Phase 3 Open‑Label Single‑Arm Study of Subcutaneous Zodasiran (ARO‑ANG3) in Adolescents With Homozygous Familial Hypercholesterolemia

The primary objective is to demonstrate a reduction in LDL‑C in adolescent participants with Homozygous Familial Hypercholesterolemia treated with zodasiran, addressing the unmet need for lipid lowering in this high‑risk population. Secondary objectives include evaluation of the effect on additional lipid parameters (apolipoprotein B, non‑HDL‑C, triglycerides, ANGPTL3, total cholesterol, and HDL‑C); determination of the proportion of participants achieving LDL‑C < 100 mg/dL; assessment of the impact on LDL‑C apheresis eligibility criteria; characterization of safety and tolerability; and evaluation of efficacy, safety, and tolerability with long‑term dosing of zodasiran.

Three participants were enrolled. The study population comprised adolescents aged 12 to < 18 years, including both females and males. All participants had a confirmed diagnosis of Homozygous Familial Hypercholesterolemia (HoFH) based on genetic testing or clinical criteria. Eligibility required a body weight of at least 35 kg, a screening LDL‑C level of ≥ 116 mg/dL, and hemoglobin A1c ≤ 9.5%. Additional laboratory limits included total bilirubin < 2 × ULN (except in Gilbert’s syndrome) and alanine aminotransferase or aspartate aminotransferase < 3 × ULN. Participants were non‑pregnant, non‑lactating, and not planning pregnancy during the trial. The cohort was classified as vulnerable due to the adolescent age range. No further lifestyle restrictions were specified.

The study is a Phase 3 single‑arm open‑label trial evaluating subcutaneous administration of 200 mg zodasiran solution for injection in adolescent participants with Homozygous Familial Hypercholesterolemia. After an initial screening visit to confirm eligibility criteria—including age 12 to < 18 years, body weight ≥35 kg, LDL‑C ≥116 mg/dL, and laboratory safety thresholds—baseline assessments are performed. Participants then receive the study drug at scheduled study visits and are followed for 12 months, with periodic visits to monitor fasting LDL‑C, apolipoprotein B, non‑HDL‑C, triglycerides, ANGPTL3, total cholesterol, HDL‑C, and safety parameters. The primary efficacy endpoint is the percent change from baseline to month 12 in fasting LDL‑C; secondary endpoints include changes in the aforementioned lipid parameters, LDL‑C apheresis eligibility, achievement of LDL‑C < 100 mg/dL, pharmacokinetic AUC, and incidence of treatment‑emergent adverse events. The end‑of‑study visit occurs at month 12 to collect final efficacy and safety data. Overall participant involvement spans the screening period plus approximately 12 months of treatment and follow‑up. Early termination may be enacted in accordance with predefined protocol criteria, such as safety concerns or withdrawal of consent. The trial recruitment is planned to commence on 31 July 2026 and conclude by 23 February 2029.

The investigational product, identified as ARO-ANG3, contains the active substance ZODASIRAN and is supplied as a solution for injection. Each dose consists of 200 mg administered by subcutaneous injection.

No comparator, placebo, or additional investigational agents are incorporated in the study; participants receive only the study medication as described.

Administration of the study drug follows the schedule specified in the protocol, with each injection delivered subcutaneously in the prescribed volume. Compliance is monitored through documented administration records and scheduled study visits to verify adherence to the dosing regimen.

The primary efficacy assessment is the percent change from baseline to month 12 in fasting LDL-C. Fasting blood samples will be collected at screening (baseline) and at month 12, and the LDL-C concentration will be measured using a validated laboratory assay. The change will be expressed as a percentage relative to the baseline value.

Secondary efficacy parameters include percent changes from baseline to month 12 in fasting apolipoprotein B (ApoB), non‑high density lipoprotein cholesterol (non‑HDL-C), triglycerides (TGs), angiopoietin‑like protein 3 (ANGPTL3), total cholesterol (Total Cholesterol), and HDL‑C (HDL‑C); the absolute change in fasting LDL‑C; the area under the plasma concentration‑time curve (AUC) for fasting LDL‑C from baseline to month 12; the number of participants meeting EU and US LDL‑C apheresis eligibility criteria at month 12; the number of participants achieving fasting LDL‑C < 100 mg/dL at month 12; longitudinal changes and percent changes in fasting LDL‑C over time; and the count of participants experiencing treatment‑emergent adverse events. These secondary endpoints will be evaluated using the same fasting blood collection schedule (baseline and month 12) with additional interim assessments as defined in the protocol for longitudinal analyses. All laboratory measurements will be performed with standardized, validated methods, and data will be analyzed using appropriate statistical techniques to compare baseline and month‑12 values.