Rationale and Design of two Phase 3 Randomized Controlled Trials (Evolution RMS 1&2) Evaluating the Bruton's Tyrosine Kinase Inhibitor Evobrutinib in Patients with Relapsing Multiple Sclerosis

Objective: To describe the rationale and design of the first Phase 3 randomized controlled trials (RCTs) (EVOLUTION RMS 1&2) evaluating the Bruton’s tyrosine kinase inhibitor (BTKi) evobrutinib in patients with relapsing multiple sclerosis (MS). Background: Evobrutinib is a highly-selective, covalent, oral BTKi, with a dual mechanism of action targeting pathogenic adaptive and innate immunity. In a Phase 2 RCT in patients with relapsing MS, evobrutinib significantly reduced the cumulative number of T1 Gd-enhancing lesions compared to placebo during Weeks 12–24 of treatment (primary endpoint) and was generally well tolerated [Montalban et al. NEJM2019;380;2406]. Design/Methods: EVOLUTION RMS 1 and 2 are global, double-blind, double-dummy, active-controlled Phase 3 studies comparing the efficacy and safety of oral evobrutinib BID versus oral teriflunomide QD. Adults with relapsing MS (RRMS or SPMS with relapses) will be randomized 1:1 to evobrutinib BID or teriflunomide 14 mg QD for 96 weeks. The primary endpoint is annualized relapse rate (ARR) over 96 weeks, based on qualified relapses. Secondary endpoints include time to first occurrence of 12- and 24-week confirmed disability progression (EDSS), MRI parameters, and safety. Additionally, EVOLUTION RMS 1&2 utilize two novel patient-reported outcomes (PROs) as secondary endpoints: the PROMIS fatigue and physical function measures. These endpoints have been validated and are supported by health authorities for inclusion in MS trials. The planned sample size is 930 patients per study, with randomization stratified by region and baseline EDSS. An interim analysis for sample size re-estimation, based on 12-week confirmed disability progression (CDP) data pooled from both studies, is planned. Results: The trials will commence enrollment in 2020. Conclusions: These two Phase 3 RCTs will determine the efficacy and safety of evobrutinib and assess its impact on PROs compared to an established standard of care (teriflunomide) in patients with relapsing forms of RMS. Disclosure: Dr. Montalban has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Alexion, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Hoffmann-La Roche, Immunic AG, Medday, Medscape, Merck, Mylan, Nervgen, Novartis, Sanofi-Genzyme, Teva Pharmaceutical and TG Therapeutics. Dr. Montalban has received research support from Abbvie, Biogen, Hoffmann-La Roche, Medday, Merck, Novartis, Sanofi-Genzyme and Teva Pharmaceutical.Dr. Arnold has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant fees from Albert Charitable Trust, Biogen, Celgene, F. Hoffmann-La Roche, Frequency Therapeutics, MedDay, Merck Serono, Novartis, Sanofi-Aventis. Dr. Arnold holds stock and/or stock options in NeuroRx Research. Dr. Arnold has received research support from Research grants from Albert Charitable Trust, Biogen, Celgene, F. Hoffmann-La Roche, Frequency Therapeutics, MedDay, Merck Serono, Novartis, Sanofi-Aventis. Amit Bar-Or has participated as a speaker in meetings sponsored by, and received consulting fees from, Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Genentech/Roche, Janssen/Actelion, MAPI, MedImmune, Merck/EMD Serono, Novartis and Sanofi-Genzyme. Grant support from Janssen/Actelion, Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Roche/Genentech, MAPI, MedImmune, Merck/EMD Serono, Novartis and Sanofi-Genzyme.Biogen, Celgene, EMD Serono, Genentech/Roche, Novartis and TG Therapeutics not outside of multi-center clinical trialsDr. Havrdova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Biogen, Celgene Corporation, Merck, Novartis, Roche, Sanofi, and Teva. Dr. Havrdova has received research support from Czech Ministry of Education, project PROGRES Q27/LF1.Dr. Stuve has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with EMD Serono, Celgene and Genzyme. Dr. Stuve has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Stuve has received research support from Teva Pharmaceuticals, Opexa Therapeutics, Sanofi-Genzyme. Dr. Weber has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with M. S. Weber received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer and Genzyme.. Dr. Weber has received personal compensation in an editorial capacity for M.S.Weber serves as an editor for PLoS One. Dr. Weber has received research support from M. S. Weber receives research support from the Deutsche Forschungsgemeinschaft (DFG; WE 3547/5-1), from Novartis, TEVA, Biogen-Idec, Roche, Merck and the ProFutura Programm of the Universitatsmedizin Gottingen.. Dr. Wiendl has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Abbvie, Actelion, Alexion, Biogen, Cognomed, Evgen, F. Hoffmann-La Roche Ltd, Genzyme, Johnson & Johnson, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Aventis, TEVA, and WebMD Global. Dr. Wiendl has received research support from Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, and Sanofi-Genzyme.Dr. Wolinsky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Received compensation for consulting, scientific advisory boards, or other activities with Alkermes, Actelion, Acorda Therapeutics, Celgene, EMD Serono, GeNeuro, GW Pharma, MedDay Pharmaceuticals, Novartis, Otsuka, PTC Therapeutics, Roche/Genentech, Sanof. Dr. Wolinsky has received royalty, license fees, or contractual rights payments from Royalties are received for out-licensed monoclonal antibodies through UTHealth from Millipore Corporation.Dr. Syed has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany. Dr. Mandel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), Sunovion Pharmaceuticals. Dr. Martin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany). Dr. Vermesch has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Sanofi-Genzyme, Novartis, Teva, Merck, Roche, Servier, Celgene. Dr. Vermesch has received personal compensation in an editorial capacity for La Revue des Microbiotes. Dr. Vermesch has received research support from Biogen, Novartis, Sanofi-Genzyme, Roche.