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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Homozygous Familial Hypercholesterolemia
• Intervention / Treatment: Drug: Placebo; Drug: zodasiran Injection

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Medical Monitor; Phone Number: 626-304-3400; Email: YOSEMITE@arrowheadpharma.com

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Recruiting
      • Research Site 13
    • Saint Leonards, New South Wales, Australia, 2065
      • Recruiting
      • Research Site 9
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Recruiting
      • Research Site 21
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Recruiting
      • Research Site 3
• Austria
  • Innsbruck, Austria, 6020
    • Recruiting
    • Research Site 40
  • Linz, Austria, 4021
    • Recruiting
    • Research Site 39
  • Vienna, Austria, 1090
    • Recruiting
    • Research Site 42
  • Vienna, Austria, 1130
    • Recruiting
    • Research Site 37
• Belgium
  • La Louvière, Belgium, 7100
    • Recruiting
    • Research Site 33
  • Leuven, Belgium, 3000
    • Recruiting
    • Research Site 34
• Brazil
  • São Paulo
    • Cerqueira César, São Paulo, Brazil, CEP-05403-000
      • Recruiting
      • Research Site 24
• Canada
  • Québec, Canada, G1V 4W2
    • Recruiting
    • Research Site 4
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 2H2
      • Recruiting
      • Research Site 5
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Recruiting
      • Research Site 6
• Czechia
  • Hradec Králové, Czechia, General E3 500 0
    • Recruiting
    • Research Site 30
• France
  • Paris, France, 75013
    • Recruiting
    • Research Site 23
• Georgia
  • Tbilisi, Georgia, 0159
    • Recruiting
    • Research Site 17
  • Tbilisi, Georgia, 160
    • Recruiting
    • Research Site 18
  • Tbilisi, Georgia, 186
    • Recruiting
    • Research Site 19
• Germany
  • Berlin, Germany, 13353
    • Recruiting
    • Research Site 35
• Israel
  • Jerusalem, Israel, 9112001
    • Recruiting
    • Research Site 10
  • Tel Litwinsky, Israel, 5265601
    • Recruiting
    • Research Site 15
• Japan
  • Fukushima, Japan, 960-1295
    • Recruiting
    • Research Site 20
  • Okayama, Japan, 700-8558
    • Recruiting
    • Research Site 16
  • Saitama, Japan, 350-0495
    • Recruiting
    • Research Site 22
  • Tokyo, Japan, 113-8510
    • Recruiting
    • Research Site 25
  • Ishikawa-ken
    • Kanazawa, Ishikawa-ken, Japan, 920-8641
      • Recruiting
      • Research Site 26
  • Osaka
    • Suita, Osaka, Japan, 564-8565
      • Recruiting
      • Research Site 27
• New Zealand
  • Christchurch, New Zealand, 8011
    • Recruiting
    • Research Site 12
• Saudi Arabia
  • Riyadh, Saudi Arabia, 12713
    • Recruiting
    • Research Site 31
• South Africa
  • Cape Town, South Africa, 7925
    • Recruiting
    • Research Site 8
  • Johannesburg
    • Parktown, Johannesburg, South Africa, 2193
      • Recruiting
      • Research Site 11
• Spain
  • Barcelona, Spain, 8907
    • Recruiting
    • Research Site 43
  • Córdoba, Spain, 14004
    • Recruiting
    • Research Site 28
  • Madrid, Spain, 28041
    • Recruiting
    • Research Site 29
• Sweden
  • Gothenburg, Sweden, 413 46
    • Recruiting
    • Research Site 32
• Turkey (Türkiye)
  • Afyonkarahisar, Turkey (Türkiye), 03200
    • Recruiting
    • Research Site 36
  • Bornova/Izmir, Turkey (Türkiye), 35100
    • Recruiting
    • Research Site 41
  • Melikgazi/Kayseri, Turkey (Türkiye), 38030
    • Recruiting
    • Research Site 38
• United States
  • Illinois
    • Park Ridge, Illinois, United States, 60068
      • Recruiting
      • Research Site 7
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Research Site 2
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Recruiting
      • Research Site 1
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • Research Site 14

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: zodasiran; 5 doses of zodasiran by subcutaneous (sc) injection (randomized period). 4 or 5 doses of zodasiran by sc injection (optional open-label period).	Drug: zodasiran Injection; ARO-ANG3 Injection; Other Names: ARO-ANG3
Placebo Comparator: Placebo; Calculated volume to match active treatment by sc injection (randomized period). 4 or 5 doses of zodasiran by sc injection (optional open-label period)	Drug: Placebo; sterile normal saline (0.9% NaCl); Drug: zodasiran Injection; ARO-ANG3 Injection; Other Names: ARO-ANG3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change from Baseline to Month 12 in Fasting Low Density Lipoprotein Cholesterol (LDL-C) (Randomized period)	Baseline, Month 12

Secondary Outcome Measures

Outcome Measure	Time Frame
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
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 to Month 12 in Fasting Lipoprotein(a) [Lp(a)] (Randomized Period)	Baseline, Month 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
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 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

Collaborators and Investigators

• Sponsor: Arrowhead Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2025
• Primary Completion (Estimated): August 20, 2027
• Study Completion (Estimated): August 20, 2027

Study Registration Dates

• First Submitted: June 17, 2025
• First Submitted That Met QC Criteria: June 17, 2025
• First Posted (Actual): June 25, 2025

Study Record Updates

• Last Update Posted (Actual): June 10, 2026
• Last Update Submitted That Met QC Criteria: June 9, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Hyperlipoproteinemia Type II; Homozygous Familial Hypercholesterolemia; zodasiran
• Other Study ID Numbers: AROANG3-3001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No