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Pharmacological Inhibition of Phosholipase A2: Results from Phase 3 Clinical Trials with Darapladib and Varespladib in Patients with Cardiovascular Disease

Nicola Ferri, Chiara Ricci and Alberto Corsini

The hydrolysis of the ester bond of glycerophospholipids is catalyzed by the family of enzymes Phospholipase A2 (PLA2), that leads to a release of free fatty acids and lysophospholipids, including the arachidonic acid, the precursor of the eicosanoids and the inflammatory cascades. The mass and the enzymatic activity of PLA2 have been positively correlated with the incidence of cardiovascular diseases in epidemiological and genetic studies. In particular, several experimental evidences have shown that PLA2, identified in the atherosclerotic plaque, are directly involved in the proatherogenic inflammatory response. From these evidences, PLA2 have become a potential pharmacological target of considerable interest and two different PLA2 inhibitors have been developed: varespladib, a reversible sPLA2 inhibitor, and darapladib, a selective Lp-PLA2 inhibitor. Both these two small molecules have been tested both on animal models, where they have shown anti-atherosclerotic properties, and in phase 2 clinical trials, where they have demonstrated positive effects on atherosclerotic plaque composition. Unfortunately, the following three phase 3 trials, which have been recently published, did not shown any additional protective action of PLA2 inhibitors neither in co-administration with statins and antiplatelet drugs, nor in coronary revascularization. In the first one, the VISTA-16 study, varespladib has been administrated to patients with acute coronary syndrome, in the second and third one, the Stability and the SOLID-TIMI 52 studies, darapladib has been administrated to patients with stable coronary heart disease and acute coronary syndrome, respectively. The present article is focused on the enzymatic properties and on the involvement of sPLA2 and Lp-PLA2 in atherogenesis, with particular attention on the results of experimental and clinical studies with both varespladib and darapladib.