The results of a recent study demonstrated that tolebrutinib delayed disability progression in people with nonrelapsing secondary progressive multiple sclerosis, where currently no treatment options are approved. These findings further support the differentiated mechanism of the oral, brain-penetrant tolebrutinib, targeting disability progression independent of relapse activity. 

The HERCULES phase 3 data demonstrated that tolebrutinib delayed the time to onset of six-month confirmed disability progression by 31 percent compared to placebo. GEMINI 1 and 2 results did not show superiority on the primary endpoint of reducing annualized relapse rate over teriflunomide. A pooled analysis for a key secondary endpoint showed that tolebrutinib delayed the time to onset of six-month confirmed disability worsening by 29 percent versus teriflunomide.

Tolebrutinib was generally well-tolerated across all arms of the studies for all participants. In HERCULES, liver enzyme elevations were observed in 4 percent of participants receiving tolebrutinib compared with 1.6 percent in the placebo group. In an analysis of the GEMINI 1 and 2 pooled safety data, adverse events observed between the tolebrutinib and teriflunomide arms were generally balanced. Liver enzyme elevations were observed in 5.6 percent of participants receiving tolebrutinib compared to 6.3 percent in the teriflunomide arms.

The safety and efficacy of tolebrutinib have not yet been determined by any regulatory authority.

Developed by Sanofi, tolebrutinib is an investigational, oral, brain-penetrant and bioactive Bruton's tyrosine kinase inhibitor specifically designed to target smoldering neuroinflammation, a key driver of disability progression in MS. Unlike conventional MS therapies that primarily address peripheral inflammation, tolebrutinib crosses the blood-brain barrier to achieve therapeutic cerebrospinal fluid concentrations, allowing it to modulate both B-lymphocytes and disease-linked microglia within the central nervous system. This mechanism is thought to directly address the underlying pathology of progressive MS by targeting the inflammatory processes that contribute to neurodegeneration and disability accumulation.

Tolebrutinib is being evaluated under priority review by the U.S. Food and Drug Administration with a target action date of Sept. 28. Regulatory submission is under review in the EU with a decision expected in early 2026.

These results were first presented at the 2024 ECTRIMS conference in Copenhagen, Denmark, and further analyses were also presented during the Clinical Trials Plenary Session at the 2025 annual meeting for the American Academy of Neurology in San Diego, Calif.

The study was published in the New England Journal of Medicine.