Participants

Jay Backstrom; President, CEO, & Director; Scholar Rock Holding Corp

Jing Marantz; Chief Medical Officer; Scholar Rock Holding Corp

Mo Qatanani; Chief Scientific Officer; Scholar Rock Holding Corp

Michael Yee; Analyst; Jefferies Group LLC

David Nierengarten; Analyst; Wedbush Securities Inc.

Etzer Darout; Analyst; BMO Capital Markets

Tessa Romero; Analyst; JPMorgan Chase & Co.

Gary Nachman; Analyst; Raymond James Financial Services, Inc.

Srikripa Devarakonda; Analyst; Truist Securities Inc.

Mark Frahm; Analyst; TD Cowen

Presentation

Operator

Good morning and welcome to Scholar Rock's second-quarter financial results and business update call. (Operator Instructions) Please note, this event is being recorded.
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 purpose 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 our 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 re-watch at a later date.
I would now like to turn the conference over to Jay Backstrom, President and CEO of Scholar Rock. Jay, please go ahead.

Jay Backstrom

Thank you, Sandra. Good morning and welcome to our Scholar Rock second-quarter 2024 business update. On behalf of our team, I'd like to thank you for joining our call. Turning to slide 4, the focus of today's call is to highlight our exciting progress in 2024.
After my introductory remarks, Jing Marantz, our Chief Medical Officer, will provide an update on our development programs, including a review of the 48-month data from TOPAZ, our apitegromab Phase 2 proof-of-concept study, followed by Mo Qatanani, our Chief Scientific Officer, who will review the progress with our SRK-439 program in obesity. I'll close with a summary of upcoming milestones and then open the call up for questions.
Moving to slide 5, we've made terrific progress over the first half of 2024, and we're on track to achieve all of our key milestones on time or ahead of schedule. The progress with our SMA program has allowed us to continue to advance toward commercialization, a goal that is coming closer into view for our lead product, apitegromab, as we remain on track to report the top-line results for SAPPHIRE, our Phase 3 registration study in Q4.
Thanks to the focus and dedication of our study team and the incredible support from our investigators, their clinical study teams, and the families participating in SAPPHIRE, we are now only a few months away. At Scholar Rock, selectivity was foundational to our approach in designing apitegromab and is the hallmark of our differentiated platform. Our research team has been incredibly productive and has delivered and continues to deliver a portfolio of potential medicines that are highly differentiated and with best-in-class potential.
We focused our industry-leading anti-myostatin programs in areas where we believe we can make substantial advances in care, creating new possibilities for those living with SMA and with obesity, high-value therapeutic areas that provide unique opportunities to fuel our growth. It is an exciting time at Scholar Rock. We are at a point in our trajectory where the next 12 to 24 months will be transformative.
Turning to slide 6, as a reminder, the scientific foundation for our company was based on deep structural insights that allow us to harness the therapeutic potential of the TGF-Beta superfamily of growth factors by hitting the right target at the right time, avoiding unwanted toxicities, and potentially maximizing efficacy.
As shown on slide 7, we've applied this highly selective approach and produced a robust pipeline of innovative and differentiated products. Starting with our anti-myostatin programs, Scholar Rock was instrumental in bringing myostatin back into the forefront as a therapeutic target. With apitegromab and SMA, we've reestablished myostatin as a neuromuscular target.
And our emerging data with SRK-439 suggest the best-in-class potential to address the muscle loss associated with GLP-1 receptor agonist treatment, leading to sustainable, healthy weight management in obesity. For our TGF-Beta-1 programs with SRK-181 and immuno-oncology, we have pierced the immunosuppressive armor to overcome checkpoint inhibitor resistance.
And for our latent TGF-Beta-1 selective monoclonal antibody for fibrosis, now referred to as SRK-373, We applied our deep structural insights and antibody engineering expertise to solve a riddle that has not been done before. SRK-373 is the first monoclonal antibody designed to uncouple the pro-inflammatory from the pro-fibrotic effects of TGF-Beta-1 with the potential to be best in class in indications such as IPF or TGF-Beta-1 and inflammation are key drivers for the disease.
As further evidence of our capabilities, we have an elegant monoclonal antibody-blocking RGMc, a validated target for unrestricted anemia, and we are excited to advance another neuromuscular program to development candidate from internal research as we embark on our next wave of innovation.
Moving to slide 8, we have been disciplined and focused on our efforts to advance the pipeline to key developmental milestones across all of the therapeutic areas. Starting with neuromuscular disorders for our lead program, apitegromab, the upcoming readout for SAPPHIRE is just around the corner, and we look forward to reporting out the top-line results in Q4.
SAPPHIRE was designed to meet regulatory requirements for approval and to demonstrate both a statistically significant and clinically meaningful difference in the primary endpoint of mean change from baseline in the Hammersmith score at 12 months compared to placebo with the ability to capture at least a two-point difference.
SAPPHIRE was optimized for clinical success based on the TOPAZ Phase 2 proof-of-concept study, and we're excited to share the TOPAZ 48-month data on today's call. As you will hear from Jing in more detail, the updated TOPAZ data continue to impress, demonstrating sustained clinical benefit through 48 months.
The sustained benefit over 48 months is particularly noteworthy when considering the long-term results of nusinersen-treated patients from the CHERISH/SHINE study recently presented by Finkel and colleagues at Cure SMA, where the initial functional gains seen with nusinersen show a decline over time, highlighting the progressive nature of the disease and the need for additional treatment options, such as apitegromab, a muscle-directed therapy.
In addition to the sustained functional improvement, the updated data continued to reinforce the safety and tolerability of apitegromab with over 90% remaining on treatment and no new safety findings. Taken together, the 48-month data further reinforce our confidence in the SAPPHIRE study and the potential for apitegromab to improve the lives of those living with SMA.
A successful SAPPHIRE study will allow apitegromab to serve as the foundation for building a neuromuscular franchise, and we are planning to extend our efforts in SMA to children under two, as well as expanding into other neuromuscular indications.
For our cardiometabolic programs, we believe our highly selective approach to blocking the pro and latent forms of myostatin can meaningfully contribute to healthy weight loss management. We formally announced our entry into the cardiometabolic area less than 10 months ago, and we've wasted no time in moving our programs forward.
Starting with EMBRAZE, our randomized Phase 2 proof-of-concept study in obesity assessing apitegromab in combination with a GLP-1 agonist, it is ahead of schedule. And we are now positioned to complete enrollment in early Q4 and have updated our guidance for the top-line results to Q2 2025. As you'll hear from Mo, the non-clinical data generated to date with SRK-439, our novel anti-myostatin, continues to support a potential best-in-class approach for preserving muscle mass, leading to healthy weight loss management.
The data presented at ADA add to the body of evidence, demonstrating an increase in lean mass and reduced fat mass regain with SRK-439 following withdrawal of the GLP-1 receptor agonist. For our TGF-Beta-1 programs with SRK-181 and immuno-oncology, we've demonstrated proof of concept and proof of mechanism and overcoming checkpoint inhibitor resistance. And we look forward to discussing the next steps with FDA at our end of Phase 1 meeting.
For SRK-373, our selective latent TGF-Beta monoclonal antibody for fibrosis, we are excited about the best-in-class potential in indications such as IPF, where TGF-Beta1 and inflammation are key drivers for disease, and we look forward to advancing the program to IND.
The strength of our platform affords us the opportunity to consider these high-value opportunities and to thoughtfully grow and advance our pipeline. It is exciting to see what has become possible given our insights into targeting the TGF-Beta superfamily of growth factors.
Turning to slide 9, as external validation of our innovation, our cutting-edge research is increasingly being recognized by the global scientific community. In the last two months alone, our data have been featured at the annual conferences for the American Society of Clinical Oncology and the American Diabetes Association.
And most recently, our unique selective latent anti-TGF-Beta-1 monoclonal antibody, SRK-373, was featured in Science Signaling as further proof of our structural insights leading to potential best-in-class therapies. As shown in slide 10, we have delivered on all of our key milestones to date and are looking forward to our next major milestone, the top-line results for SAPPHIRE in Q4, a very exciting time at Scholar Rock.
And with that, I'm pleased to turn the call over to our Chief Medical Officer, Jing Marantz, who will provide an update on our development programs, followed by our Chief Scientific Officer, Mo Qatanani, who will walk us through an update from our research team. Jing?

Jing Marantz

Thank you, Jay. If we can turn to slide 12, Molly. We have three programs in the clinic. In June, as Jay mentioned, we have updated clinical data on our 181 program that was featured at an oral session at ASCO. On today's call, I will focus on the progress of our SMA program, including an update on the 48-month data from TOPAZ and the EMBRAZE study in obesity.
To start on the left, we have a differentiated approach of selective muscle targeting based on deep insights of how skeletal muscle is regulated. Translating this into the clinic, we saw from the TOPAZ trial substantial and durable benefit across broad SMA patients. Leveraging the learnings from TOPAZ, our pivotal study is designed for clinical success.
Lastly and importantly, with over 200 patient years of exposure, the safety profile to date has been favorable, with over 90% of our patients with non-ambulatory SMA remaining on study, both of these observations support the potential for long-term use. Turning to slide 13, before I share the updated data, it's helpful to take a look at the natural trajectory of patients treated with SMN-targeted therapy.
As Jay mentioned, that recent Cure SMA meeting in June, Dr. Finkel and colleagues presented the long-term outcomes data from the CHERISH/SHINE study, which enrolled SMA patients treated with nusinersen. The orange lines represent the trajectory of patients initially randomized to nusinersen. As clear from these graphs, motor function as measured by Hammersmith improved initially.
After one to two years, Hammersmith started to plateau. And over time, it started to decline. This solid orange line on top represents this subgroup of patients who did not have any scoliosis surgery, whereas the dotted orange line represents those who underwent scoliosis surgery during the study. Scoliosis is an abnormal and progressive curvature of the spine that's part of the SMA disease pathology. The condition is commonly managed with surgery.
Scoliosis surgery is well known to be a confounding factor that impacts the motor function assessments. Therefore, it's not at all surprising for you to see that the Hammersmith declined faster for those patients with scoliosis surgery. For this reason, we'll focus on our discussion on data for those without scoliosis surgery.
To put things in context, patients enrolled in our TOPAZ study had, on average, two years of prior nusinersen treatment that's well into the interval where the Hammersmith score is expected to plateau or decline. The blue shaded area highlights the relative period of nusinersen exposure similar to that of TOPAZ patients.
Focusing on this solid orange line within this period, over the course of four years for patients without scoliosis surgery, the Hammersmith score declined greater than 1 point. The key point here is that despite treatment with a highly effective therapy, the natural trajectory of these patients is that of progressive decline after the initial increase.
So turning to slide 14, it is in this context I like to provide a preview of the updated motor function data from the TOPAZ trial at 48 months. Similar to how we previously shared our 24 months and 36 months data, these bar graphs represent the motor function outcomes measured by Hammersmith for the pooled non-ambulatory SMA patients ages 2 to 21 on the left, and the 2 to 12 subset on the right.
Hammersmith is a validated scale designed specifically for SMA that measures the growth motor function. As mentioned before, scoliosis surgery is a known confounding factor. Assessments for the surgery -- after the surgery are censored in our analysis. You can see from these graphs that Hammersmith continues to improve. The increase that we see at 6 and 12 months was maintained over the course of 48 months.
Knowing that the motor function of these patients would otherwise decline at this point of their treatment journey, it is reassuring to see that the motor function benefit that we saw earlier was sustained over the course of 48 months.
Turning to the next slide, similar trend was observed for RULM, which focuses more on the upper limb function. The improvement in RULM seen at 6 and 12 months continued to strengthen over time and was maintained over 48 months, both in the 2 to 21 group and in the 2 to 12 subset. For patients who are non-ambulatory, continued improvement in their upper limb function is particularly important as it represents their ability to perform activities of daily living, such as their ability to lift a cup or pushing a button.
Turning to slide 16, so taken together, the updated TOPAZ data would sustain a clinical benefit, consistency of findings, and favorable safety profile with low discontinuation rate, reinforces our belief that apitegromab has the potential to provide substantial benefit to patients with SMA by directly addressing the underlying muscle pathology. We plan to share additional detail at future medical meetings.
Turning to slide 17, a note on the learnings of TOPAZ, our pivotal SAPPHIRE study was designed for clinical success. Here you can see the study schematic to highlight just a few key points. The main efficacy population for SAPPHIRE reflects the population of TOPAZ that showed transformative potential. The primary endpoint is Hammersmith at 12 months, the same as TOPAZ. And the 20-mg dose was chosen based on sustained target engagement and clinical benefit observed from TOPAZ.
The trial is designed to demonstrate both statistically and clinically meaningful difference with the ability to capture at least 2-point difference on Hammersmith versus placebo. Importantly, we have been able to engage with both the FDA and EMA and align with them on key aspects of the study design. This design balances the objective to optimize for clinical success with our effort to be broadly representative of the patient population we're trying to serve.
Knowing the natural trajectory of the SMA patients instead of progressive decline over time, despite the initial improvement seen with SMN therapy, we're encouraged to see that clinical benefit from TOPAZ continues to hold. So taken together, we're optimistic about our goal to bring this potential medicine to patients.
Now turning to our cardiometabolic clinical program on slide 18, obesity is recognized as a significant unmet need. The rapid adoption of semaglutide and tirzepatide has brought about profound benefit to patients with obesity. A key issue that has risen is the significant loss of lean muscle mass associated with its use. Aside from day-to-day physical function, muscle plays an important role in energy metabolism and glucose homeostasis. And therefore, maintaining appropriate levels of lean muscle is essential to healthy living.
As a company with deep expertise in muscle, we're uniquely positioned to address this unmet need. To that end, I'm incredibly proud of our team that worked hard to enable us to initiate the EMBRAZE study ahead of schedule. We're seeing great momentum in our enrollment and now expect to report top line in Q2 of next year.
The primary objective of the study is to demonstrate the effect of a selective myostatin inhibitor to preserve lean muscle in the setting of obesity. We also want to confirm that the safety and tolerability profile in the obese population remains favorable that's supportive of long-term use. And lastly, we're interested in understanding the potential effect across a number of exploratory endpoints, including the effect on metabolic profile and physical function.
So to conclude, the study schematic is shown here. Overweight or obese patients are randomized one to one to either the combination of apitegromab plus a GLP agonist or the combination of placebo and a GLP agonist Treatment duration for the combination is 24 weeks. The primary endpoint is lean muscle mass change from baseline by DEXA scan at 24 weeks.
Secondary endpoints include safety and tolerability, PKPD, and other weight loss parameters. Exploratory endpoints on metabolic profile and physical function are also included. The study includes an additional assessment at 32 weeks so we can get a preliminary read of the durability of effect, in other words, the potential effect to attenuate rebound weight gain.
With this, I'm delighted to introduce Mo, our Chief Scientific Officer, to show you the exciting science behind our differentiated approach.

Mo Qatanani

Thank you, Jing. And good morning, everyone. Next slide, please. I'm going to start with this slide that emphasizes the points made by Jay and Jing earlier. We have a highly differentiated platform that is producing innovative and very selective candidates. Combined with our translational expertise, focus, and passion, we have translated these innovations to success in the clinic across many therapeutic areas to benefit our patients.
First, we developed apitegromab, our selective anti-myostatin for SMA, proved its efficacy in translational mouse model, took it to the clinic, and as you heard earlier, we have very promising data from our TOPAZ trial in SMA -- in SMA patients, where we saw substantial and sustained improvement in motor function over 48 months with superb safety profile. And we look forward to seeing our Phase 3 SAPPHIRE trial data in Q4.
Second, we developed SRK181, our selective anti-latent TGF-Beta-1 antibody, to overcome primary resistance to checkpoint inhibitors in patients with advanced solid tumors. We have shown its efficacy in multiple preclinical translational models, took it to the clinic where we showed promising efficacy across multiple tumor types in our Phase 1b DRAGON trial, as was highlighted in our recent oral presentation at ASCO.
Moving to SRK-439, our selective anti-latent myosin antibody that is designed for obesity, we showed its ability to preserve muscle mass and improve the metabolic profile during GLP-1-induced weight loss in multiple studies in translational obese mouse models. We will be highlighting data that we recently shared in an oral presentation at the American Diabetes Association on this call. And we look forward to filing an IND in 2025 and advancing it to the clinic.
Finally, we developed SRK-373, our selective highly differentiated anti-latent TGF-Beta-1 antibody that has the added selectivity of inhibiting TGF-Beta-1 only when presented in the matrix of tissues but not immune cells. Given this unique mechanism, potential efficacy, and safety advantage in fibrotic diseases, we showed efficacy of this molecule in multiple translational fibrotic disease models, including lung, renal, and liver fibrosis. This was recently highlighted in a publication featured on the cover of Science Signaling, and we look forward to filing an IND in 2026 and testing this unique and differentiated mechanism in the clinic.
Slide 22. Focusing on SRK-439, we have strong scientific validation and preclinical evidence that gives us confidence in its potential to drive healthier weight management during GLP-1-induced weight loss. We have shown preclinically in a translational obesity mouse model that SRK-439 leads to preservation of lean mass during GLP-1-induced weight loss, solving one of the biggest challenges in this area.
This was also accompanied by improvements in metabolic profile, namely an additional 20% reduction in blood glucose levels on top of the reduction seen with GLP-1 treatment alone. That data was shared at a Keystone meeting earlier this year. We also showed preclinically that treatment with SRK-439 leads to an increase in lean mass and attenuation of fat mass regain following GLP-1 withdrawal leading to improved body composition. This addresses another key challenge of GLP-1 receptor treatment, namely the durability of effects after treatment cessation. We will highlight some of that data today.
Finally, in a preclinical head-to-head study in the same diet-induced obesity model, we showed that SRK-439 is superior to the non-selective anti-activin receptor antibody that is currently being tested in the clinic. As highlighted earlier, muscle is critical for overall health, and the ability of SRK-439 to preserve muscle during weight loss highlights the potential it can play in driving healthier weight management and better outcomes in obese patient population. Next slide.
In addition to loss of lean mass during weight loss, another key challenge of incretin or GLP-1-induced weight loss is the durability of effect and the loss of benefits upon cessation of treatment. This slide highlights the ability of SRK-439 to address this challenge in translational obesity mouse model. The graph on the upper left shows lean mass in different treatment groups during semaglutide-induced weight loss or upon semaglutide-withdrawal.
As you can see in the blue bar, semaglutide-treatment led to considerable lean mass loss during the treatment phase of 35 days as expected. Co-treatment with SRK-439 led to the preservation of the lean mass during the semaglutide treatment phase as you can see in the green line. In addition, animals treated with SRK-439 had significantly higher lean mass after discontinuation of semaglutide if you compare the green line versus the blue line between days 35 and the end of the study.
The lower graph shows the fat mass change during the study. Cessation of semaglutide treatment on day 35 leads to rapid rebound effect and fat mass regain as expected. Co-treatment with SRK-439 led to attenuation of the fat mass regain following semaglutide withdrawal as you can see when comparing the blue line for semaglutide alone and the green line for SRK-439 for treatment. Next slide.
This slide shows the favorable body composition in the SRK-439-treated animals versus controls upon semaglutide withdrawal at the end of the study. In the graph on the left, animals treated with SRK-439 had higher proportion of lean mass after cessation of semaglutide treatment, as you can see in the green bar versus the blue bar.
In addition, if you look on the graph on the right that measures fat mass, mice treated with SRK-439 in the green bar had significantly lower regain in the fat mass percentage versus the IgG control in the blue bar. Hence, SRK-439 treatment led to a more favorable overall body composition at the end of the withdrawal period. This highlights the potential of SRK-439 in addressing a key challenge in the GLP-1-induced weight loss by supporting a more durable weight management with a more favorable and healthier body composition. Next slide.
This is data we recently shared during our Investor event in May, where we highlighted the competitive profile of SRK-439 versus a non-selective myostatin approach of another model. This is a head-to-head study in the translational diet-induced obesity mouse model, and the graph is showing the percent change in lean mass upon semaglutide treatment.
As expected, semaglutide led to significant reduction in lean mass, as you can see in the blue bar on the left SRK-439 treatment led to preservation of lean mass dose dependently and with doses as low as 0.3 mg per kg as you can see in the bars in green. Muscle preservation was achieved at significantly lower doses than the anti-activin receptor antibody where we see lean mass preservation only at the highest dose tested of 20 mg per kg as you can see in the bars in gray.
It is worth noting that we see equivalent lean mass preservation at the 1 mg per kg dose level of SRK-439 versus the 20 mg per kg dose for the anti-activin receptor antibody. Treatment with SRK-439 also was associated with enhancement of fat mass loss. This highlights the competitive profile of SRK-439 with superb efficacy in preserving muscle mass and enhancing loss of fat mass while avoiding the potential liabilities of non-selective approaches. This also supports a best-in-class subcutaneous profile versus SRK-439. Next slide.
Finally, we are leveraging our expertise in myostatin and the ability to develop anti-myostatin antibodies with exquisite selectivity to test our hypothesis and inform our obesity program. Since apitegromab is already in the clinic, it allows us to test this hypothesis really quickly in a clinical setting through our EMBRAZE proof-of-concept study. This will demonstrate that a selective anti-myostatin has the ability to preserve lean mass and influence metabolic parameters in the context of obesity during GLP-1 induced brain loss.
We announced during our Investor Day back in May that we initiated the trial ahead of schedule and the trial is enrolling well. So we now anticipate top-line data in the second quarter of 2025. We will use our learnings from the EMBRAZE trial to inform and potentially accelerate the development of SLK 439 where we expect to file an IND in 2025.
Now I'll hand it back to Jay.

Jay Backstrom

Well, thank you, Mo. So in closing, it is an exciting time for Scholar Rock. We have met or exceeded all of our goals to date, including conducting a prime pre-submission meeting with EMA in preparation for our European submission for apitegromab, initiating EMBRAZE, continuing to advance SRK-439 to IND, and we're looking forward to the top-line readout for SAPPHIRE as our next important milestone as we continue to initiate key activities in preparation for commercialization. Overall, a great time for Scholar Rock.
That concludes our formal presentation. Sandra will now open the call up for questions.

Question and Answer Session

Operator

(Operator Instructions) Michael Yee, Jefferies.

Michael Yee

Hello, good morning. Thank you, guys, for the update. We had two questions. First, obviously, you are reading out in SMA, the pivotal study, and some others are also reading out all around the same time. I guess I just wanted to understand your view on one of the competitors, Roche, because I think their antibody is similar.
And so I just wanted to understand if you have seen or believe there are any differences in that study design or readout, how to think that as it relates to your readout also coming around the same time. And on the obesity side, I wanted to understand, first, are you stratifying with tirzepatide and sema? Because I noticed you're offering both, and those drugs do have different effects. And I wanted to know if you're stratifying, and do you expect that your drug will completely eliminate the lean muscle loss and that is your base case? for both of those drugs in your readout. Thank you.

Jay Backstrom

All right. So Michael, maybe I'll go ahead and tackle this. This is Jay. I'll tackle the first question about the upcoming readouts. So clearly, we're excited to report out our top line in Q4. What we've seen as we follow others in the space, Roche in particular, they continue to suggest that they're going to report out from their, I think, early phase of the study. So they're really establishing dose and effect as opposed to reporting out their top-line Phase 3 trial, which is ongoing.
The most recent update that I'm aware of is that they're targeting somewhere in the 2026 or beyond phase. So I think it'll be interesting to see their results, but clearly in a different place, and to remind them they're studying only with risdiplam, where we're agnostic to both nusinersen and risdiplam.
And then with respect to EMBRAZE, Jen can answer. But since I'm going to comment, no, we didn't stratify by semaglutide or tirzepatide in this proof-of-concept study. We're really interested in just seeing the effect on both. We think we should have an effect on both, similar to our SMA program. We think we should be agnostic to treatment. And we'll see.
I think, ultimately, the amount of preservation for lean muscle will be interesting. I think what you saw from Mo is that the data presented at ADA were very impressive because it did show that we did actually maintain and preserve. And then of course we saw continued increase in lean muscle mass upon cessation.
I think those results likely will be reproduced in clinic, but again, we're running the proof of concept to see. So looking forward to retelling you the top-line results. I'm glad we're going fast. The team is impressive, right? We've accelerated the enrollments and looking forward to reporting out top line for both.

Michael Yee

Thank you.

Operator

David Nierengarten, Wedbush Securities.

David Nierengarten

Hey, thanks for taking the question. It's on apitegromab and SMA. Just when you look at the longer-term data, is there any effect that should be attributed to the children aging, or are you confident in the differential still from the base case or from background therapy from the historical clinical studies? Thanks.

Jay Backstrom

Yes, well, maybe I'll start. Maybe Jing wants to add about the historical data. It's really interesting, right? I think the beauty, David, as I see it with the apitegromab program is that given the safety and tolerability that this can be chronic treatment for children with SMA. And I -- we think about the physiology for maintaining and enhancing muscle growth and function, it actually would be optimal to see that continue through growth and development of these children as they get into young adults and hopefully maintain their activity of daily living and in fact, if not improve it further.
So I think that it's likely a combination. I think that the fact that we're continuing treatment is to the good. And again, what Jing said is very, very encouraging. I mean, we're very impressed as we continue to see the maintenance and sustained effect over time, particularly in light of the decline that you see with nusinersen. I don't know, Jing, if you wanted to add to that.

Jing Marantz

Yes, so I think that you covered most of it, Jay. So a couple of things to add, one is that mechanistically, I think Jay pointed out this as well, myostatin, there has been a large body of literature that really speaks to the effect of the myostatin regulating muscle throughout life from early development all the way through adulthood. And so that has been well documented. And application of myostatin has had no documented negative effect. and that's true in animals and in humans. So that's point number one.
Point number two is that the question I think Jay addressed is there is probably a component of a development. However, what's really important is that the patient population that I showed you and Dr. Finkel and colleagues presented are very similar patients.
If you look at our TOPAZ patients from the patient age, the sort of the duration of prior therapy and also type of patients enrolled in baseline functional status, all of those things point out that these patients are very similar. So compared to what these patients are otherwise expected to do, we're very encouraged to see the continued benefit hold.

David Nierengarten

Thanks.

Operator

Etzer Darout, BMO Capital Markets.

Etzer Darout

Great. Thanks for taking the question. Just a couple here. As we approach the top line SAPPHIRE data, just wondered if you had any updated insights on sort of potential access or pair dynamics for the use of apitegromab to standard of care or will you need data in hand, I guess, for more productive conversations?
And then as you advance sort of SRK-373 for fibrosis and you look sort of across your TGF-Beta portfolio as it grows, how are you sort of thinking about continue to develop these assets relative to the focus on anti-myostatin? Thanks.

Jay Backstrom

Yes, very good. So let me start with the top line and payer interaction. We've had preliminary payer interactions we've shared in previous calls, and of course, we continue to do that. I do think that there is the prior precedent set with the current therapy. So I do think that gives us some insight into the value of functional gains in these children and the ability to add and enhance that. Of course, we will continue with more payer interactions as we have the top-line data.
And as you point out, of course, that gives us a more rich and robust discussion. But I do feel from what I've seen so far, very pleased with the preliminary interactions and the recognition that these children need additional care. And I think that is further reinforced by the updated data that we've seen from CHERISH and SHINE.
It's really interesting. We've talked a bit about what to expect from the natural history. We've been looking for sources to give us information around it. We've said repeatedly that we expected it to plateau, the nusinersen effect, but we did believe everything we've heard and talked to from the community and in physicians. There is an inherent progressive nature to this disease, and in fact, the long-term data show that.
So that's the kind of the evidence behind what we've been believing. And if you put that together with the data that we're sharing with TOPAZ, where we're able to maintain and sustain, I think that will translate well into the payer interaction. And then with respect to the pipeline and where to go next, I spent some time on this call talking about the pipeline. I've been here now going on two years.
I love the pipeline. I love what Mo and team have done. And it's really finding the opportunity to really further advance. I think our strategic decisions to go into the anti-myostatin spaces will prove to be very good. As we see the upcoming SMA data and the obesity data, I feel very good about that.
The TGF-Beta-1 data is extraordinarily interesting to me. And I think when we started to highlight programs that I've touched on, but really not spoke a lot about, I think we are coming into a phase of our growth as a company that we will have more and more opportunity to further invest behind the pipeline, what I believe really holds enormous promise and great value.
So more to come as we go forward for the year. But again, to be clear to everyone listening, first and foremost, very focused company, very deliberately focusing on myostatin. And I'm really pleased with the team and their dedication to get us to the close to the readout for SAPPHIRE. It's really very exciting. It's a very good time for us.

Etzer Darout

Thank you.

Operator

Tessa Romero, JPMorgan.

Tessa Romero

Good morning, Jay and team. Thanks so much for taking our question. So the first question from us is on the longer-term data that you presented this morning. Can you tell us a little bit more about the distribution of the inputs on the Hammersmith? And what might be driving that need up from 36 months to 48 months, particularly in the 2 to 12 age group? Just curious, how wide has that range of observations been, and has this increased or decreased with time?
And then the second question we had was just if you could let us know what percent of patients have seen at least a 3 point of improvement for the age 2 to 21 group. I think it was about 39% as of 36 months. And then if I can just ask on timing for SAPPHIRE, is there any clarification you can give us on time between last patient out, which I think would be in September, and a possible top-line result? Can you give us any kind of -- what needs to be done in that timeframe? Thanks so much.

Jay Backstrom

Yes, Tessa. This is Jay. Maybe I'll tackle those. You have really good questions about the granularity around the updated 48-month data. And as Jing mentioned on the call, we have plans to really advance that and get that at a medical meeting where we can go with much more granularity about the detail, the distribution, the percent that it achieved 3-point change.
Just recall, when we were asked about 48-month data at the beginning of the year, we were planning. We know this is an important data set. We were planning to do it, just not now. We were able to do it now frankly because the team has just been so incredibly driving toward getting us in good shape for SAPPHIRE.
I didn't want to distract them from the SAPPHIRE data. That's critical to us. The 48-month data is really important, but on a priority list, SAPPHIRE took priority. They're delivering beautiful tests. So that allowed us to update the 48-month data. So as Jing said, this is a bit of a snapshot, so more to come. We'll give you more detail as we get this in front of a medical meeting.
And then that goes to your second part of the question, not to distract this team from where they're going and how to get there. The classic is we have got to clean and lock the database and be sure that the data meets all the quality checks that we have to for registration. So there's some established timeframes in there.
So I'm not going to give any more granularity on the timing in Q4, just to say this team is driving to get us there as quickly as possible with high quality to be able to allow us to really stand behind the integrity of the data. They've done a fabulous job to date. And I hope you get the energy from me on this call, right? These teams are really driving. We are driving. We are focused. We are delivering. So we'll get it as soon as we can, Tess, coming soon as I said in my remarks.

Tessa Romero

Okay. Thanks so much for taking our questions.

Operator

Gary Nachman, Raymond James.

Gary Nachman

Thanks. Good morning. So the SAPPHIRE Phase 3 study is only at the 12 months. But if positive, do you think the label could potentially include some of this longer-term data from TOPAZ that's pretty compelling and really important for these SMA patients that could also help the case with the payers?
And then secondly, just on obesity, if you'll have data from EMBRAZE in the second quarter of next year, how soon will you be able to file the IND for 439? I'm assuming it's soon after, but what would the gating factor there be? Thank you.

Jay Backstrom

Yes. Good question. So let me start, Gary, with the first one about the long-term data from TOPAZ. Clearly, we find these data of interest. And like you, I think they're meaningful for a variety of perspectives. From the regulatory perspective, if you think about it, the safety and tolerability is essential. And that will clearly contribute to our safety profile and expect to see that for the FDA and EMA looking for that data to help them with that benefit risk assessment.
And we will do everything we can to optimize the opportunity for that to be in the -- for the regulatory review to support the application. Where we move to the payer piece, I think as you know in those interactions, publication data, the additional data that we have, that entire data set will be open and available to them to review.
And to add to your comment, because I do think it's important, we think about the benefit for patients that is sustained over time. My past experience in the payer interactions, that's a meaningful data point that patients continue to benefit. So we'll definitely maximize that in those interactions.
And then from the SRK-439 program, again, these are in parallel. So Mo and his team are really driving toward the IND. We're doing the IND-enabling tox work. So that is kind of maybe the gate to it until we get that done, but it's on track and on schedule.
And as we shared at the beginning of our discussion and our journey into the obesity space, we're targeting sometime midyear next year, so they will be pretty concurrent. Although with the speed with which the EMBRAZE team has enrolled, it's likely we'll report those data out in advance. It will certainly support the target and our strategy, which will be helpful, and we'll include that in the IND interactions.

Gary Nachman

All right. Great. Thank you.

Operator

Srikripa Devarakonda, Truist Securities.

Srikripa Devarakonda

Hey, guys. Thank you so much for taking my question. I know you've just started enrolling for the obesity study with apitegromab. It looks like you're seeing better enrollment than expected. I was wondering if you can provide a little bit more color, if possible, on what sort of patients seem to be the target for this? And also, you're targeting the certain ratio between overweight and obese patients. Does it matter?
And given the -- just following up on an earlier question, the tirzepatide and semaglutide. They have slightly different profiles. So is there anything you took into account in terms of trial-powering assumptions about the distribution between tirzepatide and semaglutide? Thank you.

Jay Backstrom

Yes, good question. So Kripa, this is Jay. And maybe I'll start with the trial design, and then I'll have Jing add on to it and talk about the patient population that's being included in the study. Again, this is a proof-of-concept study, so we really wanted to be able to kind of see an effect on that preservation of lean muscle mass.
I think, to your point, tirzepatide and semaglutide both have the effect. I think the speed with which you see that decline differs between the two. And so there may be some difference in terms of when you can detect our ability to preserve that. But I think seeing the effect on either of those groups would be helpful.
So we considered it, but we didn't really -- as the earlier question came from -- on the call, we didn't stratify by that for the study. But we believe that we will be able to demonstrate the effect that we expect to see. And then Jing, about the population that we've included in the EMBRAZE study?

Jing Marantz

Yes, so Kripa, we did not strive for a particular ratio for the overweight versus the obese population. Just importantly, the objective for the study is really to have a quick proof of concept, as I mentioned, really just to kind of assess the ability to preserve lean muscle in the context of a GLP agonist.
And as to your second question about the ratio between the difference between semaglutide and tirzepatide, our view is to -- we do not think there's a fundamental difference between those two. If you look at the degree of weight reduction, I think tirzepatide probably has a greater degree of weight reduction.
But the overall safety profile is quite similar between the two, and the proportions of the lean muscle loss in the context of GLP-1 are very similar between the two, their ability to kind of reduce cardiovascular risk in both studies -- both studies have shown that.
So in our view, it's basically -- it's more thinking about the pathway of those GLP agonism to lose weight, but then lose muscle along that and how do we counter that, so we can preserve lean muscle. That's really the primary objective, and the trial is set up to do that. And so therefore, that's our focus.

Srikripa Devarakonda

Okay, great. And then just one more follow-up question on that. So this is a proof-of-concept study. Your primary endpoint is changed from baseline in lean mass by DEXA scan. By the time you're ready to do a pivotal trial, do you expect any update or change in FDA guidance in terms of how to develop muscle-preservation drugs or do you think you have all you need at this point of time?

Jay Backstrom

Yes, Srikripa. This is Jay. I think the answer is going to be -- it's going to be an evolving field, and I think FDA will begin to take into consideration the strategies to really have healthy weight loss management. Although as you know, I think regulatory change tends to be delayed. So whether we get greater insight as we go forward remains to be seen.
Having said that, I feel very good about the information we've received to date from the FDA. I think we need to demonstrate clinical benefit in addition. And I think as you see from Mo -- and what really gets me excited is we're walking through what Mo and his team are doing on the non-clinical data. I'll just ask you to take a look at that. It's starting to foreshadow where we could take this medicine, right?
We have an effect on glucose metabolism. That's a clear measure of clinical benefit. The data at the ADA showed that we preserve the lean muscle. In fact, we maintain the lean muscle and in fact increase the lean muscle mass upon withdrawal of semaglutide, and we mitigate the weight rebound, the fat rebound.
So you're seeing opportunities where what we've been saying is sustainable. And I think we can find strategies there on the maintenance side or in combination to really position, I think, those trying to lose weight to not lose it at the expense of muscle, which plays such a critical role in metabolism.

Srikripa Devarakonda

Great. Thank you so much.

Operator

Mark Frahm, TD Cowen.

Mark Frahm

Thanks for taking my questions. A lot have already been answered, but maybe to follow up on Mike's question right at the beginning, just on these differences between the molecules and the trial designs in SMA, do you guys view that those differences are so significant that they're very likely to lead to completely different outcomes for trials in terms of just outright failing to reach statistical significance or succeeding in other cases?
Or do you think that these are likely to be just more subtle kind of aspects of the overall profile that you're able to market to, that each company might be able to market to in terms of how big that efficacy signal really is and obviously the safety profile? And then I'll have a follow-up question after that.

Jay Backstrom

Yes, okay. Sorry, Mark. This is Jay. Yes, so talking about the differences in the profiles of the programs -- because I got a side distraction as you were asking the question, I want to make sure I got it correctly, in terms of what's expected to be seen from each of the different profiles? (Multiple speakers)

Mark Frahm

Is it significant enough that it's going to be very important to success failure, or is it -- or do you view it as more subtle as to just how impressive the data is going to be?

Jay Backstrom

Yes, it's really interesting. I mean, let's start first and foremost. Again, I made a comment about we're treating children and young adults, and we have plans to move even into earlier ages under 2, right? So if you think about that, as everything we said about our strategy, safety really trumps. You've got to be able to have a safe therapy. You've got to be able to administer it. It's got to be able to be administered without regard for growth and development, and we've been able to demonstrate that across. So safety is really paramount.
I think that there's differences in terms of each of the strategies, but I like our strategy on the safety side. So let's start there. I think with respect to kind of what to see from the efficacy side, again, I think we've selected the Hammersmith scale for a reason. It was what's used for nusinersen. There are other motor scales. But quite honestly, from the field, I believe this is the gold standard. And we're really looking forward to reporting out our data against that gold-standard measures. So I think that's important.
I think the tolerability, which is linked back to safety -- but the tolerability will be critical as I think about it from a payer interaction and our ability to commercialize. We have seen very little, if any, drop from our TOPAZ data going forward. That really is impressive. I recall from a previous setting that I was in and the CEO at the time would make a comment that he doesn't know what the median duration of treatment is because patients are still on.
So if you just think about the implication to that, I think we're really doing well. I'm not sure that's true across the other programs. We will see, but I like where we are going. And then the final point is I do like that we are agnostic to treatment. I think that is really important. This is an established market with several players. We have an opportunity, as you'll see going forward, to really show this in the background of gene therapy, not just SMN-upregulating therapy.
I think that is a really good place to play because we're neutral in terms of the choice, and I think that maximizes our opportunity to go forward. So all of those things together, I feel really good about where we are and frankly look like you looking forward to being able to tell you the top-line results.

Mark Frahm

Okay, that's helpful. And then just obviously, we're hoping that the trial will be positive. Can you just remind us what else you may need to gather to be ready to file that BLA? Is it really just the data and writing it up, or are there other things on the CMC side that still need to kind of come in house?

Jay Backstrom

Yes. As you know, with most applications, this is a work in progress. The beauty of it is, is that we've been preparing the BLA over the last 12 months to 18 months, to be honest, right? There are sections that you can complete and do. The non-clinical sections, that work is done. Those reports are written. They are being included. The CMC team is doing their CMC work and PPQ runs and getting all that stuff. So that's running beautifully. And then the clinical team is really working to populate the modules.
There are some things that we will incorporate. The TOPAZ data, as it was raised earlier by Gary, definitely we're going to include that in our application. But that data as well is evolving. We have enough to put in there. So all of that is coming together beautifully.
We were pleased and very fortunate to have a really outstanding Head of Regulatory come in, and he's just done a fabulous job of getting us ready for submission. So Jing and team are flying, Mo's team is hustling, and the rest of us are trying to keep up with them, Mark.

Mark Frahm

Okay. All right. Thank you.

Operator

Thank you. There are no further questions at this time.

Jay Backstrom

Okay. Well, listen, thank you all. We're going to close the call. Thanks for your interest, and I appreciate you joining us today.

Operator

This concludes today's conference call. Thank you for participating. You may now disconnect.