Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.

Drug repurposing: progress, challenges and recommendations

Background Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, bu...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2021372?articleTools=true

Colchicine in Patients with Chronic Coronary Disease

Cardiovascular disease is the leading cause of death worldwide, both in the general population and among patients with chronic kidney disease (CKD). In most cases, the underlying cause of the cardiovascular event is atherosclerosis - a chronic inflammatory disease. CKD accelerates atherosclerosis via augmentation of inflammation, perturbation of lipid metabolism, and other mechanisms. In the artery wall, subendothelial retention of plasma lipoproteins triggers monocyte-derived macrophages and T helper type 1 (TH1) cells to form atherosclerotic plaques. Inflammation is initiated by innate immune reactions to modified lipoproteins and is perpetuated by TH1 cells that react to autoantigens from the apolipoprotein B100 protein of LDL. Other T cells are also active in atherosclerotic lesions; regulatory T cells inhibit pathological inflammation, whereas TH17 cells can promote plaque fibrosis. The slow build-up of atherosclerotic plaques is asymptomatic, but plaque rupture or endothelial erosion can induce thrombus formation, leading to myocardial infarction or ischaemic stroke. Targeting risk factors for atherosclerosis has reduced mortality, but a need exists for novel therapies to stabilize plaques and to treat arterial inflammation. Patients with CKD would likely benefit from such preventive measures.

The immunology of atherosclerosis

Coronary artery disease is the leading global cause of mortality. Long recognized to be heritable, recent advances have started to unravel the genetic architecture of the disease. Common variant association studies have linked approximately 60 genetic loci to coronary risk. Large-scale gene sequencing efforts and functional studies have facilitated a better understanding of causal risk factors, elucidated underlying biology and informed the development of new therapeutics. Moving forwards, genetic testing could enable precision medicine approaches by identifying subgroups of patients at increased risk of coronary artery disease or those with a specific driving pathophysiology in whom a therapeutic or preventive approach would be most useful.

Genetics of coronary artery disease: discovery, biology and clinical translation

Mendelian randomization (MR) is a burgeoning field that involves the use of genetic variants to assess causal relationships between exposures and outcomes MR studies can be straightforward; for example, genetic variants within or near the encoding locus that is associated with protein concentrations can help to assess their causal role in disease However, a more complex relationship between the genetic variants and an exposure can make findings from MR more difficult to interpret In this Review, we describe some of these challenges in interpreting MR analyses, including those from studies using genetic variants to assess causality of multiple traits (such as branched-chain amino acids and risk of diabetes mellitus); studies describing pleiotropic variants (for example, C-reactive protein and its contribution to coronary heart disease); and those investigating variants that disrupt normal function of an exposure (for example, HDL cholesterol or IL-6 and coronary heart disease) Furthermore, MR studies on variants that encode enzymes responsible for the metabolism of an exposure (such as alcohol) are discussed, in addition to those assessing the effects of variants on time-dependent exposures (extracellular superoxide dismutase), cumulative exposures (LDL cholesterol), and overlapping exposures (triglycerides and non-HDL cholesterol) We elaborate on the molecular features of each relationship, and provide explanations for the likely causal associations In doing so, we hope to contribute towards more reliable evaluations of MR findings

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Mendelian randomization in cardiometabolic disease: challenges in evaluating causality

Background Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2. Methods In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). Results During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02). Conclusions In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).

/pdf/darapladib-for-preventing-ischemic-events-in-stable-coronary-4a3wxv9u7r.pdf

Hong Chen

Papers

Darapladib for preventing ischemic events in stable coronary heart disease.