Effects of Evobrutinib, a Bruton’s Tyrosine Kinase Inhibitor, on Slowly Expanding Lesions: An Emerging Imaging Marker of Chronic Tissue Loss in Multiple Sclerosis

Background: Slowly expanding lesions (SELs) are chronically active, demyelinated 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—targets B cells, macrophages, and microglia. In a Phase II trial (NCT02975349) in patients with relapsing MS, evobrutinib 75 mg twice daily (BID) treatment reduced T1 gadolinium-enhancing lesions (Week 24) vs placebo and annualized relapse rate (Week 48) vs placebo/evobrutinib 25 mg once daily (QD; placebo 0–24 weeks switched to evobrutinib 25 mg QD 24–48 weeks).

Objectives: To evaluate the effect of evobrutinib treatment vs comparator on SEL volume from baseline to Week 48 in a Phase II trial.

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

Results: Relative to the comparator, SEL volume decreased with increasing evobrutinib dose: -136.5 mm³ [95% CI -618.0, 309.0] (p=0.505), -246.0 mm³ [95% CI -712.0, 97.0] (p=0.192), -474.5 mm³ [95% CI -1098.0, -3.0] (p=0.047), for evobrutinib 25 mg QD, 75 mg QD, and 75 mg BID, respectively. SEL volume was significantly reduced for evobrutinib HD vs LD within the following subgroups: relapsing-remitting MS (n=89; -317.0 mm³ [95% CI -731.5, -29.0], p=0.025), baseline EDSS ≥3.5 (n=55; -652.0 mm³ [95% CI -1507.0, -100.0], p=0.020), and longer disease duration (≥8.5 years; n=44; -729.3 mm³ [95% CI -1706.5, -20.0], p=0.040).

Conclusions: Evobrutinib reduces SEL volume in a dose-dependent manner in relapsing MS. The reduction is especially apparent in patients with more advanced disease. These data provide evidence that evobrutinib impacts brain lesions associated with chronic inflammation and tissue loss, potentially via microglia.

Role of the Study Sponsor: This study was sponsored by EMD Serono (CrossRef Funder ID: 10.13039/100004755). The study sponsor was involved in the study design, collection, analysis, and interpretation of data, and was involved in the decision to submit the abstract for publication.