Tolebrutinib Versus Placebo in Non-relapsing Secondary Progressive Multiple Sclerosis: Efficacy and Safety Results from the Phase 3 HERCULES Trial
Robert J. Fox1, Amit Bar-Or2, Anthony Traboulsee3, Celia Oreja-Guevara4, Gavin Giovannoni5, Patrick Vermersch6, Sana Syed7, Ye Li8, Wendy S. Vargas8, Timothy J. Turner7, Erik Wallstroem7, Daniel S. Reich9
1Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, United States, 2Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, University of Pennsylvania, Philadelphia, United States, 3The University of British Columbia, Division of Neurology, Vancouver, Canada, 4Multiple Sclerosis Center, University Hospital San Carlos, Madrid, Spain, 5Queen Mary University London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom, 6University of Lille, Inserm U1172, CHU Lille, FHU Precise, Lille, France, 7Sanofi, Cambridge, United States, 8Sanofi, Bridgewater, United States, 9Translational Neuroradiology Section, National Institutes of Health, Bethesda, United States
Objective:
To report the results of a phase 3 trial evaluating the efficacy and safety of tolebrutinib versus placebo in non‑relapsing secondary progressive multiple sclerosis (nrSPMS).
Background:
Tolebrutinib is a brain-penetrant and bioactive Bruton’s tyrosine kinase inhibitor (BTK) that modulates persistent immune activation within the central nervous system, including disease-associated microglia and B cells, potentially affecting smoldering neuroinflammation thought to be a major driver of disability accumulation.
Design/Methods:
HERCULES (NCT04411641) was a phase 3, double-blind, placebo-controlled, event‑driven trial. Participants were 18-60 years old with secondary progressive multiple sclerosis, Expanded Disability Status Scale (EDSS) score 3.0-6.5, documented evidence of disability progression during the prior 12 months, and no clinical relapses during the 24 months before screening. Participants were randomized 2:1 to receive oral tolebrutinib (60 mg once daily) or matching placebo. The primary endpoint was time to onset of 6-month confirmed disability progression (CDP). Secondary endpoints included additional measures of disability, MRI, and safety.
Results:
A total of 1131 participants were randomized 2:1 to tolebrutinib (N=754) or placebo (N=377). Baseline characteristics were well balanced. Mean age was 48.9 years, EDSS score was 5.5 (median, 6.0), time since relapsing‑remitting multiple sclerosis symptom onset was 17.3 years, and time since most recent relapse was 7.5 years. Tolebrutinib treatment was associated with a 31% risk reduction in 6-month CDP versus placebo (P=0.0026). More participants experienced 6-month confirmed disability improvement with tolebrutinib versus placebo (a secondary endpoint). There was a slight increase in some adverse events with tolebrutinib, including respiratory infections, compared to placebo. Rare events of high liver enzyme increases were observed with tolebrutinib and occurred within 90 days of treatment start. Additional efficacy and safety data will be presented.
Conclusions:
HERCULES is the first trial to demonstrate a slowing of disability accumulation in people with nrSPMS, a population with an urgent need for treatments that delay progression.
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