Design and Baseline Characteristics of Phase 3, Double-Blind, Randomised Trials Evaluating the Efficacy and Safety of Evobrutinib Versus Teriflunomide in Relapsing Multiple Sclerosis (evolutionRMS 1 and 2)

Background/Objective(s): Bruton's tyrosine kinase (BTK) inhibition is a novel mechanism under investigation for multiple sclerosis (MS). Evobrutinib (EVO) is a highly selective, central nervous system (CNS)-penetrant, covalent BTK inhibitor with the potential to target B and myeloid cells in the periphery and CNS, which could have synergistic effects on neuroinflammation, demyelination and disability accumulation. In a Phase 2 relapsing MS (RMS) trial (NCT02975349), the efficacy and safety profile of EVO 75 mg twice daily (BID; fasted) from the double-blind period (DBP) has remained stable >4 years of treatment (DBP + open-label extension). Material(s) and Method(s): EvolutionRMS 1 and 2 (NCT04338022/NCT04338061) are multicentre, randomised, double-blind, double-dummy, active comparator-controlled trials. Eligibility criteria included age 18–55 years, RMS as relapsing–remitting (RR) or secondary progressive (SP) MS with superimposed relapses and Expanded Disability Status Scale (EDSS) score 0–5.5. Patients were randomised 1:1 to EVO (45 mg BID) or TERI (14 mg once daily) with food, up to 156 weeks (W). The primary endpoint, annualised relapse rate, will be assessed over a variable trial duration per patient, up to 156W. Secondary endpoints include disability progression/improvement outcomes; Patient Reported Outcome Measurement Information System (PROMIS) physical function/fatigue scores; magnetic resonance imaging outcomes; serum neurofilament light chain; safety and tolerability. Result(s): The trials enrolled 2285 patients (evolutionRMS 1/2: n=1122/1163) across 52 countries. Baseline mean(±SD)/median age was 37.2(±9.4)/37.2 years and 67.0% were female. Mean(±SD) EDSS was 2.8(±1.3), mean(±SD) time since diagnosis was 4.7(±5.7) years, 96.1/3.9% of patients had RRMS/SPMS, 63.5% were MS treatment-naïve and 98.2% had ≥1 relapse in the year before randomisation. Conclusion(s): On completion, these trials will provide the most comprehensive clinical evidence to date of the efficacy and safety of EVO as an RMS treatment and among the first for a new class of drugs (BTK inhibitors) for MS. Furthermore, these are the first Phase 3 RMS trials that include both fluid biomarkers and MS-specific patient-reported outcome tools among the hierarchical endpoints to provide a detailed assessment of the impact of BTK inhibitors on overall MS disease.