title: Evaluation of the toxicology, pharmacokinetics, and local tolerance of recombinant factor IX Fc fusion protein in animals.
abstract: BACKGROUND
  Recombinant factor IX Fc fusion protein (rFIXFc) is a recombinant coagulation factor composed of a single molecule of recombinant factor IX (rFIX) covalently fused to the Fc domain of human immunoglobulin G1 (IgG1) with no intervening sequence. An extensive nonclinical program was performed to support the clinical development of rFIXFc for treatment of people with hemophilia B.
  
  
  METHODS
  Repeat-dose toxicology studies of rFIXFc were performed in 2 relevant species: Sprague Dawley rats (4-week study) and cynomolgus monkeys (5- and 27-week studies). Assessments included in-life observations, electrocardiograms (monkeys only), laboratory evaluations (including hematology and blood chemistry), postmortem analyses, local tolerance, and pharmacokinetics (PK). Allometric scaling was performed with PK data from multiple species, including humans. Local tolerance (single-dose study) and thrombogenic potential (Wessler stasis model) of rFIXFc were tested in New Zealand White rabbits.
  
  
  RESULTS
  There were no significant local or systemic toxicity findings in the repeat-dose studies. Allometric scaling data suggested that animal rFIXFc PK results are predictive of human PK parameters. There were no findings from the local tolerance study in rabbits; thrombogenic activity was less than that elicited by rFIX and a prothrombin complex concentrate, and similar to vehicle control.
  
  
  CONCLUSIONS
  rFIXFc was well tolerated in toxicology studies and demonstrated a low thrombogenic potential. These results are consistent with phase 1/2a and phase 3 clinical studies of rFIXFc in people with hemophilia B.
authors.affiliation: Biogen Idec, Cambridge, MA, USA. Electronic address: jennifer.dumont@biogenidec.com.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Dumont
authors.affiliation: Biogen Idec, Cambridge, MA, USA. Electronic address: kenneth.loveday@biogenidec.com.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Loveday
authors.affiliation: Biogen Idec, Cambridge, MA, USA. Electronic address: david.light@biogenidec.com.
authors.forename: David R
authors.initials: DR
authors.lastname: Light
authors.affiliation: Biogen Idec, Cambridge, MA, USA. Electronic address: glennfpierce@gmail.com.
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Pierce
authors.affiliation: Biogen Idec, Cambridge, MA, USA. Electronic address: haiyan.jiang@biogenidec.com.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005164:Factor IX / Q000493:pharmacokinetics* / Q000633:toxicity*; D007141:Immunoglobulin Fc Fragments / Q000633:toxicity*; D008252:Macaca fascicularis; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics* / Q000633:toxicity*; D013045:Species Specificity; D013927:Thrombosis / Q000139:chemically induced* / Q000517:prevention & control
chemical_list: D000991:Antithrombins; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C000599709:factor IX Fc fusion protein; D005164:Factor IX
keywords: Allometric scaling; Factor IX; Fc fusion; Hemophilia; Toxicology; rFIXFc