Apitegromab, Scholar Rock’s muscle-directed therapy for spinal muscular atrophy (SMA), safely and effectively improved or stabilized motor function in children and young adults with types 2 and 3 disease over one year, top-line data from the Phase 2 TOPAZ trial show.
Notably, patients’ motor gains were either maintained or increased at one year relative to what was observed at six months, highlighting the durability and continuous therapeutic potential of apitegromab.
“These top-line 12-month data provide further support towards establishing apitegromab as a potential first muscle-directed therapy for patients with SMA,” Yung Chyung, MD, Scholar Rock’s chief medical officer, said in a press release.
“There looks to be promising potential for a muscle-directed therapy that will complement the unmet need still evident, and likely emerging, in many individuals with SMA who receive SMN-enhancing therapies,” said Thomas Crawford, MD, TOPAZ’s principal investigator.
Based on these findings and pending discussions with regulatory authorities, Scholar Rock plans to initiate a pivotal Phase 3 trial by year’s end to confirm apitegromab’s safety and effectiveness in a larger patient population.
“While there have been important advancements in recent years, individuals with Types 2 and 3 SMA continue to experience significant functional impairments, even after treatment with SMN [boosting] therapies,” Scholar Rock wrote in an accompanying statement for CureSMA.
Distinct from currently approved SMA disease-modifying therapies — which work to increase the levels of SMN, the missing protein in SMA — apitegromab targets muscle growth and strength.
The investigational muscle-directed therapy works by preventing the conversion of a latent form of myostatin, a protein mainly produced by skeletal muscle and that suppresses muscle growth, into its active form.
Due to its mechanism of action, apitegromab is expected to cause fewer side effects than conventional suppressors of myostatin’s active form, while still improving patients’ muscle mass and strength, and thereby their motor function.
As such, apitegromab is thought to have the potential to increase the benefits to patients of SMN-boosting therapies.
The international, proof-of-concept Phase 2 TOPAZ trial (NCT03921528) evaluated apitegromab’s safety and effectiveness in 58 patients, ages 2 to 21, with SMA types 2 and 3 (later-onset disease).
Participants were divided into three groups, in which all were given intravenous (into-the-vein) infusions of apitegromab (either a low, 2 mg/kg, or a high, 20 mg/kg, dose) once every four weeks for up to one year. Most received the therapy’s high dose (83%) and were also being treated with Spinraza (81%)— the first approved SMA disease-modifying therapy.
Changes in motor function with treatment were assessed using the Revised Hammersmith Scale in ambulatory patients (those able to walk independently), and with the Hammersmith Functional Motor Scale Expanded (HFMSE) in non-ambulatory patients.
Higher scores in both scales indicate greater motor function, and increases of at least three points in Hammersmith scores are typically considered clinically meaningful.
Previously announced six-month data showed that the therapy was safe and improved or stabilized patients’ motor abilities, with greater benefits seen with the higher dose and in the younger patients.
Top-line, one-year analysis — excluding data from four patients who missed three doses each due to COVID-19-related restrictions to site access — confirmed six-month findings, with most patients showing stable or improved motor function.
About 35% of participants achieved clinically meaningful motor function improvements, or an increase of at least three points in Hammersmith scores.
Notably, these benefits were both more pronounced and more common among younger type 2 children (59%; ages 2–6) than in older type 2 and 3 patients (22–31%; ages 7–21).
A clear apitegromab dose response was also observed in this younger group (the only that included patients on each of the two doses), with children given the high dose attaining a 7.1-point mean increase in the HFMSE score, compared with a 5.3-point mean improvement in the low-dose group.
Notably, these one-year HFMSE score raises were greater than those observed at the six-month analysis, highlighting the therapy’s ability to further improve motor skills over time, and suggesting that a motor function plateau had not yet been reached in these young children.
Apitegromab was generally well-tolerated, with no safety concerns identified. The most frequently reported adverse events were headache (24%), fever (22%), upper respiratory tract infection (22%), cough (22%), and common cold (21%).
One ambulatory type 3 patient left the trial due to moderate muscle fatigue that started prior to apitegromab’s use and that was deemed unrelated to the therapy.
Three (5%) patients developed low levels of antibodies against the therapy, which did not appear to affect treatment exposure and were not associated with an exaggerated immune reaction to treatment.
All 57 participants who completed the one-year treatment chose to enter the trial’s extension phase, and be given apitegromab for up to an additional year.
“Though much work remains to be done, I believe the results are wonderful news for the SMA community, and I am enthusiastic about the potential that apitegromab may offer for further meaningful functional improvements,” added Crawford, who is a professor of neurology at the Johns Hopkins School of Medicine.
“The findings also offer important insights into myostatin biology and our scientific approach of targeting the latent forms of growth factors,” Chyung added.
Apitegromab received orphan drug designation in both the U.S. and Europe, as well as rare pediatric disease status in the U.S. and priority medicines designation in Europe as a potential SMA treatment; all are meant to support and advance its development and review.
Scholar Rock plans to launch a proof-of-concept trial of apitegromab in Becker muscular dystrophy, a disorder characterized by progressive muscle weakness and atrophy, in 2022.
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