title: Prolonged effect of a new O-glycoPEGylated FVIII (N8-GP) in a murine saphenous vein bleeding model.
abstract: Prophylaxis in severe haemophilia significantly increases health-related quality of life for patients, but the dosing frequency still constitutes a challenge. Thus, there is a need for new treatment options, utilizing compounds with longer duration of action, while still maintaining potency. The objective of this study was to evaluate the acute and prolonged effects of a new glycoPEGylated recombinant factor VIII (rFVIII) (N8-GP) in a venous bleeding model in haemophilia A mice and to compare the efficacy and potency to turoctocog alfa (rFVIII). Following intravenous administration of turoctocog alfa or N8-GP to normal and FVIII-deficient mice, bleeding time and blood loss from a saphenous vein incision were evaluated in an acute dose-response study and a duration of action study. In the acute setting, N8-GP dose dependently reduced the number and duration of bleeding episodes as well as blood loss compared to FVIII-deficient mice, reaching statistical significance at doses as low as 5-10 U kg(-1) . In the duration of action study, a significantly prolonged and maintained effect of N8-GP was found for up to 48 h after dosing, whereas the effect of rFVIII was no longer present for any end-points 24 h after dosing. Seventy-two hours after dosing, no significant effect of either compound was found. This study shows a prolonged haemostatic effect of N8-GP compared to rFVIII supporting other recent studies that N8-GP may hold a potential to increase the quality of life for patients with haemophilia A by reducing dosing frequency.
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark; Biopharmaceuticals Research Unit, Novo Nordisk A/S, Maaloev, Bagsvaerd, Denmark.
authors.forename: A E
authors.initials: AE
authors.lastname: Pastoft
authors.forename: M
authors.initials: M
authors.lastname: Ezban
authors.forename: M
authors.initials: M
authors.lastname: Tranholm
authors.forename: J
authors.initials: J
authors.lastname: Lykkesfeldt
authors.forename: B
authors.initials: B
authors.lastname: Lauritzen
mesh_terms: D000818:Animals; D001760:Bleeding Time; D004195:Disease Models, Animal; D005169:Factor VIII / Q000032:analysis / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006467:Hemophilia A / Q000188:drug therapy*; D006470:Hemorrhage / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000627:therapeutic use*; D012501:Saphenous Vein
chemical_list: C577506:recombinant factor VIII N8; D011092:Polyethylene Glycols; D005169:Factor VIII
keywords: PEGylation; haemophilia A; mice; rFVIII; venous bleeding