Scholar Rock today announced positive final top-line results from the Phase 1 clinical trial of its product candidate, SRK-015, a highly specific inhibitor of myostatin activation, in healthy adult volunteers. Consistent with previously announced interim findings, the final results showed robust and sustained target engagement and no apparent safety signals were observed across all tested doses. Detailed results from the Phase 1 trial will be presented at the Cure SMA Researcher Meeting being held June 28-July 1, 2019 in Anaheim, CA.
Phase 1 Final Top-line Results
Safety and Immunogenicity Data. SRK-015 was observed to be well-tolerated in the Phase 1 trial with no dose-limiting toxicities identified up to the highest evaluated dose of 30 mg/kg.
- In the single-ascending dose (SAD) portion of the trial, adverse events (AEs) were observed in 30 percent (9/30) of SRK-015-treated subjects and 50 percent (5/10) of placebo-treated subjects.
- In the multiple-ascending dose (MAD) portion of the trial, AEs were observed in 35 percent (7/20) of SRK-015-treated subjects and 67 percent (4/6) of placebo-treated subjects.
- There were no discontinuations due to a treatment-related AE, no hypersensitivity reactions, and no deaths. A single serious AE (SAE) of gallstone-induced pancreatitis was observed in an SRK-015-treated subject and was assessed by the trial investigator as unrelated to treatment.
- Immunogenicity as evaluated by anti-drug antibody testing was negative for all SRK-015 treated subjects in the trial.
Biomarker/Pharmacodynamic (PD) Data. Target engagement was shown in the Phase 1 trial through increases from baseline in levels of latent myostatin.
- The levels of target engagement attained a plateau after a single dose of SRK-015 at 3 mg/kg or greater, suggesting target saturation. This plateau was sustained up to Day 84 after a single dose at 20 mg/kg.
- This durability of effect was further shown in the MAD portion of the trial, during which the plateau was sustained up to at least Day 140 after three doses given once every two weeks at 20 mg/kg or 30 mg/kg.
- In contrast, no meaningful change was observed in the latent myostatin biomarker concentrations in subjects who received placebo.
PD was evaluated through a proprietary, exploratory biomarker assay developed by Scholar Rock that measures serum concentrations of latent myostatin. This assay was used previously to measure target engagement in preclinical studies in healthy animals and a mouse model of SMA.
Pharmacokinetic (PK) Data. Drug exposure to SRK-015 was dose-proportional and SRK-015’s serum half-life was 23-33 days across dose cohorts. In these respects, SRK-015 displayed a PK profile consistent with what is commonly observed for monoclonal antibodies.
Phase 1 Trial Design
The randomized, double-blind, placebo-controlled Phase 1 clinical trial was designed to evaluate the safety and tolerability of intravenously administered SRK-015, assess the PK and PD profile, and inform dosing for the Phase 2 trial.
- Single-Ascending Dose: Enrolled 40 adult healthy volunteers, randomized 3:1 to receive a single dose of SRK-015 or placebo, and evaluated doses of 1, 3, 10, 20 and 30 mg/kg.
- Multiple-Ascending Dose: Enrolled 26 adult healthy volunteers, randomized 3:1 to receive SRK-015 or placebo every two weeks for a total of three doses (Day 0, 14 and 28). The MAD portion of the trial evaluated doses of 10, 20 and 30 mg/kg.
SRK-015 works by inhibiting myostatin. Myostatin is a protein that works with other proteins and hormones to help regulate muscle mass. In healthy individuals, myostatin limits muscle growth and differentiation, to prevent muscles from growing too large. For individuals affected by SMA, inhibiting this protein may combat the muscle weakness and atrophy that characterizes the disease. A Phase 1 clinical trial in healthy volunteers is ongoing. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) for SRK-015 for the treatment of SMA.