title: Safety of PEGylated recombinant human full-length coagulation factor VIII (BAX 855) in the overall context of PEG and PEG conjugates.
abstract: BACKGROUND
  BAX 855 is a PEGylated human full-length recombinant factor VIII (rFVIII) based on licensed rFVIII (ADVATE). The applied PEGylation technology has been optimized to retain functionality of the FVIII molecule, improve its pharmacokinetic properties and allow less frequent injections while maintaining efficacy.
  
  
  OBJECTIVE
  The aim of this study was to confirm that the excellent safety profile of ADVATE remains unchanged after PEGylation.
  
  
  METHODS
  Non-clinical safety studies with BAX 855 and its respective unbound polyethylene glycol (PEG) were conducted in several species. The distribution of a single dose of radiolabelled BAX 855 was further investigated in rats. Publically available safety data on PEG alone and PEGylated biomolecules were summarized and reviewed for specific safety findings attributable to PEG or PEGylated biopharmaceuticals.
  
  
  RESULTS
  Safety pharmacology studies in rabbits and macaques and repeated dose toxicity studies in rats and macaques identified no safety issues. Results of a distribution study in rats administered radiolabelled BAX 855 showed that radioactivity was completely excreted; urine was the major elimination route. A 28-day study in rats dosed with the unbound PEG constituent (PEG2ru20KCOOH) of BAX 855 showed no adverse or non-adverse effects. Safety data for PEG and PEG-protein conjugates indicate no safety concerns associated with PEG at clinically relevant dose levels. Although vacuolation of certain cell types has been reported in mammals, no such vacuolation was observed with BAX 855 or with the unbound PEG constituent.
  
  
  CONCLUSIONS
  Non-clinical safety evaluation of PEG and BAX 855 identified no safety signals; the compound is now in clinical development for the treatment of patients with haemophilia A.
authors.affiliation: Baxalta Innovations GmbH, Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Stidl
authors.affiliation: Baxalta Innovations GmbH, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Nektar Therapeutics, Huntsville, AL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bossard
authors.affiliation: Baxalta Innovations GmbH, Vienna, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Siekmann
authors.affiliation: Baxalta Innovations GmbH, Vienna, Austria.
authors.forename: P L
authors.initials: PL
authors.lastname: Turecek
authors.affiliation: Baxalta Innovations GmbH, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Putz
mesh_terms: D000818:Animals; D005169:Factor VIII / Q000009:adverse effects* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000737:chemistry*; D011817:Rabbits; D051381:Rats; D012449:Safety; D014018:Tissue Distribution; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: D011092:Polyethylene Glycols; C000609799:BAX 855; D005169:Factor VIII
keywords: BAX 855; PEG; conjugation; factor VIII; haemophilia; safety