Study of ARO-ANG3 in Adults With Mixed Dyslipidemia

Study Overview
=================
Brief Summary
-----------------
The purpose of AROANG3-2001 is to evaluate the efficacy and safety of ARO-ANG3 in participants with mixed dyslipidemia. Participants will initially receive 2 subcutaneous injections of ARO-ANG3 or placebo. Participants who complete the double-blind treatment period may opt to continue in an open-label extension during which they will receive up to 8 doses of ARO-ANG3.

Official Title
-----------------
A Double-blind, Placebo-controlled Phase 2b Study to Evaluate the Efficacy and Safety of ARO-ANG3 in Adults With Mixed Dyslipidemia

Conditions
-----------------
Mixed Dyslipidemia

Intervention / Treatment
-----------------
* Drug: ARO-ANG3
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Based on medical history, evidence of TG ≥ 150 mg/dL but ≤ 499 mg/dL Fasting levels at Screening of LDL-C ≥ 70 mg/dL OR non-HDL-C ≥ 100 mg/dL after at least 4 weeks of stable diet and stable optimal statin therapy Mean fasting TG ≥ 150 mg/dL and ≤ 499 mg/dL during Screening collected at two separate and consecutive visits and at least 7 days apart and not more than 17 days apart Willing to follow diet counseling and maintain a stable diet per Investigator judgment based on local standard of care Participants of childbearing potential must agree to use highly-effective contraception during the study and for at least 24 weeks from 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 medication for ≥ 2 menstrual cycles prior to Day 1 Men must not donate sperm during the study and for at least 24 weeks following the last dose of study medication Able and 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 siRNA or antisense oligonucleotide molecule Active pancreatitis within 12 weeks prior to Day 1 Any planned bariatric surgery or similar procedures to induce weight loss from consent to end of study Acute coronary syndrome event within 24 weeks of Day 1 Major surgery within 12 weeks of Day 1 or planned surgery during the study Planned coronary intervention (e.g., stent placement or heart bypass) during the study Uncontrolled hypertension Human immunodeficiency virus (HIV) infection, seropositive for Hepatitis B (HBV), seropositive for Hepatitis C (HCV) Uncontrolled hypothyroidism or hyperthyroidism Hemorrhagic stroke within 24 weeks of Day 1 History of bleeding diathesis or coagulopathy Current diagnosis of nephrotic syndrome Systemic use of corticosteroids or anabolic steroids within 4 weeks prior to Day 1 or planned use during the study Malignancy within the last 2 years prior to date of consent requiring systemic treatment (some exceptions apply) Note: additional inclusion/exclusion criteria may apply per protocol

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARO-ANG3<br>Two doses of ARO-ANG3 by subcutaneous (sc) injection during double-blind treatment period. Up to 8 doses of ARO-ANG3 by sc injection during the open-label extension period. | Drug: ARO-ANG3<br>* ARO-ANG3 Injection<br>|
| Placebo Comparator: Placebo<br>Calculated volume to match active treatment by sc injection during the double-blind treatment period. Up to 8 doses of ARO-ANG3 by sc injection during the open-label extension period. | Drug: ARO-ANG3<br>* ARO-ANG3 Injection<br>Drug: Placebo<br>* Sterile Normal Saline (0.9% NaCl)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change from Baseline in Fasting Triglycerides (TG) at Week 24 |  | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change from Baseline in Fasting TG Over Time |  | Baseline, up to Week 36 (double-blind treatment period), up to Month 24 (open-label extension) | 
| Percent Change from Baseline in Fasting Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24 |  | Baseline, Week 24 | 
| Percent Change from Baseline in Fasting Non-HDL-C Over Time |  | Baseline, up to Week 36 (double-blind treatment period), up to Month 24 (open-label extension) | 
| Percent Change from Baseline in Fasting Total Apolipoprotein B (ApoB) at Week 24 |  | Baseline, Week 24 | 
| Percent Change from Baseline in Fasting Total ApoB Over Time |  | Baseline, up to Week 36 (double-blind treatment period), up to Month 24 (open-label extension) | 
| Percent Change from Baseline in Fasting Low-density Lipoprotein-Cholesterol (LDL-C) Using Ultracentrifugation at Week 24 |  | Baseline, Week 24 | 
| Percent Change from Baseline in Fasting LDL-C Using Ultracentrifugation Over Time |  | Baseline, up to Week 36 (double-blind treatment period), up to Month 24 (open-label extension) | 
| Percent Change from Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 24 |  | Baseline, Week 24 | 
| Percent Change from Baseline in ANGPTL3 Over Time |  | Baseline, up to Week 36 (double-blind treatment period), up to Month 24 (open-label extension) | 
| Percent Change from Baseline in Fasting High-Density Lipoprotein-Cholesterol (HDL-C) at Week 24 |  | Baseline, Week 24 | 
| Percent Change from Baseline in Fasting HDL-C Over Time |  | Baseline, up to Week 36 (double-blind treatment period), up to Month 24 (open-label extension) | 
| Plasma Concentrations of ARO-ANG3 Over Time |  | Baseline, up to Week 12 (double-blind treatment period), up to Month 24 (open-label extension) | 
| Number of Participants with Adverse Events (AEs) and/or Serious Adverse Events (SAEs) at Week 24 |  | Week 24 | 
| Number of Participants with AEs and/or SAEs Over Time in the Double-Blind Treatment Period |  | up to Week 36 (double-blind treatment period) | 
| Number of Participants with AEs and/or SAEs Over Time in the Open-Label Extension |  | up to Month 24 (open-label extension) |