Zerlasiran: The Twice-a-Year siRNA That Cut Lp(a) by Over 80% — and Why Its Phase 3 Is Waiting (August 8, 2026)
Table of Contents
The risk factor genetics deal you at birth
Lipoprotein(a) — written Lp(a) and spoken 'L-P-little-a' — is one of the most important cardiovascular risk factors most people have never heard of. Roughly one in five people worldwide inherit high levels, and it is a causal driver of heart attack, stroke, peripheral artery disease, and calcific aortic valve stenosis. The frustrating part is that your Lp(a) is set almost entirely by your genes. It barely moves with diet, exercise, or weight loss, and the cholesterol drugs most people know — statins and even the powerful PCSK9 inhibitors — do little or nothing to it. For decades that left millions of people with a measurable, inherited risk and no way to lower it. A new class of gene-silencing injections is trying to change that, and zerlasiran is one of the furthest along.
What zerlasiran is
Zerlasiran — developed by Silence Therapeutics and previously known as SLN360 — is an investigational injectable. It is not a peptide or an antibody but a small interfering RNA, an siRNA: a short, double-stranded piece of genetic material that works through the RNA-interference pathway your cells already use to regulate their own genes. A sugar tag called GalNAc (N-acetylgalactosamine) acts as a homing beacon that delivers the drug to liver cells. Once inside, zerlasiran hands its guide strand to the cell's RISC machinery — the RNA-induced silencing complex — which then finds and chops up the messenger RNA for apolipoprotein(a), the protein that defines the Lp(a) particle. With that mRNA destroyed, the liver makes far less apo(a) and assembles far fewer Lp(a) particles. Cut production at the source, and blood levels fall.
The differentiator: infrequent dosing and a cumulative effect
Every drug in the Lp(a)-lowering race silences the same gene, so what separates them is chemistry, dosing, and how far along their trials are. Zerlasiran's signature is infrequent dosing paired with a cumulative effect. In its Phase 2 study it was given as little as every 16 to 24 weeks — roughly two to three times a year — and rather than plateauing, each successive dose pushed Lp(a) progressively lower. That points toward a maintenance schedule of just a few injections a year. It sits between Amgen's olpasiran (studied on a quarterly, every-12-week schedule) and Lilly's lepodisiran (engineered for once- or twice-yearly dosing), and alongside the antisense oligonucleotide pelacarsen, which is dosed monthly.
How well does it lower Lp(a)?
In the Phase 2 ALPACAR-360 trial (NCT05537571), 178 adults with atherosclerotic cardiovascular disease and high Lp(a) — at least 125 nmol/L — were randomized to zerlasiran 300 mg every 16 or 24 weeks, 450 mg every 24 weeks, or placebo. Over 36 weeks, zerlasiran produced greater than 80% mean time-averaged, placebo-adjusted reductions in Lp(a), with maximal reductions exceeding 90% (about a 90% median decrease at week 36). The effect was durable, persisting out to 60 weeks after initial dosing, with no safety concerns flagged. Those results were presented as a late-breaker at the American Heart Association's 2024 Scientific Sessions and published simultaneously in JAMA on November 18, 2024. An earlier Phase 1 study of SLN360, called APOLLO, was published in JAMA back in 2022 and first established the proof of concept.
The catch: a Phase 3 that hasn't started
Here is the crucial caveat, and it is not a scientific one. Robust Lp(a) lowering is now well established across this entire class — but no one has yet proven that lowering Lp(a) actually prevents heart attacks and strokes. That answer can only come from a large, expensive, multi-year cardiovascular outcomes trial. For zerlasiran, that Phase 3 study has not yet begun. In 2026, Silence Therapeutics — a smaller biotech than the giants developing rival compounds — stated that it will only initiate the pivotal outcomes trial once a development partner is secured, choosing to share the financial risk rather than go it alone. So while zerlasiran's Phase 2 data are among the strongest in the field, its definitive test is on hold pending a business deal, not a lab result. That is a meaningful distinction: the science is promising, but the outcomes evidence — and any path to approval — is waiting on funding.
Where zerlasiran sits in the class
The Lp(a)-lowering pipeline has become a genuine race. Pelacarsen (Ionis/Novartis), an antisense oligonucleotide, is furthest along with its Phase 3 outcomes trial already reading out. Olpasiran (Amgen) and lepodisiran (Eli Lilly) are siRNAs with large Phase 3 cardiovascular outcomes trials underway — lepodisiran's is notable for being the first to enroll primary-prevention patients. Zerlasiran belongs squarely in the siRNA group on mechanism and delivery, and its infrequent dosing is a real advantage; what it lacks, for now, is a running Phase 3. Whichever compound crosses the outcomes finish line first will answer the question the whole class is built on.
The bottom line
Zerlasiran is an investigational, long-acting siRNA that silences the LPA gene in the liver and cut lipoprotein(a) by more than 80% in a well-conducted Phase 2 trial published in JAMA, with dosing as infrequent as two to three times a year. It is not approved anywhere, it is a prescription clinical-stage medicine rather than a supplement or research chemical, and — unlike statins or PCSK9 inhibitors — it targets Lp(a) specifically. Its biggest open question is not whether it lowers Lp(a) (it clearly does) but whether it will get the chance to prove that matters: as of 2026, its pivotal cardiovascular outcomes trial is waiting on a development partner before it can begin.
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Citations
- [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) Source
- [2] ALPACAR-360 — Zerlasiran (SLN360) in Participants With Elevated Lp(a) (ClinicalTrials.gov NCT05537571) Source
- [3] Silence Therapeutics Announces Positive Topline 48-Week Data from Phase 2 Study of Zerlasiran (2024) Source
- [4] Nissen SE, et al. — Single Ascending Dose Study of SLN360 (APOLLO Phase 1), JAMA (2022) Source
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