Enhancement of factor VIIa haemostatic efficacy by formulation with PEGylated liposomes

Recombinant activated factor VII (rFVIIa) is an effective treatment of the haemophilia patient with inhibitors and acquired haemophilia. However, on account of its relatively short half‐life (HL), achieving therapeutic efficacy with FVIIa requires repeated injections. The development of a long‐acting FVIIa product would therefore be beneficial. The formulation of factor VIII with PEGylated liposomes (PEGLip) was previously shown to extend the bleeding‐free period in haemophilia patients. We report here an enhancement of haemostatic efficacy by similarly formulating FVIIa with PEGLip. Surface plasmon resonance analysis indicated that FVIIa binds non‐covalently but with high affinity and specificity to PEGLip. A one‐stage clotting assay demonstrated that formulation of FVIIa with PEGLip does not affect FVIIa activity and stability. A pharmacokinetic study in rats demonstrated that PEGLip formulation of FVIIa extends circulation time and results in higher FVIIa levels several hours after injection. Thromboelastography experiments indicated that PEGLip‐FVIIa induces faster clot formation and higher clot stability than standard formulated FVIIa. These results suggest that formulation of FVIIa with PEGLip may lead to a safe and effective long‐acting FVIIa that improves the care of haemophilic patients with inhibitors and acquired haemophilia.