Olpasiran

What It Is

Olpasiran (AMG 890) is a GalNAc-conjugated small interfering RNA (siRNA) being developed by Amgen to lower lipoprotein(a) — usually written Lp(a) — a genetically determined, independent, causal risk factor for heart attack, stroke, peripheral artery disease, and calcific aortic valve stenosis that affects roughly one in five people and cannot be meaningfully lowered by diet, exercise, statins, or PCSK9 inhibitors. Where the antisense oligonucleotide pelacarsen and the siRNAs lepodisiran and zerlasiran all attack the same target, olpasiran works through the RNA-interference pathway: a sugar tag (GalNAc, N-acetylgalactosamine) delivers the double-stranded siRNA to liver cells, where it engages the RISC (RNA-induced silencing complex) to catalytically degrade the messenger RNA for apolipoprotein(a) — the LPA gene product that defines the Lp(a) particle. Because RISC recycles, a single dose keeps suppressing apo(a) production for months, which is why olpasiran is given as a subcutaneous injection only once every 12 weeks. In the Phase 2 OCEAN(a)-DOSE trial (281 patients with atherosclerotic cardiovascular disease and Lp(a) above 150 nmol/L), olpasiran produced dramatic, durable reductions: the 75 mg every-12-week dose lowered Lp(a) by roughly 97% (placebo-adjusted) at 36 weeks, with higher doses reaching similar near-total suppression, and the effect persisted well after dosing stopped. Those results were published in the New England Journal of Medicine in 2022. The pivotal Phase 3 OCEAN(a)-Outcomes trial (NCT05581303) enrolled about 7,000 patients with established atherosclerotic cardiovascular disease and Lp(a) of at least 200 nmol/L into a global, randomized, double-blind, placebo-controlled study testing whether 225 mg of olpasiran every 12 weeks reduces major coronary events — a composite of coronary heart disease death, myocardial infarction, or urgent coronary revascularization. The trial began in December 2022, is now active and no longer recruiting, and is expected to read out around December 2026 — placing it alongside pelacarsen's Lp(a)HORIZON among the landmark cardiovascular catalysts of the year. Amgen has also begun an imaging substudy using coronary CT angiography (NCT07293260) to examine effects on plaque. Olpasiran is investigational and not approved anywhere; it is a clinical-stage prescription biologic, not a supplement or research chemical.

Regulatory Status

Why Researchers Study It

Olpasiran is one of a small handful of therapies that can do something no established drug can: dramatically and durably lower lipoprotein(a), an inherited cardiovascular risk factor that statins and PCSK9 inhibitors barely touch. Researchers study it both as a potential first-in-class treatment for the ~20% of people born with high Lp(a) and as a key test of the field's central, still-unproven hypothesis — that lowering Lp(a) actually prevents heart attacks and strokes. Its Phase 3 OCEAN(a)-Outcomes trial is, alongside pelacarsen's Lp(a)HORIZON, one of the first cardiovascular outcomes trials for any Lp(a)-lowering drug, and because it uses the RNA-interference mechanism it also serves as a bellwether for the siRNA arm of the class (which includes lepodisiran and zerlasiran). A positive readout would validate Lp(a) as a modifiable target and a quarterly injection as a practical way to reach it; a null result would reshape how the field thinks about the risk factor.

Proposed Mechanisms

• GalNAc-conjugated small interfering RNA (siRNA) delivered selectively to hepatocytes
• Loads into the RNA-induced silencing complex (RISC), which catalytically cleaves apolipoprotein(a) [LPA] messenger RNA in the liver
• Suppresses apo(a) synthesis so the liver assembles far fewer Lp(a) particles, lowering circulating Lp(a) by up to ~97%
• Catalytic, recycling RISC mechanism yields prolonged suppression, enabling once-every-12-weeks subcutaneous dosing
• Aims to reduce the atherogenic, pro-inflammatory, and pro-thrombotic cardiovascular risk carried by Lp(a) independent of LDL cholesterol

Evidence Snapshot

Commonly Discussed Benefits

Safety & Cautions

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Citations

1. [1] Nissen SE et al. — Olpasiran for Lowering Lipoprotein(a) in ASCVD (OCEAN(a)-DOSE Phase 2), New England Journal of Medicine (2022) PubMed
2. [2] OCEAN(a)-Outcomes — Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction (ClinicalTrials.gov NCT05581303) PubMed
3. [3] Amgen Presents Late-Breaking Phase 2 Olpasiran Data at ESC 2023 PubMed
4. [4] Off-Treatment Effects of Olpasiran on Lp(a) Lowering: OCEAN(a)-DOSE Extension Results (PubMed) PubMed
5. [5] Lipoprotein(a): An Independent Risk Factor for CV Disease — American College of Cardiology PubMed

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