Page 122 - Haematologica Vol. 107 - September 2022

ARTICLE - Hemostasis
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
Katarina D. Kovacevic,1 Jürgen Grafeneder,1 Christian Schörgenhofer,1 Georg Gelbenegger, Gloria Gager,1 Christa Firbas,1 Peter Quehenberger,2 Petra Jilma-Stohlawetz,2 Andrea Bileck,3 Shuhao Zhu,4 James C. Gilbert,4 Martin Beliveau,5 Bernd Jilma1 and Ulla Derhaschnig1
1Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; 2Clinical Institute of Laboratory Medicine, Medical University of Vienna, Vienna, Austria; 3Joint Metabolome Facility, University of Vienna & Medical University of Vienna, Vienna, Austria, 4Guardian Therapeutics Inc., Lexington, KY, USA and 5Certara, Montreal, Quebec, Canada
Abstract
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, double- blind 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<0.001), without increasing VWF propeptide levels, indicating decreased VWF/FVIII clearance. This, in turn, increased thrombin generation and accelerated clotting. Desmopressin-induced VWF/FVIII release had additive effects on a background of BT200. Tolerability and safety were generally good, but exaggerated pharmacology was seen at saturating doses. This trial identified a novel mechanism of action for BT200: BT200 dose-dependently increases VWF/FVIII by prolonging half-life at doses well below those which inhibit VWF-mediated platelet function. This novel property can be exploited therapeutically to enhance hemostasis in congenital bleeding disorders.
Introduction
von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary hemostasis and clotting, respectively.1 VWF plays a dual role in hemostasis: firstly, it is crucial for platelet adhesion as it bridges glycoprotein GpIb on platelets via the A1 do- main to collagen localized in the subendothelial matrix of damaged vessels,2 secondly it reduces the clearance of coagulation FVIII.3 Deficiency of VWF (Willebrand disease or syndrome) causes primarily mucocutaneous bleeding,4,5 and deficiency of FVIII (hemophilia A) leads to joint and muscle bleeding. Both of these disorders can result in dis- astrous bleeding during surgery or after trauma, and
necessitate substitution of VWF or FVIII, or non-factor re- placement therapy in severe cases.6
Only recently, VWF has become a target for therapeutic in- terventions in prothrombotic diseases. As VWF mediates thrombus formation under high shear rates, therapeutic in- hibition of VWF is a potential target for cardiovascular dis- eases.7-9 Proof of this concept was first established by demonstrating: (i) that inhibition of the VWF A1-domains reduced the number of microembolic signals during carotid endarterectomy;10 and (ii) that it improved thrombocytope- nia in thrombotic thrombocytopenic purpura,11 a condition caused by a congenital or acquired deficiency of the VWF cleaving enzyme (ADAMTS-13).12 This led to small13,14 and larger clinical trials,15-17 which eventually led to the success-
Haematologica | 107 September 2022
2121
Correspondence: K. Kovacevic katarina.kovacevic@meduniwien.ac.at
Received:
Accepted:
Prepublished: https://doi.org/10.3324/haematol.2021.279948
©2022 Ferrata Storti Foundation Published under a CC BY-NC license
September 6, 2021. October 21, 2021. November 25, 2021.