Lp(a) contributes to cardiovascular risk through oxidation of these lipoproteins to the coronary arterial wall, resulting in inflammation, atherosclerosis, and thrombosis, although the specific pathophysiology remains under investigation. Lp(a)-lowering therapies currently under investigation include pelacarsen, olpasiran, SLN360, LY3473329, and LY3819469.

Pelacarsen, also known as ISIS 681257, IONIS APO(a)-LRx, AKCEA-APO(a)-LRx, and TQJ230, is a hepatocyte-directed antisense oligonucleotide that targets the LPA gene mRNA, thus inhibiting Lp(a) synthesis in the liver.

Olpasiran is a small interfering RNA (siRNA) agent directed towards the LPA gene that prevents assembly of the Lp(a) particle in hepatocytes by preventing translation of the apolipoprotein(a) protein.

SLN360 is a siRNA targeting the LPA gene. It is involved in the ongoing randomized phase II trial SLN360, evaluating varying doses of SLN360 and its effect on LpA levels in adults at high risk of ASCVD events and with Lp(a) > 150 nmol/L.

The drug LY3473329, or muvalaplin, is a small-molecule inhibitor of Lp(a) formation and siRNA. It is currently the only orally administered Lp(a)-lowering therapy under investigation.

LY3819469, or lepodisiran, is another siRNA targeting the Lp(a) gene. It was previously evaluated in a phase I trial, in which it showed reductions in Lp(a) and was well tolerated.

Efficacy data from phase II trials indicate that these therapies have favorable side-effect profiles, with no differences in overall adverse events, myalgias, renal or liver function, or neuropathy compared to placebo. Local hypersensitivity and injection site reactions are the most commonly reported adverse events associated with these therapies.