Zerlasiran

What It Is

Zerlasiran (formerly SLN360) is a GalNAc-conjugated small interfering RNA (siRNA) developed by Silence Therapeutics 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 siRNAs olpasiran and lepodisiran and the antisense oligonucleotide pelacarsen, zerlasiran attacks the same target: a sugar tag (GalNAc, N-acetylgalactosamine) delivers the double-stranded siRNA to liver cells, where its guide strand 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 — so the liver assembles far fewer Lp(a) particles. Its distinguishing feature within the class is infrequent, quarterly-or-longer dosing paired with a cumulative effect: successive doses drove Lp(a) progressively lower. In the Phase 2 ALPACAR-360 trial (NCT05537571; 178 adults with atherosclerotic cardiovascular disease and Lp(a) ≥125 nmol/L, randomized to zerlasiran 300 mg every 16 or 24 weeks, 450 mg every 24 weeks, or placebo), zerlasiran produced greater than 80% mean time-averaged, placebo-adjusted reductions in Lp(a) over 36 weeks, with maximal reductions exceeding 90% (about a 90% median decrease at week 36), and the effect persisted out to 60 weeks with no safety concerns. Those results were presented as a late-breaker at the American Heart Association 2024 Scientific Sessions and published simultaneously in JAMA on November 18, 2024 (Nissen SE, Wang Q, Nicholls SJ, et al.). An earlier Phase 1 study (APOLLO) of single ascending doses of SLN360 was published in JAMA in 2022. Despite the strong Phase 2 data, Silence Therapeutics announced in 2026 that it will only initiate the pivotal Phase 3 cardiovascular outcomes study once a development partner is secured, prioritizing a collaboration over solo development to manage financial risk — so zerlasiran's outcomes trial has not yet begun. Zerlasiran is investigational and not approved anywhere; it is a clinical-stage prescription medicine, not a supplement or research chemical.

Regulatory Status

Why Researchers Study It

Zerlasiran is one of a small group 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 features within the Lp(a)-lowering class are infrequent dosing — as little as every 16 to 24 weeks — and a cumulative effect in which successive doses push Lp(a) progressively lower. Researchers study it as part of the field's central, still-unproven test: whether lowering Lp(a) actually prevents heart attacks and strokes. Zerlasiran also illustrates a business-model reality shaping the class — a small biotech with strong Phase 2 data seeking a partner to fund the large, expensive Phase 3 cardiovascular outcomes trial that any Lp(a) drug ultimately needs.

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 more than 80% (maximal >90%)
• Long-acting chemistry supports infrequent dosing (every 16–24 weeks), with successive doses producing cumulative Lp(a) lowering
• 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, Wang Q, Nicholls SJ, et al. — Zerlasiran, A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial (ALPACAR-360), JAMA (2024) PubMed
2. [2] ALPACAR-360 — A Study of Zerlasiran (SLN360) in Participants With Elevated Lp(a) at High Risk of ASCVD Events (ClinicalTrials.gov NCT05537571) PubMed
3. [3] Silence Therapeutics Announces Positive Topline 48-Week Data from Phase 2 Study of Zerlasiran — Silence Therapeutics (2024) PubMed
4. [4] Nissen SE, et al. — Single Ascending Dose Study of SLN360 (APOLLO Phase 1), JAMA (2022) PubMed
5. [5] Lipoprotein(a): An Independent Risk Factor for CV Disease — American College of Cardiology PubMed

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