EPS-3903 Is a Potent and Selective Oral STAT6 Inhibitor that Blocks Th2 Inflammation in an Ovalbumin Asthma Mouse Model 2253997

Abstract

Abstract Introduction 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 the treatment of asthma. Our aim is to develop an oral small molecule that selectively inhibits activation of STAT6 for the treatment of allergic diseases. Here, we evaluate EPS-3903 in the ovalbumin (OVA) asthma mouse model, characterized by eosinophilic infiltration, IgE production, and Th2 inflammation, mimicking key features of the human disease. Methods In vitro EPS-3903 potency was assessed in cellular assays measuring phosphorylated STAT6 and TARC secretion. Ex vivo target engagement was evaluated in IL-4-stimated whole blood from mice orally dosed with EPS-3903. In vivo efficacy was assessed in the OVA asthma model in mice administered with EPS-3903 or an anti-mouse IL-4/IL-13 (control) in a therapeutic setting. Inhibition of Th2 markers of inflammation was evaluated in lung, bronchio-alveolar lavage fluid (BALF), and serum. Results EPS-3903 inhibited IL-4-stimulated pSTAT6 in mouse splenocytes, with an IC50 of 9 nM. In whole blood collected from mice treated with EPS-3903, pSTAT6 was suppressed >90% for 24h. In the OVA asthma model, EPS-3903 robustly suppressed pSTAT6 in lung tissue without degrading total STAT6, leading to decreases in OVA-induced Th2 inflammation, including lung TARC and eotaxin, serum OVA-IgE, and BALF eosinophils. Histological improvements comparable to anti-mouse IL-4/IL-13 were observed with reductions in both inflammation and goblet cell hyperplasia. Conclusion EPS-3903 is an orally bioavailable and potent allosteric inhibitor of STAT6 with robust efficacy in a mouse model of allergic asthma. EPS-3903 may offer therapeutic potential for the treatment of allergic diseases such as asthma and atopic dermatitis. Funding Source n/a Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)