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Lipidomics of Health and Disease | EK30


Phosphatidylinositol as Pharmacodynamic Biomarker for Inhibition of Endothelial Lipase by MEDI5884 in Cynomolgus Macaques and Healthy and Stable Coronary Artery Disease Subjects


Mar 24, 2021 12:00am ‐ Mar 24, 2021 12:00am

Description

Phosphatidylinositol as Pharmacodynamic Biomarker for Inhibition of Endothelial Lipase by MEDI5884 in Cynomolgus Macaques and Healthy and Stable Coronary Artery Disease Subjects Anton I. Rosenbaum*, Yue Huang, Ruipeng Mu, Kristina Kovacina, Meina Liang, B. Timothy Hummer, Denise ChaoYu Jin, Joseph Grimsby AstraZeneca Endothelial lipase (EL) promotes HDL phospholipid degradation, increases catabolism of HDL and is an attractive target for potential treatment for cardiovascular disease. Inhibition of EL using a monoclonal neutralizing antibody MEDI5884 demonstrated increased quantity and function of HDL. Determinants of anti-atherosclerotic function of HDL comprise of the interplay of various components of HDL structure-activity relationship: size, shape and composition. Single doses of MEDI5884 administered to healthy monkeys resulted in a dose-dependent increase in plasma phospholipids (PL). A targeted lipidomic approach revealed that administration of MEDI5884 caused a particularly prominent increase in phosphatidylinositols (PI) and cholesteryl esters (CE). PI was shown previously to possess anti-atherosclerotic properties and lead to increases in HDL-C and RCT. The mechanism by which CE levels increase as the result of MEDI5884 administration can be attributed to the observed increase in both substrates of the LCAT reaction: PC/PE and cholesterol as the consequence of EL inhibition. We analyzed PI levels in two clinical trials in healthy (NCT03001297) and stable Coronary Artery Disease (CAD) subjects (NCT03351738). The comparison of the two studies revealed that healthy subjects levels of PI are consistently higher across PI species compared to CAD subjects. Treatment with MEDI5884 restores near-normal levels of PI in CAD patients. PI increases in both HV and CAD patients were dose-dependent, correlated with exposure and saturated at approximately 200 mg SC dose in CAD patients. Comparison of PD effects of repeat SC 200 mg doses of MEDI5884 in CAD patients revealed greater and more rapid increases in PI levels compared to HDL-C and HDL-PL. The increase in PI species was inversely correlated with decreases in free EL mass levels. Further characterization of the underlying biological mechanisms responsible for the decrease of the PI biomarker in CAD patient population relative to healthy subjects as well as in conjunction with pharmacological intervention by MEDI5884 may reveal more information on this clinically-relevant biomarker.

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