How does apitegromab work?
A specific monoclonal antibody, apitegromab 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, therefore, is to block 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. Such approaches 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 been shown to have greater muscle mass and strength. Blocking myostatin 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.
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 enrolled 58 participants, ages 2 to 21, at centers in the U.S., Italy, the Netherlands, and Spain.
Investigators divided participants into three groups, with those in groups 1 and 2 receiving 20 mg/kg of apitegromab by intravenous (into-the-vein) infusion once every four weeks. Group 1 included people with SMA type 3 who can walk, whereas group 2 included SMA type 2 patients and also type 3 patients who are unable to walk. Those in group 3, all SMA type 2 patients, were randomly selected to receive apitegromab infusions of 20 mg/kg or 2 mg/kg once every four weeks.
The participants were treated for up to one year. Most (83%) received the higher dose of the medication and also were being treated with Spinraza (81%), an approved disease-modifying therapy for SMA.
The trial’s primary goals were 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).
Six-month interim data from the TOPAZ trial showed that 67% of patients had at least a one-point increase in their Hammersmith scores, while 35% had scores increase by three or more points. Of note, increases of at least three points in Hammersmith scores are typically considered clinically meaningful.
The data also showed a dose-related response in group 3 patients receiving the highest dose. Specifically, these participants had a mean average 5.6-point increase compared with 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.
Top-line results from TOPAZ, released in April 2021, confirmed the six-month findings, with most participants showing stable or improved motor function. About a third of participants experienced clinically meaningful motor function improvements, or an increase of at least three points in HFMSE scores. These benefits were both more pronounced and more common among younger children, ages 2-6, with type 2 SMA (59%) as compared with older individuals — those ages 7-21 — with type 2 or 3 (22-31%).
The top-line data also showed a clear dose-response for the younger group, with average improvements of 7.1 points on the HFMSE for the higher dose and 5.3 points for the lower dose. Notably, the increases in HFMSE scores after one year were higher than those seen after six months. This indicates that apitegromab treatment can continually increase motor function over time, and suggests that these young children may experience further improvements.
Participants generally tolerated apitegromab treatment well, with researchers recording no severe or life-threatening adverse events (side effects). The most commonly reported side effects were headache (24%), fever (22%), upper respiratory tract infection (22%), cough (22%), and common cold (21%). Three participants (5%) developed low levels of antibodies against the therapy, but this did not appear to cause clinically meaningful problems or affect the treatment’s efficacy.
The 57 participants who completed the trial have all chosen to enter its extension phase, in which each will receive treatment with apitegromab for up to an additional year.
The U.S. Food and Drug Administration granted apitegromab orphan drug designation in March 2018 and rare pediatric disease status in August 2020. The European Medicines Agency also designated the treatment an orphan drug in December 2018. Such designations provide financial and regulatory incentives to aid a therapy’s approval.
Scholar Rock was awarded a U.S. patent for apitegromab as a treatment for SMA and other muscle conditions in 2021. The company has announced plans to launch, in 2022, a proof-of-concept trial investigating apitegromab for Becker muscular dystrophy, a disorder characterized by progressive muscle weakness and atrophy.
Last updated: April 15, 2021
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 health provider 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.