The von Willebrand factor A-1 domain binding aptamer BT200 elevates plasma levels of von Willebrand factor and factor VIII: a first-in-human trial

Autor: Katarina D. Kovacevic, Jürgen Grafeneder, Christian Schörgenhofer, Georg Gelbenegger, Gloria Gager, Christa Firbas, Peter Quehenberger, Petra Jilma-Stohlawetz, Andrea Bileck, Shuhao Zhu, James C. Gilbert, Martin Beliveau, Bernd Jilma, Ulla Derhaschnig
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Haematologica, Vol 107, Iss 9 (2021)
Druh dokumentu: article
ISSN: 0390-6078
1592-8721
DOI: 10.3324/haematol.2021.279948
Popis: Von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary hemostasis and clotting, respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomized, placebo-controlled, doubleblind trial tested the hypothesis that BT200 is well tolerated and has favorable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: a single ascending dose of BT200 (0.18-48 mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterized, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin-induced aggregation, platelet function under high shear rates, and thrombin generation. The mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dose-dependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagen-adenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (P
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