Zodasiran, an RNAi therapeutic targeting ANGPTL3, for treating patients with homozygous familial hypercholesterolaemia (GATEWAY): an open-label, randomised, phase 2 trial

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

doi:10.1016/s2213-8587(25)00290-6

Lipids & metabolic liver disease

Zodasiran, an RNAi therapeutic targeting ANGPTL3, for treating patients with homozygous familial hypercholesterolaemia (GATEWAY): an open-label, randomised, phase 2 trial

Lancet Diabetes EndocrinolPublished 18 Dec 2025Randomised controlled trial

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Authors' conclusion

Quarterly dosed zodasiran shows evidence of reductions in LDL cholesterol with a favourable safety profile, in patients with HoFH receiving background lipid-lowering therapy. Further investigation in phase 3 trials is warranted.

Study context

Population: Patients aged ≥16 years with documented homozygous familial hypercholesterolaemia (HoFH) on stable lipid-lowering therapy and low-fat diet, screening LDL-C ≥2.6 mmol/L, TG <3.4 mmol/L; 7 sites in Australia, Canada, South Africa and USArandomised 1:1
Participants: 18 patients

Comparison: Zodasiran 200 mg vs 300 mg
Zodasiran 200 mgn = 9
Zodasiran 300 mgn = 9
Primary endpoint: Percentage change from baseline in fasting LDL-C
Follow-up: Month 6

Methodological detailsopen-label, phase 2, adaptive design, multicentre (7 sites), Interim, non-binding aggregate analysis used to select 200 mg every 3 months for 24-month open-label extension

Open-label
Phase 2
Adaptive design
Multicentre (7 sites)
Interim, non-binding aggregate analysis used to select 200 mg every 3 months for 24-month open-label extension

Primary result

As reported in the abstract

Percentage change in fasting LDL-C

Group	Value	95% CI
Zodasiran 200 mg	mean −35.7 (SD 28.6) %	−57.6 to −13.7
Zodasiran 300 mg	mean −39.9 (SD 18.1) %	−53.9 to −26.0

Value

Zodasiran 200 mgmean −35.7 (SD 28.6) %

Zodasiran 300 mgmean −39.9 (SD 18.1) %

95% CI

Zodasiran 200 mg−57.6 to −13.7

Zodasiran 300 mg−53.9 to −26.0

Further findings

Outcome	Values
Fasting LDL-C change in open-label extension (pooled doses) · additional 12 monthsStudy stopped early for business reasons	Pooled doses mean −40.7 (SD 22.3) %

Fasting LDL-C change, subset on PCSK9 inhibitor

Month 6 of randomised period, mean (SD): −55.8% (19.1)
Month 12 of open-label extension, mean (SD): −51.9% (11.6)

Safety

Treatment-emergent AEs · randomised treatment period

Zodasiran 200 mg67%

Zodasiran 300 mg67%

Nasopharyngitis · randomised treatment period

Zodasiran 200 mg22%

Zodasiran 300 mg22%

Dizziness · randomised treatment period

Zodasiran 200 mg22%

Zodasiran 300 mg11%

Upper respiratory tract infections · randomised treatment period

Zodasiran 200 mg11%

Zodasiran 300 mg11%

Discontinuations, drug-related severe AEs and deaths

There were no drug discontinuations, drug-related severe adverse events, or deaths

AEs in open-label extension (pooled doses)

Any AE: 11 (61%) of 18 patients
COVID-19: five [28%]
Nasopharyngitis: five [28%]

Original publication

Zodasiran, an RNAi therapeutic targeting ANGPTL3, for treating patients with homozygous familial hypercholesterolaemia (GATEWAY): an open-label, randomised, phase 2 trial. Lancet Diabetes Endocrinol. Published 18 December 2025. doi:10.1016/s2213-8587(25)00290-6

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