Scholar Rock 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.

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

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 6 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 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.