Prehospital treatment with zalunfiban (RUC-4) in patients with ST‐ elevation myocardial infarction undergoing primary percutaneous coronary intervention: Rationale and design of the CELEBRATE trial

Rikken, Sem A O F; Selvarajah, Abi; Hermanides, Renicus S; Coller, Barry S.; Gibson, C. Michael; Granger, Christopher B.; Lapostolle, Frédéric; Postma, Sonja; Wetering, Henri van de; Vliet, Risco C W van; Montalescot, Gilles; Berg, Jürrien M. ten; Hof, Arnoud W J van ‘t

doi:10.1016/j.ahj.2022.12.015

Cited by 11 publications

(2 citation statements)

References 39 publications

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“…Although in vitro spiking studies may not directly translate to the clinical setting, and thus additional ex vivo pharmacokinetic and PD studies may be needed, the present findings warrant further investigation into the potential benefits of the short-acting GPIIb-IIIa inhibitor zalunfiban for patients at risk for further ischemic events. The ongoing phase III double-blinded, randomized, placebo-controlled trial (CeleBrate), will provide more definitive answers and shed further light on the role of these inhibitors in improving outcomes for such patients (NCT04825743) [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation

Curry¹,

Rikken

Gibson

et al. 2023

J Thromb Thrombolysis

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Understanding the pharmacodynamic effects of platelet inhibitors is standard for developing more effective antithrombotic therapies. An example is the antithrombotic treatment of acute coronary syndrome (ACS), in particular ST-elevated myocardial infarction (STEMI) patients who are in need for rapid acting strong antithrombotic therapy despite the use of aspirin and oral P2Y12-inhibitors. In this study, we evaluated two injectable platelet inhibitors under clinical development (the P2Y12 antagonist selatogrel and the GPIIb-IIIa antagonist zalunfiban) that may be amenable to pre-hospital treatment of STEMI patients. Platelet reactivity was assessed at inhibitor concentrations that represent clinically relevant levels of platelet inhibition (IC20-50%, 1/2Cmax, and Cmax). Light transmission aggregometry (LTA), was used to evaluate the initial rate of aggregation (primary slope, PS) and maximal aggregation (MA). Both adenosine diphosphate (ADP) and thrombin receptor agonist peptide (TRAP) were used as agonists. Zalunfiban demonstrated similar inhibition of platelet aggregation when blood was collected in PPACK or TSC, whereas selatogrel demonstrated greater inhibition in PPACK. In this study, using PPACK anticoagulant, selatogrel and zalunfiban affected PS in response to ADP equivalently at all drug concentrations tested. In contrast, zalunfiban had significantly greater potency at its Cmax concentration compared to selatogrel using TRAP as agonist. Upon evaluation of MA responses at lower doses, selatogrel had greater inhibition of MA in response to ADP than zalunfiban; however, at concentrations that represent Cmax, the drugs were equivalent. Zalunfiban also had greater inhibition of MA in response to TRAP at the Cmax dose. These data suggest that zalunfiban may provide greater protection in reducing thrombus formation than selatogrel, especially since thrombin is an early, key primary agonist in the pathophysiology of thrombotic events.

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Section: Discussionmentioning

confidence: 99%

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation

Curry¹,

Rikken

Gibson

et al. 2023

J Thromb Thrombolysis

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show abstract

“…Additional data will come in the future from the ongoing Phase 3, randomized, placebo‐controlled trial CELEBRATE (CeleCor Blinded Randomized Trial in STE‐Elevation Myocardial Infarction; NCT04825743) that is scheduled to evaluate 2499 STEMI patients, two‐thirds of whom will receive zalunfiban. 94 …”

Section: Potential Role Of Zalunfiban In Determining the Mechanism(s)...mentioning

confidence: 99%

Critical Analysis of Thrombocytopenia Associated With Glycoprotein IIb/IIIa Inhibitors and Potential Role of Zalunfiban, a Novel Small Molecule Glycoprotein Inhibitor, in Understanding the Mechanism(s)

Rikken,

van 't Hof,

ten Berg

et al. 2023

JAHA

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Thrombocytopenia is a rare but serious complication of the intravenous glycoprotein IIb/IIIa (GPIIb/IIIa; integrin αIIbβ3) receptor inhibitors (GPIs), abciximab, eptifibatide, and tirofiban. The thrombocytopenia ranges from mild (50 000–100 000 platelets/μL), to severe (20 000 to <50 000/μL), to profound (<20 000/μL). Profound thrombocytopenia appears to occur in <1% of patients receiving their first course of therapy. Thrombocytopenia can be either acute (<24 hours) or delayed (up to ~14 days). Both hemorrhagic and thrombotic complications have been reported in association with thrombocytopenia. Diagnosis requires exclusion of pseudothrombocytopenia and heparin‐induced thrombocytopenia. Therapy based on the severity of thrombocytopenia and symptoms may include drug withdrawals and treatment with steroids, intravenous IgG, and platelet transfusions. Abciximab‐associated thrombocytopenia is most common and due to either preformed antibodies or antibodies induced in response to abciximab (delayed). Readministration of abciximab is associated with increased risk of thrombocytopenia. Evidence also supports an immune basis for thrombocytopenia associated with the 2 small molecule GPIs. The latter bind αIIbβ3 like the natural ligands and thus induce the receptor to undergo major conformational changes that potentially create neoepitopes. Thrombocytopenia associated with these drugs is also immune‐mediated, with antibodies recognizing the αIIbβ3 receptor only in the presence of the drug. It is unclear whether the antibody binding depends on the conformational change and whether the drug contributes directly to the epitope. Zalunfiban, a second‐generation subcutaneous small molecule GPI, does not induce the conformational changes; therefore, data from studies of zalunfiban will provide information on the contribution of the conformational changes to the development of GPI‐associated thrombocytopenia.

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Prepercutaneous coronary intervention Zalunfiban dose-response relationship to target vessel blood flow at initial angiogram in st-elevation myocardial infarction – A post hoc analysis of the cel-02 phase IIa study

Rikken¹,

Bor²,

Selvarajah³

et al. 2023

American Heart Journal

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Prehospital treatment with zalunfiban (RUC-4) in patients with ST‐ elevation myocardial infarction undergoing primary percutaneous coronary intervention: Rationale and design of the CELEBRATE trial

Cited by 11 publications

References 39 publications

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation

Critical Analysis of Thrombocytopenia Associated With Glycoprotein IIb/IIIa Inhibitors and Potential Role of Zalunfiban, a Novel Small Molecule Glycoprotein Inhibitor, in Understanding the Mechanism(s)

Prepercutaneous coronary intervention Zalunfiban dose-response relationship to target vessel blood flow at initial angiogram in st-elevation myocardial infarction – A post hoc analysis of the cel-02 phase IIa study

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