Recombinant Factor VIII Combined With Recombinant Von Willebrand Factor In Patients With Severe Hemophilia A: A Prospective Clinical Study Of Safety and Pharmacokinetics
Authors: Lissitchkov Toshko , Windyga Jerzy , Konkle Barbara A. , Draxler Wolfgang , Chapman Miranda , Wong Wing-Yen , Sørensen Benny , Ewenstein Bruce M. 
Published: October 2019

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 1 FVIII PK up to 120 hours after infusion with rFVIII alone or combined with rVWF PK Parameter Infusion N Geometric mean (GM) 95% confidence interval for GM AUC0-120h [h*IU/mL] rFVIII 12 1376.58 847.67 to 2235.52 rFVIII + rVWF (low dose) 12 1396.94 889.90 to 2192.88 rFVIII + rVWF (high dose) 11 1963.30 1602.77 to 2404.93 AUC0-inf [h*IU/mL] rFVIII 12 1410.06 877.76 to 2265.17 rFVIII + rVWF (low dose) 12 1433.29 928.97 to 2211.39 rFVIII + rVWF (high dose) 11 1994.53 1632.55 to 2436.76 Mean residence time [h] rFVIII 12 15.17 11.62 to 19.81 rFVIII + rVWF (low dose) 12 16.38 13.23 to 20.27 rFVIII + rVWF (high dose) 11 18.06 14.97 to 21.79 Clearance [mL/kg/h] rFVIII 12 0.035 0.022 to 0.057 rFVIII + rVWF (low dose) 12 0.035 0.023 to 0.054 rFVIII + rVWF (high dose) 11 0.025 0.021 to 0.031 Terminal Half-Life [h] rFVIII 12 12.05 8.95 to 16.24 rFVIII + rVWF (low dose) 12 12.74 10.11 to 16.05 rFVIII + rVWF (high dose) 11 13.74 11.44 to 16.52 Volume at a steady state [mL/kg] rFVIII 12 0.54 0.36 to 0.79 rFVIII + rVWF (low dose) 12 0.57 0.40 to 0.82 rFVIII + rVWF (high dose) 11 0.46 0.39 to 0.54 AUC: area under the plasma concentration/time curve from time Table 2 Baseline VWF:Ag levels and geometric mean FVIII:C in individual patients after infusion Subject Baseline VWF:AG FVIII T ½ after rFVIII alone FVIII T½ after rFVIII + rVWF (high dose) Ratio of T½ after rFVIII + rVWF (high dose) over T½ after rFVIII alone 1 106 16.65 15.22 0.91 2 298 26.63 23.97 0.90 3 90 9.12 10.34 1.13 4 121 13.26 13.78 1.04 5 126 10.63 12.24 1.15 6 90 8.24 12.17 1.48 7 79 5.81 8.75 1.51 8 108 9.36 12.13 1.30 9 139 14.68 15.93 1.09 10 181 26.60 18.16 0.68 11 161 11.88 13.91 1.17
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 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.