PT - JOURNAL ARTICLE AU - Helmut Glantschnig AU - Alexander Bauer AU - Karima Benamara AU - Michael Dockal AU - Veronika Ehrlich AU - Herbert Gritsch AU - Gerald Höbarth AU - Frank M. Horling AU - Alexandra Kopic AU - Peter Leidenmühler AU - Birgit M. Reipert AU - Hanspeter Rottensteiner AU - Tanja Ruthsatz AU - Gerald Schrenk AU - Maria Schuster AU - Peter L. Turecek AU - Alfred Weber AU - Martin Wolfsegger AU - Friedrich Scheiflinger AU - Werner Höllriegl TI - Evaluation of Factor VIII Polysialylation: Identification of a Longer-Acting Experimental Therapy in Mice and Monkeys AID - 10.1124/jpet.119.260067 DP - 2019 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 95--105 VI - 371 IP - 1 4099 - http://jpet.aspetjournals.org/content/371/1/95.short 4100 - http://jpet.aspetjournals.org/content/371/1/95.full SO - J Pharmacol Exp Ther2019 Oct 01; 371 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 [polysialyic acid (PSA) rFVIII] with improved pharmacokinetics (PK), prolonged pharmacology, and maintained safety attributes to enable longer-acting rFVIII therapy. In factor VIII (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 hours) compared with unmodified recombinant FVIII (rFVIII), as well as a potentially favorable immunogenicity profile. Reduced binding to a scavenger receptor (low-density lipoprotein receptor-related protein 1) 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 versus rFVIII was confirmed in cynomolgus monkeys [mean residence time: 23.4 vs. 10.1 hours; exposure (area under the curve from time 0 to infinity): 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 of 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 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 nonclinical safety profile of the experimental therapeutic.