title: Randomised clinical trial: anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV.
abstract: BACKGROUND
  The ANA773 is an oral prodrug of a small-molecule toll-like receptor (TLR)7 agonist. Preclinical and healthy volunteer clinical studies with ANA773 have demonstrated induction of endogenous interferon-α (IFN-α) of multiple subtypes, which supports the potential utility in the treatment of chronic hepatitis C virus (HCV) infection.
  
  
  OBJECTIVE
  To examine safety, tolerability, pharmacodynamics, pharmacokinetics and anti-viral activity of ANA773.
  
  
  METHODS
  The ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment-naïve or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000mg). In each group, six to eight patients received ANA773 and two received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600mg) or 10days (2000mg).
  
  
  RESULTS
  Mild to moderate adverse events were reported, with an increase in frequency and intensity with increasing dose. No serious AEs were reported and there were no early discontinuations. There were dose-related increases in various markers of IFN-α response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and -1.26log(10) in the placebo, 800, 1200, 1600 and 2000mg cohorts, respectively. At the 2000mg dose, ANA773 significantly (P=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10log(10) ).
  
  
  CONCLUSIONS
  The ANA773 was generally well tolerated and resulted in a dose-related IFN-dependent response leading to a significant decrease in serum HCV RNA levels in the 2000mg dose group.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Hospital, Rotterdam, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Bergmann
authors.forename: J
authors.initials: J
authors.lastname: de Bruijne
authors.forename: D M
authors.initials: DM
authors.lastname: Hotho
authors.forename: R J
authors.initials: RJ
authors.lastname: de Knegt
authors.forename: A
authors.initials: A
authors.lastname: Boonstra
authors.forename: C J
authors.initials: CJ
authors.lastname: Weegink
authors.forename: A A
authors.initials: AA
authors.lastname: van Vliet
authors.forename: J
authors.initials: J
authors.lastname: van de Wetering
authors.forename: S P
authors.initials: SP
authors.lastname: Fletcher
authors.forename: L A
authors.initials: LA
authors.lastname: Bauman
authors.forename: M
authors.initials: M
authors.lastname: Rahimy
authors.forename: J R
authors.initials: JR
authors.lastname: Appleman
authors.forename: J L
authors.initials: JL
authors.lastname: Freddo
authors.forename: H L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: H W
authors.initials: HW
authors.lastname: Reesink
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007369:Interferon Inducers / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012313:RNA / Q000097:blood; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D007369:Interferon Inducers; D016898:Interferon-alpha; D011355:Prodrugs; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D012313:RNA