Tolebrutinib phase 3 data published in NEJM demonstrate benefit on disability progression in multiple sclerosis
- Results from the HERCULES phase 3 study showed delay in disability progression in people living with non-relapsing secondary progressive multiple sclerosis
- Tolebrutinib has the potential to be the first therapy to modulate immunologic drivers of chronic inflammation behind the blood–brain barrier, a key driver of disability accumulation in MS
- Tolebrutinib is being evaluated under priority review in the US with a target action date of 28 September 2025; regulatory submission dossier is under review in the EU with a decision expected in Q1 2026
Paris, April 8, 2025. The New England Journal of Medicine (NEJM) published positive results from the HERCULES phase 3 study demonstrating that tolebrutinib delayed disability progression in people with non-relapsing secondary progressive multiple sclerosis (nrSPMS), where there are currently no treatment options approved. These findings further support the differentiated mechanism of oral, brain-penetrant tolebrutinib, targeting disability progression independent of relapse activity. These results were first presented at the ECTRIMS conference on September 20, 2024 in Copenhagen, Denmark and further analyses were also presented today during the Clinical Trials Plenary Session at the 2025 Annual Meeting for the American Academy of Neurology (AAN) in San Diego, California.
Robert Fox, MD
Vice Chair of Research at Cleveland Clinic’s Neurological Institute, Cleveland, Ohio, US, and chair of the HERCULES global steering committee
“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.”
Dr Fox is a paid advisor to Sanofi for the HERCULES study.
Erik Wallström, MD, PhD
Global Head of Neurology Development
“By targeting disability progression mechanisms behind the blood-brain barrier, tolebrutinib has the potential to be a practice-changing therapeutic option for people living 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.”
The HERCULES data demonstrated that tolebrutinib delayed the time to onset of 6-month confirmed disability progression (CDP) by 31% compared to placebo (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.55-0.88; p=0.003). Additionally, results from the GEMINI 1 and 2 phase 3 studies, evaluating tolebrutinib in people with relapsing multiple sclerosis (RMS) were also published in NEJM and presented today during the Clinical Trials Plenary Session at the AAN 2025 Annual Meeting.
The GEMINI 1 and 2 results did not show superiority on the primary endpoint of reducing annualized relapse rate (ARR) over teriflunomide. The ARR during the study period was 0.13 in the tolebrutinib group and 0.12 in the teriflunomide group in GEMINI 1 (adjusted rate ratio, 1.06; 95% CI 0.81-1.39; p=0.67) and was 0.11 in both groups in GEMINI 2 (adjusted rate ratio, 1.00; 95% CI 0.75-1.32; p=0.98). A pooled analysis for a key secondary endpoint, not controlled for multiplicity, showed that tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29% versus teriflunomide (HR 0.71; 95% CI 0.53 to 0.95).
Tolebrutinib was generally well-tolerated across all arms of the studies for all participants. In HERCULES, liver enzyme elevations (>3xULN) were observed in 4.0% of participants receiving tolebrutinib compared with 1.6% in the placebo group. A small (0.5%) proportion of participants in the tolebrutinib group experienced peak ALT increases of >20xULN, all occurring within the first 90 days of treatment. All but one case of liver enzyme elevations resolved without further medical intervention. Prior to the implementation of more frequent liver enzyme monitoring following treatment initiation, one participant in the tolebrutinib arm received a liver transplant and died due to post-operative complications. The implementation of more frequent liver monitoring may help to mitigate serious liver sequelae. Other deaths in the study were assessed as unrelated to treatment by investigators; deaths were even across the placebo and tolebrutinib arms at 0.3%.
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 (>3xULN) were observed in 5.6% of participants receiving tolebrutinib compared to 6.3% in the teriflunomide arms. A small (0.5%) proportion of participants in the tolebrutinib group experienced peak ALT increases of >20xULN, all occurring within the first 90 days of treatment. Deaths were balanced across the teriflunomide and tolebrutinib arms, at 0.2% and 0.1% respectively, and were assessed as unrelated to treatment by the investigators.
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https://www.sanofi.com/en/media-room/press-releases/2025/2025-04-08-17-11-11-3057931
