Srk-015 myostatin blocker

Apitegromab (SRK-015) is an experimental muscle-directed therapy being developed by Scholar Rock for spinal muscular atrophy (SMA). It is designed to improve motor abilities in SMA patients.

How does apitegromab work?

Apitegromab is a lab-made (synthetic) monoclonal antibody that works by selectively binding to the precursor, or latent form, of myostatin, preventing its conversion into its active, or mature, form. Myostatin is a protein mainly found in skeletal muscles, or muscles used for movement, that suppresses muscle growth to maintain healthy muscle mass.

By reducing the levels of mature myostatin, the therapy, infused directly into the bloodstream, is expected to increase muscle mass and improve motor function in people with SMA, an inherited disease characterized by muscle weakness and wasting.

A study in mice showed that apitegromab improved muscle mass and strength, and increased lean body mass, particularly in the fast-twitch skeletal muscle fibers. Fast-twitch muscle fibers are those under voluntary control that allow faster movement of short duration, and which are more susceptible to damage in SMA.

The therapy also was shown to effectively increase muscle mass and function in a mouse model of SMA, while also improving the animals’ bone structure.

Notably, apitegromab is expected to cause fewer side effects than conventional suppressors of the active form of myostatin, which typically also block the activity of closely related factors that are involved in other biological processes, such as bone formation and vascular health.

As a muscle-directed therapy, its mechanism of action is distinct from currently approved disease-modifying therapies for SMA, all of which work by increasing the levels of SMN, a protein essential for motor neuron and muscle health and whose production is impaired in SMA patients.

As such, Scholar Rock believes that apitegromab has the potential to be an add-on to background SMN-directed therapies.

Apitegromab in clinical trials

Promising findings from a Phase 1 clinical trial prompted the launch of a proof-of-concept, international Phase 2 trial, called TOPAZ (NCT03921528). The study is evaluating the safety and effectiveness of two doses of apitegromab (2 or 20 mg/kg) in 58 children and young adults, ages 2 to 21, with SMA types 2 or 3 (later-onset disease).

Participants were divided into three groups based on their age, disease type, and/or ability to walk, and were given into-the-vein (intravenous) infusions of apitegromab once every four weeks for up to one year. More than 80% received the therapy’s higher dose and also were being treated with Biogen’s Spinraza (nusinersen), the first approved SMA disease-modifying therapy.

Consistent with interim findings, top-line, one-year results showed that apitegromab was generally safe and improved or stabilized patients’ motor abilities, with greater benefits seen with the higher dose and in younger children, ages 2–6, with SMA type 2.

In this younger group of patients, motor function continued to improve from six months to one year of treatment. This highlighted the therapy’s ability to further improve motor skills over time, and suggested that these young children could further benefit from continued treatment.

All 57 patients who completed the one-year treatment period chose to enter the trial’s extension phase, in which all will continue to receive apitegromab for up to an additional year.

To date, the most commonly reported adverse events with apitegromab included headache, fever, upper respiratory tract infection, cough, and the common cold.

Scholar Rock now is preparing the launch of a pivotal, global Phase 3 trial, called SAPPHIRE (NCT05156320), which will test whether apitegromab is safe and effective as an add-on therapy. That trial will involve up to 204 type 2 and 3 patients, ages 2 to 21, who are unable to walk.

Participants will receive either one of two doses of apitegromab (10 or 20 mg/kg) or a placebo for up to one year, in addition to their regular SMN-targeted treatment. This may include Spinraza or Roche’s Evrysdi (risdiplam), the first disease-modifying oral therapy approved for SMA.

SAPPHIRE plans to enroll patients across 55 sites, including in the U.S. and Europe. After completing the trial, participants will have the option of enrolling in an open-label extension study, in which all will receive the experimental therapy for a longer period.

Other information

Apitegromab received orphan drug designation, rare pediatric disease status, and fast track designation in the U.S., and orphan drug status and priority medicines designation in Europe, for the treatment of SMA. These designations are meant to speed the therapy’s clinical development and regulatory review by providing financial and regulatory incentives.

Scholar Rock also was awarded a U.S. patent in 2021 for apitegromab as a treatment for SMA and other muscle conditions.

The company is planning to launch a proof-of-concept trial testing apitegromab in people with Becker muscular dystrophy, another inherited disorder characterized by progressive muscle weakness and atrophy.


How it’s used
Apitegromab is a fully human anti-proMyostatin monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/lambda isotype that specifically binds to human pro/latent myostatin with high affinity inhibiting myostatin activation. SRK-015 will be administered every 4 weeks by intravenous (IV) infusion.