Phase 3 Studies Find Mixed Results for Investigational MS Drug

An investigational drug for patients with multiple sclerosis (MS) yielded mixed results in a trio of phase 3 trials.

Tolebrutinib, an oral brain-penetrant bioactive Bruton’s tyrosine kinase inhibitor, met its primary endpoint of improvement over placebo in delaying time to onset of confirmed disability progression in patients with nonrelapsing secondary progressive MS in the HERCULES study, maker Sanofi reported. However, in the GEMINI 1 and GEMINI 2 studies, tolebrutinib failed to meet its primary endpoint of reducing annualized relapse rates compared with teriflunomide in patients with relapsing MS.

Results from the studies will be presented at the European Committee for Treatment and Research in Multiple Sclerosis medical meeting in Copenhagen, Denmark, on September 20, 2024.

The drug’s mechanism of action modulates B lymphocytes and activated microglia in the central nervous system, with an aim to address underlying mechanisms of disability accumulation in MS.

“Addressing disability accumulation, thought to be driven by smoldering neuroinflammation, remains the greatest unmet medical need in people with nonrelapsing secondary progressive MS today,” said Houman Ashrafian, MD, PhD, head of research and development at Sanofi.

HERCULES was a randomized, double-blind phase 3 clinical trial evaluating the efficacy and safety of tolebrutinib compared with placebo in participants with nonrelapsing secondary progressive MS. In addition to demonstrating tolebrutinib delayed time to onset of confirmed disability progression at 6 months, preliminary analysis found liver safety was consistent with previous studies of tolebrutinib, Sanofi reported.

GEMINI 1 and GEMINI 2 were randomized, double-blind phase 3 clinical trials evaluating the efficacy and safety of tolebrutinib compared with teriflunomide in patients with relapsing MS. Tolebrutinib did not meet its primary endpoint of reducing the annualized relapse rate for up to 36 months compared with teriflunomide, but 6-month pooled data did show a delay to onset of confirmed disability worsening, which was a secondary endpoint of the study.

Another phase 3 trial called PERSEUS is evaluating time to onset of confirmed disability progression with tolebrutinib in patients with primary progressive MS. Results from the study are expected in 2025.

Reference

Tolebrutinib meets primary endpoint in HERCULES phase 3 study, the first and only to show reduction in disability accumulation in non-relapsing secondary progressive multiple sclerosis. News release. Sanofi; September 2, 2024. Accessed September 12, 2024.