Brepocitinib (PF-06700841): A Comprehensive Monograph on a Novel Dual TYK2/JAK1 Inhibitor

Executive Summary

Brepocitinib (PF-06700841) is an orally available, investigational small molecule that represents a targeted therapeutic approach to immunomodulation through the dual inhibition of Tyrosine Kinase 2 (TYK2) and Janus Kinase 1 (JAK1). This mechanism is designed to provide broad-spectrum suppression of key pro-inflammatory cytokine signaling pathways implicated in a wide range of autoimmune and inflammatory diseases. Developed initially by Pfizer and now being advanced by Priovant Therapeutics, Brepocitinib has undergone one of the most extensive Phase 2 clinical programs for a drug of its class, demonstrating consistent and potent clinical activity across numerous distinct disease states.

Pharmacologically, Brepocitinib is a potent inhibitor of its target kinases, with half-maximal inhibitory concentrations (IC50​) of 23 nM for TYK2 and 17 nM for JAK1. However, its selectivity against Janus Kinase 2 (JAK2) is modest (IC50​ = 77 nM), suggesting that at clinically relevant doses, significant JAK2 inhibition is likely. This profile results in a safety and tolerability signature that is largely consistent with the broader JAK inhibitor class, including risks of serious infections and laboratory parameter changes, without offering a clear differentiation from first-generation agents. The drug's pharmacokinetic profile is favorable for oral administration, characterized by rapid and nearly complete absorption, high bioavailability (~75%), and clearance primarily through hepatic metabolism.