Developed by Scholar Rock, apitegromab’s potential to improve muscle strength and motor function in people with spinal muscular atrophy (SMA) is currently under investigation in clinical trials.
How does apitegromab work?
Apitegromab is a specific monoclonal antibody that 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 a healthy muscle mass.
In SMA, muscle tissue is weak and atrophied. A plausible approach to increasing muscle mass is, therefore, to inhibit myostatin activity.
When injected into the bloodstream, apitegromab selectively binds to latent myostatin. This binding prevents the conversion of myostatin to its active form in muscle tissues.
Apitegromab 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, apitegromab may have fewer side effects than other myostatin inhibitors.
Animal models lacking myostatin have greater muscle mass and strength. Myostatin inhibition with apitegromab has shown similar results in preclinical studies. A study in mice reported that apitegromab 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 apitegromab effectively increased muscle mass and function in a mouse model of SMA, and also improved the animals’ bone structure.
Apitegromab in clinical trials
A placebo-controlled and double-blind Phase 1 clinical trial tested ascending doses of apitegromab in healthy adult volunteers. Positive final results, announced in June 2019, showed that the participants tolerated apitegromab well across all doses up to 30 mg/kg, with no dose-limiting toxicities.
Ongoing clinical trials
A Phase 2 trial called TOPAZ (NCT03921528) started dosing participants with apitegromab in May 2019 to evaluate the treatment’s safety and efficacy in people with SMA type 2 and type 3. The trial planned to enroll 55 patients, ages 2 to 21, at centers in the U.S., Italy, the Netherlands, and Spain.
Investigators divided patients into three groups, and are treating them all for one year. Those in groups 1 and 2 receive 20 mg/kg of apitegromab by intravenous infusion once every four weeks. Group 1 includes SMA type 3 patients who can walk. Group 2 includes SMA type 2 patients and also type 3 patients who are unable to walk. Those in group 3, all SMA type 2 patients, are randomly receiving apitegromab infusions of 20 mg/kg or 2 mg/kg once every four weeks for one year. All patients can also use an approved SMN upregulation therapy.
The trial’s 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 (HFMSE).
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 received a single dose of apitegromab and were evaluated after four weeks. No safety issues were reported.
Six-month interim data from the TOPAZ trial showed that 67% of patients had at least a one-point increase in their Hammersmith scores and 35% had scores increase by three or more points. The data also showed a dose-related response in group 3 patients receiving the highest dose — a mean average 5.6-point increase compared to an average 2.4-point increase in those given the lowest dose. HFMSE scores also continued to increase as treatment continued, according to the data.
Participants generally tolerated apitegromab treatment well, with researchers recording no severe or life-threatening adverse events. The most common adverse events were headache, upper respiratory infections, fever, common cold, and cough.
The TOPAZ trial is expected to be completed in April 2021 with 12-month topline data expected in June 2021.
The U.S. Food and Drug Administration granted apitegromab an orphan drug designation in March 2018 and a rare pediatric disease designation in August 2020. The European Medicines Agency also designated the treatment an orphan drug in December 2018.
Last updated: Feb. 3, 2021
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