Early Data Support SRK-015 Development for SMA Types 2–3, Scholar Rock Says

SRK-015, an experimental treatment for spinal muscular atrophy (SMA), continues to produce promising results in preclinical studies and in a Phase 1 trial of healthy volunteers, its developer, Scholar Rock, has announced.

“We are excited for the potential role of SRK-015 as the first muscle-directed therapy to address the continued functional deficits experienced by some patients with SMA,” Nagesh Mahanthappa, PhD, company president and CEO, said in a news release.

The findings further support the recently started Phase 2 trial TOPAZ (NCT03921528), which will evaluate SRK-015’s efficacy and safety for improving motor function in children and adults with SMA types 2 and 3. Two doses will be tested — 2 mg/kg or 20 mg/kg — given every four weeks for up to 12 months.

Enrollment is ongoing at multiple sites in the U.S. and Europe, with the aim of enrolling 55 patients from 2 to 21 years old. More information on contacts and locations is available here. TOPAZ is anticipated to be completed in April 2021.

Updated preclinical and Phase 1 results were highlighted at the 24th International Annual Congress of the World Muscle Society (WMS), held Oct. 1–5 in Copenhagen, Denmark, in a poster titled “SRK-015, a Fully Human Monoclonal Antibody Inhibiting Myostatin Activation, Offers Sustained Target Engagement Across Multiple Species, Including Humans.”

SRK-015 has been designed to improve muscle strength and motor function in patients with SMA. It inhibits the activation of myostatin, a growth factor produced primarily in skeletal muscle cells to suppress muscle growth.

As SRK-015 targets the latent form of myostatin (pre-active), scientists expect it to result in fewer side effects than targeting its activated form or receptor.

The recently completed Phase 1 trial showed that all tested doses of SRK-015 — 1, 3, 10, 20, and 30 mg/kg, given by infusion into the vein — were well-tolerated and led to durable effects in healthy adult volunteers.

The latest data presented at the 2019 WMS congress confirm and add to these results.

In line with previous results, no dose-limiting toxicities were identified up to the highest evaluated dose of 30 mg/kg.

Pharmacodynamic (how the body responds to a therapy) data showed that SRK‑015 successfully binds latent myostatin in a robust and durable manner. A single dose of 3 mg/kg or greater led to increases in latent myostatin levels, which was sustained for at least 84 days following single doses of 20 or 30 mg/kg.

SRK‑015’s pharmacokinetic profile — the time course of its absorption, availability, distribution, metabolism, and elimination in the body — was also favorable.

The treatment’s half-life — the time the body takes to eliminate half of its amount — was 23–33 days across the different doses, which favors a dosing of SRK-015 once every four weeks.

In addition, the latest preclinical findings showed the treatment’s favorable pharmacological profile in different animal models, including rats and monkeys. Its benefits in muscle strength were verified in mouse models of early and late restoration of survival motor neuron, the missing protein in people with SMA.

Treatment with muSRK-015P (a mouse version of SRK-015) increased the force applied by limb muscles by 20%–51% and led to a greater proportion of muscle fibers, compared with a placebo.

This was accompanied by an over 10-fold rise in blood levels of latent myostatin following the treatment, which confirms the presence of the target (latent myostatin) in an SMA-like setting, according to the researchers.

Additionally, serum levels of latent myostatin were low before treatment in mice, which supports the idea that most of SRK-015’s target lies within skeletal muscle, and is not circulating in the bloodstream.

Prior work in mice had revealed that SRK-105 prevented additional atrophy and showed potential to improve muscle mass and function in healthy animals.

“Collectively, these preclinical and Phase 1 healthy volunteer data provided the basis for advancing SRK-015 to our TOPAZ Phase 2 clinical trial,” Mahanthappa said.

“We look forward to data from the upcoming clinical read-outs of the TOPAZ trial, starting with the preliminary PK/PD results at the end of 2019 and the interim efficacy and safety data in the first half of 2020,” he added.

SRK-15 has received orphan drug status from both the U.S. Food and Drug Administration and the European Commission for the treatment of SMA.