Validation of Platelet Expression of FcɣRIIa as a Precision Tool

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ABSTRACT The American Heart Association estimates that, in 2022, about 720,000 Americans will have a first coronary event and 335,000 will have a recurrent event, of which, approximately 87% are ischemic (thrombotic). Anti- thrombotic therapy reduces the risk of recurrent ischemic events at the cost of a greater incidence of bleeding complications. Patients at low thrombotic/ischemic risk should benefit from shortened treatment whereas patients at high thrombotic/ischemic risk should derive greater absolute benefit from longer term treatment with more powerful antiplatelet therapy. Currently available tools such as clinical risk scores and platelet function testing are inadequate to effectively individualize cardiovascular care, and effective precision medicine strategies to enable clinicians to target patients with high residual risk are lacking. Platelet function tests effectively identify patients at risk but failed when used in trials designed to guide treatment. Key weaknesses of platelet function tests include that they demonstrate substantial intra-individual variability, are influenced by both assay conditions as well as the treatment of the patient, and that they measure platelet reactivity in response to a select agonist or group of agonists. To address this gap in patient care, Prolocor identified a biomarker, FcγRIIa, on the surface of platelets. When platelets activate, FcγRIIa amplifies platelet activation. Thus, increased platelet FcγRIIa increases platelet reactivity and leverages the prognostic implications of platelet function tests. Compared to currently available platelet function tests, expression of FcγRIIa shows less intra-individual variability, is substantially less sensitive to perturbations related to assay conditions, and predicts increased platelet reactivity in response to a variety of agonists. In a preliminary study of 197 patients, Cox regression analysis demonstrated that platelet expression of FcγRIIa was the sole covariate (hazard ratio 3.9, p=0.035) associated with an increased risk of heart attack, stroke, and death when age, diabetes, and prior revascularization were included as covariates. Thus, quantifying platelet FcγRIIa expression is a novel method to identify cardiovascular risk and should serve as a powerful precision medicine tool. Prolocor has since refined the assay by developing antibodies that bind to FcyRIIa on the surface of platelets that have been fixed with formaldehyde. Initial analytic testing has demonstrated excellent precision (coefficient of variation of repeated tests <5%). The Proposed SBIR is designed to provide comprehensive analytic validation of the assay in accordance with FDA Quality System Regulation, demonstrating that the measurement of platelet FcɣRIIa expression is accurate, precise, and reproducible. The analytic validation will be paired with clinical validation provided by prospective observational studies in acute coronary syndrome, stroke and cancer. The combination of the analytic and clinical validation will enable Prolocor to submit an FDA application for the Prolocor diagnostic tool, and allow for the uptake of FcγRIIa to the field of cardiovascular medicine as a diagnostic tool for assessing cardiovascular risk.