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

Abstract

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 (T1/2) of FVIII (8 to 14 h). In vivo, FVIII binds to, and is stabilized by, von Willebrand factor (VWF). Studies have shown that the T1/2 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 T1/2 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 T1/2 was observed. Subjects with lower VWF:Ag levels at baseline tended to have a more pronounced increase in rFVIII T1/2 after infusion with rFVIII combined with rVWF compared with rFVIII alone (Table 2).Table 2Baseline VWF:Ag levels and geometric mean FVIII:C in individual patients after infusionSubjectBaseline VWF:AGFVIII T ½ after rFVIII aloneFVIII T½ after rFVIII + rVWF (high dose)Ratio of T½ after rFVIII + rVWF (high dose) over T½ after rFVIII alone110616.6515.220.91229826.6323.970.903909.1210.341.13412113.2613.781.04512610.6312.241.156908.2412.171.487795.818.751.5181089.3612.131.30913914.6815.931.091018126.6018.160.681116111.8813.911.17In 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 T1/2 associated with lower baseline VWF:Ag levels. These findings provide insight into the FVIII/VWF interaction and its potential impact on therapy. Disclosures:Windyga:Baxter, Bayer, Behring, Novo Nordisk, Octapharma, Pfizer: Honoraria, Research Funding. Draxler:Baxter: Employment. Chapman:Baxter: Employment. Wong:Baxter: Employment. Sørensen:Baxter: Employment. Ewenstein:Baxter: Employment.