To describe the rationale and design of the first Phase 3 randomized controlled trials (RCTs) (EVOLUTION RMS 1&2) evaluating the Bruton’s tyrosine kinase inhibitor (BTKi) evobrutinib in patients with relapsing multiple sclerosis (MS).

Evobrutinib is a highly-selective, covalent, oral BTKi, with a dual mechanism of action targeting pathogenic adaptive and innate immunity. In a Phase 2 RCT in patients with relapsing MS, evobrutinib significantly reduced the cumulative number of T1 Gd-enhancing lesions compared to placebo during Weeks 12–24 of treatment (primary endpoint) and was generally well tolerated [Montalban et al. NEJM2019;380;2406].

EVOLUTION RMS 1 and 2 are global, double-blind, double-dummy, active-controlled Phase 3 studies comparing the efficacy and safety of oral evobrutinib BID versus oral teriflunomide QD. Adults with relapsing MS (RRMS or SPMS with relapses) will be randomized 1:1 to evobrutinib BID or teriflunomide 14 mg QD for 96 weeks. The primary endpoint is annualized relapse rate (ARR) over 96 weeks, based on qualified relapses. Secondary endpoints include time to first occurrence of 12- and 24-week confirmed disability progression (EDSS), MRI parameters, and safety. Additionally, EVOLUTION RMS 1&2 utilize two novel patient-reported outcomes (PROs) as secondary endpoints: the PROMIS fatigue and physical function measures. These endpoints have been validated and are supported by health authorities for inclusion in MS trials. The planned sample size is 930 patients per study, with randomization stratified by region and baseline EDSS. An interim analysis for sample size re-estimation, based on 12-week confirmed disability progression (CDP) data pooled from both studies, is planned.

The trials will commence enrolment in 2020.

These two Phase 3 RCTs will determine the efficacy and safety of evobrutinib and assess its impact on PROs compared to an established standard of care (teriflunomide) in patients with relapsing forms of RMS.