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J Clin Transl Sci. 2019 Jun;3(2-3):65-74. doi: 10.1017/cts.2019.382. Epub 2019 Jun 28.

Preclinical Studies of RUC-4, a Novel Platelet αIIbβ3 Antagonist, in Non-Human Primates and With Human Platelets.

Author information

1
Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY, USA.
2
Biomere, Worcester, MA, USA.
3
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
4
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD.
5
Department of Biomedical and Pharmaceutical Sciences, Touro College of Pharmacy, New York NY, USA.

Abstract

Introduction:

We are developing the novel αIIbβ3 antagonist, RUC-4, for subcutaneously (SC)-administered first-point-of-medical-contact treatment for ST Segment Elevated Myocardial Infarction (STEMI).

Methods:

We studied the: 1. pharmacokinetics (PK) of RUC-4 at 1.0, 1.93, and 3.86 mg/kg IV, IM, and SC in non-human primates (NHPs); 2. impact of aspirin on RUC-4 IC50 in human platelet-rich plasma (PRP); 3. effect of different anticoagulants on the RUC-4 IC50 in human PRP; and 4. relationship between αIIbβ3 receptor blockade by RUC-4 and inhibition of ADP-induced platelet aggregation.

Results:

1. All doses of RUC-4 were well tolerated, but animals demonstrated variable temporary bruising. IM and SC RUC-4 reached dose-dependent peak levels within 5-15 min, with T½ s between 0.28 and 0.56 hrs. Platelet aggregation studies in NHPs receiving IM RUC-4 demonstrated >80% inhibition of the initial slope of ADP-induced aggregation with all 3 doses 30 minutes post-dosing, with subsequent dose-dependent loss of inhibition over 4-5 hours. 2. The RUC-4 IC50 for ADP-induced platelet aggregation was unaffected by aspirin treatment (40±9 nM vs. 37±5 nM; p=0.39). 3. The RUC-4 IC50 was significantly higher in PRP prepared from PPACK-anticoagulated blood compared to citrate-anticoagulated blood using either TRAP (122±17 vs. 66±25 nM; p=0.05; n=4) or ADP (102±22 vs. 54±13; p<0.001; n=5). 4. There was a close correspondence between receptor blockade and inhibition of ADP-induced platelet aggregation, with aggregation inhibition beginning with ~40% receptor blockade and becoming nearly complete at >80% receptor blockade.

Discussion:

Based on these results and others, RUC-4 has now progressed to formal preclinical toxicology studies.

KEYWORDS:

Antiplatelet therapy; Integrin receptors; Platelets; ST segment elevation myocardial infarction (STEMI); αIIbβ3 antagonists

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