Biohaven’s Taldefgrobep Shows Benefits In Spinal Muscular Atrophy And Advances Towards Obesity Treatment

Biohaven Ltd., a clinical-stage biopharmaceutical company, has shared updates on its taldefgrobep alfa development programs in spinal muscular atrophy (SMA) and obesity. In the RESILIENT SMA trial, taldefgrobep showed improvements in motor function across all time points on the MFM-32 scale. However, the treatment group did not achieve statistical significance on the primary endpoint at 48 weeks compared to placebo plus standard of care (SOC). Notable efficacy signals were observed in specific subgroups, particularly among patients with measurable baseline myostatin levels. For instance, in the predominantly Caucasian cohort, taldefgrobep demonstrated a significant 1.4-point placebo-adjusted improvement on the MFM-32 scale at Week 48, with half of these patients achieving a clinically meaningful ≥3-point improvement. In contrast, non-Caucasian participants showed higher than expected placebo responses, potentially influenced by genetic polymorphisms that affect myostatin inhibition, which are now under further analysis.

Lindsey Lair, MD, MBA, Vice President of Neurology and Clinical Lead for SMA at Biohaven, added, "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."

The study also revealed significant changes in body composition. Participants receiving taldefgrobep experienced a more substantial reduction in fat mass and increased lean muscle mass and bone density than the placebo group. These effects, measured by DXA, suggest that taldefgrobep acts through mechanisms beyond myostatin inhibition, including pathways involving activin A and other ligands. Remarkably, taldefgrobep is the first myostatin blocker to demonstrate favourable changes in fat mass in SMA patients, underscoring its potential as a treatment for obesity in broader populations. Biohaven plans to accelerate clinical development in obesity, incorporating a self-administered autoinjector to enhance usability.

Cliff Bechtold, Taldefgrobep Development Lead and President of Biohaven Ireland commented, "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. 

He also said. “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." 

Taldefgrobep was well-tolerated in the trial, with no treatment-related serious adverse events reported. Most participants (97%) opted to continue in the open-label extension phase, which remains active pending discussions with the FDA. Biohaven is conducting further biomarker analyses and post-hoc evaluations to understand better the drug’s potential in SMA and other indications. Full results from the trial will be presented at an upcoming scientific meeting, and the company intends to engage with regulatory authorities to define the next steps for development.