Lepodisiran
Medium EvidenceAn investigational, long-duration injectable small interfering RNA (siRNA) from Eli Lilly that lowers lipoprotein(a) [Lp(a)] by nearly 94% by silencing the LPA gene in the liver. A single dose keeps Lp(a) suppressed for a year or more, and its Phase 3 ACCLAIM-Lp(a) trial (~12,500 patients) is the first Lp(a) outcomes trial to include people who have not yet had a cardiovascular event.
What It Is
Lepodisiran (LY3819469) is a GalNAc-conjugated small interfering RNA (siRNA) being developed by Eli Lilly to lower lipoprotein(a) — 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. Like the antisense oligonucleotide pelacarsen and the siRNAs olpasiran and zerlasiran, lepodisiran attacks the same target, but it is engineered for exceptional duration: a sugar tag (GalNAc, N-acetylgalactosamine) delivers the double-stranded siRNA to liver cells, where it loads 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. Its chemistry, including a stabilizing tetraloop that joins the two RNA strands, gives it an unusually long duration of action, so that a single subcutaneous injection can keep Lp(a) suppressed for a year or more. In the Phase 2 ALPACA trial (320 adults with elevated Lp(a); doses of 16, 96, or 400 mg), the 400 mg dose lowered Lp(a) by 93.9% (placebo-adjusted, time-averaged over days 60–180) — the primary endpoint — with the 96 mg and 16 mg doses producing 75.2% and 40.8% reductions; the effect was strikingly durable, still around 91% below baseline at roughly one year and about 74% below baseline at 1.5 years after a single dose, with no serious drug-related adverse events. Those results were presented at the American College of Cardiology 2025 Scientific Sessions and published in the New England Journal of Medicine in 2025. The pivotal Phase 3 ACCLAIM-Lp(a) trial (NCT06292013) enrolled about 12,500 patients randomized 1:1 to lepodisiran or placebo on top of standard care, and is notable as the first Lp(a)-lowering outcomes trial to include primary-prevention patients (people at risk for a first cardiovascular event) alongside secondary-prevention patients with established atherosclerotic cardiovascular disease. Dosing is infrequent — the first three subcutaneous doses are given six months apart, then every 12 months thereafter. It is an event-driven study of roughly 4.75 years testing whether lowering Lp(a) reduces major adverse cardiovascular events, with completion expected around 2029. Lilly has also begun a coronary-plaque imaging trial (NCT07613294). Lepodisiran is investigational and not approved anywhere; it is a clinical-stage prescription medicine, not a supplement or research chemical.
Regulatory Status
Lepodisiran is not approved for any use anywhere. It is being evaluated in the pivotal Phase 3 ACCLAIM-Lp(a) cardiovascular outcomes trial (NCT06292013; ~12,500 patients randomized 1:1 to lepodisiran or placebo, including both primary- and secondary-prevention patients with elevated Lp(a)), an event-driven study of roughly 4.75 years with completion expected around 2029. Subcutaneous dosing: the first three doses are six months apart, then every 12 months. The primary endpoint is a composite of major adverse cardiovascular events. A coronary-plaque imaging trial (NCT07613294) is also underway. Developed by Eli Lilly.
Effective: 2026
View FDA SourceWhy Researchers Study It
Lepodisiran 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. Its distinguishing feature within the Lp(a)-lowering class is duration — a single injection can suppress Lp(a) for a year or more — raising the prospect of once- or twice-yearly dosing. Researchers also study it because its Phase 3 ACCLAIM-Lp(a) trial is the first Lp(a) outcomes trial to enroll primary-prevention patients, meaning it could speak not only to people who have already had a cardiovascular event but to the much larger population born with high Lp(a) who have not. Like the rest of the class, it is a key test of the field's central, still-unproven hypothesis — that lowering Lp(a) actually prevents heart attacks and strokes.
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 nearly 94% at the top dose
- Stabilizing chemistry (including a tetraloop joining the two RNA strands) gives an unusually long duration, so a single dose can suppress Lp(a) for a year or more
- Aims to reduce the atherogenic, pro-inflammatory, and pro-thrombotic cardiovascular risk carried by Lp(a) independent of LDL cholesterol
Evidence Snapshot
| Study Type | Model | Outcome | Link |
|---|---|---|---|
| Phase 2 (ALPACA, dose-finding, NCT05565742) | 320 adults with elevated Lp(a); lepodisiran 16/96/400 mg subcutaneous (dosed at day 1 and day 180) vs placebo | Primary endpoint met: the 400 mg dose lowered Lp(a) by 93.9% (placebo-adjusted, time-averaged days 60–180); 96 mg and 16 mg produced 75.2% and 40.8% reductions. No serious drug-related adverse events. Published in NEJM (2025) | Source |
| Phase 2 (durability of single dose) | ALPACA participants followed after a single 400 mg injection | Reductions were exceptionally durable: Lp(a) remained ~91% below baseline at roughly one year and ~74% below baseline at 1.5 years after a single dose, supporting infrequent (once- or twice-yearly) dosing | Source |
| Phase 3 (ACCLAIM-Lp(a), cardiovascular outcomes, NCT06292013) | ~12,500 adults with elevated Lp(a), including both primary- and secondary-prevention patients; lepodisiran vs placebo (first 3 doses 6 months apart, then every 12 months) — global, randomized, double-blind, placebo-controlled | Tests whether lowering Lp(a) reduces major adverse cardiovascular events. Event-driven, ~4.75 years; first Lp(a) outcomes trial to include primary prevention; completion expected ~2029 | Source |
Commonly Discussed Benefits
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Safety & Cautions
- Investigational — not approved for any use anywhere; whether its ~94% Lp(a) lowering translates into fewer cardiovascular events is exactly what the ongoing ACCLAIM-Lp(a) trial (completion ~2029) is designed to test
- Robust Lp(a) reduction is well established, but cardiovascular outcome benefit has not yet been demonstrated for any Lp(a)-lowering drug
- A prescription clinical-stage medicine given by subcutaneous injection under medical supervision — not a supplement, nootropic, or research chemical
- Any 'lepodisiran' or 'LY3819469' offered by a vendor is unverified and not a legitimate source of this investigational medicine
- Targets Lp(a) and is NOT interchangeable with LDL-lowering statins or PCSK9 inhibitors, which do not meaningfully lower Lp(a)
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Citations
- [1] Nissen SE et al. — Lepodisiran, A Long-Duration Small Interfering RNA Targeting Lipoprotein(a) (ALPACA Phase 2), New England Journal of Medicine (2025) PubMed
- [2] ACCLAIM-Lp(a) — A Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events (ClinicalTrials.gov NCT06292013) PubMed
- [3] Lilly's lepodisiran reduced Lp(a) by nearly 94% at the highest tested dose — Eli Lilly and Company (ACC 2025) PubMed
- [4] ALPACA — A Study of LY3819469 (Lepodisiran) in Participants With Elevated Lp(a) (ClinicalTrials.gov NCT05565742) PubMed
- [5] Lipoprotein(a): An Independent Risk Factor for CV Disease — American College of Cardiology PubMed
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WVE-007
Low EvidenceWVE-007 is Wave Life Sciences' investigational GalNAc-conjugated siRNA that silences the liver gene INHBE to lower the hepatokine Activin E, aiming to produce muscle-sparing fat loss. In the Phase 1 INLIGHT trial a single subcutaneous dose reduced visceral and total fat while preserving or increasing lean mass, with durable target knockdown that could support once- or twice-yearly dosing.
Pelacarsen
Medium EvidenceA first-in-class, once-monthly injectable antisense oligonucleotide (ASO) from Ionis and Novartis that lowers lipoprotein(a) [Lp(a)] by shutting down apolipoprotein(a) production in the liver. Its pivotal Lp(a)HORIZON trial (8,323 patients) is the first-ever cardiovascular outcomes trial for any Lp(a)-lowering drug, with a landmark topline readout due in 2026.
Olpasiran
Medium EvidenceAn investigational, once-every-12-weeks injectable small interfering RNA (siRNA) from Amgen that lowers lipoprotein(a) [Lp(a)] by up to ~97% by silencing the LPA gene in the liver. Its Phase 3 OCEAN(a)-Outcomes cardiovascular outcomes trial (~7,000 patients) is one of the pivotal readouts — due December 2026 — that will help decide whether lowering Lp(a) prevents heart attacks and strokes.
Zerlasiran
Medium EvidenceAn investigational, long-acting injectable small interfering RNA (siRNA) from Silence Therapeutics that lowers lipoprotein(a) [Lp(a)] by more than 80% by silencing the LPA gene in the liver. Dosed only every 16–24 weeks, it produced durable ~90% reductions in its Phase 2 ALPACAR-360 trial (published in JAMA, 2024); as of 2026 the company is seeking a partner before starting its Phase 3 cardiovascular outcomes study.