The Biological Efficacy Profile of a Chemically Modified Recombinant Factor VIII Molecule,

Abstract 3324

Prophylactic administration of anti-hemophilic factor concentrates can prevent bleeding and limit the complications of hemophilia. The current regimes for prophylaxis require factor concentrates to be administered frequently. This need for frequent venipuncture poses one of the major barriers to more widespread use of prophylaxis. Development of drugs with a longer circulating half-life and duration of action would be beneficial in reducing this requirement and result in less demanding treatment regimes.

In this study the duration of the effect of a chemically modified recombinant factor VIII based on the ADVATE™ manufacturing process (CMrFVIII) in comparison to unmodified ADVATE™ (rFVIII) was determined in a murine model of hemophilic joint bleeding.

CMrFVIII and rFVIII were infused at a concentration of 280 IU/Kg at specified time points prior to joint injury to induce hemarthrosis. Animals were sacrificed three days following injury and assessed for the presence of blood in the joint.

CMrFVIII and rFVIII both prevented bleeding, assessed by the total bleeding score (TBS). Pretreatment with CMrFVIII protected against bleeding more effectively compared to rFVIII at all time points assessed after 24 hours (figure). 17% of mice pretreated with CMrFVIII had bleeding at 72 hours compared to 100% of those pretreated with rFVIII.

Our data indicate that the effective duration of action in protecting against joint bleeding was longer after prophylaxis with CMrFVIII compared to rFVIII. This mouse model is an inexpensive, rapid and reliable tool to assess new factor concentrates in clinical development for hemophilia.