How does SRK-015 work?
SRK-015 is a specific monoclonal antibody. It selectively binds to the latent or inactive form of myostatin. Myostatin inhibits muscle growth by working in concert with other growth factors and hormones. Its main role is to help maintain healthy muscle mass.
In SMA, muscle tissue is weak and atrophied. A plausible approach to increasing muscle mass is, therefore, by inhibiting myostatin activity.
When injected into the bloodstream, SRK-015 selectively binds to latent or inactive myostatin. This binding prevents the conversion of myostatin to its active form in muscle tissues.
SRK-015 does not affect the activity of other closely related factors, such as GDF-11 or activin A, in contrast to traditional treatment approaches that block already activated (mature) myostatin or the myostatin receptor. Researchers think that in this way, SRK-015 may have fewer side effects than other myostatin inhibitors.
Animals in models lacking in myostatin have greater muscle mass and strength. Myostatin inhibition with SRK-015 has shown similar results in preclinical studies.
A study in mice reported that SRK-015 helped improve muscle capacity and strength, and increased lean body mass, particularly in the fast-twitch muscle fibers that are affected in SMA.
Another study found that SRK-015 effectively increased muscle mass and function in a mouse model of SMA, and also improved the animals’ bone structure.
SRK-015 in clinical trials
A placebo-controlled and double-blind Phase 1 clinical trial tested ascending doses of SRK-015 in healthy volunteers. Positive final results, announced in June 2019, showed that participants tolerated SRK-015 well across all doses up to 30 mg/kg, with no dose-limiting toxicities.
A Phase 2 trial called TOPAZ (NCT03921528) opened in May 2019 to evaluate the safety and efficacy of SRK-015 in people with SMA type 2 and type 3. The trial has enrolled 58 patients, ages 2 to 21, at centers in the U.S., Italy, the Netherlands, and Spain.
Patients are divided into three groups, and all are being treated for one year. Those in groups 1 and 2 are being given 20 mg/kg of SRK-015 by intravenous infusion once every four weeks; group 1 includes ambulatory type 3 patients, and group 2 type 2s and 3s who are not able to walk. Those in group 3, all type 2 patients, are randomly receiving SRK-015 infusions of 20 mg/kg or 2 mg/kg once every four weeks for one year. Patients can also be using an approved SMN upregulator therapy. Its primary goals are measures of safety, and clinically meaningful changes in motor function or physical abilities based on the revised Hammersmith scale and the expanded Hammersmith functional motor scale.
Preliminary trial data released in November 2019 showed a dose-dependent increase of up to 100-fold in blood levels of latent or inactive myostatin. The analysis included 29 patients in total: 12 from group 1, eight from group 2, and nine from group 3. All had been given a single dose of SRK-015 and researchers evaluated them after four weeks. They reported no safety issues.
Scholar Rock plans to analyze interim safety and efficacy in a subset of patients after six months of treatment, and expects to announce findings late in 2020. Topline results for the entire 12-month treatment period are likely in 2021, when researchers expect to complete this trial.
The therapy received a rare pediatric disease designation from the FDA in August 2020.
Last updated: Aug. 27, 2020
SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.