Phase 3 Study to Evaluate the Efficacy and Safety of Zodasiran in Adolescent and Adult Subjects with Homozygous Familial Hypercholesterolemia (YOSEMITE)

The primary objective is to demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) with zodasiran compared with placebo in subjects with homozygous familial hypercholesterolemia (HoFH). This objective addresses the critical need for effective LDL-C lowering in this rare genetic disorder characterized by severely elevated cholesterol levels and premature cardiovascular disease.

The secondary objectives include:

• To evaluate the effect of zodasiran compared with placebo on other lipid parameters, including apolipoprotein B (ApoB), non-HDL cholesterol, triglycerides (TGs), angiopoietin-like protein 3 (ANGPTL3), total cholesterol, HDL cholesterol, and lipoprotein(a) (Lp[a]) in subjects with HoFH.

• To evaluate the proportion of subjects achieving LDL-C levels below 100 mg/dL (2.6 mmol/L) in subjects with HoFH, representing a clinically meaningful therapeutic target.

• To evaluate the effect of zodasiran compared with placebo on LDL-C apheresis eligibility criteria in subjects with HoFH, which may have implications for reducing the burden of this intensive therapeutic intervention.

• To evaluate the safety and tolerability of zodasiran in subjects with HoFH.

This clinical trial enrolled a total of **42 participants** diagnosed with **Homozygous Familial Hypercholesterolemia (HoFH)**. The study population included both **male** and **female** subjects aged **12 years and older**, with a minimum body weight requirement of **35 kg** at screening. Participants were selected based on either a supportive genetic test or a clinical diagnosis of HoFH, which included criteria such as total cholesterol exceeding 500 mg/dL or treated **low-density lipoprotein cholesterol (LDL-C)** concentration of at least 300 mg/dL, accompanied by specific parental cholesterol levels or the presence of cutaneous or tendinous **xanthoma** before 10 years of age. Key inclusion criteria required participants to have LDL-C levels of at least 70 mg/dL, or 116 mg/dL for adolescents aged 12 to less than 18 years, and **hemoglobin A1c (HbA1c)** levels not exceeding 9.5%. All participants were required to be on maximally tolerated **lipid-lowering therapy** as standard of care. Female participants were required to be non-pregnant, non-lactating, and not planning to become pregnant during the study. The trial also included a **vulnerable population** component, reflecting the inclusion of adolescent subjects.

This is a **Phase 3**, **randomized**, **placebo-controlled** clinical trial evaluating the efficacy and safety of **zodasiran** in adolescent and adult subjects with **Homozygous Familial Hypercholesterolemia** (HoFH). The study employs a double-blind design to assess the investigational medicinal product, which is administered as a solution for injection via **subcutaneous injection**. The active substance, zodasiran, is a nucleic acid-based therapy targeting **ANGPTL3 mRNA**. Participants will receive either zodasiran at a maximum daily dose of 200 mg or matching placebo, with a maximum total dose of 2000 mg over a treatment period of 24 months. The trial is designed to demonstrate reduction of **low-density lipoprotein cholesterol** (LDL-C) with zodasiran compared with placebo in subjects with HoFH.

The study is estimated to commence recruitment in February 2026 and is expected to conclude in August 2028. Eligible participants include individuals aged 12 years or older with a body weight of at least 35 kg at screening. Diagnosis of HoFH must be supported by genetic testing or clinical criteria, including total cholesterol greater than 500 mg/dL or treated LDL-C concentration of at least 300 mg/dL with additional familial or clinical features. Participants must have baseline **LDL-C** levels of at least 70 mg/dL, or at least 116 mg/dL for adolescents aged 12 to less than 18 years. Additional inclusion criteria require **hemoglobin A1c** (HbA1c) not exceeding 9.5%, total bilirubin less than two times the upper limit of normal (except in confirmed Gilbert's syndrome), and liver enzyme levels within acceptable ranges. All participants must be on maximally tolerated lipid-lowering therapy as standard of care.

The primary endpoint is the percent change from baseline to month 12 in fasting LDL-C during the randomized period. Secondary endpoints include percent changes in **apolipoprotein B** (ApoB), **non-high density lipoprotein cholesterol** (non-HDL-C), **triglycerides**, **ANGPTL3**, total cholesterol, and **high-density lipoprotein cholesterol** (HDL-C) from baseline to month 12. Additional assessments include the area under the plasma concentration versus time curve for fasting LDL-C, the proportion of participants meeting apheresis eligibility criteria according to European Union and United States guidelines, and the proportion achieving fasting LDL-C below 100 mg/dL at month 12. Changes in **lipoprotein(a)** [Lp(a)] and temporal changes in LDL-C over the course of the study are also evaluated.

The study involves a screening visit to assess eligibility and establish baseline measurements, followed by a randomized treatment period extending to month 12. Participants will attend scheduled follow-up visits for administration of the investigational product, safety monitoring, and collection of efficacy data. The end-of-study visit will occur at the completion of the 24-month treatment period. The expected duration of participant involvement is approximately 24 months. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol violations, unacceptable adverse events, or investigator determination that continued participation is not in the participant's best interest.

The experimental medication investigated in this clinical trial is **zodasiran**, also known as ARO-ANG3. Zodasiran is a double-stranded siRNA oligonucleotide against ANGPTL3 mRNA conjugated to N-acetyl galactosamine, classified as a nucleic acid substance. The investigational product is supplied as a **solution for injection** in a pre-filled syringe and is administered via **subcutaneous injection**. The maximum daily dose is **200 mg**, with a maximum total dose of **2000 mg** over the treatment period. The maximum treatment duration is **24 months**. The investigational product is manufactured by Arrowhead Pharmaceuticals Inc.

The comparator treatment consists of **placebo** of zodasiran, which is administered to subjects in the control group. The placebo is designed to match the experimental medication in appearance and administration method to maintain blinding throughout the study. Specific details regarding the pharmaceutical form, route of administration, and dosing schedule of the placebo are matched to the active treatment to ensure consistency in study conduct and compliance monitoring.

Efficacy will be assessed through the evaluation of lipid parameters and biomarkers in subjects with **homozygous familial hypercholesterolemia**. The primary endpoint is the percent change from baseline to Month 12 in fasting **low-density lipoprotein cholesterol (LDL-C)** during the randomized period. Secondary endpoints include the percent change from baseline to Month 12 in fasting **apolipoprotein B (ApoB)**, fasting **non-high-density lipoprotein cholesterol (non-HDL-C)**, fasting **triglycerides (TGs)**, fasting **angiopoietin-like protein 3 (ANGPTL3)**, fasting **total cholesterol**, fasting **high-density lipoprotein cholesterol (HDL-C)**, and fasting **lipoprotein(a) [Lp(a)]**. Additional secondary endpoints consist of the absolute change from baseline to Month 12 in fasting LDL-C, the area under the plasma concentration versus time curve from baseline to Month 12 for fasting LDL-C, and the change from baseline in fasting LDL-C over time as well as the percent change from baseline in fasting LDL-C over time during the randomized period. The proportion of participants meeting European Union LDL-C apheresis eligibility criteria per the German Apheresis Working Group at Month 12, the proportion of participants meeting United States apheresis eligibility criteria per the National Lipid Association at Month 12, and the proportion of participants with fasting LDL-C less than 100 mg/dL at Month 12 will also be evaluated during the randomized period.