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Background Tolebrutinib, an oral, brain-penetrant, bioactive Bruton’s tyrosine kinase inhibitor that modulates persistent immune activation within the central nervous system, demonstrated a significant benefit on disability accumulation versus placebo in a non-relapsing secondary progressive MS population. Here, we present baseline characteristics of participants in the PERSEUS phase 3 trial ( NCT04458051), evaluating the efficacy, safety, and tolerability of tolebrutinib in primary progressive MS (PPMS).Methods PERSEUS is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial. Enrollment criteria included age 18–55 years, diagnosis of PPMS according to the 2017 McDonald criteria, Expanded Disability Status Scale (EDSS) score of 2.0–6.5 at screening, positive cerebrospinal fluid findings (oligoclonal bands and/or elevated immunoglobulin G index), and, in some countries early in study enrollment with subsequent global implementation, either no access to ocrelizumab (due to being unavailable nationally or not being reimbursed for the approved indication) or intolerance (due to adverse effects or safety reasons) or treatment failure to ocrelizumab. Participants were randomized 2:1 to receive tolebrutinib 60 mg or placebo, once daily.Results 767 participants with a mean age of 45.3 years (54% male and 83% white) were enrolled. At baseline, mean EDSS was 4.9 (median, 5.0; n=766), mean time since symptom onset was 7.7 years, and mean time since PPMS diagnosis was 4.2 years. 59% participants were treatment naïve. On MRI, 89% of participants had no gadolinium-enhancing lesions, and median T2 lesion volume was 10.8 cm 3.Conclusion This trial (results anticipated in 2025) will comprehensively assess tolebrutinib’s efficacy and safety in the PPMS population.