Biohaven Ltd. has announced that its investigational drug, taldefgrobep alfa, did not meet the primary endpoint in the Phase 3 RESILIENT SMA study for spinal muscular atrophy (SMA). The trial, which assessed the efficacy of taldefgrobep alfa in improving motor function, showed no statistically significant difference compared to placebo at 48 weeks, as measured by the Motor Function Measurement-32 scale (MFM-32). Despite this setback, the company is moving forward with plans to develop taldefgrobep alfa as a treatment for obesity, buoyed by positive effects on body composition observed in the SMA trial.
RESILIENT SMA Trial Results
The RESILIENT SMA study included both ambulatory and non-ambulatory SMA patients aged 4 to 21 years. While the overall study population did not achieve statistical significance on the primary outcome, subgroup analyses revealed encouraging signals. Specifically, Caucasian patients (87% of the study population) treated with taldefgrobep alfa showed a 2.2-point improvement on the MFM-32 at Week 48 compared to a 1.1-point improvement in the placebo group (p < 0.039). This improvement was further increased to a 1.4-point placebo-adjusted change from baseline (p=0.02) in subjects with measurable myostatin levels at baseline.
"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," said Cliff Bechtold, Taldefgrobep Development Lead and President of Biohaven Ireland.
Notably, 35% of subjects had no measurable myostatin levels at baseline, and imbalances in genetic factors (SMN2 copy number, race) were observed across treatment arms. Non-Caucasian subjects (n=26) had a higher than expected placebo response and did not separate from placebo on the MFM-32 at Week 48 (p=0.24).
Body Composition Improvements
Beyond motor function, the RESILIENT SMA study also assessed the impact of taldefgrobep alfa on body composition. Results showed a greater reduction in the percent change in total body fat mass in the taldefgrobep arm compared to the placebo arm (p=0.008), as measured by dual energy x-ray absorptiometry (DXA). The taldefgrobep arm also showed numerically larger increases in lean muscle mass and bone density compared to the placebo arm. These favorable effects on body composition were consistent across different races and baseline myostatin levels.
Advancing Taldefgrobep Alfa for Obesity
Based on these findings, Biohaven intends to accelerate the clinical development of taldefgrobep alfa for obesity. The company plans to initiate a Phase 2 placebo-controlled trial by the end of 2024, using a user-friendly, self-administered autoinjector in adults living with overweight and obesity.
"Taldefgrobep demonstrated an important beneficial effect on body composition which supports our plans to accelerate development in broader populations with obesity," added Bechtold.
Taldefgrobep alfa is a fully human recombinant protein designed to inhibit both myostatin and activin receptor signaling. By blocking the formation of the myostatin-activin receptor complex, taldefgrobep prevents downstream activity that leads to muscle atrophy and accumulation of fat mass. It is the first and only myostatin blocking agent that has shown the ability to favorably change fat mass in people with SMA.
Future Plans
Biohaven remains committed to exploring the potential of taldefgrobep alfa in SMA and will engage with the FDA to discuss a path forward. Full topline data from the RESILIENT SMA study will be presented at an upcoming scientific meeting. The company also has an ongoing open-label extension study for RESILIENT, with 97% of subjects continuing into the extension.
