Coronary interventions

Pharmacokinetics, pharmacodynamics, and tolerability of subcutaneous administration of a novel glycoprotein IIb/IIIa inhibitor, RUC-4, in patients with ST-segment elevation myocardial infarction

EuroIntervention 2021;17:401-410. DOI: 10.4244/EIJ-D-21-00287

Willem  L. Bor
Willem L. Bor1, MD; Kai L. Zheng1, MD; Anne H. Tavenier2, MD; C. Michael Gibson3, MD; Christopher B. Granger4, MD; Ohad Bentur5, MD; Rita Lobatto6, MD, MPH; Sonja Postma7, PhD; Barry S. Coller5, MD; Arnoud W.J. van ’t Hof2,8,9,10, MD, PhD; Jurrien M. ten Berg1,8,9, MD, PhD
1. Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands; 2. Isala Hospital, Zwolle, the Netherlands; 3. Beth Israel Deaconess Medical Center, Boston, MA, USA; 4. Duke University School of Medicine, Durham, NC, USA; 5. Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY, USA; 6. RP & L Consultancy B.V., Wassenaar, the Netherlands; 7. Diagram B.V., Zwolle, the Netherlands; 8. University Medical Center Maastricht, Maastricht, the Netherlands; 9. Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands; 10. Zuyderland Hospital, Heerlen, the Netherlands

Background: Pre-hospital platelet inhibition in patients with ST-segment elevation myocardial infarction (STEMI) may improve outcomes. RUC-4 is a novel, second-generation glycoprotein IIb/IIIa inhibitor designed for first-point-of-medical-contact treatment for STEMI by subcutaneous injection.

Aims: The open-label, phase 2A, CEL-02 trial aimed to assess the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of RUC-4 in STEMI patients undergoing primary PCI (pPCI).

Methods: A total of 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before pPCI in escalating doses (0.075 mg/kg [n=8], 0.090 mg/kg [n=9], or 0.110 mg/kg [n=10]).

Results: The primary PD endpoint of high-grade (≥77%) inhibition of the VerifyNow iso-TRAP assay at 15 minutes was met in 3/8, 7/8, and 7/8 patients in the three cohorts with a dose-response relationship (mean inhibition [min - max] of 77.5% [65.7%-90.6%], 87.5% [73.8%-93.1%], and 91.7% [76.4%-99.3%], respectively; ptrend=0.002). Fifty percent (50%) inhibition remained after 89.1 (38.0-129.7), 104.2 (17.6-190.8), and 112.4 (19.7-205.0) minutes. Injection site reactions or bruising were observed in 1 (4%) and 11 (41%) patients, respectively. Mild access-site haematomas occurred in 6 (22%), and severe access-site haematomas occurred in 2 patients (7%). No thrombocytopaenia was observed within 72 hours post dose.

Conclusions: In patients with STEMI, a single subcutaneous dose of RUC-4 at 0.075, 0.090, and 0.110 mg/kg showed dose-response high-grade inhibition of platelet function within 15 minutes.

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