Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects
Understanding of the B-cell receptor signalling pathway led to the identification of a suitable drug target to addresses autoimmunity and inflammation in areas such as MS, RA, pemphigus and SLE. There are currently 22 BTKis in various stages of clinical development. However, AEs such as cardiovascular and bleeding side effects, as well as rash, diarrhoea and infections have been associated with the inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain.
Based on clinical studies and evidence for ibrutinib, acalabrutinib and zanubrutinib, indicated for use in leukaemia and lymphoma, this review aimed to correlate inhibition profiles of BTKis with reported AEs.
Although possible underlying mechanisms for AEs associated with BTKi have been proposed, the fact that the mains studies are in patients with B-cell malignancies means that it is not possible to separate AEs caused only by the inhibition of kinases from indirect effects caused by the specific contribution from the tumour and its environment.