title: Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus.
abstract: CPG 10101, a synthetic oligodeoxynucleotide (ODN), is a toll-like receptor 9 (TLR9) agonist with antiviral and immunomodulatory properties that could potentially influence chronic infection with HCV. In this multicenter Phase 1b trial, 60 HCV-positive patients (50 genotype 1 HCV) were randomized and received either placebo or CPG 10101 at 0.25, 1, 4, 10, or 20 mg subcutaneously (SC) twice weekly for 4 weeks or at 0.5 or 0.75 mg/kg SC once weekly for 4 weeks. Dose-dependent cytokine induction was observed after administration of CPG 10101. At 24 hours after administering the highest dose of 0.75 mg/kg CPG 10101, interferon (IFN)-gamma-inducible protein 10 (IP-10) had a mean increase over baseline levels (+/-SD) of 15,057 (+/-9769) pg/ml (P < 0.01, compared to placebo); IFN-alpha had a 106 (+/-63.3) pg/ml increase (P < 0.01); and 2'5'-oligoadenylate synthetase (OAS) had a 163 (+/-120.6) pmol/dl increase (P < 0.01). Decreases in HCV RNA also were dose-dependent, with the greatest group geometric mean maximum reduction of 1.69 +/- 0.618 log(10) (P < 0.05) observed in the 0.75 mg/kg dose group. Decreases >/=1 log(10) were seen in 22 of 40 patients who received >/=1 mg CPG 10101, with 3 patients exceeding a 2.5-log(10) reduction. CPG 10101 was well tolerated, and adverse events were consistent with CPG 10101's mechanism of action.
  
  
  CONCLUSIONS
  In this Phase 1 study, CPG 10101 was associated with dose-dependent increases in markers of immune activation and decreases in HCV RNA levels. The data support further clinical studies of CPG 10101 for treating chronic HCV infection.
authors.affiliation: ALT (Alliance for Liver Therapy) Group, Division of Gastroenterology & Hepatology and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA. mchut001@mc.duke.edu
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bacon
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Gordon
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Mitchell
authors.initials: M
authors.lastname: Shiffman
authors.forename: Nezam H
authors.initials: NH
authors.lastname: Afdhal
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.forename: Andrew
authors.initials: A
authors.lastname: Muir
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Adhami
authors.forename: Mary L
authors.initials: ML
authors.lastname: Morris
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lekstrom-Himes
authors.forename: Susan M
authors.initials: SM
authors.lastname: Efler
authors.forename: Heather L
authors.initials: HL
authors.lastname: Davis
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004311:Double-Blind Method; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012367:RNA, Viral / Q000097:blood; D051217:Toll-Like Receptor 9 / Q000819:agonists
chemical_list: D000998:Antiviral Agents; C523579:CPG 10101; D009838:Oligodeoxyribonucleotides; D012367:RNA, Viral; D051217:Toll-Like Receptor 9