Olpasiran reduced levels of oxidized phospholipids and lipoprotein(a): JAMA

A new study published in the Journal of American Medical Association showed that the innovative small interfering RNA (siRNA) medication olpasiran (Amgen) can effectively reduce lipoprotein(a) and oxidized phospholipids (OxPL), although this does not result in a decrease in inflammatory indicators.

Although it is yet unknown how reducing Lp(a) reduces cardiovascular risk, even in those with low LDL cholesterol, scientists have long believed that doing so would stop the inflammatory process. It is thought that OxPL is a powerful inducer of atherosclerosis and inflammation. By causing the apolipoprotein(a) messenger RNA to degrade, olapsiran prevents the synthesis of Lp(a).

It is unclear how olapsiran affects OxPL and systemic inflammatory markers. Thus, in the OCEAN(a)-DOSE randomized clinical trial, Robert Rosenson and team carried out this investigation to evaluate the impact of olpasiran on OxPL, hs-C-reactive protein (hs-CRP), and high-sensitivity interleukin 6 (hs-IL-6).

This multinational, multicenter, phase 2 placebo-controlled, dose-finding randomized clinical study was carried out from July 2020 to November 2022. A total of 281 individuals with Lp(a) levels more than 150 nmol/L and atherosclerotic cardiovascular disease were included. 1 of 4 active subcutaneous doses of olpasiran vs a placebo was randomly assigned to each participant:

(1) 10 mg given every 12 weeks (Q12W);

(2) 75 mg given every 12 weeks (Q12W);

(3) 225 mg given every 12 weeks (Q12W); or

(4) 225 mg given every 24 weeks (Q24W).

hs-CRP, hs-IL-6, and OxPL on apolipoprotein B (OxPL-apoB) were measured in 272 patients at baseline, week 36, and week 48. The main result was the change in OxPL-apoB from baseline to week 36, corrected for placebo.

Nearly, 86 individuals (31.6%) were female, and the median (IQR) age of the 272 participants was 62 years (56-69). The initial median (IQR) concentrations of Lp(a) and OxPL-apoB were 260.3 nmol/L (198.1-352.4) and 26.5 nmol/L (19.7-33.9), respectively.

For the 10-mg Q12W dosage, the placebo-adjusted mean percentage change in OxPL-apoB from baseline to week 36 was -51.6%; for the 75-mg Q12W dose, it was -89.7%; for the 225-mg Q12W dose, it was -92.3%; and for the Q24W dose, it was -93.7%.

These results persisted till week 48. For patients receiving olpasiran, there was a significant association between the percentage decrease in Lp(a) and OxPL-apoB. When compared to a placebo at weeks 36 or 48, olapsiran had no discernible effect on hs-CRP or hs-IL-6 (P >.05). Overall, Olpasiran significantly and sustainably decreased OxPL-apoB in the OCEAN(a)-DOSE multicenter randomized clinical study but had no discernible impact on hs-CRP or hs-IL-6.

Source:

Rosenson, R. S., López, J. A. G., Gaudet, D., Baum, S. J., Stout, E., Lepor, N. E., Park, J.-G., Murphy, S. A., Knusel, B., Wang, J., Wilmanski, T., Wang, H., Wu, Y., Kassahun, H., Sabatine, M. S., O’Donoghue, M. L., & OCEAN(a)-DOSE Trial Investigators. (2025). Olpasiran, oxidized phospholipids, and systemic inflammatory biomarkers: Results from the OCEAN(a)-DOSE trial. JAMA Cardiology. https://doi.org/10.1001/jamacardio.2024.5433