NEJM Publishes HERCULES Results Showing Tolebrutinib Slows Disability In Non-Relapsing MS

The New England Journal of Medicine (NEJM) has published promising results from the HERCULES Phase 3 trial, showing that tolebrutinib was successful in significantly delaying disability progression in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS), a population with no approved treatments. These findings, presented at the 2024 ECTRIMS conference and the 2025 AAN Annual Meeting, further support tolebrutinib’s unique mechanism of action, independent of relapse activity. 

Erik Wallström, MD, PhD, Global Head of Neurology Development, said, “By targeting disability progression mechanisms behind the blood-brain barrier, tolebrutinib can be a practice-changing therapeutic option for people with multiple sclerosis. The data published in NEJM support our larger commitment to the multiple sclerosis patient community, transforming the treatment paradigm to defy disability across the disease spectrum.”

In addition to HERCULES, data from the GEMINI 1 and 2 Phase 3 studies, which evaluated tolebrutinib in relapsing MS (RMS), were also released. Although tolebrutinib did not outperform teriflunomide in reducing annualised relapse rates (the primary endpoint), the secondary analysis suggested a 29% delay in disability worsening for those on tolebrutinib. The relapse rates between the two treatment arms were nearly identical in both GEMINI studies, showing no statistically significant difference and are generally well tolerated.

Robert Fox, MD, a Vice Chair of Research at Cleveland Clinic’s Neurological Institute, Cleveland, Ohio, US, and chair of the HERCULES global steering committee, commented, “Tolebrutinib represents a new class of therapy for the treatment of multiple sclerosis. 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.”

Tolebrutinib was generally well tolerated, though liver enzyme elevations were observed, particularly within the first 90 days of treatment. One serious case required a liver transplant, leading to a fatal post-surgical complication, prompting the implementation of stricter liver monitoring protocols. Safety profiles in the GEMINI trials were largely balanced between tolebrutinib and teriflunomide, with low mortality rates reported in both arms. Regulatory submissions for tolebrutinib are now under priority review by the FDA (target decision date: September 28, 2025) and are also being assessed by EU regulators.