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Original article

IDX184 in combination with pegylated interferon-α2a and ribavirin for 2 weeks in treatment-naive patients with chronic hepatitis C

Jacob Lalezari, Terry Box, William O’Riordan, Purvi Mehra, Tuan Nguyen, Fred Poordad, Edwin DeJesus, Paul Kwo, Eliot Godofsky, Shannon Lawrence, Gloria Dubuc-Patrick, Jie Chen, Joseph McCarville, Keith Pietropaolo, Xiao-Jian Zhou, John Sullivan-Bólyai, Douglas Mayers

Corresponding author name: Jacob Lalezari
Corresponding author e-mail: drjay@questclinical.com

Citation: Antiviral Therapy 2013; 18:755-764
doi: 10.3851/IMP2552

Date accepted: 10 January 2013
Date published online: 25 February 2013

Abstract

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-α2a and ribavirin (P/R) in treatment-naive patients with genotype-1 HCV. A total of 81 patients with baseline HCV RNA≥5 log10 IU/ml, alanine aminotransferase ≤3× 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 log10) 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 log10 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.

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