Abstract 11050: Antisense Inhibition of Apolipoprotein(a) in Cynomolgus Monkeys Significantly Reduces Plasma Apolipoprotein(a) Levels Without Affecting Plasminogen or Other Major Lipid Classes

Abstract

The lipoprotein(a) [Lp(a)] particle was identified nearly 50 years ago and is comprised of a highly unique LDL particle in which one apolipoprotein B (apoB) protein is linked via a disulfide bond to a single apolipoprotein (a) [apo(a)] protein. Apo(a) shares a high degree of homology with plasminogen, particularly within the kringle IV type 2 repetitive domain. Levels of circulating Lp(a) are inversely proportional to the number of kringle IV type 2 variable repeats present in the molecule and as both alleles are co-expressed, individuals, can display heterogeneous plasma isoform profiles. In recent years, Lp(a) has been recognized as an independent risk factor for myocardial infarction, stroke, peripheral vascular disease and abdominal aortic aneurysm. Further, in the Precocious Coronary Artery Disease (PROCARDIS) study, robust and independent associations between coronary heart disease and plasma Lp(a) concentrations. To date, therapeutic strategies to directly target apo(a) have been limited to Lp(a) apheresis, ribozyme oligonucleotides and more recently, antisense oligonucleotides (ASO). In the later antisense study, a second generation ASO reduced apo(a) plasma protein and oxidized phospholipid levels by 86% and 92.5%, respectively, in apo(a) transgenic mice. In order evaluate the safety and pharmacodynamics of an optimized human apo(a) antisense drug, a 12 week study was performed in cynomolgus monkeys. The lead compound was administered at 40mg/kg/wk for 12 weeks and plasma and liver samples were collected for apo(a) protein and mRNA quantitation, respectively. The apo(a) ASO significantly reduced both plasma apo(a) and hepatic mRNA expression greater than 80% with no change in plasminogen mRNA expression. Interestingly, total cholesterol, HDL, LDL-C and apoB levels were unchanged during the entire course of drug treatment. Finally, the apo(a) ASO was well tolerated as indicated by the lack of effects on aminotransferase levels. Thus, a human apo(a) ASO demonstrated safe, potent and selective reduction in apo(a) levels in cynomolgus monkeys and may represent an attractive therapeutic modality for patients at enhanced risk for cardiovascular events due to chronically elevated plasma Lp(a) levels.