Scholar Rock Holding Corporation

Good morning and welcome to Scholar's Rock second quarter financial results and business update call. All participants will be in listen-only mode. After the company's prepared remarks, call participants will have an opportunity to ask questions. To ask a question, you may press star, then one and one on your touch-tone phone. To withdraw your question, please press star, then one and one again. Please note this event is being recorded. Before we begin, I'd like to point out that we will be marking various statements about school artworks' 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 ScholarRock. Jay, please go ahead.

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 four, the focus of today's call is to highlight our exciting progress in 2024. After my introductory remarks, Jing Morantz, our chief medical officer, will provide an update on our development programs, including a review of the 48-month data from Topaz, our Pitocramab phase two proof of concept study. followed by Mo Katanani, our chief scientific officer, who will review the progress with our SRK439 program in obesity. I'll close with a summary of upcoming milestones and then open the call up for questions. Moving to slide five. 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, the Pitigramab, as we remain on track to report the top line results for SAFIRE, our phase three 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 SAFIRE, we are now only a few months away. At Scholar Rock, selectivity was foundational to our approach in designing a Pitigramab 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 Scholarock. We are at a point in our trajectory where the next 12 to 24 months will be transformative. Turning to slide six, 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 super family of growth factors by hitting the right target at the right time, avoiding unwanted toxicities, and potentially maximizing efficacy. As shown on slide seven, 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 the Pitigramab and SMA, we've reestablished myostatin as a neuromuscular target and our emerging data with SRK439 suggest the best-in-class potential to address the muscle loss associated with GLP-1 receptor agonist treatment, leading to sustainable healthy weight management and obesity. For our TGF-beta-1 programs with SRK181 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 SRK373. We applied our deep structural insights and antibody engineering expertise to solve a riddle that has not been done before. SRK373 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 our internal research as we embark on our next wave of innovation. Moving to slide eight, we have been disciplined and focused in our efforts to advance the pipeline to key developmental milestones across all of the therapeutic areas. Starting with neuromuscular disorders for our lead program, epitogramab, the upcoming readout for SAFIRE is just around the corner and we look forward to reporting out the top line results in Q4. SAFIRE was designed to meet regulatory requirements for approval and to demonstrate both the 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. SAFIRE was optimized for clinical success based on the TOPAS Phase II proof of concept study, and we're excited to share the TOPAS 48-month data on today's call. As you will hear from Jing in more detail, the updated TOPAS 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 CHERI-SHINE study recently presented by Finkel and colleagues at CURE-SMA, where the initial functional gains seen with nusinertin show a decline over time, highlighting the progressive nature of the disease and the need for additional treatment options, such as epitogramab, a muscle-directed therapy. In addition to the sustained functional improvement, the updated data continue to reinforce the safety and tolerability of epitogramab, with over 90% remaining on treatment and no new safety findings. Taking together the 48-month data further reinforce our confidence in the SAFIRE study and the potential for epitogrammab to improve the lives of those living with SMA. A successful SAFIRE study will allow epitogrammab 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 two proof-of-concept study in obesity, assessing epitigrimab 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 SRK439, 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 SRK439 following withdrawal of the GLP-1 receptor agonist. For our TGF-beta-1 programs with SRK181 and immuno-oncology, we've demonstrated proof of concept and proof of mechanism in overcoming checkpoint inhibitor resistance, and we look forward to discussing the next steps with FDA at our end of Phase 1 meeting. For SRK373, 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-beta-1 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 nine, 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 Late-Nanti TGF beta-1 monoclonal antibody, SRK373, 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 SAFIRE and Q4, a very exciting time at ScholarOn. And with that, I'm pleased to turn the call over to our Chief Medical Officer, Jing Maransk, who will provide an update on our development programs, followed by our Chief Scientific Officer, Mo Katsunani, who will walk us through an update from our research team. Jane?

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 one-on-one program that was featured at an oral session at ASCO. On today's call, I'll focus on the progress of our SMA program, including an update on the 48-month data from Topaz and the EMBRACE 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-amphetotransom A 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 Shay mentioned, that recent QRIS May meeting in June, Dr. Finkel and colleagues presented the long-term outcomes data from the Cherish Shine study, which enrolled SMA patients treated with Nusniracin. The orange lines represent the trajectory of patients initially randomized to Nusniracin. 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. The solid orange line on top represents the 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 functioning assessments. Therefore, it's not at all surprising for you to see that the hemorrhage must decline 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 TOPAS study had, on average, two years of prior loose nursing 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 loose nursing exposure similar to that of TOPAS 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 one 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'd 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 Hemersmith for the pooled non-ambulatory SMA patients ages 2 to 21 on the left and the 2 to 12 subset on the right. Hemersmith is a validated scale. designed specifically for SMA that measures the gross motor function. As mentioned before, scoliosurgery is the 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 RUM, which focuses more on the upper limb function. The improvement in RUM 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 lung 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. Turn into slide 16. So taken together, The updated topaz data with sustained clinical benefit, consistency of findings, and favorable safety profile with low discontinuation rate reinforces our belief that epiglomab 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. Turn it to slide 17. Both on the learnings of Topaz, our pivotal SAFIRE 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 SAFIRE reflects the population in Topaz that showed transformative potential. The primary endpoint is Hammersmith at 12 months, the same as Topaz, and the 20-meg 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 two 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 OMET need, the rapid adoption of semaglutide and chazapatide 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 EMBRACE study ahead of schedule. We're seeing great momentum in our enrollment and now expect to report to applying in Q2 of next year. The primary objective of the study is to demonstrate the effect of a selective myelostat 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, thus 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 epidicromab 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.