A new analysis of a phase 2 clinical trial has found that olpasiran, an RNA inhibitor, significantly reduces lipoprotein(a) [Lp(a)], a type of “bad cholesterol” associated with a high risk of cardiovascular events. The study, led by researchers at Mount Sinai and published on February 12, 2025, in JAMA Cardiology, reported that higher doses of olpasiran lowered Lp(a) levels by more than 95% in participants with atherosclerotic cardiovascular disease.
“Our study is the first clinical trial to investigate the association between oxidized phospholipids on lipoprotein(a) and inflammatory mediators,” said Dr. Robert Rosenson, lead author of the analysis and Professor of Medicine (Cardiology) at the Icahn School of Medicine at Mount Sinai. “We found that in addition to its beneficial effects on lowering lipoprotein(a), olpasiran reduced levels of oxidized phospholipids, which are presumed to promote atherosclerosis.”
Why Lipoprotein(a) Matters
Lipoprotein(a), or Lp(a), is a known driver of inflammation and atherosclerosis, contributing to the buildup of dangerous plaques in arteries. Research suggests that elevated Lp(a) levels increase the risk of heart attacks, strokes, aortic stenosis, and peripheral artery disease—posing a cardiovascular risk five to six times greater than LDL cholesterol (commonly referred to as “bad cholesterol”).
Olpasiran, developed by Amgen, works by targeting apolipoprotein(a) messenger RNA (mRNA), which is essential for Lp(a) production. By degrading this mRNA, olpasiran prevents the body from producing excessive amounts of Lp(a), thereby reducing its harmful effects.
Study Findings: A 95% Reduction in Lp(a)
The OCEAN(a)-DOSE phase 2 clinical trial enrolled 282 patients with cardiovascular disease and Lp(a) levels above 150 nmol/L (60 mg/dL), a threshold associated with increased clotting and inflammation risks.
Patients receiving 75 mg or higher of olpasiran every 12 weeks experienced a 95% or greater reduction in Lp(a) levels compared to the placebo group at week 36.
- In the placebo group, Lp(a) levels increased by an average of 3.6% over the study period.
- In contrast, all olpasiran-treated groups saw substantial Lp(a) reductions, demonstrating the drug’s powerful and sustained impact.
- The rates of adverse events were similar between the olpasiran and placebo groups, suggesting that the drug is well-tolerated.
Effects on Inflammation and Heart Disease Risk: Olpasiran
Beyond lowering Lp(a), the study also examined whether olpasiran had an impact on inflammatory markers—a key driver of cardiovascular disease.
“Results of our trial revealed that olpasiran led to a significant and sustained reduction in oxidized phospholipids on apolipoprotein B,” Dr. Rosenson explained. “However, we observed no significant effects on the secretion of the proinflammatory cytokine interleukin-6 or C-reactive protein compared to the placebo group.”
This finding challenges the current understanding of how Lp(a) contributes to heart disease and highlights the need for further research into its role in inflammation and cardiovascular risk.
Reference: Robert S. Rosenson, J. Antonio G. López, Daniel Gaudet, Seth J. Baum, Elmer Stout, Norman E. Lepor, Jeong-Gun Park, Sabina A. Murphy, Beat Knusel, Jingying Wang, Tomaz Wilmanski, Huei Wang, You Wu, Helina Kassahun, Marc S. Sabatine, Michelle L. O’Donoghue. Olpasiran, Oxidized Phospholipids, and Systemic Inflammatory Biomarkers. JAMA Cardiology, 2025.
