Effects of Evobrutinib, a Bruton’s Tyrosine Kinase Inhibitor, on Slowly Expanding Lesions: An Emerging Imaging Marker of Chronic Tissue Loss in Multiple Sclerosis
Douglas Arnold1, Colm Elliott1, Xavier Montalban2, Emily Martin3, Yann Hyvert4, Davorka Tomic5
1NeuroRx Research, 2Department of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, 3EMD Serono, 4The healthcare business of Merck KGaA, 5Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA
Objective:
To evaluate the effect of evobrutinib treatment versus comparator on SEL volume from baseline to Week 48 in a phase II trial.
Background:
Slowly expanding lesions (SELs) are chronically active, demyelinated multiple sclerosis (MS) lesions, likely driven by sustained microglia/macrophage activity, resulting in irreversible neural tissue damage and axonal loss. Evobrutinib, a highly selective Bruton’s tyrosine kinase inhibitor (BTKi), targets B cells, macrophages, and microglia. In a phase II trial (NCT02975349) in patients with relapsing MS, evobrutinib 75mg twice-daily (BID) reduced T1 gadolinium-enhancing lesions (Week 24) vs placebo.
Design/Methods:

SELs were identified, via MRI, as radially expanding areas of pre-existing T2 lesions of ≥10 contiguous voxels (size ~30mm3). Analysis of SEL volume, stratified by baseline T2 lesion volume tertiles, was based on Week 48/end-of-treatment values (completers + discontinuers); treatment effect was analyzed via stratified Hodges-Lehman estimate of distribution shift and stratified Wilcoxon rank sum test. Evobrutinib dose groups (25mg once-daily [QD], n=50; 75mg QD, n=51; 75mg BID, n=53) were compared with placebo/evobrutinib 25mg QD (n=53). Pooled groups (evobrutinib high doses [HD; 75mg QD and BID] vs low dose [LD; placebo and evobrutinib 25mg QD]) were used for subgroup analyses.

Results:
Relative to the comparator, SEL volume decreased with increasing evobrutinib dose (25mg QD, -136.5mm3 [p=0.505]; 75mg QD, -246.0mm3 [p=0.192]; 75mg BID, -474.5mm3 [p=0.047]). SEL volume was significantly reduced for evobrutinib HD vs LD within the following subgroups: baseline EDSS ≥3.5 (-652.0mm3 [p=0.020]), relapsing-remitting MS (-317.0 mm3 [p=0.025]) and longer disease duration (≥8.5 years; -729.3mm3 [p=0.040]). Analysis of SEL volume as a percentage of baseline T2 lesion volume provided similar results.
Conclusions:
Evobrutinib reduces SEL volume in a dose-dependent manner in relapsing MS and is especially apparent in more advanced disease. This is the first evidence that a BTKi impacts brain lesions associated with chronic inflammation and tissue loss, probably via microglia.