A randomised pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease

Summary

Desmopressin aggravates thrombocytopenia in type 2B von Willebrand disease (VWF type 2B) by release of large and hyper-adhesive von Wille-brand Factor (VWF) multimers. This pilot study investigated whether the anti-VWF aptamer ARC1779 can prevent desmopressin-induced thrombocytopenia and interferes with the excessive VWF turnover in patients with VWF type 2B. Concentration effect curves of ARC1779 were established for five patients in vitro and two patients with VWF type 2B were treated by infusion of ARC1779, desmopressin, or their combination in a randomised, controlled, double-blind design. ARC1779 concentrations in the range of 1–3 μg/ml blocked free A1 domain binding sites by 90% in vitro. In vivo, desmopressin alone induced a profound (-90%) drop in platelet counts in one of the patients. ARC1779 (4–5 μg/ml) completely inhibited VWF A1 domains and prevented this desmopress-in-induced platelet drop. Desmopressin alone increased VWF antigen two- to three-fold, accompanied by concordant changes in VWF Ristocetin cofactor activity (RCo) and coagulation factor VIII activity. ARC1779 substantially enhanced the desmopressin-induced maximal increase in these parameters, and improved multimer patterns. No treatment related adverse events were observed and no bleeding occurred despite marked thrombocytopenia. These data provide first proof of concept in humans and evidence that ARC1779 is a potent inhibitor of VWF. ARC1779 prevented the rapid consumption of VWF multimers together with agglutinated platelets that occurred in response to desmopressin challenge in patients with VWD type 2B.

Clinical Trial registration number: NCT00632242.

Keywords

Clinical trials - antiplatelet drugs - von Willebrand factor - thrombocytopenia - desmopressin

• References

• 1 Lillicrap D. Genotype/phenotype association in von Willebrand disease: is the glass half full or empty?. J Thromb Haemost 2009; 7 (Suppl. 01) 65-70.
• 2 Sadler JE, Budde U, Eikenboom JC. et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Wille-brand Factor. J Thromb Haemost 2006; 4: 2103-2114.
• 3 Ruggeri ZM, Mannucci PM, Lombardi R. et al. Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand’s disease subtypes. Blood 1982; 59: 1272-1278.
• 4 Casonato A, Steffan A, Pontara E. et al. Post-DDAVP thrombocytopenia in type 2B von Willebrand disease is not associated with platelet consumption: failure to demonstrate glycocalicin increase or platelet activation. Thromb Haemost 1999; 81: 224-228.
• 5 Nichols WL, Hultin MB, James AH. et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14: 171-232.
• 6 Ruggeri ZM, Zimmerman TS. von Willebrand factor and von Willebrand disease. Blood 1987; 70: 895-904.
• 7 Becker RC, Povsic T, Cohen MG. et al. Nucleic acid aptamers as antithrombotic agents: Opportunities in extracellular therapeutics. Thromb Haemost 2010; 103: 586-595.
• 8 Huang RH, Fremont DH, Diener JL. et al. A structural explanation for the anti-thrombotic activity of ARC1172, a DNA aptamer that binds von Willebrand factor domain A1. Structure 2009; 17: 1476-1484.
• 9 Gilbert JC, DeFeo-Fraulini T, Hutabarat RM. et al. First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers. Circulation 2007; 116: 2678-2686.
• 10 Diener JL, Daniel Lagasse HA, Duerschmied D. et al. Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779. J Thromb Haemost 2009; 7: 1155-1162.
• 11 Wadanoli M, Sako D, Shaw GD. et al. The von Willebrand factor antagonist (GPG-290) prevents coronary thrombosis without prolongation of bleeding time. Thromb Haemost 2007; 98: 397-405.
• 12 Siller-Matula JM, Krumphuber J, Jilma B. Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases. Br J Pharmacol 2010; 159: 502-517.
• 13 Spiel AO, Mayr FB, Ladani N. et al. The aptamer ARC1779 is a potent and specific inhibitor of von Willebrand Factor mediated ex vivo platelet function in acute myocardial infarction. Platelets 2009; 20: 334-340.
• 14 Knobl P, Jilma B, Gilbert JC. et al. Anti-von Willebrand factor aptamer ARC1779 for refractory thrombotic thrombocytopenic purpura. Transfusion 2009; 49: 2181-2185.
• 15 Reiter RA, Mayr F, Blazicek H. et al. Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Blood 2003; 102: 4594-4599.
• 16 Siller-Matula JM, Gouya G, Wolzt M. et al. Cross validation of the Multiple Electrode Aggregometry. A prospective trial in healthy volunteers. Thromb Haemost 2009; 102: 397-403.
• 17 Panzer S, Badr-Eslam R, Schneller A. et al. Loss of high-molecular-weight von Willebrand factor multimers mainly affects platelet aggregation in patients with aortic stenosis. Thromb Haemost 2010; 103: 408-414.
• 18 Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction. J Lab Clin Med 2001; 138: 152-163.
• 19 Harrison P. The role of PFA-100 testing in the investigation and management of haemostatic defects in children and adults. Br J Haematol 2005; 130: 3-10.
• 20 van Vliet HH, Kappers-Klunne MC, Leebeek FW. et al. PFA-100 monitoring of von Willebrand factor (VWF) responses to desmopressin (DDAVP) and factor VIII/VWF concentrate substitution in von Willebrand disease type 1 and 2. Thromb Haemost 2008; 100: 462-468.
• 21 Crescente M, Di Castelnuovo A, Iacoviello L. et al. PFA-100 closure time to predict cardiovascular events in aspirin-treated cardiovascular patients: a meta-analysis of 19 studies comprising 3,003 patients. Thromb Haemost 2008; 99: 1129-1131.
• 22 Gori AM, Marcucci R, Paniccia R. et al. Thrombotic events in high risk patients are predicted by evaluating different pathways of platelet function. Thromb Haemost 2008; 100: 1136-1145.
• 23 Derhaschnig U, Jilma B. Assessment of platelets and the endothelium in patients presenting with acute coronary syndromes--is there a future?. Thromb Haemost 2009; 102: 1144-1148.
• 24 Jilma B, Dirnberger E, Eichler HG. et al. Partial blockade of nitric oxide synthase blunts the exercise-induced increase of von Willebrand factor antigen and of factor VIII in man. Thromb Haemost 1997; 78: 1268-1271.
• 25 Reiter RA, Knobl P, Varadi K. et al. Changes in von Willebrand factor-cleaving pro-tease (ADAMTS13) activity after infusion of desmopressin. Blood 2003; 101: 946-948.
• 26 Favaloro EJ. Phenotypic identification of platelet-type von Willebrand disease and its discrimination from type 2B von Willebrand disease: a question of 2B or not 2B?. A story of nonidentical twins? Or two sides of a multidenominational or multifaceted primary-hemostasis coin? Semin Thromb Hemost 2008; 34: 113-127.
• 27 Sieghart W, Homoncik M, Jilma B. et al. Antiviral therapy decreases GpIIb/IIIa activation of platelets in patients with chronic hepatitis C. Thromb Haemost 2006; 95: 260-266.
• 28 Stiegler G, Stohlawetz P, Peck-Radosavljevic M. et al. Direct evidence for an increase in thrombopoiesis after liver transplantation. Eur J Clin Invest 1998; 28: 755-759.
• 29 Favaloro EJ. The utility of the PFA-100 in the identification of von Willebrand disease: a concise review. Semin Thromb Hemost 2006; 32: 537-545.
• 30 de Romeuf C, Mazurier C. Comparison between von Willebrand factor (VWF) and VWF antigen II in normal individuals and patients with von Willebrand disease. Thromb Haemost 1998; 80: 37-41.
• 31 Reiter RA, Varadi K, Turecek PL. et al. Changes in ADAMTS13 (von-Willebrand-factor-cleaving protease) activity after induced release of von Willebrand factor during acute systemic inflammation. Thromb Haemost 2005; 93: 554-558.
• 32 Spiel AO, Mayr FB, Firbas C. et al. Validation of rotation thrombelastography in a model of systemic activation of fibrinolysis and coagulation in humans. J Thromb Haemost 2006; 4: 411-416.
• 33 Homoncik M, Blann AD, Hollenstein U. et al. Systemic inflammation increases shear stress-induced platelet plug formation measured by the PFA-100. Br J Haematol 2000; 111: 1250-1252.
• 34 Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008; 112: 11-18.
• 35 Mayr FB, Knobl P, Jilma B. et al. The aptamer ARC1779 blocks von Willebrand factor-dependent platelet function in patients with thrombotic thrombocytopenic purpura ex vivo. Transfusion 2010; 50: 1079-1087.
• 36 Spiel AO, Gilbert JC, Jilma B. von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation 2008; 117: 1449-1459.
• 37 Goel S, Desai K, Macapinlac M. et al. A phase I safety and dose escalation trial of docetaxel combined with GEM231, a second generation antisense oligonucleo-tide targeting protein kinase A R1alpha in patients with advanced solid cancers. Invest New Drugs 2006; 24: 125-134.
• 38 Henry SP, Novotny W, Leeds J. et al. Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense Nucleic Acid Drug Dev 1997; 7: 503-510.