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Primary analysis of a randomised, placebo-controlled, phase 2 study of the Bruton's tyrosine kinase inhibitor evobrutinib (M2951) in patients with relapsing multiple sclerosis
ECTRIMS Online Library. Montalban X. Oct 12, 2018; 232075
Xavier Montalban
Xavier Montalban
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Abstract
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Abstract: 322

Type: Scientific Session

Abstract Category: N/A

Background: Evobrutinib (M2951) is a highly specific, irreversible, oral inhibitor of Bruton´s tyrosine kinase (BTK) that functionally impairs activation of B-cells and macrophages in vivo and may be effective in autoimmune disease. This study (NCT02975349) evaluated evobrutinib in clinically and radiologically active RMS.
Methods: In this double-blind, placebo (PBO)-controlled, 48-wk, Ph 2 study, patients (pts) aged 18-65 years with RRMS or SPMS with superimposed relapses were randomised to evobrutinib 25mg QD, 75mg QD, 75mg BID, PBO or open-label dimethyl fumarate (240mg BID; reference arm). The primary endpoint was the sum of T1 Gd+ lesions at wks 12, 16, 20, and 24. Key secondary endpoints included annualised relapse rate (ARR) at wk 24 and safety. Primary analysis (evobrutinib groups versus PBO) was planned when all pts reached 24 wks of treatment or prematurely discontinued.
Results: 243 (91%) of 267 randomised pts completed 24 wks of treatment. Baseline characteristics were balanced across groups. Mean (SD) total T1 Gd+ lesions (wks 12-24) was 4.07 (5.76), 5.23 (12.52), 1.69 (4.69) and 1.39 (3.85) in the PBO, evobrutinib 25mg QD, 75mg QD and 75mg BID groups, respectively. T1 Gd+ lesions per scan were significantly reduced with evobrutinib 75mg QD (lesion rate ratio [RR]=0.38; p=0.01) and 75mg BID (RR=0.48; p=0.05), but not 25mg QD (RR=1.54; p=0.22) vs PBO; a dose-response relationship was seen (p=0.003). A trend towards a reduction in ARR (unadjusted [95% CI]) was seen with evobrutinib 75mg QD (0.13 [0.03-0.38]; p=0.15) and BID (0.08 [0.01-0.30]; p=0.10) vs PBO (0.33 [0.14-0.64]), with evidence of dose-response (p=0.03). Rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were comparable with evobrutinib 25 and 75mg QD and PBO, but higher with evobrutinib 75mg BID (driven by asymptomatic increases in liver transaminases). Grade 3 TEAEs were more frequent with evobrutinib 75mg BID; most were asymptomatic, reversible transaminase elevations with no Hy's Law cases. There were no serious infections with evobrutinib and no other emerging safety signals.
Conclusions: The primary endpoint was met, with evobrutinib 75mg QD and 75mg BID significantly reducing the number of T1 Gd+ lesions vs PBO. In this 24 wk analysis, evobrutinib led to numerical and clinically relevant decreases in ARR, with evidence of a dose response and a manageable safety profile. These data support a role for evobrutinib in MS, warranting evaluation in larger trials.
Disclosure: X Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Almirall, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Oryzon Genomics, Roche, Sanofi-Genzyme and Teva Pharmaceutical.
D Arnold reports consultant fees and/or grants from Acorda, Adelphi, Alkermes, Biogen, Celgene, Frequency Therapeutics, Genentech, Genzyme, Hoffman LaRoche, Immune Tolerance Network, Immunotec, MedDay Pharmaceuticals, Merck-Serono, Novartis, Pfizer, Receptos, Roche, Sanofi-Aventis, Canadian Institutes of Health Research, MS Society of Canada, International Progressive MS Alliance, and an equity interest in NeuroRx Research.
MS 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 Universitätsmedizin Göttingen. MS Weber is serving as an editor for PLoS One. He received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer and Genzyme.
Ivan Staikov has no conflicts of interest to declare.
Karolina Piasecka-Stryczynska has no conflicts of interest to declare.
J Wolinsky has received royalties from Millipore (Chemicon International) Corporation, and compensation for consulting, serving scientific advisory or data monitoring committees, or other activities with AbbVie, Actelion, Alkermes, Bayer HealthCare, Biogen, Bionest, Celgene, Clene Nanomedicine, EMD Serono, Forward Pharma, GeNeuro, McDonnel Boehnen Hulbert & Berghoff, MedDay Pharmaceuticals, Novartis, Otsuka, PTC Therapeutics, Roche/Genentech, Sanofi-Genzyme, Takeda, or speaking activities for AcademicCME, CMSC, France Foundation, Masters MS, PlatformQ Health Education, PRIME, Strategic Consultants International, and WebMD.
E Martin and F Dangond are employed by EMD Serono Research & Development Institute, Inc., Billerica, MA, USA (a business of Merck KGaA, Darmstadt, Germany).
J Willmer was employed by EMD Serono Research & Development Institute, Inc., Billerica, MA, USA (a business of Merck KGaA, Darmstadt, Germany) during the study and development of this abstract.

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