title: BAX 855, a PEGylated rFVIII product with prolonged half-life. Development, functional and structural characterisation.
abstract: A longer acting recombinant FVIII is expected to serve patients' demand for a more convenient prophylactic therapy. We have developed BAX 855, a PEGylated form of Baxter's rFVIII product ADVATE™ based on the ADVATE™ manufacturing process. The conjugation process for preparing BAX 855 uses a novel PEG reagent. The production process was adjusted to yield a rFVIII conjugate with a low PEGylation degree of about 2 moles PEG per FVIII molecule. This optimised modification degree resulted in an improved PK profile for rFVIII without compromising its specific activity. PEGylation sites were identified by employing various HPLC- and MS-based methods. These studies not only indicated that about 60% of the PEG chains are localised to the B-domain, which is cleaved off upon physiological activation during the coagulation process, but also demonstrated an excellent lot to lot consistency with regard to PEGylation site distribution. Detailed biochemical characterization further showed that PEGylated FVIII retained all the physiological functions of the FVIII molecule with the exception of binding to the LRP clearance receptor which was reduced for BAX 855 compared to ADVATE™. This might provide an explanation for the prolonged circulation time of BAX 855 as reduced receptor binding might slow-down clearance. Preclinical studies showed improved pharmacokinetic behaviour and clinically relevant prolonged efficacy compared to ADVATE™ without any signs of toxicity or elevated immunogenicity. The comprehensive preclinical data package formed the basis for approval of the phase 1 clinical study by European authorities which started in 2011.
authors.affiliation: Baxter Innovations GmbH, Vienna, Austria. peter_turecek@baxter.com
authors.forename: P L
authors.initials: PL
authors.lastname: Turecek
authors.forename: M J
authors.initials: MJ
authors.lastname: Bossard
authors.forename: M
authors.initials: M
authors.lastname: Graninger
authors.forename: H
authors.initials: H
authors.lastname: Gritsch
authors.forename: W
authors.initials: W
authors.lastname: Höllriegl
authors.forename: M
authors.initials: M
authors.lastname: Kaliwoda
authors.forename: P
authors.initials: P
authors.lastname: Matthiessen
authors.forename: A
authors.initials: A
authors.lastname: Mitterer
authors.forename: E-M
authors.initials: EM
authors.lastname: Muchitsch
authors.forename: M
authors.initials: M
authors.lastname: Purtscher
authors.forename: H
authors.initials: H
authors.lastname: Rottensteiner
authors.forename: A
authors.initials: A
authors.lastname: Schiviz
authors.forename: G
authors.initials: G
authors.lastname: Schrenk
authors.forename: J
authors.initials: J
authors.lastname: Siekmann
authors.forename: K
authors.initials: K
authors.lastname: Varadi
authors.forename: T
authors.initials: T
authors.lastname: Riley
authors.forename: H J
authors.initials: HJ
authors.lastname: Ehrlich
authors.forename: H P
authors.initials: HP
authors.lastname: Schwarz
authors.forename: F
authors.initials: F
authors.lastname: Scheiflinger
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004355:Drug Stability; D005169:Factor VIII / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006467:Hemophilia A / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D008081:Liposomes; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D005169:Factor VIII