title: VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection.
abstract: OBJECTIVE
  To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV.
  
  
  METHODS
  In total, 152 treatment-naive patients received VX-222+telaprevir ('DUAL' regimen; n=47), with ribavirin ('TRIPLE' regimen; n=46), or with peginterferon+ribavirin ('QUAD' regimen; n=59) for 12 weeks. Patients with detectable HCV RNA at weeks 2 and/or 8 received peginterferon+ribavirin for 24 (DUAL and TRIPLE) or 12 (QUAD) additional weeks.
  
  
  RESULTS
  VX-222 (100 or 400 mg twice daily) was well tolerated, with an increased rate of gastrointestinal adverse events observed with the higher dose. Across VX-222 400-mg twice-daily regimens, the QUAD was associated with the highest frequency of grade 3/4 adverse events. The DUAL was discontinued because of high viral breakthrough before week 12. Sustained virologic response (SVR) 24 weeks after end of treatment (SVR24), including patients treated with 12 or 24 additional weeks of peginterferon+ribavirin, was 67% for TRIPLE (VX-222 400 mg twice daily) and 79 and 90% for QUAD (VX-222 100 and 400 mg twice daily, respectively).
  
  
  CONCLUSIONS
  These results provide valuable information regarding the safety, tolerability, and efficacy of telaprevir combined with a non-nucleoside polymerase inhibitor, as dual therapy or with ribavirin without or with peginterferon. Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy.
authors.affiliation: aDepartment of Internal Medicine, Saint Louis University Liver Center, St Louis, Missouri bJohns Hopkins University School of Medicine, Baltimore, Maryland cWeill Cornell Medical College, New York, New York dUniversity of Florida, Gainesville, Florida eVertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA fUniversity of Auckland, Auckland, New Zealand.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Di Bisceglie
authors.forename: Mark
authors.initials: M
authors.lastname: Sulkowski
authors.forename: Ed
authors.initials: E
authors.lastname: Gane
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.forename: David
authors.initials: D
authors.lastname: Nelson
authors.forename: Cynthia
authors.initials: C
authors.lastname: DeSouza
authors.forename: Katia
authors.initials: K
authors.lastname: Alves
authors.forename: Shelley
authors.initials: S
authors.lastname: George
authors.forename: Tara
authors.initials: T
authors.lastname: Kieffer
authors.forename: Eileen Z
authors.initials: EZ
authors.lastname: Zhang
authors.forename: Robert
authors.initials: R
authors.lastname: Kauffman
authors.forename: Mohammed
authors.initials: M
authors.lastname: Asmal
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Koziel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects; D003511:Cyclohexanols / Q000008:administration & dosage* / Q000009:adverse effects; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003511:Cyclohexanols; D016898:Interferon-alpha; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C000592793:lomibuvir; C486464:telaprevir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C100416:peginterferon alfa-2a