Investigational Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis

ABSTRACT

Introduction: The Tec family of non-receptor tyrosine kinases comprises five members. The cellular expression and function of these kinases has implicated them as potential drug targets for the treatment of both malignant and autoimmune diseases. Most attention has focused on inhibitors of BTK kinase with ibrutinib already approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukaemia. Multiple BTK inhibitors are being developed for both oncology and autoimmune disease indications.

Areas covered: BTK inhibitors being evaluated in rheumatoid arthritis are considered. Both inhibitors which have progressed to early clinical development, and those demonstrating activity in rodent models of arthritis are reviewed. These include both reversible and irreversible inhibitors of the kinase, most of which target the cysteine-481 residue of BTK. The selectivity of these inhibitors for Tec family kinases is considered.

Expert opinion: Developing inhibitors of any kinase to treat of rheumatoid arthritis has proved problematic with regard to both efficacy and selectivity. It is anticipated that the more selective BTK inhibitors may prove more useful in treating arthritis, with the use of reversible inhibitors possibly offering a better strategy. Chronic dosing may exacerbate the emergence of drug resistance, with resistant mutations already observed in ibrutinib-treated patients.

KEYWORDS:

• Autoimmune disease
• B cell
• Btk kinase
• ibrutinib
• rheumatoid arthritis
• spebrutinib

Article highlights

• Btk inhibitors are viewed as having therapeutic potential for the treatment of rheumatoid arthritis and other autoimmune diseases in addition to the lymphoma indication for which ibrutinib has been approved.

• At least six Btk inhibitors are currently in early (phase I or IIa) clinical development for the treatment of rheumatoid arthritis.

• Several other companies have also indicated their intention to develop Btk inhibitors to treat rheumatoid arthritis.

• Rodent studies have shown that both reversible and irreversible Btk inhibitors are effective in collagen-induced arthritis models.

• No Btk inhibitor has yet demonstrated clinical validation of this approach to treating rheumatoid arthritis.

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Declaration of interests

P Norman has his own consultancy company. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.