title: ARC15105 is a potent antagonist of von Willebrand factor mediated platelet activation and adhesion.
abstract: OBJECTIVE
  We investigated the stability, pharmacokinetic, and pharmacodynamic profile of the 2(nd) generation anti-von Willeband factor aptamer ARC15105.
  
  
  RESULTS
  Platelet plug formation was measured by collagen/adenosine diphosphate-induced closure time with the platelet function analyzer-100 and platelet aggregation by multiple electrode aggregometry. Platelet adhesion was measured on denuded porcine aortas and in a flow chamber. Aptamer stability was assessed by incubation in nuclease rich human, monkey, and rat serum for up to 72 hours. Pharmacokinetic and pharmacodynamic profiles were tested in cynomolgus monkeys after IV and SC administration. The median IC(100) and IC(50) to prolong collagen/adenosine diphosphate-induced closure timewere 27 nmol/L and 12 nmol/L, respectively. ARC15105 (1.3 μmol/L) completely inhibited ristocetin-induced platelet aggregation in whole blood (P<0.001), but also diminished collagen, ADP, arachidonic acid, and thrombin receptor activating peptide-induced platelet aggregation to some extent (P<0.05). ARC15105 (40 nmol/L) decreased platelet adhesion by >90% on denuded porcine aortas (P<0.001), which was comparable to the degree of inhibition obtained with abciximab. ARC15105 (100 nmol/L) also inhibited platelet adhesion to collagen under arterial shear in a flow chamber by >90% (P<0.001). The IV and SC terminal half-lives in cynomolgus monkeys were 67 and 65 hours, respectively, and the SC bioavailability was ≈98%. Allometric scaling estimates the human T(1/2) would be ≈217 hours. Pharmacodynamic analysis confirms that ARC15105 inhibits von Willeband factor activity >90% in blood samples taken 300 hours after a 20 mg/kg IV or SC dose in monkeys.
  
  
  CONCLUSIONS
  The potency, pharmacokinetic profile, and SC bioavailability of ARC15105 support its clinical investigation for chronic inhibition of von Willeband factor -mediated platelet activation.
authors.affiliation: Department of Cardiology, Medical University of Vienna, Austria.
authors.forename: Jolanta M
authors.initials: JM
authors.lastname: Siller-Matula
authors.forename: Yahye
authors.initials: Y
authors.lastname: Merhi
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanguay
authors.forename: Daniel
authors.initials: D
authors.lastname: Duerschmied
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: McGinness
authors.forename: P Shannon
authors.initials: PS
authors.lastname: Pendergrast
authors.forename: Jou-Ku
authors.initials: JK
authors.lastname: Chung
authors.forename: Xianbin
authors.initials: X
authors.lastname: Tian
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schaub
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
mesh_terms: D000368:Aged; D000818:Animals; D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D052158:Aptamers, Peptide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001317:Austria; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D001900:Boston; D016022:Case-Control Studies; D003094:Collagen / Q000378:metabolism; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood*; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010979:Platelet Function Tests; D011485:Protein Binding; D011792:Quebec; D051381:Rats; D013552:Swine; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C572071:ARC15105; D052157:Aptamers, Nucleotide; D052158:Aptamers, Peptide; D010975:Platelet Aggregation Inhibitors; D014841:von Willebrand Factor; D003094:Collagen