Network-driven drug repurposing in cardiovascular disease: NDRA clinical trial planning

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Summary Despite optimized treatments with lipid lowering drugs, such as the well-validated statins or novel PCSK9 inhibitors, cardiovascular disease still remains the main cause of morbidity and mortality worldwide. Inflammation is a known key driver in the development of atherosclerotic plaques at high-risk for causing severe clinical events (such as myocardial infarction and stroke) and represents a promising therapeutic target to further reduce cardiovascular risk. However, up until recently, clinical translation of new therapies, or the repurposing of already FDA-approved drugs that lower cardiovascular risk by targeting inflammation, has proven difficult. Part of the challenge faced by these studies is that these therapeutic compounds have been identified based on single- target drug discovery. However, the biological architecture of common complex disorders, like cardiovascular disease, is better explained by gene regulatory networks (GRN) acting within and across tissues. Identifying new uses for existing drugs to restore the function of GRN in atherosclerotic vessels is a groundbreaking and cost- effective strategy to treat CVD. Using an innovative and rigorous combination of systems genetics and computational drug repurposing analyses, we have previously identified existing compounds predicted to influence the function of four key driver genes in RGN 42, a CVD-causal network acting in the atherosclerotic arterial wall of patients that affect foam cell formation. In previous work (R21TR001739), we rigorously validated the pre-clinical efficacy of Auranofin, the top-hit compound targeting RGN42 using a multimodality approach encompassing in vitro experiments, in vivo mouse work and translational in vivo 18F-FDG PET imaging of inflammation in a rabbit model of atherosclerosis. Our data demonstrates that auranofin alone or in combination with statin effectively reduces atherosclerotic plaque inflammatory cells (macrophages) content and halts the development of plaque inflammation in the rabbit model. Based on these results, we propose to engage in the planning of a clinical trial to test the effects of Auranofin in patients with cardiovascular disease. Our specific aims for this application are i) to identify the optimal target population, as we as treatment dose and duration for Auranofin; ii) to determine the general study design and surrogate imaging endpoints to determine drug efficacy in our patient population; and iii) to identify blood biomarkers and molecular signatures related to drug efficacy, and to ingrate these markers with imaging results. We anticipate that the results of our future clinical trial will represent the basis for future, more extensive Phase III clinical studies to better establish the use of Auranofin in cardiovascular disease.