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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 eficacy- 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.

Original languageEnglish (US)
Pages (from-to)755-764
Number of pages10
JournalAntiviral Therapy
Volume18
Issue number6
DOIs
StatePublished - Dec 1 2013

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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