title: Preclinical studies of PF-04849285, an interferon-α8 fusion protein for the treatment of HCV.
abstract: BACKGROUND
  This study presents preclinical data of a novel interferon (IFN)-α8 fusion protein, PF-04849285, and compares it with IFN-α2 and pegylated IFN-α2; the latter being the current standard of care for HCV.
  
  
  METHODS
  The antiviral properties were evaluated in vitro using the HCV replication assay (replicon) and the general encephalomyocarditis virus assay. The binding affinity to both IFNR-subunits was assessed using surface plasmon resonance. Ex vivo experiments using cynomolgus monkey and human blood were used for the evaluation of induction of IFN-inducible biomarkers (interferon inducible protein 10 [IP-10], 2'-5'-oligoadenylate synthetase [OAS2] and interleukin-6 [IL-6]). The molecule was tested intravenously and subcutaneously in cynomolgus monkey in a single dose study for two weeks at 0.01, 1, 5 and 20 mg/kg. Each route and dose combination was given to a single male animal, blood samples were collected for evaluation of biomarkers and pharmacokinetics. The compound was also tested in cynomolgus monkey in a multiple dose study for four weeks, with a twice-a-week dosing prior to a three-week wash-out period for toxicokinetics, pharmacokinetics, and biomarker evaluation at 20, 50 or 100 mg/kg subcutaneously and 20 mg/kg intravenously.
  
  
  RESULTS
  The molecule is 10× more potent than the pegylated IFN-α2a, with potency similar to the unmodified IFN-α2a. No unanticipated findings were observed in cynomolgus monkey when dosed up to 20 mg/kg, >10,000-fold margin over the anticipated efficacious human dose.
  
  
  CONCLUSIONS
  The biomarker and toxicological findings were consistent with a potent IFN molecule. The potency and pharmacokinetic properties of the molecule are consistent with dosing at least every two weeks with the potential for monthly dosing' and not 'at least twice daily' as presented in the original [corrected].
authors.affiliation: Antivirals Group, Pfizer Inc., Sandwich, UK. v.flores@btinternet.com
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Flores
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hickling
authors.forename: Sasha
authors.initials: S
authors.lastname: Sreckovic
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fidock
authors.forename: Nigel
authors.initials: N
authors.lastname: Horscroft
authors.forename: Madan
authors.initials: M
authors.lastname: Katragadda
authors.forename: Boris
authors.initials: B
authors.lastname: Savic
authors.forename: Jaiessh
authors.initials: J
authors.lastname: Rawal
authors.forename: Oona E
authors.initials: OE
authors.lastname: Delpuech-Adams
authors.forename: Nicola
authors.initials: N
authors.lastname: Robas
authors.forename: Thomas
authors.initials: T
authors.lastname: Corey
authors.forename: Linda
authors.initials: L
authors.lastname: Nelms
authors.forename: Michael
authors.initials: M
authors.lastname: Lawton
authors.forename: John
authors.initials: J
authors.lastname: Marcek
authors.forename: Makeida
authors.initials: M
authors.lastname: Stubbs
authors.forename: Michael
authors.initials: M
authors.lastname: Westby
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ciaramella
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004686:Encephalomyocarditis virus / Q000187:drug effects; D005260:Female; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008252:Macaca fascicularis; D008297:Male; D017471:Receptors, Interferon / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; C577353:PF-04849285; D017471:Receptors, Interferon; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C076799:interferon-alpha 8