Nagesh Mahanthappa, Interim CEO of Scholar Rock Shares Insights on Treatment Options for Spinal Muscular Atrophy

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Nagesh Mahanthappa, Interim CEO of Scholar Rock Shares Insights on Treatment Options for Spinal Muscular Atrophy


  • Nagesh talked about how Spinal Muscular Atrophy (SMA) is affecting people all over the world and how Scholar Rock’s treatment options are improving the lives of those living with this disease
  • Nagesh also spoke about Scholar Rock’s lead product in SMA, apitegromab, highlighting its trial designs (TOPAZ & SAPPHIRE trials), outcomes, and real-world data
  • The interview provides a profound understanding of Scholar Rock’s aim to develop treatment options for serious diseases to improve patient lives

Smriti: Thank you for connecting with us. As we know Spinal Muscular Atrophy (SMA) is a debilitating condition that affects many people around the globe, tell us how Scholar Rock is playing an important role in the treatment of patients.

“Our work in SMA is aligned with the company’s overall focus on the development of monoclonal antibodies that locally and selectively target activation of the precursor forms of growth factors within the disease microenvironment”

Nagesh Mahanthappa: At Scholar Rock, we are focused on developing new approaches and treatments for serious diseases in which signaling by protein growth factors plays a fundamental role. Our lead investigational candidate is apitegromab (SRK-015), a selective inhibitor of the activation of latent myostatin, which we are developing with the aim of improving the motor function of those living with SMA. 

For background, SMA is caused by a mutation in the SMN1 gene that results in a deficiency of SMN protein, which is critical to the function and survival of motor neurons that control muscle function. The deficiency of SMN protein may also impact other systems, pathways, and processes causing debilitating and potentially fatal muscle weakness, significantly impacting the quality of life of those with the disease.  

While currently approved therapies are focused on targeting SMN deficiency, apitegromab offers a muscle-directed modality to be used with the disease-stabilizing effects of SMN-targeted therapies and drive improvements in motor function rather than only prevent functional decline. This potentially impacts a patient’s ability to live independently for longer, which also can have a direct impact on the level and intensity of caregiving support needed. 

Protein growth factors, such as myostatin, can be difficult to target with the right level of selectivity. Myostatin is a member of what is called the TGFβ superfamily of protein growth factors, which is a group of more than 30 related growth factors that mediate diverse biological processes. The active, mature form of myostatin shares considerable structural similarity with other TGFβ family members, making it difficult to create antibodies that can specifically target myostatin without interfering with structurally-related targets which may result in unintended systemic adverse events.
Our work in SMA is aligned with the company’s overall focus on the development of monoclonal antibodies that locally and selectively target activation of the precursor forms of growth factors within the disease microenvironment, thereby preventing the release of the active growth factor in the first place. As we are studying with apitegromab, through this approach, we hope to achieve heightened specificity for the targeted growth factor while minimizing interactions with structurally similar and related growth factors, thereby reducing the risk of undesirable side effects. 

Smriti: Shed some light on your prime product in SMA, apitegromab (its MOA, ROA, formulation, pathway, etc.)

Nagesh Mahanthappa: Apitegromab is an investigational selective inhibitor of the activation of latent myostatin that is being developed for the treatment of people with SMA. Essentially, apitegromab specifically binds the precursor forms of myostatin with high affinity and prevents activation and release of the mature myostatin growth factor, which inhibits muscle growth and strength. The precursor forms, pro/latent forms of myostatin are the predominant forms of myostatin in skeletal muscle, allowing apitegromab to inhibit myostatin activation directly in the target tissue. By specifically inhibiting the release of mature myostatin from the inactive precursor, apitegromab has the potential to minimize off-target effects that have been implicated as the cause of adverse effects of other less selective myostatin-directed agents.

Discovered by scientists at Scholar Rock, apitegromab is the first and only muscle-directed myostatin therapy to show proof-of-concept, is continuing to show improvements over 24 months in the phase 2 TOPAZ extension studies, and is currently being studied in a pivotal Phase 3 trial that is enrolling patients globally. There is still an incredible unmet need for people living with SMA in terms of new, safe, and effective complementary treatment options for improving muscle function, and we are motivated by the potential of apitegromab to improve outcomes for patients, including their quality of life.

Smriti: Discuss the trial designs of TOPAZ & SAPPHIRE trials and on what structure of populations these trials are conducted.

“Many patients suffer from substantial motor function deficits at the time of diagnosis and there’s a clear need for therapies that can make them stronger and increase muscle function”
Nagesh Mahanthappa: Our TOPAZ trial was a proof-of-concept, multi-cohort, active treatment Phase 2 study to evaluate the safety and efficacy of apitegromab with motor function endpoints in ambulatory and non-ambulatory patients with Type 2 and Type 3 SMA. The trial enrolled 58 patients between the ages of 2 and 21 in the U.S. and Europe across three distinct cohorts. All non-ambulatory patients received apitegromab once every four weeks with an approved SMN-targeted therapy over a 12-month treatment period. The primary efficacy endpoints measure motor function based on clinically meaningful outcome measures validated in SMA, such as the Hammersmith Functional Motor Scale Expanded (HFMSE) which is a widely used clinical measure to assess a child’s ability to do common activities such as lying down, rolling, crawling, kneeling, or standing. These are daily activities that are easily taken for granted in healthy children, but in the case of SMA, it’s not self-evident, for instance, that a child can roll from side to side or raise their arm to their head. Many patients suffer from substantial motor function deficits at the time of diagnosis and there’s a clear need for therapies that can make them stronger and increase muscle function.

Additional endpoints assessed included mean change from baseline in the Revised Upper Limb Module (RULM) which assesses upper limb function in patients with SMA. We continued into an extension period for those patients who chose to continue therapy, with 55 patients completing a 24-month extension period, and 54 of those patients opting to continue treatment in a 36-month extension period.

The results of TOPAZ informed the design of SAPPHIRE, a randomized, double-blind, placebo-controlled, Phase 3 clinical trial. Approximately 156 patients aged 2-12 years old with non-ambulatory Type 2 and Type 3 SMA are anticipated to be enrolled in the main efficacy population of the study. Patients on an SMN-targeted therapy will receive either apitegromab or a placebo every 4 weeks for 12 months. Separately from the main efficacy population, an exploratory population of approximately 48 patients aged 13-21 years old with non-ambulatory Type 2 and Type 3 SMA on an SMN-targeted therapy will also be evaluated. SAPPHIRE is currently enrolling across 55 sites in the U.S. and Europe and more information can be found on www.clinicaltrials.gov (NCT05156320).

Smriti: Give us some insights from the new data from the P-II TOPAZ trial and what were its outcomes.

Nagesh Mahanthappa: We announced topline results from our Phase 2 TOPAZ study in 2021, which evaluated the safety and efficacy of apitegromab with an approved SMN-targeted therapy. We observed that the majority of patients with non-ambulatory Type 2 and Type 3 SMA showed a clinical improvement (≥1-point increase) in HFMSE scores. A 1- or 2-point improvement in HFMSE could mean the difference in an individual’s ability to live more independently for longer, which can be incredibly meaningful for the patient as well as their caregivers. Our TOPAZ extension data further underscored the findings of the 12-month primary treatment period, demonstrating sizable and sustained motor function improvement at 24 months with apitegromab for non-ambulatory patients with Types 2 and 3 SMA. This durability and continued increase in motor function demonstrated by these data support the transformative potential of apitegromab for patients suffering from SMA.   

We observed significant improvements in the two main clinical measures used to evaluate motor function in SMA – the HFMSE and the RULM. At 24 months, TOPAZ demonstrated a 4.0 and 1.9 mean change from baseline in the HFMSE and RULM respectively in non-ambulatory patients. Increases in the HFMSE scale by as little as 1 point could represent a measurable impact on quality of life, such as a child being able to roll over at night without the aid of a caregiver. The RULM tracks activities closely aligned with activities of daily living, and examples include being able to push a button or lift a cup to the mouth. The safety profile of apitegromab in TOPAZ remains favorable, without any issue or concern, over 12 and 24 months of administration in participants with SMA.

Smriti: We are also keen to know about the P-III SAPPHIRE clinical trial that is evaluated in Type 2 and Type 3 SMA. Can you provide us with more specifics?

Nagesh Mahanthappa: We are very encouraged by the positive results seen in TOPAZ and are continuing to evaluate apitegromab’s potential as an essential muscle-targeted therapy to be used with an approved SMN-targeted therapy for the treatment of SMA in our pivotal Phase 3 SAPPHIRE trial (NCT05156320). The trial is currently enrolling across 55 sites in the U.S. and Europe. Approximately 156 patients aged 2-12 years old with non-ambulatory Type 2 and Type 3 SMA are anticipated to be enrolled in the main efficacy population.

This randomized, double-blind, placebo-controlled Phase 3 clinical trial is evaluating apitegromab for patients currently being treated with nusinersen or risdiplam. Patients will be randomized 1:1:1 to receive either apitegromab 20 mg/kg, apitegromab 10 mg/kg, or placebo by intravenous (IV) infusion every 4 weeks for 12 months. We are both motivated and excited by patients’ and providers’ enthusiastic responses to the trial.

Smriti: Can you share with us some results/instances of patient treatment benefits of apitegromab?
Nagesh Mahanthappa: SMA typically manifests in young children and has a significant impact on a patient's ability to live independently, with symptoms including limited mobility, breathing issues, and problems with eating and swallowing. As a result, patients living with SMA often need multiple caregivers’ support in various areas, from healthcare to daily life. As noted earlier, the clinical data suggest that apitegromab can have a significant positive impact on patients and their caregivers. 
Given the heterogeneous nature of SMA, there may be different perspectives for those living with the disease, so to gain insights into potential treatment benefits from the perspective of a patient or caregiver, we retrospectively gathered qualitative data from patients in the TOPAZ trial through semi-structured interviews. From our initial observations, we heard first-hand insights into apitegromab’s potential across a variety of areas, including changes in muscle endurance and fatigue measures related to the quality of life (QoL) in non-ambulatory patients with Types 2 or 3 SMA, changes in the bladder, bowel, and bulbar functional-related QoL and impact to activities of daily living. One caregiver shared the importance of her daughter “…just being able to do more of the little things, the little small motor things that she wants to be independent doing, like opening things or just live the everyday life of playing with her friends…” Our initial findings were presented at the Annual CURE SMA 2022 conference in June. Though further exploration is needed, real-world data studies can serve complementary roles to our current clinical trials and can help to inform future research and design of clinical trials, and we look forward to continuing this research to help us better understand endpoints of interest to patients and their caregivers. 

Smriti: Is Scholar Rock planning to assess any other molecules in other neurological or motor disorders in the pipeline?

Nagesh Mahanthappa: Currently, our focus is on investigating the potential of apitegromab as a muscle-targeted therapy for the treatment of SMA. We are also in the early stages of exploring the full potential of apitegromab in other myostatin-related disorders.  

Apitegromab is a unique molecule, its mechanism of action is unique, and its locus of activity is unique. It speaks to a dimension of SMA that hasn’t been directly addressed before and that’s what makes it exciting for us now, it’s exciting for the patients and we’re pushing forward with full enthusiasm and hope for the patients. 

Smriti: What are the other therapeutic areas in which you are developing your prime products?

Nagesh Mahanthappa: As part of our commitment to developing treatments for an array of serious diseases in which protein growth factors play a fundamental role, we are also investigating SRK-181 as a potential treatment in immuno-oncology. SRK-181 is a selective inhibitor of latent TGFβ1 activation being developed with the aim of overcoming primary resistance to and increasing the number of patients who may benefit from checkpoint inhibitor therapy.

Enrollment is currently ongoing for Part B of the Phase 1 DRAGON proof-of-concept clinical trial for SRK-181. Safety and pharmacokinetic results from the Part A dose escalation portion of DRAGON supported Part B dose selection, which is estimated to offer drug exposure at levels exceeding those hypothesized as needed for anti-tumor effect.  

DRAGON Part B consists of multiple proof-of-concept cohorts focused on evaluating the ability of SRK-181 to overcome primary resistance to anti-PD-(L)1 therapy. Each cohort will enroll up to 40 patients with various solid tumors, including urothelial carcinoma (UC), cutaneous melanoma (MEL), non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (ccRCC), and other solid tumors. The biomarker strategy in part B of DRAGON will explore early signs of SRK-181 activity, including target engagement and pathway modulation. This will include measuring effects on both circulating and tumor immune contexture, such as CD8+ T cell infiltration and reductions in myeloid-derived suppressor cell (MDSC) populations as well as analysis of TGFβ-related pathway signaling.

Smriti: Thank you for an informative interview! We at PharmaShots appreciate your valuable time and presence

Disclaimer: This interview was conducted on Sep 9, 2022, and since then there have been organizational changes in the company. Please feel free to get in touch with us for more information.

About the Author:

Dr. Nagesh K. Mahanthappa is the founding employee of Scholar Rock and has served as Interim CEO since August 2021. Previously, he served as a Director, President, and Chief Executive Officer from 2012 to 2020. Nagesh received his Ph.D. in Neurobiology from the California Institute of Technology and completed his post-doctoral training at the E.K. Shriver Center for Mental Retardation (then affiliated with Massachusetts General Hospital) and Harvard Medical School. Nagesh received his M.B.A. from the F.W. Olin Graduate School of Management at Babson College and his B.A. in Biology and Chemistry from the University of Colorado, Boulder.

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Senior Editor at PharmaShots. She is curious and very passionate about recent updates and developments in the life sciences industry. She covers Biopharma, MedTech, and Digital health segments along with different reports at PharmaShots.

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