title: Prolonged half-life of glycoPEGylated rFVIIa variants compared to native rFVIIa.
abstract: BACKGROUND
  Bleeding episodes in haemophilia patients with inhibitors are primarily treated with by-passing agents such as recombinant activated FVII (rFVIIa). Prophylactic treatment with rFVIIa has been shown to significantly reduce the number of bleeding episodes as compared to conventional on-demand haemostatic therapy, and a reduced dosing frequency could present an improved treatment option in inhibitor patients.
  
  
  METHODS
  A series of glycoPEGylated rFVIIa derivatives (5-40K PEG) has been produced and their effect and pharmocokinetics have been investigated in several animal species.
  
  
  RESULTS
  The glycoPEGylated rFVIIa derivatives exhibit significant prolongation of half-life in mice, dogs and pigs as measured by rFVIIa clot activity. The clearance of rFVIIa, rFVIIa-5K PEG, rFVIIa-10K PEG, rFVIIa-20K PEG and rFVIIa-40K PEG in minipigs were estimated to 59, 27, 22, 8.7 and 3.1 ml/h/kg, respectively. Across species a reduction in clearance as a function of the size of the attached PEG was observed. By allometric scaling, the compiled pharmacokinetics predicts a human half-life for rFVIIa-10K PEG and rFVIIa-40K PEG of approximately 7 and 12h, respectively. The rFVIIa-10K PEG and rFVIIa-40K PEG are efficacious in stopping a bleed in the haemophilia A mouse tail-bleeding model after intravenous administration.
  
  
  CONCLUSIONS
  GlycoPEGylation of rFVIIa significantly increases the rFVIIa exposure in three animal models, glycoPEGylated rFVIIa compounds are effective in vivo and thus, represents a potential prophylactic treatment option for patients with inhibitors.
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, Maalov, Denmark. DKpf@Novonordisk.com
authors.forename: Ditte M
authors.initials: DM
authors.lastname: Karpf
authors.forename: Brit B
authors.initials: BB
authors.lastname: Sørensen
authors.forename: Mette B
authors.initials: MB
authors.lastname: Hermit
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Holmberg
authors.forename: Mikael
authors.initials: M
authors.lastname: Tranholm
authors.forename: Britta V
authors.initials: BV
authors.lastname: Bysted
authors.forename: Andreas V
authors.initials: AV
authors.lastname: Groth
authors.forename: Søren E
authors.initials: SE
authors.lastname: Bjørn
authors.forename: Henning R
authors.initials: HR
authors.lastname: Stennicke
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D015942:Factor VIIa / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006031:Glycosylation; D006207:Half-Life; D006467:Hemophilia A / Q000378:metabolism*; D006470:Hemorrhage / Q000209:etiology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature; D013623:Tail / Q000098:blood supply
chemical_list: D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C103587:recombinant FVIIa; D015942:Factor VIIa