Tolebrutinib Delays Disability Progression For Secondary Progressive Multiple Sclerosis
Data from the HERCULES phase 3 trial were presented at the 2025 Annual Meeting for the American Academy of Neurology for non-relapsing secondary progressive multiple sclerosis.
Tolebrutinib delayed disability progression for patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS) in the HERCULES (NCT04411641) phase 3 study. The data were published in The New England Journal of Medicine and presented at the 2025 Annual Meeting for the American Academy of Neurology (AAN) in San Diego, California.1,2
Data from the HERCULES phase 3 trial were presented at the 2025 Annual Meeting for the American Academy of Neurology for non-relapsing secondary progressive multiple sclerosis. | Image Credit: ralwel - stock.adobe.com
“Tolebrutinib represents a new class of therapy for the treatment of multiple sclerosis,” Robert Fox, MD, vice chair of research at the Neurological Institute at the Cleveland Clinic and paid advisor to Sanofi, said in a news release.1 “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.”
Investigators aimed to determine the efficacy of tolebrutinib compared with the placebo in delaying disability progression and evaluate the efficacy of the drug on magnetic resonance imaging lesions, cognitive performance, physical function, and quality of life as clinical end points. Furthermore, the investigators evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics, according to the clinical trial information. Patients who completed treatment had the option to be enrolled in a separate long-term study evaluating safety.3
Patients aged 18 years to 60 years were included, and they had a diagnosis of non-relapsing secondary progressive multiple sclerosis with documented evidence of disability progression within the 12 months prior to screening. The primary end point included 6-month confirmed disability progression, and secondary outcomes included 3-month confirmed disability progression, new and enlarging lesions, time to onset of confirmed disability improvement, brain volume loss, change in cognitive function, safety, tolerability, and change in quality of life.3
Treatment was randomized 2 to 1 for either tolebrutinib or matching placebo. Investigators included 1131 individuals, with 754 and 377 in each group, respectively. Patients had a median follow-up of 133 weeks, according to the study authors. For at least 6 months, 22.6% of the tolebrutinib group had confirmed sustained disability progression compared with 30.7% in the placebo group, equating to a delayed time to onset of 6-month disability progression by 31%.1,2
Further, the serious adverse events occurred in approximately 15% of the tolebrutinib group compared with 10.4% of the placebo group, and 4% and 1.6% had increases in alanine aminotransferase levels more than 3 times the upper limit of the normal range, according to the study authors.2
“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,” Erik Wallström, MD, PhD, global head of neurology development at Sanofi, said in the news release.1
Results from the GEMINI 1 (NCT04410978) and 2 (NCT04410991) studies were also presented at the AAN 2025 Annual Meeting and published in NEJM.1
READ MORE: Neurology Resource Center
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