This multicenter, randomized, placebo-controlled study will evaluate the efficacy and safety of zodasiran subcutaneous (SC) injection in subjects 12 years of age and older with genetically or clinically diagnosed Homozygous familial hypercholesterolemia (HoFH). After completion of the double blind (DB) treatment period subjects will be eligible to continue in the optional open-label extension (OLE) period of the study. All placebo subjects who opt to continue will transition to active drug during the OLE Period.

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