Progress is being made to develop a muscle-strengthening drug in SMA. Scholar Rock, Inc. has just announced interim results of a phase-2 clinical trial of their experimental drug SRK-015.

SRK-015 aims to improve muscle strength in people with spinal muscular atrophy by allowing growth of muscle tissue. The drug is a selective myostatin inhibitor – it reduces the amount of the protein called myostatin that is available to the muscles. Since myostatin’s role in the body is to block excessive growth of muscle tissue, researchers are testing whether a compound like SRK-015 could effectively increase the muscle mass. It is known that people and animals who have a reduced level of myostatin due to a disease or genetic mutation develop unusually strong muscles.

Scholar Rock today announced preliminary pharmacokinetic (PK) and pharmacodynamic (PD) data from the TOPAZ Phase 2 trial of SRK-015 in SMA patients. SRK-015 is a selective inhibitor of myostatin that has been shown to increase muscle mass and strength in animal models. The preliminary PK/PD analysis showed dose-dependent increases of serum latent myostatin levels following treatment with SRK-015, confirming the presence of latent myostatin in patients with SMA and demonstrating robust target engagement. No clinically significant safety signals have been observed as of the data cutoff for this analysis.

CAMBRIDGE, Mass., Nov. 19, 2019 (GLOBE NEWSWIRE) — Scholar Rock (NASDAQ: SRRK), a clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, today announced preliminary pharmacokinetic (PK) and pharmacodynamic (PD) results from the TOPAZ Phase 2 proof-of-concept trial of SRK-015 for the treatment of patients with spinal muscular atrophy (SMA).  The planned preliminary PK/PD analysis, which includes data from 29 patients with SMA across all three cohorts, showed dose-proportional drug exposure and demonstrated target engagement, as evidenced by dose-dependent increases of up to 100-fold in the serum levels of latent myostatin following SRK-015 treatment (2 mg/kg and 20 mg/kg doses).  SRK-015 is a highly selective inhibitor of the precursor, or latent form, of myostatin, and was specifically designed to avoid interactions with related targets such as activins, GDF-11, or BMPs, to potentially improve the therapeutic profile compared to traditional non-selective inhibitors.

“We are pleased with the progress we have made to date towards our goal of developing SRK-015 as a muscle-directed therapy to address the functional deficits that remain a significant unmet need for patients with SMA despite advancements with SMN upregulators,” said Yung Chyung, M.D., Chief Medical Officer of Scholar Rock. “These preliminary PK/PD results positively address two important questions for the program by both confirming the presence of latent myostatin in patients with SMA and further corroborating the ability of SRK-015 to engage this drug target, including in pediatric patients with SMA.”

“These results represent a key milestone for Scholar Rock by showing that we can indeed bring together cutting-edge monoclonal antibody technology with deep structural biology insights to target latent forms of growth factors in the context of human disease,” said Nagesh Mahanthappa, Ph.D., President and CEO of Scholar Rock.  “We look forward to building upon these insights as we advance a growing portfolio of product candidates.”

TOPAZ Phase 2 Preliminary PK/PD Results
The Phase 2 proof-of-concept trial is evaluating the safety and efficacy of SRK-015 dosed intravenously every four weeks (Q4W) over a 12-month treatment period.  The trial is anticipated to enroll approximately 55 patients with Type 2 or Type 3 SMA in the U.S. and Europe across three distinct cohorts.  Patients in Cohorts 1 and 2 are being treated with 20 mg/kg of SRK-015 Q4W and patients in Cohort 3 are randomized to either 20 mg/kg or 2 mg/kg Q4W.  The primary objectives of the cohorts are to assess safety and clinically meaningful motor functional outcomes, such as the Revised Hammersmith Scale (RHS) and the Hammersmith Functional Motor Scale Expanded (HFMSE).  The TOPAZ trial is ongoing and further details about the trial can be found on clinicaltrials.gov.

The preliminary PK/PD analysis of the TOPAZ trial includes data from 29 patients across the three cohorts; 12 patients in Cohort 1, eight patients in Cohort 2, and nine patients in Cohort 3. These patients had received one dose of SRK-015 and were evaluated for four weeks as of the data cutoff. The preliminary results are as follows:

• Dose-dependent increases of up to 100-fold in serum latent myostatin levels following treatment with SRK-015 (2 mg/kg and 20 mg/kg doses) confirms the presence of latent myostatin in patients with SMA and demonstrates robust target engagement.
• Fold-increases from baseline in serum latent myostatin levels in the first four weeks following SRK-015 treatment were comparable between SMA patients in the TOPAZ trial and healthy adult volunteers in the Phase 1 trial.
• In patients with SMA, SRK-015 displayed a preliminary PK profile exhibiting dose proportionality and low variability, consistent with PK observations from the Phase 1 trial in healthy adult volunteers.
• No clinically significant safety signals had been observed as of the data cutoff for this preliminary PK/PD analysis.

An interim efficacy and safety analysis is planned, encompassing a subset of patients with at least six months of treatment exposure. The interim results are expected in the first half of 2020 with top-line results for the full 12-month treatment period expected starting in the fourth quarter of 2020 and through the first quarter of 2021.

About SRK-015
SRK-015 is a selective inhibitor of the activation of myostatin and is an investigational product candidate for the treatment of patients with spinal muscular atrophy (SMA).  Myostatin, a member of the TGFβ superfamily of growth factors, is expressed primarily by skeletal muscle cells and the absence of its gene is associated with an increase in muscle mass and strength in multiple animal species.  Scholar Rock believes the inhibition of the activation of myostatin with SRK-015 may promote a clinically meaningful increase in muscle strength.  A Phase 2 clinical trial in patients with Type 2 and Type 3 SMA is ongoing.  The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD), and the European Commission (EC) has granted Orphan Medicinal Product Designation, to SRK-015 for the treatment of SMA.  The effectiveness and safety of SRK-015 have not been established and SRK-015 has not been approved for any use by the FDA or any other regulatory agency.