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

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.