Recombinant von Willebrand Factor for von Willebrand Disease

Authors: Gill JC et al., Blood 2015 Oct 22; 126:2038

Outcomes were excellent in 96.9% of bleeds in patients with severe disease.

Patients with severe von Willebrand disease (VWD) have persistent, recurrent episodes of mucosal bleeding, menorrhagia, and bleeding with surgery or trauma. Treatment with plasma-derived von Willebrand factor (VWF) concentrates controls bleeding but exposes patients to potential infection by viruses and other microbes. A prior phase I trial showed that a recombinant VWF (rVWF) stabilized factor VIII (FVIII) and was not associated with thrombotic events (Blood 2013; 122:648).

To examine the pharmacokinetics and hemostatic efficacy of rVWF, an international group of investigators conducted an industry-sponsored, phase III trial involving 37 patients with severe VWD. For the treatment of bleeding episodes, the first of up to four infusions of rVWF was given with a single dose of recombinant FVIII (rFVIII).

For 192 treated bleeds in 22 patients, outcomes were excellent in 96.9% and good in 3.1%, and only a single infusion of rVWF was required for 81.8% of bleeds. The median doses of rVWF and rFVIII were 46.5 and 33.6 U/kg, respectively. The levels of high molecular weight multimers of VWF rose to 30% 15 minutes after infusion of rVWF and then declined over the next 12 to 24 hours, whereas FVIII gradually increased to 86 U/dL at 24 hours and hemostatic levels were sustained for 72 hours. Adverse events were infrequent and generally mild; one patient had two episodes of chest discomfort and tachycardia, which resolved during hospitalization. No thrombotic events occurred, and no patient developed neutralizing or binding antibodies.

Comment The development of a safe and effective recombinant VWF is an important milestone in the treatment of patients with severe VWD. The investigators gave rFVIII along with rVWF to achieve rapid hemostasis, but combined therapy might be unnecessary; bleeding stopped in some patients who inadvertently did not receive rFVIII. An economic analysis of this trial should be conducted to show whether combining rVWF and rFVIII is cost effective.