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

BACKGROUND: ANGPTL3 plays a key part in lipoprotein metabolism. Zodasiran, a liver-targeted RNA interference therapeutic, inhibits ANGPTL3 expression and reduces atherogenic lipoproteins through mechanisms independent of the LDL receptor (LDLR). This approach is relevant to patients with homozygous familial hypercholesterolaemia (HoFH) who have extreme elevations of LDL cholesterol due to markedly impaired LDLR function and, as a result, very high risk of premature adverse cardiovascular events. We aimed to evaluate the long-term safety and efficacy of zodasiran in patients with HoFH. METHODS: GATEWAY was an open-label, randomised, phase 2 study done at seven clinical sites in Australia, Canada, South Africa, and the USA. Patients aged 16 years or older with documented HoFH who were receiving stable lipid-lowering therapy, were on a low-fat diet, had a screening LDL cholesterol of 2·6 mmol/L (100 mg/dL) or higher, and had triglycerides less than 3·4 mmol/L (300 mg/dL) were randomly assigned (1:1) using a block design to receive subcutaneous injections of 200 mg or 300 mg zodasiran on day 1 and month 3. When a majority of patients completed 6 months of treatment, an interim, non-binding, aggregate analysis of efficacy and safety data was conducted according to an adaptive study design to decide whether a single dose could be used for longer-term evaluation. After 9 months of follow-up, patients could opt for long-term open-label extension for an additional 24 months of subcutaneous zodasiran 200 mg injections every 3 months, as established following the planned interim analysis. The primary endpoint was percentage change from baseline to month 6 in fasting LDL cholesterol and was assessed in all randomly assigned patients who received at least one dose of study drug. Safety was assessed in all patients who received one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05217667, and is ongoing (recruitment has now ended). FINDINGS: Between April 1 and Nov 12, 2022, 18 patients (mean age 43·0 years [SD 19·4] and 14 [78%] White) were randomly assigned to receive zodasiran 200 mg (n=9) or 300 mg (n=9). Mean baseline LDL cholesterol concentration was 9·8 mmol/L (SD 5·7) despite background lipid-lowering therapy. At month 6, patients showed substantial dose-responsive reductions in fasting LDL cholesterol (mean -35·7% [SD 28·6; 95% CI -57·6 to -13·7] with 200 mg and -39·9% [18·1; -53·9 to -26·0]) with 300 mg, which was consistent with the interim results of more than 40% reduction in both groups. Following partial washout, all patients entered the open-label extension, in which zodasiran showed evidence of continued effect, with reductions in fasting LDL cholesterol (mean -40·7% [SD 22·3] for the pooled doses) observed for an additional 12 months, as the study was stopped early for business reasons. Reductions were greater in a subset of patients in whom lipid-lowering therapy included a PCSK9 inhibitor (mean -55·8% [SD 19·1] at month 6 of the randomised treatment period and -51·9% [11·6] at month 12 of the open-label extension). There were no drug discontinuations, drug-related severe adverse events, or deaths. In the randomised treatment period, treatment-emergent adverse events occurred in six (67%) of nine patients in the zodasiran 200 mg group and six (67%) of nine patients in the zodasiran 300 mg group, with the most frequent adverse events being nasopharyngitis (two [22%] vs two [22%]), dizziness (two [22%] vs one [11%]), and upper respiratory tract infections (one [11%] vs one [11%]). Adverse events occurred in 11 (61%) of 18 patients in the open-label extension, and the most frequent adverse events were COVID-19 (five [28%]) and nasopharyngitis (five [28%]). INTERPRETATION: 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. FUNDING: Arrowhead Pharmaceuticals.