Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: Pioneering the Path Towards Treatment of Progression?

In multiple sclerosis (MS) persisting disability can derive from acute relapses or, alternatively, from slow and steady deterioration, termed chronic progression. Emerging data suggest that the latter process occurs largely independent from relapse activity or development of new central nervous system (CNS) inflammatory lesions. Pathophysiologically, acute relapses develop as a consequence of de novo CNS infiltration of immune cells, while MS progression appears to be driven by a CNS-trapped inflammatory circuit between CNS-established hematopoietic cells as well as CNS-resident cells, such as microglia, astrocytes, and oligodendrocytes. Within the last decades, powerful therapies have been developed to control relapse activity in MS. All of these agents were primarily designed to systemically target the peripheral immune system and/or to prevent CNS infiltration of immune cells. Based on the above described dichotomy of MS pathophysiology, it is understandable that these agents only exert minor effects on progression and that novel targets within the CNS have to be utilized to control MS progression independent of relapse activity. In this regard, one promising strategy may be the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of B cells as well as myeloid cells, such as macrophages and microglia. In this review, we discuss where and to what extent BTK is involved in the immunological and molecular cascades driving MS progression. We furthermore summarize all mechanistic, preclinical, and clinical data on the various BTK inhibitors (evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, orelabrutinib, BIIB091) that are currently in development for treatment of MS, with a particular focus on the potential ability of either drug to control MS progression.

Automated summary

Progression of multiple sclerosis (MS) can occur through acute relapses or chronic deterioration. Recent data suggests that chronic progression is largely independent of relapse activity or new CNS inflammatory lesions. Acute relapses result from infiltration of immune cells into the central nervous system (CNS), while MS progression is driven by an inflammatory circuit between CNS-established hematopoietic cells and CNS-resident cells. Current therapies for MS primarily target peripheral immune system and CNS infiltration, resulting in limited effects on progression. Inhibition of the enzyme Bruton's tyrosine kinase (BTK) may be a promising strategy to control MS progression by targeting B cells and myeloid cells. This review explores the involvement of BTK in the immunological and molecular cascades driving MS progression and summarizes the preclinical and clinical data on various BTK inhibitors currently in development for MS treatment.