title: Evaluation of Nonacog Beta Pegol Long-term Safety in the Immune-deficient Rowett Nude Rat (Crl:NIH-Foxn1rnu).
abstract: Nonacog beta pegol is a 40-kDa polyethylene glycosylated (PEGylated) human recombinant coagulation factor IX, intended for the treatment of hemophilia B. Human coagulation factors are immunogenic in animals; therefore, to evaluate the long-term toxicity of nonacog beta pegol, an immune-deficient, athymic rat (Rowett nude; Crl:NIH-Foxn1(rnu)) was used. Rats (n = 216) were given intravenous nonacog beta pegol 0, 40, 150, 600, or 1,200 IU/kg every 5th day for 26 weeks. To avoid infections, the animals were housed in a full-barrier environment with sterilized food and bedding. Standard toxicity end points were unaffected by treatment. All treated animals were exposed to nonacog beta pegol throughout the study, and no animals developed antidrug antibodies. Immunohistochemical staining revealed PEG in choroid plexus epithelial cells in a dose-dependent manner. Transmission electron microscopy showed that PEG was distributed in cytoplasmic vesicles of these cells, with no apparent effect on cellular organelle structures. Fourteen (6.5%) animals were euthanized or died prematurely due to nontreatment-related infections in the urogenital system and skin. In conclusion, the athymic rat is a suitable model for testing chronic toxicity of human proteins that are immunogenic in animals. Nonacog beta pegol was generally well tolerated, with no adverse effect of PEG on choroid plexus epithelial cells.
authors.affiliation: Non-clinical Development, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Rasmussen
authors.affiliation: Non-clinical Development, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Jette
authors.initials: J
authors.lastname: Nowak
authors.affiliation: Non-clinical Development, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Larsen
authors.affiliation: Envigo (previously Huntingdon Life Sciences), Huntingdon, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Bottomley
authors.affiliation: Envigo (previously Huntingdon Life Sciences), Huntingdon, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Rowles
authors.affiliation: Non-clinical Development, Novo Nordisk A/S, Maaloev, Denmark haof@novonordisk.com.
authors.forename: Hanne
authors.initials: H
authors.lastname: Offenberg
mesh_terms: D000818:Animals; D005164:Factor IX / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols / Q000633:toxicity*; D051381:Rats; D011923:Rats, Nude; D011994:Recombinant Proteins / Q000633:toxicity
chemical_list: D011994:Recombinant Proteins; C000592276:nonacog beta pegol; D011092:Polyethylene Glycols; D005164:Factor IX
keywords: N9-GP; athymic rat; chronic toxicity; polyethylene glycol