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

• ClinicalTrials.gov Identifier: NCT05217667
• Recruitment Status: Active, not recruiting
• First Posted: February 1, 2022
• Last Update Posted: February 27, 2023
• Sponsor: Arrowhead Pharmaceuticals
• Information provided by (Responsible Party): Arrowhead Pharmaceuticals

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Homozygous Familial Hypercholesterolemia	Drug: ARO-ANG 3 Injection	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study to Evaluate the Safety and Efficacy of ARO-ANG3 in Subjects With Homozygous Familial Hypercholesterolemia (HOFH)
• Actual Study Start Date: April 22, 2022
• Estimated Primary Completion Date: July 2023
• Estimated Study Completion Date: May 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Percent Change from Baseline in Fasting Calculated Low-Density Lipoprotein-Cholesterol (LDL-C) and LDL-C by Preparative Ultracentrifugation (LDL-C [PUC]) up to Week 24 [ Time Frame: Baseline, up to Week 24 ]

Secondary Outcome Measures :

1. Percent Change from Baseline in Fasting LDL-C (PUC) Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
2. Absolute Change from Baseline in Fasting LDL-C (PUC) Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
3. Percent Change from Baseline in Fasting Calculated LDL-C Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
4. Absolute Change from Baseline in Fasting Calculated LDL-C Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
5. Percent Change from Baseline in Fasting Angiopoietin-like 3 (ANGPTL3) Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
6. Absolute Change from Baseline in Fasting ANGPTL3 Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
7. Percent Change from Baseline in Fasting Total Apolipoprotein B (ApoB) Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
8. Absolute Change from Baseline in Fasting Total ApoB Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
9. Percent Change from Baseline in Fasting High-Density Lipoprotein-Cholesterol (HDL-C) Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) 36 ]
10. Absolute Change from Baseline in Fasting HDL-C Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
11. Percent Change from Baseline in Fasting Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
12. Absolute Change from Baseline in Fasting Non-HDL-C Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
13. Percent Change from Baseline in Fasting Very-Low-Density Lipoprotein-Cholesterol (VLDL-C) Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
14. Absolute Change from Baseline in VLDL-C Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
15. Percent Change from Baseline in Fasting Total Cholesterol (TC) Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
16. Absolute Change from Baseline in Fasting TC Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
17. Percent Change from Baseline in Fasting Triglycerides (TG) Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
18. Absolute Change from Baseline in Fasting TG Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
19. Number of Participants with Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
20. Number of Participants with Anti-Drug Antibodies (ADAs) to ARO-ANG3 Over Time [ Time Frame: Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) ]
21. Proportion of Participants meeting United States National Lipid Association Apheresis Eligibility Criteria of LDL-C ≥ 300 mg/dL at Week 24 [ Time Frame: Week 24 ]
22. Proportion of Participants Meeting European Union (EU) Apheresis Eligibility Criteria per German Apheresis Working Group at Week 24 [ Time Frame: Week 24 ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, New York

Icahn School of Medicine at Mt. Sinai

Mount Sinai, New York, United States, 10029

United States, Ohio

Metabolic and Atherosclerosis Research Center

Cincinnati, Ohio, United States, 45227

Australia, New South Wales

Royal Prince Alfred Hospital

Camperdown, New South Wales, Australia, 2050

Australia, Western Australia

Linear Clinical Research

Nedlands, Western Australia, Australia, 6009

Canada, Quebec

Ecogene-21

Chicoutimi, Quebec, Canada, G7H 7K9

Clinique des Maladies Lipidiques de Quebec Inc

Québec, Quebec, Canada, G1V 4W2

South Africa

WCR-Lipids, Carbohydrate Metabolism Unit Area 551, Department of Medicine

Johannesburg, South Africa, 2193

Sponsors and Collaborators

Arrowhead Pharmaceuticals

More Information

• Responsible Party: Arrowhead Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT05217667
• Other Study ID Numbers: AROANG3-2003
• First Posted: February 1, 2022
• Last Update Posted: February 27, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hyperlipoproteinemia Type II; Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Hyperlipoproteinemias