title: SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders.
abstract: OBJECTIVE
  SCH 503034 is a novel and potent oral hepatitis C virus (HCV) protease inhibitor. In this phase Ib study, we assessed safety parameters and virologic response of combination of SCH 503034 plus pegylated (PEG) interferon (IFN) alpha-2b in patients with HCV genotype 1 infections who were previously nonresponders to PEG-IFN-alpha-2b +/- ribavirin therapy.
  
  
  METHODS
  This was a multicenter, open-label, 2-dose level, 3-way crossover, randomized (to crossover sequence) study carried out in 3 medical centers in Europe. Adult patients received SCH 503034 200 mg (n = 14) or 400 mg (n = 12) 3 times daily orally and PEG-IFN-alpha-2b 1.5 microg/kg subcutaneously once each week. Patients received SCH 503034 as monotherapy for 1 week, PEG-IFN-alpha-2b as monotherapy for 2 weeks, and combination therapy for 2 weeks with washout periods between each treatment period.
  
  
  RESULTS
  Combination therapy with SCH 503034 and PEG-IFN-alpha-2b was well tolerated, with no clinically significant changes in safety parameters. Mean maximum log(10) changes in HCV RNA were -2.45 +/- 0.22 and -2.88 +/- 0.22 for PEG-IFN-alpha-2b plus 200 mg and 400 mg SCH 503034, respectively, compared with -1.08 +/- 0.22 and -1.61 +/- 0.21 for SCH 503034 200 mg and 400 mg, respectively, and -1.08 +/- 0.22 and -1.26 +/- 0.20 for PEG-IFN-alpha-2b alone in the 200 mg and 400 mg SCH 503034 groups, respectively.
  
  
  CONCLUSIONS
  SCH 503034 plus PEG-IFN-alpha-2b was well tolerated in patients with HCV genotype 1 nonresponders to PEG-IFN-alpha-2b +/- ribavirin. These preliminary results of antiviral activity of the combination suggest a potential new therapeutic option for this hard-to-treat, nonresponder patient population.
authors.affiliation: Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.forename: Regine
authors.initials: R
authors.lastname: Rouzier
authors.forename: Frank
authors.initials: F
authors.lastname: Wagner
authors.forename: Nicole
authors.initials: N
authors.lastname: Forestier
authors.forename: Dominique
authors.initials: D
authors.lastname: Larrey
authors.forename: Samir K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Musaddeq
authors.initials: M
authors.lastname: Hussain
authors.forename: Amrik
authors.initials: A
authors.lastname: Shah
authors.forename: David
authors.initials: D
authors.lastname: Cutler
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D005060:Europe; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008163:Luminescent Measurements; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012367:RNA, Viral / Q000032:analysis*; D011994:Recombinant Proteins; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase