First Human Use of RUC-4: A Nonactivating Second-Generation Small-Molecule Platelet Glycoprotein IIb/IIIa (Integrin αIIbβ3) Inhibitor Designed for Subcutaneous Point-of-Care Treatment of ST-Segment-Elevation Myocardial Infarction

J Am Heart Assoc. 2020 Sep;9(17):e016552. doi: 10.1161/JAHA.120.016552. Epub 2020 Aug 26.

Abstract

Background Despite reductions in door-to-balloon times for primary coronary intervention, mortality from ST-segment-elevation myocardial infarction has plateaued. Early pre-primary coronary intervention treatment of ST-segment-elevation myocardial infarction with glycoprotein IIb/IIIa inhibitors improves pre-primary coronary intervention coronary flow, limits infarct size, and improves survival. We report the first human use of a novel glycoprotein IIb/IIIa inhibitor designed for subcutaneous first point-of-care ST-segment-elevation myocardial infarction treatment. Methods and Results Healthy volunteers and patients with stable coronary artery disease receiving aspirin received escalating doses of RUC-4 or placebo in a sentinel-dose, randomized, blinded fashion. Inhibition of platelet aggregation (IPA) to ADP (20 μmol/L), RUC-4 blood levels, laboratory evaluations, and clinical assessments were made through 24 hours and at 7 days. Doses were increased until reaching the biologically effective dose (the dose producing ≥80% IPA within 15 minutes, with return toward baseline within 4 hours). In healthy volunteers, 15 minutes after subcutaneous injection, mean±SD IPA was 6.9%+7.1% after placebo and 71.8%±15.0% at 0.05 mg/kg (n=6) and 84.7%±16.7% at 0.075 mg/kg (n=6) after RUC-4. IPA diminished over 90 to 120 minutes. In patients with coronary artery disease, 15 minutes after subcutaneous injection of placebo or 0.04 mg/kg (n=2), 0.05 mg/kg (n=6), and 0.075 mg/kg (n=18) of RUC-4, IPA was 14.6%±11.7%, 53.6%±17.0%, 76.9%±10.6%, and 88.9%±12.7%, respectively. RUC-4 blood levels correlated with IPA. Aspirin did not affect IPA or RUC-4 blood levels. Platelet counts were stable and no serious adverse events, bleeding, or injection site reactions were observed. Conclusions RUC-4 provides rapid, high-grade, limited-duration platelet inhibition following subcutaneous administration that appears to be safe and well tolerated. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NTC03844191.

Trial registration: ClinicalTrials.gov NCT03844191.

Keywords: GPIIb/IIIa; STEMI; myocardial infarction; platelet inhibitor.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aspirin / therapeutic use*
  • Case-Control Studies
  • Coronary Artery Disease / drug therapy
  • Female
  • Humans
  • Injections, Subcutaneous
  • Male
  • Middle Aged
  • Placebos / administration & dosage
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Platelet Count / statistics & numerical data
  • Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
  • Point-of-Care Systems / standards
  • Pyrimidinones / administration & dosage
  • Pyrimidinones / adverse effects
  • Pyrimidinones / pharmacokinetics
  • Pyrimidinones / therapeutic use*
  • ST Elevation Myocardial Infarction / drug therapy*
  • Thiadiazoles / administration & dosage
  • Thiadiazoles / adverse effects
  • Thiadiazoles / pharmacokinetics
  • Thiadiazoles / therapeutic use*
  • Treatment Outcome
  • Young Adult

Substances

  • Placebos
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Pyrimidinones
  • RUC-4 compound
  • Thiadiazoles
  • Aspirin

Associated data

  • ClinicalTrials.gov/NCT03844191