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Thromb Haemost 2011; 105(03): 545-552
DOI: 10.1160/TH10-08-0520
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura

Petra Jilma-Stohlawetz   *
1   Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
,
Monika E. Gorczyca   *
2   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
Bernd Jilma
2   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
Jolanta Siller-Matula
2   Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
,
James C. Gilbert
4   Archemix Corp, Cambridge, Massachusetts, USA
,
Paul Knöbl
3   Department of Internal Medicine I, Div. of Haematology and Haemostasis, Medical University of Vienna, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Received: 11 August 2010

Accepted after minor revision: 25 November 2010

Publication Date:
27 November 2017 (online)

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Summary

Thrombotic thrombocytopenic purpura (TTP) can cause severe organ damage due to enhanced platelet aggregation by ultra-large von Wille-brand factor (VWF) multimers. Thus inhibition of VWF by the anti-VWF ARC1779 might potentially be beneficial for TTP patients. This prospective trial tested the safety, pharmacokinetics and pharmacodynamics of the anti-VWF aptamer ARC1779 added to plasma exchange therapy (PEX) in patients with acute TTP. Seven patients received bolus primed continuous i.v. infusions of ARC1779 (1–2 μg/kg/min) in addition to PEX until remission of TTP was induced or for 14 days. Mean steady state ARC1779 plasma concentrations of 9.9 μg/ml reduced VWF activity to 5% (mean baseline activity was 125% in TTP patients compared to a reference plasma). PEX reduced ARC1779 levels by 50%, but steady state concentrations were restored rapidly with a mini-bolus. After discontinuation of PEX, ARC1779 alone further increased platelet counts in one patient. Stopping ARC1779 was associated with an immediate drop of platelet counts in this patient. This suggests that ARC1779 can block the progression of TTP in patients with severe ADAMTS13 is deficiency. ARC1779 was generally well tolerated without any signs of bleeding. Pharmacokinetics and pharmacodynamics of ARC1779 were well predictable and in agreement with those observed in a previous trial with healthy volunteers. Based on its mechanism of action and the observed effect on platelet counts, ARC1779 used as an adjunctive to PEX may help accelerate recovery from organ dysfunction.

Keywords

Aptamer - ARC1779 - thrombotic thrombocytopenic purpura (TTP) - platelets - von Willebrand factor (VWF)

* These authors contributed equally.


 

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