C34-04 EPS-3903 is a Potent and Selective Oral STAT6 Inhibitor that Blocks Th2 Inflammation in a House Dust Mite-Induced Asthma Mouse Model

Abstract Rationale STAT6 is a key transcription factor central to type 2 inflammation and activated by interleukins IL-4 and IL-13. Inhibition of the IL-4/IL-13 pathway is clinically validated for treatment of asthma. Our aim is to develop an oral small molecule that selectively inhibits activation of STAT6 for treatment of allergic diseases. Here, we evaluated EPS-3903, a potent orally bioavailable allosteric STAT6 inhibitor, in the house dust mite (HDM) asthma mouse model, characterized by eosinophilic infiltration, IgE production, and Th2 inflammation, mimicking key features of the human disease. Methods EPS-3903 is a highly potent and selective oral STAT6 inhibitor. In vitro efficacy of EPS-3903 was assessed in lung A549 cells for pSTAT6 nuclear translocation. In addition, STAT6-regulated periostin secretion was evaluated in primary human bronchial cells. In vivo, EP-3903 was orally administered once daily to transgenic mice expressing human IL-4/IL-4Rα in a 4-week HDM-induced asthma model. Dupilumab, an approved anti-IL-4/IL-13 monoclonal antibody, was administered biweekly via subcutaneous injection as a comparator control. Th2 markers of inflammation were evaluated in lung, bronchio-alveolar lavage fluid (BALF), and serum. Immune cell infiltration into BALF was quantified by flow cytometry in addition to histological evaluation of lung tissue by hematoxylin/eosin and periodic acid Schiff staining. Results EPS-3903 blocked IL-4-induced pSTAT6 translocation in lung A549 cells and periostin production in primary human bronchial cells with nanomolar potency. In the HDM asthma model, EPS-3903 robustly suppressed pSTAT6 in lung tissue without degrading total STAT6, leading to decreased HDM-induced Th2 inflammation, including lung TARC and eotaxin, total serum IgE, and BALF eosinophils. Histological improvements were observed with reduced inflammation and attenuated goblet cell hyperplasia. Notably, EPS-3903 demonstrated efficacy comparable to the injectable IL-4/Il-13 antagonist dupilumab across all end points evaluated. Conclusions EPS-3903 is a potent, orally bioavailable allosteric STAT6 inhibitor that demonstrates robust efficacy comparable to dupilumab in a mouse model of allergic asthma, highlighting its potential as an oral therapeutic for type 2 inflammatory diseases such as asthma and atopic dermatitis. This abstract is funded by: None