high retention rate in our TOPAZ study. And as we think about how we'll fit into future SMA treatment, we have the flexibility to be used with either nusinersen or risdiplam. And we've also learned that pokes with the needle are preferred and that monthly dosing is a preferred regimen for muscle targeted therapy. We believe this attractive profile represents a significant opportunity for apitegromab. We believe the global revenue potential for apitegromab is over $1 billion, and we're often asked how we consider a potentially competitive landscape with more than one muscle-targeted therapy. And I can say that we consider more than 1 muscle-targeted therapy in this opportunity. And if you look to the SMA market today, you see that there are 3 approved therapies all targeting the survival motor neuron and that market has grown to over $4.5 billion. More is still needed, and we're excited and confident about the potential for apitegromab to address that need. There are 3 key elements to our commercialization approach. The first is engagement, continuing to listen and partner with the SMA community. The next is to ensure and design an excellent patient experience. And ultimately, it comes down to execution, and we have a thoughtful and phased approach to building the organization to deliver commercial success. I've mentioned we've spent years building deep insights within the SMA community, and we will continue to engage now and throughout launch. We have an MSL team on the ground today, meeting with SMA treaters and care teams. We have spent time and developed a well-established and deep relationships within the advocacy community, and we're going to continue to listen and learn from them. And in fact, we are amplifying what we have heard from the patient voice about the need to address muscle weakness with the first-ever muscle focused campaign in SMA Life Takes Muscle, which will launch next month. An excellent patient experience starts with access. And if you speak to any one who's launched a medicine in the last decade, they will tell you engaging with payers early is critical. Even in a space like SMA, where the need is recognized and where value framework exists. We will be engaging with payers early and focused on value demonstration. As we think about designing our treatment experience. We want to seamlessly fit into the current practice today, and that may mean administration in a physician's office or it may mean administration in a patient's home. SMA is a highly individualized disease, and we want to offer maximum flexibility with our treatment. And we also want to ensure that our roles and services provides port to the patients and families, but also to the physicians from prescription to getting our medicine to staying on medicine throughout the patient journey. We have a thoughtful approach to building to realizing commercial successes. We have a small team today, but Jay mentioned their passion, and I challenge anyone to find a more passionate team about bringing a medicine to market. They have experience in launch in rare disease and specifically in SMA. As we look to next year, we'll enhance our commercial footprint, and we believe we can have a successful U.S. launch with an efficient customer facing footprint of 30 to 50 FTEs. And beyond that, we intend to commercialize apitegromab on our own in core markets in Europe, and we recognize that SMA is a Global disease, and we will work with partners and distributors on the path to achieving commercial success with apitegromab, and there are favorable market dynamics for our launch. We have the right medicine there is a competitive and attractive profile with apitegromab. And we have the right plan. It starts with engagement. It remains patient-focus, and we have a phased approach to execution that we believe will deliver the overall revenue profile and potential for apitegromab. With that, I'm going to invite the speakers and our CFO and COO, Ted Myles, to the stage for Q&A.

Good morning, everyone. Hopefully, everyone is as energized as I am listening to these great speakers and excited to dive into Q&A. So audience and also we have online portal questions coming in. So Gary, first one up?

Gary Nachman from Raymond James. First question for Dr. Castro. Any reason to think apitegromab would work better with the different SMN treatments, whether nusinersen or risdiplam? And what about for different age groups, whether 2 to 12 or 13 to 21? Maybe just start with that. And then I have a follow-up.

That's a great question. I really don't think that there is going to be a big difference between using one or the other medication. Every patient responds different. And we -- when we started patients in nusinersen. Initially, we didn't have anything else. When risdiplam came, I switch many of my patients to risdiplam. Some of them had to go back to nusinersen so it really depends on the patient response, but I don't think that there's going to be a difference pairing this medication with nusinersen or with risdiplam. In terms of age, I think more than age is function. Anytime you have the potential of increasing that order function, the potential of improving fatigue, you have a gap to fill, right? It's really not -- I don't see it as -- because you see the example of the little girl, right? She is very young, and you will expect to have a higher function, well, she has, but she still has a lot to go. But then think about an older patient who still is not able to go through a full day even sitting in a computer, right? Like for them, that's something that keeping their trunk sometimes takes a lot of energy and a lot of work to be able to hold. So I don't think that there is really age related. It's more function related, how much we can get.

Okay. Great. And then just a follow-up. First for the company, just talk about what type of improvement you need to see on the Hammersmith scale in the SAPPHIRE study to achieve statistical significance based on what you saw in TOPAZ. And then maybe for you, Dr. What do you think you need to see to show that it's clinically meaningful? What type of improvement?

So just real quick on the stats plan, we're continuing to not provide a lot of details on the stats plan. Certainly open up -- Jing, maybe comment on your views on winning, what does winning look like for SAPPHIRE and certainly, Dr. Castro, what is clinical patient experience look like?

Yes, we're not sharing this detailed statistical plan, but I can tell you what successful it takes to me. As Dr. Castro pointed out, even 1 point change matters. It's clinically meaningful. We talk to numerous patients, caregivers, clinicians, and that view is broadly shared. But built on the strength of [indiscernible] data, and we showed you substantial benefit that's beyond what you would expect in this type of patients. So to me, there are 2 aspects to winning. What that looks like, first is efficacy. It's clinical meaningful benefit across different outcome measures, including motor functions, Hammersmith and Ram and also caregiver based outcomes that matter to the patients. And on the safety side, we really expected to confirm the favorable safety and tolerability profile. It's the totality of the data and its consistency of findings of results across all the outcome measures, which we have seen in TOPAZ and SAPPHIRE really is designed to optimize all the aspects of the key design and also trying to be representative of the patients. I do want to add like one point about the question that you had about the risdiplam versus nusinersen. Both of them are targeting SMN2. So essentially, what they're trying to do is raise the expression level of SMN2 proteins. And so therefore, functionally, mechanistically, they're very similar. And on top of that, if you think about myostatin, there is tremendous amount of [ loders ] out there that really showed that myostatin regulates muscle growth and function throughout life, regardless. And then the other thing to keep in mind, I showed you the nusinersen and risdiplam long-term follow-up. There's actually detailed data that really separates out the ages. And you can see that the initial rise younger patients tended to go a little bit longer that they also plateau, regardless of the age, they plateau. In fact, the older patients tended to plateau deeper. So I think that what you will see, and we look forward to the top line data is the separation, the ability of these -- of myostatin to regulate muscle and therefore, apitegromab to benefit patients should be regardless of the age or the type of underlying SMN target therapies.

Jay, do you want to comment?

Yes. And just a final comment on the protocol. Just recall that we did discuss the protocol both with FDA and EMA. So as we kind of look forward to the results, upon success of that trial, that should be the base is for regulatory approval, right? So we looked at the TOPAZ data with the 4-point change. We certainly didn't design the trial to show a 4-point change but I think within that range of 2 to 4, we're really good. But I think at the end, what we pointed out and we really underscore this in the totality of the data, any improvement matters, 1 point matters. 2 is really incredible. 3 and up is even better. I think we've got a very good program going forward. Upon success, we should be able to go forward to the regulatory approvals. .

Coming back to the question, I think Dr. Castro mentioned goosebumps, maybe you can articulate what's goosebumps for you when you say...

Yes. So I think the scales are great, right? All the scales that were presented. They're great because there is an objective way for us to see the improvement. But something that I want to remind you is there are challenges that we have in clinic because let's say that keeps come this morning and he's having a temper tantrum and he doesn't want to cooperate during the clinic visit, it's just sometimes we have that limitation. So what I get a lot from the families is not only videos, but I get descriptions about things that they are gaining that are amazing and important that sometimes we cannot even see by ourselves, we cannot even measure them. And I would like to give a quick example that I said that before, but I think I really like this because it's a Type 2 girl that I have one of my patients who lost the ability, every time she went forward. She fell forward. She could not pick up herself. She couldn't get up. So she had to wait calling her sister, calling her mom to be able to go back. After she started SMN targeting therapy, she was able to start pushing and sitting back. That is not in a scale. I cannot -- I don't have that in a scale that says, you are able to, right? So I think that it's important for us clinicians to be able to capture every single detail. Every single thing we have, and that's what I do in my clinic is really see and take long time telling -- listening to them to all the improvement they see that sometimes were still missing. So to me, improvements in scales of 1 point, 2 points are significant. There are a lot of other improvements that are meaningful for the families and the patients that were not able necessarily to capture.

So one question about this [indiscernible] that we talk about. The patients who started on SMN therapies in less than 5 years and more than 5 years. I think TOPAZ and SAPPHIRE have been -- they were initiated at different time points in terms of the availability of the other 2 drugs. So do you have a sense of what the ratios might be in between these 2 [ crucial ] patients and how might that affect you [indiscernible] as one? And when you talk about the exploratory study beyond what years of age that you're looking at? On the same endpoint it is going to be including valuable if you're looking at other aspects as well [indiscernible]?

So I'll summarize for those online. So Question 1 about stratification of patients and how the world has sort of moved to treat earlier and how that could impact us and what we think -- what we saw in TOPAZ and what we expect to see in SAPPHIRE [indiscernible] to comment? And then maybe we'll go to the 13 to 21 exploratory question. Jing?

Yes. No, great question. So we are not sharing all the details about the patient makeup. We look forward to sharing those upcoming medical conferences. So having said that, I'll say a couple of things. One is that we have learned a lot from the TOPAZ study and the SAPPHIRE study is designed to really kind of get the most salient points into the design, as I pointed out earlier. So mechanistically, there's no reason to believe that younger versus older or initiated earlier versus older is going to make a major difference. We've taken that into account as we designed the SAPPHIRE study. What I can tell you is that we are actively monitoring the study and everything is sort of exactly tracking our assumptions. So that's underlying the confidence we have about the clinical success of SAPPHIRE.

Jay, do you want to comment on the landscape a little bit? .

Yes. I mean I think to your point, and I think we heard that very well from Dr. Castro. With newborn screening, there's opportunity for initiation of SMN therapies early. I think one of the reasons why we built that stratification factor and from TOPAZ is I think the field's time equal motor neuron, we've heard that, the longer you take to initiate it then probably the less function will be available to kind of improve. I can say that the study is reflecting practice. So let's just say that, right? Without giving the details if it's 80% or 60%, it's basically reflecting practice, which is really important for a Phase III study because we can generalize. I think in the end, it's going to be a benefit for patients. And I think it actually gives us an opportunity to improve more function with [ apitegromab ] as a background. So it's an advantage, both for the program and my perspective because it's an advantage for the children. So I think that's the first thing. And then if I -- since I'm speaking, so the 13 to 21, it's going to be the same end points. I mean I think Jing had described it. We view it almost as a predefined subgroup. So it will be the Hammersmith is the primary. It will be the same click-through on the endpoints for that group as for the 2 to 12. And we believe that, that gives us the opportunity to really have the broadest label possible. So that's really the intention. I think Jing said that to really be representative. We're looking forward to reporting out the results, I have to say.

Mike.

Michael Yee from Jefferies. Maybe for Dr. Castro. If you go back to the Phase II data, I think that the most striking part was the plot of the individual patient Hammersmith score improvements, which got as high as 15 points, I think, in some cases, but the average, I think, was 4 to 6, I think, was what Jay was saying. And I believe that one would say that an open-label data, hard to interpret because there's no control arm. But if you look at the Spinraza data there is a plateauing of effect. However, that data does have air bars, I think, around it. And so the air bars are within a couple of points. So my question is based on your clinical experience, how do you interpret the range of what patients do on spinraza over long term and the clinical validation of the Hammersmith score with 5 to 15-point improvements that you're seeing here, even though there's no control arm? That would be question one. And then Question two is for Jay. I did notice that your pivotal study is both 20 and 10, although 10 would seem to, I think, have effects because you think even 2 had effect. So can you remind us if there's a polling ability to pull the data, anything that you would look at there and also the idea that age groups may matter if you look at the [ Sarepta ] situation as well, they're going through that? And so how do you think about age differences there in the study?

So we'll turn to Dr. Castro first. I think a quick reminder that as most of you know, the patients were introduced and patients in TOPAZ were introduced to apitegromab about 2.5 years into Spinraza therapy. So we believe, pretty far into that plateau phase, but certainly want to...

And your question is more of how can I tell the difference between what the patient is at and how much are we getting, right? So yes, yes. I mean we see this patient -- I see these patients every 6 months. For newborns, I see them every 3 months. So it's really a constant evaluation of the patient that, again, is not only for the physical therapy to go and do those scales. It's for me, well, doing the physical examination, I do motor testing whenever they are able to do. So I'm checking muscle by muscle. [ Delta], biceps all of them. And also the scales obviously are helpful. But again, going back to what I was saying when you see it and start -- let me tell you a quick example. For example, one of my patients treat loss their ability to get -- so I have our own combined therapy. I have from 2 therapies right now. She lost one of them. And what I was clear for the mom was that -- in the morning, she was able to stand up, go and get her face wash, brush her teeth, come downstairs. When she lost one of the therapies, she was not able to stand up from the bed anymore. She wasn't able to get to clean up herself, and she had to go and help her getting down. So we can tell, and again, I cannot put that in a scale, right? So I can tell when there is improvement in those kind of activities of daily living that otherwise, I'm not going to be able to capture anywhere else but in the discussion I have. So I think it's a whole assessment of things that we can tell if the patient is really improving or not. Are there patients that don't improve? Yes. There are always patients that are not going to have a perfect response, and I show you that newborn, that girl who has done amazing but still is not perfect. And I want to make that point always because I want to make sure people understands medicine is not perfect, and we still have a lot -- a long way to go. So I think that that's the best answer I can give you, it's a whole assessment as a patient. It's not only 1 scale.

And then to your question around dose. So to the point, we do have 2 doses in there. When we take a look, we do believe that 10 will certainly look comparable to 20, although 20, as you know, from the TOPAZ study was the dose that we wanted to go -- we selected to go forward within the protocol. We're going to explore dose throughout this protocol. So we'll have an opportunity to look at 20, at 10 and in addition to look at combined. So we'll take full advantage of all the data within that protocol to really understand the effect that it has on apitegromab -- on the improvement.

And it's interesting because when we do the studies, we're blinded, right? But we -- sometimes we can tell. There are things that you can see in terms of quality of movement. I didn't mention that. And when I show you the case of this goal using all these accessory muscles or just doing it straight up, it's -- we can tell those things where we see the patients. We can tell the imporvement. Even when they are blinded. Obviously, I remember I won't say anything to the families. But I'm seeing things that I was not seeing before.

David, question.

Just a quick question on the age groups again. Is there any reason to think that the benefit changes or the trajectory changes as the children go through puberty. So the -- I mean go from 12 to 14 or anything on the study, is that a valid thought or consideration?

I'll ask Dr. Castro to comment on her clinical experience as patients move through puberty.

That's a great question and I love you're asking that because what I tell all my families, not only with SMA, [indiscernible] muscular dystrophy, any other kind of condition to treat is during puberty, we see a little bit of -- it's not that you're losing a function. It's almost like the bodies adapting at a different growth rate. So I always tell them, have you ever seen a teenager, a graceful teenager. They're never graceful. They're always looking to control their body because they're adapting to a higher -- to the high and the weight. And that's exactly what I see in neuromuscular is that period of time where do you see the change in function sometimes that is not related to the number, to amount of function is just related to the timing life. But they will always come back to where they were before. And that is clear, but that's an excellent question.

[ Jess ].

Dr. Castro thanks for being here as well. How sensitive is the Hammersmith scale overall in your experience? And from clinician to clinician, how much variability is there? And then just to double-click on some points that have been already made here. Like where do you ultimately think the control arm performs? And how do you get there? You talked a little bit about baseline quality of function as being a key variable. And then I have a quick follow-up for the Scholar Rock team.

So maybe I'll ask Dr. Castro to comment on her clinical experience about Hammersmith and then also ask Jay or Jing to comment around how we're -- how we've managed not only SAPPHIRE but also TOPAZ in terms of training physical therapists and making sure we have maximum control and consistency.

Well, and I can start commenting about that. Actually, my therapist is -- she had a long experience with the patients with SMA, but it's incredible every time we do a SMA trial, she gets retrained every single time, even though this is what she does in clinic every single day of her life, but they do have reliability testing, so they have to perform the first evaluations in front other therapies who is evaluating their performance. They recorded the testing, then it is evaluated by somebody else. So there are really is definitely there. And again, these therapies get trained 1,000, 2,000, 3,000 times. So I don't have questions about that. To this scores, again, I think they are great scores. And these specific scores, which is specific for spinal muscular astrophy? It's great. But we always have to remember to try to keep the best we can in terms of the patient, when do we do the testing? So when I schedule the patients for research, I always tell them we're going to schedule the patient in the morning. After the patient comes from, have had breakfast, then we do it. And we try to keep that every time. We make sure that the patient is not sick. We make sure that the patient has had a good night sleep. So all of these -- if you're able to control as much as you can, all of the other factors, I think this cores per se are great. Not forgetting that there are many things that we cannot tell. Many things that I just get through video. Most of my patients have my cell phone, which some people think I'm crazy. But I think it's amazing because if things I get in the videos, I think that sometimes, I will never be able to see in the clinic because they may not having a good day. So we have great scale. We have great therapies that are doing the work and the companies make sure that they are well trained.

Jing, do you want to comment on the study and broadly?

Yes, I want to say a couple of things. I think Dr. Castro covered it very well. I just want to just add a couple of minor points, which is that we have a very experienced clinical team. It's the same team that has conducted the TOPAZ study. We also have very experienced sites. We have extraordinary discipline in training them. As Dr. Castro said, we have actually a physical therapy, advisory board, they oversee everything. So -- and we believe the study is also well designed. So that -- Jay, do you want to add anything?

No, that's it. We've built that in test. I mean, I think you're right. It's the primary endpoint. So we've got a lot of, I think, quality checks built around it. But importantly, we've selected centers and therapists that do this all the time with training and an advisory group around them.

[Jess, ] do you have a follow-up question?

Quick follow-up. For the Scholar Rock team, can you just remind us the key inputs that informed your internal assumption about where the control arm will fall?

Yes, I think it's fair. I mean I think you're designing a trial, you look to see what's available in the external world, what's published, what you see with other programs. I think we spent a lot of time talking about the plateau, what nusinersen does, what the likelihood of the trajectory is. I think what you heard from Jing is when you see that plateau, it's hovering around a 1 point variability, which you could argue if it's flat, you would basically say it's going to stay the same. But I do think what we're hearing and what we're seeing, this is an inherently progressive disease. It's inherently progressive. And I think, frankly, there is the potential, if you look at the control arm that they will actually lose some points over time. Lose points over time rather than staying flat. And if you think about that and if our assumption was basically flat and now they're losing, that certainly, I believe, advantages the intervention arm, right? So just to put that color around it.

Ally, did you have a question?

Ally Bratzel at Piper Sandler. So I had a follow-up question for Dr. Castro. Just hoping you could expand on how you would see incorporating apitegromab into your care for SMA patients? How many of your patients under management would be eligible for treatment? On top of SMN background therapy, what would make a patient a good candidate? And is it your expectation that you would see a continual deepening of effect over time as treatment goes on? And I have a follow-up for the company.

So I think the ideal patient is pretty much any patient that requires that extra help, extra step. I will tell you which will probably not be an ideal patient. And I'm thinking about I treat adults as well. So when you have patients that are extremely, extremely advanced, where the movement, it's really none. They have severe contractures, including their elbows, wrist, fingers. They cannot move their wheel chairs by themselves. I think that's a patient that likely is now going to be a candidate for extra therapy. But even when you're able to push the joystick and you are independent in that sense, that as a patient that I want to be able to keep that. Even that, it's extremely important because that's the way that patient functions. I have patients adult patients that actually function extremely independent with severe levels of weakness. It's amazing how they can do things. So preserving fingers, preserving any function is extremely important. But there are some of them that are past that point, and I don't think there is going to be a change for them. Was that your other -- there was something else?

Deepening of effect. Would you expect to see a deepening of effect over continuous treatment?

I don't think so. I think that my experience, at least with the patients that I had in TOPAZ, my experience is been seeing them getting older and seeing them gaining more function as they get older. Again, these are kids. So kids supposed to continue gaining function, right? Or gaining milestones as you get older. So at least I can talk about those kids. Definitely, I haven't seen stagnation, I have seen actual improvement through life.

Yes. Now just for the Scholar Rock team, could you talk more about access barriers you're anticipating for apitegromab? How actively do you anticipate payers are going to manage muscle-targeted therapies? And how much are the launches or experiences with SPINRAZA and risdiplam good analogs for what you expect with the launch of apitegromab?

Sure. So in terms of access, I think we benefit from the fact that there are established frameworks and understanding amongst the payer community of the benefit of treatment in SMA. We've engaged with payers and know already that they would value a treatment that brings a new meaningful benefit to patients. And so our plan, of course, is never to take that for granted and engage. But I think relative to launching a medicine where that understanding doesn't exist, we're starting from a platform of understanding, which is valuable. I'm sorry, second question?

She was asking about the SMN treatments that are out there. Are they analoging? I don't know that the -- we would say they're analogs, but they've certainly done a lot to pave the road to patients.

Yes. Sure. So obviously, as we're closer to launch, we'll think about metrics in terms of guidance for uptake. But again, I think different from when those medicines were approved, patients are diagnosed early. Patients are identified, patients are treated, that proactivity and identification is there, which, again, I think is favorable for our launch situation. .

Etzer.

Etzer at BMO Capital Markets. Obviously, sort of SAPPHIRE takes a lot of the learnings from TOPAZ and incorporated that into the design. Just wonder kind of ahead of another sort of Phase III SMA readout this year, just kind of identify some of the key differences, right, in that study versus this -- versus SAPPHIRE. And what you view as sort of being kind of important when you think about sort of treating patients early in the disease specificity of the molecule and sort of the population. What you kind of think are sort of the key metrics, if you will, in terms of that population, that design, it's sort of ahead of the SAPPHIRE readout.

So you're asking about the -- another program muscle-targeted therapy that are ahead of us or around when we expect to read out. I think it's really a -- probably a clinical angle to that question, maybe a biology angle. I ask Jay to comment on and then there's probably a commercial angle.

Yes. I mean I think it's -- of course, it's a common question as we're approaching readouts of programs. I think the way we've addressed it, we've talked about the science. I really do like our selective strategy of targeting late blocking it before it's activated. I think there is the potential that could enhance efficacy because you're not dealing with the active already circulating trying to kind of absorb it. So I think that's a really important biologic difference in our strategy. And I think what Jing said is we really in Phase III trial was informed by the proof of concept. I think that advantages us, right? So we carried forward the same endpoints. We carried forward the same population we thought would really enhance. So I think having a more homogeneous population in our study from my experience in clinical development that tends to be an advantage because heterogeneity sometimes can cause some interference with the signal. So it may not show the effect that you want. So those, I think, are really key points. I think from our program, it's 2 and above, right? So I think that we are able to get into to get into research early. I think there's a difference in the age inclusion criteria in the other program. And it's very much an all-comers program with a different endpoint in measure. So I think the way I think about it is we should celebrate success in our industry. We absolutely should. I mean we're talking about improving outcomes for children and parents fighting to get access and care, we should celebrate any success. I think that success would read through beautifully to because I believe we have the mechanism and the design to win. On the other hand, I would look at it if, in fact, if it unfortunately doesn't succeed, I wouldn't then carry forward that to our strategy or to my standards of target because I think mechanistically, it's different. I think the popular Inflation is different and heterogeneity may be a challenge. So that's kind of how we think about kind of the upcoming events.

And then playing that forward on a commercial standpoint. If they are successful, then there's a 2-horse race in the commercial market. Do you want to comment on that, Tracey?

Sure. Yes. I mean, certainly, as we think about the revenue potential for apitegromab, we consider a scenario where there's more than 1 muscle targeted therapy, and we look to the SMA market today, where there are 3 approved SMN targeted therapies and significant growth in that market. The need is there. Among muscle targeted therapies. We feel really confident about our profile that we aim to demonstrate with efficacy and an SMA specific scale with treatment and safety experience in SMA patients for over 4 years, which is really critical. This is a chronic disease. And obviously, the flexibility to be used with either nusinersen or risdiplam and monthly dosing. So we feel really strong about our potential profile.

I want to -- I know there's a lot of folks online, I think a lot of questions coming in. Rushmie, do you want to pick a couple of them, then get back to the room.

There's a double question from an online participant. So the first 1 is the dissemination strategy for the SAPPHIRE data. Do we plan to close at a conference or in other means. And then the second question from them was an update on the subcu formulation.

Jay, you want to take the first one and Tracey, the second one?

Yes. So we absolutely will plan to disclose the top line results in any from that we can that's appropriate. I think we've been asked questions around baseline demographics and where we would like to present those. If you think forward, those lend themselves to conference presentations, we can really get good discussions, so we certainly intend to do that. But we will share the top line results if it doesn't tie it up to a conference, we'll certainly do that as a separate call. And we'll give deep color on to the top line results from subgroup analysis to the primary endpoint. So that will certainly be a plan.

And we're confirming that will happen in Q4, standing by the guidance, so that is Q4.

My point about execution, on-time delivery. Yes, that we're absolutely on track for that.

Thoughts on subcu, Tracey?

Sure. Yes. I mean our goal is to provide maximum flexibility. It's an individualized disease. We are planning to launch with the IV formulation, which again, we feel really confident about. And as I mentioned, we're designing a treatment experience to offer the flexibility of administration in a physician's office or at home. We've seen patients stay on this medicine out to 4 years in TOPAZ. But of course, developing subcu alongside or behind that is important because there may be patients that want that optionality. And so that's something we look to the future post launch to bring forward.

Other questions from online?

Can you talk about the differentiation between our asset and Roche's program, their latent myostatin compound?

Jay, do you want to?

Yes, I'll take that. I think the beauty of Scholar Rock's foundation is we're the innovators with targeting latent myostatin. I mean that was the scientific insight for our founders. And so we're there with a great patent state. I would say that the Roche/Chugai program kind of follow that lead, if you will, and build a program around it. So their targets are similar, a little bit different approach. I like what we've done. When we take a look at the sort of the landscape, again, my interpretation of the Roche strategy makes perfect sense to me. It's combined with risdiplam. That's their marketed product. You benefit from that portfolio. And they've been focusing more on a different segment of the population. I think it's important to recognize within SAPPHIRE or we describe it as nonambulatory. Ambulatory by -- we saw videos of it, children with different difficulty with gate. The definition even within the trial is able to walk with some assistants just not being able to really like do a 50-meter walk. I mean, there's limitations to that. So we would certainly include that in the group. But I say that because I think the focus for the Roche program has been in that different population setting. And of course, it didn't compete with our trial at all. And frankly, what we see competitively is it sounds like that they're on track to report out beyond when we would expect to commercialize. So strategy is similar but I mean, in terms of the target, but our approach, I think, is very, very good, and I think we have a bit of an advantage given time.

Can we ask Dr. Castro of comment on the ambulatory that is a point of judgment sometimes, right, in the clinic?

There is actually a definition that we use. Sometimes, the sponsors will ask a specific, but for us, any patient that can walk 10 meters with any -- with assistance, meaning assistance or a cane, a gate trade or something, we include that as a patient that is still within the nonambulatory, meaning they cannot do it without help of one of those.

Yes. And if I could just add to that, right, because of the scales that we've talked about giving you a personal opinion now, I really like to revise that upper end module scale. It focuses on upper extremity. And you showed a beautiful video of the little girl being able to now throw. Now think about someone who needs assistance to walk, that strength, I think, really could advantage them, right? So -- and we saw the graph on -- the revised are going to model, just continues to show some nice effect. So to be clear, that subgroup is caught into our trial. That's part of our definition. And I do believe we have an opportunity to really improve outcomes for those patients.

Great. We'll bring it back into the room. I think there's another question here.

Dr. Castro, for the initiation of therapy, how are you thinking of if apitegromab is approved? Will you be initiating therapy with standard of care? Or would you wait for standard care to see that plateau that we'll be talking about after 2 years or...

That is a great question. I think that it depends the age that we're treating the -- the time on treating the patient, right? When I talk to -- let's think about our newborn. I tell the families we're going to treat the baby, and we're going to have at least a period of 9 to 12 months, we're really identifying what changes. What are we seeing, we're not seeing. In the case I presented, she actually by very early. If he already had these stages. So I had to act on earlier than I would with other cases. Because at the same time as much as I want to give them what they need, there are some families that really will everything, right? I mean, it's your child, you will do anything. So they wanted -- they think that they just more is better. So I think that it depends the time with the -- how the patient is responding to that therapy, but increase of the newborn. In other cases, where you're thinking about already a patient with Type 2 who is sitting or a patient with Type 3 who has lost ambulation that act exactly like a Type 2, I will start them on because I can tell you already today that there is a deficit, that there is a need. So I wouldn't wait until because I don't think I have much to wait for that specific group. But for a newborn yes, I think it will be a little bit different by the time they're going to need the extra therapy or not. If you ask me, will I treat this little girl? Yes. I'm waiting for that actually. I'm waiting to do something else for her. And I have other babies like that, that we're waiting to get the extra push.

Will you continue therapy past a point of plateau? Or is there a reason for you to stop therapy?

No, I will continue. I think this disease is like what you see in the scale is what would we see in clinic where these patients really get to a good point, but they stay there. And then they start complaining about other things that again, sometimes we cannot measure but fatigue being one of those. They need to go through the day. They really need to see the whole day with your straight trunk, things like that, that we see are better, but even with time, you start seeing some deterioration like you were saying, we definitely see that. And I just want to make a point about something that we don't think about is long function when you're seating. So once you lose ambulation or once you're sitting, and if you start losing also function in your arms, your lung function correlates very well to that. So you start losing on function. And it's very important to think that the control of the trunk is also important for your lung function. So if you have low tone and if you have weakness, you're going to start going to the one side, you're going to start getting kind of leaning forward, your lung function start decreasing. So that's why it's so important to keep trunk and to keep thinking about the upper extremity because that has an internal correlation. So for payers, when I talk to them, and I tell them because they say, "Oh, well, they are sitting". Yes, they are sitting, but they are using their arms. If we don't treat that, you're going to have a patient that is going to have more complications like pneumonia, aspirations, difficulties eating and so on that are going to reflect just by the fact that you're losing strong strength.

So we started with very strong patient focus, and I think it's a great place to end the Q&A with that great patient-focused comment. We're up on time. I think we have a brief break, then we'll resume in a few minutes to get into the cardiometabolic obesity part of the day. Sound right?

Yes.

Thank you, Dr. Castro. Thank you, speakers, and thank you all for being here this morning.