Correlation between endogenous VWF:Ag and PK parameters and bleeding frequency in severe haemophilia A subjects during three-times-weekly prophylaxis with rFVIII-FS

Abstract

Patients with severe haemophilia A experience frequent and spontaneous bleeding, causing debilitating damage to joints and decreasing quality of life. Prophylaxis with factor VIII (FVIII) reduces joint damage if initiated early. Circulating FVIII levels may be influenced by endogenous von Willebrand factor (VWF), a chaperone protein that binds and stabilizes FVIII. The aim of this study was to determine whether endogenous VWF antigen (VWF:Ag) levels are correlated with FVIII pharmacokinetic (PK) parameters and clinical outcomes in patients with severe haemophilia A. Previously treated, non-inhibitor patients in a multinational, randomized, double-blind, Ph II study received prophylaxis with once-weekly BAY 79-4980 (35 IU kg(-1)) or thrice-weekly recombinant sucrose-formulated FVIII (rFVIII-FS; 25 IU kg(-1)). PK parameters were evaluated at weeks 1 and 26. The number of bleeds per patient during the study was captured as part of the core efficacy endpoint. Spearman rank correlations assessed relationships of VWF:Ag levels with patient age, PK and annualized bleeding rate. Of 131 study patients (aged 13-64 years; BAY 79-4980, n = 63; rFVIII-FS, n = 68), 27 (21%; n = 15 and 12 respectively) were evaluable for PK assessment. Baseline VWF:Ag levels correlated with patient age (P < 0.0001). There was no significant difference in PK results between treatments; thus, PK parameters and VWF levels of all patients were analysed together. AUC(norm) and T1/2 significantly increased with increased VWF:Ag (P < 0.001); clearance significantly decreased with increased VWF:Ag (P = 0.002). Annualized bleeding rate in patients treated with 3× per week rFVIII-FS significantly correlated with VWF:Ag and age (P = 0.038 and 0.021 respectively). PK parameters as well as the clinical outcome significantly correlated with endogenous VWF:Ag. The improved clinical outcome in subjects with high VWF:Ag levels may be explained by VWF:Ag influence on FVIII PK.

Keywords: age; factor VIII; pharmacokinetics; von Willebrand factor.

Fig 1

Study design schematic. Subjects were randomly allocated to receive either BAY 79–4980 once a week at a dose of 35 IU kg⁻¹ body weight plus two dummy infusions, or rFVIII-FS three times a week at a dose of 25 IU kg⁻¹ body weight for a total evaluation period of 52 weeks. All subjects then underwent a run-in period of 3 weeks, during which time they received their first three liposomal infusions in the hospital under medical supervision before the home treatment was initiated. The N represents the planned enrolment number.

Fig 2

Correlation between von Willebrand factor (VWF):Ag with FVIII clearance. A decreased rate of FVIII clearance was correlated with increased levels of patient VWF:Ag at baseline. The figure demonstrates the data at week 26 during the study, however, week 1 results are not significantly different from the data shown.

Fig 3

Correlation between von Willebrand factor (VWF):Ag with T_1/2. Increased FVIII half-life was found to correlate with increased levels of patient VWF:Ag at baseline. The figure demonstrates the data at week 26 during the study, however, week 1 results are not significantly different from the data shown.