Homozygous Familial Hypercholesterolemia
Conditions
Brief summary
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.
Interventions
DRUGzodasiran Injection
ARO-ANG3 Injection
DRUGPlacebo
sterile normal saline (0.9% NaCl)
Sponsors
Arrowhead Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change from Baseline to Month 12 in Fasting Low Density Lipoprotein Cholesterol (LDL-C) (Randomized period) | Baseline, Month 12 |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
Countries
Australia, Austria, Belgium, Brazil, Canada, Czechia, France, Georgia, Germany, Israel, Japan, New Zealand, Saudi Arabia, South Africa, Spain, Sweden, Turkey (Türkiye), United States
Outcome results
None listed