KT-621, an Oral, Once Daily, Targeted STAT6 Degrader: First-in-Human Phase 1a Safety, Pharmacokinetics, Pharmacodynamics and Th2 Biomarker Effects

Abstract

STAT6 is an essential transcription factor in the IL-4/IL-13 signaling pathways and the central driver of Th2 inflammation in allergic/atopic diseases. Multiple gain of function mutations of STAT6 have been identified to cause severe atopic/allergic diseases in humans. Dupilumab, an injectable monoclonal antibody that blocks IL-4/IL-13 signaling, is an approved therapy for multiple atopic/allergic diseases therefore targeting STAT6 in these diseases is supported by both human genetics and dupilumab’s clinical activity. STAT6 functions through protein-protein and protein-DNA interactions. It has been challenging to selectively and potently inhibit STAT6 with traditional small molecule inhibitors. However, STAT6 is well suited for a novel targeted protein degradation approach, where a simple binding event is sufficient to drive degradation of the protein and fully block its functions.