Comparative Efficacy and Safety of Tolebrutinib Versus Biologic Agents in Relapsing Multiple Sclerosis: A Systematic Review and Network Meta-Analysis

Introduction: Relapsing multiple sclerosis (RMS) is a chronic autoimmune disease with an expanding range of treatment options, including monoclonal antibodies and emerging oral agents such as tolebrutinib. This network meta-analysis aims to compare the efficacy and safety of tolebrutinib with those of established antibody-based therapies for RMS. Methods: A systematic review and network meta-analysis were conducted using a frequentist framework in R. Randomized controlled trials (RCTs) were systematically searched. The primary outcomes were annualized relapse rate (ARR), confirmed disability progression (CDP), and serious adverse events (SAEs). Mean differences (MDs) and odds ratios (ORs) were calculated, along with their corresponding 95% confidence intervals (CIs). Results: Ten RCTs involving 11,365 patients with RMS evaluated tolebrutinib, ocrelizumab, ofatumumab, ublituximab, alemtuzumab, and natalizumab. For ARR compared to placebo, natalizumab showed the highest efficacy (MD: −50%, 95% CI: −64% to −40%), followed by alemtuzumab (MD: −51%, 95% CI: −69% to −33%) and ocrelizumab (MD: −39%, 95% CI: −48% to −29%). Compared to tolebrutinib, all biologics demonstrated greater ARR reduction, with statistically significant differences for alemtuzumab (MD: −31%, 95% CI: −53% to −10%), natalizumab (MD: −32%, 95% CI: −47% to −17%), and ocrelizumab (MD: −21%, 95% CI: −41% to -1%). For CDP, ocrelizumab ranked the highest (OR: 0.16, 95% CI: 0.06 to 0.42), followed by alemtuzumab (OR: 0.30, 95% CI: 0.12 to 0.75) and natalizumab (OR: 0.35, 95% CI: 0.13 to 0.91). Tolebrutinib demonstrated moderate efficacy, with no significant inferiority compared to antibody-based treatments. Regarding SAEs, natalizumab exhibited the most favorable safety profile (OR: 0.22, 95% CI: 0.07 to 0.67), while that of tolebrutinib was comparable to other agents. Conclusion: Monoclonal antibodies such as natalizumab, alemtuzumab, and ocrelizumab remain among the most effective therapies for RMS. Tolebrutinib provides a convenient oral alternative with comparable safety and moderate efficacy in preventing disability progression.