Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials.

Autor:	Montalban X; Department of Neurology, Centre d'Esclerosi Múltiple de Catalunya, Hospital Universitario Vall d'Hebron, Barcelona, Spain. Electronic address: xavier.montalban@cem-cat.org., Vermersch P; University Lille, Inserm U1172 LilNCog, Centre Hospitalier Universitaire de Lille, Lille, France., Arnold DL; NeuroRx Research, Montreal, QC, Canada; Montreal Neurological Institute, Montreal, QC, Canada., Bar-Or A; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Cree BAC; Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA., Cross AH; Section of Multiple Sclerosis and Neuroimmunology, Washington University School of Medicine, St Louis, MO, USA., Kubala Havrdova E; General University Hospital, Charles University, Prague, Czech Republic., Kappos L; Departments of Headorgans, Spine and Neuromedicine, Clinical Research, and Biomedical Engineering, Research Center for Clinical Neuroimmunology and Neuroscience, University Hospital Basel, University of Basel, Basel, Switzerland., Stuve O; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Wiendl H; Department of Neurology with Institute of Translational Neurology, University Hospital, Münster, Germany., Wolinsky JS; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA., Dahlke F; Impulze, Zürich, Switzerland., Le Bolay C; Merck Santé, an affiliate of Merck KGaA, Lyon, France., Shen Loo L; EMD Serono, an affiliate of Merck KGaA, Billerica, MA, USA., Gopalakrishnan S; Merck KGaA Healthcare, Darmstadt, Germany., Hyvert Y; Merck KGaA Healthcare, Darmstadt, Germany., Javor A; Ares Trading, an affiliate of Merck KGaA, Eysins, Switzerland., Guehring H; Merck KGaA Healthcare, Darmstadt, Germany., Tenenbaum N; EMD Serono, an affiliate of Merck KGaA, Billerica, MA, USA., Tomic D; Ares Trading, an affiliate of Merck KGaA, Eysins, Switzerland.
Jazyk:	angličtina
Zdroj:	The Lancet. Neurology [Lancet Neurol] 2024 Nov; Vol. 23 (11), pp. 1119-1132. Date of Electronic Publication: 2024 Sep 19.
DOI:	10.1016/S1474-4422(24)00328-4
Abstrakt:	Background: Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis. Methods: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated). Findings: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy's law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment. Interpretation: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis. Funding: Merck. Competing Interests: Declaration of interests XM received speaking honoraria or travel expenses, or both, for participation in scientific meetings; and has been a steering committee member of clinical trials and participated in advisory boards with AbbVie, Actelion (Janssen [Johnson & Johnson]), Alexion (AstraZeneca), Bayer, Biogen, Celgene (Bristol Myers Squibb), EMD Serono, Immunic, Janssen (Johnson & Johnson), MedDay, Merck, Mylan, Nervgen, Novartis, Roche, Sandoz, Sanofi, Teva, TG Therapeutics, Excemed, Multiple Sclerosis International Federation, and National Multiple Sclerosis Society. PV received honoraria and consulting fees from AB Science, Ad Scientiam, Biogen, Celgene (Bristol Myers Squibb), Imcyse, Janssen (Johnson & Johnson), Merck, Novartis, Roche, and Sanofi; and received research support from Novartis, Roche, and Sanofi. DLA received personal compensation for serving as a consultant for Alexion (AstraZeneca), Biogen, Celgene, Eli Lilly, Frequency Therapeutics, Merck, Novartis, Roche, Sanofi, and Shionogi; and holds an equity interest in NeuroRx Research. AB-O holds the Melissa and Paul Anderson Chair; received research funding from the Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, National Institutes of Health, and National Multiple Sclerosis Society; was a speaker in sponsored meetings and received consulting fees from Accure, Actelion (Janssen [Johnson & Johnson]), Atara Biotherapeutics, Biogen, Celgene (Receptos [Bristol Myers Squibb]), EMD Serono, Gossamer Bio, GSK, Medimmune, Merck, Novartis, Roche, and Sanofi; and received grant support to the University of Pennsylvania from Biogen, EMD Serono, Merck, Billerica, Novartis, and Roche. BACC received personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal (Sandoz), Horizon, Immunic AG, Kyverna, Neuron23, Novartis, Sanofi, Siemens, and TG Therapeutics; and received research support from Genentech. AHC received funding for this study from the Hope Center for Neurological Disorders (Washington University, St Louis, MO, USA); a salary from the Manny and Rosalyn Rosenthal Dr John L Trotter Multiple Sclerosis Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation; grant support from the National Institutes of Health, US Department of Defense, and National Multiple Sclerosis Society USA; consulting fees from Genentech (Roche), TG Therapeutics, Bristol Myers Squibb, Janssen (Johnson & Johnson), and Novartis; payment or honoraria for lectures from the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024, University of Arizona, University of Maryland, University of South Alabama, University of Miami, Mayo Foundation, Consortium of Multiple Sclerosis Centers, and Biogen; payment or honoraria for writing chapters of the American Academy of Neurology; payment or honoraria for construction of continuing medical education talks and written documents from Catamount, Projects in Knowledge, Vindico Medical Education, and WebMD; payment or honoraria for preparation of educational materials from Indy Airone; financial support for attending scientific or medical meetings from EMD Serono, Novartis, Genentech, and Hoffmann-La Roche; financial support for attending advisory boards from Novartis, Genentech, Biogen, Bristol Myers Squibb, Janssen (Johnson & Johnson), TG Therapeutics, Octave, and Horizon; holds a patent (US patent 15060–630 [015875); participated on a data safety monitoring board or advisory board for Novartis for the ASCLEPIOS trials on ofatumumab, EMD Serono for the evolutionRMS trials on evobrutinib, and Genentech for the OBOE study on ocrelizumab; is the president of the board of governors for the Consortium of Multiple Sclerosis Centers; is on the programme nominating committee for ACTRIMS; was a member and chair of the Research Programs Advisory Committee for the National Multiple Sclerosis Society; is a member representing the National Multiple Sclerosis Society and a member of the nominating committee for the International Progressive Multiple Sclerosis Alliance; and received medical writing support from Genentech, EMD Serono, and Novartis. EKH received personal compensation for consulting, for serving on a scientific advisory board or data safety monitoring board, and for serving as an expert witness from Actelion (Janssen [Johnson & Johnson]), Biogen, Celgene, Merck, Novartis, Roche, and Sanofi. LK received research support to the institution (University Hospital Basel, Basel, Switzerland) including steering committee, advisory board, and consultancy fees from Actelion (Janssen [Johnson & Johnson]), Bayer, Biogen, Bristol Myers Squibb, GSK, Janssen (Johnson & Johnson), Japan Tobacco, Merck, Novartis, Roche, Sanofi, Santhera, and Shionogi, and TG Therapeutics; speaker fees from Bayer, Biogen, Merck, Novartis, Roche, and Sanofi; support of educational activities from Allergan, Bayer, Biogen, CSL Behring, Desitin, Merck, Novartis, Pfizer, Roche, Sanofi, Shire, and Teva; license fees for Neurostatus platform access; and grants from Bayer, Biogen, EU, InnoSwiss, Merck, Novartis, Roche, Swiss Multiple Sclerosis Society, and Swiss National Research Foundation. OS received personal compensation for consulting from EMD Serono, Novartis, and Octave Bioscience; grants from EMD Serono; and for serving as an editorial board member of Therapeutic Advances in Neurological Disorders. HW received personal compensation for consulting, for serving on a scientific advisory board, speaking and traveling or attending meetings from AbbVie, Actelion (Janssen [Johnson & Johnson]), Alexion (AstraZeneca), Argenx, Beckton Dickinson, Biogen, Bristol Myers Squibb (Celgene), EMD Serono, Fondazione Cariplo, Gossamer Bio, Idorsia, Immunic, Immunovant, Janssen (Johnson & Johnson), Lundbeck, Merck, Neurodiem, NexGen, Novartis, Ology, Roche, Sandoz, Sanofi, Teva, WebMD, and Worldwide Clinical Trials; contracted research with Alexion (AstraZeneca), Amicus Therapeutics, Argenx, Biogen, CSL Behring, Merck, Novartis, Roche, and Sanofi. JSW received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Cleveland Clinic Foundation, EMD Serono, Inmagene, Novartis, Roche, Sandoz, and Zenas BioPharma; and royalties for out-licensing monoclonal antibodies through UTHealth from Millipore Corporation. FD provides consultancy to Merck through Impulze. CLB is an employee of Merck Santé. YH, HG, and SG are employees of Merck and own stock or stock options. AJ and DT are employees of Ares Trading. DT received stock or an ownership interest from Novartis. NT and LSL are employees of EMD Serono. (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
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