Longer-Term Efficacy and Safety of Zodasiran in Patients with Mixed Hyperlipidaemia

BACKGROUND: Mixed hyperlipidaemia, characterized by elevated cholesterol and triglyceride levels, is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). Angiopoietin-like protein 3 (ANGPTL3) regulates lipid metabolism through inhibition of lipoprotein and endothelial lipases. Loss-of-function variants in ANGPTL3 are associated with lower plasma triglycerides, cholesterol, and reduced ASCVD risk. Zodasiran, a hepatocyte-targeted small interfering RNA (siRNA) against ANGPTL3, demonstrated significant lipid lowering in the Phase 2b ARCHES-2 trial. AIMS: To evaluate the long-term safety and efficacy of zodasiran in adults with mixed hyperlipidaemia participating in the open-label extension (OLE) of ARCHES-2 (NCT04832971). METHODS: Adults with mixed hyperlipidaemia (fasting triglycerides 1.7-5.6 mmol/L and LDL-C ≥ 1.8 mmol/L or non-HDL-C ≥ 2.59 mmol/L) who completed 9 months of randomised treatment with placebo or zodasiran (50-, 100-, or 200-mg subcutaneously Q3 M) were eligible for the OLE. The primary endpoint in the randomised doubleblind study was percent change in median triglycerides from baseline to Month 6. Here, lipid parameters were assessed through 21 months of the OLE; with total follow-up of 24 months. RESULTS: Of 191 participants completing randomised treatment, 156 (82%) enrolled in the OLE. Over 24 months, zodasiran was generally well tolerated; five participants (3.2%) discontinued due to adverse events; one (0.6%) death, not considered treatment-related, occurred. Injection site reactions were mild. By Month 21, median triglycerides were reduced by -55% (95% CI, 64, 43); remnant cholesterol by -57% (SD: 32); LDL-C by -5% (SD: 40); and ApoB by -13% (SD: 21). CONCLUSIONS: Zodasiran produced sustained reductions in triglycerides and atherogenic lipoproteins over 30 months and was well tolerated, supporting its potential as a long-term therapeutic option for mixed hyperlipidaemia.