Abstract 3212: OQL06x, a gut-restricted janus kinase inhibitor to control epidermal growth factor receptor inhibitor-induced diarrhea

Background: Epidermal growth factor receptor inhibitors (EGFRIs) are widely used; however, therapy-related adverse effects (AEs) are common with diarrhea being the most frequent (e.g., afatinib up to 90% for all grades). Currently, there is no effective treatment or prevention, and severe diarrhea (~30%) results in EGFRi dose reduction or discontinuation. EGFRIs disrupt the gut epithelium and induce an inflammatory response characterized by cytokine release and neutrophil and T-cell infiltration. Janus kinase inhibitors (JAKIs) are immunosuppressive drugs and a candidate treatment for EGFRi-associated inflammation/diarrhea. However, oral JAKIs are associated with serious AEs (e.g., CV events, VTE, cancer, infections) and may lead to EGFR inhibitor resistance. We developed a gut-restricted JAKI with minimal systemic exposure that may reduce AEs and decrease the incidence of EGFRi-induced diarrhea. Methods: Multiple compounds were tested in vitro for their physiochemical properties (e.g., solubility, stability, and enzyme activity) and potential for inhibiting the activation of the JAK pathway and subsequent signal transducers transcription 3 (STAT3) after cytokine IL-6 activation in human peripheral blood mononuclear cells (hPBMC). Selected compounds were tested in vivo with afatinib (40mg/kg) plus OQL06x, tofacitinib, or placebo started on Day 1 and continued for 10 days in a rat EGFRi-induced diarrhea model. Orally administered OQL06x pharmacokinetics (PK) were tested in mice (5-25 mg/kg) and rats (2-5 mg/kg). Oral tofacitinib was used as a control. Results: OQL06x demonstrated favorable pharmaceutical properties and superior JAK enzyme inhibition (e.g., IC50: JAK1: OQL06x 0.06nM vs. tofacitinib 1.4nM). In vitro, hPBMC treated with OQL06x vs. tofacitinib showed greater inhibition of the IL-6, JAK-induced STAT3 activation (IC50: OQL06x 30nM vs. tofacitinib 222nM). OQL06x and tofacitinib showed a significant decrease in diarrhea compared with placebo control (both reduced diarrhea grade by 1.4 units vs. control, p < 0.01, two-way ANOVA). OQL06x was gut-specific vs. tofacitinib, with a significantly higher gut:blood ratio of up to 2000:1 vs. tofacitinib up to 20:1, p < 0.001, two-way ANOVA). Importantly, low bioavailability of OQL06x was found in both mouse (1.50%) and rat (0.23%) models demonstrating OQL06x’s limited systemic exposure. Moreover, no CYP inhibition was found (IC50 > 50µM), which favors a low drug-drug interaction potential. Conclusion: Our re