Abstract Details

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

Topic Multiple Sclerosis

Presentation(s) S14 - MS Therapeutics (5:06 PM-5:18 PM)

Poster/Presentation
Number 009

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.

Objective To evaluate the effect of evobrutinib treatment versus comparator on SEL volume from baseline to Week 48 in a phase II trial.

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.

Authors/Disclosures
Douglas L. Arnold, MD, FAAN (Montreal Neurological Institute, McGill Univ) PRESENTER	Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BMS. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Frequency Therapeutics. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Dr. Arnold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Arnold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shionogi. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Xfacto communications. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biohaven. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Find therapeutics. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GSK. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Idorsia. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kiniksa. Dr. Arnold has stock in NeuroRx.
Colm Elliott (NeuroRx Research)	Colm Elliott has received personal compensation for serving as an employee of NeuroRx Research.
Xavier Montalban, MD, PhD, FAAN (Vall Hebron University Hospital-Multiple Sclerosis Centre of Catalonia)	The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck/ EMD Serono. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Hoffmann-La Roche. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion/ Janssen. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for BMS/ Celgene. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi/ Genzyme. Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion/ Janssen. Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS/ Celgene. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck/ EMD Serono. Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffmann-La Roche. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi-Genzyme. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic Therapeutics. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viatris/ Mylan. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. The institution of Dr. Montalban has received research support from Biogen. The institution of Dr. Montalban has received research support from Hoffmann-La Roche. The institution of Dr. Montalban has received research support from Sanofi/ Genzyme. The institution of Dr. Montalban has received research support from Merck/ EMD Serono. The institution of Dr. Montalban has received research support from Novartis. The institution of Dr. Montalban has received research support from Teva Pharmaceuticals. The institution of Dr. Montalban has received research support from Actelion/ Janssen. The institution of Dr. Montalban has received research support from BMS/ Celgene.
Emily C. Martin	Emily Martin has received personal compensation for serving as an employee of EMD Serono.
Yann Hyvert, PhD (Merck Healthcare KGaA)	Dr. Hyvert has received personal compensation for serving as an employee of The healthcare business of Merck KGaA, Darmstadt, Germany. An immediate family member of Dr. Hyvert has received personal compensation for serving as an employee of The healthcare business of Merck KGaA, Darmstadt, Germany.
Davorka Tomic	Davorka Tomic has stock in Meck KGaA.