PDF: OVERLORD-MS
(2026)Objective
To determine whether rituximab is noninferior to ocrelizumab for suppressing disease activity in adults with newly diagnosed relapsing multiple sclerosis.
Study Summary
• Relapse rates, disability outcomes, and cognitive-performance profiles were similar between groups (annualized relapse rate 0.09 vs 0.04; freedom from relapse 92% vs 95%)
• Infections were more common with rituximab (82% vs 69%), but serious adverse events were similar (8% vs 7%)
Intervention
Intravenous rituximab (1000 mg baseline, then 500 mg every 6 months) versus intravenous ocrelizumab (600 mg baseline and every 6 months) for 24 months.
Inclusion Criteria
Adults 18-60 years with newly diagnosed relapsing multiple sclerosis (diagnosis within previous 12 months), recent inflammatory disease activity (≥1 clinical relapse or ≥1 new/enlarging MRI lesion within previous 12 months), and EDSS score 0-4.0.
Study Design
Arms: Rituximab 1000 mg then 500 mg q6mo (n=132) vs Ocrelizumab 600 mg q6mo (n=84)
Patients per Arm: Rituximab n=132; Ocrelizumab n=84
Outcome
• Confirmed disability progression: 3% (rituximab) vs 7% (ocrelizumab); disability improvement 29% vs 24%
• Infections higher with rituximab (82% vs 69%); serious adverse events similar (8% vs 7%)
Bottom Line
In newly diagnosed relapsing MS, rituximab was noninferior to ocrelizumab in suppressing MRI disease activity from month 6 to 24, with similar serious adverse events, supporting biosimilar rituximab as a cost-effective alternative to ocrelizumab.
Major Points
- First phase 3 randomized head-to-head trial of rituximab vs ocrelizumab in newly diagnosed relapsing MS
- Rituximab met prespecified noninferiority for MRI activity suppression (risk difference -2.6 pp, 95% CI -9.4 to 4.3; noninferiority margin -10 pp)
- Between months 6 and 24, 92.2% (rituximab) vs 94.8% (ocrelizumab) had no new/enlarging T2 lesions
- Clinical outcomes (relapse rates, disability, cognition) were similar between groups
- Infections more common with rituximab (82% vs 69%), but serious adverse events similar (8% vs 7%)
- Findings support use of biosimilar rituximab as a lower-cost alternative to ocrelizumab
Study Design
- Study Type
- Phase 3, multicenter, double-blind, noninferiority randomized controlled trial
- Randomization
- Yes
- Blinding
- Double-blind (participants and trial personnel unaware of assignments; trial medications prepared by unblinded pharmacy personnel with identical infusion setup)
- Sample Size
- 218
- Follow-up
- 24 months, with prespecified blinded follow-up at month 30
- Centers
- 12
- Countries
- Norway, Sweden
Primary Outcome
Definition: Absence of new or enlarging lesions on T2-weighted MRI from month 6 to month 24
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 94.8% (78/84 observed; 93%) | 92.2% (117/132 observed; 89%) | - (-9.4 to 4.3 percentage points) | 0.03 (two-sided, for noninferiority) |
Limitations & Criticisms
- Population limited to Norway and Sweden — generalizability to more diverse populations uncertain
- Implementation error in randomization at some sites (initial 2:1 allocation reversed) required corrective adjusted 9:1 allocation lists
- Unequal group sizes (3:2 allocation) reduces power for ocrelizumab arm
- Brain volume outcomes analyzed only descriptively due to missing data
- No formal multiplicity adjustment for secondary end points — should not be interpreted as causal
- Noninferiority margin of -10 percentage points may be considered generous
- 24-month follow-up limits long-term safety and efficacy conclusions
Citation
N Engl J Med 2026;395:44-53