A Phase 3 Study of Zodasiran in Adolescent and Adult Subjects With Homozygous Familial Hypercholesterolemia (YOSEMITE)

• zodasiran Injection (Drug), also known as ARO-ANG3: ARO-ANG3 Injection
• Placebo (Drug): sterile normal saline (0.9% NaCl)

Primary outcomes

• Percent Change from Baseline to Month 12 in Fasting Low Density Lipoprotein Cholesterol (LDL-C) (Randomized period) [Baseline, Month 12]

Secondary outcomes

• Change and Percent Change from Baseline to Month 12 in Fasting Apolipoprotein B (ApoB) (Randomized Period) [Baseline, Month 12]
• Change and Percent Change from Baseline to Month 12 in Fasting Non-High Density Lipoprotein Cholesterol (non-HDL-C) (Randomized Period) [Baseline, Month 12]
• Change from Baseline to Month 12 in Fasting LDL-C (Randomized Period) [Baseline, Month 12]
• Area Under the Plasma Concentration Versus the Time Curve (AUC) from Baseline to Month 12 for Fasting LDL-C (Randomized Period) [Baseline, Month 12]
• Change and Percent Change from Baseline to Month 12 in Fasting Triglycerides (TGs) (Randomized Period) [Baseline, Month 12]
• Change and Percent Change from Baseline to Month 12 in Fasting Angiopoietin-like Protein 3 (ANGPTL3) (Randomized Period) [Baseline, Month 12]
• Change and Percent Change from Baseline to Month 12 in Fasting Total Cholesterol (Randomized Period) [Baseline, Month 12]
• Change and Percent Change from Baseline to Month 12 in Fasting High-Density Lipoprotein Cholesterol (HDL-C) (Randomized Period) [Baseline, Month 12]
• Proportion of Participants who Meet European Union (EU) LDL-C Apheresis Eligibility Criteria (per German Apheresis Working Group) at Month 12 (Randomized Period) [Month 12]
• Proportion of Participants who Meet United States (US) Apheresis Eligibility Criteria (per National Lipid Association) at Month 12 (Randomized Period) [Month 12]
• Proportion of Participants with Fasting LDL-C <100 mg/dL (2.6 mmol/L) at Month 12 (Randomized Period) [Month 12]
• Change from Baseline in Fasting LDL-C Over Time (Randomized Period) [Baseline, Day 1, Months 1, 2, 3, 4.5, 6, 7.5, 9, 10.5, and 12]
• Percent Change from Baseline in fasting LDL-C Over Time (Randomized Period) [Baseline, Day 1, Months 1, 2, 3, 4.5, 6, 7.5, 9, 10.5, and 12]
• Percent Change from Baseline to Month 12 in Fasting Lipoprotein(a) [Lp(a)] (Randomized Period) [Baseline, Month 12]

Sex: All, ages: 12 Years to any

Inclusion Criteria:

* Age ≥12 years, non pregnant, non lactating, do not plan to become pregnant during the study
* Body weight ≥35 kg at Screening as patients could theoretically be <35 kg as the study continues.
* HoFH based on a supportive genetic test or a clinical diagnosis (total cholesterol >500 mg/dL\[13 mmol/L\] OR treated LDL-C concentration of ≥300 mg/dL \[≥8 mmol/L\] either accompanied by TGs <300 mg/dL \[3.4 mmol/L\] AND both parents with documented total cholesterol >250 mg/dL \[6.5 mmol/L\] OR cutaneous or tendinous xanthoma before 10 years of age)
* LDL-C ≥70 mg/dL (1.8 mmol/L). For adolescents 12 to <18 years of age, screening LDL-C ≥116 mg/dL (3 mmol/L).
* Hemoglobin A1c (HbA1c) ≤9.5%
* Total bilirubin <2xULN, unless in previously confirmed cases of Gilbert's syndrome
* Alanine aminotransferase or aspartate aminotransferase <3×ULN
* On standard of care, maximally tolerated lipid-lowering therapy to include a maximally tolerated statin, ezetimibe, and a PCSK9 inhibitor

Exclusion Criteria:

* Use of a hepatocyte-targeted siRNA within 365 days before Day 1 (except inclisiran, which is permitted; administration of inclisiran and study drug must be separated by at least 4 weeks)
* Use of an antisense oligonucleotide molecule within 3 months before Day 1 (except inclisiran, which is permitted; administration of inclisiran and study drug must be separated by at least 4 weeks)
* Use of evinacumab within 3 months before Day 1. Evinacumab use is prohibited during the study.
* Non-response to evinacumab, defined as LDL-C reduction <15% from baseline after 2 doses
* Use of any other investigational agent or device within 30 days or 5 half-lives (whichever is longer) before Day 1
* Use of systemic corticosteroids (unless used as replacement therapy for pituitary/adrenal disease with a stable regimen)
* Estimated glomerular filtration rate <30 mL/min

NOTE: Additional Inclusion/exclusion criteria may apply per protocol