title: Antiviral activity of danoprevir (ITMN-191/RG7227) in combination with pegylated interferon α-2a and ribavirin in patients with hepatitis C.
abstract: BACKGROUND
  Current therapy options for patients with chronic hepatitis C virus (HCV) infection genotype 1 are effective in <50%. Danoprevir (ITMN-191/RG7227) is a potent, selective, and orally active inhibitor of the HCV NS3/4A serine protease.
  
  
  METHODS
  The safety and antiviral efficacy of danoprevir was examined over 14 days in combination with pegylated interferon α-2a (180 μg once weekly) and ribavirin (1000-1200 mg/day) in a double-blind, placebo-controlled, phase 1b, multiple ascending dose study consisting of 6 dose cohorts (400 mg, 600 mg, and 900 mg twice daily and 100 mg, 200 mg, and 300 mg 3 times daily).
  
  
  RESULTS
  Danoprevir in combination with pegylated interferon α-2a and ribavirin was safe and generally well tolerated. The median change in HCV RNA level from baseline to the end of treatment with danoprevir at 400 mg, 600 mg, and 900 mg twice daily was -4.7 log(10) IU/mL, -5.4 log(10) IU/mL, and -5.3 log(10) IU/mL, respectively, and at 100 mg, 200 mg, and 300 mg 3 times daily was -5.5 log(10) IU/mL, -5.7 log(10) IU/mL, and -5.6 log(10) IU/mL, respectively. Placebo administered in combination with standard of care resulted in median decrease in HCV RNA level of -2.6 log(10) IU/mL (with twice daily regimen) and -2.0 log(10) IU/mL (with 3 times daily regimen).
  
  
  CONCLUSIONS
  Our study showed substantial antiviral efficacy of danoprevir in combination with pegylated interferon α-2a and ribavirin. Exploration of the safety and antiviral efficacy of danoprevir in longer clinical studies is warranted.
authors.affiliation: JW Goethe University Hospital, Frankfurt, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Forestier
authors.forename: Dominique
authors.initials: D
authors.lastname: Larrey
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Dominique
authors.initials: D
authors.lastname: Guyader
authors.forename: Alain
authors.initials: A
authors.lastname: Patat
authors.forename: Regine
authors.initials: R
authors.lastname: Rouzier
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Qin
authors.forename: Sharlene
authors.initials: S
authors.lastname: Lim
authors.forename: Williamson
authors.initials: W
authors.lastname: Bradford
authors.forename: Steven
authors.initials: S
authors.lastname: Porter
authors.forename: Scott D
authors.initials: SD
authors.lastname: Seiwert
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D054833:Isoindoles; D007769:Lactams / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D011392:Proline / Q000031:analogs & derivatives; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011092:Polyethylene Glycols; D011392:Proline; D011994:Recombinant Proteins; D012254:Ribavirin; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C553752:danoprevir; C100416:peginterferon alfa-2a