212 Phase 2, randomized, double-blind, placebo-controlled, dose-finding study, evaluating the Bruton’s tyrosine kinase inhibitor evobrutinib in patients with systemic lupus erythematosus: study design

Background Evobrutinib is a highly specific, oral inhibitor of Bruton9s tyrosine kinase, a key regulator of B cell and macrophage functions implicated in SLE. Evobrutinib was shown to be well tolerated in healthy volunteers in a phase 1b study and subsequently advanced to phase 2. Methods In this double-blind, placebo-controlled, potentially pivotal, 52-week dose-finding study with an optional open-label extension (OLE) and a 4-week safety follow-up period (NCT02975336), patients are randomized 1:1:1:1 to receive low, mid or high dose evobrutinib, or placebo (figure 1). Eligible patients are aged 18–75 years, with an SLE diagnosis (SLICC criteria or ≥4/11 ACR classification criteria) ≥6 months prior to screening, a SLEDAI-2K total score of ≥6 (including SLEDAI-2K clinical score ≥4) at screening, and are positive for anti-ds DNA, anti-Sm, and/or anti-nuclear antibodies. Exclusion criteria include: active, clinically significant, interstitial lung disease/pulmonary arterial hypertension; proteinuria >4 g/day and/or eGFR 30 mg/day prednisone equivalent, injectable corticosteroids, or change in dose of corticosteroids within 2 weeks prior to or during screening. The primary efficacy endpoint family comprises response based on SLE Responder Index (SRI)-4 among all patients and SRI-6 in patients with high disease activity (baseline SLEDAI-2K ≥10) at Week 52. Success on either endpoint will support a conclusion of efficacy. Primary safety endpoints include nature, severity, and incidence of adverse events (AEs) and serious AEs. Secondary endpoints include the time to first severe flare up to Week 52, SRI-4 and SRI-6 response at Week 52 in the serologically active subgroup, and disease activity over time, including attaining low disease activity, and change from baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)-A at each study visit. The primary analysis is planned when all patients have completed the safety follow up for the 52-week blinded portion of the study, entered the OLE, or have discontinued prematurely from the study. Results Recruitment is ongoing. Target enrolment is 432 to 468 participants. The first patient was randomized on 20 January 2017; study completion is expected end of 2019. Conclusions This study will provide clinical proof of concept of the efficacy and safety of evobrutinib in SLE. Funding Source(s): Merck KGaA, Darmstadt, Germany