First-in-Human Data Show One siRNA Can Lower Both LDL-C and Triglycerides

Treating mixed hyperlipidemia often takes separate therapies to lower LDL cholesterol (LDL-C) and triglycerides. Now, first-in-human findings suggest that a dual-function small interfering RNA (siRNA) therapeutic may be able to target both at once to help reduce the risk of atherosclerotic cardiovascular disease.

In the single-ascending-dose portion of a phase 1/2a trial, ARO-DIMER-PA sustained suppression of both PCSK9 and APOC3 proteins and substantially reduced LDL-C and triglycerides. It also was generally well tolerated across the doses evaluated.

The results were presented among other late-breaking clinical studies at the American Heart Association’s 2026 Scientific Sessions.

“siRNA is a new, rapidly expanding class of medications,” says Cleveland Clinic cardiologist Luke Laffin, MD, who presented the study. “There are siRNA drugs available now that target PCSK9 alone (inclisiran) or APOC3 alone (plozasiran), but this is the first-ever reported bifunctional therapy. It’s a single molecule that can silence both PCSK9 and APOC3 genes in the liver, potentially offering a more durable and streamlined approach to lipid management.”

It’s one of several siRNA dimers currently in development for cardiovascular disease, says the study’s senior author Steven Nissen, MD, Chief Academic Officer of Cleveland Clinic’s Heart, Vascular & Thoracic Institute, and leader of the Cleveland Clinic Coordinating Center for Clinical Research (C5Research).

“Mixed hyperlipidemia is the most common lipid disorder we see, and patients often have both high LDL cholesterol and high triglycerides,” Dr. Nissen says. “What’s novel here is that a single siRNA molecule has the potential to lower both by very large amounts.”

Two targets, one molecule

ARO-DIMER-PA is designed to suppress two liver proteins involved in atherogenic lipid metabolism: PCSK9 and APOC3. PCSK9 promotes degradation of LDL receptors, which limits LDL clearance, while APOC3 inhibits the breakdown and clearance of triglyceride-rich lipoproteins.

Through RNA interference, the drug targets the messenger RNA for both proteins in the liver and prevents their production. Less PCSK9 means more LDL receptors on hepatocytes and better LDL clearance. Less APOC3 means faster clearance of triglyceride-rich particles.

Generally well tolerated

The study included 31 adults with mixed hyperlipidemia (triglycerides 150-499 mg/dL and either non-HDL cholesterol ≥100 mg/dL or LDL-C ≥70 mg/dL). Participants received one dose of ARO-DIMER-PA (25 mg, ≤50 mg, ≤100 mg, ≤200 mg or ≤400 mg) or placebo.

ARO-DIMER-PA was generally well tolerated. Treatment-emergent adverse events showed no clear dose-related pattern, and no serious adverse events were reported. The most common adverse event was injection-site erythema, affecting 95% of those who received the drug.

Platelet counts and HbA1c did not change in clinically meaningful ways, and there were no clear signs of hepatotoxicity. Occasionally, high-sensitivity C-reactive protein rose temporarily around the time of injection.

Steep reductions in LDL-C and triglycerides

A single dose of ARO-DIMER-PA substantially reduced both target proteins and their associated lipids. Mean PCSK9 levels fell 50% to 89% from baseline, and mean APOC3 levels fell 43% to 95%. Mean LDL-C dropped 26% to 65%, and median triglycerides dropped 56% to 78%. Suppression of both proteins was sustained over time.

Durable Reductions in PCSK9 and APOC3 Over Time With ARO-DIMER-PA

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Reductions in LDL-C and Triglycerides Over Time With ARO-DIMER-PA

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The effects extended beyond LDL-C and triglycerides. Mean ApoB fell 32% to 66%, and mean remnant cholesterol fell 52% to 73%, suggesting broader effects on atherogenic lipoproteins. Whether those changes translate into lower cardiovascular risk will take further study.

A new strategy for mixed hyperlipidemia

PCSK9 and APOC3 have each been targeted before, but this study provides clinical proof of concept that a single siRNA molecule can modulate both pathways at once. It also supports further study of dual PCSK9/APOC3 inhibition as a single-agent strategy for mixed hyperlipidemia.

“What’s exciting is what this could mean with this particular drug and beyond,” Dr. Laffin says. “It suggests we may be able to design RNA interference therapies that address multiple pathways at once, whether they’re involved in one disease or in related cardiometabolic diseases.”

What repeat dosing could reveal

The multiple-ascending-dose portion of the phase 1/2a trial is now underway to evaluate the safety and efficacy of repeat dosing and help select a dose for pivotal studies. Investigators also want to understand the cumulative effects of treatment and how often it might need to be given.

“Whether that ends up being every three months, every six months or some other interval remains to be determined,” Dr. Laffin says. “It’s still early in development, but we’re enthusiastic about what we’ve seen so far and look forward to learning more as the program moves forward.”

This clinical trial was funded by Arrowhead Pharmaceuticals, which is developing ARO-DIMER-PA.

Dr. Laffin reports that he has served as a consultant to and/or on steering committees for Arrowhead Pharmaceuticals and other pharmaceutical and device companies.

Dr. Nissen reports that the Cleveland Clinic Coordinating Center for Clinical Research (C5Research) has received funding to conduct clinical trials from multiple biopharmaceutical companies, including Arrowhead Pharmaceuticals. He reports that he is involved in conducting these trials but receives no personal remuneration for his participation. He also consults for these companies but does not accept compensation.