Olpasiran Shows‌ Promise in Reducing Cardiovascular Risk

Updated Feb. ​12, 2025

A new study indicates that the RNA ‌inhibitor olpasiran‍ effectively reduces lipoprotein(a) [Lp(a)], a type of “bad cholesterol”​ linked to increased cardiovascular risk. Research led by a Mount Sinai scientist showed that higher doses of the drug lowered Lp(a) levels by more⁣ than 95% in individuals with atherosclerotic cardiovascular disease.The findings appeared in the journal ​ JAMA Cardiology.

Dr. Robert Rosenson, professor of medicine (cardiology) ​at the icahn School of Medicine at Mount Sinai, led the ‍analysis. He said the‌ study is the first clinical trial to explore the link between oxidized phospholipids on lipoprotein(a) and inflammatory mediators. ⁢Rosenson added ⁢that ⁢olpasiran not only lowered Lp(a) but also reduced levels of oxidized phospholipids, which are thought to contribute to atherosclerosis.

Lp(a) is considered a major carrier of ⁣oxidized phospholipids, a driver of inflammation and atherosclerosis. Olpasiran, developed ‌by Amgen,⁣ works by blocking lp(a) ⁤production thru the degradation of apolipoprotein(a) messenger RNA (mRNA). ⁢Apolipoprotein(a), along with apolipoprotein B (apoB), ‍is a key protein‍ component of lipoprotein(a).

The OCEAN(a)-DOSE phase 2 clinical trial ‍involved 282 cardiovascular⁤ disease patients with Lp(a) levels exceeding 150 nmol/L (60 mg/dL). These elevated levels are believed to promote clotting‌ and inflammation, significantly raising‍ the risk of⁣ heart attack, stroke, aortic stenosis, and peripheral‌ artery disease. Lp(a) can accumulate in blood vessel walls, forming plaques similar to⁢ those ⁢caused by low-density lipoprotein (LDL), a known cardiovascular risk​ factor. Actually, Lp(a) is estimated to ⁣carry a cardiovascular risk five to⁢ six times greater than LDL cholesterol.

The research team reported ‌that patients ⁢receiving 75‍ mg or more of olpasiran every 12 weeks experienced a ⁣95% or‍ greater reduction in⁢ Lp(a) compared to the placebo group after‌ 36 weeks. At week 36,Lp(a) ⁣increased by‌ an average of 3.6% in the placebo group, while ‍substantial reductions were observed in⁢ all olpasiran groups.⁢ Adverse event rates ⁢were ⁣similar between ‌the olpasiran and placebo groups.

Rosenson, who⁤ also directs​ the Metabolism and Lipids Program for Mount ⁣Sinai Fuster Heart Hospital,​ noted that the trial‍ results showed olpasiran ⁢led‌ to a meaningful and sustained reduction ‍in oxidized phospholipids on apolipoprotein B. He added that the team observed ‌no ‍significant‌ effects of olpasiran⁢ on the‌ secretion of the proinflammatory cytokine interleukin-6 or C-reactive protein compared to ⁢the placebo group.

“Our study is the first clinical trial to investigate the ⁤association between oxidized phospholipids on lipoprotein(a) and inflammatory mediators,” said ⁤Rosenson.‌ “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.”

What’s next

Rosenson believes his analysis ‍challenges the leading hypothesis of Lp(a)-associated risk for cardiovascular disease. He emphasized the need for further research, stating that OCEAN will⁤ help in selecting patients for future trials⁣ who are likely​ to show an anti-inflammatory response from⁢ selective​ RNA inhibitors of ⁢lipoprotein(a). ⁢A phase ‌3 outcomes trial for olpasiran,sponsored by Amgen,Inc., is currently underway, led by the TIMI ‍Study⁢ Group.