Beyond relapses: How BTK inhibitors are shaping the future of progressive MS treatment

Abstract

Multiple sclerosis is a biologically and clinically heterogenous inflammatory demyelinating disease, driven by relapsing and progressive mechanisms, all individuals experiencing varying degrees of both. Existing highly effective therapies target peripheral inflammation and reduce relapse rates but have limited efficacy in progressive MS due to poor blood-brain barrier penetration and inability to address neurodegeneration. Bruton's tyrosine kinase (BTK) inhibitors represent an emerging therapeutic class offering a novel mechanism targeting BTK, which is expressed by both B cells and myeloid cells, including microglia within the CNS. Pre-clinical, Phase II, and Phase III clinical trials have demonstrated promising results in modulating progressive disease in both relapsing and non-relapsing MS patients. In contrast, the evidence regarding impact on relapse biology remains mixed and somewhat inconclusive. This review highlights gaps in current therapeutic strategies, examines the latest evidence for the efficacy and safety of BTK inhibitors in MS, and explores the future landscape of MS treatment.

Keywords: Bruton’s tyrosine kinase (BTK) inhibitors; Clinical trials; Compartmentalized inflammation; Neuroinflammation; Progressive multiple sclerosis (PMS).