Biohaven Updates on Taldefgrobep Alfa for SMA and Obesity Development

In the RESILIENT SMA study, taldefgrobep alpha demonstrated significant improvements in motor function across all measured points using the Motor Function Measurement-32 scale (MFM-32). However, at the 48-week mark, the primary outcome did not show statistical separation between the treatment group and the placebo plus standard of care (SOC) group. Efficacy signals were detected among clinically relevant and biomarker-defined subgroups, which included factors such as age, ambulation status, background therapy, and initial myostatin levels.

In analyses focusing on subgroups by race and ethnicity, 87% of the study population identified as Caucasian (n=180). This group exhibited meaningful improvements on the MFM-32 at all timepoints compared to the placebo+SOC group, with a statistical significance noted at p < 0.05. Further analyses of the Caucasian subjects with measurable baseline myostatin (n=123) indicated an enhanced efficacy signal in this myostatin-positive subgroup (p=0.02).

Biohaven plans to discuss potential next steps with the FDA and will present the study's data at an upcoming conference. The long-term extension phase of the trial will continue, awaiting further data analysis and regulatory discussions. Prespecified outcome measures showed that the taldefgrobep arm experienced a more significant reduction in total body fat mass compared to the placebo+SOC arm (p=0.008) at Week 48, as measured by dual energy x-ray absorptiometry (DXA). Additionally, the taldefgrobep group exhibited numerically larger increases in lean muscle mass and bone density.

Given the robust changes in body composition (including reductions in fat mass and increases in lean muscle mass and bone density), Biohaven aims to advance taldefgrobep into a placebo-controlled Phase 2 obesity study in the fourth quarter of 2024, utilizing a user-friendly, self-administered autoinjector. Taldefgrobep demonstrated strong target engagement in the RESILIENT study by reducing myostatin levels below detectable levels in all treated subjects over 48 weeks.

Taldefgrobep was well-tolerated, with 97% of subjects continuing into the optional long-term extension phase. There were no treatment-related serious adverse events (SAEs). The RESILIENT study highlighted the drug's potential benefits on motor function, especially in subgroups with measurable myostatin levels at baseline. Despite not achieving statistical significance in the primary outcome across the broad study population, notable improvements were observed in the majority subgroup.

Statistical analysis revealed a 2.2-point change from baseline improvement on the MFM-32 at Week 48 in the largest study population (87% Caucasian; n=180) treated with taldefgrobep, compared to a 1.1-point change in the placebo+SOC group (p < 0.039). When analyzing subjects with measurable baseline myostatin, the improvement increased to a 1.4-point placebo-adjusted change from baseline (p=0.02). Further benefits were observed in the open-label extension through Extension Week 24. A responder analysis in the myostatin-positive subgroup showed that 50% of taldefgrobep-treated subjects achieved a ≥ 3-point change from baseline on the MFM-32 at Week 48, compared to 30% in the placebo+SOC arm.

In non-Caucasian subjects (n=26), a higher-than-expected placebo response was noted, and no separation from placebo was observed on the MFM-32 at Week 48 (p=0.24). This could be attributed to the significant presence of genetic polymorphisms among non-Caucasian subjects, which might confer myostatin-inhibitory independence.

Overall, changes in body composition, particularly the decrease in fat mass, were consistent across race and baseline myostatin levels, suggesting that taldefgrobep's effects on body fat are mediated through multiple pathways, including activin A. The positive impact on body composition supports the potential use of taldefgrobep in treating obesity across a broad population. Biohaven plans to expedite taldefgrobep's clinical development for obesity, leveraging the observed efficacy and target engagement data from the RESILIENT study. Further evaluations and consultations with the FDA are ongoing, with plans to present full topline data at an upcoming scientific meeting.

Taldefgrobep alfa is designed to inhibit both myostatin and activin receptor signaling. This inhibition prevents muscle atrophy and reduces fat mass accumulation by blocking the myostatin-activin receptor complex formation. SMA is a rare genetic disorder characterized by motor neuron loss, muscle atrophy, and progressive weakness, often diagnosed in young children. Biohaven continues to focus on developing life-changing treatments for various diseases, leveraging their experience and innovative drug development platforms.