Rituximab Noninferior to Ocrelizumab in Newly Diagnosed Relapsing MS, Head-to-Head Trial Finds

In the first randomized, double-blind, head-to-head trial comparing rituximab and ocrelizumab in newly diagnosed relapsing multiple sclerosis (MS), rituximab was noninferior to ocrelizumab in suppressing new MRI lesion activity over 24 months, with broadly comparable clinical and safety outcomes. The findings, published July 2, 2026 in the New England Journal of Medicine, fill a long-standing evidence gap for neurologists weighing two agents that are widely used but had never been compared in a controlled trial.¹

Led by Øivind Torkildsen, MD, PhD, Professor of Neurology and Head of Section for Neurology at the University of Bergen and a consultant neurologist at Haukeland University Hospital in Bergen, Norway, the OVERLORD-MS trial was conducted at 12 neurology departments in Norway and Sweden without commercial involvement in the design or analysis.

Both agents are anti-CD20 monoclonal antibodies that deplete B cells and are among the most effective therapies available for relapsing MS. Ocrelizumab (Ocrevus; Roche) received FDA approval in 2017 based on phase 3 data showing superiority over interferon beta-1a.² Rituximab has been used off-label for MS since the mid-2000s, and the availability of biosimilar versions at considerably lower cost has driven widespread use, particularly in Scandinavian countries and resource-limited settings. Comparative evidence had been limited to observational studies subject to residual confounding and dosing heterogeneity.

The trial enrolled 218 participants aged 18 to 60 with a recent MS diagnosis, evidence of inflammatory activity in the prior 12 months, an EDSS score of 0 to 4.0, and no prior exposure to disease-modifying therapy. Participants were randomized 3:2 to intravenous rituximab (1000 mg at baseline, then 500 mg every 6 months) or ocrelizumab (600 mg at baseline and every 6 months) for 24 months. A prespecified blinded follow-up visit at month 30 assessed confirmed disability outcomes. Trial medications were provided as part of routine hospital procurement rather than through industry supply.

The primary endpoint was the absence of new or enlarging lesions on T2-weighted MRI from month 6 to month 24, with month 6 used as the reference to allow for full B-cell depletion and minimize confounding from preexisting inflammatory activity. Noninferiority required the lower bound of the 95% CI for the risk difference to be no less than negative 10 percentage points.

Of 216 participants who received at least one infusion, 117 of 132 in the rituximab group (89%) and 78 of 84 in the ocrelizumab group (93%) had no new or enlarging T2 lesions during the primary window, corresponding to model-estimated probabilities of 92.2% and 94.8%. The risk difference was negative 2.6 percentage points (95% CI, negative 9.4 to 4.3; P = .03), meeting the noninferiority criterion.¹ Results were consistent across sensitivity analyses.

READ MORE: Ublituximab Meets Primary End Point in Phase 3 ENHANCE Trial for Relapsing Multiple Sclerosis

Secondary outcomes were broadly similar. Annualized relapse rates were low in both groups: 0.09 with rituximab and 0.04 with ocrelizumab (between-group difference, 0.05; 95% CI, negative 0.02 to 0.12). Freedom from relapse at 24 months was 92% and 94%, respectively. Confirmed disability progression sustained for at least 6 months occurred in 3% versus 7%. No contrast-enhancing lesions were detected at any follow-up scan. Cognitive outcomes showed no apparent between-group differences. The trial was not powered for these secondary comparisons, and confidence intervals were wide throughout.

The one meaningful safety difference was infection rate: 82% of rituximab-treated participants experienced at least one infection versus 69% of those receiving ocrelizumab, driven mostly by upper respiratory tract infections and COVID-19. Serious infections were rare and evenly distributed (four participants per group). Serious adverse events occurred in 8% and 7% of the respective groups, with no deaths. One malignant melanoma occurred in the ocrelizumab group. Hypogammaglobulinemia was not observed in the rituximab group and occurred in 2% of the ocrelizumab group.

The investigators flagged the cost dimension as clinically and policy-relevant. Rituximab is considerably less costly than ocrelizumab and is included on the WHO Model List of Essential Medicines, which may expand access to high-efficacy B-cell-depleting therapy in resource-limited settings globally.¹

Key limitations include that the trial was powered only for noninferiority on the primary MRI endpoint, limiting precision for secondary analyses and precluding subgroup comparisons. Follow-up of 30 months cannot rule out longer-term efficacy or safety differences. Approximately half the participants were enrolled at a single high-volume center, and the population was predominantly of Northern European ancestry, limiting generalizability to more diverse populations. Larger studies will be needed to assess superiority.

REFERENCES
1. Torkildsen O, Brustad HK, Høgestøl EA, et al.; for the OVERLORD-MS Investigators. Rituximab versus ocrelizumab in newly diagnosed relapsing multiple sclerosis. N Engl J Med. 2026;395:44-53. doi:10.1056/NEJMoa2600993. https://doi.org/10.1056/NEJMoa2600993
2. Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376:221-234. doi:10.1056/NEJMoa1601277. https://doi.org/10.1056/NEJMoa1601277
3. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358:676-688. doi:10.1056/NEJMoa0706383. https://doi.org/10.1056/NEJMoa0706383