RT Journal Article
SR Electronic
T1 Evaluation of factor VIII polysialylation: Identification of a longer-acting experimental therapy in mice and monkeys
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.119.260067
DO 10.1124/jpet.119.260067
A1 Helmut Glantschnig
A1 Alexander Bauer
A1 Karima Benamara
A1 Michael Dockal
A1 Veronika Ehrlich
A1 Herbert Gritsch
A1 Gerald Hobarth
A1 Frank M Horling
A1 Alexandra Kopic
A1 Peter Leidenmuhler
A1 Birgit M Reipert
A1 Hanspeter Rottensteiner
A1 Tanja Ruthsatz
A1 Gerald Schrenk
A1 Maria Schuster
A1 Peter L Turecek
A1 Alfred Weber
A1 Martin Wolfsegger
A1 Friedrich Scheiflinger
A1 Werner Hollriegl
YR 2019
UL http://jpet.aspetjournals.org/content/early/2019/07/30/jpet.119.260067.abstract
AB Extended half-life (EHL) factor therapies are needed to reduce the burden of prophylaxis and improve treatment adherence in patients with hemophilia. BAX 826 is a novel polysialylated full-length recombinant factor VIII (PSArFVIII) with improved pharmacokinetics, prolonged pharmacology, and maintained safety attributes to enable longer acting rFVIII therapy. In FVIII-deficient hemophilic mice, PSArFVIII showed a substantially higher mean residence time (>2-fold) and exposure (>3-fold), and prolonged efficacy in tail-bleeding experiments (48 vs. 30 h) compared with unmodified rFVIII, as well as a potentially favorable immunogenicity profile. Reduced binding to scavenger receptor (LRP1) and von Willebrand factor (VWF) as well as a largely VWF-independent circulation time in mice provide a rationale for prolonged BAX 826 activity. The significantly improved PK profile vs. rFVIII was confirmed in cynomolgus monkeys (mean residence time: 23.4 vs.10.1 h; exposure [AUC0-∞]: 206 vs. 48.2 IU/ml*h) and is in line with results from rodent studies. Finally, safety and toxicity evaluations did not indicate increased thrombogenic potential, and repeated administration of BAX 826 to monkeys and rats was well-tolerated. The favorable profile and mechanism of this novel experimental therapeutic demonstrated all the requirements for an EHL-rFVIII candidate, and thus BAX 826 was entered into clinical assessment for the treatment of hemophilia A.SIGNIFICANCE STATEMENT Prolongation of FVIII half-life aims to reduce the burden of prophylaxis and to improve treatment outcomes in patients with hemophilia. This study shows that polysialylation of PSArFVIII resulted in prolongations of rFVIII circulation time and procoagulant activity, together with a favorable non-clinical safety profile of the experimental therapeutic.