Study of ARO-ANG3 in Participants With Homozygous Familial Hypercholesterolemia (HOFH) (Gateway)

Phase 2 Study to Evaluate the Safety and Efficacy of ARO-ANG3 in Subjects With Homozygous Familial Hypercholesterolemia (HOFH)

Participants with documented homozygous familial hypercholesterolemia (HoFH) who have provided informed consent will receive 2 open-label doses of ARO-ANG3 and be evaluated for safety and efficacy parameters through 36 weeks. Participants who complete the first 36 week treatment period may opt to continue in an additional 24-month extension period during which they will receive up to 8 doses open-label doses of ARO-ANG3.

Study Overview

• Status: Terminated
• Conditions: Homozygous Familial Hypercholesterolemia
• Intervention / Treatment: Drug: ARO-ANG 3 Injection

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Research Site 8
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Research Site 3
• Canada
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Research Site 2
    • Québec, Quebec, Canada, G1V 4W2
      • Research Site 1
• South Africa
  • Johannesburg, South Africa, 2193
    • Research Site 7
• United States
  • New York
    • Mount Sinai, New York, United States, 10029
      • Research Site 4
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Research Site 5

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Fasting LDL-C >100 mg/dL at Screening
• Weight of ≥ 40 kg and body mass index ≥ 18.5 and ≤ 40 kg/m2
• Diagnosis of HoFH based on a supportive genetic test or clinical diagnosis
• On stable maximally tolerated lipid lowering therapy
• Willing to abide by stable low-fat, low-cholesterol, heart-healthy diet for at least 4 weeks prior to Day 1
• Participants of childbearing potential (males & females) must agree to use highly-effective contraception during the study and for at least 24 weeks from the last dose of study medication.
• Women of childbearing potential must have a negative pregnancy test and cannot be breastfeeding
• Women of childbearing potential on hormonal contraceptives must be stable on the medications for > 2 menstrual cycles prior to Day 1
• Willing to provide written informed consent and to comply with study requirements

Exclusion Criteria:

• Current use or use within 365 days from Day 1 of any hepatocyte targeted small interfering RNA oligonucleotides (siRNA) or antisense oligonucleoside molecule
• Use of evinacumab (some exceptions apply)
• Fasting TG > 300 mg/dL at Screening
• Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins
• Newly diagnosed (within 3 months prior to informed consent) or poorly controlled diabetes (Hemoglobin A1c > 9%)
• Use of systemic corticosteroids (some exceptions apply)
• Symptoms of myocardial ischemia or severe left ventricular dysfunction
• History of metastatic malignancy within 3 years of Day 1 (some exceptions apply)
• Planned cardiac procedure/surgery such as coronary artery bypass graft (CABG) surgery, percutaneous coronary intervention (PCI), carotid surgery or stenting, or carotid revascularization

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: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ARO-ANG3 Dose 1; ARO-ANG3 Dose Level 1 subcutaneous (SC)	Drug: ARO-ANG 3 Injection; Participants will be randomized to receive ARO-ANG3 SC on Day 1 and Day 84 during the initial 36 Weeks of the study and on Day1 and Months 3, 6, 9, 12, 15, 18, and 21 of the extension period
Experimental: ARO-ANG3 Dose 2; ARO-ANG3 Dose Level 2 SC	Drug: ARO-ANG 3 Injection; Participants will be randomized to receive ARO-ANG3 SC on Day 1 and Day 84 during the initial 36 Weeks of the study and on Day1 and Months 3, 6, 9, 12, 15, 18, and 21 of the extension period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Fasting LDL-C at Week 24	LDL-C, computed using Friedewald formula, Martin-Hopkins methodology and preparative ultracentrifugation (PUC).	Baseline, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Fasting LDL-C (PUC) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting LDL-C (PUC) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Calculated LDL-C (Friedewald Formula) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting Calculated LDL-C (Friedewald Formula) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Calculated LDL-C (Martin-Hopkins Methodology) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting Calculated LDL-C (Martin-Hopkins Methodology) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Angiopoietin-like 3 (ANGPTL3) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting ANGPTL3 Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Total Apolipoprotein B (ApoB) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting Total ApoB Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting High-Density Lipoprotein-Cholesterol (HDL-C) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting HDL-C Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Non-HDL-C Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting Non-HDL-C Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Very-Low-Density Lipoprotein-Cholesterol (VLDL-C) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting VLDL-C Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Total Cholesterol (TC) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting TC Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Triglycerides (TG) Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting TG Over Time		Baseline, Weeks 4, 8, 12, 16, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	An adverse event (AE) is any untoward medical occurrence, which does not necessarily have to have a causal relationship with this treatment. A serious adverse event (SAE) is an AE occurring during any study phase that: results in death; is immediately life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medically important event or reaction that may require medical intervention to prevent one of the outcomes listed above. AEs are considered treatment-related if the relationship to the study drug is 'possibly related', 'probably related'. A TEAE is defined as an AE that occurs following IP administration or a pre-existing condition exacerbated following IP administration. Injection site reactions are assessed at every visit starting on Day 1 and include any Preferred Term containing 'Injection Site'.	From first dose of study drug up to Week 36 (initial treatment period), and up to Month 24 (extension period)
Number of Participants With Anti-Drug Antibodies (ADAs) to ARO-ANG3 Over Time		Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period)
Percentage of Participants Meeting United States National Lipid Association Apheresis Eligibility Criteria of LDL-C ≥ 300 mg/dL at Week 24	Apheresis is the extracorporeal process of removing one or more blood constituents from whole blood and returning the remainder to the circulation.The National Lipid Association outlines eligibility criteria for apheresis, particularly for patients with familial hypercholesterolemia who have not achieved target LDL cholesterol levels despite maximally tolerated pharmacotherapy. LDL-C ≥ 300 mg/dL is a criterion.	Week 24
Percentage of Participants Meeting European Union (EU) Apheresis Eligibility Criteria Per German Apheresis Working Group at Week 24	Apheresis is the extracorporeal process of removing one or more blood constituents from whole blood and returning the remainder to the circulation. The European Union (EU) apheresis eligibility criteria (per German Apheresis Working Group) include the following categories: A patient with primary cardiovascular disease (CVD) prevention is considered as meeting German apheresis eligibility criteria if LDL-C >160 mg/dL; A patient with secondary CVD prevention is considered as meeting German apheresis eligibility criteria if LDL-C >120 mg/dL	Week 24

Collaborators and Investigators

• Sponsor: Arrowhead Pharmaceuticals

Publications and helpful links

General Publications

• Dimitriadis K, Theofilis P, Iliakis P, Pyrpyris N, Dri E, Sakalidis A, Soulaidopoulos S, Tsioufis P, Fragkoulis C, Chrysohoou C, Tsiachris D, Tsioufis K. Management of dyslipidemia in coronary artery disease: the present and the future. Coron Artery Dis. 2024 Sep 1;35(6):516-524. doi: 10.1097/MCA.0000000000001375. Epub 2024 Apr 29.
• Raal FJ, Bergeron J, Gaudet D, Rosenson RS, Sullivan DR, Turner T, Hegele RA, Ballantyne CM, Knowles JW, Leeper NJ, Goldberg IJ, Zhou R, Muhsin M, Hellawell J, Hamilton J, Watts GF. Zodasiran, an RNAi therapeutic targeting ANGPTL3, for treating patients with homozygous familial hypercholesterolaemia (GATEWAY): an open-label, randomised, phase 2 trial. Lancet Diabetes Endocrinol. 2026 Feb;14(2):123-136. doi: 10.1016/S2213-8587(25)00290-6. Epub 2025 Dec 18.

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2022
• Primary Completion (Actual): May 2, 2023
• Study Completion (Actual): November 13, 2025

Study Registration Dates

• First Submitted: January 20, 2022
• First Submitted That Met QC Criteria: January 20, 2022
• First Posted (Actual): February 1, 2022

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 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
• Other Study ID Numbers: AROANG3-2003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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