Cognitive effects of ocrelizumab vs interferon β-1a in relapsing multiple sclerosis: A post hoc analysis of the OPERA I/II trials
- PMID: 39965438
- DOI: 10.1016/j.msard.2025.106310
Cognitive effects of ocrelizumab vs interferon β-1a in relapsing multiple sclerosis: A post hoc analysis of the OPERA I/II trials
Abstract
Background: Cognitive impairment is a well-recognized symptom of multiple sclerosis (MS) that can manifest early in the disease course. Deficits in cognitive function can have a major impact on daily life. However, cognitive decline is often under-examined in clinical trials and clinical practice due to lack of adequate data. The objective of this study was to examine the longitudinal effect of ocrelizumab vs interferon beta (IFNβ)-1a on cognitive impairment in 2 phase 3 studies in relapsing MS (RMS).
Methods: The pooled population of participants with RMS (n = 1656) from the OPERA I/II clinical trials received subcutaneous IFNβ-1a (44 μg; n = 829) 3 times weekly or intravenous ocrelizumab (600 mg; n = 827) every 24 weeks. Cognition was assessed with a Symbol Digit Modalities Test (SDMT), administered in written or oral form according to each site investigator's choice, that primarily measured cognitive processing speed at baseline and every 12 weeks until the end of the double-blind treatment (96 weeks). Treatment effects were investigated based on longitudinal linear models for the change from baseline in SDMT and Cox regression for the time to 12- or 24-week confirmed decline of ≥4 points.
Results: Among the participants with an SDMT assessment at baseline and ≥1 postbaseline time point (IFNβ-1a, n = 749; ocrelizumab, n = 766), ocrelizumab treatment was associated with a greater mean SDMT improvement over 96 weeks than IFNβ-1a treatment (5.4 [95 % CI, 4.4-6.5] vs 4.0 [95 % CI, 3.0-5.1]; adjusted mean difference, 1.4 [95 % CI, 0.05-2.72]; P = 0.042). The risk of a clinically meaningful SDMT decline (≥4 points) was lower for those treated with ocrelizumab for both ≥12 weeks (IFNβ-1a, 18.4 %; ocrelizumab, 12.7 %; hazard ratio, 0.63 [95 % CI, 0.47-0.85]; P = 0.003) and ≥24 weeks (IFNβ-1a, 12.9 %; ocrelizumab, 7.9 %; HR, 0.57 [95 % CI, 0.39-0.82]; P = 0.003).
Conclusion: Ocrelizumab treatment resulted in better cognitive outcomes as measured by SDMT in participants with RMS compared with IFNβ-1a treatment. However, methodological limitations need to be considered when interpreting these data.
Clinicaltrials: gov: NCT01247324, NCT01412333.
Keywords: Cognitive impairment; DMT; Multiple sclerosis; Ocrelizumab; SDMT.
Copyright © 2025. Published by Elsevier B.V.
Conflict of interest statement
Declaration of competing interest Ralph HB Benedict has received research support from Bristol Myers Squibb; consultancy fees from Bristol Myers Squibb, Novartis, Roche, Sanofi and Immunic AG; speaking fees from EMD Serono; and royalties from Psychological Assessment Resources, Inc. Ludwig Kappos’s institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof. Kappos’ activities as principal investigator and member or chair of planning and steering committees or advisory boards for trials sponsored by Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, EXCEMED, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, F. Hoffmann-La Roche Ltd, Sanofi-Aventis, Santhera, Teva and Vianex and license fees for Neurostatus-UHB products; the Research Center for Clinical Neuroimmunology and Neuroscience in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, Innosuisse, the European Union and Roche Research Foundation. Aaron Miller reports the following financial relationships with industry during 2015 and/or 2016. Please note that this information may differ from information posted on corporate sites due to timing or classification differences. Dr Miller has received fees for consulting with Acorda Therapeutics Inc, Biogen Idec, CVS Caremark, EMD Serono, Inc (Merck & Co, Inc), Genzyme Corporation, Gerson Lehrman Group, GSK and Nuron Biotech Inc. MSSM faculty occasionally give lectures at events sponsored by industry, but only if the events are free of any marketing purpose; Dr Miller reports fees for lectures sponsored by Letters & Sciences, LLC, and the Scienomics Group (Omnicom Group). Finally, Dr Miller has served on scientific advisory boards for HealthSTAR Communications, Questcor Pharmaceuticals, Inc, and Sanofi-Aventis. Hans-Peter Hartung has received honoraria for consulting, serving on steering committees and speaking at scientific symposia with approval from the rector of Heinrich Heine University Düsseldorf from Bayer, Biogen, BMS Celgene, F. Hoffmann-La Roche Ltd, GeNeuro SA, MedImmune, Merck, Novartis, Octapharma, Sanofi and TG Therapeutics. James Overell is an employee and shareholder of F. Hoffmann-La Roche Ltd. During his previous employment he received personal compensation for consulting, serving on a scientific advisory board and speaking or other activities with Teva, Biogen, Celgene, EMD Serono, MedDay, Novartis, Roche, Sanofi Genzyme, Web MD Global and Allergan. His research and department were supported by grants from Sanofi Genzyme, Biogen, Novartis and Roche. Jinglan Pei is an employee of Genentech, Inc, and a shareholder of F. Hoffman-La Roche Ltd. Frank Dahlke is an employee of Impulze GmbH, Zurich, Switzerland, and provided consultancy services to Roche at the time of the study. Corrado Bernasconi was a contractor of F. Hoffmann-La Roche Ltd during completion of the work related to this manuscript. Harold Koendgen was an employee and shareholder of F. Hoffmann-La Roche Ltd at the time of the study. Qing Wang and Ulrike Bonati are employees and shareholders of F. Hoffmann-La Roche Ltd. Stanley Cohan has received research support from Biogen, Bristol Myers Squibb, Genentech, Genzyme, Mallinckrodt, MedDay and Novartis, has received honoraria for speaking from Acorda, Biogen, Bristol Myers Squibb, Genentech, Genzyme, Icometrix and Novartis, and serves on advisory boards and/or steering committees for Biogen, Genzyme, Icometrix and Novartis.
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