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.

Expression of Bruton´s tyrosine kinase in different type of brain lesions of multiple sclerosis patients and during experimental demyelination

“…BTK inhibition is an emerging treatment of multiple sclerosis based on completed and ongoing phase II and III clinical trials (9,(15)(16)(17). Given that BTKi can cross the blood-brain barrier (BBB) and modulate both B cell and microglia/macrophage functions (9), it potentially allows direct manipulation of pathological drivers and mechanisms of MS within the CNS.…”

“…Irreversible covalent binding allows for lower, less frequent drug doses due to increased affinity and prolonged action. However, it could potentially enhance immunogenicity (9,(15)(16)(17).…”

“…So far, five BTKi are under clinical evaluation for both relapsing and progressive MS: evobrutinib, tolebrutinib, remibrutinib and orelabrutinib with irreversible covalent binding, and fenebrutinib with reversible non-covalent binding (9,(15)(16)(17). The pharmacokinetics and pharmacodynamics of these BTKi vary.…”

“…Two identical ongoing phase III studies (GEMINI 1 and 2) are evaluating ARR compared to teriflunomide for approximately 36 months in people with relapsing MS. Phase III studies in inactive secondary progressive MS and primary progressive MS (HERCULES and PERSEUS) examine the effect of tolebrutinib on 6-month confirmed disability progression up to approximately 48 months compared to placebo (9,(15)(16)(17).…”