It’s a good week to be working on drugs targeting STAT6. Kymera Therapeutics Inc.’s, KT-621, the first oral STAT6 degrader candidate to enter the clinic, surpassed expectations with impressive safety, pharmacokinetic and biomarker data from a phase I trial, while potential fast-followers from Nurix Therapeutics Inc. and Recludix Pharma Inc. advanced via respective partnerships with Sanofi SA.

STAT6 plays a central role in regulating Th2-driven immune responses. Recent studies have identified gain-of-function mutations in the STAT6 gene that are associated with early-onset, severe allergic diseases. As a result, STAT6 has emerged as a promising therapeutic target in conditions such as asthma, eosinophilic inflammation, food allergies and atopic dermatitis, particularly in cases that are refractory to standard therapies.

Kymera Therapeutics Inc. has received IND clearance from the FDA for KT-621, an investigational first-in-class, once-daily, oral STAT6 degrader.

In allergic diseases, STAT6 is a critical transcription factor in the IL-4 and IL-13 signaling pathways and the key driver of Th2 inflammation. Because STAT6 functions through protein-protein and protein-DNA interactions, selectively and potently inhibiting STAT6 with traditional small-molecule inhibitors has been a challenge. However, it is well suited for a targeted protein degradation approach, whereby a binding event is adequate to direct degradation.