Abstract Rationale: STAT6 is an essential transcription factor in the IL-4/IL-13 signaling pathways and the central driver of TH2 inflammation in atopic/allergic 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. STAT6 targeting in these diseases is therefore validated by both human genetics and dupilumab's clinical pathway validation. STAT6 functions through protein-protein and protein-DNA interactions. It has been challenging to selectively and potently inhibit STAT6 with traditional small molecule inhibitors. It is, however, well suited for a novel targeted protein degradation approach, where a simple binding event is sufficient to drive degradation. Methods: We have developed a highly potent, selective, orally administered degrader of STAT6, KT-621, and assessed TH2 functional inhibition in disease-relevant human primary cells in vitro. Additionally, KT-621 was assessed in vivo across multiple preclinical species for STAT6 degradation. We also compared the efficacy of KT-621 to dupilumab in vivo in HDM-induced asthma models in the IL4/IL4RA humanized mice. Results: KT-621 potently and selectively degraded STAT6 in various disease-relevant human primary cells including lymphocytes, myeloid cells, lung epithelial cells, bronchial smooth muscle cells, and vascular endothelial cells. As a result of STAT6 degradation, KT-621 fully blocked various IL-4/IL-13 functions in these cells with low picomolar potencies superior to dupilumab, and did not degrade or inhibit any other STAT transcription factors or other proteins. In addition, KT-621 showed potent STAT6 degradation and IL-4/IL-13 functional inhibition in human whole blood. At low oral doses, KT-621 demonstrated deep in vivo STAT6 degradation, suppressed TH2 biomarkers, and was well-tolerated in multiple preclinical studies. In the intranasal HDM-induced asthma model in the hIL4/hIL4RA humanized mice, orally administered KT-621 demonstrated excellent in vivo efficacy comparable to that of an IL-4R saturating dose of dupilumab included in the same prophylactic study. Furthermore, in the HDM-induced asthma model with a treatment regimen, KT-621 administered orally after disease establishment not only fully prevented disease progression but also reversed pre-established disease. Conclusions: STAT6 degradation is a potential novel oral approach for blocking the IL-4/IL-13 signaling pathways involved in TH2 inflammation. These data demonstrate the potential of KT-621 for the treatment of asthma, chronic obstructive pulmonary disease (COPD), and other allergic diseases with best-in-pathway potential given its biologics-like activity profile and oral bioavailability. KT-621 is currently in Phase 1 clinical testing.