How does apitegromab work?
Apitegromab 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, apitegromab selectively binds to latent or inactive 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.
Animals in models lacking in 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 volunteers. Positive final results, announced in June 2019, showed that participants tolerated apitegromab 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 apitegromab 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 apitegromab 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 apitegromab 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 (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 been given a single dose of apitegromab and researchers evaluated them after four weeks. They reported no safety issues.
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 3 or more points. The data also showed a dose-related response in group 3 patients receiving the highest dose having an average 5.6 point increase compared to an average 2.4 point increase in the lowest dose. HFMSE scores also continued to increase as treatment continued, according to the data.
Treatment with apitegromab was generally well-tolerated with no severe or life-threatening adverse events. The most commonly reported 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 the second quarter of 2021.
The therapy received a rare pediatric disease designation from the FDA in August 2020.
Last updated: Jan. 3, 2021
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