• Novel GPI RUC-4 Shows Rapid, but Short Duration, Dose-Respondent Platelet Function Inhibition in Phase IIa Study

    The novel small-molecule second-generation glycoprotein IIb/IIIa inhibitor (GPI) RUC-4 has shown dose-response high-grade inhibition of platelet function within 15 minutes in 27 ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention in its Phase IIa study.

    Results from the open-label CEL-02 trial were reported Tuesday morning at the EuroPCR conference by Jurrien M. Ten Berg, MD, PhD, of St. Antonius Hospital, University Medical Center Maastricht and Cardiovascular Research Institute Maastricht, the Netherlands.

    The findings were published simultaneously in EuroIntervention.

    Current guidelines recommend giving dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor to acute coronary syndrome patients to reduce thrombotic effects.

    The researchers noted that pre-hospital platelet inhibition in STEMI patients may improve outcomes but that the onset of oral P2Y12 inhibitors is slow, “often requiring as long as 4 – 6 hours in the setting of STEMI, independent of higher loading doses.”

    Delayed gastrointestinal absorption, cardiogenic shock and vomiting of the loading dose of concomitant use of opioids could all be possible reasons for the delayed onset of action, they speculated.

    Although GPI drugs have been shown to improve pre-primary PCI target vessel patency, these therapies are associated with bleeding risk. 

    RUC-4 is a second-generation GPI designed to fill that gap in initial optimal platelet inhibition within the “crucial first hours of STEMI,” the researchers noted, adding that phase I studies in healthy subjects and patients with coronary artery disease treated with aspirin show the drug was well-tolerated up to 0.075 mg/kg, achieved high-grade inhibition of platelet function measured by light transmission aggregometry (LTA) in response to 20 µM adenosine diphosphate (ADP) within 15 minutes, and a return of platelet function within 2 hours.

    The phase IIa study – funded by the drug’s manufacturer, CeleCor Therapeutics – therefore set out to assess the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of RUC-4 in STEMI patients undergoing primary PCI.

    The 27 STEMI patients recruited were majority male (74%), white (96%) and had a mean age of 62. Hypertension was present in 37% and hypercholesterolemia in 33%.

    They received a weight-adjusted subcutaneous injection of RUC-4 before primary PCI in escalating doses of 0.075 mg/kg for eight patients, 0.090 mg/kg for nine or 0.110 mg/kg for 10 of the subjects.

    For the three groups, the primary PD endpoint of high-grade inhibition by 77% or more of the VerifyNow iso-TRAP assay at 15 minutes was met in 3 out of 7 for the lowest dose group, and 7 out of 8 respectively in each of the higher dose groups – a dose-response relationship with mean inhibition of 77.5% (interquartile range [IQR] 65.7% to 90.6%), 87.5% (IQR 73.8% to 93.1%), and 91.7% (IQR 76.4% to 99.3%), respectively (p trend = 0.002).

    The inhibition of platelet function was greatest at 15 minutes and then began to decrease, reaching 50% inhibition on the iso-TRAP (thrombin receptor activating peptide) assay at 89.1 minutes (95% confidence interval [CI]: 38 to 129.7), 104.2 minutes (95% CI: 17.6 to 190.8) and 112.4 minutes (95% CI: 19.7 to 205.0) after administration in the cohorts, respectively.

    The comparable times with a Base channel assay were 89.1 minutes (95% CI: 36.9 to 141.3), 120.8 minutes (95% CI: 6.2 to 235.4) and 128.9 minutes (95% CI: 41.6 to216.2).

    Adverse events including injection-site reaction and bruising happened in 12 patients of the overall cohort, while mild access-site hematoma occurred in six and severe access-site hematoma in two patients. No thrombocytopenia was observed within 72 hours post-dose.

    Being open-label without a placebo arm, the study had limitations, the researchers said, but stressed that “this design is unlikely to influence the PD and PK data of our study.”

    “The results of this study warrant further research on pre-hospital treatment with RUC-4 as a bridge to onset of oral antiplatelet agents,” the researchers concluded.

    “There is an unmet need in the acute phase of STEMI for easily administered platelet inhibitors that on the one hand are rapidly acting and potent, thereby reaching maximal efficacy quickly, and on the other hand have limited duration of action, thereby reducing the risk of bleeding.”

    Source:

    Bor WL, Zheng KL, Tavenier AH, et al. Pharmacokinetics, pharmacodynamics, and tolerability of subcutaneous administration of a novel glycoprotein IIb/IIIa inhibitor, RUC-4, in patients with ST-segment elevation myocardial infarction. EuroInterv 2021 May 18 (Article in press).

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