Enhancing Hemostasis in Hemophilia: The Synergistic Effect of PF-06741086 and Recombinant Factor VIIa

Hemophilia, characterized by a deficiency in Factor VIII or IX, is a genetic bleeding disorder. The tissue factor pathway inhibitor (TFPI) regulates thrombin generation in the coagulation process, and its inhibition could be beneficial in hemophilia treatment by enhancing the extrinsic pathway. PF-06741086 is a monoclonal antibody under development that neutralizes TFPI's inhibitory activity, offering a potential new treatment for hemophilia, including cases with inhibitors.

The study examined the impact of PF-06741086 on thrombin generation in severe hemophilia A plasma with varying concentrations of recombinant Factor VIIa (rFVIIa). A dose-dependent increase in thrombin generation was observed with the addition of rFVIIa. The combination of PF-06741086 with rFVIIa led to higher peak thrombin levels and reduced lag time, with similar effects at concentrations of 0.2, 2, and 20 μg/mL of rFVIIa, indicating a potential saturation point.

The research also explored PF-06741086's effect on thrombin generation in hemophilia A and B plasmas, including those with inhibitors. A selected rFVIIa concentration of 2 μg/mL was used, reflecting levels achievable post-FVIIa dosing. PF-06741086, at a concentration of 16 μg/mL, was found to increase thrombin generation in hemophilia A and B plasma, with or without inhibitors, leading to higher peak thrombin concentrations and shortened lag times compared to rFVIIa alone.

In non-hemophilic plasma, the addition of PF-06741086, either alone or combined with rFVIIa, similarly increased thrombin generation without causing excessive coagulation. The peak thrombin levels induced by PF-06741086, with or without rFVIIa, were comparable to those in non-hemophilic plasma and did not surpass the levels seen with non-hemophilic plasma treated with PF-06741086 alone.

In conclusion, the combination of PF-06741086 and rFVIIa enhances thrombin generation in hemophilia A and B plasmas, including those with inhibitors, without leading to excessive coagulation, suggesting a potential therapeutic approach for hemophilia treatment.