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

Abstract

• rVWF is safe, well tolerated, and has a PK profile generally comparable to pdVWF, but promotes enhanced stabilization of endogenous FVIII.Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a 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 plasmaderived (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 (AUC 0-' ) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved. This trial was registered at www.clinicaltrials.gov as #NCT00816660. (Blood. 2013;122(5):648-657)

A von Willebrand factor fragment containing the D′D3 domains is sufficient to stabilize coagulation factor VIII in mice

“…The prolonged plasma survival of D9D3-Fc resulted in a corresponding prolongation in the elevation of FVIII levels ( Figure 4B). FVIII levels in mice receiving wtVWF or D9D3 peaked at 2 to 10 hours posttransfusion, lagging behind VWF levels as observed in VWD patients receiving VWF concentrates, 38 and returned to baseline by 48 hours. D9D3-Fc markedly elevated plasma FVIII levels, which were sustained through the entire period of observation ( Figure 4B).…”

Preoperative Detection of Low Von Willebrand Factor Activity and Operative Blood Loss in Pediatric Scoliosis Patients Undergoing Posterior Spinal Fusion

“…It may be reasonable to speculate the blood losses could have been much higher if the patients were not pretreated with VWF, however a prospective randomized study design will be necessary to truly clarify that. Lastly the recent introduction of recombinant VWF into clinical use [25] needs research to examine if it confers an advantage over the currently used human derived VWF.…”

Von Willebrand Disease: Range of the Disease, and Management

“…The observed enhanced stability of endogenous FVIII further supported the concept of use of rVWF alone for treatment of VWD to maintain sufficient VWF and FVIII activity for an extended period of time. This property of rVWF is potentially useful for use in clinical situations, for example the post-operative period and continuous prophylaxis, however, more studies in larger clinical trials are necessary to validate this initial finding [49].…”