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

T E Coyle, M T Reding, J C Lin, L A Michaels, A Shah, J Powell, T E Coyle, M T Reding, J C Lin, L A Michaels, A Shah, J Powell

Abstract

Background: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (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 BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A.

Patients/methods: This 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days 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) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses.

Results: BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed.

Conclusions: This phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III 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.

Figures

Fig 1
Fig 1
Schematic of the structure of BAY 94-9027. PEG, poly(ethylene glycol). Adapted from Ivens et al. [19].
Fig 2
Fig 2
Study design. PK, pharmacokinetic; rFVIII-FS, sucrose-formulated recombinant factor VIII.
Fig 3
Fig 3
Concentration–time curves of chromogenic factor VIII activity for a single dose of sucrose-formulated recombinant FVIII (rFVIII-FS) given at (A) 25 IU kg−1 and (B) 50 IU kg−1, and after single and multiple doses of BAY 94-9027 given at (A) 25 IU kg−1 and (B) 60 IU kg−1. The data shown are mean ± 90% confidence interval.
Fig 4
Fig 4
Individual subject half-life (t½) values for sucrose-formulated recombinant factor VIII (rFVIII-FS) and BAY 94-9027 (last dose). Data were derived from all subjects from both cohorts who had data for the single dose of rFVIII-FS and the last dose of BAY 94-9027 (n = 13).
Fig 5
Fig 5
Relationship of baseline von Willebrand factor levels to half-life following the initial BAY 94-9027 dose.

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