Bruton's tyrosine kinase inhibitors in the treatment of multiple sclerosis

Abstract

Purpose: In this review, we have highlighted a new class of drugs, Bruton's tyrosine kinase (BTK) inhibitors, and summarized the results of recent clinical trials in the treatment of multiple sclerosis.

Views: Multiple sclerosis (MS) is considered an autoimmune disease of the central nervous system, in which B-lymphocytes and myeloid cells, such as macrophages and microglia, play an important role in the pathogenesis. B-cells induce pathological processes by presenting autoantigens to T-lymphocytes, secreting pro-inflammatory cytokines, and forming ectopic lymphoid follicle-shaped clusters. Accordingly, the activation of microglia contributes to the development of chronic inflammation due to the production of chemokines, cytokines, reactive oxygen, and nitrogen species. BTK is an enzyme important in the activation and function of both B-lymphocytes and microglia. The demand for highly effective and well-tolerated drugs still remains at all stages of MS despite the availability of a number of effective drugs against the disease. Thus, in recent years BTK inhibitors have been the newest approach in the treatment of MS, since they affect the leading links of the pathogenesis of this disease and are able to pass through the blood-brain barrier.

Conclusions: The study of new mechanisms of the development of MS continues in combination with the elaboration of new treatment methods, i.e., Bruton's tyrosine kinase inhibitors. The review provided the analysis of core studies evaluating the safety and efficacy of these drugs. In the future, positive results of these studies will be able to greatly expand the therapy for various forms of MS.

Keywords: Bruton’s tyrosine kinase inhibitors; clinical trials; multiple sclerosis.

Figure I

Schematic diagram of the role of Bruton’s tyrosine kinase in the B-cell signaling. The engagement and aggregation of the B-cell receptor leads to a cascade of changes. This generates a signaling complex consisting of Syk and Lyn. All of this ultimately allows the activation of BTK. Evobrutinib, orelabrutinib, tolebrutinib, and remibrutinib are irreversible BTKi that deactivate BTK by binding to Cys481. Fenebrutinib is a reversible BTKi that deactivates BTK independently of Cys481. Abbreviations: BTK – Bruton’s tyrosine kinase, LYN – Lck/Yes kinase, SYK – spleen tyrosine kinase, Cys481 – cysteine at position 481 of the BTK