Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation
Authors: Zhu Chao , Kalincik Tomas , Horakova Dana , Zhou Zhen , Buzzard Katherine , Skibina Olga , Alroughani Raed , Izquierdo Guillermo , Eichau Sara , Kuhle Jens , Patti Francesco , Grand’Maison Francois , Hodgkinson Suzanne , Grammond Pierre , Lechner-Scott Jeannette , Butler Ernest , Prat Alexandre , Girard Marc , Duquette Pierre , Macdonell Richard A. L. , Weinstock-Guttman Bianca , Ozakbas Serkan , Slee Mark , Sa Maria Jose , Van Pesch Vincent , Barnett Michael , Van Wijmeersch Bart , Gerlach Oliver , Prevost Julie , Terzi Murat , Boz Cavit , Laureys Guy , Van Hijfte Liesbeth , Kermode Allan G. , Garber Justin , Yamout Bassem , Khoury Samia J. , Merlo Daniel , Monif Mastura , Jokubaitis Vilija , van der Walt Anneke , Butzkueven Helmut ,   MSBase Study Group, Leist Thomas P , Habib Lily  , Udugama Paarami  , Gray Orla  , Horakova Dana  , Sartori Charlotte  , More Rein  , Siddiqui Ana  , Farr Pamela  , Stupar Dusko  , Tang Cynthia  , Le Alison  , Smirnova Sonya  , Palshetkar Gaurang  , Spelman Tim  
Published: June 2023

ImportanceNatalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses.ObjectivesTo compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab.Design, Setting, and ParticipantsIn this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023.ExposuresDimethyl fumarate, fingolimod, and ocrelizumab.Main Outcomes and MeasuresPrimary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method.ResultsAmong 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab.Conclusion and RelevanceStudy results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.