Decade of OPERA Data Supports Early Ocrelizumab Treatment Initiation in Relapsing Multiple Sclerosis

A newly published study showed that patients with relapsing multiple sclerosis (RMS) who started ocrelizumab (Ocrevus; Genentech) at randomization had a significantly lower risk of 48-week confirmed disability progression (CDP) over 10 years than those who began the therapy after 2 years on interferon beta-1a (IFN). Published in JAMA Neurology, these findings comes from a pooled post hoc analysis of the phase 3 OPERA I (NCT01247324) and OPERA II (NCT01412333) trials.¹

Additional data revealed that continuous treatment was associated with a 24% reduction in the hazard of CDP, and no new safety signals emerged over the 8-year open-label extension (OLE). The findings from the analysis, conducted by lead author Stephen Hauser, MD, director of the Weill Institute for Neurosciences at UCSF, and colleagues, add a decade of randomized trial follow-up to the evidence for early high-efficacy therapy, which has relied largely on observational comparisons.

Study Overview

OPERA I and II enrolled adults aged 18 to 55 years with RMS, an Expanded Disability Status Scale (EDSS) score of 0 to 5.5, and recent relapse activity. Patients were randomized 1:1 to intravenous ocrelizumab 600 mg every 24 weeks or subcutaneous IFN 44 μg 3 times weekly for a 96-week double-blind period (DBP). After the DBP, all patients could receive ocrelizumab in the OLE.² The pooled population included 1656 patients (66.0% female; mean age, approximately 37 years). Of these, 1325 entered the OLE and 853 completed the study. Outcomes included 48-week CDP, progression independent of relapse activity (PIRA), EDSS milestones, relapse rates, no evidence of disease activity (NEDA-3), MRI measures, and safety.

Key Findings

Over 10 years, 82.2% of patients receiving continuous ocrelizumab remained free of 48-week CDP (hazard ratio [HR], 0.76; 95% CI, 0.61-0.95; P = .02). Most of this benefit accrued during the DBP. After rebaselining at the start of the OLE, hazards were similar between arms (HR, 1.02). Continuous treatment also reduced the hazard of reaching EDSS 6.0, the threshold for requiring a walking aid, by 43% (HR, 0.57; 95% CI, 0.40-0.82; P = .002). Differences in PIRA (HR, 0.86; P = .24) and in reaching EDSS 4.0 (HR, 0.66; P = .06) were not statistically significant.

READ MORE: Ocrelizumab Shows MRI Benefits vs Fingolimod in Phase 3 Pediatric-Onset Multiple Sclerosis Study

More patients in the continuous arm remained relapse free (73.0% vs 63.2%; HR, 0.62; P <.001). In that arm, the annualized relapse rate fell from 0.139 in year 1 to 0.016 in year 10. NEDA-3 was achieved by 58.6% vs 38.0% of patients. Across 10,813.5 patient-years (PY) of exposure, rates of adverse events and serious adverse events did not increase over time. Serious infections occurred at 1.8 per 100 PY, and IgG remained above the lower limit of normal in 84.5% of patients. Malignancy rates were similar to general population and MS registry reference rates.

Clinical Context and Interpretation

The global prevalence and diagnosed incidence of MS have risen over the past 2 decades.³ Relapses drive much of the early disability in MS, while PIRA becomes the dominant contributor as disease advances.⁴ In the original OPERA trials, ocrelizumab produced roughly 50% lower relapse activity and 40% lower disability progression than IFN.² These effects were sustained through 5 years of follow-up.¹

The authors concluded that a 2-year treatment delay left a disability gap that did not close despite at least 8 years of subsequent ocrelizumab. However, the similar hazards after rebaselining suggest the gap reflects divergence during the controlled period rather than an ongoing advantage. That distinction may help clinicians frame the magnitude of benefit for patients.

Limitations and Future Research

The analysis was post hoc and lacked a control arm during the OLE, leaving room for rater bias. Only about half of randomized patients completed 10 years. Those who discontinued had slightly higher progression rates, although inverse probability of censoring weighting yielded consistent results (HR, 0.75). Roughly 90% of participants were White, and Roche funded the trials. Notably, a single-center case series from an OPERA I site previously reported interstitial lung disease after a mean of 10.5 years of ocrelizumab, a late effect that pooled analyses may not capture. Longer-term comparisons with other anti-CD20 therapies and more data in older patients may be needed.

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REFERENCES
1. Hauser SL, Bar-Or A, Giovannoni G, et al. Ten Years of Ocrelizumab in Relapsing Multiple Sclerosis: The OPERA I and II Randomized Clinical Trials. JAMA Neurol. Published online October 5, 2026. doi:10.1001/jamaneurol.2026.3507
2. auser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221-234. doi:10.1056/NEJMoa1601277
3. Portaccio E, Magyari M, Havrdova EK, et al. Multiple sclerosis: emerging epidemiological trends and redefining the clinical course. Lancet Reg Health Eur. 2024;44:100977. Published 2024 Aug 22. doi:10.1016/j.lanepe.2024.100977
4. Lublin FD, Häring DA, Ganjgahi H, et al. How patients with multiple sclerosis acquire disability. Brain. 2022;145(9):3147-3161. doi:10.1093/brain/awac016
5. Spelman T, Magyari M, Piehl F, et al. Treatment Escalation vs Immediate Initiation of Highly Effective Treatment for Patients With Relapsing-Remitting Multiple Sclerosis: Data From 2 Different National Strategies. JAMA Neurol. 2021;78(10):1197-1204. doi:10.1001/jamaneurol.2021.2738