Abstract| Volume 37, 101603, January 2020

Efficacy and Safety of the Bruton's Tyrosine Kinase Inhibitor Evobrutinib in Patients with Relapsing Multiple Sclerosis Over 48 Weeks: A Randomized, Placebo-Controlled, Phase 2 Study

      Evobrutinib (M2951) is a highly selective oral inhibitor of Bruton's tyrosine kinase, a key regulator of B cell and myeloid cell functions implicated in multiple sclerosis (MS). This was a Phase 2 study to compare evobrutinib with placebo in relapsing MS (RMS).
      In this double-blind study (NCT02975349), adults with RMS were randomized to evobrutinib 25 mg once-daily (QD), 75 mg QD, 75 mg twice-daily (BID), open-label dimethyl fumarate (240 mg BID; reference), or placebo for 48 weeks. Placebo-treated patients were switched to evobrutinib 25 mg QD after 24 weeks. Primary endpoint: total number of T1 gadolinium enhancing (T1 Gd+) lesions over Weeks 12–24. Secondary endpoints included annualized relapse rate (ARR), magnetic resonance imaging measures, and safety. The study received full patient and Institutional Review Board approval.
      Of 267 randomized patients, 227 (85.0%) completed 48 weeks. Evobrutinib 75 mg QD and BID significantly reduced the total number of T1 Gd+ lesions over Weeks 12–24 versus placebo (primary endpoint; Table). There was no evidence of change in effect on T1 Gd+ lesions (mean±SD; Wilcoxon signed-rank test) between Weeks 24 and 48 with evobrutinib 75 mg BID (0.24±0.88 to 0.49±1.22; p=0.23) or evobrutinib 75 mg QD (0.28±0.91 to 0.85±2.87; p=0.57). ARR (unadjusted [95% confidence interval]) over 48 weeks was 0.25 (0.12–0.44) for evobrutinib 75 mg QD, 0.11 (0.04–0.25) for 75 mg BID, and 0.37 (0.21–0.59) for placebo (Table). All evobrutinib doses appeared well-tolerated. Transaminase elevations were predominantly mild; some Grade 3–4 events were observed; all had their onset within the first 24 weeks; transaminase elevations were asymptomatic and reversible on evobrutinib withdrawal.
      To our knowledge, evobrutinib is the first BTK inhibitor to demonstrate disease activity reduction in MS. The observed benefit-risk profile of evobrutinib in this Phase 2 study supports further clinical development in RMS.