Idx184 In Combination With Pegylated Interferon-Alpha 2a And Ribavirin For 2 Weeks In Treatment-Naive Patients With Chronic Hepatitis C

Background: IDX184 is a liver-targeted nucleotide prodrug that selectively inhibits HCV NS5B polymerase.Methods: This randomized, double-blind, placebo-controlled, ascending-dose study investigated the antiviral activity, safety and pharmacokinetics of IDX184 plus pegylated interferon-alpha 2a and ribavirin (P/R) in treatment-naive patients with genotype-1 HCV. A total of 81 patients with baseline HCV RNA= 5 log(10) IU/ml, alanine aminotransferase = 3x upper limit of normal and compensated liver disease were dosed. Sequential cohorts of 20 patients, randomized 16:4 (active: placebo), received IDX184 for 14 days at rising daily doses of 50, 100, 150 or 200 mg in combination with P/R for 14 days.Results: At the end of triple dosing, HCV RNA changes from baseline (mean +/- sd log 10) and proportion of patients achieving undetectable viral load (< 15 IU/ml) based on the efficacy-evaluable population were -2.7 +/- 1.3 (13%), -4.0 +/- 1.7 (50%), -4.2 +/- 1.9 (50%), -4.1 +/- 1.2 (40%), -4.3 +/- 1.5 (29%) and -3.7 +/- 1.2 (25%) for the 50 mg once daily, 50 mg twice daily, 100 mg once daily, 150 mg once daily, 100 mg twice daily and 200 mg once daily IDX184 doses, respectively. P/R alone resulted in a reduction of -1.5 +/- 1.3 log(10) with only 6% of patients with undetectable viral load. Patients with genotypes-1a or -1b responded similarly. No viral breakthrough or resistance associated with IDX184 was observed. Anti-HCV activity of IDX184 correlated with plasma exposure of its nucleoside metabolite 2'-methylguanosine. Most adverse events were mild or moderate in severity and were consistent with those associated with P/R. The most common adverse events were fatigue and headache.Conclusions: IDX184 in combination with P/R for 14 days was well tolerated and demonstrated greater antiviral activity with more patients achieving undetectable viral load than P/R.