Darapladib and its potential for plaque stabilization and prevention of cardiac events

Abstract

Darapladib is a novel oral compound that selectively inhibits lipoprotein-associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is intimately involved in inflammation and postulated to play an important role in the development of unstable atherosclerotic plaques. Lp-PLA2 is found in vulnerable human coronary and carotid plaques.Epidemiological studies have shown that Lp-PLA2 is related to the occurrence of myocardial infarction, stroke and vascular death. Darapladib inhibits the activity of Lp-PLA2 in plasma and reduces Lp-PLA2 in human carotid plaques. In a trial of 330 patients with coronary artery disease receiving standard of care medications, darapladib halted necrotic core progression in coronary arteries over a 12-month period. Two large Phase III trials, the Stabilization of Atherosclerotic Plaque By Initiation of Darapladib Therapy and the Stabilization of Plaques Using Darapladib – Thrombolysis in Myocardial Infarction 52 trials, are expected to randomize approximately 27,000 patients with chronic coronary heart disease and acute coronary syndromes, respectively, to darapladib or placebo with a primary composite outcome of cardiovascular death, myocardial infarction or stroke. Darapladib has the potential to provide clinical benefit by modulating mechanisms of disease that have not been addressed by current treatments.