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R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin.

AbstractUNLABELLED:
R1626, a prodrug of the hepatitis C virus (HCV) RNA polymerase inhibitor R1479, showed time-dependent and dose-dependent reduction of HCV RNA levels in a previous study. The present study evaluated the efficacy and safety of R1626 administered for 4 weeks in combination with peginterferon alfa-2a +/- ribavirin in HCV genotype 1-infected treatment-naive patients. Patients were randomized to: DUAL 1500 (1500 mg R1626 twice daily [bid] + peginterferon alfa-2a; n = 21); DUAL 3000 (3000 mg R1626 bid + peginterferon alfa-2a; n = 32); TRIPLE 1500 (1500 mg R1626 bid + peginterferon alfa-2a + ribavirin; n = 31); or standard of care (SOC) (peginterferon alfa-2a + ribavirin; n = 20). At 4 weeks HCV RNA was undetectable (<15 IU/mL) in 29%, 69%, and 74% of patients in the DUAL 1500, DUAL 3000, and TRIPLE 1500 arms, respectively, compared with 5% of patients receiving SOC, with respective mean reductions in HCV RNA from baseline to week 4 of 3.6, 4.5, 5.2, and 2.4 log(10) IU/mL. Synergy was observed between R1626 and peginterferon alfa-2a and between R1626 and ribavirin. There was no evidence of development of viral resistance. Adverse events (AEs) were mainly mild or moderate; seven patients had nine serious AEs (including one patient with one serious AE in SOC). The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in DUAL 1500, DUAL 3000, TRIPLE 1500, and SOC, respectively, and was the main reason for dose reductions.
CONCLUSION:
A synergistic antiviral effect was observed when R1626 was combined with peginterferon alfa-2a +/- ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. Dosing of R1626 was limited by neutropenia; a study of different dosages of R1626 in combination with peginterferon alfa-2a and ribavirin is underway.
AuthorsPaul J Pockros, David Nelson, Eliot Godofsky, Maribel Rodriguez-Torres, Gregory T Everson, Michael W Fried, Reem Ghalib, Stephen Harrison, Lisa Nyberg, Mitchell L Shiffman, Isabel Najera, Anna Chan, George Hill
JournalHepatology (Baltimore, Md.) (Hepatology) Vol. 48 Issue 2 Pg. 385-97 (Aug 2008) ISSN: 1527-3350 [Electronic] United States
PMID18570306 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)
Chemical References
  • 4'-azidocytidine
  • Antiviral Agents
  • Interferon-alpha
  • Nucleosides
  • Prodrugs
  • RNA, Viral
  • Recombinant Proteins
  • peginterferon alfa-2a
  • Polyethylene Glycols
  • Ribavirin
  • Cytidine
  • interferon alfa-2a
  • Alanine Transaminase
  • balapiravir
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Alanine Transaminase (blood)
  • Antiviral Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
  • Cytidine (analogs & derivatives, blood)
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Resistance, Viral
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Hepacivirus (enzymology, genetics)
  • Humans
  • Interferon-alpha (adverse effects, therapeutic use)
  • Male
  • Middle Aged
  • Neutropenia (chemically induced)
  • Nucleosides (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
  • Polyethylene Glycols (adverse effects, therapeutic use)
  • Prodrugs (administration & dosage, adverse effects, metabolism, pharmacokinetics, therapeutic use)
  • RNA, Viral (antagonists & inhibitors, blood)
  • Recombinant Proteins
  • Ribavirin (adverse effects, therapeutic use)
  • Treatment Outcome
  • Viral Load

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