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Hemostatic efficacy, safety and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease

Joan C. Gill, Giancarlo Castaman, Jerzy Windyga, Peter Kouides, Margaret Ragni, Frank W.G. Leebeek, Ortrun Obermann-Slupetzky, Miranda Chapman, Sandor Fritsch, Borislava G. Pavlova, Isabella Presch and Bruce Ewenstein
This article has an Erratum 127(22):2777

Key points

  • rVWF:rFVIII is safe and hemostatically effective in severe VWD patients for a variety of bleeding symptoms.

  • rVWF induces sustained stabilization of endogenous FVIII, which could obviate the need for rFVIII after the first infusion.

Abstract

This phase 3 trial (www.clinicaltrials.gov, NCT01410227) evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with rFVIII and subsequently alone, so long as hemostatic FVIII:C levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized crossover design (rVWF vs. rVWF:rFVIII at 50IU VWF:RCo/kg). Bleed control for all treated bleeds (N=192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119/122 minor, 59/61 moderate, and 6/7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9h for rVWF and 19.6h for rVWF:rFVIII). FVIII:C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours post-infusion. Eight AEs (6 non-serious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII:C, which may eliminate the need for rFVIII after the first infusion.

  • Submitted February 23, 2015.
  • Accepted June 25, 2015.