Biohaven’s Taldefgrobep Alfa Fails to Achieve Statistical Significance in Treating Spinal Muscular Atrophy

Image Credit: Adobe Stock Images/sorin

Biohaven announced that taldefgrobep alfa failed achieve statistical significance in treating spinal muscular atrophy (SMA) at week 48 compared to placebo. However, results from the RESILIENT SMA study also found that taldefgrobep demonstrated clinically meaningful motor function improvements on the Motor Function Measurement-32 scale (MFM-32). Moving forward, Biohaven intends to continue analyzing data and engaging with the FDA to determine the next steps for the treatment.¹

"SMA is a devastating rare disease and although we are disappointed that taldefgrobep did not achieve a statistically significant difference in the broad study population on the MFM-32, we are encouraged that a majority subgroup did show a treatment benefit compared to the placebo arm. The observed treatment effect on motor function, which had a similar magnitude on the MFM-32 after 1 year of treatment as approved therapies (i.e., risdiplam), 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. Additionally, taldefgrobep demonstrated an important beneficial effect on body composition which supports our plans to accelerate development in broader populations with obesity,” said Cliff Bechtold, taldefgrobep development lead, president, Biohaven Ireland, in a press release.

RESILIENT SMA is a Phase III randomized, placebo-controlled trial with a 48-week double-blind phase and 48-week open-label extension. Participants included patients between 4 and 21 years of age. All participants received either weekly weight-based subcutaneous injections of taldefgrobep or a matching placebo. Patients previously treated with a myostatin inhibitor were excluded.²

Results found that 35% of patients in the trial had no measurable levels of myostatin at baseline and imbalances in some genetic factors across all treatment arms. Additionally, analyses of prespecified subgroups by race and ethnicity found that Caucasian patients demonstrateda 2.2-point change-from-baseline improvement with taldefgrobep treatment on the MFM-32 at Week 48 compared to a 1.1-point change-from-baseline improvement in the corresponding placebo and standard of care group. Further, improvements in this subgroup were further increased to a 1.4-point placebo adjusted change-from-baseline when analyzed by subjects who had measurable myostatin levels at baseline.

Taldefgrobep also showed significant reductions in body fat mass, increased lean muscle mass, and bone density, suggesting effects beyond myostatin inhibition, potentially mediated by activin A signaling. Biohaven suggests that this could support advancing taldefgrobep for obesity treatment using a self-administered autoinjector.¹

According to Medscape, SMAs are the second most common autosomal-recessive inherited disorders after cystic fibrosis. SMA type I affects approximately 1 per 10,000 live births, while the more chronic forms of type II and type III affect 1 per 24,000 births. SMA types I and III each account for about one fourth of cases, whereas SMA type II is the largest group and accounts for one half of all cases. Globally, the incidence of SMA is about 1 in 10,000 live births with a carrier frequency of approximately 1 in 50 people. For patients with type I, the median survival is seven months, with a mortality rate of 95% by age 18 months. In type II, the age of death varies, but death is most often due to respiratory complications.³

"Biohaven remains committed to fighting rare diseases and will engage SMA experts and regulatory authorities regarding the full dataset from the RESILIENT study. 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,” said Lindsey Lair, MD, MBA, VP, neurology, clinical chair, SMA, Biohaven, in the press release.

References

1. Biohaven Provides Update on Taldefgrobep Alfa Development Program for Spinal Muscular Atrophy and Obesity. Biohaven. November 25, 2024. Accessed November 26, 2024. https://ir.biohaven.com/news-releases/news-release-details/biohaven-provides-update-taldefgrobep-alfa-development-program

2. The Phase 3 RESILIENT Study: Taldefgrobep Alfa in Spinal Muscular Atrophy (P2-11.008). AAN. April 9, 2024. Accessed November 26, 2024. https://www.neurology.org/doi/10.1212/WNL.0000000000205020

3. Spinal Muscular Atrophy. Medscape. Accessed November 26, 2024. https://emedicine.medscape.com/article/1181436-overview#showall