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Background Tolebrutinib, a brain-penetrant, bioactive, Bruton’s tyrosine kinase inhibitor modulates persistent immune activation, including disease-associated microglia and B-cells, potentially affecting smoldering neuroinflammation, a major driver of disability accumulation. We report results of a phase-3 trial evaluating efficacy and safety of tolebrutinib versus placebo in non-relapsing secondary progressive MS (nrSPMS).Methods HERCULES ( NCT04411641) was a phase-3, double-blind, placebo-controlled, event-driven trial. Participants were 18–60 years old with secondary progressive MS, Expanded Disability Status Scale (EDSS) score 3.0–6.5, documented evidence of disability progression during prior 12-months, no clinical relapses during 24-months before screening. Participants were randomized 2:1 to receive oral tolebrutinib (60mg once daily) or matching placebo. Primary endpoint was time to onset of 6-month confirmed disability progression (CDP). Secondary endpoints included additional measures of disability, MRI, and safety.Results 1131 participants were randomized 2:1 to tolebrutinib (N=754) or placebo (N=377) with well-balanced baseline characteristics (mean age:48.9 years, EDSS score:5.5 [median, 6.0], time since relapsing remitting MS symptom onset:17.3 years, and time since most recent relapse:7.5 years). Tolebrutinib treatment was associated with 31% risk reduction in 6-month CDP versus placebo ( P=0.0026). More participants experienced 6-month confirmed disability improvement with tolebrutinib versus placebo (secondary endpoint). There was a slight increase in 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.Conclusion HERCULES is the first trial to demonstrate a slowing of disability accumulation in people with nrSPMS.