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Longer-Term Efficacy and Safety of Zodasiran in Patients with Mixed Hyperlipidaemia
Robert S Rosenson1, Daniel Gaudet2, Christie M Ballantyne3
1Lipids and Metabolism Program Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, USA.
Insights
Zodasiran effectively lowers triglycerides and atherogenic lipoproteins in adults with mixed hyperlipidaemia. This ANGPTL3 inhibitor shows sustained efficacy and good tolerability over 30 months, supporting its use for long-term treatment.
Area of Science:
- Cardiovascular medicine
- Pharmacology
- Genetics
Background:
- Mixed hyperlipidaemia increases atherosclerotic cardiovascular disease (ASCVD) risk.
- Angiopoietin-like protein 3 (ANGPTL3) inhibition lowers lipids and ASCVD risk.
- Zodasiran, an ANGPTL3 siRNA, showed lipid reduction in Phase 2b.
Purpose of the Study:
- Evaluate long-term safety and efficacy of zodasiran.
- Assess zodasiran in adults with mixed hyperlipidaemia.
- Extend findings from the ARCHES-2 trial.
Main Methods:
- Open-label extension (OLE) of the ARCHES-2 trial.
- 156 adults with mixed hyperlipidaemia enrolled.
- Lipid parameters assessed up to 21 months in OLE; 24 months total follow-up.
Main Results:
- Zodasiran generally well tolerated over 24 months.
- Median triglyceride reduction of -55% by Month 21.
- Reductions observed in remnant cholesterol (-57%), LDL-C (-5%), and ApoB (-13%).
Conclusions:
- Zodasiran provides sustained triglyceride and atherogenic lipoprotein reduction.
- Demonstrates good tolerability for long-term use.
- Supports zodasiran as a potential therapeutic option for 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.
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