Ofatumumab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis: A Nationwide Cohort Study

B-cell-depleting therapy with anti-CD20 monoclonal antibodies is a highly effective and increasingly used treatment strategy for multiple sclerosis (MS); however, comparative effectiveness of anti-CD20 therapies is unclear. In this study, we aimed to evaluate the effectiveness of ofatumumab compared with ocrelizumab in relapsing-remitting MS (RRMS).

This was an observational cohort study based on data extracted from the Danish Multiple Sclerosis Registry. Patients with RRMS initiating ofatumumab or ocrelizumab treatment were included between January 2022 and November 2025. Primary outcomes were annualized relapse rate (ARR) rate ratio between the ofatumumab and ocrelizumab groups and hazard ratio (HR) for time to first relapse. Secondary outcomes were time to first 24-week confirmed disability worsening (CDW), progression independent of relapse activity (PIRA), and brain MRI lesion activity. We used the inverse probability of treatment weighting based on propensity scores to estimate the average treatment effects adjusted for baseline confounders. Main analyses followed an intention-to-treat (ITT) principle, with additional per-protocol (PP) analyses performed.

A total of 1,870 patients were included in the study, of whom 485 started ocrelizumab treatment at baseline (mean age 41.1 years, 65.2% female) and 1,385 started ofatumumab (mean age 41.3 years, 72.0% female). In the ITT analysis, the mean ARR was 0.05 (95% CI 0.04-0.06) for the ofatumumab group and 0.03 (0.02-0.04) for the ocrelizumab group, with a rate ratio of 1.65 (1.09-2.50) (p = 0.018). The median follow-up time was 2.0 (interquartile range 1.3-2.7) years for the ofatumumab group and 2.5 (1.3-3.4) years for the ocrelizumab group. No statistically significant differences were found in the time to first relapse (HR 1.50, 95% CI 0.99-2.29), CDW (HR 0.83, 95% CI 0.58-1.20), PIRA (HR 0.78, 95% CI 0.53-1.15), or brain MRI lesion activity (HR 1.72, 95% CI 0.95-3.13). PP analyses yielded consistent results.

The study indicates that ofatumumab treatment is associated with a marginally increased relapse rate compared with ocrelizumab treatment in patients with RRMS. However, the ARR was very low with both anti-CD20 therapies, and the difference is of limited clinical relevance. Important limitations include the observational design and the risk of residual indication bias.

This study provides Class II evidence that in patients with RRMS, ofatumumab is associated with a marginally increased ARR compared with ocrelizumab, with both drugs having very low ARRs.