Preclinical Data In Cynomolgus (cyn) Monkeys Of ASTX727, a Novel Oral Hypomethylating Agent (HMA) Composed Of Low-Dose Oral Decitabine Combined With a Novel Cytidine Deaminase Inhibitor (CDAi) E7727

Abstract

Abstract Background Hypomethylating agents (HMAs) such as decitabine and azacitidine have been successfully used in the clinic to treat hematological malignancies by parenteral administration (IV or SC). Due to low oral bioavailability of these agents, relatively high doses are required to achieve therapeutic systemic exposures by the oral route. Higher oral doses can be associated with significant GI toxicities due to intestinal enterocytes being exposed to high concentrations of these agents in the lumen. One of the main factors contributing to low oral bioavailability of HMAs is the high first-pass effect due to cytidine deaminase in GI and liver. Methods In this study, E7727, a novel CDA inhibitor (CDAi) was combined with decitabine (3 mg/kg) for oral administration in cynomolgus (cyn) monkeys at E7727 doses of 0.1-10 mg/kg. Results Systemic AUC exposures for decitabine increased from 21.7 ng*hr/mL (without E7727) to as high as 1,494 ng*hr/mL at 10mg/kg E7727. At a dose combination of 1 mg/kg CDAi and 3 mg/kg decitabine (corresponding to a human equivalent dose of 36 mg/m2), AUC exposures were 301±94 ng*hr/mL, which are slightly higher than the published clinical therapeutic range after decitabine IV infusion of 20 mg/m2 (115-220 ng*hr/mL), suggesting that a combination approach for oral CDAi+decitabine is feasible to achieve required clinical exposures at a range of relatively low-dose(s). In addition, the concentration-time profile of decitabine when combined with CDAi resembled that achieved with IV decitabine over 1 hour infusion. The effect of drug-drug interaction between CDAi and decitabine was modeled based on a relationship between CDAi Ki (∼ 0.14 µM based on IC50) and Cmaxlevels and appeared to predict the observed fold-increases in decitabine AUC with high concordance. In addition, low dose oral decitabine+CDAi achieved decitabine exposures that produce potent hypomethylation as observed by LINE-1 assay. Conclusion Pronounced increase in oral decitabine exposures was achieved when combined with the novel CDA inhibitor E7727. Cyn monkeys appear to be a relevant model for human PK based on similar background of circulating serum cytidine levels reflective of similar CDA status between humans and cyn monkeys. These data support the initiation of clinical First in Human (FIH) study of ASTX727, a novel oral HMA combining oral decitabine with the CDAi E7727. Disclosures: Oganesian: Astex Pharmaceuticals: Employment. Redkar:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals Inc.: Employment. Joshi-Hangal:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals Inc.: Employment.