First-in-Human Evaluation of Anti–von Willebrand Factor Therapeutic Aptamer ARC1779 in Healthy Volunteers

Abstract

Background-ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic agent for use in patients with acute coronary syndromes. Methods and Results-This was a randomized, double-blind, placebo-controlled study in 47 healthy volunteers of doses of ARC1779 from 0.05 to 1.0 mg/kg. Pharmacodynamic effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer. In terms of pharmacokinetics, the concentration-time profile of ARC1779 appeared monophasic. The observed concentration and area under the curve were dose proportional. The mean apparent elimination half-life was Ϸ2 hours, and mean residence time was Ϸ3 hours. The mean apparent volumes of distribution (at steady state and during terminal phase) were approximately one half the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance ranged from Ϸ10% to Ϸ21% of the glomerular filtration rate, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. Inhibition of vWF A1 binding activity was achieved with an EC 90 value of 2.0 g/mL (151 nmol/L) and of platelet function with an EC 90 value of 2.6 g/mL (196 nmol/L). ARC1779 was generally well tolerated, and no bleeding was observed. Adverse events tended to be minor and not dose related. Conclusions-This is the first-in-human evaluation of a novel aptamer antagonist of vWF. ARC1779 produced dose-and concentration-dependent inhibition of vWF activity and platelet function with duration of effect suitable for the intended clinical use in acute coronary syndromes.

The kinetics of αIIbβ3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy

“…Confirming this hypothesis, interventions that predominantly inhibit thrombosis under arterial shear conditions, such as inhibitors of the GPIb-von Willebrand factor interaction, do not markedly affect hemostasis in laboratory animals or humans. [31][32][33][34] Based on these studies, we propose inhibition of CalDAG-GEFI (or other molecules that are important for the first phase of ␣IIb␤3 activation) as a new strategy for antiplatelet therapy. CalDAG-GEFI plays a unique and critical role downstream of all agonist receptors that stimulate the activation of phospholipase C. Thus, inhibition of 1 molecule will affect multiple activation pathways.…”

Inhibition of cell adhesion by anti–P-selectin aptamer: a new potential therapeutic agent for sickle cell disease

“…They include antivon Willebrand factor aptamer ARC1779, which has completed a phase I clinical study with healthy volunteers and is now in a phase II study in patients with von Willebrand factor-related platelet function disorders. 15,45,46 REG1, anti-factor IX aptamer, was evaluated in both phase I and phase II studies of cardiopulmonary bypass surgery. 47,48 NU172, a direct thrombin inhibitor, has completed a phase I study.…”

Aptamers Are New Pharmacological Substances for the Development of Anticoagulants

“…Ингибирование активности фВБ сопро-вождалось резким и насыщаемым (при высо-ких дозировках) удлинением времени оста-новки тока крови («closure time») через специ-альный картридж, покрытый коллагеном и АДФ, в приборе PFA (Platelet Function Analyzer, анализатор функции тромбоцитов), что свиде-тельствовало о подавлении фВБ-зависимых реакций тромбоцитов. Благодаря защитным модификациям аптамера и присоединению 20-кДа ПЭГ, время полужизни (t1/2) ARC1779 составило около 2 часов после болюсного вве-дения (немодифицированные аптамеры обыч-но выводятся из кровотока в течение 10-15 мин) [9]. Дальнейшие клинические испытания ARC1779 в рамках фазы II проводились по двум основ-ным направлениям.…”