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

Willem L. Bor; Kai L. Zheng; Anne H. Tavenier; C. Michael Gibson; Christopher B. Granger; Ohad Bentur; Rita Lobatto; Sonja Postma; Barry S. Coller; Arnoud W. J. van 't Hof; Jurrien M. Ten Berg

doi:10.4244/EIJ-D-21-00287

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

Willem L. Bor, Kai L. Zheng, Anne H. Tavenier, C. Michael Gibson, Christopher B. Granger, Ohad Bentur, Rita Lobatto, Sonja Postma, Barry S. Coller, Arnoud W. J. van 't Hof, Jurrien M. Ten Berg^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	401-410
Number of pages	73
Journal	Eurointervention
Volume	17
Issue number	5
DOIs	https://doi.org/10.4244/EIJ-D-21-00287
Publication status	Published - Aug 2021

Keywords

2017 ESC
ANTIPLATELET THERAPY
IMPACT
PERCUTANEOUS CORONARY INTERVENTION
PREHOSPITAL INITIATION
PRIMARY ANGIOPLASTY
STEMI
THROMBOCYTOPENIA
TICAGRELOR
TIROFIBAN
adjunctive pharmacotherapy
clinical research
clinical trials
innovation
ALPHA-IIB-BETA-3 ANTAGONIST

Access to Document

10.4244/EIJ-D-21-00287

Cite this

Bor, W. L., Zheng, K. L., Tavenier, A. H., Gibson, C. M., Granger, C. B., Bentur, O., Lobatto, R., Postma, S., Coller, B. S., van 't Hof, A. W. J., & Ten Berg, J. M. (2021). 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, 17(5), 401-410. https://doi.org/10.4244/EIJ-D-21-00287

@article{14ad768a8f4c49f1a9c0ea409d761b12,

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

abstract = "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.",

keywords = "2017 ESC, ANTIPLATELET THERAPY, IMPACT, PERCUTANEOUS CORONARY INTERVENTION, PREHOSPITAL INITIATION, PRIMARY ANGIOPLASTY, STEMI, THROMBOCYTOPENIA, TICAGRELOR, TIROFIBAN, adjunctive pharmacotherapy, clinical research, clinical trials, innovation, ALPHA-IIB-BETA-3 ANTAGONIST",

author = "Bor, {Willem L.} and Zheng, {Kai L.} and Tavenier, {Anne H.} and Gibson, {C. Michael} and Granger, {Christopher B.} and Ohad Bentur and Rita Lobatto and Sonja Postma and Coller, {Barry S.} and {van 't Hof}, {Arnoud W. J.} and {Ten Berg}, {Jurrien M.}",

note = "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 {\textquoteleft}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: {\textcopyright} Europa Digital & Publishing 2021. All rights reserved.",

year = "2021",

month = aug,

doi = "10.4244/EIJ-D-21-00287",

language = "English",

volume = "17",

pages = "401--410",

journal = "Eurointervention",

issn = "1774-024X",

publisher = "Europa Digital & Publishing",

number = "5",

}

Bor, WL, Zheng, KL, Tavenier, AH, Gibson, CM, Granger, CB, Bentur, O, Lobatto, R, Postma, S, Coller, BS, van 't Hof, AWJ & Ten Berg, JM 2021, '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, vol. 17, no. 5, pp. 401-410. https://doi.org/10.4244/EIJ-D-21-00287

Pharmacokinetics, pharmacodynamics, and tolerability of subcutaneous administration of a novel glycoprotein IIb/IIIa inhibitor, RUC-4, in patients with ST-segment elevation myocardial infarction. / Bor, Willem L.; Zheng, Kai L.; Tavenier, Anne H. et al.
In: Eurointervention, Vol. 17, No. 5, 08.2021, p. 401-410.

Research output: Contribution to journal › Article › Academic › peer-review

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 -