Lipoprotein(a) [Lp(a)] formation

Class

oral small-molecule Lp(a) inhibitor

Pathway

Inhibits hepatic Lp(a)/apo(a) particle formation, lowering circulating Lp(a); licensed by Merck (MSD) from Jiangsu Hengrui for ~$2bn, currently in Phase 2/3 in China with global Phase III planned

Lipoprotein(a), abbreviated Lp(a), is a low-density lipoprotein-like particle that carries an additional protein, apolipoprotein(a), covalently attached to apolipoprotein B100. Plasma Lp(a) concentration is determined almost entirely by genetics, chiefly the size and copy number of the gene encoding apolipoprotein(a), and remains largely unresponsive to diet or exercise. Elevated Lp(a) is a well-established, independent, and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis, thought to act both by delivering cholesterol into the arterial wall and by carrying oxidized phospholipids that promote inflammation and calcification. Because conventional lipid-lowering therapies such as statins have little effect on Lp(a), there has been long-standing interest in agents that act further upstream, at the point of particle assembly in the liver, to reduce circulating levels directly. An oral small-molecule inhibitor of hepatic Lp(a)/apolipoprotein(a) particle formation works by interfering with the intracellular steps that link apolipoprotein(a) to apolipoprotein B100 before secretion, reducing the number of Lp(a) particles released into the bloodstream. This mechanism is relevant across cardiovascular disease broadly, particularly for individuals with genetically high Lp(a) who have limited options for addressing this component of their residual risk.