17 AZD4205, A SELECTIVE, GI TRACT-ENRICHED SELECTIVE JAK1 INHIBITOR FOR CROHN’S DISEASE: PRECLINICAL EVIDENCE AND PHASE I DATA

Abstract

Abstract Background AZD4205 is an oral, ATP-competitive, JAK1 selective inhibitor. Nonclinical data showed its higher drug concentration within the gastrointestinal (GI) tract relative to plasma in the rodents, suggesting its potential as an effective and safe treatment option for patients with Crohn’s disease (CD). AZD4205 also has been evaluated in a phase I study in healthy volunteers (HVs). Here we report AZD4205 preclinical data in cells and animal models, and phase I data from HVs. Method Enzymatic activity of AZD4205 was assessed in in vitro biochemical assay with human isolated JAK kinase domains. The cellular activity of AZD4205 was evaluated in human peripheral blood mononuclear cells (PBMCs) by assessing cytokine induced phosphorylated-STATs (pSTATs). The in vivo efficacy of AZD4205 was assessed in a murine CD model induced by subcutaneous injection of 10 mg/kg indomethacin, and AZD4205 was orally administered at different doses for 5 consecutive days. The ileum and bone marrow tissues were collected post AZD4205 treatment to measure pSTAT3 expression using immunohistochemistry. The drug concentration of AZD4205 in ileum and plasma were measured by HPLC. Phase I study of HVs (Clinicaltrial.gov Identifier: NCT03728023) comprised of single ascending dose (SAD) of 5 to 150 mg, food effect (FE) with 50 mg single dosing with or without food, and multiple ascending dose (MAD) of 25 to 100 mg once daily for 14 days. Safety monitoring was conducted, and blood samples were collected to assess PK of AZD4205. Result In enzymatic assay, AZD4205 exhibits greater than 200-400-fold selectivity over other JAK family kinases. AZD4205 inhibits pSTAT1, pSTAT3, and pSTAT5 in human PBMCs with IC50 of 50, 308, and 90 nM, respectively. The drug concentration of AZD4205 in murine ileum was around 100-fold higher than that in plasma. In murine CD model, the pSTAT3 was inhibited by 93% in ileum but only 43% in bone marrow at 4 hr post AZD4205 treatment. AZD4205 exhibited a dose-dependent effect on improving body weight loss and decreasing colon density in this model. In the NCT03728023 study, 66HVs were dosed with AZD4205 or matched placebo, SAD (n=20 in AZD4205, n=10 in placebo), FE (n=12 in AZD4205) and MAD (n=18 in AZD4205, n=6 in placebo). AZD4205 was well-tolerated, and no ≥ G3 drug related AE was observed. A dose-proportional increase of AZD4205 plasma concentrations was detected in HVs. The T1/2 was close to 48 hr and hence accumulation of about 3-fold in Cmax and AUC was observed after multiple once daily dosing. No relevant food effect was observed to significantly impact AZD4205 PK. Conclusion Based on preclinical murine data, AZD4205 has unique GI-tract enriched PK properties, as a promising agent for CD. Clinical data in HVs demonstrated its favorable safety and PK profiles. A phase II study in moderate to severe CD is planned.