SMA Candidate SRK-015 Shows Promise in Healthy Volunteers; Trial Ongoing

Top-line results from a Phase 1 trial showed that SRK-015 had a positive safety profile and durable effects in healthy adult volunteers.

These findings supported the start of the Phase 2 study TOPAZ (NCT03921528) to evaluate SRK-015’s efficacy to improve motor function of SMA patients. TOPAZ is currently enrolling at Stanford University and Columbia University, and plans to include 50–60 patients with SMA types 2 and 3. For more information on trial sites and contacts, go here.

Scholar Rock — the company developing SRK-015 — will present the Phase 1 findings at the Cure SMA Annual Conference, in Anaheim, California, June 28–July 1.

“These data provide initial safety and mechanistic insights for SRK-015 and support our Phase 2 program,” Yung Chyung, MD, Scholar Rock’s chief medical officer, said in a press release.

Nagesh Mahanthappa, PhD, Scholar Rock’s president and CEO, commented that the pharmacological Phase 1 data offer initial proof-of-mechanism for the company’s “unique therapeutic approach of targeting the latent form of growth factors.” He added that Scholar Rock looks forward to advancing the development of growth factor modulators for other diseases.

SRK-015 is a man-made antibody engineered to block the activation of latent (immature) myostatin, a negative regulator of muscle mass largely found in skeletal muscle cells. When active, myostatin is known to inhibit muscle growth, and lowering its activity levels is associated with greater muscle mass and strength.

The SMA treatment candidate has received orphan drug status from both the U.S. Food and Drug Administration and the European Commission.

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The double-blind Phase 1 trial had two parts. The first part was a single-ascending dose (SAD) study in 40 healthy adult volunteers to evaluate the safety, tolerability, and pharmacological profile of SRK-015, given via intravenous infusion. Doses of 1, 3, 10, 20, and 30 mg/kg were tested.

The second multiple-ascending dose (MAD) part included 26 volunteers who received SRK-015 at 10, 20, or 30 mg/kg or a placebo every two weeks for a total of three doses on days 0, 14, and 28.

No dose-limiting toxicities were found up to the highest tested dose. In the SAD portion of the trial, 30% of the volunteers given SRK-015 (9 of 30) and 50% of those on a placebo (5 of 10) experienced adverse events. In the MAD part, adverse events were seen in 35% (7 of 20) of participants receiving SRK-015 and 67% of those given placebo (4 of 6).

As shown in a preliminary analysis, no treatment-related adverse events led to discontinuations and there were no hypersensitivity or immune reactions. The single serious adverse event in the SRK-015-treated group, a case of gallstone-induced pancreatitis, was deemed unrelated to treatment.

The results also showed that a single dose of 3 mg/kg was sufficient to durably increase serum levels of latent myostatin (in contrast with the active form of the protein, found in SMA patients). This increase, measured with an exploratory biomarker assay developed by Scholar Rock, was maintained up to day 84 with the 20 mg/kg dose in the first single-ascending dose part, while the multiple-ascending dose portion of the trial showed sustained effects up to at least day 140 with three 20 or 30 mg/kg doses. No such increases in myostatin were found in the placebo group.

SRK-015’s serum half-life — the time the body takes to halve its amount — was 23–33 days across the different doses. This is in line with other monoclonal antibodies, the company stated.

Participants in TOPAZ will receive SRK-015 intravenously every four weeks up to 12 months, either alone or in combination with an approved SMN protein upregulator therapy.

Changes in motor function will be assessed with the Hammersmith Functional Motor Scale Expanded (HFMSE) in non-ambulatory patients and the Revised Hammersmith Scale (RHS) in ambulatory participants.