Tolebrutinib Not Shown to Reduce Confirmed Disability Progression in Adults with Primary Progressive Multiple Sclerosis

Treatment with the investigational Bruton tyrosine kinase (BTK) inhibitor tolebrutinib (Sanofi, Bridgewater, NJ) did not significantly delay disability progression in people with primary progressive multiple sclerosis (PPMS) according to results from the phase 3 PERSEUS trial (NCT04458051) presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026.

PERSEUS was a global, randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of oral tolebrutinib in adults with PPMS. Participants were randomized 2:1 to receive oral tolebrutinib (n=515) or placebo (n=252) once daily for up to 60 months. Eligible participants were aged 18 to 55 years, met the 2017 revised McDonald criteria for PPMS, had an Expanded Disability Status Scale (EDSS) score between 2.0 and 6.5 at screening, and had positive cerebrospinal fluid findings. Participants also had no access to, intolerance of, or inadequate response to Ocrevus (ocrelizumab; Genentech, South San Francisco, CA). The primary end point was time to 6-month confirmed composite disability progression (cCDP), defined by sustained worsening on EDSS, the Timed 25-Foot Walk, or the 9-Hole Peg Test. Secondary end points included time to onset of 6-month CDP (EDSS only), time to onset of 3-month cCDP, total number of new or enlarging T2 lesions, time to onset of 6-month confirmed disability improvement (CDI), and percent change in brain volume, and safety outcomes.

Key results from the study include the following:

• Tolebrutinib treatment did not reduce the risk of 6-month cCDP versus placebo (hazard ratio [HR], 1.01; 95% CI, 0.81 to 1.26; P=.94).
• Tolebrutinib treatment a numerical reduction in risk of 6-month CDP versus placebo, but the difference was not statistically significant (HR, 0.86; 95% CI, 0.64 to 1.15; P=.32).
• There was no between-group difference in the risk of 3-month cCDP (HR, 1.03; 95% CI, 0.84 to 1.26; P=.78).
• Tolebrutinib treatment was associated with fewer new/enlarging T2 lesions versus placebo (adjusted rate ratio, 0.54; 95% CI, 0.35 to 0.83; nominal P=.005).
• There was no significant between-group difference in the rate of 6-month CDI (HR, 0.91; 95% CI, 0.52 to 1.60; P=.75).
• Tolebrutinib treatment was associated with less brain volume loss at end of study versus placebo (least squares mean difference, 0.17; 95% CI, 0.04 to 0.30; P=.01).
• Safety findings, including the risk of drug-induced liver injury, were consistent with those observed in previous phase 3 tolebrutinib trials in individuals with non-relapsing secondary progressive MS and relapsing MS.

Source: Reich DS, Bar-OR A, Vermersch P, et al. Efficacy and safety of tolebrutinib versus placebo in primary progressive multiple sclerosis: results from the phase 3 PERSEUS trial. Presented at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026, Presentation #777.