Lepodisiran is a small interfering RNA (siRNA) that disables messenger RNA involved in producing apolipoprotein(a), a component essential for the assembly of lipoprotein(a) (Lp(a)) particles that is synthesized in the liver. The drug is a Dicer substrate short interfering RNA with a tetraloop structure attached to the sugar N-Acetylgalactosamine (GalNAc), which allows it to be carried into liver cells possessing GalNAc receptors. 
Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Multiple factors are involved in CVD, and emerging data indicate that lipoprotein(a) is an independent risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Lipoprotein(a) is a cholesterol-transporting protein made in the liver, and when circulating at elevated levels it contributes to the accumulation of plaque in arteries, greatly increasing the risk of cardiovascular disease, heart attacks and strokes. Unfortunately, Lp(a) levels are mostly determined genetically, so improving diet and exercise won’t reduce that risk.
In the phase 1 study of 48 participants with elevated lipoprotein(a) levels, lepodisiran was well tolerated and produced dose-dependent, long-duration reductions in serum lipoprotein(a) concentrations - just one single injection of lepodisiran lowered Lp(a) to undetectable levels for almost a year by interfering with its mechanism of production.
- Nissen SE, Linnebjerg H, Shen X, Wolski K, Ma X, Lim S, Michael LF, Ruotolo G, Gribble G, Navar AM, Nicholls SJ. (2023). Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a): A Randomized Dose-Ascending Clinical Trial. JAMA. doi: 10.1001/jama.2023.21835. PMID: 37952254.
- Lampsas, S., Xenou, M., Oikonomou, E., Pantelidis, P., Lysandrou, A., Sarantos, S., ... & Siasos, G. (2023). Lipoprotein (a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment. Molecules, 28(3), 969. PMID: 36770634 PMC9918959 DOI: 10.3390/molecules28030969
- Trial registration: ClinicalTrials.gov Identifier: NCT04914546.