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 journalArticle

9 Citations (Scopus)

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

Fingerprint

Ribavirin
Chronic Hepatitis C
Interferons
Viral Load
Therapeutics
Antiviral Agents
Genotype
Placebos
RNA
Prodrugs
IDX184
Alanine Transaminase
Nucleosides
Fatigue
Headache
Liver Diseases
Nucleotides
Pharmacokinetics
Safety
Liver

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

IDX184 in combination with pegylated interferon-α2a and ribavirin for 2 weeks in treatment-naive patients with chronic hepatitis C. / Lalezari, Jacob; Box, Terry; O'Riordan, William; Mehra, Purvi; Nguyen, Tuan; Poordad, Fred; DeJesus, Edwin; Kwo, Paul; Godofsky, Eliot; Lawrence, Shannon; Dubuc-Patrick, Gloria; Chen, Jie; McCarville, Joseph; Pietropaolo, Keith; Zhou, Xiao Jian; Sullivan-Bólyai, John; Mayers, Douglas.

In: Antiviral Therapy, Vol. 18, No. 6, 01.12.2013, p. 755-764.

Research output: Contribution to journalArticle

Lalezari, J, Box, T, O'Riordan, W, Mehra, P, Nguyen, T, Poordad, F, DeJesus, E, Kwo, P, Godofsky, E, Lawrence, S, Dubuc-Patrick, G, Chen, J, McCarville, J, Pietropaolo, K, Zhou, XJ, Sullivan-Bólyai, J & Mayers, D 2013, 'IDX184 in combination with pegylated interferon-α2a and ribavirin for 2 weeks in treatment-naive patients with chronic hepatitis C', Antiviral Therapy, vol. 18, no. 6, pp. 755-764. https://doi.org/10.3851/IMP2552
Lalezari, Jacob ; Box, Terry ; O'Riordan, William ; Mehra, Purvi ; Nguyen, Tuan ; Poordad, Fred ; DeJesus, Edwin ; Kwo, Paul ; Godofsky, Eliot ; Lawrence, Shannon ; Dubuc-Patrick, Gloria ; Chen, Jie ; McCarville, Joseph ; Pietropaolo, Keith ; Zhou, Xiao Jian ; Sullivan-Bólyai, John ; Mayers, Douglas. / IDX184 in combination with pegylated interferon-α2a and ribavirin for 2 weeks in treatment-naive patients with chronic hepatitis C. In: Antiviral Therapy. 2013 ; Vol. 18, No. 6. pp. 755-764.
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AU - Box, Terry

AU - O'Riordan, William

AU - Mehra, Purvi

AU - Nguyen, Tuan

AU - Poordad, Fred

AU - DeJesus, Edwin

AU - Kwo, Paul

AU - Godofsky, Eliot

AU - Lawrence, Shannon

AU - Dubuc-Patrick, Gloria

AU - Chen, Jie

AU - McCarville, Joseph

AU - Pietropaolo, Keith

AU - Zhou, Xiao Jian

AU - Sullivan-Bólyai, John

AU - Mayers, Douglas

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N2 - 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.

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