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.

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.

• Authors: Dean J Kereiakes, Tim D Henry, Anthony N DeMaria, Ohad Bentur, Marilyn Carlson, Corinne Seng Yue, Linda H Martin, Jeff Midkiff, Michele Mueller, Terah Meek, Deborah Garza, C Michael Gibson, Barry S Coller
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 9 Issue 17 Pg. e016552 (09 2020) ISSN: 2047-9980 [Electronic] England
• PMID: 32844723 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, adverse effects, pharmacokinetics, therapeutic use)
• ST Elevation Myocardial Infarction (drug therapy)
• Thiadiazoles (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome
• Young Adult