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

Dean J Kereiakes, Tim D Henry, Anthony N DeMaria, Ohad Bentur, Marilyn Carlson, Corinne Seng Yue, Linda H Martin, Jeff Midkiff, Michele Mueller, Terah Meek, Deborah Garza, C Michael Gibson, Barry S Coller, Dean J Kereiakes, Tim D Henry, Anthony N DeMaria, Ohad Bentur, Marilyn Carlson, Corinne Seng Yue, Linda H Martin, Jeff Midkiff, Michele Mueller, Terah Meek, Deborah Garza, C Michael Gibson, Barry S Coller

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.clini​caltr​ials.gov; Unique identifier: NTC03844191.

Trial registration: ClinicalTrials.gov NCT03844191.

Keywords: GPIIb/IIIa; STEMI; myocardial infarction; platelet inhibitor.

Conflict of interest statement

Dr Barry S. Coller reports that he 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. Dr Coller served as a nonvoting scientific consultant to the Safety Review Committee. Specifically, he made no determinations about adverse events related to RUC‐4. Dr Gibson reports grants and personal fees from Angel Medical Corporation, Bayer Corp., CSL Behring, Janssen Pharmaceuticals, and Johnson & Johnson Corporation; personal fees from The Medicines Company, Boston Clinical Research Institute, Cardiovascular Research Foundation, Eli Lilly and Company, Gilead Sciences, Inc., Novo Nordisk, WebMD, UpToDate in Cardiovascular Medicine, Amarin Pharma, Amgen, Boehringer Ingelheim, Chiesi, Merck & Co., Inc., PharmaMar, Sanofi, Somahlution, St. Francis Hospital, Verreseon Corporation, Boston Scientific, Duke Clinical Research Institute, Impact Bio, LTD, MedImmune, Medtelligence, Microport, PERT Consortium, GE Healthcare, Caladrius Bioscience, CeleCor Therapeutics, Thrombolytic Science, AstraZeneca, Eidos Therapeutics, and Kiniksa Pharmaceuticals; grants and personal fees from Portola Pharmaceuticals; other from nference; nonfinancial support from Baim Institute; and grants from Bristol‐Myers Squibb and SCAD Alliance. The remaining authors have no disclosures to report.

Figures

Figure 1. RUC‐4 phase I dose‐escalation study…
Figure 1. RUC‐4 phase I dose‐escalation study design.
CAD indicates coronary artery disease; and Red, placebo treated.
Figure 2. Inhibition of ADP‐induced platelet aggregation…
Figure 2. Inhibition of ADP‐induced platelet aggregation over time after subcutaneous RUC‐4 in (A) healthy volunteers, and (B) patients with stable coronary artery disease receiving aspirin.
Figure 3. Mean concentration time profiles of…
Figure 3. Mean concentration time profiles of RUC‐4 by dose level (semi‐log scale).
Figure 4. Correlation between inhibition of platelet…
Figure 4. Correlation between inhibition of platelet aggregation and RUC‐4 concentration.
Figure 5. Effect of sex, weight, body…
Figure 5. Effect of sex, weight, body mass index (BMI), or aspirin on clearance (area under the curve/ total dose).
Only weight significantly influenced the pharmacokinetic model.

References

    1. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli‐Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST‐segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST‐segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;119–177.
    1. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, et al. 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST‐elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST‐elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2016;1135–1147.
    1. De Luca G, van't Hof AW, Gibson CM, Cutlip D, Zeymer U, Noc M, Maioli M, Zorman S, Gabriel HM, Emre A, et al. Impact of time from symptom onset to drug administration on outcome in patients undergoing glycoprotein IIb‐IIIa facilitated primary angioplasty (from the EGYPT cooperation). Am J Cardiol. 2015;711–715.
    1. Hassan AK, Liem SS, van der Kley F, Bergheanu SC, Wolterbeek R, Bosch J, Bootsma M, Zeppenfeld K, van der Laarse A, Atsma DE, et al. In‐ambulance abciximab administration in STEMI patients prior to primary PCI is associated with smaller infarct size, improved LV function and lower incidence of heart failure: results from the Leiden MISSION! acute myocardial infarction treatment optimization program. Catheter Cardiovasc Interv. 2009;335–343.
    1. Menees DS, Peterson ED, Wang Y, Curtis JP, Messenger JC, Rumsfeld JS, Gurm HS. Door-to‐balloon time and mortality among patients undergoing primary PCI. N Engl J Med. 2013;901–909.
    1. Nallamothu BK, Normand ST, Wang Y, Hofer TP, Brush JEJ, Messenger JC, Bradley EH, Rumsfeld JS, Krumholz HM. Relation between door‐to‐balloon times and mortality after primary percutaneous coronary intervention over time: a retrospective study. Lancet. 2015;1114–1122.
    1. Francone M, Bucciarelli‐Ducci C, Carbone I, Canali E, Scardala R, Calabrese FA, Sardella G, Mancone M, Catalano C, Fedele F, et al. Impact of primary coronary angioplasty delay on myocardial salvage, infarct size, and microvascular damage in patients with ST‐segment elevation myocardial infarction: insight from cardiovascular magnetic resonance. J Am Coll Cardiol. 2009;2145–2153.
    1. Rakowski T, Zalewski J, Legutko J, Bartus S, Rzeszutko L, Dziewierz A, Sorysz D, Bryniarski L, Zmudka K, Kaluza GL, et al. Early abciximab administration before primary percutaneous coronary intervention improves infarct‐related artery patency and left ventricular function in high‐risk patients with anterior wall myocardial infarction: a randomized study. Am Heart J. 2007;360–365.
    1. Maioli M, Bellandi F, Leoncini M, Toso A, Dabizzi RP. Randomized early versus late abciximab in acute myocardial infarction treated with primary coronary intervention (RELAx‐AMI Trial). J Am Coll Cardiol. 2007;1517–1524.
    1. De Luca G, Gibson CM, Bellandi F, Murphy S, Maioli M, Noc M, Zeymer U, Dudek D, Arntz H‐R, Zorman S, et al. Early glycoprotein IIb‐IIIa inhibitors in primary angioplasty (EGYPT) cooperation: an individual patient data meta‐analysis. Heart. 2008;1548–1558.
    1. van't Hof AW, Ten Berg J, Heestermans T, Dill T, Funck RC, van Werkum W, Dambrink JE, Suryapranata H, van Houwelingen G, Ottervanger JP, et al. Prehospital initiation of tirofiban in patients with ST‐elevation myocardial infarction undergoing primary angioplasty (On‐TIME 2): a multicentre, double‐blind, randomised controlled trial. Lancet. 2008;537–546.
    1. Orzalkiewicz M, Hodson J, Kwok CS, Ludman PF, Giblett JP, George S, Doshi SN, Khan SQ, Kinnaird T, Hildick‐Smith D, et al. Comparison of routine versus selective glycoprotein IIb/IIIa inhibitors usage in primary percutaneous coronary intervention (from the British Cardiovascular Interventional Society). Am J Cardiol. 2019;373–380.
    1. Xu Q, Yin J, Si L. Efficacy and safety of early versus late glycoprotein IIb/IIIa inhibitors for PCI. Int J Cardiol. 2013;210–219. DOI: 10.1016/j.ijcard.2012.06.001
    1. Parodi G, Valenti R, Bellandi B, Migliorini A, Marcucci R, Comito V, Carrabba N, Santini A, Gensini GF, Abbate R, et al. Comparison of prasugrel and ticagrelor loading doses in ST‐segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol. 2013;1601–1606.
    1. Valgimigli M, Tebaldi M, Campo G, Gambetti S, Bristot L, Monti M, Parrinello G, Ferrari R. Prasugrel versus tirofiban bolus with or without short post‐bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or Shortening Infusion Line in Patients With ST‐segment Elevation Myocardial Infarction Compared to or on Top of PRasugrel Given at Loading dOse) Trial. JACC Cardiovasc Interv. 2012;268–277.
    1. Zeymer U, Mochmann HC, Mark B, Arntz HR, Thiele H, Diller F, Montalescot G, Zahn R. Double‐blind, randomized, prospective comparison of loading doses of 600 mg clopidogrel versus 60 mg prasugrel in patients with acute ST‐segment elevation myocardial infarction scheduled for primary percutaneous intervention: the ETAMI trial (Early Thienopyridine Treatment to Improve Primary PCI in Patients With Acute Myocardial Infarction). JACC Cardiovasc Interv. 2015;147–154.
    1. Parodi G, Xanthopoulou I, Bellandi B, Gkizas V, Valenti R, Karanikas S, Migliorini A, Angelidis C, Abbate R, Patsilinakos S, et al. Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study. J Am Coll Cardiol. 2015;511–512.
    1. Furtado RH, Nicolau JC, Guo J, Im K, White JA, Sabatine MS, Newby LK, Giugliano RP. Morphine and cardiovascular outcomes among patients with non‐ST-segment elevation acute coronary syndromes undergoing coronary angiography. J Am Coll Cardiol. 2020;289–300.
    1. Chintala M, Shimizu K, Ogawa M, Yamaguchi H, Doi M, Jensen P. Basic and translational research on proteinase‐activated receptors: antagonism of the proteinase‐ activated receptor 1 for thrombin, a novel approach to antiplatelet therapy for atherothrombotic disease. J Pharmacol Sci. 2008;433–438.
    1. Kim JS, Han DC, Jeong YH, Park DW, Sohn CB, Hwang KW, Lee SH, Choi JH, Chon MK, Lee SY, et al. Antiplatelet effect of ticagrelor compared to tirofiban in non‐ ST-segment elevation ACS patients undergoing PCI. The result of the TE‐CLOT trial. Thromb Haemost. 2016;213–221.
    1. Iyu D, Glenn JR, White AE, Fox SC, van Giezen H, Nylander S, Heptinstall S. Mode of action of P2Y(12) antagonists as inhibitors of platelet function. Thromb Haemost. 2011;96–106.
    1. Celi A, Merrill‐Skoloff G, Gross P, Falati S, Sim DS, Flaumenhaft R, Furie BC, Furie B. Thrombus formation: direct real‐time observation and digital analysis of thrombus assembly in a living mouse by confocal and widefield intravital microscopy. J Thromb Haemost. 2003;60–68.
    1. Xiao T, Takagi J, Coller BS, Wang JH, Springer TA. Structural basis for allostery in integrins and binding to fibrinogen‐mimetic therapeutics. Nature. 2004;59–67.
    1. Springer TA, Zhu J, Xiao T. Structural basis for distinctive recognition of fibrinogen gammaC peptide by the platelet integrin alphaIIbbeta3. J Cell Biol. 2008;791–800.
    1. Zhu J, Choi WS, McCoy JG, Negri A, Zhu J, Naini S, Li J, Shen M, Huang W, Bougie D, et al. Structure‐guided design of a high‐affinity platelet integrin αIIbβ3 receptor antagonist that disrupts Mg(2)(+) binding to the MIDAS. Sci Transl Med. 2012;125ra32.
    1. Li J, Vootukuri S, Shang Y, Negri A, Jiang JK, Nedelman M, Diacovo TG, Filizola M, Thomas CJ, Coller BS. RUC‐4: a novel αIIbβ3 antagonist for prehospital therapy of myocardial infarction. Arterioscler Thromb Vasc Biol. 2014;2321–2329.
    1. Bougie DW, Wilker PR, Wuitschick ED, Curtis BR, Malik M, Levine S, Lind RN, Pereira J, Aster RH. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand‐occupied GPIIb/IIIa. Blood. 2002;2071–2076.
    1. Coller BS. αIIbβ3: structure and function. J Thromb Haemost. 2015;65–74.
    1. Vootukuri S, Li J, Nedelman M, Thomas C, Jiang JK, Babayeva M, Coller BS. Preclinical studies of RUC-4, a novel platelet alphaiibbeta3 antagonist, in non-human primates and with human platelets. J Clin Transl Sci. 2019;3:65–74.
    1. Coller BS, Franza BR Jr., Gralnick HR. The pH dependence of quantitative ristocetin‐induced platelet aggregation: theoretical and practical implications‐ a new device for maintenance of platelet‐rich plasma pH. Blood. 1976;841–854.
    1. Garcia‐Dorado D, Garcia del Blanco B. Door-to‐balloon time and mortality. N Engl J Med. 2014;179.
    1. Bagai A, Al‐Khalidi HR, Sherwood MW, Munoz D, Roettig ML, Jollis JG, Granger CB. Regional systems of care demonstration project: Mission: Lifeline STEMI Systems Accelerator: design and methodology. Am Heart J. 2014;15–21.e3.
    1. Jollis JG, Al‐Khalidi HR, Roettig ML, Berger PB, Corbett CC, Dauerman HL, Fordyce CB, Fox K, Garvey JL, Gregory T, et al. Regional systems of care demonstration project: American Heart Association Mission: Lifeline STEMI Systems Accelerator. Circulation. 2016;365–374.
    1. Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything? Am J Cardiol. 2003;824–826.
    1. Betriu A, Masotti M. Comparison of mortality rates in acute myocardial infarction treated by percutaneous coronary intervention versus fibrinolysis. Am J Cardiol. 2005;100–101.
    1. ten Berg JM, van 't Hof AW, Dill T, Heestermans T, van Werkum JW, Mosterd A, van Houwelingen G, Koopmans PC, Stella PR, Boersma E, et al. Effect of early, pre‐hospital initiation of high bolus dose tirofiban in patients with ST‐segment elevation myocardial infarction on short‐ and long‐term clinical outcome. J Am Coll Cardiol. 2010;2446–2455.
    1. Gilchrist IC, O’Shea JC, Kosoglou T, Jennings LK, Lorenz TJ, Kitt MM, Kleiman NS, Talley D, Aguirre F, Davidson C, et al. Pharmacodynamics and pharmacokinetics of higher‐dose, double‐bolus eptifibatide in percutaneous coronary intervention. Circulation. 2001;406–411.
    1. Saucedo JF, Lui HK, Garza L, Guerra GJ, Jacoski MV, Jennings LK. Comparative pharmacodynamic evaluation of eptifibatide and abciximab in patients with non‐ST-segment elevation acute coronary syndromes: the TAM2 study. J Thromb Thrombolysis. 2004;67–74.
    1. Jennings LK, Jacoski MV, White MM. The pharmacodynamics of parenteral glycoprotein IIb/IIIa inhibitors. J Interv Cardiol. 2002;45–60.
    1. Steinhubl SR, Talley JD, Braden GA, Tcheng JE, Casterella PJ, Moliterno DJ, Navetta FI, Berger PB, Popma JJ, Dangas G, et al. Point-of‐care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU‐Assessing Ultegra) multicenter study. Circulation. 2001;2572–2578.
    1. Steinhubl SR, Kottke‐Marchant K, Moliterno DJ, Rosenthal ML, Godfrey NK, Coller BS, Topol EJ, Lincoff AM. Attainment and maintenance of platelet inhibition through standard dosing of abciximab in diabetic and nondiabetic patients undergoing percutaneous coronary intervention. Circulation. 1999;1977–1982.
    1. Tardiff BE, Jennings LK, Harrington RA, Gretler D, Potthoff RF, Vorchheimer DA, Eisenberg PR, Lincoff AM, Labinaz M, Joseph DM, et al. Pharmacodynamics and pharmacokinetics of eptifibatide in patients with acute coronary syndromes: prospective analysis from PURSUIT. Circulation. 2001;399–405.
    1. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo‐controlled trial. Lancet. 2000;2037–2044.
    1. Huxtable LM, Tafreshi MJ, Rakkar AM. Frequency and management of thrombocytopenia with the glycoprotein IIb/IIIa receptor antagonists. Am J Cardiol. 2006;426–429.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner