Subgroup Analyses of the Phase Three Tolebrutinib in Non-relapsing Secondary Progressive Multiple Sclerosis (nrSPMS) 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, 4Departamento de Neurologia, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain; Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, 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:
Evaluate the effects of tolebrutinib compared to placebo on 6-month confirmed disability progression (CDP).
Background:
Tolebrutinib is an oral, brain-penetrant and bioactive Bruton’s tyrosine kinase inhibitor that modulates persistent immune activation within the central nervous system, including disease-associated microglia and B cells. In the phase 3 HERCULES trial, tolebrutinib 60 mg once daily with food reduced the risk of 6-month CDP by 31% relative to placebo in non-relapsing secondary progressive MS participants. All 6-month CDP events occurred independent of relapse activity.
Design/Methods:
Pre-specified subgroups included baseline age (>40, ≤40), sex (male, female), region (Eastern Europe, Western Europe, North America, rest of world), Expanded Disability Status Scale score (≤4.5, >4.5), duration since first relapsing-remitting multiple sclerosis symptom (≤5 years, >5 to ≤10 years, >10 years), gadolinium-enhancing T1 lesions (absence, presence) and adjudicated relapse during the trial (yes, no). The annualized adjudicated relapse rate, which was a tertiary endpoint, will also be reported.
Results:
All pre-specified subgroups favored tolebrutinib compared to placebo with some differences in effect size across the subgroups. The adjusted annualized adjudicated relapse rate during the trial was low for both tolebrutinib (0.033; 95% CI: 0.024 to 0.045) and placebo (0.032; 95% CI: 0.021 to 0.049), as expected.
Conclusions:
Compared to placebo, tolebrutinib demonstrated an overall consistent effect on disability accumulation across all subgroups.
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