Bruton tyrosine kinase inhibitors for multiple sclerosis

Abstract

Current therapies for multiple sclerosis (MS) effectively reduce relapses and relapse-associated worsening assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, they are less effective at slowing disability accumulation in MS, likely reflecting in part their lack of relevant effects on CNS-compartmentalized inflammation. Bruton’s tyrosine kinase (BTK) is an intracellular signalling molecule regulating maturation, survival, migration, and activation of B cells and microglia. CNS-compartmentalized B cells and microglia are considered central players in immunopathogenesis of progressive disease mechanisms; accordingly, CNS-penetrant inhibitors of BTK (BTKis) hold promise to curtail disease progression by targeting immune cells on both sides of the blood-brain barrier. Originally developed as a B-cell malignancy treatment, currently five BTKis are undergoing clinical trials in MS. These BTKis differ in selectivity, strength of BTK inhibition, binding mechanisms, and ability to modulate immune cells within the CNS. Here, we review BTK function in signalling pathways of different immune cells relevant to MS, provide an overview of preclinical data, and discuss clinical trial results.