RNAi Therapy Zodasiran Cuts LDL Cholesterol by Up to 40 Percent in Homozygous FH: GATEWAY Trial
USA: A novel RNA interference (RNAi) therapy targeting angiopoietin-like protein 3 (ANGPTL3) has shown promising lipid-lowering effects in patients with homozygous familial hypercholesterolaemia (HoFH), a rare genetic disorder associated with extremely high low-density lipoprotein (LDL) cholesterol levels and a markedly elevated risk of premature cardiovascular disease.
The findings are from the GATEWAY phase 2 trial, published in The Lancet Diabetes & Endocrinology by Prof Frederick J Raal of the University of the Witwatersrand, Johannesburg, South Africa, and colleagues.
HoFH is characterised by severely impaired or absent LDL receptor function, rendering many conventional lipid-lowering therapies less effective. ANGPTL3 plays a central role in lipoprotein metabolism, and its inhibition offers a receptor-independent strategy to reduce atherogenic lipoproteins. Zodasiran is a liver-targeted RNAi therapeutic designed to suppress ANGPTL3 expression, thereby lowering LDL cholesterol through mechanisms that do not rely on LDL receptor activity.
The open-label, randomised, phase 2 GATEWAY study was conducted across seven clinical sites in Australia, Canada, South Africa, and the United States. It enrolled patients aged 16 years and older with genetically confirmed HoFH who were receiving stable background lipid-lowering therapy, adhering to a low-fat diet, and had persistently elevated LDL cholesterol levels despite treatment. Eligible participants were randomly assigned in a 1:1 ratio to receive subcutaneous injections of zodasiran at doses of 200 mg or 300 mg on day 1 and again at month 3.
The primary endpoint was the percentage change in fasting LDL cholesterol from baseline to month 6. An interim adaptive analysis was planned to guide longer-term dosing decisions. After completing nine months of follow-up, participants were given the option to enter an open-label extension phase, receiving zodasiran 200 mg every three months for up to an additional two years.
Key findings were as follows:
- Between April and November 2022, 18 patients (mean age 43 years) were enrolled, all with markedly elevated LDL cholesterol despite intensive background lipid-lowering therapy.
- At six months, zodasiran achieved dose-dependent LDL cholesterol reductions of about 36% with 200 mg and 40% with 300 mg, consistent with interim analyses showing reductions above 40%.
- After partial washout, all patients entered the open-label extension, with sustained LDL cholesterol lowering observed for an additional 12 months across pooled doses.
- Patients receiving concomitant PCSK9 inhibitor therapy experienced greater LDL cholesterol reductions, exceeding 50% during both the randomised and extension phases.
- Zodasiran was well tolerated, with no treatment discontinuations, drug-related serious adverse events, or deaths reported.
- Most adverse events were mild to moderate, commonly including nasopharyngitis, dizziness, upper respiratory tract infections, and COVID-19.
The authors conclude that quarterly dosing of zodasiran provides meaningful and sustained LDL cholesterol reduction with a favourable safety profile in patients with HoFH. While the study was limited by its small sample size and early termination for non-clinical reasons, the results support further evaluation of zodasiran in larger phase 3 trials to confirm its long-term efficacy and cardiovascular benefit in this high-risk population.
Reference:
Raal FJ, Bergeron J, Gaudet D, Rosenson RS, Sullivan DR, Turner T, Hegele RA, Ballantyne CM, Knowles JW, Leeper NJ, Goldberg IJ, Zhou R, Muhsin M, Hellawell J, Hamilton J, Watts GF. Zodasiran, an RNAi therapeutic targeting ANGPTL3, for treating patients with homozygous familial hypercholesterolaemia (GATEWAY): an open-label, randomised, phase 2 trial. Lancet Diabetes Endocrinol. 2025 Dec 18:S2213-8587(25)00290-6. doi: 10.1016/S2213-8587(25)00290-6. Epub ahead of print. PMID: 41422812.
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