Open AccessThe von Willebrand factor A-1 domain binding aptamer BT200 elevates plasma levels of von Willebrand factor and factor VIII: a first-in-human trial
Author(s) -
Katarina Kovačević,
Juergen Grafeneder,
Christian Schörgenhofer,
Georg Gelbenegger,
Gloria M. Gager,
Christa Firbas,
Peter Quehenberger,
Petra JilmaStohlawetz,
Andrea Bileck,
Shuhao Zhu,
James C. Gilbert,
Martin Béliveau,
Bernd Jilma,
Ulla Derhaschnig
Publication year - 2021
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2021.279948
Subject(s) - von willebrand factor , clotting factor , pharmacology , pharmacokinetics , hemostasis , pharmacodynamics , platelet , bleeding time , desmopressin , medicine , chemistry , endocrinology , platelet aggregation
Von Willebrand Factor (VWF) and Factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary haemostasis 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, randomised, placebo-controlled, double-blind trial tested the hypothesis that BT200 is well tolerated and has favourable pharmacokinetic and pharmacodynamic effects in 112 volunteers.Participants received one of the following: Single ascending dose of BT200 (0.18-48mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterised, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin induced aggregation, platelet function under high shear rates, and thrombin generation.Mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dosedependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagenadenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (p