Apitegromab (SRK-015) for spinal muscular atrophy

Last updated July 18, 2024, by Marisa Wexler, MS
Fact-checked by Ana de Barros, PhD

What is apitegromab for SMA?

Apitegromab (SRK-015) is an experimental muscle-directed infusion therapy being developed by Scholar Rock as an add-on treatment to improve motor function in people with spinal muscular atrophy (SMA).

Apitegromab has received fast track status and orphan drug and rare pediatric disease designations by the U.S. Food and Drug Administration (FDA). It also won orphan medicinal product status and priority medicines eligibility in the European Union. Such designations are intended, in various ways, to speed a therapy’s clinical development.

Therapy snapshot

How does apitegromab work?

In SMA, genetic mutations result in a deficiency of the SMN protein, which leads the nerve cells that control movement, called motor neurons, to sicken and die. This ultimately causes symptoms such as muscle weakness and wasting.

There are several approved disease-modifying treatments for SMA, which work to slow the disease’s progress by increasing levels of SMN.

Apitegromab is being developed as an add-on to SMN-targeting treatments. Rather than addressing the root cause of the disease, apitegromab is designed to boost patients’ muscle strength by targeting the muscle protein myostatin.

Myostatin is primarily present in skeletal muscles — those used for movement — to regulate muscle growth by inhibiting its development, thereby helping to maintain a balanced and healthy muscle mass under typical conditions.

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. By reducing the levels of mature myostatin, apitegromab should increase muscle mass and improve motor function in people with SMA.

Because apitegromab does not target the active version of myostatin it potentially results in fewer side effects compared with conventional myostatin inhibitors, which can affect other biological processes like bone formation and blood vessel health due to their interaction with related factors.

A study in mice showed apitegromab improved muscle mass and strength, and increased lean body mass, particularly in the fast-twitch skeletal muscles, a group of muscle fibers that allow faster movement of short duration, and which are more susceptible to damage in SMA. The therapy was also shown to effectively increase muscle mass, boost motor function, and improve bone structure in a mouse model of SMA.

How will apitegromab be administered?

Apitegromab is administered via infusion into the bloodstream (intravenous). In earlier clinical trials, the therapy was administered every four weeks at doses of 2 or 20 mg/kg.

An ongoing Phase 3 clinical trial is testing two doses of apitegromab, 10 or 20 mg/kg every four weeks.

Apitegromab in clinical trials

Apitegromab has been tested in a Phase 1 study in healthy volunteers which showed positive safety results and indicated the therapy was blocking myostatin activity as designed. This led Scholar Rock to launch the Phase 2 TOPAZ study (NCT03921528) and the Phase 3 SAPPHIRE trial (NCT05156320) in people with SMA.

Phase 2 TOPAZ trial

TOPAZ evaluated the safety and effectiveness of two doses of apitegromab (2 or 20 mg/kg) in 58 children and young adults, ages 2-21, with SMA type 2 or type 3 (later-onset disease).

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

Results from TOPAZ showed that, after a year, standardized measures of motor function were stable for most patients — a marked contrast from the natural course of SMA, where motor function usually gets progressively worse over time. Some patients had clinically meaningful improvements in motor function after a year on apitegromab, particularly those who were younger at the time the therapy was initiated. Among nonambulatory patients ages 2 and older who had started treatment with Spinraza before age 5, more than half (59%) reported clinically meaningful improvements.

All 57 patients who completed a year of treatment chose to enter the trial’s extension phase where all continue to receive apitegromab for up to an additional year. Two-year data indicated patients’ motor function generally stabilized or further improved after another year on the therapy, and measures of muscle fatigue and life quality also generally were stable or improved. Three-year data continues to show motor function has generally stabilized or improved, with some patients hitting new motor milestones.

Phase 3 SAPPHIRE trial

Scholar Rock is conducting a global Phase 3 trial called SAPPHIRE, which is testing two doses of apitegromab (10 or 20 mg/kg) against placebo in 188 people with SMA types 2 or 3 who are on stable treatment with Spinraza or Evrysdi (risdiplam). SAPPHIRE enrolled patients ages 2-21 who are unable to walk, but can sit independently. As in TOPAZ, patients are receiving intravenous infusions of apitegromab once every four weeks for a year.

The study’s main goal is to evaluate the effect of apitegromab on a standardized measure of motor function called the Hammersmith Functional Motor Scale Expanded (HFMSE). The trial completed enrollment in late 2023 and results are expected by the end of 2024. If the results are positive, Scholar Rock is expected to use the study’s findings as the main basis for regulatory applications of apitegromab.

Ongoing trials

Patients who completed both SAPPHIRE and TOPAZ were eligible to enter the open-label ONYX Phase 3 study (NCT05626855), which is evaluating apitegromab’s long-term safety and efficacy. This study gives all participants, including those who previously received a placebo, the opportunity to be treated with apitegromab.

Common side effects of Apitegromab

In the Phase 2 TOPAZ trial, the most common adverse events (side effects and other safety issues) included:

• headache
• upper respiratory tract infection
• fever
• cough
• common cold.

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 healthcare providers 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.