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.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - 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/