This paper potentially hasn’t been peer-reviewed and looks at the differences between natalizumab and ocrelizumab and does a virutal head to head with the conclusion that anti-CD20 is more effective than natalizumab on disability progression and concludes that ocrelizumab is better….So is this bad news for the anti-CD49d. However, currently in Europe, ocrelizumab can be used first (or second line) but natalizumab is more typically second line meaning failure of a different drug first line) and in the study the disability in the natalizumab group was different.
However, perhaps this does not surprise me much because although they adjusted and estimate the progression data, they will not have adjusted for treatment failure from anti drug responses, which can occur following anti-CD49d treatment…..The frequency of neutralizing antibodies, that can stop natalizumab working is reported as about 6% of people in the product characteristics. We will soon explain this—watch this space.
I do not think the frequency of such an effect will be the same for anti-CD20 depleters. We know with ublituzimab that depletion occurs is most people within a day and with rituximab this is known too, ocrelizumab depletion is known to occur within a couple of weeks. We don’t know about this effect because the results are not easy to find and anti-drug responses are typically not measured. In this study they did rituximab and ocrelizumab and combined they were more effective than natalizumab…However similar studies have not concluded the same message for a difference so perhaps a real head to head is warranted
Yamout B, Alroughani R, Mohamed SFA, et al. Comparative effectiveness of natalizumab and anti-CD20 monoclonal antibodies in relapsing-remitting multiple sclerosis: a real-world propensity-score matched study. J Neurol, Neurosurg Psychiatry 2025; jnnp-2024-335704.
Iaffaldano P, Lucisano G, Guerra T, et al. A comparison of natalizumab and ocrelizumab on disease progression in multiple sclerosis. Ann Clin Transl Neurol 2024; 11: 2008–2015.
etc.
Comparative effectiveness of natalizumab versus ocrelizumab in multiple sclerosis: a real-world propensity score–matched study
Ocrelizumab versus Natalizumab in Relapsing-Remitting Multiple Sclerosis: A Registry-Linked Electronic Health Records Study.Huang F, Zhu W, Hou J, Morini Sweet S, Han Y, Wen J, Liao KP, Cai T, Chitnis T, Bourgeois FT, Xia Z, Cai T .medRxiv [Preprint]. 2025 Dec 2:2025.12.01.25341331. doi: 10.64898/2025.12.01.25341331.
Background: Ocrelizumab and natalizumab are commonly prescribed high-effectiveness disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS). However, no randomized clinical trial and few real-world studies have directly compared their effectiveness in reducing disability progression. Subtype classification and disability status are critical for multiple sclerosis (MS) research, but these data are often missing in electronic health records (EHRs), limiting robust real-world evidence generation.
Objective: To compare the effectiveness of ocrelizumab and natalizumab in two-year rater-assessed disability progression among RRMS patients using longitudinal registry-linked EHR data.
Design: Retrospective cohort study.
Setting: A large healthcare system that includes both academic and community practices.
Participants: Patients diagnosed with MS who initiated ocrelizumab or natalizumab between 2012 and 2020, with at least 6-month EHR data before treatment initiation and no prior exposure to other high-effectiveness DMTs.
Exposures: Treatment with ocrelizumab vs natalizumab.
Measurements: We developed an ensemble machine learning model to impute RRMS subtype and disability outcomes using structured and narrative EHR data. The primary outcome was moderate/severe rater-assessed disability at 2 years (observed or imputed Expanded Disability Status Scale [EDSS]≥4) after treatment initiation. We estimated the average treatment effects using semi-supervised doubly robust approach with comprehensive confounder adjustment and calibration to mitigate imputation bias. Covariates included standard demographic and clinical features such as baseline disability as well as knowledge graph-selected features. Sensitivity analyses used observed EDSS scores in registry-derived RRMS patients. Exploratory analyses included rituximab, another B-cell-depleting therapy, with adjustments for differences in patient profiles.
Results: Among RRMS patients, those treated with ocrelizumab (n=543) had a significantly lower two-year risk of moderate/severe disability compared with those treated with natalizumab (n=205) based on imputed outcomes (risk difference, -5.87%; 95% CI: -11.28% to -0.46%; p=0.033) after confounder adjustment. Sensitivity analyses yielded consistent findings using imputed or observed EDSS outcomes in registry-derived RRMS patients.
Conclusion and relevance: In this real-world comparative effectiveness study using a novel semi-supervised doubly-robust framework, ocrelizumab was associated with a lower risk of disability progression than natalizumab among RRMS patients. This approach provides a roadmap for generating robust large-scale real-world evidence in settings of missing key inclusion features and outcomes.
coi: Multiple disclaimer : My views
Source: multiple-sclerosis-research.org