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

Prior treatment

• 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.
• Use of any other investigational agent or device within 30 days or 5 half-lives (whichever is longer) before Day 1

Other illness

• Use of systemic corticosteroids (unless used as replacement therapy for pituitary/adrenal disease with a stable regimen)

Other

• Non-response to evinacumab, defined as LDL-C reduction \<15% from baseline after 2 doses
• Estimated glomerular filtration rate \<30 mL/min
  • NOTE: Additional Inclusion/exclusion criteria may apply per protocol

• 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