TY - JOUR
T1 - Pharmacokinetics, pharmacodynamics, and tolerability of subcutaneous administration of a novel glycoprotein IIb/IIIa inhibitor, RUC-4, in patients with ST-segment elevation myocardial infarction
AU - Bor, Willem L.
AU - Zheng, Kai L.
AU - Tavenier, Anne H.
AU - Gibson, C. Michael
AU - Granger, Christopher B.
AU - Bentur, Ohad
AU - Lobatto, Rita
AU - Postma, Sonja
AU - Coller, Barry S.
AU - van 't Hof, Arnoud W. J.
AU - Ten Berg, Jurrien M.
N1 - Funding Information:
M. Gibson receives research support from Johnson & Johnson. He receives consulting support from AstraZeneca, Johnson & Johnson, and Janssen & Bayer. C. Granger reports consultancy or research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CeleCor, Daiichi Sankyo, Janssen, Pfizer, Novartis, NHLBI, and the FDA. O. Bentur reports research fees from CeleCor and Pulmoquine Therapeutics. B.S. Coller receives royalties from the sales of abciximab (Centocor/Janssen) and the VerifyNow assays (Accumetrics/Instrumentation Laboratories). He is also an inventor of RUC-4, a founder and equity holder in CeleCor, and a consultant to CeleCor. B.S. Coller served as a nonvoting scientific consultant to the Safety Review Committee and was supported in part by grant 19278 from the National Heart, Lung and Blood Institute and Clinical and Translational Science grant UL1 TR001866 from the National Center for Advancing Translational Science. A.W.J. van ‘t Hof reports institutional unrestricted grants from Medtronic, Boehringer Ingelheim, AstraZeneca and Abbott, not related to this work. J.M. ten Berg reports lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia. He received institutional research grants from ZonMw, and AstraZeneca. The other authors have no conflicts of interest to declare.
Funding Information:
This study was supported by a grant and materials provided by CeleCor Therapeutics.
Publisher Copyright:
© Europa Digital & Publishing 2021. All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - 2017 ESC
KW - ANTIPLATELET THERAPY
KW - IMPACT
KW - PERCUTANEOUS CORONARY INTERVENTION
KW - PREHOSPITAL INITIATION
KW - PRIMARY ANGIOPLASTY
KW - STEMI
KW - THROMBOCYTOPENIA
KW - TICAGRELOR
KW - TIROFIBAN
KW - adjunctive pharmacotherapy
KW - clinical research
KW - clinical trials
KW - innovation
KW - ALPHA-IIB-BETA-3 ANTAGONIST
U2 - 10.4244/EIJ-D-21-00287
DO - 10.4244/EIJ-D-21-00287
M3 - Article
C2 - 34031019
SN - 1774-024X
VL - 17
SP - 401
EP - 410
JO - Eurointervention
JF - Eurointervention
IS - 5
ER -