title: 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.
  
  
  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 approximately 2 hours, and mean residence time was approximately 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 approximately 10% to approximately 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 EC(90) value of 2.0 mug/mL (151 nmol/L) and of platelet function with an EC(90) value of 2.6 mug/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.
authors.affiliation: Archemix Corp., 300 Third St, Cambridge, MA 02142, USA. jgilbert@archemix.com
authors.forename: James C
authors.initials: JC
authors.lastname: Gilbert
authors.forename: Tia
authors.initials: T
authors.lastname: DeFeo-Fraulini
authors.forename: Renta M
authors.initials: RM
authors.lastname: Hutabarat
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Horvath
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Merlino
authors.forename: H Nicholas
authors.initials: HN
authors.lastname: Marsh
authors.forename: Judith M
authors.initials: JM
authors.lastname: Healy
authors.forename: Sleiman
authors.initials: S
authors.lastname: Boufakhreddine
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Holohan
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schaub
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000293:Adolescent; D000328:Adult; D000368:Aged; D052157:Aptamers, Nucleotide / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010979:Platelet Function Tests; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000819:agonists; D017434:Protein Structure, Tertiary; D013997:Time Factors; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors*
chemical_list: C526287:ARC 1779; D052157:Aptamers, Nucleotide; D005343:Fibrinolytic Agents; D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor