Abstract

Objective: Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.

Methods: We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring).

Results: The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68).

Conclusion: The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Conflict of interest statement

Competing interests: TK served on scientific advisory boards for Roche, Genzyme-Sanofi, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Genzyme-Sanofi, Teva, BioCSL and Merck and received research support from Biogen. EKH received speaker honoraria and consultant fees from Actelion, Biogen, Celgene, Merck, Novartis, Roche, Sanofi and Teva, and support for research activities from Czech Ministry of Education (project PROGRES Q27/LF1). DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme and Novartis, as well as support for research activities from Biogen and Czech Ministry of Education (project PROGRES Q27/LF1). GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. PD served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis and Genzyme. PG is a Merck, Novartis, Teva-Neuroscience, Biogen and Genzyme advisory board member, consultant for Merck, received payments for lectures by Merck, Teva-Neuroscience and Canadian Multiple Sclerosis Society, and received grants for travel from Teva-Neuroscience and Novartis. AL served as a Bayer, Biogen, Merck, Novartis, Roche, Sanofi/Genzyme and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations and speaker honoraria from Bayer, Biogen, Merck, Novartis, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis. LK received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer Health Care, Bayer Schering, Bayhill Therapeutics, Biogen, Elan, European Union, Genmab, Gianni Rubatto Foundation, GlaxoSmithKline, Glenmark, MediciNova, Merck, Novartis, Novartis Research Foundation, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, Swiss MS Society, Swiss National Research Foundation, Teva Neuroscience, UCB and Wyeth. JK received consulting fees from Novartis, Protagen; speaker fees from the Swiss MS Society, Biogen, Novartis, Roche, Genzyme; travel expenses from Merck Serono, Novartis; grants from ECTRIMS Research Fellowship Programme, University of Basel, Swiss MS Society, Swiss National Research Foundation, Bayer (Schweiz), Genzyme and Novartis. MT received travel grants from Novartis, Bayer Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. JLS accepted travel compensation from Novartis, Biogen and Merck. Her institution receives the honoraria for talks and advisory board commitment from Bayer Health Care, Biogen, Genzyme Sanofi, Merck, Novartis and Teva; has been involved in clinical trials with Biogen, Novartis and Teva. CB received conference travel support from Biogen, Novartis, Bayer Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. FGM received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. JP accepted travel compensation from Novartis, Biogen, Genzyme and Teva and speaking honoraria from Biogen, Novartis, Genzyme and Teva. PS served on scientific advisory boards for Biogen Idec and TEVA; she has received funding for travel and speaker honoraria from Biogen Idec, Merck, Teva, Sanofi Genzyme, Novartis and Bayer and research grants for her institution from Bayer, Biogen, Merck, Novartis, Sanofi and Teva. DF received travel grants and/or speaker honoraria from Merck, TEVA, Novartis, Biogen and Sanofi Genzyme. FG received an institutional research grant from Biogen and Sanofi Genzyme; served on scientific advisory boards for Biogen, Novartis, Merck, Sanofi Genzyme and Roche; received funding for travel and speaker honoraria from Biogen, Merck and Sanofi-Aventis. MT received speaker honoraria from Biogen-Idec, Bayer Schering, Sanofi Aventis, Merck, Teva, Novartis and Almirall; has received research grants for her Institution from Biogen-Idec, Merck and Novartis. RB received speaker honoraria from Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva; research grants from Bayer Schering, Biogen, Merck, Novartis, Sanofi-Aventis and Teva; congress and travel/accommodation expense compensations by Almirall, Bayer Schering, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva. EP served on scientific advisory boards for Merck, Genzyme and Biogen; he has received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva; he has received travel grants and equipment from 'Associazione Marchigiana Sclerosi Multipla e altre malattie neurologiche'. VVP received travel grants from Biogen, Bayer Schering, Genzyme, Merck, Teva and Novartis Pharma. His institution receives honoraria for consultancy and lectures from Biogen, Bayer Schering, Genzyme, Merck, Roche, Teva and Novartis Pharma as well as research grants from Novartis Pharma and Bayer Schering. BVW received research and travel grants, honoraria for MS-Expert advisor and speaker fees from Bayer Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche and Teva. CS served on scientific advisory boards for Merck, Genzyme, Almirall and Biogen; received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva. CRT received research funding, compensation for travel or speaker honoraria from Biogen, Novartis, Genzyme and Almirall. MS has participated in, but not received honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi Aventis and Novartis. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi Genzyme. DLS received honoraria as a consultant on scientific advisory boards by Bayer Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. JLSM accepted travel compensation from Novartis and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in a clinical trial by Biogen. RA received conference travel support from Novartis, Teva, Biogen, Bayer and Merck and has participated in a clinical trial by Biogen, Novartis, Teva and Actelion. SH received honoraria and consulting fees from Merck, Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. Ricardo Fernandez Bolaños received speaking honoraria from Biogen, Novartis, Merck and Teva. VJ received conference travel support from Teva, Novartis and Merck, and speaker honoraria from Biogen. TS received honoraria for consultancy, funding for travel and compensation for serving on scientific advisory boards from Biogen and speaker honoraria from Novartis. HB served on scientific advisory boards for Biogen, Novartis and Sanofi-Aventis and has received conference travel support from Novartis, Biogen and Sanofi Aventis. He serves on steering committees for trials conducted by Biogen and Novartis, and has received research support from Merck, Novartis and Biogen.