title: Novel antiplatelet drug revacept (Dimeric Glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans.
abstract: BACKGROUND
  Blocking of glycoprotein VI-dependent pathways by interfering in vascular collagen sites is commonly seen as an attractive target for an antiplatelet therapy of acute atherosclerotic diseases such as myocardial infarction or stroke. Revacept (soluble dimeric glycoprotein VI-Fc fusion protein) has been shown to reduce platelet adhesion by blocking vascular collagen in plaques or erosion and to be safe in preclinical studies. A dose-escalating clinical phase I study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of Revacept in humans.
  
  
  RESULTS
  In a first-in-humans study, 30 healthy men received a single intravenous administration of 10, 20, 40, 80, or 160 mg Revacept. The serum concentration-time courses of each dosage of Revacept showed a narrow variation and a concentration and time dependence. Revacept did not significantly affect the bleeding time. Collagen-induced platelet aggregation was dose-dependently inhibited up to 48 hours at lower doses and for 7 days after higher dose levels. In contrast, ADP- or thrombin receptor activating peptide-dependent platelet aggregation remained unaltered. There were no relevant drug-related adverse events or drug-related changes in laboratory parameters (biochemistry, hematology, and coagulation parameters). There were no drug-related changes in blood pressure, pulse rate, or ECG parameters (including 24-hour Holter monitoring). No anti-Revacept antibodies were detected.
  
  
  CONCLUSIONS
  This phase I study demonstrated that Revacept is a safe and well-tolerated new antiplatelet compound with a clear dose-dependent pharmacokinetic profile with specific, dose-related inhibition of platelet aggregation despite completely unaltered general hemostasis.
  
  
  BACKGROUND
  URL: www.clinicaltrials.gov. Unique identifier: NCT 01042964. URL: eudract.ema.europa.eu. Identifier: 2005-004656-12.
authors.affiliation: Martinsried, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Ungerer
authors.forename: Kai
authors.initials: K
authors.lastname: Rosport
authors.forename: Andreas
authors.initials: A
authors.lastname: Bültmann
authors.forename: Richard
authors.initials: R
authors.lastname: Piechatzek
authors.forename: Kerstin
authors.initials: K
authors.lastname: Uhland
authors.forename: Peter
authors.initials: P
authors.lastname: Schlieper
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.forename: Götz
authors.initials: G
authors.lastname: Münch
mesh_terms: D000328:Adult; D000818:Animals; D016466:CHO Cells; D003094:Collagen / Q000008:administration & dosage; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000008:administration & dosage*; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000009:adverse effects; D007275:Injections, Intravenous; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010976:Platelet Count; D010980:Platelet Membrane Glycoproteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D006023:Glycoproteins; D007141:Immunoglobulin Fc Fragments; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C559357:Revacept; C098341:platelet membrane glycoprotein VI; D003094:Collagen