Rituximab Matches Ocrelizumab in Head-to-Head MS Trial

Rituximab (Rituxan; Genetech and Biogen) was noninferior to ocrelizumab (Ocrevus; Genetech) in preventing new or enlarging brain lesions in patients with newly diagnosed relapsing multiple sclerosis (MS) with recent disease activity, according to the first randomized, double-blind, head-to-head comparison of 2 anti-CD20 monoclonal antibodies in MS. The results were published in New England Journal of Medicine.¹

The OVERLORD-MS trial fills an evidence gap for a drug class that has been an established treatment for relapsing MS but had never been compared in a head-to-head trial. It was investigator-initiated and publicly funded by the Research Council of Norway, the Swedish Research Council, and others, and was conducted across 12 Norwegian and Swedish neurology departments.

Conducting the OVERLORD-MS Trial

The trial screened 219 participants between November 2020 and November 2022. Of those initially screened, 218 were randomized, and 216 received at least one infusion. Treatment-naïve adults aged 18 to 60, with an Expanded Disability Status Scale (EDSS) score of 0 to 4.0 and a diagnosis within the previous 12 months, who had evidence of recent disease activity, were eligible for enrollment at sites with certified EDSS evaluators and MRI capability.

Participants were randomized 3:2 to receive intravenous rituximab (132 patients; 1000 mg at baseline, then 500 mg every 6 months) or intravenous ocrelizumab (84 patients; 600 mg at baseline and every 6 months). Premedication included intravenous methylprednisolone (100 mg), an oral antihistamine, and an antipyretic agent.

Efficacy Comparison: Rituximab Is Noninferior to Ocrelizumab

The trial’s primary end point was freedom from new or enlarging lesions on MRI between months 6 and 24. Results showed 89% of patients on rituximab (117 of 132) met this end point, compared with 93% on ocrelizumab (78 of 84). After adjusting for baseline factors, the model-estimated probabilities were 92.2% and 94.8%, respectively, for a risk difference of –2.6 percentage points (95% CI, –9.4 to 4.3; P = .03), which fell within the prespecified noninferiority margin of –10 points.

Secondary outcomes were broadly comparable between the 2 drugs. The annualized relapse rate was 0.09 with rituximab versus 0.04 with ocrelizumab (a between-group difference of 0.05; 95% CI, –0.02 to 0.12), and 92% of patients on rituximab remained relapse-free at 24 months versus 94% on ocrelizumab. Confirmed disability progression occurred in 3% of the rituximab group versus 7% of the ocrelizumab group, while confirmed disability improvement occurred in 29% versus 24%, a secondary measure that numerically favored rituximab, though the trial wasn't designed to detect a difference on this outcome. No new contrast-enhancing lesions were detected in either group during follow-up.

Adverse Events of Rituximab vs Ocrelizumab

Infections occurred in 82% of patients on rituximab vs 69% of patients on ocrelizumab, most commonly mild cases of COVID-19, nasopharyngitis, and influenza. Serious infections were rare, occurring in 4 patients in each arm. Serious adverse events (AEs) occurred in 8% of the rituximab group and 7% of the ocrelizumab group. There was one melanoma case in the ocrelizumab arm. Additionally, there were no deaths reported in either group.

Treatment discontinuation due to AEs occurred in 2% of the rituximab group with 1 colitis and 1 infusion reaction versus 1% of the ocrelizumab group with 1 infusion reaction. Infusion-related reactions were similar between groups, with 23% on rituximab versus 25% on ocrelizumab, with no anaphylaxis in either group. Hypogammaglobulinemia occurred only in 2% of patients in the ocrelizumab group.

The findings contrast a previous study that found patients taking rituximab had higher rates of all-cause hospitalization than those taking ocrelizumab. The rate of hypogammaglobulinemia was also higher with rituximab in both cohorts, and the risk of common infections was elevated in patients receiving rituximab in some instances.² However, this previous study was a real-world retrospective analysis of 1400 patients across the University of California health system, not a randomized study.

Affordable and Accessible Treatment for MS

The study's authors note that MS treatment costs “have risen substantially,” and that rituximab "is considerably less costly than ocrelizumab and is included on the World Health Organization Model List of Essential Medicines," which "potentially improves access to high-efficacy therapy in resource-limited settings."

The authors also note that earlier observational comparisons between rituximab and ocrelizumab produced mixed results, including one large study that found higher relapse rates with rituximab. That discrepancy is attributed to differences in which patients tended to receive each drug in real-world practice, rather than a true difference in effectiveness.

The trial's sample size was calculated to test noninferiority on its primary MRI end point only, meaning secondary clinical outcomes of relapse and disability measures carried wide confidence intervals and were not adjusted for multiplicity. Various factors limit how broadly the results can be generalized: about half of participants enrolled at a single high-volume center, the population was predominantly of Northern European ancestry drawn from a publicly funded health system, and follow-up was capped at 30 months. The authors were explicit that larger trials are still needed to test for superiority, not just noninferiority.¹

References

1. Torkildsen Ø, Brustad HK, Høgestøl EA, et al. Rituximab versus ocrelizumab in newly diagnosed relapsing multiple sclerosis. N Engl J Med. 2026;395(1):44-53. doi:10.1056/NEJMoa2600993
2. Kaltwasser J. Ocrelizumab leads to lower hospitalization rates vs rituximab in MS. AJMC^®. November 26, 2025. Accessed August 6, 2026. https://www.ajmc.com/view/ocrelizumab-leads-to-lower-hospitalization-rates-vs-rituximab-in-ms