Rituximab versus Ocrelizumab in Newly Diagnosed Relapsing Multiple Sclerosis

Rituximab versus Ocrelizumab in Newly Diagnosed Relapsing Multiple Sclerosis Published July 1, 2026 N Engl J Med 2026;395:44-53 DOI: 10.1056/NEJMoa2600993 Abstract Background Anti-CD20 monoclonal antibodies are effective for relapsing multiple sclerosis. However, data from head-to-head trials are lacking. Methods In this phase 3, multicenter, double-blind, noninferiority trial, we randomly assigned adults with newly diagnosed relapsing multiple sclerosis and recent disease activity in a 3:2 ratio to receive rituximab or ocrelizumab every 6 months for 24 months. The primary end point was the absence of new or enlarging lesions on T2-weighted magnetic resonance imaging (MRI) from month 6 to month 24. Noninferiority was defined as a lower limit of the 95% confidence interval for the risk difference (rituximab minus ocrelizumab) of greater than or equal to −10 percentage points. Secondary end points included efficacy and safety. Results A total of 218 participants underwent randomization; 216 received treatment (132 assigned to the rituximab group and 84 assigned to the ocrelizumab group). Between months 6 and 24, the estimated probability of having no new or enlarging lesions detected on T2-weighted MRI was 92.2% with rituximab and 94.8% with ocrelizumab, corresponding to a risk difference of –2.6 percentage points (95% confidence interval, –9.4 to 4.3), which met the prespecified noninferiority criterion. Relapse rates, disability outcomes, and cognitive-performance profiles appeared to be similar in the two groups. Infections were more common in the rituximab group than in the ocrelizumab group (in 82% vs. 69% of participants), although the percentage of participants with serious adverse events was similar in the two groups (8% and 7%, respectively). Conclusions In participants with newly diagnosed relapsing multiple sclerosis and recent disease activity, rituximab was noninferior to ocrelizumab in suppressing disease activity as detected by MRI from 6 to 24 months, with a similar incidence of serious adverse events. (Funded by the Research Council of Norway and others; OVERLORD-MS ClinicalTrials.gov number, NCT04578639; EudraCT number, 2020-001205-23; EU Clinical Trials Register number, 2024-510716-71-00.) Are you a member of an institution such as a university or hospital?Learn more about Institutional Access Notes A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. Supported by a grant (288164) from the Research Council of Norway and a grant (201902) from KLINBEFORSK. Additional funding was provided by a grant (2023-02639) from the Swedish Research Council, a grant (FoUI-987565) from Region Stockholm, a grant (FO2023-0336) from the Swedish Brain Fund, the Erling Perssons Foundation, and the Horizon Europe Framework Program (project number 101136991). Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank the trial nurses, the members of the data and safety monitoring board, and all the patients who provided informed consent and participated in the trial. Supplementary Material Information & Authors Information Published In Copyright Copyright © 2026 Massachusetts Medical Society. All rights reserved. For personal use only. Any commercial reuse of NEJM Group content requires permission. History Published online: July 1, 2026 Published in issue: July 2, 2026 Topics Authors Metrics & Citations Metrics Altmetrics Citations Export citation Select the format you want to export the citation of this publication. Cited by - Advances in Multiple Sclerosis, New England Journal of Medicine, 395, 1, (54-68), (2026)./doi/full/10.1056/NEJMra2501195 Loading...