Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: A prospective clinical trial

Pier Mannuccio Mannucci, Christine Kempton, Carolyn Millar, Edward Romond, Amy Shapiro, Ingvild Birschmann, Margaret V. Ragni, Joan Cox Gill, Thynn Thynn Yee, Robert Klamroth, Wing Yen Wong, Miranda Chapman, Werner Engl, Peter L. Turecek, Tobias M. Suiter, Bruce M. Ewenstein

Research output: Contribution to journalArticlepeer-review

Abstract

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined ata fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞)(P <.01). Thesedata support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.

Original languageEnglish
Pages (from-to)648-657
Number of pages10
JournalBlood
Volume122
Issue number5
DOIs
Publication statusPublished - Aug 1 2013

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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