Safety and efficacy of evobrutinib in relapsing multiple sclerosis: a GRADE-assessed systematic review and meta-analysis

Background Bruton’s tyrosine kinase (BTK) inhibitors are emerging as a potential therapy for multiple sclerosis (MS) by targeting both peripheral and central nervous system–compartmentalized inflammation. Evobrutinib is the first BTK inhibitor evaluated in randomized controlled trials (RCTs) for relapsing multiple sclerosis (RMS). We conducted a systematic review and meta-analysis to assess its safety and efficacy. Methods Following PRISMA 2020 guidelines, we searched PubMed/MEDLINE, Cochrane CENTRAL, ScienceDirect, and ClinicalTrials.gov without language restrictions. Eligible studies were RCTs comparing evobrutinib with placebo or active disease-modifying therapy in RMS. Primary efficacy outcomes included annualized relapse rate (ARR) and confirmed disability progression (CDP). Safety outcomes included serious adverse events (SAEs) and adverse events (AEs) of clinical interest. Data were pooled using a random-effects model, and certainty was assessed using GRADE. Results Three multinational RCTs involving 2,551 participants (1,297 evobrutinib, 1,254 control) were included. Mean age ranged from 36 to 43 years, with 1,715 females and 836 males; most had relapsing–remitting MS (n = 2,429). Evobrutinib showed no significant reduction in ARR (RR: 0.98; 95% CI: 0.80–1.21; p = 0.87), CDP (HR: 0.90, 95% CI: 0.69–1.19, p = 0.47), or MRI lesion counts, except in a sensitivity analysis for gadolinium-enhancing T1 lesions after excluding one trial. Safety analysis revealed a higher risk of SAEs (OR: 1.41; 95% CI: 1.04–1.92; p = 0.03) but fewer discontinuations due to AEs (OR: 0.77; 95% CI: 0.61–0.96; p = 0.02). Elevated liver enzymes occurred more frequently with evobrutinib, while infection rates were similar between groups. Conclusions Across high-quality RCTs, evobrutinib did not improve relapse or disability outcomes compared with placebo or teriflunomide, though MRI benefits were observed in limited settings. Its safety profile was generally acceptable but included higher rates of SAEs and liver enzyme elevations. These findings suggest limited clinical benefits of evobrutinib in RMS, underscoring the need for further investigation into BTK inhibitors with greater CNS penetration or alternative dosing strategies.