Abstract 3218: Pharmacokinetics, Pharmacodynamics, and Safety of an Anti-von Willebrand Factor Therapeutic Aptamer, ARC1779, in Healthy Volunteers

Abstract

Background: The prominent role played by vWF in arterial thrombogenesis suggests that vWF inhibition may offer an effective adjunct therapy to PCI in ACS patients. ARC1779 is a PEG-conjugated aptamer that blocks platelet activation through inhibition of vWF A1 domain binding to platelet receptor GPIb. Design: This was an ascending-dose, double-blind, placebo-controlled study in 47 healthy volunteers at doses of 0 (placebo, n = 6) or 0.05 to 1.0 mg/kg ARC1779 (n = 41) given via IV push, “slow bolus” IV infusion over 15 minutes, or “slow bolus” followed by 4-hour IV infusion. PK parameters were estimated from plasma ARC1779 concentrations determined with a validated assay. PD effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer, the PFA-100 ® . PK: The concentration-time profiles for ARC1779 after IV push or slow bolus appeared monophasic, though the terminal phase may not have been fully captured. The C max and AUC values were dose-proportional. The highest exposure was observed after 1.0 mg/kg slow bolus, with mean C max of 21.15 μg/mL and AUC (0-∞) of 80.92 μ g·hr/mL. The mean apparent elimination half-life (t 1/2β ) was ~2 hours and mean residence time (MRT) was ~3 hours. The mean apparent volumes of distribution (V z and V ss ) were ~1/2 of the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance (CL) values ranged from ~10% to 21% of GRF, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. PD: Inhibition of vWF A1 binding was achieved in a dose- and concentration-dependent manner, with respective EC 50 and EC 90 values of 0.22 μ g/mL (17 nM) and 1.98 μg/mL (151 nM). Platelet function inhibition (PFA-100 ® closure time) was achieved, with respective EC 50 and EC 90 values of 0.75 μ g/mL (57 nM) and 2.57 μg/mL (196 nM). vWF activity returned in a dose- and concentration-dependent manner. Safety: ARC1779 was generally well tolerated and no bleeding was observed. Adverse events tended to be minor and not dose related. One volunteer had a hypersensitivity reaction to IV push administration, but no such reactions occurred at higher doses given by slow bolus or infusion. Conclusion: The PK, PD and safety profile of ARC1779 supports its therapeutic potential for use in ACS.