BACKGROUND AND OBJECTIVES: Patients with multiple sclerosis (MS) may demonstrate better disease control when treatment is initiated on high-efficacy disease-modifying therapies (DMTs) from onset. This subgroup analysis assessed the long-term efficacy and safety profile of the high-efficacy DMT ocrelizumab (OCR) as first-line therapy for early-stage relapsing MS (RMS). METHODS: Post hoc exploratory analyses of efficacy and safety were performed in a subgroup of treatment-naive patients with RMS who received ≥1 dose of OCR in the multicenter OPERA I/II (NCT01247324/NCT01412333) studies. Patients were randomized to OCR or interferon β-1a for 96 weeks (double-blind controlled treatment period [DBP]), before switching to OCR in the open-label extension (OLE). Efficacy assessments included no evidence of disease activity (NEDA-3), 24-week confirmed disability progression (CDP), MRI lesion activity, change in whole-brain volume; with safety outcomes assessed over a 9-year treatment period. RESULTS: Overall, 757 patients were included (interferon-treated n = 382, mean age 36.3 years, 65.7% female; OCR-treated n = 375, mean age 35.5 years, 64.0% female); 505 of 757 (66.7%) completed 9 years of follow-up. The difference in NEDA status between OCR-treated and interferon-treated patients achieved during the DBP (72.5% and 43.8%, respectively, odds ratio 3.48, 95% CI 2.52-4.81) was maintained throughout the 7-year OLE (48.2% vs 25.7%; odds ratio 2.72, 95% CI 1.94-3.82). No 24-week CDP was observed in 78.7% of OCR-treated patients over 9 years. Brain volume loss over the entire study period remained numerically higher among patients starting OCR later (p = 0.09 at OLE at week 336). During the DBP, safety profiles in both groups were similar; no new safety signals were observed during the OLE. Over >9 years of continuous OCR treatment, the rate of infections remained low and stable over time. DISCUSSION: A higher proportion of OCR-treated patients achieved NEDA status compared with interferon-treated patients during the DBP, which was maintained throughout the OLE. After switching to OCR, disability accrual and brain volume loss among interferon-treated patients became similar to the OCR-OCR group, but disability and brain volume loss accrued during interferon treatment were not recovered. Possible study limitations include assessment bias due to unmaintained blinding during the OLE. These data support OCR as first-line therapy for these patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that OCR delays disease progression in treatment-naïve patients with early-stage RMS.

Center of Clinical Neuroscience Department of Neurology University Clinic Carl Gustav Carus Dresden University of Technology Germany

Department of Neurology and Center of Clinical Neuroscience 1st Medical Faculty General University Hospital and Charles University Prague Czech Republic

Department of Neurology Morriston Hospital Swansea United Kingdom

Department of Neurology Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus University of Colorado Denver

Department of Neurology School of Medicine Technical University of Munich Germany

Department of Neurology UCSF Weill Institute for Neurosciences University of California San Francisco

Division of Neurology University of British Columbia Vancouver Canada

F Hoffmann La Roche Ltd Basel Switzerland

Genentech Inc San Francisco CA

IQVIA Inc Paris France; and

Life and Health Sciences Research Institute School of Medicine University of Minho Braga Portugal

Multiple Sclerosis Center of Excellence Oklahoma Medical Research Foundation Oklahoma City

Neurology Unit Neurophysiology Service Neurorehabilitation Unit Neuroimaging Research Unit Division of Neuroscience IRCCS San Raffaele Scientific Institute Milan Italy

Vita Salute San Raffaele University Milan Italy

doi: 10.1212/WNL.0000000000210307 PubMed

Neurology. 104:e210307. PubMed

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