Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A

Background BAY94-9027 is a B-domain-deleted recombinant factorVIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia. Objectives To assess the pharmacokinetics and safety of BAY94-9027 after single and repeated administration in subjects with severe hemophiliaA. Patients/Methods This 8-week, prospective, multicenter, open-label, phaseI trial was conducted in 14 subjects aged 21-58years with FVIII of <1%, >= 150days of exposure to FVIII, and no history of FVIII inhibitors. After a >= 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort1 [n=7], 25IUkg(-1); cohort2 [n=7], 50IUkg(-1)) for a 48-h pharmacokinetic (PK) study. After another >= 3-day washout, cohort1 received twice-weekly BAY94-9027 at 25IUkg(-1) (16 doses), and cohort2 received once-weekly BAY94-9027 at 60IUkg(-1) (nine doses). A 168-h PK study was performed after the first and last BAY94-9027 doses. Results BAY94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~19h (vs. ~13.0h for rFVIII-FS). BAY94-9027 was well tolerated, and no immunogenicity was observed. Conclusions This phaseI study demonstrates that BAY94-9027 has an extended half-life in subjects with hemophiliaA and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phaseIII study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.