Olpasiran's infrequent dosing could make it a cost-effective route to profound Lp(a) reduction, review argues, with phase 3 OCEAN(a)-OUTCOMES now underway (Cardiol Rev 2025)

Elevated lipoprotein(a) [Lp(a)] has shown association with atherosclerotic cardiovascular disease and has been identified as a risk-enhancing factor contributing to the global morbidity and mortality associated with cardiovascular diseases. Lp(a) levels are not easily altered by classic lipid-lowering therapies such as statins. Recent developments in RNA-based therapeutics have led to the generation of drugs targeted to lowering Lp(a) levels by a variety of mechanisms. In this review, we discuss the advances and current understanding regarding one such drug, olpasiran. Olpasiran's mechanism of action involves RNA interference technology by utilizing synthetic small interfering RNA duplexes to silence the LPA gene, which encodes apo(a), a key structural component of Lp(a). The OCEAN(a)-DOSE phase 2 trial showed profound and sustained reductions in Lp(a) with the use of olpasiran, with no significant safety concerns reported. A large phase 3 outcomes trial, OCEAN(a)-OUTCOMES is underway to further assess clinical efficacy and the effect of olpasiran on cardiovascular outcomes. Olpasiran also has the potential to be a cost-effective treatment due to the infrequent dosing needed to achieve a high degree of Lp(a) reduction. Other similar nucleic acid therapeutic agents, such as pelacarsen, zerlasiran, and lepodisiran, have also shown efficacy in reducing Lp(a) levels in early trials, creating an exciting avenue for cardiovascular prevention in the coming decade.