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056 Efficacy and safety of the Bruton’s tyrosine kinase inhibitor evobrutinib (M2951) in patients with relapsing multiple sclerosis over 48 weeks: a randomized, placebo-controlled, phase 2 study
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  1. Xavier Montalban1,2,
  2. Douglas L Arnold3,4,
  3. Martin S Weber5,6,
  4. Ivan Staikov7,
  5. Karolina Piasecka-Stryczynska8,
  6. Alan Gillett9,
  7. Emily C Martin10,
  8. Sana Syed10,
  9. Fernando Dangond10,
  10. Jerry S Wolinsky11
  1. 1Vall d’Hebron University Hospital, Barcelona, Spain
  2. 2University of Toronto, Toronto, Canada
  3. 3Montreal Neurological Institute and Hospital, Montreal, Canada
  4. 4NeuroRx Research, Montreal, Canada
  5. 5Institute of Neuropathology, Universitätsmedizin Göttingen, Göttingen, Germany
  6. 6Department of Neurology, Universitätsmedizin Göttingen, Göttingen, Germany
  7. 7Department of Neurology, Acibadem City Clinic Tokuda Hospital, Sofia, Bulgaria
  8. 8Outpatient Neurology Clinic, Hanka Hertmanowska MS Care Center, Plewiska, Poland
  9. 9EMD Serono, Mississaugua, ONTARIO, Canada
  10. 10Global Clinical Development Center, EMD Serono, Billerica, MA, USA
  11. 11McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

Abstract

Introduction Evobrutinib (M2951) is a highly specific oral inhibitor of Bruton’s tyrosine kinase, a key regulator of B cell and macrophage functions implicated in MS.

Methods In this double-blind, phase 2 study (NCT02975349), adult patients (≤65 years) with relapsing MS (RMS) were randomized to evobrutinib 25 mgQD, 75 mgQD, 75 mgBID, placebo, or open-label dimethyl fumarate (240 mgBID; reference arm) for 48 weeks; placebo-treated patients switched to evobrutinib 25 mgQD after 24 weeks. The primary endpoint was the total number of T1 gadolinium-enhancing (T1Gd+) lesions at Weeks 12, 16, 20, and 24. Secondary endpoints included annualized relapse rate (ARR), MRI measures at Weeks 24 and 48, and safety.

Results Among 261 patients, the sum of T1Gd+ lesions over Weeks 12–24 was reduced with evobrutinib 75 mgQD (p=0.002) and 75 mgBID (p=0.03); a dose response was observed (p=0.001). There was no evidence of change in effect on T1Gd+ lesions (mean±SD; Wilcoxon signed-rank test) between Weeks 24 and 48 with evobrutinib 75 mgQD (0.28±0.91 to 0.85±2.87; p=0.57) or 75 mgBID (0.24±0.88 to 0.49±1.22; p=0.23). ARR (unadjusted [95%CI]) was 0.25 (0.12–0.44) for evobrutinib 75 mgQD and 0.11 (0.04–0.25) for 75 mgBID over 48 weeks, and 0.37 (0.17–0.70) for placebo over 24 weeks. Evobrutinib appeared well-tolerated. Shifts to Grade 3–4 ALT and AST elevations from normal (grade 0) occurred in 8 (5.4%) and 6 (3.9%) evobrutinib-treated patients respectively, driven by events with onset within the first 24 weeks.

Conclusions Evobrutinib is the first BTK inhibitor to demonstrate disease activity reduction in RMS. The observed benefit-risk profile supports further clinical development.

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