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 two 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 neurologist 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 one 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 A.M. 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 in 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 TGF-beta 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, there's three 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 into 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's been executing on our strategy and our goals, and the next 12-24 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 franchise as a roadmap for value creation, and then finally, a glimpse or a view of the road ahead. But it starts with selectivity. Selectivity is the key to safely harnessing the therapeutic potential of TGF-beta 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've been on a way to overcome that challenge, and as a result, we've 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, as you're gonna hear from Mo and Jing, we myostatin and only myostatin. As a result, as demonstrated in our TOPAZ data, we have unparalleled safety with now over four 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 applied 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 TGF-beta 1, 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 SRK-439 into the cardiometabolic space. But in addition, the research teams are focusing on a new neuromuscular program, driving that to development candidacy, as it can add then 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 3 study in SAPPHIRE later this year, and was very pleased with the team to announce that we've opened the enrollment for the EMBRAZE study in obesity. So very good execution. 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'll 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 roadmap 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 and SMA and SRK-439 into two, two 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 two distinct areas, two high-value areas. But importantly, we believe we have differentiated products that can really make a meaningful difference. And you're gonna 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 wanna be in.
But if we think about the market and the opportunity, you're gonna hear from Tracey why we believe that commercializing apitegromab on our own in the U.S. and 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 to SRK-439, highly differentiated. I think you're gonna hear later today, we believe we have the 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 driven teams that are driving to success and to improve outcomes, or to benefit from the power of partnership in 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 meaningfully contribute, and global rights across the portfolio. And those building blocks, we're gonna leverage what will be at a transformative period of time for the company as we've become, we come 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.
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 gonna deliver. I said from the podium at the J.P. Morgan Healthcare Conference that we would spend time building out and developing flanking studies on... that can run as soon as we have SAPPHIRE data. The team have delivered on that. We've got an under 2 protocol that 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 five years, the promise and the opportunity is extraordinarily bright for the company. Five years, I see us as a multibillion-dollar neuromuscular franchise built around the apitegromab, on 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 gonna continue to move. I see five programs in clinic. One of those is a new neuromuscular asset that will build out our neuromuscular franchise. At least one partnered program in that five clinical programs, and continued mining of our research team.
There's more value that we can create.... Our scientists have, can do more with TGF-beta biology, but considering we're world-class at 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 the space of TGF-beta 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's on a roll. We're a company on the move, and with that, I thank you for your attention. I'm gonna 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. Thank you, Dr. Castro.
Thank you so much. Good morning, everybody. I'm Diana Castro. I have been treating patients with spinal muscular atrophy for more than a decade. Neuromuscular specialist, and I wanna 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. Where 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 the information through the nerve to 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 atrophy, survival motor neuron 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 atrophic and to get weakness. So that's what happened in this condition. So again, not only the anterior horn cell is affected, but everything from that point on, it's affected. Humans, we have SMN, we have SMN1 and SMN2 genes. This is humans. For us, for most of us in this room, we have... We really depend on what we call SMN1 . Why? Because SMN1 produces 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 non-functional. So again, most of us in this room, we don't really care about SMN2 . But what happened with a patient with spinal muscular atrophy? 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 determinants of how strong the patient is gonna be. So we have, let's say, an old classification, because now we have therapies that have changed the disease, so we have to call it in different ways sometimes. But what we have in the past, it's a classification from one to four.
Type 1 was a patient, usually with 2 copies of SMN2. So you're gonna see the less copies of SMN2, the weaker the patient is, right? So a patient with 2 copies of SMN2 will be a patient that was never able to sit, never able to stand and walk, and a patient that will develop respiratory dysfunction and difficulties eating. A Type 2, it's a patient with 3 copies of SMN2, usually, and they will call it the sitters. They will never be able to walk. A Type 3, it's a walker. Patients that were able to walk with 3-4 copies of SMN2. 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 gonna progress.
So even if you're able to walk, you're gonna lose the ability to walk. Even if you are able to sit, you're gonna lose the ability to sit. That's why it's so important to treat these patients. And there are other modifiers, and I 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. Patient will be trach, vent, G-tube dependent. They could not move at all, and they develop these contractures everywhere because when you get weak, you get contracted.
Then you have a type two. It's a little girl who is able to sit, but you see already some of the difficulties she has with her arms. And the problem is, as she gets older-
Aw!
She doesn't get better. She gets worse with time.
You were doing so good, though.
And then, before I play this video, these brothers, I have been taking care of them since they were very little. In this family, I can show you what I was telling you, where this kid has SMA type two, so he was never able to walk. He's still not able to walk. Then his brother has type three, so who is able to walk. You see, it's an abnormal gait, and again, it's a patient that with time, if we don't treat, they are going to lose that capacity of walking.... Let me tell you about the current treatment landscape and the unmet needs. Since we start treatments, I have been working on the research. I, I did pretty much all the research that was-- that took us to the place we are, where we have three therapies that are approved.
We have seen tremendous improvement. When I was telling you about the classification has changed, it's because now we treat patients early, and they go from being what they were gonna look as a type one, now they look like a type three. 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 the point I wanna make today, that it's not a perfect... it's not perfect medicine. And what I tell the families is, I have to set the expectations very clear.
These are not cures, these are not perfect, and we still have to keep an eye on these patients as they go older because they have difficulties. So what difficulties we still have? We have patients that have mobility difficulties, patients that even though we treat early, they still never able to stand up and walk. They will only able to get to be sitting and using their arms. They will get fatigue. So we have patients that tell me, "You know, I go through the day, I'm able to work, but then I get home, I'm destroyed. I cannot do anything else. I cannot enjoy my wife, I cannot enjoy my children because my energy is completely gone." Emotional difficulties, obviously, and educational and work difficulties because of their motor function.
This graphic, the reason I include it, is because it's an easy way to see what I'm trying to show you. So we have a score called Hammersmith. The Hammersmith score shows you... We use it before we treat the patient, and then we're gonna continue having this score through life. And what I wanna see is, what I wanna show you is that even in patients that were treated with nusinersen, the max point they get is around their twenties. So look at all of this space. 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 and 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...
I have patients that are lawyers, patients that are bankers, patients, all kind of professional, professionals, so they actually are quite productive people. But the treatments we have right now are targeting this area only, the anterior horn cell. The three 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 gonna 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 eight months, but he was never able to stand up and walk, so we call it a sitter. So this is a type two patient with three copies. He was diagnosed.
We start him on nusinersen at 3 years of age, but unfortunately, when he was 3.5 years of age, he lost the ability to crawl. He was crawling already, but like I say, if you don't treat, the patients are gonna lose function. Even sometimes when we treat them, they still are losing function. So you see the difficulties he's trying. He's getting to, you know, to try to get to a crawling 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 gonna 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.
I remember when I got this video from the mom. This was one of the most exciting days for me, because, again, I, I get goosebumps every time I think about that video, because the mom said he regained, he regained the ability to move around by himself. He regained independence. I think that's where we have to go through, is thinking about: How can we push these patients to take the next step, to be able to have a better life? Then a year later into the trial, he was also able to use a gait trainer. Again, this is huge because he has to go to school. He can move at 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's, she was eight months when the parents started noticing again, she could not walk. I diagnosed her and saw her nusinersen at two years of age. And what I want you to see. And you see they are beautiful kids, all of them, I swear. Every patient is just, they're gorgeous kids. But what I want you to pay attention to is whenever she tries to bring this board up with, with her arm, you're gonna see that she turns a little bit to the side, and she has to do this, right? She has to use other kind of muscles to be able to get to that movement.
When she was, I was able to get her into the TOPAZ trial, so she continued nursing, 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 not doing this-
Good throwing!
She's doing this.
Awesome job.
So not only we're improving the function, but the quality of the movement. And now we're gonna, she's gonna 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 the mom doesn't want to share the videos, but I, I just saw him actually in, 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, you know, we all take it as, as it, you know, we're able to do these things.
We don't think about picking up our head or doing this stuff, but for them, it's a big, big deal. So the last case I wanna show you, it's a newborn, because when I talk to the payers, when I talk to patients, when I talk to everybody, I want them to understand that not because we're treating them early, 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 six days of life. Her physical examination was completely normal, but she tested positive for SMA. I start her on treatment.
She got on onasemnogene on day of life 22, and on day of life 31, at a month of age, she started coughing and sounding gurgling whenever she was getting fed. I sent her to the hospital, they did a video swallow study, and she did have difficulty swallowing. So it was clear that she could not take anything by mouth because she 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 a once and let's see what happened. So I... Right here, you see her where she is holding her head at 3 months of age. Do you see her with her little tube in there?
She's doing.
This is a normal time for this milestone, holding head around three months.
Hey.
That's perfect. She was able to get her legs anti-gravity.
Very good.
So you see her, she gets definitely stronger. 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 she was sitting just for a few seconds, so they always had to have somebody behind her because she would flop. By 6 months of age, you should be able to sit independently without any help. So what happened? I'm seeing her. She still has a lot of low muscle tone. She's sitting, but sitting for a few seconds. She's unable to roll. She's still eating only through the G-tube. She could not eat anything by mouth, so I decided to at least risdiplam at 9.5 months of age. What did I get?
I got, obviously, amazing milestones coming, so rolling over by 11 months of age, then cruising. With cruising is just holding and walking, holding to something, and then finally walking by 23 months of age. But pay attention to the way she walks. Is this a perfect walk? No. Is this a perfect gait? 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 falls every day. She gets tired. She cannot stand up from the floor without assistance. She cannot run. So what's gonna happen? She's gonna get to school. 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... 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, with this 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 use another therapy, like a therapy that can target the muscle. And I think that was my lesson, and I will let Jing come in. How about that, huh?
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. Six years ago, in 2018, apitegromab entered a 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 two 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 three 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 four key elements that really underline our confidence. Top on the left, the differentiated approach of selective muscle targeting, 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 four 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 three 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 inhibits 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 non-clinical setting in disease, translational disease models. We now have also shown you that in a clinical setting. So here we show you the phase 2 TOPAZ data. These bar graphs represent motor function measures measured by Hammersmith on the left and RULM 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. Each point on the Hammersmith increase means the child is able to do go from, like, not being able to do something, to being able to do something with help, or to be able to do something with ease or with less difficulty, as Dr. Castro illustrated earlier. The RULM function really measures primarily the upper limb function. As you can see here, both outcome measures improve from baseline. What you see at 6 months and 12 months are sustained over the course of 36 months. 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'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 mg per kg dose was chosen based on sustained target engagement and the 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.
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 Hammersmith at 12 months. We included a population ages 13 to 21, just to be more representative of the patient population. Importantly, we're also measuring additional endpoints, such as caregiver-reported outcomes, clinical benefit that matters to patients. The objective for this study are outlined here. The primary goal for us is to demonstrate improved motor function, both Hammersmith and RULM, across broad SMA patients. In addition, caregiver-reported outcomes, such as those we included in TOPAZ, were also included here, including PROMIS Fatigue and PEDI-CAT. These will give us the ability to demonstrate clinical benefit that matters most to patients.
Lastly, we also expect to confirm the safety and tolerability profile in the SAPPHIRE remains favorable. Lastly, an important element underlines our confidence is really the safety and tolerability profile. As Jay pointed out earlier, we now have four 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 anti-drug 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 underlies 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. Then the next four 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 axis 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 Hammersmith score within that time band from 15 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 the secondary endpoint. 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 is 3-point increase, and that's well above what you would expect from these patients that I just showed you in the previous slide. That benefit is durable. As you can see, the increase is sustained over the course of 36 months. 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 two different dose levels, 20 mg dose and a 2 mg dose. You can see that the Hammersmith motor function increased from baseline quickly after initiation of therapy with both doses. However, clear separation was seen between those two 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 axis is the Hammersmith score. We're trying to look at the correlation between those two 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 PEDI-CAT, which measures the daily activities of the patients. What's on the bottom is PROMIS 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 spoke 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 marker and draw, that can crawl 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 four years of treatment, over 90% of patients remain on therapy.
In fact, 94% of the patients of the non-ambulatory cohort, the combined cohort, remain on therapy. This is a powerful statement about the motivation of these patients, but also the perceived benefit that they see. Now, I'm gonna 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 topline 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 gonna take you through our 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 Zolgensma.
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. To conclude, built on the strengths of the TOPAZ results, 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 clinical development 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. 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.
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. 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. When we asked 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. We've built deep insights to understand where SMA has gone and where it needs to go. 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, access 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 10-15%. A lot of this is due to the fact that there's a highly engaged and organized patient advocacy community that have led to these successes. Today, patients are diagnosed, they're treated, and they're treated by experts. We also heard that more is needed, and we've heard it from all of our stakeholders, 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 US and Europe, they indicated that they would prescribe a muscle-targeted therapy to over 70% of their SMA patients today. As we look to the US market, we see that over one-third of lives covered by commercial plans today already have coverage, which we heard today, of treatment with an SMN-targeted therapy and a 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. We hear from payers that improving and restoring motor function to enable practical improvements of daily lives and independence is needed. 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 is alignment across stakeholders on the need. There is concentrated and proactive care. Patients are treated, and they're treated by experts. There's a highly engaged and organized patient advocacy community that has lent to the successes today, but who are also not satisfied and agree that more is needed, and they're aligned on the need for muscle-targeted therapy.
Amongst the payers with three 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 apitegromab. We're demonstrating efficacy in a gold standard measure in SMA. The Hammersmith is an SMA-specific and validated functional scale that is used in daily practice today with physicians and peers. We're the only muscle-targeted therapy with four years of clinical experience in SMA patients, and we heard from Jay that we remain with a high retention rate in our TOPAZ study.
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 fewer pokes with a 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. I can say that we consider more than one muscle-targeted therapy in this opportunity. If you look to the SMA market today, you see that there are three 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 three 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 gonna continue to listen and learn from them.
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 we'll launch next month. An excellent patient experience starts with access, and if you speak to anyone 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 a 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.
We also want to ensure that our roles and services provide support to the patients and families, but also to the physicians from prescription to getting on medicine, to staying on medicine throughout the patient journey. We have a thoughtful approach to building, to realizing commercial success. 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 30-50 FTEs.
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 in the remaining Europe and the rest of world. We're on the path to achieving commercial success with apitegromab. We are in the right market. There is a clear unmet need, 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-focused, 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 Miles, to the stage for Q&A.
Good morning, everyone. Hopefully everyone's 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?
Hi, Gary Nachman with Raymond James. Thank you for the presentation. 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 2-12 or 13-21? 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 gonna be a big difference between using one or the other medication. Every patient responds different, and when we started patients on nusinersen, initially, we didn't have anything else. When risdiplam came, I switched 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 gonna 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 motor function, the potential of improving fatigue, you have a gap to fill, right? It's really not. I don't see it because you see the example of the little girl, right?
She's 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 out of it.
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 and the SAPPHIRE study to achieve statistical significance based on what you saw in TOPAZ. And then maybe for you, doctor, 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... You know, Jing, maybe comment on your views on winning. What does winning look like for SAPPHIRE? And certainly, Dr. Castro, what does clinical patient experience look like?
Yeah, so good question. Yeah, we're not, we're not sharing this, detailed statistical plan, but I can tell you what success looks like to me. As Dr. Castro pointed out, even one-point change matters. It's clinically meaningful. We talked to numerous patients, caregivers, clinicians, and that view is broadly shared. But build on the strengths of the TOPAZ data, and we showed you substantial benefit that's beyond what you would expect from this type of patient. So to me, there are two aspects to winning, what that might looks like. First is efficacy. It's clinical and meaningful benefit across different outcome measures, including motor, motor functions, Hammersmith and ROM, and also caregiver-based, outcomes that matters to patients. And on the safety side, we really expect it 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. SAPPHIRE really is designed to optimize all the aspects of the key design and also trying to be representative of the patients. I do wanna 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, of SMN2 proteins, and so therefore, functionally, mechanistically, they're very similar. On top of that, if you think about myostatin, there is tremendous amount of literature out there that really showed that myostatin regulates muscle growth and function throughout life, regardless. Then the other thing to keep in mind, and, I showed you the, 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 in younger patients tended to go a little bit longer, but they also plateau. Regardless of the age, they plateau. In fact, 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-targeting therapies.
James, do you want to comment?
Yeah, just 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, you know, upon success of that trial, that should be the basis for our regulatory approval, right? So we looked at the TOPAZ data with the four-point change. We certainly didn't design the trial to show a four-point change, but I think within that range of two to four, you know, 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. One point matters, two is really incredible, three is, and upward is even better. So 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, you know, Dr. Castro mentioned goosebumps. Maybe you can articulate what, what's goosebumps for you when you see-
Yeah, so, 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 wanna remind you is that there are challenges that we have in clinic, because let's say that kids come this morning, and he's having a temper tantrum, and he doesn't wanna cooperate during the clinic visit. So 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 amazingly important, that sometimes we cannot even see by ourselves. We cannot even measure them.
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 two 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 sit and take long time listening to them, to all the improvement they see that sometimes we're 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 we're not able necessarily to capture.
Thank you. Hi, Kripa. Go ahead. You can ask the question. I can repeat it.
Thank you so much for all the cover. So one question about the stratification that you talked about, of patients who started, you know, SMN therapies less than five years and more than five years. Now, I think TOPAZ and SAPPHIRE have been... They were initiated at different time points in terms of the availability of the other therapies. So, do you have a sense of what the ratios might be in between these two groups of patients? And how might that affect the results? That's one. And, you know, when you talk about the exploratory study beyond twelve years of age that you're looking at, are the same endpoints going to be equally valuable, or will you be looking at other aspects as well for that?
So I'll summarize for those online. So question one 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. I'll ask Jing to comment, and then maybe we'll go to the 13-21 exploratory question. Jing?
Yeah, no, great question. So we are not sharing all the details about the patient makeup. We look forward to sharing those at 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 gonna make a major difference. We've taken that into account as we designed the SAPPHIRE study. What I can tell you is that we're 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, you wanna comment on the landscape a little bit?
Yeah. I mean, I think to your, 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 in from TOPAZ is I think the field is time equals 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. 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 3 study because we can generalize. I think in the end, it's gonna be 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 to the 13 to 21, it's gonna be the same endpoints. I mean, I think Jing had described it. We view it almost as a predefined subgroup. So it'll be the Hammersmith as the primary. It'll 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 2 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 4-6, I think was what Jay was saying. 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 error bars, I think, around it, and so the error 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 I think even 2 had effects.
So, can you remind us if there's pooling ability to pool 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. So how do you think about age differences there in the study?
So we'll turn to Dr. Castro first. I think, quick reminder, that as, 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 hear from Dr. Castro.
And your question is more, is how can I tell the difference between what the patient is at and how much are we getting, right? So, yeah, yeah. I mean, we see these patients... I see these patients every six months. For newborns, I see them every three months. So it's really a, 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 while doing the physical examination. I do motor testing whenever they are able to do, so I'm checking muscle by muscle, deltoid, biceps, all of them. And also, the scales obviously are helpful. But again, going back to what I was saying, when you see it in a stark... Let me tell you a quick example.
For example, one of my patients, she lost the ability to get. So I have her on combined therapy. I have her on two therapies right now. She lost one of them, and what was clear for the mom was that she, in the morning, she was able to stand up, go and get her face washed, 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 I see 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 gonna have a perfect response, and I show you that newborn, that girl who has done amazing, but still is not perfect. I want to make that point always because I want to make sure people understand medicine is not perfect, and we still have a long way to go. So I think that's the best answer I can give you. It's a whole assessment as a patient.
It's not only one scale.
Then to your question around dose. So to the point, we do have two 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 we wanted to go forward with, we selected to go forward with in the protocol. We're gonna 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 the apitegromab or on the improvement.
It's interesting because when we do the studies, we're blinded, right?
We sometimes can tell, you know, there are things that you can see in terms of quality of movement. I didn't mention that. When I show you the case of this girl using all these accessory muscles or just doing it straight up, it's... We can tell those things when we see the patients. We can tell the improvement.
Even when they are blinded. Obviously, I remain blinded. I don'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 their benefit changes or the trajectory changes as the children go through puberty, you know, I mean, go from 12 to 14 or anything on the studies? Is that a valid thought or, you know, consideration?
I'll ask Dr. Castro to comment on her clinical experience as patients move through puberty.
That, that's a great question, and I love you're asking that because what I tell all my families, not only with SMA, but Duchenne muscular dystrophy, any other kind of condition they treat, is during puberty, we see a little bit of, it's not that you're losing function, it's almost like the body's 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 like they cannot control their body, because they're adapting to a higher, to the height and the weight.
That's exactly what I see in neuromuscular, is that period of time where you see the change in function sometimes that is not related to the number, the amount of function, it's just related to the time in life, but they will always come back to where they were before, and that is clear. But that's an excellent question.
Tess?
... Thanks so much for all of the presentations. 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, you talked a little bit about baseline quality of functioning 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 on how we've managed not only SAPPHIRE, but also TOPAZ, in terms of training physical therapists and making sure we have maximum, you know, control and consistency.
Well, and I can start commenting about that. Actually-
Please.
My therapist is, she's had a long experience with the patients with SMA, but it's incredible. Every time we do 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 of another therapist who is evaluating their performance. They record the testing, then it is evaluated by somebody else, so the reliability is definitely there. And again, these therapists get trained 1 to 3,000 times. So I don't have questions about that. To the scores, again, I think they are great scores, and these specific scores, which is specific for Spinal Muscular Atrophy, 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 gonna schedule the patient in the morning. After the patient comes home, 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's sleep. So all of these, if you're able to control as much as you can, all of the other factors, I think the scores, 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 the things I get in the videos are things that sometimes I'll never be able to see in the clinic because they may not having a good day. So we have a great scale, we have great therapists are doing the work, and the companies make sure that they are well-trained.
Jing, you wanna comment on the study and broadly?
Yeah. I wanna say a couple things. I think Dr. Castro covered it very well. I just wanna just add a couple 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 that oversee everything. So, and we believe the study is also well designed. So that, you know, 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. Tess, you had a follow-up question?
Quick follow-up. Thank you very much for all of the color. 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?
Yeah, I think it's fair. I mean, I think, you know, 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 gonna 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?
Yeah. Thanks. Thanks, Allison Bratzel at Piper Sandler. So I had a follow-up question for Dr. Castro. Just hoping you could, you know, expand on how you would see incorporating apitegromab into your care for SMA patients. You know, how many of your patients under management would be eligible for treatment on top of SMN background therapy? You know, what would make a patient a good candidate? And is it your expectation that you would, you know, 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 advanced, where their movement is really none, they have severe contractures, including their elbows, wrists, fingers, they cannot move their wheelchair by themselves, I think that's a patient that likely is not gonna be a candidate for extra therapy. But even when you're able to push the joystick and you are independent in that sense, that's a patient that I wanna be able to keep that. Even that, it's extremely important because that's the way that patient functions.
I have, 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 gonna be a change for them, unfortunately. Was that your other que-- There was something else?
Deepening of effect.
Say it again.
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 has 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 a stagnation. I have seen actual improvement through life.
Ali, you had a follow-up question?
Yeah, thank you. Yeah, now just for the Scholar Rock team, could you talk more about access barriers you're anticipating for apitegromab? You know, how actively do you anticipate payers are going to manage muscle-targeted therapies in SMA? And just, you know, how much are the launches or experiences with Spinraza and risdiplam good analogs for, you know, what you expect with the launch of apitegromab?
Sure. So in terms of access, you know, 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, your second question?
I think she was asking about, the SMN treatments that are out there. Are they analogs?
Oh, sure.
I don't know that they... We would say they're analogs, but they've certainly done a lot to pave the road to the patient.
Yeah, sure. So, you know, 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 , BMO Capital Markets. Thanks for taking the question. Obviously, sort of SAPPHIRE takes a lot of the learnings from TOPAZ and incorporate that into the design. Just wondering, kind of ahead of another sort of Phase 3, SMA readout this year, just kind of identify some of the key differences, right, in, in, 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 on the disease, you know, specificity of the molecule and sort of, you know, the population. What, what, what do you kind of think are sort of the key metrics, if you will, in terms of that population, that design, it's just sort of ahead of, of, of, of, of sort of the SAPPHIRE, readout?
So you're asking about another program, muscle-targeted therapy-
Key differences in that design.
Readout ahead of us or around when we expect to read out.
Yeah.
I think there's really a, probably a clinical angle to that question, maybe a biology angle. Ask Jay and Jing to comment on, and then there's probably a commercial angle.
Yeah, I mean, I think it's, of course, it's a common question as we're approaching readouts of programs. You know, I think the way we've addressed it, we've talked about the science. I really do like our selective strategy of targeting latent, blocking it before it's activated. I think there is the potential that could enhance efficacy 'cause you're not dealing with the act of already circulating, trying to kind of absorb it. So I think that's a really important biologic difference in our, our strategy. You know, I think what Jing said is that, you know, we really in phase 3 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, you know, some interference with the signal, so it may not show the effect that you want. So those, I think, are really key points. You know, I think from our program, it's 2 and above, right? So I think that we are able to get into it 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 and measure. So I think way I think about it is, you know, we should celebrate success in our industry. We absolutely should. I mean, we're talking about improving outcomes for children, you know, and parents fighting to get access and care.
We should celebrate any success. I think that success would read through beautifully to us 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 myostatin as a target, because I think mechanistically it's different, I think the population is different, and heterogeneity may be a challenge. So that, that's kind of how we, we think about, you know, kind of the upcoming events.
And then playing that forward on the commercial standpoint, if they are successful, then there's a, you know, there's a, there's a two, two-horse race in the commercial market. You wanna comment on that, Tracey?
Sure. Yeah. I mean, certainly as we think about the revenue potential for apitegromab, we consider a scenario where there's more than one muscle-targeted therapy, and we look to the SMA market today, where there are three approved SMN-targeted therapies and significant growth in that market. The need is there. Among those muscle-targeted therapies, we feel really confident about our profile that we aim to demonstrate with efficacy in an SMA-specific scale, with treatment and safety experience in SMA patients for over four 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 wanna, I know there's a lot of folks online, that I think a lot of questions coming in. Rushmie, do you wanna pick a couple, and then we'll get back to the room?
There's a double question from an online participant. So the first one is, the dissemination strategy for the SAPPHIRE data. Do we plan to disclose at a conference or in other means? And then the second question from them was an update on the subQ formulation.
Jay, you wanna take the first one, and Tracey, the second one?
Yes. So we absolutely will plan to disclose the top-line results in any forum that we can, that's appropriate. I think, you know, we've been asked questions around baseline demographics and where we would like to present those. You know, 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 up to a conference, we'll certainly do that as a separate call. And we'll give deep color onto the top-line results, from subgroup analysis to the primary endpoint. So that'll certainly be our plan.
We're confirming that'll happen in Q4. We're standing by the guidance-
Yes, absolutely.
That is a Q4.
My point about execution on time delivery, yes, that we're absolutely on track for that.
Thoughts on subQ, Tracey?
Sure. Yeah, 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 four years in TOPAZ. But of course, developing subQ 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, you wanna...?
Yeah, I'll take that. I think, you know, 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 estate. You know, I would say that the Roche Chugai program kind of followed that lead, if you will, and built 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 sort of the landscape, you know, 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, while we describe it as non-ambulatory, you know, ambulatory, you know. You know, we saw videos of it, you know, children with different difficulty with gait. You know, the definition, even within the trial, is able to walk with some assistance, just not being able to really, like, do a 50-meter walk. I mean, there, 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.
Strategy, similar, but, I mean, in terms of the target, but our, our approach, I think, is very, very good, and I think we have a bit of an advantage given time.
Could we ask Dr. Castro to 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 assistance, meaning assistance or a cane, a gait trainer, 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.
Yeah, and if I could just add to that, right? Because of the scales that we've talked about, I'm giving you a personal opinion now. I really like the Revised Upper Limb Module scale. It focuses on upper extremity, and you showed a beautiful video of that 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?
We saw the graph on the Revised Upper Limb Module just continues to show some nice effect. To be clear, that subgroup is the cohort in 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. We had, I think, saw a question here. Yep.
For Dr. Castro, for the initiation of therapy, how are you thinking if apitegromab is approved? Will you be initiating therapy with standard of care, or will you wait for standard of care to see that plateau that we'll be talking about after two years or at what point?
That is a great question. I think that it depends the age that we're treating the patient, the time I'm treating the patient, right? When I talk to... Let's think about a newborn. I tell the families, we're gonna treat the baby, and we're gonna have at least a period of 9-12 months, where we're really identifying what changes, what are we seeing, what are not, we're not seeing. In the case I presented, she actually, by very early, she already had these stages, so I had to act on earlier than I would've with other cases. Because at the same time, as much as I wanna give them what they need, there are some families that really will like everything, right? I mean, it's your child, you will do anything. So they wanna, they think that they just more is better.
So I think that it depends on the time with the patient, where, how the patient is responding to that therapy, but in the case 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 acts 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 that 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 gonna 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.
Would you continue therapy past a point of plateau, or, 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 scales, is what 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. The ability to go through the day, the ability to see the whole day with your, you know, straight trunk, things like that, that we see are better. But even with time, you start seeing some deterioration, like you were saying.
Mm-hmm.
We definitely see that. And I just wanna make a point about something that we don't think about, is lung function when you're sitting. 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 lung 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 gonna start going to the one side, you're gonna 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, well, they are sitting." Yeah, they are sitting, but they are using their arms. If we don't treat that, you're gonna have a patient that is gonna have more complications like pneumonias, aspirations, difficulties eating, and so on, that are gonna reflect just by the fact that you're losing trunk strength.
We started with a very strong patient focus, and I think it's a great place to end the Q&A with that great patient, 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.
Thank you.
Hi, everybody. Wanna keep on time. Can we resume? Everyone's caffeined up. We're very thrilled to have Dr. Jastreboff here to kick us off in the cardiometabolic obesity portion of this morning's session. Dr. Jastreboff.
Thank you. Thank you so much. Thank you for joining us this morning. So we're gonna pivot and talk about obesity now. Usually, I'm an endocrinologist, and I speak to scientists and clinicians, and this is really a unique opportunity for me because all of you sitting in this room have the opportunity to actually pivot the field in the direction where it needs to go. What I'm going to speak to you about today is to give you a landscape idea of where we are right now, but also where we need to go. That is that when we're treating obesity, it's not for weight reduction, it's for optimizing health. That's really why muscle matters. These are my disclosures. So let me ask you a question. Why are we all here today?
I would say it's because we want to help our patients lead healthier lives, and specifically our patients with obesity. If you think about obesity, it's truly a unique disease, because what other disease could you treat and mitigate, prevent, or treat 200 other obesity-related diseases? Diabetes, cardiovascular disease, 13 types of cancer.... How many diseases can you say you can treat and potentially treat all these others? Now, in terms of obesity, it's a significant problem, and by 2030, nearly half of Americans will have obesity. Half. The question is: can we pivot? Can we do this appropriately? Can we change this landscape and truly help people lead healthier lives? This fact, this half of Americans, there's another thing that it raises, and that's the important point of half of Americans did not wake up one morning and choose to have obesity.
This is not a behavioral choice. And so why is it so difficult to lose and maintain weight loss? Well, it turns out that we have this amazing, beautiful biology, where hormones communicate with our brain, and they tell us how much energy we should store. If we could not store energy, we would die, we would starve. And the way that our body stores energy is by storing fat. And so our brain and our body wants to defend an appropriate amount of fat, and we call that the defended fat mass or the set point. Now, one might say, "Well, if you have this beautiful biology, why in the world do half of us have obesity?" Well, it turns out that our obesogenic environment evolved much more quickly than our biology. So let me just take two slides to show you what I mean.
So here's a house with a thermostat, and let's say that thermostat is set to 70 degrees. Great. Okay, so what happens when it's hot outside? Well, the thermostat senses this, and the air conditioner turns on. We're not aware of this. We don't walk over to the air conditioner. It just happens. Now, the same thing happens when it's cold outside. So when it's cold outside, the furnace turns on, and that temperature set point is maintained. Now, what happens in the middle of summer? It is July or August in New York City, extremely hot. Well, what happens is sometimes that temperature set point goes up. We open the windows, we try and do everything that we can, but the temperature goes up. And it turns out our body does this with many things. It regulates many body functions, and we call this homeostasis.
So whether it's body temperature, immune function, or electrolyte balance, and it does this with body fat. So now let's look at our bodies. Our brain is the thermostat, and our brain sets a defended fat mass or set point. Now, when we gain weight, or specifically when we gain fat mass, this signals to our brain via various hormones that now we're very familiar with, to increase thermogenesis and decrease appetite. So burn more and eat less. That's what should happen. Now, the opposite happens when we lose weight or when we lose fat mass. But now superimpose on this the obesogenic environment, an environment filled with ultra-processed food, with lack of sleep, lack of physical activity, leading to unhealthy muscle, a lot of stress, and our body is responding to this obesogenic environment.
Now, this is critical because when we think about obesity and this increase in defended fat mass, when we're talking about obesity, we're talking about an inappropriate setting or dysregulation of the defended fat mass. So on a population level, the amount of fat that we carry has been increased, and so any treatment that we utilize has to target this biology. Now, there's something key here. All the therapies that we have right now contribute to weight loss. There's nothing that targets just fat loss. So basically, patients lose both fat and lean mass, and that's why we're here today. Okay, so we're in the midst of this transformation with these new medications, and I'm going to spend a few minutes speaking about this, laying the groundwork of where we are.
I'm going to show you two patients, one who was treated with older medications and one who was treated with a newer medication. Now, I'm not including the names of the medications, and this is purposeful. That's not the point of these cases. The two things I want to highlight, the first is combination therapy, critical, and the second thing is that the second patient responded very well, but what proportion of that was fat mass loss versus lean mass loss? Okay, so the first patient, 18-year-old, who I saw, her BMI was 57. At age 18, she already had obesity-related diseases, sleep apnea, prediabetes. Both her parents had diabetes. She was so afraid she would develop diabetes. So this is what happened over the course of about 3-4 years when I treated her. So I started her on a medication.
She began to lose weight. We continued the first medication and added a second. Then I added two additional medications, a combination therapy. What you can see here is that over the course of about 3-4 years, she lost 140 pounds, which was 45% of her body weight, almost half of her body weight. Her BMI came down to 30, 31.6, and her A1C normalized. The key for this patient was combination therapy. So we need to figure out what those combinations are, what combinations can maximize the quality of the weight reduction and her health. Now, the second patient is a 49-year-old. I saw her when her BMI was 34. Now, her story is one that we see with many patients. The issue was not losing weight. Look at how many times she lost weight.
The issue was gaining it back, which is, again, what our body is designed to do. It wants to store energy or fat. So when I saw her, she also already had obesity-related diseases, and this is what happened when we treated her with one of these new medications over the course of 1 year. She lost nearly 100 pounds in 1 year, and that was 45% of her body weight, so nearly half of her body weight. And the key here is what we don't know with this patient is how much of that was fat and how much of that was lean. Now, of course, we want to maximize the amount of fat loss while preserving muscle mass. So great response. Can we do better? Okay, so we are clearly at this watershed brought on by the recent introduction of highly effective anti-obesity medications.
We have the older ones that I showed you that are highly effective in combination, and now moving forward with semaglutide, tirzepatide, bringing on all of these new anti-obesity medications in development. The ones that are leading the charge that I'm going to spend a few minutes on are nutrient-stimulated, hormone-based therapies such as semaglutide and tirzepatide. Now, we also have many other classes that are being developed. One key one, and the reason we're here today, are myostatin activin pathway inhibitors. These are shown here in blue. Now, these have the potential for preserving muscle mass while people are losing fat. There are other medications in development as well. There's an MC4 agonist that's already approved for monogenic obesity, and there are other mechanisms currently being explored. Okay, so let's spend a few minutes talking about nutrient-stimulated hormones and these therapies.
So what the heck are nutrient-stimulated hormones? Well, simply put, they're any hormone that's secreted when we eat food. Now, the one that we're the most familiar with is GLP-1, because it's been used, the receptor agonist for this hormone, have been used for the treatment of diabetes for almost two decades. Now, what do these hormones do? Well, they communicate with various tissues in our body as well as our brain, about energy homeostasis. How full are we? How hungry are we? How much energy do we want to burn? That's what these hormones tell our brain. And so currently, what the focus has been is on combining these various different hormones or receptor agonism for these different hormones with GLP-1 as dual agonist and triple agonist. But know that there are also monotherapies of these hormones in development, such as PYY and amylin.
Where are we with this certain class of medications? Well, these are just the medications in phase 2 and 3 of development. Here's the ones in phase 3, and these are the two that are FDA approved. I'm just going to focus in on a few of these today to demonstrate where we are currently. So semaglutide, as we all know, was the first one that demonstrated this double digit average weight reduction of 16.9% on treatment with an average weight reduction of 34 pounds. This is also effective in teenagers and is now FDA approved for age 12 and above. Now, importantly, when we're treating obesity, we're working to optimize health, and here are the cardiometabolic measures, all of which improved in the STEP 1 trial when patients were treated with this medication.
Now, the question is, do these improvements in cardiometabolic measures translate to actual improvement, for example, in cardio protection? The answer is yes. The SELECT trial enrolled over 17,000 individuals with obesity without type 2 diabetes and demonstrated a 20% reduction in cardiovascular death, non-fatal MI, and non-fatal stroke. Clear improvements in health. Top line results of another trial are also demonstrating kidney benefit. Now, what about tirzepatide? This medication is a GIP/GLP-1 receptor agonist, so a dual agonist, recently FDA approved for obesity as well. I was very fortunate to lead this trial, where we looked at over 2,500 patients, and what we demonstrated was that with the highest dose of tirzepatide, on average, patients lost 22.5% of their body weight, which translated to about 52 pounds of weight reduction in just 72 weeks.
Additionally, nearly 40% of participants lost more than a quarter of their body weight. So someone weighing 200 pounds at the start of the trial would have lost down to 150 pounds. Now, again, we saw these improvements in cardiometabolic measures, and the question is, will this translate to improvements in health? And the SURMOUNT-MMO cardiovascular outcomes trial is ongoing, looking at not only secondary prevention, but very importantly, primary prevention of cardiovascular events. It's also looking at kidney outcomes, and top-line recent data also showed improvements in obstructive sleep apnea. Okay, so one of the questions that we had in this study was: Did patients actually reach weight plateau? So when patients are losing weight, when we start these medications, they have a weight reduction phase and then a weight plateau. And so we weren't sure.
The SURMOUNT-4 trial actually gave us this answer because the trial was longer. It was 88 weeks. So everyone received tirzepatide for the first 36 weeks, then they were randomized to placebo or tirzepatide. And what you can see is that when patients were treated with tirzepatide, they actually lost on average 26% of their total body weight. And so most people, on average, lost up to 62 pounds, and more than 50% achieved weight reduction of 25% of their body weight. So we learned a couple of things from this trial. One is that the weight plateau does potentially take longer, the more efficacious an agent is, and weight regain does happen. Now, there's variability in both the weight reduction response as well as the weight regain, because there's not one type of obesity, there's many different types of obesities.
We just don't have a way to phenotype them yet. The other important thing is we don't know what amount of weight regain was due to, fat or, and what amount was due to muscle. So we don't know what patients are regaining after this rapid weight reduction, and that's also important. Now, this highlights this need to treat obesity chronically, and that's because obesity is a chronic disease. We need to treat it as we would treat any other chronic disease. So let me give you the example of hypertension really quick to illustrate this. So say you have a patient with high blood pressure. They come in, you start them on a medication, their blood pressure goes down. Awesome. Now, what happens when that medication is discontinued?... Well, the blood pressure goes up, and we're not surprised. Of course, the blood pressure goes up.
You stop the therapy, it stops working. What about a patient with obesity? So they come in, and they have an elevated defended fat mass. And what happens? We start a medication, they start to lose weight. Now, what happens when we stop that medication? Well, the defended fat mass goes back up, and the weight follows. And so we should not be surprised that when we stop the treatment for obesity, then the weight is regained, just as for any other chronic disease. Okay, so now what's next in the pipeline? So an amylin analog, cagrilintide, is being paired with semaglutide, showing average weight reduction of 17.1 at 20 weeks. Glucagon GLP-1 receptor agonist, so for example, survodutide, demonstrating average weight reduction of 18.7% at 46 weeks.
A triple hormone receptor agonist, retatrutide, combining GIP, glucagon, and GLP-1 receptor agonism. I also led this trial, and it was just 48 weeks, so just 11 months. At 11 months, participants on average were losing 24.2% of their body weight, and they had not plateaued. We need to do the longer phase 3 trial to see the full efficacy results. On average, participants were losing about 58 pounds, and it was really impressive to see that with the two highest doses, all participants lost at least 5% of their body weight. This is all to illustrate that we have now achieved weight reduction. We know how to reduce weight. What we don't know how to do is target fat while preserving muscle, and that's why we're here.
Okay, so in case you're worried that your patient cannot take a weekly injectable, that's all the ones I showed. There are orals in development as well, daily oral medications. So oral semaglutide is a peptide and demonstrated average weight reduction of 17.4% at 68 weeks, and orforglipron, which is a small molecule in development, demonstrating 14.7% weight reduction at 36 weeks. And in case your patient cannot take a weekly injection or a daily oral, there is a monthly GIP receptor antagonist, GLP-1 receptor agonist in development, MariTide, and that is in phase 2, and we await those results. Okay, so we can achieve 15, 20, 25 total body weight reduction. We are there. We're now beyond weight reduction. When we're treating obesity, our goal is improving health. And how can we do that?
Well, the quality of the weight reduction is critical. So when we think about treating obesity, we have to take into account body composition and muscle function. As we treat obesity, maintaining muscle mass is key for optimizing health. It's key for that goal of why we're treating obesity in the first place. So why is that? So in terms of muscle, we know that it contributes to increased metabolic rate, improvement in insulin sensitivity, improvement in the metabolic profile of our patients, reduced total body fat, and improved strength, and you're gonna hear more about this today. Now, you may be asking, "Well, what proportion of the weight lost is lean body mass from any form of treatment, whether it's diet, surgery, or medications?
Is one better than the other?" So on the y-axis, what I'm showing is the proportion of weight loss from lean mass as a percent. On the x-axis, what you're seeing is all the studies that have been done to actually look at this. Okay, so let's look at diet first or caloric restriction. Okay, so low-calorie diet, what do you see? Lean mass loss, some loss, some, in some of the studies, 20%, in some of the studies, nearly 40%. Ah, but you might say, and somebody asked me right before this, "What if you add in exercise? What happens then?" Great question. If you add in exercise, you're still losing somewhere around 20%, right? So you maybe we can make some kind of a dent, but really not fix the issue. So 20%-40%, let's say 30%. What about surgery?
Is it better with surgery? Do we not lose lean mass with surgery? Well, we do. So different types of bariatric surgery procedures, you're still losing lean mass. And, for example, some of them have even higher degrees of lean mass loss. What about medications? So specifically, GLP-1 receptor agonist. Here you see liraglutide, exenatide, and semaglutide. And again, what you're seeing is that same or similar range. It's about a third of the weight loss is as lean mass. So let's look a little bit more closely at semaglutide and tirzepatide. So for this first one, this is a sub-study, a DEXA study in the STEP 1 trial of 140 participants. Semaglutide is shown in maroon. So first, in terms of fat mass loss, and this is in kgs.
In kgs, patients who received semaglutide lost about 10 kgs in terms of fat, 10.4 kgs. What about lean mass? Well, participants who received semaglutide lost nearly 7 kgs of lean mass. So this is significant, right? Can we do better? Now, what about tirzepatide? Now, this data is in percent of the weight loss. It's in 160 participants. Again, a DEXA sub-study of the SURMOUNT-1 trial, and tirzepatide is in dark blue. So first, fat mass loss. So the fat mass loss was about 33.9%, and the lean mass loss was about 10.9%. So again, patients are losing a significant amount of weight, but can we maximize the amount of fat they lose while minimizing the amount of lean mass that they lose?
And so that brings me to beyond just weight reduction to optimizing health. And we really can do this by improving the quality of weight reduction through combination therapy. So think back to those first two patients that I showed you. Would it be possible to maximize the amount of fat that they lost but minimize or preserve their muscle? And I think potentially we can. So let's say that we were to pair nutrient-stimulated hormone-based therapy such as semaglutide and tirzepatide, and at the same time that they're starting the semaglutide or tirzepatide, pairing it with a myostatin activin pathway inhibitor, pairing it with a therapy that targets muscle. And so with this, can we improve the weight reduction? Can we maximize the amount of fat that is lost while preserving the muscle mass?
And it doesn't end here in terms of the potential applications for these medications. What if we paired them with bariatric surgery? What if patients were to start one of these muscle-targeting therapies at the time that they undergo bariatric surgery? Could we also help them preserve that lean mass at that time? And so with that, I hope I've taken you beyond just weight reduction to optimizing health when we're treating obesity, because that is our goal. And so we want to improve the quality of weight reduction, maximizing the amount of fat that patients lose while preserving muscle mass, and that's why muscle matters. Thank you so much for your attention, and I really look forward to your questions in the Q&A. And now I'll turn it over to Mo.
Thank you very much, Dr. Jastreboff, for a great overview of obesity therapeutics as well as the importance of muscle. My name is Mo Qatanani. I'm the CSO at Scholar Rock. It is my pleasure to be with you today to talk to you about our differentiated platform in discovering and developing selective antibodies, and in particular, about SRK-439, a selective anti-myostatin designed for optimal profile in obesity. This is what I'll plan to cover with you today, and we'll start with talking about the best-in-class platform that we have to develop the antibodies that are highly selective. At Scholar Rock, we have a differentiated approach in discovering and developing antibodies, and that is driven by deep structural insights into validated targets, including growth factors.
Instead of targeting the mature growth factors like most do, we actually target the latent forms or the precursors of these growth factors. What that does is our antibodies bind to these inactive forms, the precursors, and prevent them from being activated. So these growth factors don't have a chance to even signal within the tissue that they act in. That gives us a profile that is optimized for efficacy as well as for safety, because we're selective, so we mitigate off-target effects. We have a great track record in translating our platform and our science, our exciting science, to the clinic to benefit our patient. First, with apitegromab, as you heard earlier, this is a selective anti-myostatin that was developed for SMA.
We took it through preclinical models of SMA, and we're really excited to show increase in muscle strength in these preclinical models, and that supported the rationale to push it forward in the clinic. As you heard earlier from Jing, we were very excited to see the data from our TOPAZ that showed substantial and sustained improvement in motor function, and we cannot wait until Q4 to see the data from SAPPHIRE. Second, SRK-181, that is a selective anti-latent TGF-β1 antibody. The emphasis is on the TGF-β1 because it's been a challenge to be selective for that isoform. So we discovered and developed this antibody, and we took it into tumor models that are resistant to checkpoint inhibitors, and it's being developed for patients with advanced solid tumors.
So we showed efficacy in preclinical models, several preclinical models of checkpoint inhibitor resistant models. And we also showed proof of mechanism, and that is the increase in the inflammatory microenvironment of the tumors. Then we took that into the clinic with our DRAGON phase 1b, and we're seeing very promising data across tumor types, as well as proof of mechanism of overcoming the immune exclusion that are seen in these tumors. And we look forward to sharing with you more data at our ASCO oral presentation in a week or ten days. And now, today's focus is on SRK-439. That is our anti-latent myostatin, that is selective, that is designed for obesity.
We'll show you today, and we'll highlight some of the data that we had when we took it in translational models in diet-induced obesity, where it's driving preservation of lean mass during GLP-1-induced weight loss. We cannot wait to file the IND in 2025 and push it to the clinic right after. Next, I'm gonna talk to you a little bit about the importance of muscle, as well as the different approaches that people have taken to improve muscle or to preserve muscle, and why we believe being selective to myostatin is the right approach. As you heard earlier, muscle is critical for overall health. It is the biggest metabolic organ in our body. It's also an endocrine organ, so it secretes factor of
It secretes factors that affect different systems. It plays a role in multiple biologies, including increasing basic metabolic rate, as well as being the driver of glucose disposal and hence insulin sensitivity. So preserving muscle is important. We believe that myostatin is the right target for muscle growth. Myostatin is specific to muscle, is predominantly expressed in muscle and acts locally to inhibit muscle growth. It is genetically validated, so loss of function mutation across different species, including humans, leads to muscle growth with no evident safety liabilities. It's pretty safe. Inhibition in adults leads to muscle growth. We've seen that. And earlier, as Jing had highlighted, selective targeting leads to improved motor function, as seen in the TOPAZ trial, with favorable tolerability profile observed in more than 200 patient years. So inhibiting myostatin will lead to muscle growth and preservation....
Now, there are other approaches that people have pursued to increase muscle growth, but we believe that being selective to myostatin is the right approach to do it safely. These approaches, including targeting the receptor itself, which is by its nature, non-selective. So by targeting the receptor, you're targeting the different ligands the receptor actually binds, including activins, GDF11s, and other ligands that are not listed here. Other approaches include ligand traps as well, which are also non-selective, where you're inhibiting activin, GDF11, and other ligands. Now, if you look at the expression of these receptors and the ligands, they are expressed beyond muscle. They are expressed in key tissues, including kidney, liver, the gut, pancreas, you name it.
So we'd expect that when you inhibit these ligands or the receptor, you're not only gonna get muscle growth, but you'll get other effects that you don't want. And here's a list of some of these adverse events that we're seeing by inhibiting these ligands or receptors, including activin. And that would include health risk, GI problems, diarrhea, as well as pancreatitis, nosebleeds, epistaxis, which is really important, and a reduction in reproductive hormones. activins actually were discovered because they drove FSH production. So when you inhibit it, you lead to the reduction of FSH and reproductive hormones. Also seen were acne, rashes, and skin abscesses. This is linked to the biology of activins and other factors because they drive immunology, they drive proliferation and differentiation of epithelial and endothelial cells.
So when you inhibit them, you expect to see some of these effects. So selectivity is important to drive muscle growth safely. Next, I'm going to spend the next few slides to talk to you about SRK-439, its differentiated approach, and why we're excited to push it forward to the clinic to preserve muscle during weight loss. This is why we're confident about SRK-439. It is a new anti-myostatin that we specifically designed and discovered for obesity. It has exquisite selectivity, and that is important, as I highlighted earlier. So it only targets myostatin, and myostatin does one thing only: that is, inhibits muscle. It has strong...
We have strong scientific validation with SRK-439, and I'll highlight some of that data that we have here, that gives us confidence in pushing forward, and pursuing and advancing it to the clinic. These are the three different aspects that we believe differentiate SRK-439, and I'm gonna take you through them in the next few slides. First, starting with selectivity. SRK-439 discovery and development is a combination of years of experience that we had at Scholar Rock, targeting myostatin and selectively targeting myostatin. And if you look on the right, this is a binding assay. On the y-axis, you see the intensity of the binding, and on the x-axis is the different concentration of SRK-439. As you can appreciate, when you increase the concentration of SRK-439 in green, you see an increase in the binding.
You see absolutely no binding to the related factors. That is latent GDF11 and latent activin A. So targeting latent growth factors and latent myostatin gives you exquisite selectivity, and this is what we're showing here. Now, to take you through some of the data that gives us, that shows the potential of SRK-439 to drive healthier weight management, by preserving lean muscle mass during weight loss. And this is a study conducted in diet-induced obesity. This is the standard model that people use in the field. On the y-axis, this is % change of lean mass. This is quantitative NMR, in these animals. And you look at percentages of changes in lean mass from the start of the study to the end of the study. And on the x-axis, these are the different treatment groups.
So we treated with semaglutide as a GLP-1 receptor agonist, and as you can appreciate in purple here, you see significant reduction in lean mass as a percentage. Now, when we add SRK-439, you see dose-dependently preservation of that lean mass, which is what we want. And these are preservations starting with doses as low as 0.3 mg per kg, which is really exciting. What we also saw is dose-dependent enhancement of fat mass observed in this study, which is also exciting because as you think about it, as Dr. Jastreboff earlier highlighted, now you're pushing weight loss towards fat mass and preserving your lean mass, and hence, hopefully, the potential for long-term metabolic benefits that we'll see in these in these studies. Which is also what we see in this study.
So this is the same diet-induced obesity study, and as we highlighted earlier, muscle is important in glucose disposal and glucose homeostasis, so we looked at glucose. And again, the y-axis is the fasting glucose, x-axis is the different treatment groups. You can see that with semaglutide, as expected, you see a reduction in fasting glucose. But when you add SRK-439 on top of semaglutide, you see additional reduction of glucose, again, starting at doses at 0.3 mg per kg, about 20% additional reduction in glucose. So SRK-439 has the potential to improve the metabolic profile, as we see here, by preserving muscle mass. So I'm gonna show you some data today that we haven't shared before, and that data relates to this question....
It's been established that targeting myostatin selectively is safe, but are you limiting efficacy by being selective to myostatin? And the answer to that question is no, and I'll take you through that data. So this is a head-to-head study that we conducted in diet-induced obesity model that looks at SRK-439 compared to an anti-activin receptor antibody, which is the murine equivalent to the, to the molecule being tested currently in the clinic. Again, this is QNMR, looking at lean mass, with the y-axis being percentage reduction in in lean mass or percentage change in lean mass from the start to the end of the study. And then the x-axis is the treatment group. Again, as you appreciate, in purple, semaglutide leads to significant reduction in lean mass from the start to the end of the study.
What you see when you add SRK-439, you see a dose-dependent preservation of lean mass with doses starting as low as 0.3 mg per kg. Now, when you look at the anti-activin receptor antibody, you only see preservation at the highest dose, which is at 20 mg per kg. We chose that dose, the 20 mg per kg, because that's the only published dose in diet-induced obesity that been published on. When you look at lower doses of anti-activin receptor, you really don't see any improvement in muscle preservation. Compare the highest dose muscle preservation to actually our 1 mg per kg versus the 20 mg per kg. Selectively targeting myostatin will give you the efficacy and will also potentially mitigate the off-target effects that you'll see in hitting the receptor or the other ligands like activin.
So this is a table that highlights the best-in-class potential for SRK-439 versus the other approaches that people have taken to inhibit myostatin in obesity. And as you can appreciate and see here, SRK-439 checks all the boxes that we believe is, are important to achieve this potential or the best-in-class profile. In summary, SRK-439 has an exceptional profile to drive healthier weight loss and healthier weight management safely. It has the right target, the right tissue, the right safety profile, and the right product profile, and we really can't wait to drive SRK-439 into the clinic. And with that, I want to welcome Jing that will talk to you about our clinical plans for obesity.
Thanks. Wow! Those are two tough acts to follow. Thank you, Dr. Jastreboff and Mo, for painting such an exciting picture about the therapeutic space. I personally cannot think of a more exciting place to be than to be part of this, with one exception, perhaps for SMA. All right, let's get into this. So first, I wanted to speak about the opportunity, specifically how a muscle-targeted therapy fits into the overall picture. And then we'll share with you the plan for 439. So as Dr. Jastreboff pointed out, the approval of the two GLP-1 agonists has really taken the field by storm. The rapid uptake speaks to the tremendous opportunities that has been built over decades, and that continued to rise.
As we sit, stand here, really appreciate the benefit of these amazing medicines bringing to patients, we're also quickly learning about the challenges that comes with their use. Tolerability issues, for example, primarily GI side effect, that has led to early discontinuation in some patients, and the rebound weight gain that follows after discontinuation. And importantly, Dr. Jastreboff highlighted eloquently, a significant proportion of the weight loss comes from lean muscle mass. So what can we do then, to address these issues, and why is muscle so important? So to briefly recap what has been said earlier, muscle is the largest metabolic and endocrine organ, with a plethora of important functions to play. Central to the benefit of muscle is the foundational role that enables physical activities that we do every single day.
But what's less appreciated is the beneficial effect of muscle on metabolic profile, on energy metabolism, and glucose homeostasis. So in a nutshell, preserving appropriate amount of lean muscle is essential to healthy living. So in this context, we have an amazing offering that Mo just teased a little bit with the non-clinical data. Nature has showed us the way. Myostatin is our body's natural mechanism to regulate muscle mass and function. We've already showed you that a selective myostatin can improve motor function. So preserving muscle has the ability to improve the durability of weight loss because it could potentially raise the basal metabolic rate. In addition, preserving new muscle could also benefit, improve the quality of weight loss. So in summary. On top of that, our unique approach of upstream targeting and high selectivity that minimizes the off-target side effect is uniquely suited for long-term use.
So now let's talk about the plan for 439. I've already showed you this before. Selective myostatin improves motor function, and what I wanted to say here is that myostatin regulates muscle growth and function throughout life. That is true to the extent that muscle integrity is maintained, and that includes the setting of obesity. So because apitegromab is already in the clinic, we can actually test this hypothesis really quickly. You can see on top the SMA program in phase 3, and we announced this morning that the EMBRAZE study has been initiated ahead of schedule. As we stand here, we have 2 patients screened and going, and based on that learning, we can then design the development program for 439. So what do we want to see?
The primary objective of the proof of concept study is to demonstrate that a selective myostatin has the ability to preserve lean muscle in the context of obesity, receiving a GLP-1 agonist. In addition, we wanted to see that the favorable safety and tolerability profile that we come to be familiar with now is validated in the obesity setting. Lastly, we also would like to investigate the potential effects of a selective myostatin against a number of exploratory endpoints that will be used for as we think about the development plan for SRK-439. Here's the study design. Overweight and obese patients are randomized 1:1 to the combination of apitegromab and a GLP-1 agonist, or the placebo and a GLP-1 agonist. Patients are assigned to either tirzepatide or semaglutide. The treatment duration is 24 weeks.
The primary endpoint is lean muscle mass change from baseline by DEXA scan. We included secondary endpoint that are safety, PK/PD, and additional weight loss measures. We're also including a bunch of exploratory endpoints, specifically to assess the metabolic profile and physical function. We also plan to have an additional assessment at 32 weeks that will allow us to take a preliminary read at the potential durability of effect. In other words, the potential ability to attenuate the weight rebound. So what is the regulatory pathway forward? Well, the FDA has clear guidance with respect to our approach, and they're supportive of a combination strategy. The key is to demonstrate added clinical benefit that can be attributed to the combination. So I'm showing you here on the right, a couple mechanisms to do that.
The most direct one is to do a randomized study with weight loss as the primary endpoint, and to include secondary endpoints to assess potential clinical benefit that is attributed to preserving lean muscle. With respect to outcome measures to assess the clinical benefit, I have included a couple of examples here. You know, one example is really to look at the effect on metabolic parameters, such as hemoglobin A1C, which has been recognized as an accepted FDA surrogate endpoint. Other outcome measures that can assess clinical benefit include the physical function and the ability to improve the durability of weight loss. Reflecting on our track record that Mo has spoke about eloquently, we have exceptional antibody engineering based on deep biological insights. We've built robust nonclinical evidence in translational disease models and ultimately clinical evidence across a number of diseases with transformative potential.
And so we're uniquely suited to take advantage of this and bring our expertise to the obesity space. To conclude, the EMBRAZE study takes advantage of a clinical asset to really quickly assess the hypothesis and the beneficial effect of preserving lean muscle. And SRK-439, with the best-in-class profile, is optimally designed for obesity, and we have strong scientific rationale to demonstrate clinical success required for regulatory approval. And so with that, I'd like to invite the speakers to come to the stage and then Ted to moderate the Q&A.
Thank you, Jing. Oh, that works.
Okay, we have a lot of hands up. Okay, David, please go ahead.
Questions. First off, on the activin agents and their safety profile, is—Just straight up, is there any way to actually safely target activin, in your opinion, that does not, you know, affect follistatin or other, you know, biochemical markers? And then the second, and it's been almost 30 years since I took a biochemistry course, but.
... As I recall, one of the mechanisms or the reasons why you have a catabolism of muscle when you're dieting is to generate essential amino acids. Is there any kind of, you know, control over protein intake or anything like that in the patient's diets when you think about that for the future? Or if that's not a concern.
Mo, you want to start with the biochemistry lesson?
No, I'll start with the activin.
Okay, go ahead.
I'll find the muscle to maybe to Ania to comment on it. In my opinion, the answer is probably no. If you look at the expression pattern of activins, they're pretty much all over the place, right? They're in the body versus myostatin, which is really I mean, if you go to the Human Protein Atlas, it's in the muscle, myostatin. And then you look at the activins, it's pretty much in a lot of different tissues. And they play a role throughout, not just in development, throughout adulthood, in endothelial cells, proliferation, differentiation, in immune biology. So safely targeting activin, I'm not sure that strategy will be able to get there. I think if you want to safely target muscle growth, myostatin is the target.
In terms of the protein intake, it's an interesting question, and right now, what we do when we start patients on these medications is we counsel them about both resistance exercise as well as protein intake, just as we would if they underwent bariatric surgery. Now, I showed you the data with bariatric surgery, and all of those patients are required to have exercise counseling as well as nutrition counseling before and after bariatric surgery, including high-protein shakes and really prioritizing protein when they're eating because they're eating significantly less, especially in the acute phase after bariatric surgery. The same thing is the case when we prescribe these new, highly effective medications. And, you know, the short answer is we don't know how much of that we can potentially prevent.
If you look at the bariatric surgery data, it doesn't look like we can prevent a lot of that lean mass loss, but we're going to keep on trying, and I think those studies are needed. Potentially we can prevent some of it, but certainly not all of it. By the way, one other thing, everyone, you guys can call me Dr. Ania. I know my last name is slightly challenging.
Okay, thank you. Mike?
Thanks. Michael Yee from Jefferies. Maybe for the team, can you describe your thoughts around how much muscle mass, or in this case, muscle preservation, is likely to predict what amount of clinical benefit on what endpoints? So yes, we are definitely preserving muscle, but how does that predict actual clinical benefit, and how much? The second question is, perhaps after one year of treatment of GLP-1, what do you think is going on with lean muscle? And do you need to treat with the drug longer than the time course of which you are losing weight?
Do you want to take the first one?
Jay, you want to-
Yes, maybe I'll start. I mean, I think we're still early days to determine exactly what is the quantity that we need to preserve on the lean muscle mass. You know, I think as we take a look at the... maybe, you know, Dr. Jastreboff can comment, you look at the steepness of the decline. You know, as we think about it, it would be good to flatten that decline and kind of keep as much of that lean mass as possible. So I think that would be the first measure. We saw with Mo's scientific experiment with the nonclinical models, where we actually had further reduction in glucose metabolism. That's really of interest to me, as we think about what we potentially can do enhancing the metabolic profile.
And we might have a pretty good gauge as we start to see the level of preservation, whether that influences that measure. I think we'll learn more as we go forward. So I'm looking forward to, to Jing and delighted that the team has really advanced that EMBRAZE proof of concept study. That'll give us some insight. So maybe that's the first point. You had another point that I-
Do you need to keep treating, or is it?
Hmm.
The time course, which you wait, like, they generally trough?
Yeah, that's really an interesting question. Again, we're starting in our development program to answer some very discrete questions, and I'll kind of get to that answer. I think first and foremost, from EMBRAZE, it is, can we preserve lean muscle with our highly selective strategy? Yes, no. That'll be very clear. Then beyond, the question is, well, how can we maintain that? Can we do that? Can we get enough growth that we could have more of a maintenance-type strategy to continue? I think that'll be of interest. I think the potential to measure in the EMBRAZE study, where we can see whether or not once we stop therapy, whether we still maintain that DEXA scan, will be interesting. That'll give us some idea of that maintenance portion, and then we can further explore that when we get SRK-439 at the clinic.
There's some really intriguing questions, I think, as we look at this going forward, that subsequent studies will answer. But I do think there's an opportunity for preservation, for maintenance, and, and we'll see, and I think hopefully to enhance the metabolic profile. Because I think we're very much aligned with our interest in this area, with healthy weight loss management and try to improve outcomes.
We have Tess in the back.
Thanks again for these presentations. And thank you for the details on the EMBRAZE trial design. Congratulations on the kickoff. What dose are you using? And then, did you consider adding a monotherapy arm for apitegromab to the GLP-1 arms? And then-
It looks like you might have put just on the screening criteria. Just kind of wanted to dig in a little bit on your thought process behind those. I'm sure there was a lot of thought. Like, just curious on the enrollment criteria around BMI, what drove that, that criteria there? I think it looks like you might have put a cap at 45. So why at that level? Thanks.
Sounds like great questions for Jing. You wanna pack that study a little more?
Yeah, so let me keep it straight, right? So the three questions you wanna just make sure I-
The criteria around BMI.
Right, right.
Why we didn't or did we consider a monotherapy arm?
Right.
And-
And then the dose.
The dose.
- is the one that I forgot. Okay, let's start with the dose. So we actually studied apitegromab, as you know, in healthy volunteer. We also studied it in SMA. We have a fair amount of data of different dose levels across those two populations. So the dose we chose is 10 mg/kg, and this is based on the thinking that the projected exposure of this 10 mg/kg in the obesity setting is essentially equivalent to the exposure of 20 mg dose in SMA setting. That's the reason behind it. There's a bit of more nuance behind that, but that's the overall big picture. So in terms of the eligibility criteria, you know, the apitegromab is in the clinical setting for SMA in the pivotal study.
So a bit of thought is around the fact that how do we design a study to answer some of the key questions without getting too far ahead of the ski? So I think we... The eligibility criteria with the BMI, actually, I'm gonna—I can point to Dr. Jastreboff, because she's involved in the design. The eligibility criteria is actually quite consistent with pretty much all the major trials, is basically 30 and 27 with comorbidities. It's pretty standard. And we have age... The actual detail is disclosed, or will be disclosed, I should say, in the ClinicalTrials.gov shortly.
The last piece was, did we consider a monotherapy arm?
Oh, did-
apitegromab only.
Yeah, so a monotherapy. I'll invite Jay to comment on that as well. So we already know what a monotherapy, specific anti-myostatin study can do. We wanted to really get the study quickly up and running. We felt our design can answer all the key questions we want to answer.
Yeah, I mean, I think what we heard very clearly is the current treatment is gonna be involving one of these newer agents, so that's clearly the strategy. Again, to celebrate our industry's innovation, these are amazing therapies. So the monotherapy arm really is not the question we want to answer. The question is: Can we preserve lean muscle in the setting of basically standard of care treatment? So that, that's the very clean, very simple questions from this program. Can we preserve lean muscle through our selective strategy? And the other thing I'm looking forward to, 'cause again, we've talked a lot about it, we'll be able to show side-by-side safety profile, the safety data from the tirzepatide or semaglutide, plus or minus the apitegromab.
Based on the data we have in SMA, I don't expect to see any additional added toxicities to that profile, and so we'll really also further underscore that this safety will matter as we carry forward. Then just final comment, this is chronic therapy, right? We just heard that. You beautifully stated, we shouldn't stop therapy. This is chronic therapy. Just final comment on interfering with TGF-beta biology. Chronic treatment, you're gonna perturb something you don't want to perturb, I think. It's gonna likely be the case. So that's why we go back to the therapeutic strategy of selectivity really matters. I think you're gonna see that when you start to see more longer-term chronic treatment. And we're already showing four years of data that show extraordinarily clean profile in the SMA setting.
Selectivity is key. Muscle matters, right? Gary?
Yeah. Hi. Thanks again for the presentation. Gary Nachman at Raymond James. So first, in the preclinical data for 439, you showed a really nice dose response going up to 3 mg per kg. Any reason to think you could go higher than that, potentially, and maybe not just preserve the muscle, but also potentially increase muscle? So that, as you know, if you have a good safety profile, would you envision any issues at higher doses? That's the first question.
To answer the first question is we've went higher than three mg per kg, and I think we saturate the target somewhere between 1 and 3 mg per kg. The beauty of SRK-439 is that we start seeing effects at low as low as 0.3 mg per kg. That supports the profile of completely inhibiting the myostatin, as well as the sub-Q profile that we're driving towards, is low, low volumes eventually to enable sub-Q dosing. So we've gone beyond, but we pretty much saturate the effect on between 1 and 3 mg per kg. The question that we're still working on now is the duration. Like, if you treat longer, would you be able to actually get higher?
That's a good question to have the expectation that we might be.
Okay. And then just in terms of the clinical studies for these agents, if the primary endpoint is showing an incremental benefit in weight loss, what do you think is the threshold there that FDA is gonna need to see? And just, you know, it would seem that maybe the exploratory endpoints would be even more relevant in terms of the metabolic measures, and then also improvement in function.
Maybe Jing can comment, and also Dr. Jastreboff. She's obviously involved in a lot of these studies.
Yeah. No, I think it's a great question. I think that it's too early to really... We very much look forward to the results readout in 2025, but your point is well taken. The proof of concept study is really designed to demonstrate that it does preserve lean muscle in the context of GLP-1 agonist. And then we've included a number of different points to really explore which one of these things is going to show up in the context of the duration of the concomitant administration with GLP-1 agonist? So the precise view about which one of these is going to take us forward is a little bit too early for us to speak about. Maybe, Jay, you can comment on that.
Yeah, I mean, I think to your point, right, so from the weight loss criteria, I think FDA's current definition, you can make sure I'm correct on that, is probably less than 5%. So if you're looking at are you bringing that additional weight loss, that may be expectation for combination. But our approach really is the more of what can we do to the metabolic profile, so that those exploratory endpoints are really key. And then there will be functional measures. I believe there will be a subset of patients that really will demonstrate that they really need to have functional improvement, and we can work on that. But I'm very, very much intrigued by the metabolic potential, 'cause, you know, hemoglobin A1C is a clear regulatory endpoint. So those exploratory data, I think, will be important as we think about going forward on a regulatory path.
Dr. Jastreboff , any comment?
Yeah. I'll just also comment. So the FDA guidance on, they call them weight loss medications, they're anti-obesity medications. They're not weight loss, 'cause people stay on them, but they don't continue to lose weight indefinitely, otherwise they would disintegrate and die. So they're anti-obesity medications. The guidance is from 2007, so hugely outdated. And if you think about it, you know, we had, for example, GLP-1 receptor agonists for almost 20 years, and yet we didn't have the space for treating obesity. What it took was highly effective medications like tirzepatide and semaglutide to really kind of create this space and the opportunity to treat. And I think, you know, medications in this space, these new medications, are potentially going to help move the guidance forward. Why are we focusing on 5% total body weight reduction?
I mean, there is metabolic benefit, but we should be looking at other things. Is it % fat loss? Is it retention of muscle mass? What are the other parameters we should be looking at that really focus on optimizing health rather than just focusing on weight reduction? So I think therapies like this could potentially change that guidance and impact it in a clinically meaningful way.
Okay, and then that was helpful. Then last question for you, Dr. Ania. While muscle matters for all these patients, how much more important do you think it is for the older patients that are at a higher risk of falls and fractures? And we just saw some of that data coming out of the SELECT study. And then for the company, are you leaning more towards those types of patients when you're exploring these agents? Thanks.
Yeah, that's such a great point. Sarcopenic obesity can happen at any age, but certainly individuals who are older have more propensity to that. So my oldest patient is 95. You know, what, what is my goal for her? It's certainly not a certain BMI, right? It's her function. I'm assessing DEXA also for bone, right? So there's all these other factors to consider. So I think older populations are a key target for these types of therapies, but I think all patients could potentially benefit. I'll give you an example. So clinically, we don't assess DEXA on patients for muscle, right? It's... Right now, it's used as a research tool. But I have patients who come in, and in general, it tends to be men who are over age 50, which is not very old at all.
I'm almost 50, so, and they say-
Everyone up on stage agrees with that.
But I'm a woman, not a man. But anyway, it tends to be the men who come in and say to me, "You know, I'm so grateful, you know, I've lost 40, 50 pounds. I feel amazing, my health has improved, my cholesterol is great, blah, blah, blah. I kind of feel weaker." And right now, we're not assessing any of this. And they're like: "You know how you told me to do resistance exercise and increase protein intake? I kinda wish I had done that." And I said, "It's not too late. Let's try now. Let's see how..." And I don't know what proportion of that muscle mass can be, you know, I guess, resurrected or, or whatever. My patients who are 20, they're not complaining about it, but that doesn't mean it's not happening, right?
I think we need to focus on protein intake, resistance exercise, any kind of exercise would be awesome, as well as therapies that can actually preserve muscle mass. I think we're just not assessing it right now. I think those tools are being developed, both to assess percent fat mass as well as, you know, potentially muscle. We'll have to wait and see. Again, I think we can't ignore it just because we're not assessing it. To the point about function, what is key here, when you're thinking about patients with obesity, measures like sit to stand, walking up the stairs. We can't really assess chasing after your grandkids, but these are the stories that our patients are telling us. "Now I can chase after my grandkids.
Now I can do all these things." And we need to make sure, especially to your point about older patients, that we're focusing on those ADLs, those activities of daily living and the things that they're able to do.
And then just maybe to comment, right? Because I think we talk about it. If we want to be able to demonstrate an effect, we could look at different studies, potentially different populations with different endpoints to really show that, right? I think we just heard it, so our future plans are going to be broad, right? We've just. It's like one step at a time. At the break, I was talking, like, we had so many ideas in our head. There are so many plans we want to take forward. But I think as we move forward, Gary, it'll be looking at subsets of patients where functional improvement really matters with good measures, but also a subset that might be pre-diabetic, that might be on different strategies where that effect on hemoglobin A1c and preserving muscle can help.
I think there's lots of really good opportunities for us to do really nice studies going forward.
There's a question of mine that relates to what Dr. Jastreboff said. If I could just-
Oh, yeah.
Take that. It
... It's commenting on the slides you showed about how much weight loss, 25% body mass. The question, I guess, they're posing that if muscle weighs more than fat, would you be willing to give up some body mass loss or weight loss for that healthier—like, how do you think about that potential trade-off? Would you, would you sacrifice 25% for 20%? Is that a good clinical outcome?
Yeah.
That's the gist of the question.
I mean, absolutely. I mean, our goal is optimizing health, and our patients even tell us that when, you know, when they start taking medications, their body composition may start to change, that's not quantifiable. But again, if it's improving their health, that's the goal. It's not bigger, faster, stronger, you know, who can lose the most in the shortest amount of time. In fact, quickly losing weight may actually be detrimental. We don't know yet. Personally, in clinic, I limit the amount of weight reduction to no more than 1% per week. So if somebody's losing more than 1% of their body weight per week, I actually slow down the dose titration. And with these therapies, again, the idea is can we pair them so that patients are optimizing their health by having more muscle mass or retaining more lean mass?
So, I would absolutely do that, and I think all clinicians, again, our goal is optimizing health, not weight loss alone.
Thank you. Ed, you've been patient. Go ahead.
Great, I had a question for Dr. Jastreboff . I guess along the lines of what you were just speaking about, if you sort of seen enough sort of patients that are sort of on these sort of anti-obesity drugs, or whether it's bariatric surgery, that, you know, are compliant or not compliant to sort of the strategies around sort of protein shakes, sort of lean muscle exercise, to kinda get to a place where you've seen enough to observe anything from a, you know, ultimately measurable clinical endpoint, right? That you could ultimately use in the clinic, just based on your observations, if you've seen anything that kinda stands out to you around sort of compliant versus noncompliant patients, in terms of the things they could do to maintain lean muscle.
Yeah, I mean, the trials that are done, right? Obviously, they have the most oversight. Most of my patients, I can tell you this: they eat extremely healthy food. They track every morsel of food that they eat. They have tried everything for the last 20, 30 years. I also take care of younger patients as well, but they have tried everything. And the second patient that I showed you, the one that had, you know, lost and gained weight, she literally still tracks every morsel of food, even while she's on these meds. It's just what she does. And the reason I do what I do is because the question in my mind was, why can some people eat the salad and the fruit and not lose any weight, and others eat the burger and the fries and never gain any weight?
Mm-hmm.
To me, I was like, "This is biology. It's gotta be the brain." In terms of assessing, you know, whether people are, are doing exactly what we would like them to do in terms of lifestyle intervention, yes, you know, there are tools. They're imperfect. We can track food, we can track physical activity. It's imperfect. But think about it this way: if a patient has diabetes or a patient has hypertension, would we say, "Well, you have high blood pressure, and you didn't adhere to your low-salt diet. We're not gonna give you a therapy that's gonna help you"? We would never say that. So I think it's obesity bias if we're saying, "Well, you gotta do XYZ before you can have ABC treatment." I think we need to do both. It's not one or the other.
It's medications that optimize health and it's lifestyle intervention, because there's no medicine that can help us eat more healthfully or move more.
Hmm.
Great. Thanks for taking my questions. Andres Maldonado from H.C. Wainwright. Just in the context of all the discussions around muscle protection, just curious how we should be thinking about normal cellular turnover in the context of smooth and non-smooth muscle, in regards to patients' normal injuries. Is mechanistically this class, either, 439 or their general class, affect the muscle's ability to repair at normal homeostatic levels?
Sounds like a question for Mo to start us off.
Yeah, so myostatin is predominantly made in skeletal muscle, and it's affected on skeletal muscle. So I don't anticipate any effect on smooth muscle, and that has been shown in whether it's loss of function mutations in animals and humans, as well as in the inhibitors. As far as the repair, you would anticipate that you'd do better in repairing muscle because there's an effect also on satellite cells and stem cells by inhibiting myostatin, that you encourage these cells to actually make more muscle. So I would expect a positive there.
Great, very helpful. And maybe one for Dr. Ania, Curious, you'd said that, you know, obesity is a kind of a spectrum, kind of disorder that leads to a lot of other etiologies. Curious on, you know, prospectively looking, particularly in oncology, as these class starts to really expand utilization, where do you see the greatest impacts on the reduction of incidence, particularly in, you know, in the oncogenic setting?
The reduction in incidence of obesity-related diseases?
Within oncology, that-
Within oncology?
Yeah.
13 types of obesity-related cancers that have already been identified. And so, you know, whether it's colon cancer, post-menopausal breast cancer, if you look on the CDC website, there's a beautiful picture diagram of those 13 obesity-related cancers that are clearly there. I think there's more than 13. And, you know, one of the questions that arises is, there's been this increase in cancer in young people, and is that because of obesity? And, you know, again, I, I'm trained in both pediatric and adult endocrinology, and I think we really need to be treating early if we really wanna be preventing all of these other diseases. Obesity is a disease in and of itself, so we need to be treating it....
but just thinking about the potential for transforming our entire healthcare system, if we treat this one disease, rather than putting Band-Aids on all these other diseases, we can treat the root cause. So I think cancer is key. Cardiovascular is where we are now. We're moving into kidney and, you know, and OSA, and I think cancer is the next thing. The meetings I'm going to now, besides the obesity and endocrinology meetings, are cardiovascular and cancer.
Question in the back, Kripa, and then Ami.
Hi, this is Kripa from Truist. Maybe this is a strange question to ask, given the presentation you guys have given, but we get a lot of pushback from, I would call them GLP evangelists, who say you're solving a problem that doesn't really exist, or at least not in a majority of patients. Dr. Ania, I'd love to get your take on what percentage of patients do you think would benefit from a muscle drug? That's the number one question.
So, part of your question was, you're saying some people don't think that we need GLP-1 receptor agonists or-
No, no.
No.
The GLP evangelists-
They think GLP-
who think that that is enough. You're benefiting a lot of patients who are on GLPs, get enough cardiovascular disease and other benefits to other comorbidities, that you don't really necessarily need myostatin drugs for a lot of the patients. It's only a fraction of patients that need this drug.
I see. I see your question. So my answer would be, you know what? We're not looking for it. And the thing is, the trials that we are doing are not assessing things like muscle strength, muscle function, weakness. They're just not. So until we listen to our patients, which is what I try and do, I just sit and I listen. That's when we learn these things, and that's what we're hearing, at least, you know... Again, I gave the example of men who are older than 50. I'm not—I haven't been asking my patients: How do you feel? How are you doing? How are—How is your function? So we haven't been looking for it. Just because we haven't been looking for it, doesn't mean we don't need to address it. The other point is, we haven't had medications this effective until-
Mm-hmm.
Two years ago, right? I mean, so semaglutide was FDA approved for diabetes treatment in 2017, but patients who have type 2 diabetes lose less weight than people who don't yet have type 2 diabetes. It's more efficacious for weight reduction in people who have obesity alone. The same is the case for tirzepatide. So we actually haven't had highly effective tools, and there are negative effects of losing weight, bone loss, muscle loss, hair loss, right? We see hair loss with bariatric surgery. Now we're seeing it with these medications. It's transient, but it happens. We haven't been looking for the negative effects. Just because we don't look at them, doesn't mean they don't exist. And if we have the opportunity to optimize health by preserving muscle mass, then why would we not do that?
Got it. Thank you. And you mentioned bone loss, and then there was also the study which showed that there's increased incidence of fractures in people who are on GLPs. Do you think there's a direct effect on bone? And just like we have something that's increasing or preserving muscle, do you think we need something else that would help bone health as well?
So that's also an interesting question. I'll just raise the issue that all GLP-1 receptor agonists, which again, this is why I call them nutrient-stimulated hormone-based therapies or NuSHs, because they're not all GLP-1 based, but they're different. They're targeting different hormones. So for example, there are receptors for GIP in bone. If we think about amylin, it may also have different effects. So yeah, not all of these are created equally, and we need to look at the specific outcomes with each of these, whether they're beneficial or detrimental, and for what age, what population, we don't know. I mean, if any of you have ever heard me speak at any of these scientific meetings, my big take-home whenever I'm asked any of these questions is: We need to be doing DEXA in every single trial on every single patient. Because here, I showed you substudies.
What if there's nobody in that substudy who's 75? What if it's... I mean, most of the obesity trials are, they're 70% women, and it's because we cap it at 70% women. If we didn't cap it, it would be 85% women, because as a society, we've made it culturally, you know, not acceptable to have obesity if you're a woman, which is ridiculous, right? We need to treat all people, and we need to include all people in these trials. So doing DEXA only on a substudy, you know, I think is misleading, and we need to be doing it on all individuals with obesity.
Got it. One question, one last question for the company. Mo, you know, beautiful data from 439 today. Given the difference, you know, I think higher affinity for myostatin, I think that's what you talked about with 439 , is there any likelihood when we see data from apitegromab next year, that 439 could be even better?
I think what apitegromab is for SMA. Correct. And neuromuscular, and we're fully committed to that market and that patient population. That's where apitegromab is gonna be. Right. 43... Yep.
For obesity.
Yep, and-
Based on the data that we've seen.
Great.
Of course, you're taking 439-
Yep.
People will be looking at apitegromab data next year, mid-2025.
Apitegromab in obesity, yeah.
Even better.
The EMBRAZE study, right. So maybe not predict where clinical studies are gonna go, but—yeah, right. We're sitting here doing trial designs already, right? To answer your question.
They're both fantastic, right? And they're selective. And it's like we said, apitegromab is designated for SMA. We're committed to that, and SRK-439 is for obesity. It's gonna be also a matter of dose. With apitegromab, we're at the 10 and 20 mg per kg.
... which is not conducive to be in an obese population where you're, we have, right? So, and IV for SRK-439, we're at lower doses, so that enables lower dosing volumes and for obesity to enable the sub-Q-
Yeah.
from the get-go.
Yeah, that's what I was gonna say. We'll need to optimize the dosing for 439. We'll do that when we get into clinic. And, you know, the question around dose, you know, Jing answered, it's basically on exposure, so it's the equivalent of 20. But there's a potential that we could maximize and optimize the dose in 439, right? So I think it'll give us direction, but I do think 439 will stand on its own as we go forward.
Amy, did you have a question?
Quick one. A couple of the other questions were answered. Maybe just for Dr. Ania.
Mm-hmm.
Can you talk about what is a target lean muscle mass level? And do patients that are taking GLP-1s, do they start with a relatively lower lean muscle mass to begin with? And from a clinical trial perspective, what is the bar for success? Is it to maintain it or is it to increase it?
Okay, so we got three questions here. Let me... That's why I always bring a notepad. Okay.
Smart.
In terms of target, what a great question! The answer is, we don't know, and this is why we're doing the studies. We need better targets for obesity treatment for our patients. Again, a target of, you know, losing 5% of your body weight is not a target. A target of BMI of 25 is not a target. You can have a BMI of 25 and have much higher % fat than lean mass, right? These are not targets. As a field, as an obesity medicine field, we are working on what should those targets be? So for muscle mass, we don't have a target. For fat mass, one could argue we don't have a target that needs to be age appropriate, sex appropriate. We need to develop all of this, right?
In terms of, do patients have lower lean mass? So patients with obesity actually have a higher lean mass because they're carrying more weight. The question is the proportion of lean to fat mass that is lost, right?
Mm.
So if they lose a significant amount of lean mass as well as fat mass, are they getting weak, weaker? And again, this is, this is what we're hearing from certain patients, but is that the case, right? So, so they don't start at a lower lean mass. Now, there are instances of sarcopenic obesity or even sarcopenic, what you would not define as obesity by BMI. Again, those are people who maybe have very little physical activity and have a higher percent of fat mass, but by BMI, they may not actually meet the criteria of obesity. So that also exists. So there's a spectrum. And then in terms of your question, I wrote bear, B-A... I don't remember. What was your last question? I wrote it.
What is the bar for success?
Bar. Bar. Okay. I wrote bear instead of bar. Okay, is there a bar for success? So in terms of, So again, I mean, I think preservation of lean mass would be amazing, right? There's nothing. There's no therapy, whether it's diet, bariatric surgery, or medications, where we actually can preserve lean mass, and only target fat loss, does not exist. So I think that would be a great first bar. In terms of increasing, I mean, I don't know. That would be maybe an added bonus, especially if somebody has sarcopenic obesity. But let's start with not losing as much of this lean mass as we're seeing.
Time for a couple more questions. Yep, in the back.
Quick question of it. I think throughout this Q&A, we had touched upon this a little bit, but not quite precisely. When these patients lose body fat and also lean muscle mass, it seems that not everybody can keep taking this medication. There is severe side effects. They get off of it, and they gain back weight. And it's a presumption from my side that most of that quick gain is going to be fat, not lean muscle mass. How long until you think these GLP-1s continue to report data from the regaining of weight, and it becomes evident to the community that it's quite risky to take these medications because of the lean muscle mass loss? And once you get onto your second or third cycle, I feel like that will be the point when this becomes essential, not just a good to have.
Because you have gotten through multiple cycles of weight loss, and after you're gaining back potentially only fat, it's gonna be harder and harder to lose, you know, muscle mass, and it's gonna be harder to maintain that lean muscle mass. So how long do you think until safety data or real evidence comes out from the other therapies where this becomes essential, not just a, you know, good to have?
Yeah. So some good points in your question. First, let me address tolerability. The tolerability of these medications, the GLP-1 receptor agonists or the nutrient-sensing hormone-based therapies, is actually very good. What we see in trials is protocolized, meaning that patients are titrated up very quickly because the FDA needs 52 weeks of data on a specific dose. In clinic, that's not how we use the medications, and we're trying to educate other providers. Again, these are new therapies. We're trying to educate other providers that slow uptitration is the best way to mitigate side effects. I can count on one hand how many patients I've had who have had vomiting. The GI side effects can be mitigated by slow up titration. We titrate to what the patient needs, not what the label says, right? That's, so that's the first thing.
So actually, they're very well tolerated. And let me tell you, in terms of adherence, patients come back, because if they start seeing any amount of weight regain, they come right back to me, right? So tolerability is not the issue that the media has portrayed. They are actually very well tolerated. But let's say someone does cycle off. Let's say insurance doesn't cover it. Let's say there's a shortage, which clearly there is. There's no doses available of many of these medications. We don't know what is regained. So it's an interesting question that you ask. Is it fat mass that is regained? We need to do these studies. We need to look at that. We actually don't know.
I think likely it's, it's a little bit of both, because, again, when you weigh more, you have a somewhat more lean mass because you're trying to carry more weight. So, you know, whether you're, you're initially gaining back more fat mass than lean mass, I don't know. We don't have the answers. That's why trials that are looking at DEXA systematically over time are so critical, 'cause we don't have those answers. And your question about cycling, that's an excellent question. What about people who have used caloric restriction throughout their life, right? And have lost weight and then gained it back, lost weight, and then gained it back. How does that impact their body composition? And the answer is, we don't know. So, I think the short answer is, we need more research. Great points.
Time. Yep, go ahead.
Just, just to follow up on the endpoints, ignoring what the regulatory agencies may require in terms of approvable endpoints, what would you need to see in order to broadly prescribe a muscle therapy? Like, would just preservation of lean mass be enough, or would you like to see functional endpoints before you sort of, like, prescribe to whatever proportion of patients you think need it?
Yeah, I mean, that's a really good question. I would personally want to see both some sort of measure. And again, they're objective, but there are things that we would ask patients to do, whether it's an objective test or questionnaires that ask about function and how people feel. But I think, again, it's important to do both. Now, if we see improvement in, you know, preservation of lean mass, and there's also improvement in A1C, improvement, you know, in insulin sensitivity and all these other factors that we assessed, that would also be enough, right? So I think it's mass plus. Whether the FDA, you know, where they will land on that, I don't know. But again, I think it's important to assess both.
And then I'll say one other thing to the question in the back, just to say, you know, your question leads to this idea of if people are cycling on other therapies, would this help potentially preserve their lean mass through that cycling? And again, we don't know the answer to that question either.
So there's one additional question or a couple online, and we're running short on time. I'll ask Dr. Jastreboff , if you're familiar with the EMBRAZE study that-
Mm-hmm.
Jing unveiled today. We're thrilled to have started it up, like, a couple of months early, but we're really thrilled to have it up and running. What are your thoughts on that study? How do you think about enrollment and what we're going to learn from that study?
Yeah, I mean, I think it's, it's incredibly important, critically important. We need to know the answers to these, you know, to, to these questions. And I think in terms of enrollment, at least what I see from, from my site, is that there's like 30, 40, 50 people for every spot. Meaning that... I mean, and, and people will just, like, call my cell phone. I don't know how they get my phone number, but anyway, they'll just call my cell phone, and they're like, and part of it is, you know, people see these transformations and people's lives and health being transformed, and they wanna be part of that. And so they're clamoring to get into these trials. So we, you know, in, in most of the trials that I do, we recruit extremely quickly.
You know, and I think people are excited.
Great. Thank you. We are at time. I'd like to thank the crew here for the Q&A, and have Jay come up and provide some closing remarks. Thank you.
Yes. Well, first and foremost, I'm really grateful and thankful for Dr. Castro and Dr. Ania for joining today. I hope you found that very informative. Thank you for your attention. You know, I said, "Leave with three things in mind," and so I'm gonna give you the three things in mind, so you definitely leave with that. You heard from us. We believe selectivity really does matter with TGF- beta biology. We think we're very good at that, so that's a key point. I like where our strategy has taken us. I think it gives us great opportunity to go forward. But I hope you also agree with me that the team that was assembled here today is first class. We've got a really experienced team that's driving the company.
I feel very good about where we are, and I look forward to doing some additional questions if you need to. We have a lunch upstairs. If you can join us, please do. But once again, on behalf of all of us and all the employees at Scholar Rock, thank you for your attention and your interest.