August 26, 2020Open Access
View Full PaperFirst 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
Structured PICO
Does subcutaneous RUC-4 provide rapid inhibition of platelet aggregation in healthy volunteers and patients with stable coronary artery disease?
P
Population
Healthy volunteers and patients with stable coronary artery disease receiving aspirin
I
Intervention
Escalating doses of RUC-4 (up to 0.075 mg/kg) via subcutaneous injection
C
Comparator
Placebo
O
Outcome
Inhibition of platelet aggregation (IPA) to ADP (20 μmol/L) within 15 minutessurrogate
Subcutaneous RUC-4 provides rapid, high-grade, and limited-duration platelet inhibition, demonstrating potential as a point-of-care treatment for STEMI.
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.clinicaltrials.gov; Unique identifier: NTC03844191.