Subgroup Analysis of the Phase Three Tolebrutinib HERCULES Trial: Disability Accumulation Outcomes in North American Participants
Patricia Coyle1, Amit Bar-Or2, Daniel Reich3, Anthony Traboulsee4, Sana Syed5, Ye Li5, Wendy Vargas5, Robert Fox6
1Stony Brook University Renaissance School of Medicine, 2University of Pennsylvania, 3Translational Neuroradiology Section, National Institutes of Health, 4University of British Columbia, 5Sanofi, 6Cleveland Clinic
Objective:
To evaluate the baseline characteristics and effects of tolebrutinib on disability accumulation in North American participants in HERCULES.
Background:
Tolebrutinib is an oral, brain-penetrant and bioactive Bruton’s tyrosine kinase inhibitor that modulates persistent immune activation within the CNS, including disease-associated microglia and B cells. In the phase 3 HERCULES trial, tolebrutinib reduced the risk of 6-month confirmed disability progression (CDP) by 31% versus placebo in non-relapsing secondary progressive multiple sclerosis (nrSPMS).
Design/Methods:
HERCULES (NCT04411641) was a 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 with food) or matching placebo. Cox regression was used to estimate hazard ratios.
Results:
Of the 1131 randomized participants, 14.3% resided in North America (9.8% within the US and 4.5% in Canada). Mean age was 51.8 years for North American participants and 48.9 years for the overall population. Females comprised 73.5% of the North American subgroup and 61.5% of the overall population. At baseline, mean (median) EDSS was 5.2 (6.0) in North American participants and 5.5 (6.0) in the overall population. Gadolinium-enhancing T1 lesions were present at baseline in 4.4% of North American participants and 12.7% of the overall population. Time-to-onset of 6-month CDP favored tolebrutinib versus placebo across all regions; the hazard ratio (95% CI) was 0.46 (0.24-0.89) for the North American subgroup and 0.38 (0.16-0.90) for the US subgroup compared to 0.69 (0.55-0.88) overall. A limitation of this analysis is the small sample size of the subgroups.
Conclusions:
Tolebrutinib demonstrated a significant effect on disability accumulation versus placebo in nrSPMS, with consistent benefit observed for participants residing in North America, including the US.
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