Zodasiran siRNA Lowers Triglycerides and LDL Cholesterol in Phase 1 Trial

A phase 1 basket trial of zodasiran, an investigational small interfering RNA (siRNA) therapeutic, has demonstrated a significant ability to lower triglycerides and low-density lipoprotein (LDL) cholesterol in patients with various forms of dyslipidemia. The results, published in Nature Medicine on April 7, 2026, indicate that the drug effectively targets the angiopoietin-like protein 3 (ANGPTL3) to reduce lipid levels in patients who are already receiving lipid-lowering therapy.

Zodasiran is a GalNAc-conjugated RNA interference (RNAi) therapeutic designed to selectively silence the expression of ANGPTL3 in the liver. By inhibiting this protein, the drug aims to lower triglycerides, LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B.

Trial Design and Patient Cohorts

The 16-week phase 1 trial included three distinct patient cohorts based on their specific lipid disorders. These included nine patients with hyperlipidemia (including a placebo control arm), 17 patients with familial hypercholesterolemia, and six patients with moderate-to-severe hypertriglyceridemia.

Participants received zodasiran via subcutaneous injection on day 1 and day 29. Following the initial 16-week period, 13 patients in the familial hypercholesterolemia cohort entered a 48-week open-label extension, where the drug was administered every 12 weeks.

Key Findings and Efficacy

The trial reported that all cohorts experienced significant reductions in serum ANGPTL3 and triglycerides 12 weeks after dosing. Specifically, serum ANGPTL3 levels decreased by up to 85.4%, while triglycerides were reduced by up to 67.1%.

In patients with heterozygous familial hypercholesterolemia, the therapy lowered both triglycerides and low-density lipoprotein cholesterol. For those with severe hypertriglyceridemia, the drug successfully lowered triglyceride levels.

The reduction in ANGPTL3 was sustained through the end of the open-label extension for the familial hypercholesterolemia group. Research suggests that zodasiran may be particularly useful for populations with limited LDL receptor function, such as those with homozygous familial hypercholesterolemia, suggesting a potential for LDL receptor-independent lipid lowering.

Safety and Tolerability

The primary endpoint of the trial was the observation of serious treatment-related adverse events, and no such events were reported. The study found that zodasiran was well-tolerated, with minimal adverse events and no drug discontinuations.

Clinical monitoring showed no elevations in the following markers:

• Hepatic aminotransferases
• Bilirubin
• Glycated hemoglobin

Medical Context and Future Outlook

The targeting of ANGPTL3 is based on the observation that loss-of-function variants in the gene encoding this protein are associated with lower cardiovascular risk and decreased levels of triglycerides and LDL cholesterol.

Compared to other agents targeting ANGPTL3, zodasiran may offer advantages regarding its duration of action, dosing frequency, and hepatic specificity. This makes it a promising candidate for treating a wide spectrum of dyslipidemias and addressing residual atherosclerotic cardiovascular disease (ASCVD) risk.

Despite these positive early results, researchers note that long-term safety and cardiovascular outcome data are currently lacking. Future research will require large-scale trials to evaluate clinical endpoints, optimize the selection of patients, and determine cost-effective strategies for broader medical access.