Last updated Nov. 29, 2022, by Marisa Wexler, MS
Fact-checked by Ana de Barros, PhD
What is apitegromab for SMA?
As a muscle-directed therapy, apitegromab’s mechanism of action is distinct from currently approved disease-modifying therapies for SMA, all of which work by increasing the levels of the SMN whose deficit causes the disease. As such, Scholar Rock believes apitegromab has the potential to be an add-on to background SMN-directed therapies.
How does apitegromab work in SMA?
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, the muscles used for movement. It works to suppress muscle growth, which under normal circumstances can help balance muscle growth to maintain a healthy muscle mass. By reducing the levels of mature myostatin, apitegromab is expected to increase muscle mass and improve motor function in people with SMA, which is characterized by muscle weakness and wasting.
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 also was shown to effectively increase muscle mass, boost motor function, and improve bone structure in a mouse model of SMA.
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.
How will apitegromab be administered in SMA?
Apitegromab is administered via infusion into the bloodstream. In clinical trials, the therapy has been administered every four weeks at doses ranging from 2 to 20 mg/kg.
Apitegromab in SMA clinical trials
Phase 2 TOPAZ trial
After a Phase 1 study in healthy volunteers showed positive safety results and indicated apitegromab was blocking the activity of myostatin as designed, Scholar Rock launched 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.
Top-line results from TOPAZ showed that, after one 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 experienced clinically meaningful improvements in motor function after a year on apitegromab, particularly those who were younger at the time of therapy initiation: 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 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. Two-year data indicated that patients’ motor function was generally stabilized or further improved after an additional year on the therapy. Measures of muscle fatigue and life quality also generally were stable or improved after two years of apitegromab treatment.
Phase 3 SAPPHIRE trial
Scholar Rock now is conducting a global Phase 3 trial, called SAPPHIRE (NCT05156320), which is testing two doses of apitegromab (10 or 20 mg/kg) against placebo in 204 people with SMA type 2 or 3 who are on stable treatment with Spinraza or Evrysdi (risdiplam). The study’s main goal is to evaluate the effect of one year of apitegromab on a standardized measure of motor function called the Hammersmith Functional Motor Scale Expanded (HFMSE).
SAPPHIRE is open to patients ages 2 to 21 who are unable to walk but can sit independently.
Common side effects of apitegromab
In the TOPAZ clinical trial, the most common safety-related events reported were generally in line with what would be expected for SMA patients on Spinraza. These included:
- urinary tract infection
- the common cold
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