2. Academic Validation
  3. PAR1 (Protease-Activated Receptor 1) Pepducin Therapy Targeting Myocardial Necrosis in Coronary Artery Disease and Acute Coronary Syndrome Patients Undergoing Cardiac Catheterization: A Randomized, Placebo-Controlled, Phase 2 Study

PAR1 (Protease-Activated Receptor 1) Pepducin Therapy Targeting Myocardial Necrosis in Coronary Artery Disease and Acute Coronary Syndrome Patients Undergoing Cardiac Catheterization: A Randomized, Placebo-Controlled, Phase 2 Study

  • Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):2990-3003. doi: 10.1161/ATVBAHA.120.315168.
Athan Kuliopulos 1,  Paul A Gurbel 2,  Jeffrey J Rade 3,  Carey D Kimmelstiel 4,  Susan E Turner 1,  Kevin P Bliden 2,  Elizabeth K Fletcher 1,  Daniel H Cox 1,  Lidija Covic 1,  TRIP-PCI Investigators
Affiliations

Affiliations

  • 1 Center for Hemostasis and Thrombosis Research, Tufts Medical Center, Tufts University School of Medicine, Boston, MA (A.K., S.E.T., E.K.F., D.H.C., L.C.).
  • 2 Inova Center for Thrombosis Research and Translational Medicine, Inova Fairfax Hospital, Falls Church, VA and Sinai Hospital of Baltimore, MD (P.A.G., K.P.B.).
  • 3 Division of Cardiology, Department of Medicine, University of Massachusetts Memorial Medical Center, University of Massachusetts Medical School, Worcester (J.J.R).
  • 4 Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA (C.D.K.).
PMID: 33028101 DOI: 10.1161/ATVBAHA.120.315168
Abstract

Objective: Arterial thrombosis leading to ischemic injury worsens the prognosis of many patients with Cardiovascular Disease. PZ-128 is a first-in-class pepducin that reversibly inhibits PAR1 (Protease-activated Receptor 1) on platelets and Other vascular cells by targeting the intracellular surface of the receptor. The TRIP-PCI (Thrombin Receptor Inhibitory Pepducin in Percutaneous Coronary Intervention) trial was conducted to assess the safety and efficacy of PZ-128 in patients undergoing cardiac catheterization with intent to perform percutaneous coronary intervention. Approach and Results: In this randomized, double-blind, placebo-controlled, phase 2 trial, 100 patients were randomly assigned (2:1) to receive PZ-128 (0.3 or 0.5 mg/kg), or placebo in a 2-hour infusion initiated just before the start of cardiac catheterization, on top of standard oral antiplatelet therapy. Rates of the primary end point of bleeding were not different between the combined PZ-128 doses (1.6%, 1/62) and placebo group (0%, 0/35). The secondary end points of major adverse coronary events at 30 and 90 days did not significantly differ but were numerically lower in the PZ-128 groups (0% and 2% in the PZ-128 groups, 6% and 6% with placebo, p=0.13, p=0.29, respectively). In the subgroup of patients with elevated baseline cardiac troponin I, the exploratory end point of 30-day major adverse coronary events + myocardial injury showed 83% events in the placebo group versus 31% events in the combined PZ-128 drug groups, an adjusted relative risk of 0.14 (95% CI, 0.02-0.75); P=0.02.

Conclusions: In this first-in-patient experience, PZ-128 added to standard antiplatelet therapy appeared to be safe, well tolerated, and potentially reduced periprocedural myonecrosis, thus providing the basis for further clinical trials. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02561000.

Keywords

acute coronary syndrome; coronary artery disease; myocardial infarction; percutaneous coronary intervention; troponin.

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