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

Study Overview
=================
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.

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

Conditions
-----------------
Homozygous Familial Hypercholesterolemia

Intervention / Treatment
-----------------
* Drug: ARO-ANG 3 Injection


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARO-ANG3 Dose 1<br>ARO-ANG3 Dose Level 1 subcutaneous (SC) | Drug: ARO-ANG 3 Injection<br>* 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<br>|
| Experimental: ARO-ANG3 Dose 2<br>ARO-ANG3 Dose Level 2 SC | Drug: ARO-ANG 3 Injection<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | Baseline, up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change from Baseline in Fasting LDL-C (PUC) Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Absolute Change from Baseline in Fasting LDL-C (PUC) Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Percent Change from Baseline in Fasting Calculated LDL-C Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Absolute Change from Baseline in Fasting Calculated LDL-C Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Percent Change from Baseline in Fasting Angiopoietin-like 3 (ANGPTL3) Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Absolute Change from Baseline in Fasting ANGPTL3 Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Percent Change from Baseline in Fasting Total Apolipoprotein B (ApoB) Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Absolute Change from Baseline in Fasting Total ApoB Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Percent Change from Baseline in Fasting High-Density Lipoprotein-Cholesterol (HDL-C) Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) 36 | 
| Absolute Change from Baseline in Fasting HDL-C Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Percent Change from Baseline in Fasting Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Absolute Change from Baseline in Fasting Non-HDL-C Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Percent Change from Baseline in Fasting Very-Low-Density Lipoprotein-Cholesterol (VLDL-C) Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Absolute Change from Baseline in VLDL-C Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Percent Change from Baseline in Fasting Total Cholesterol (TC) Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Absolute Change from Baseline in Fasting TC Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Percent Change from Baseline in Fasting Triglycerides (TG) Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Absolute Change from Baseline in Fasting TG Over Time |  | Baseline, up to Week 36 (initial treatment period), up to Month 24 (extension period) | 
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) |  | Baseline, up to Week 36 (initial treatment period), 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) | 
| Proportion of Participants meeting United States National Lipid Association Apheresis Eligibility Criteria of LDL-C ≥ 300 mg/dL at Week 24 |  | Week 24 | 
| Proportion of Participants Meeting European Union (EU) Apheresis Eligibility Criteria per German Apheresis Working Group at Week 24 |  | Week 24 |