Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis

Abstract

Background and Objectives Chronic active lesions (CALs) are demyelinated multiple sclerosis (MS) lesions with ongoing microglia/macrophage activity, resulting in irreversible neuronal damage and axonal loss. Evobrutinib is a highly selective, covalent, CNS-penetrant, Bruton tyrosine kinase inhibitor. This post hoc analysis evaluated the effect of evobrutinib on slowly expanding lesion (SEL) volume, an MRI marker of CALs, assessed baseline–week 48 in a phase 2, double-blind, randomized trial (NCT02975349) in relapsing MS (RMS). Methods In the 48-week, double-blind trial, adult patients received evobrutinib (25 mg once daily [QD], 75 mgQD, or 75 mg twice daily [BID]), placebo (switched to evobrutinib 25 mgQD after week 24), or open-label dimethyl fumarate (DMF) 240 mg BID. SELs were defined as slowly and consistently radially expanding areas of preexisting T2 lesions of ≥10 contiguous voxels (;30 mm3) over time. SELs were identified byMRI and assessed by the Jacobian determinant of the nonlinear deformation from baseline to week 48. SEL volume analysis, stratified by baseline T2 lesion volume tertiles, was based on week 48/end-of-treatment status (completers/non- completers). Treatment effect was analyzed using the stratified Hodges-Lehmann estimate of shift in distribution and stratifiedWilcoxon rank-sum test. Comparisons ofevobrutinib andDMF vs placebo/evobrutinib 25 mgQD were made. Subgroup analyses used pooled treatment groups (evobrutinib high dose [75 mg QD/BID] vs low dose [placebo/evobrutinib 25 mg QD]). Results The SEL analysis set included 223 patients (mean [SD] age: 42.4 [10.7] years; 69.3% female; 87.4% relapsing/remittingMS). Mean (SD) SEL volume was 2,099 (2,981.0) mm3 with evobrutinib 75 mg BID vs 2,681 (3,624.2) mm3 with placebo/evobrutinib 25 mg QD.Median number of SELs/patient ranged from 7 to 11 across treatments. SEL volume decreased with increasing evobrutinib dose vs placebo/evobrutinib 25 mgQD, and no difference with DMFvs placebo/evobrutinib 25 mgQDwas noted. SEL volume significantlydecreased with evobrutinib 75mg BID vs placebo/evobrutinib 25mg QD (−474.5 mm3 [−1,098.0 to −3.0], p = 0.047) and vs DMF (−711.6 [−1,290.0 to −149.0], p = 0.011). SEL volume was significantly reduced for evobrutinib high vs low dose within baseline Expanded Disability Status Scale ≥3.5 and longer disease duration (≥8.5 years) subgroups. Discussion Evobrutinib reduced SEL volume in a dose-dependent manner in RMS, with a significant reduction with evobrutinib 75 mg BID. This is evident that evobrutinib affects brain lesions associated with chronic inflammation and tissue loss