title: Evaluation of the toxicology and pharmacokinetics of recombinant factor VIII Fc fusion protein in animals.
abstract: BACKGROUND
  Recombinant factor VIII Fc fusion protein (rFVIIIFc) is a novel recombinant factor VIII with a prolonged half-life, developed for the treatment of hemophilia A. Studies that evaluated the toxicological effects of rFVIIIFc in 2 pharmacologically relevant species, cynomolgus monkeys and Sprague Dawley rats, are reported here.
  
  
  METHODS
  In repeat-dose toxicology studies, rats and monkeys received 0, 50, 250, or 1000 IU/kg rFVIIIFc every other day for 4 weeks. In a high-dose tolerance study, monkeys received 1 rFVIIIFc dose of 3000, 10,000, or 20,000 IU/kg. Evaluations included in-life observations, laboratory and post-mortem evaluations, pharmacokinetics, and local tolerance. Allometric scaling, using data from 4 animal species and humans, was used to evaluate the relationship between animal and human pharmacokinetics.
  
  
  RESULTS
  rFVIIIFc was well tolerated with no adverse toxicological findings directly attributable to rFVIIIFc. As expected, antibodies to this fully human protein developed in rats and monkeys in a time-dependent fashion following repeated dosing, leading to increased clearance in both species. There were no local reactions (infusion site) or evidence of thrombosis at high doses in rats and monkeys. Allometric scaling demonstrated more rapid clearance in small animals compared with humans and a volume of distribution (steady state) proportional to body weight across species, suggesting that animal pharmacokinetics are predictive of human pharmacokinetics.
  
  
  CONCLUSIONS
  Repeated doses of rFVIIIFc in 2 relevant animal species and high doses of rFVIIIFc in monkeys were well tolerated. These results supported the clinical safety of rFVIIIFc observed in phase 1/2a and phase 3 clinical trials.
authors.affiliation: Biogen, Cambridge, MA, USA. Electronic address: jennifer.dumont@biogen.com.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Dumont
authors.affiliation: Biogen, Cambridge, MA, USA. Electronic address: kenneth.loveday@biogen.com.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Loveday
authors.affiliation: Biogen, Cambridge, MA, USA. Electronic address: david.light@biogen.com.
authors.forename: David R
authors.initials: DR
authors.lastname: Light
authors.affiliation: Biogen, Cambridge, MA, USA. Electronic address: glennfpierce@gmail.com.
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Pierce
authors.affiliation: Biogen, Cambridge, MA, USA. Electronic address: haiyan.jiang@biogen.com.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D005169:Factor VIII / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D057809:HEK293 Cells; D006467:Hemophilia A / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry* / Q000633:toxicity; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D011994:Recombinant Proteins / Q000493:pharmacokinetics* / Q000633:toxicity; D013045:Species Specificity; D013927:Thrombosis / Q000276:immunology
chemical_list: D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D005169:Factor VIII
keywords: Fc fusion; factor VIII; hemophilia; rFVIIIFc; toxicology