Abstract Rationale Dysregulated macrophage polarization, particularly toward the M2 phenotype (alternative macrophage activation), is a hallmark of severe asthma that contributes to type 2 inflammation and pathogenic airway remodeling. The signal transducer and activator of transcription 6 (STAT6) is a master regulator of this macrophage activation pathway and its downstream signaling is critical for initiating allergic inflammation. Consequently, inhibiting STAT6 in macrophages and airway epithelial cells presents a compelling strategy for asthma treatment. Here, we characterize EPS-3903, a novel, potent, and orally bioavailable small-molecule STAT6 inhibitor which demonstrates a favorable pharmacokinetic profile with low drug-drug interaction (DDI) potential. Methods Intracellular uptake of EPS-3903 was assessed in lung epithelial cells and macrophages across multiple species, including mice, rats and humans. To determine in vivo drug distribution, EPS-3903 was administered orally at 25 mg/kg in mice and rats. Drug concentrations in plasma, brain, lung, and alveolar macrophages (AMs) were quantified by LC/MS/MS. DDI potential was evaluated by in vitro assays, including transporter inhibition, cytochrome P450 (CYP) enzyme inhibition, and pregnane X receptor (PXR) activation. Results The intracellular-to-extracellular concentration ratios of EPS-3903 were 2.8 in mouse, 3.9 in rat, and 5.4 in human lung epithelial cells. Moreover, EPS-3903 exhibited highly favorable macrophage uptake in vitro, with intracellular-to-extracellular uptake ratios of 41.8 in mouse, 49.6 in rat, and 52.6 in human macrophages. Consistent with in vitro observations, EPS-3903 showed preferential distribution to lung tissue (lung-to-plasma ratio: 1.9) with no brain penetration in rats. EPS-3903 achieved substantially higher accumulation in AMs, with an observed AM-to-plasma exposure ratio of 35.1 in mice. EPS-3903 did not activate PXR or inhibit any CYP isoforms (including CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5) with IC50 40 µM. No inhibition of major renal and hepatic transporters was observed, including P-glycoprotein, bile salt export pump, and multidrug resistance-associated protein (IC50 20 µM), indicating a low potential for drug-induced liver injury and DDIs. Conclusion EPS-3903 exhibits preferential distribution to the lung and alveolar macrophages, the target tissue/cells in asthmatic patients. Furthermore, the low potential for drug-drug interactions minimizes the risk of adverse effects, facilitates use of EPS-3903 in combination therapy and expands the eligible patient population. These data support further development of EPS-3903 as an oral therapeutic for the treatment of asthma. This abstract is funded by: Enanta Pharmaceuticals, Inc.
Jiang et al. (Fri,) studied this question.