The New England Journal of Medicine (NEJM) published results from the HERCULES phase 3 research, revealing that tolebrutinib reduced disability progression in persons with non-relapsing secondary progressive multiple sclerosis (nrSPMS), for which no treatment choices are currently available. These findings provide additional support for the distinct mechanism of oral, brain-penetrant tolebrutinib, which targets disability progression regardless of relapse activity. These findings were first presented at the ECTRIMS conference in Copenhagen, Denmark, on September 20, 2024, and additional analyses were given today during the Clinical Trials Plenary Session at the American Academy of Neurology’s (AAN) 2025 Annual Meeting in San Diego, California.
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.
Robert Fox
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.
Erik Wallström
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The HERCULES study found that tolebrutinib delayed the 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). Furthermore, the results of the GEMINI 1 and 2 phase 3 studies, which evaluated tolebrutinib in adults with relapsing multiple sclerosis (RMS), were published in NEJM and presented today during the Clinical Trials Plenary Session at the AAN 2025 Annual Meeting.
GEMINI 1 and 2 studies did not reveal superiority over teriflunomide in terms of reducing annualized relapse rate (ARR). During the trial period, the ARR 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 0.11 in both groups in GEMINI 2 (adjusted rate ratio, 1.00; 95% CI 0.75-1.32; p=0.98). A pooled study of a critical secondary objective, not controlled for multiplicity, revealed that tolebrutinib delayed the onset of 6-month verified disability deterioration by 29% compared to teriflunomide (HR 0.71; 95% CI 0.53 to 0.95).
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Tolebrutinib was generally well tolerated by all subjects across all study arms. In HERCULES, 4.0% of patients receiving tolebrutinib had elevated liver enzymes (>3xULN), compared to 1.6% in the placebo group. A modest (0.5%) number of individuals in the tolebrutinib group exhibited peak ALT elevations of more than 20xULN, all within the first 90 days of therapy. Except for one patient, liver enzyme increases cleared without further medical intervention. Prior to the adoption of more frequent liver enzyme testing after treatment beginning, one participant in the tolebrutinib arm underwent a liver transplant and died from post-operative complications. More frequent liver monitoring may help to reduce major liver sequelae. Other deaths in the study were classified as unrelated to therapy by investigators; deaths were evenly distributed between the placebo and tolebrutinib groups at 0.3%.
A review of the GEMINI 1 and 2 pooled safety data revealed that adverse events observed in the tolebrutinib and teriflunomide arms were fairly balanced. Liver enzyme increases (>3xULN) were seen in 5.6% of patients taking tolebrutinib versus 6.3% in the teriflunomide group. A modest (0.5%) number of individuals in the tolebrutinib group exhibited peak ALT elevations of more than 20xULN, all within the first 90 days of therapy. Deaths were evenly distributed throughout the teriflunomide and tolebrutinib arms (0.2% and 0.1%, respectively), and the investigators determined that they were not associated with treatment.
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No regulatory body has determined the safety or efficacy of tolebrutinib.
The US Food and Drug Administration is prioritizing the regulatory filing for tolebrutinib to treat nrSPMS and decrease disability accumulation in adult patients independent of relapse activity, with a target action date of September 28, 2025. A regulatory submission is also being reviewed in the EU.
Tolebrutinib is an experimental, oral, brain-penetrant, and bioactive Bruton’s tyrosine kinase (BTK) inhibitor that targets smoldering neuroinflammation, a significant driver of disability progression in multiple sclerosis. Tolebrutinib, unlike conventional MS medications that focus on peripheral inflammation, passes the blood-brain barrier to obtain therapeutic cerebrospinal fluid concentrations, allowing it to control both B-lymphocytes and disease-associated microglia in the central nervous system. This method is considered to directly treat the underlying pathophysiology of progressive MS by targeting the inflammatory mechanisms that cause neurodegeneration and disability buildup.
Source: Sanofi
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