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. 2023 Aug 1;80(8):789-797.
doi: 10.1001/jamaneurol.2023.1625.

Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis

Izanne Roos  1   2 , Stella Hughes  3 , Gavin McDonnell  4 , Charles B Malpas  1   2 , Sifat Sharmin  2 , Cavit Boz  5 , Raed Alroughani  6 , Serkan Ozakbas  7 , Katherine Buzzard  1   8   9 , Olga Skibina  8   9   10 , Anneke van der Walt  10   11 , Helmut Butzkueven  10   11 , Jeannette Lechner-Scott  12   13 , Jens Kuhle  14 , Murat Terzi  15 , Guy Laureys  16 , Liesbeth Van Hijfte  16 , Nevin John  17   18 , Pierre Grammond  19 , Francois Grand'Maison  20 , Aysun Soysal  21 , Ana Voldsgaard Jensen  22 , Peter Vestergaard Rasmussen  23 , Kristina Bacher Svendsen  23 , Ismael Barzinji  24 , Helle Hvilsted Nielsen  25 , Tobias Sejbæk  26   27 , Sivagini Prakash  28 , Morten Leif Munding Stilund  29 , Arkadiusz Weglewski  30   31 , Nadia Mubder Issa  32 , Matthias Kant  33 , Finn Sellebjerg  22 , Orla Gray  34 , Melinda Magyari  22 , Tomas Kalincik  1   2 ; MSBase Study GroupDanish MS Registry Study Group
Collaborators, Affiliations

Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis

Izanne Roos et al. JAMA Neurol. .

Erratum in

  • Error in Figures.
    [No authors listed] [No authors listed] JAMA Neurol. 2023 Oct 1;80(10):1119. doi: 10.1001/jamaneurol.2023.2958. JAMA Neurol. 2023. PMID: 37603329 Free PMC article. No abstract available.

Abstract

Importance: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab.

Objective: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS.

Design, setting, and participants: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country.

Exposure: Treatment with ocrelizumab or rituximab after 2015.

Main outcomes and measures: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups.

Results: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses.

Conclusion: In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Roos reported receiving grants from the National Health and Medical Research Council, MS Australia, and the Trish Multiple Sclerosis Research Foundation and served on scientific advisory boards, received conference travel support and/or speaker honoraria from Roche, Novartis, Merck, and Biogen outside the submitted work. Dr Hughes reported receiving unrestricted educational grants or speaking honoraria from Biogen, Merck Serono, Novartis, Roche, and Sanofi Genzyme. Dr Malpas reported receiving received conference travel support from Merck, Novartis, and Biogen and research support from the National Health and Medical Research Council, Multiple Sclerosis Research Australia, The University of Melbourne, The Royal Melbourne Hospital Neuroscience Foundation, and Dementia Australia. Dr Boz reported receiving conference travel support from Biogen, Novartis, Roche, Bayer-Schering, Merck, and Teva and has participated in clinical trials by Sanofi Aventis, Roche, and Novartis. Dr Alroughani reported receiving honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi Genzyme outside the submitted work. Dr Buzzard reported receiving grants from CSL and the National Health and Medical Research Council and honoraria and consulting fees from Biogen, Teva, Novartis, Genzyme Sanofi, Roche, Merck, CSL, and Grifols outside the submitted work. Dr Skibina reported receiving honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen, and Genzyme companies. Dr Van der Walt reported serving on advisory boards and receiving unrestricted research grants from Novartis, Biogen, Merck, and Roche; grant support from the National Health and Medical Research Council of Australia and MS Research Australia; and speaker honoraria and travel support from Novartis, Roche, and Merck outside the submitted work. Dr Butzkueven reported receiving institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL, and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd, and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd, and Merck; and has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee outside the submitted work. Dr Lechner-Scott reported receiving travel compensation from Novartis, Biogen, Roche, and Merck and honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, Teva, and Novartis during the conduct of the study. Dr Kuhle reported receiving grants from the Swiss MS Society, Swiss National Research Foundation, Novartis, Roche, Biogen, Merck, and Bristol Myers Squibb outside the submitted work. Dr Terzi reported receiving travel grants from Novartis, Bayer-Schering, Merck, and Teva and has participated in clinical trials by Sanofi Aventis, Roche, and Novartis. Dr Laureys reported receiving travel and/or consultancy compensation and/or research grants from Sanofi Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen, and Bristol Myers Squibb outside the submitted work. Dr John reported receiving grants from Sanofi, Novartis, Biogen, and Amicus as a principal investigator for a sponsored study and grants outside the submitted work. Dr Grammond reported receiving advisory board fees from Novartis, EMD Serono, Roche, Biogen, IDEC, Sanofi Genzyme, Pendopharm, and Roche; grant support from Genzyme and Roche; and research grants for his institution from Biogen, IDEC, Sanofi Genzyme, and EMD Serono. Dr Grand-Maison reported receiving reported grants from Roche, Novartis, Alexa, and Biogen and honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, and Atara Pharmaceuticals during the conduct of the study. Drs Jensen and Rasmussen reported having served on scientific advisory boards for, served as consultant for, received support for congress participation, or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme. Dr Rasmussen reported receiving advisory board fees from Novartis, Roche, Merck, and Biogen outside the submitted work. Dr Svendsen reported receiving travel grants from Bristol Myers Squibb and research support from Roche outside the submitted work. Dr Stilund reported serving on scientific advisory boards for Sanofi, receiving support for congress participation, or receiving speaker honoraria from Biogen, Teva, Merck, Roche, and Sanofi; grants for his research from Novartis; and being currently engaged in sponsor-initiated research projects by Bayer, Jansen, Shionogi, and Sanofi outside the submitted work. Dr Weglewski reported serving on scientific advisory boards for Merck and Roche; receiving conference travel support from Biogen, Merck, Roche, and Sanofi; and receiving speaker honoraria from Roche, Merck, and Sanofi outside the submitted work. Dr Sellebjerg reported serving on scientific advisory boards, being on the steering committees of clinical trials, serving as a consultant, receiving support for congress participation, receiving speaker honoraria, or receiving research support for his laboratory from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, Bristol Myers Squibb, and Teva outside the submitted work. Dr Gray reported receiving honoraria as consultant on scientific advisory boards for Genzyme, Biogen, Merck, Roche, and Novartis; receiving travel grants from Biogen, Merck, Roche, and Novartis; participating in clinical trials by Biogen and Merck; and receiving research grant support from Biogen outside the submitted work. Dr Magyari reported receiving grants from Roche, Biogen, Novartis, Sanofi, and Merck during the conduct of the study; serving on scientific advisory boards for AbbVie, Biogen, Merck, Novartis, Roche, Sanofi, and Teva; receiving honoraria for lecturing from Biogen, Genzyme, Merck, Novartis, and Sanofi; and receiving support for congress participation from Biogen, Genzyme, Roche, and Teva outside the submitted work. Dr Kalincik reported grants from the National Health and Medical Research Council, MS Australia, Novartis, Biogen, Roche, Merck, and Celgene outside the submitted work; serving on scientific advisory boards for MS International Federation and World Health Organization, BMS, Roche, Sanofi Genzyme, Novartis, Merck, and Biogen; serving on the steering committee for Brain Atrophy Initiative by Sanofi Genzyme; receiving conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi Genzyme, Teva, BioCSL, and Merck; and receiving research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Flow Diagram
Patients previously treated with the comparator therapy were treated with ocrelizumab or rituximab after 2015 but had previously received the comparator therapy. Patients excluded due to insufficient follow-up while receiving treatment did not have a baseline visit (with Expanded Disability Status Scale score recorded) within a caliper of 180 days before or 30 days after commencement of therapy or had fewer than 2 visits after baseline more than 6 months apart. Of patients with progressive multiple sclerosis (MS), 393 had secondary progressive MS, and 225 had primary progressive MS.
Figure 2.
Figure 2.. Comparison of Relapse Outcomes for Rituximab vs Ocrelizumab
A, Annualized relapse rate (mean and 95% CI). B, Annualized relapse rate ratio (mean and 95% CI) with noninferiority margin indicated by the dashed line. C, Cumulative hazard of relapses.
Figure 3.
Figure 3.. Comparison of Disability Outcomes for Rituximab vs Ocrelizumab
A, Cumulative hazard of disability accumulation. B, Cumulative hazard of disability improvement. HR indicates hazard ratio.
Figure 4.
Figure 4.. Persistence While Receiving Study Therapy
HR indicates hazard ratio.
See this image and copyright information in PMC

Comment in

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