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Assessing the Pharmacodynamics of RUC-4 (Zalunfiban), a Novel αIIbβ3 Antagonist, Using VerifyNow Assays in Patients with ST-Segment Elevation Myocardial Infarction (STEMI) Treated with Aspirin and Ticagrelor

O.S. Bentur1, W.L. Bor2, K.L. Zheng2, A.H. Tavenier3, A. van ’t Hof4, J.M. ten Berg2,4, B.S. Coller1

1The Rockefeller Univesity, New York, United States, 2St. Antonius Hospital, Department of Cardiology, Nieuwegein, Netherlands, 3Isala Hospital, Zwole, Netherlands, 4University Medical Center Maastricht, Maastricht, Netherlands

Abstract Number: OC 72.3

Meeting: ISTH 2021 Congress

Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Platelet Antagonists and Novel Therapeutics

Background: RUC-4 (zalunfiban) is a novel αIIbβ3 antagonist designed for first-point-of-contact therapy of STEMI. Phase 1 studies demonstrated rapid onset (15 minutes) of high-grade (~80%) inhibition of ADP-induced platelet aggregation measured by light transmission aggregometry (LTA) after subcutaneous administration. LTA is difficult to perform, however, in STEMI.

Aims: To study the application of auxiliary VerifyNow point-of-care assays to assess the pharmacodynamic effects of RUC-4 and ticagrelor in a Phase 2 study of patients with STEMI.

Methods: The study was approved by an ethics committee and informed consent was obtained. STEMI patients received aspirin and ticagrelor prehospital and RUC-4 (0.075-0.110 mg/kg) in-hospital. To measure RUC-4 pharmacodynamics, we used 3 different VerifyNow assays in which platelet activation was achieved with: 1) 20 mM ADP + 0.02 mM PGE1 (ADP); 2) ~3 µM thrombin receptor activating peptide (iso-TRAP), or 3) 20 mM iso-TRAP + 800 mM PAR4 agonist peptide (Base).

Results: Twenty-two patients received ticagrelor (180 mg) and aspirin (300 mg) 25-94 minutes before hospital arrival. On arrival, P2Y12-mediated platelet inhibition (defined as PRU≤208) was evident in only 7 patients (32%). Fifteen minutes after RUC-4 administration, all three VerifyNow assays were profoundly inhibited (Figure), reflecting RUC-4’s effects on iso-TRAP and ADP-induced platelet activation. Over the next 3 hours, as RUC-4’s blood concentration decreased (Table) and ticagrelor’s effects increased, the ADP assay remained inhibited, the Base assay returned to pre-treatment levels, and the iso-TRAP assay returned toward pre-treatment levels, but not as completely as with the Base assay, reflecting modest inhibition of the iso-TRAP assay by ticagrelor.

VerifyNow (VN) assay Reaction Units (mean ± SD) in STEMI patients treated with aspirin, ticagrelor, and RUC-4. Note: one patient’s Base assay data were excluded because of technical problems.

Time after RUC-4 administration (minutes) RUC-4 whole blood concentration (Mean ± SD, µM)
0 0.00 ± 0.00 
15 0.29 ± 0.07
45 0.22 ± 0.22
90 0.09 ± 0.07
120 0.07 ± 0.07
180 0.02 ± 0.01

Pharmacokinetics of RUC-4. Note: RUC-4 whole blood concentration (mean ± SD) associated with half-maximal inhibition of 20 µM ADP-induced platelet aggregation as measured by LTA in the Phase 1 studies was 0.09 ± 0.02 µM.

Conclusions: Combining VerifyNow assays provides important information: 1) the Base assay is best suited for measuring the isolated effect of RUC-4 after co-therapy with ticagrelor, and 2) when the Base assay returns to baseline, the ADP assay provides an accurate assessment of the ticagrelor effect.

To cite this abstract in AMA style:

Bentur OS, Bor WL, Zheng KL, Tavenier AH, van ’t Hof A, ten Berg JM, Coller BS. Assessing the Pharmacodynamics of RUC-4 (Zalunfiban), a Novel αIIbβ3 Antagonist, Using VerifyNow Assays in Patients with ST-Segment Elevation Myocardial Infarction (STEMI) Treated with Aspirin and Ticagrelor [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/assessing-the-pharmacodynamics-of-ruc-4-zalunfiban-a-novel-%ce%b1iib%ce%b23-antagonist-using-verifynow-assays-in-patients-with-st-segment-elevation-myocardial-infarction-stemi-treated-with-aspir/. Accessed May 16, 2022.

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