Thrombosis and Haemostasis 108.2/2012 284 © Schattauer 2012 Blood Coagulation, Fibrinolysis and Cellular Haemostasis The anti-von Willebrand factor aptamer ARC1779 increases von Willebrand factor levels and platelet counts in patients with type 2B von Willebrand disease Petra Jilma-Stohlawetz 2 ; Paul Knöbl 3 ; James C. Gilbert 4 ; Bernd Jilma 1 1 Department of Clinical Pharmacology, Medical University of Vienna, Austria; 2 Department of Blood Group Serology & Transfusion Medicine, Medical University of Vienna, Austria; 3 Department of Internal Medicine I, Division of Haematology, Medical University of Vienna, Austria; 4 Archemix Corporation, Cambridge, Massachusetts, USA Summary Blockade of hyperactive von Willebrand factor (VWF) by ARC1779 blunted the platelet drop induced by desmopressin in patients with type 2B von Willebrand disease (VWD). Thus, we hypothesised that ARC1779 may increase VWF levels and correct thrombocytopenia. Three thrombocytopenic patients suffering from type 2B VWD received a loading dose of 0.23 mg/kg ARC1779 followed by 4 μg/kg/min intra- venously for 72 hours in a prospective clinical trial. ARC1779 was well tolerated and safe. Plasma concentrations of ARC1779 increased to 76 μg/ml (59–130) leading to an immediate decrease of free VWF A1 do- mains. VWF/FVIII levels increased as early as 12 h after start of infusion, peaked near the end of infusion, and returned to baseline at follow-up. Correspondence to: Bernd Jilma, MD Department of Clinical Pharmacology Medical University of Vienna Währinger Guertel 18–20 1090 Vienna, Austria Tel.: +43 1 40400 2981, Fax: +43 1 40400 2998 E-mail: Bernd.Jilma@meduniwien.ac.at VWF ristocetin cofactor activity (VWF:RCo) showed a median 10-fold increase 8 hours after end of infusion, while the median VWF-antigen and FVIII increase was less (5-fold and 4-fold, respectively). Most impor- tantly inhibition of hyperactive VWF rapidly increased platelet counts from 40x10 9 /l (38–58 x10 9 /l) to a maximum of 146 x10 9 /l (107–248 x10 9 /l). In conclusion, ARC1779 markedly increases VWF/FVIII levels and most importantly improves or even corrects thrombocytopenia in VWD type 2B patients. This underscores the in vivo potency of ARC1779. Keywords von Willebrand disease, thrombocytopenia, aptamer Received: December 23, 2012 Accepted after major revision: May 3, 2012 Prepublished online: June 28, 2012 doi:10.1160/TH11-12-0889 Thromb Haemost 2012; 108: 284–290 Introduction Von Willebrand disease type 2B (VWD type 2B) is a rare disorder which is caused by gain of function mutations of VWF(1). The molecular defects in VWD type 2B enhance the affinity of VWF for glycoprotein Ib which results in increased platelet binding (2). The mutant VWF molecules spontaneously bind to normal platelets, and the high-molecular-weight multimers are digested by the metalloprotease ADAMTS-13 (3) to form inactive proteolytic fragments (4). As a consequence, VWD type 2B patients become deficient in both large VWF multimers and platelets, which defi- ciencies are established risk factors for bleeding in VWD type 2B (5). As with other types of VWD, spontaneous mucosal bleedings occur (e.g. epistaxis, menorrhagia, or gastrointestinal bleeding), and severe bleeding can result from trauma, surgery, or childbirth. Aptamers are a new class of oligonucleotide drugs (6) that, similar to antibodies, are able to block protease activity and/or pro- tein-protein interactions, including those with pro- or anticoagu- lant functions. ARC1779 is a synthetically manufactured aptamer which binds to the A1 domain of human VWF with high affinity, preventing interaction with platelet GpIb; the crystal structure of its parent compound has recently been characterised (7). The core aptamer portion of ARC1779 (molecular weight, ≈13.7 kDa with- out pegylation), is a 40-mer modified DNA/RNA oligonucleotide, which is conjugated with a 20-kDa polyethylene glycol moiety to form the active pharmaceutical ingredient, ARC1779 (molecular weight, ≈33 kDa) (8). The potent anti-thrombotic activity of ARC1779 has been demonstrated in vivo in a cynomolgus monkey carotid electrical injury thrombosis model (9). ARC1779 dose- dependently prolongs the bleeding time, although to a lesser de- gree than abciximab (9). Thus, similar to other VWF antagonists it has little effect on the bleeding time and may potentially confer a lower risk of bleeding than other classes of anti-thrombotic agents (10). Based on the demonstration that ARC1779 prevented the des- mopressin induced drop in platelet counts and enhanced VWF lev- els after desmopressin infusion in VWD type 2B patients (11), we hypothesized that ARC1779 would correct the thrombocytopenia and increase VWF levels by inhibiting excessive VWF activity (12) in patients with VWD type 2B. For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2018-04-02 | ID: 1001066444 | IP: 54.70.40.11