Evaluation of factor VIII polysialylation: Identification of a longer-acting experimental therapy in mice and monkeys

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.