Data Regarding Tolebrutinib Treatment for Nonrelapsing Secondary Progressive MS Presented and Published

Treatment with tolebrutinib (Sanofi, Bridgewater NJ), a Bruton’s tyrosine kinase (BTK) inhibitor, significantly delayed disability progression in people with non-relapsing secondary progressive multiple sclerosis (nrSPMS). The full set of results from the phase 3 HERCULES clinical trial (NCT04411641) was presented at the American Academy of Neurology (AAN) 2025 Annual Meeting and published in The New England Journal of Medicine, positioning tolebrutinib as a potential therapeutic option for a patient population with limited treatment choices.

HERCULES was a double-blind, randomized phase 3 clinical trial evaluating the safety and efficacy of tolebrutinib treatment in people aged 18 to 60 years with nrSPMS and expanded disability status scale (EDSS) scores between 3.0 and 6.5. Participants were randomly assigned 2:1 to receive either tolebrutinib (n=752) or matched placebo (n=375) by oral daily dosing for 48 months. The primary end point was 6-month confirmed disability progression (CDP), which was defined as a ≥1.0-point increase in EDSS for participants with a baseline EDSS score of ≤5.0, and a ≥5.0-point increase for participants with a baseline EDSS of >5.0. Secondary end points included change in 9-hole peg test and timed 25-foot walk (T25-FW) test at 3 months, as well as 3-month CDP assessed by EDSS score, the presence of MRI lesions, and change in cognitive function.

As previously reported from the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS):

• Tolebrutinib was associated with a 31% reduction in risk of 6-month CDP compared with placebo (P=.0026).
• A higher proportion of participants in the tolebrutinib group experienced 6-month confirmed disability improvement compared with placebo.
• There were serious adverse events reported in 15% of participants taking tolebrutinib compared with 10.4% of those in the placebo group.
• 4% of those taking tolebrutinib experienced significant increases in alanine aminotransferase levels compared with <2% in the placebo group.

“Tolebrutinib represents a new class of therapy for the treatment of multiple sclerosis,” said Robert Fox, MD, Vice Chair of Research at Cleveland Clinic’s Neurological Institute, Chair of the HERCULES global steering committee, and advisor to Sanofi for the HERCULES study. “In this large phase 3 study, tolebrutinib was found to slow the progression of disability in a subset of multiple sclerosis for which we have no approved therapies – non-relapsing secondary progressive disease. The results of this study signal a new chapter in multiple sclerosis because we finally found a potential way to treat non-relapsing secondary progressive forms.”

Source: Fox RJ, Bar-Or A, Traboulsee A. Tolebrutinib versus placebo in non-relapsing secondary progressive multiple sclerosis: efficacy and safety results from the phase 3 HERCULES trial. Presented at: American Academy of Neurology Annual Meeting; April 5–9, 2025; San Diego, CA.

Fox RJ, Bar-Or A, Traboulsee A, et al. Tolebrutinib versus Placebo in Nonrelapsing Secondary Progressive Multiple Sclerosis. N Engl J Med. 2025;390(15):1413-1424.