Enhanced Efficacy of Recombinant Factor VIII in Non-Covalent Complex with PEGylated Liposome in Hemophilia A Mice.

BAY 79-4980, a non-covalent complex of rFVIII (Kogenate® FS) reconstituted in PEGylated Liposome (PEG-Lip) diluent, was reported to double the bleed-free days in severe hemophilia A patients from 7 to 13 days (35 IU/kg) and 6 to 11 days (25 IU/kg), as compared to respectively corresponding doses of rFVIII¹. However, in a more recent phase I trial, the FVIII pharmacokinetics (PK) in plasma was virtually identical in patients who received either rFVIII or BAY 79-4980. To understand the mechanism of action of BAY 79-4980, we compared the pharmacological efficacy and PK of BAY 79-4980 to rFVIII in Hemophilia A (HemA) mice. A tail vein transection model was established, in which the survival of animals following the injury correlated to the rFVIII dose administered at 24 hrs prior to the injury, and a 2.5 to 3-fold difference in rFVIII dose led to significantly different survival rates (p<0.05). In this bleeding model, BAY 79-4980 (13 IU/kg) demonstrated significantly enhanced (p=0.018) survival compared to rFVIII at 24 hrs post dosing. The formation of a non-covalent complex of rFVIII with PEG-Liposome prior to the administration is required for the improved efficacy of BAY 79-4980, as sequential infusion of rFVIII and PEG-Liposome was no longer different from the identical dose of rFVIII alone. The plasma PK of FVIII in HemA mice treated with either BAY 79-4980 or rFVIII displayed two-compartmental decay with comparable incremental recovery, clearance and volume of distribution. However, BAY 79-4980 showed a modest (13%) but significant (p=0.024) increase in terminal half-life, and a noticeable (42%) but not statistically significant (p>0.05) increase in AUC, compared to rFVIII. Similar results were also observed in a whole blood PK study in HemA mice that received ¹²⁵I-labeled rFVIII reconstituted in PEG-liposome versus buffer. While the difference in plasma FVIII levels resulting from different terminal half-lives of BAY 79-4980 and rFVIII may account for the improved efficacy of BAY 79-4980 in HemA mice, other mechanisms, such as the association of PEG-liposome with platelets and monocytes, thereby altering their pro-hemostatic functions, are under investigation.