Recombinant Factor VIII Combined With Recombinant Von Willebrand Factor In Patients With Severe Hemophilia A: A Prospective Clinical Study Of Safety and Pharmacokinetics

Hemophilia A is an X-linked recessive, congenital bleeding disorder caused by a deficiency of circulating coagulation FVIII. Treatment regimens include on-demand or prophylactic FVIII substitution. An important challenge for patient compliance and treatment success is the need for frequent infusions due to the short circulating terminal half-life (T_1/2) of FVIII (8 to 14 h). In vivo, FVIII binds to, and is stabilized by, von Willebrand factor (VWF). Studies have shown that the T_1/2 of FVIII is positively correlated to baseline levels of VWF. The present study hypothesizes that co-administration of recombinant FVIII (rFVIII) with recombinant VWF can improve the pharmacokinetic (PK) properties of rFVIII.

The PK and safety of a rFVIII (ADVATE, Baxter) co-administered with an investigational rVWF were investigated in a prospective clinical trial of 12 previously-treated patients with severe hemophilia A (FVIII:C <1%), aged 18 to 60 years. Subjects were administered 3 infusions 8 to 14 days apart with: 1) rFVIII alone, 2) rFVIII combined with rVWF (low VWF ristocetin co-factor activity [VWF:RCo] dose), and 3) rFVIII combined with rVWF (high VWF:RCo dose). rFVIII was administered at the same dose for each PK infusion. FVIII activity was assessed using a one-stage clotting assay.

rFVIII co-administered with rVWF up to the highest investigated dose was well tolerated and safe in hemophilia A patients. No serious adverse events (AEs) and no treatment related AEs occurred, including no signs or symptoms of thrombosis, development of neutralizing antibodies to rVWF or rFVIII, or hypersensitivity reactions were observed.

A trend suggesting a prolongation of FVIII activity by the addition of rVWF was observed as shown by an increased area under the concentration curve (AUC), mean residence time (MRT) and T_1/2 after infusion of rFVIII combined with rVWF as compared with rFVIII alone, with a greater improvement associated with the higher of the 2 rVWF doses investigated (Table 1). An association between VWF antigen (VWF:Ag) level and rFVIII T_1/2 was observed. Subjects with lower VWF:Ag levels at baseline tended to have a more pronounced increase in rFVIII T_1/2 after infusion with rFVIII combined with rVWF compared with rFVIII alone (Table 2).

In summary, rVWF was safe and well tolerated when co-administered with rFVIII in hemophilia A patients and slightly sustained FVIII activity, with the highest improvement in circulating FVIII T_1/2 associated with lower baseline VWF:Ag levels. These findings provide insight into the FVIII/VWF interaction and its potential impact on therapy.