Faster onset of effect and greater efficacy of NN1731 compared with rFVIIa, aPCC and FVIII in tail bleeding in hemophilic mice

Background: Recombinant factor VIIa (rFVIIa, Novoseven((R))) is currently used to control bleeding in hemophiliacs with inhibitors. A new rFVIIa variant, NN1731, with increased activity on the surface of activated platelets, has demonstrated a more potent and faster onset of reactivity than rFVIIa in various in vitro models. The present study aimed to investigate whether this translates into greater efficacy and faster promotion of hemostasis in vivo. Method and results: In a severe tail-bleeding model in hemophilia A mice, NN1731 demonstrated significantly greater efficacy than rFVIIa, plasma-derived activated prothrombin complex concentrate (pd-aPCC, FEIBA((R))) or FVIII (Refacto((R))). Assessment of the blood loss over time showed that NN1731 significantly and dose-dependently reduced the blood loss in the first 5-min observation period, whereas the effect of rFVIIa, FVIII and pd-aPCC first became evident 5-10 min after injury. Conclusion: This study shows that NN1731 has a greater efficacy and faster resolution of bleeding in a severe bleeding model in hemophilia A mice compared with any of the other agents tested.