966 IDX184, A LIVER-TARGETED NUCLEOTIDE HCV POLYMERASE INHIBITOR: RESULTS OF A FIRST-IN-MAN SAFETY AND PHARMACOKINETIC STUDY

Abstract

Background and Aims: IDX184 is a liver-targeted nucleotide prodrug designed to enhance formation of its active triphosphate in the liver, while minimizing systemic exposure to the parent drug and its nucleoside metabolite (NM). Multilog viral load reductions were observed in HCVinfected chimpanzees receiving 10mg/kg IDX184 for 3 days. This firstin-man study investigated single ascending dose safety and the pharmacokinetics of IDX184. Methods: Single ascending oral doses of 5, 10, 25, 50, 75 and 100mg IDX184 were administered sequentially to cohorts of 8 healthy subjects randomized 6:2, active: placebo. Plasma levels of IDX184 and NM were quantitated using a validated LC-MS/MS methodology. Results: IDX184 was rapidly absorbed (median Tmax: 0.25−0.5 h) and eliminated (mean t1/2: 0.6−1 h). Plasma concentrations of NM increased gradually (median Tmax: 4−6 h). Plasma exposure of IDX184 and NM was low and dose-related: the respective mean Cmax values ranged from 1.1 to 17 and 1.7 to 19 ng/mL, and mean total AUC values ranged from 1.2 to 22.7 and 17.3 to 334 ng*h/mL. Mean NM plasma concentrations 24 h after dosing were 0.6−3 ng/mL for 25–100mg doses. Mean t1/2 for NM ranged from 18 to 43 h for doses 25mg.IDX184 was well tolerated with no discontinuations, SAEs, dose-limiting toxicities, or dose-dependence of AEs. Overall, the incidence of AEs and laboratory abnormalities was low and similar among subjects receiving IDX184 or placebo. Dizziness was the most common AE which occurred more frequently in placebo subjects. All AEs were mild to moderate and resolved at the end of study. Conclusions: IDX184 appeared to be safe and well tolerated in this study. Consistent with a liver-targeting approach, systemic exposure of parent drug and metabolite was low. Importantly, systemic levels of NM obtained with 25 to 100mg doses of IDX184 in this study are comparable to those associated with potent antiviral effects in HCV-infected chimpanzees. The favorable safety and pharmacokinetic profiles warrant further clinical development of IDX184 in HCV-infected patients.