Taldefgrobep alfa aids muscle mass for Caucasian patients in pivotal trial
Taldefgrobep alfa did not significantly improve motor function across the total population of treated spinal muscular atrophy (SMA) patients in a pivotal Phase 3 clinical trial, but significant improvements were seen among Caucasian participants.
That’s according to trial results announced by the therapy’s developer, Biohaven Pharmaceuticals. The company now plans to discuss results with the U.S. Food and Drug Administration (FDA) to help determine next steps for taldefgrobep alfa.
“SMA is a devastating rare disease and although we are disappointed that taldefgrobep alfa did not achieve a statistically significant difference in the broad study population on the [Motor Function Measurement-32 scale], we are encouraged that a majority subgroup did show a treatment benefit compared to the placebo arm,” Cliff Bechtold, taldefgrobep development lead and president of Biohaven Ireland, said in a company press release.
Taldefgrobep alfa designed to prevent muscle atrophy due to SMA
Taldefgrobep alfa is designed to block the activity of myostatin, a protein that normally acts to limit muscle growth, and to inhibit the activity of another protein called activin. The treatment acts by lowering myostatin directly and by blocking its signaling mechanisms. In so doing, the experimental therapy aims to bolster muscle growth and muscle strength, according to Biohaven. The company has been developing taldefgrobep alfa as a potential add-on to disease-modifying therapies that target the underlying cause of SMA.
Biohaven ran a global Phase 3 clinical trial called RESILIENT (NCT05337553) to test taldefgrobep alfa against a placebo in more than 200 people with SMA, ages 4 to 21, who were on disease-modifying treatment. The study’s main goal was to see if taldefgrobep alfa would improve motor function as assessed by scores on the Motor Function Measure (MFM-32) scale after about a year of treatment.
Results did not show a statistically meaningful difference in MFM-32 scores for patients given taldefgrobep or the placebo at the end of the yearlong study. But despite negative findings in the overall population, prespecified analyses showed a statistically significant improvement in MFM-32 scores in the large subgroup of patients who were Caucasian (about 87% of all trial participants).
Genetic variants across racial groups may affect myostatin-blocking therapies
In Caucasian patients with measurable myostatin levels at the study’s start, average MFM-32 scores were 1.4 points better with taldefgrobep alfa than with a placebo after one year.
Among non-Caucasian patients, no difference in MFM-32 scores were evident between those given taldefgrobep or the placebo. According to Biohaven, this may be because certain genetic variants that can reduce the efficacy of myostatin-blocking therapies are more common in non-Caucasian populations. Although further studies will be needed to confirm, this suggests it may be possible to use genetic tests to identify patients most likely to benefit from taldefgrobep alfa, the company said.
Biohaven also noted that pharmacological data from RESILIENT indicated taldefgrobep alfa was binding to and lowering myostatin as designed.
“The observed treatment effect on motor function … along with the strong biomarker evidence of target engagement, suggests that taldefgrobep may play a potentially beneficial role in a majority subgroup population of SMA patients,” Bechtold said.
Across all treated patients, gains seen in body fat, muscle mass, bone density
Another trial goal was to see how taldefgrobep alfa treatment affected patients’ body composition. Results indicated that, in the overall study population, the treatment was associated with reductions in body fat and increases in lean muscle mass and bone density relative to the placebo.
The effects on fat mass were seen across racial groups, which Biohaven suggests could be due to taldefgrobep alfa’s effects on other molecular targets apart from myostatin. Springboarding off these data, the company is looking to explore taldefgrobep alfa as a potential treatment for obesity.
“Taldefgrobep demonstrated an important beneficial effect on body composition which supports our plans to accelerate development in broader populations with obesity,” Bechtold said.
Safety data showed the therapy was well tolerated overall, with no treatment-related serious side effects reported. Almost all patients who completed RESILIENT opted to continue or start with taldefgrobep alfa in an open-label study extension. The extension will remain open pending further analyses and discussions with the FDA, according to Biohaven.
“Biohaven remains committed to fighting rare diseases and will engage SMA experts and regulatory authorities regarding the full dataset from the RESILIENT study,” said Lindsey Lair, MD, vice president of neurology and clinical lead for SMA at Biohaven. “We are extremely grateful to the international SMA community — especially the participants and their families, investigators and their teams, and patient advocacy groups who made the trial possible.”
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