ProfG has argued that Slowly Expanding Lesions are the indicators for progressive MS and that we need to target these to inhibit the “realMS”. At the centre of these lesions we have microglia and these could be inhibited by Brutons tyrsoine kinases which inhibit B cell and macrophage function
Douglas Arnold et al. Effects of Evobrutinib, a Bruton’s Tyrosine Kinase Inhibitor, on Slowly Expanding Lesions: An Emerging Imaging Marker of Chronic Tissue Loss in Multiple Sclerosis
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.
So targeting microglial may be a good thing. Evobrutinib is not the only drug being developed against this target
Ross Gruber et al. Evaluating the Effect of BTK Inhibitor Tolebrutinib in Human Tri-culture
Objective:Characterize pharmacological properties of the CNS-penetrant Bruton’s tyrosine kinase (BTK) inhibitor tolebrutinib in human neural cells by using a human tri-culture system.
Conclusions: We extend our previous findings on the role of BTK in microglia to show that BTK-dependent inflammatory signalling in human microglia and tri-cultures can be modulated using tolebrutinib in vitro.