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(Circulation. 2007;116:2678-2686.)
© 2007 American Heart Association, Inc.

Coronary Heart Disease

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

James C. Gilbert, MD; Tia DeFeo-Fraulini, MS; Renta M. Hutabarat, PhD; Christopher J. Horvath, DVM; Patricia G. Merlino, MS; H. Nicholas Marsh, PhD; Judith M. Healy, PhD; Sleiman BouFakhreddine, MD; Thomas V. Holohan, MD; Robert G. Schaub, PhD

From Archemix Corp., Cambridge, Mass (J.C.G., T.D.-F., R.M.H., C.J.H., P.G.M., H.N.M., J.M.H., R.G.S.), and Bioanalytical Systems, Inc, Baltimore, Md (S.B., T.V.H.).

Correspondence to James C. Gilbert, MD, Archemix Corp., 300 Third St, Cambridge, MA 02142. E-mail jgilbert{at}archemix.com

Received July 3, 2007; accepted September 18, 2007.

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 2 hours, and mean residence time was 3 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 10% to 21% 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 EC₉₀ value of 2.0 µg/mL (151 nmol/L) and of platelet function with an EC₉₀ value of 2.6 µg/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.

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