D2.151 - HZ-Y030, an Oral STAT6 Degrader, Attenuates Type 2 Inflammation in Preclinical Asthma Models

Interleukin (IL)-4 and IL-13 are central drivers of type 2 (T2) inflammation underlying allergic diseases. Targeting the IL-4/IL-13 signaling axis is a clinically validated therapeutic strategy for T2-mediated disorders. Signal transducer and activator of transcription 6 (STAT6) is the key downstream transcription factor uniquely required for IL-4/IL-13 signaling. Importantly, gain-of-function mutations in STAT6 have been identified in patients with severe T2 diseases, supporting STAT6 as a compelling therapeutic target. HZ-Y030 is a novel STAT6 degrader identified using Healzen’s Druggability-Targeted Protein Degrader (DaTProD) platform, exhibiting picomolar STAT6 degradation potency, high oral bioavailability, and biologics-like in vivo efficacy.

In vitro STAT6 degradation was evaluated in human primary immune cells and epithelial cells. Inhibition of IL-4/IL-13 signaling was assessed in IL-4- or IL-13-stimulated primary human B cells and peripheral blood mononuclear cells (PBMCs). In vivo STAT6 degradation was assessed in mice and non-human primates following oral administration. Therapeutic efficacy was evaluated in a mouse intranasal house dust mite (HDM)-induced asthma model.

HZ-Y030 induced potent STAT6 degradation at picomolar concentrations in human immune and epithelial cells. HZ-Y030 markedly suppressed IL-4- or IL-13-induced activation of PBMCs and B cells, demonstrating substantially greater potency than dupilumab in vitro. In the intranasal HDM-induced asthma model conducted in IL-4/IL-4R humanized mice, once-daily oral administration of HZ-Y030 significantly reduced serum total IgE levels, T2-associated inflammatory cell counts in bronchoalveolar lavage fluid (BALF), and BALF cytokine levels. The observed efficacy was comparable to that achieved with a saturating dose of anti–IL-4Rα antibody Dupilumab. In addition, HZ-Y030 exhibits favorable DMPK properties in both rodents and non-rodent animals and shows large safety window.

HZ-Y030 is a novel, orally bioavailable STAT6 degrader that robustly inhibits IL-4/IL-13 signaling. Its therapeutic potential in T2 inflammatory disease is supported by efficacy in a preclinical asthma model. These findings support continued development of HZ-Y030, which is currently in IND-enabling studies.