JAK Inhibitors for Treatment of Psoriasis: Focus on Selective TYK2 Inhibitors

Abstract

Despite advances in the treatment of psoriasis, there is an unmet need for effective and safe oral treatments. The Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway plays a significant role in intracellular signalling of cytokines of numerous cellular processes, important in both normal and pathological states of immune-mediated inflammatory diseases. Particularly in psoriasis, where the interleukin (IL)-23/IL-17 axis is currently considered the crucial pathogenic pathway, blocking the JAK-STAT pathway with small molecules would be expected to be clinically effective. However, relative non-specificity and low therapeutic index of the available JAK inhibitors have delayed their integration into the therapeutic armamentarium of psoriasis. Current research appears to be focused on Tyrosine kinase 2 (TYK2), the first described member of the JAK family. Data from the Phase II trial of BMS-986165-a selective TYK2 inhibitor-in psoriasis have been published and clinical results are encouraging, with a large Phase III programme ongoing. Further, the selective TYK2 inhibitor PF-06826647 is being tested in moderate-to-severe psoriasis in a Phase II clinical trial. Brepocitinib, a potent TYK2/JAK1 inhibitor, is also being evaluated, as both oral and topical treatment. Results of studies with TYK2 inhibitors will be important in assessing the clinical efficacy and safety of these drugs and their place in the therapeutic armamentarium of psoriasis. This article reviews current data on the impact of JAK inhibitors in the treatment of adult patients with moderate-to-severe psoriasis.