A Study of ALN-AAT02 in Healthy Participants and Participants With ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and tolerability of single or multiple doses of ALN-AAT02. The study will be conducted in 2 sequential phases in which Part A will be a single-ascending dose (SAD) phase in healthy participants, and Part B will be a multiple-ascending dose (MAD) phase in participants with ZZ type alpha-1 antitrypsin deficiency (PiZZ) and biopsy-proven alpha-1 antitrypsin (AAT) deficiency-associated liver disease.

Official Title
-----------------
A Phase 1/2, Randomized, Double-blind, Placebo-controlled, Single-ascending and Multiple-dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered ALN-AAT02 in Healthy Adult Subjects and Patients With ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease

Conditions
-----------------
ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease

Intervention / Treatment
-----------------
* Drug: ALN-AAT02
* Drug: Placebo
* Drug: ALN-AAT02


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, aged 18 to 65 years, inclusive; Has normal 12-lead electrocardiogram (ECG); Has body mass index (BMI) between 18 and 30 kg/m^2, inclusive; Has been a nonsmoker for at least 5 years before screening; Part A only: Has Alpha-1 antitrypsin (AAT) levels within normal limits; Part A only: Has adequate Forced Expiratory Volume in 1 second (FEV1) and adequate FEV1/forced vital capacity ratio; Part B only: Has documented ZZ type AAT by genotype; Part B only: Has liver biopsy within 90 days of the first dose of study drug demonstrating ZZ type alpha-1 antitrypsin deficiency (PiZZ AATD) liver disease; Part B only: Has adequate post-bronchodilator FEV1 and adequate diffusing capacity of the lung for carbon monoxide; Part B only: If on any maintenance medication, is likely to be able to remain on a stable medication regimen for the duration of the study (no new medications within 30 days prior to first dose of study drug). Exclusion Criteria: Has known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; Has clinically significant abnormal laboratory results; Received an experimental drug within 30 days of dosing; Has a history of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-acetylgalactosamine (GalNAc); Part A only: Has estimated glomerular filtration equal to or below 60 mL/min/1.73 m^2 at screening; Part A only: Has a history of asthma or recurrent or chronic lung disease, excluding resolved childhood asthma; Part A only: Has a history of chronic liver disease; Part B only: Has estimated glomerular filtration equal to or below 45 mL/min/1.73 m^2 at screening; Part B only: Received an augmentation therapy for AAT deficiency within 8 weeks of first dose of study drug; Part B only: Has a history of chronic liver disease from any known cause other than ZZ type AAT deficiency; Part B only: Has a history of hepatic encephalopathy; Part B only: Has a history of gastrointestinal bleeding or ascites.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: SAD: ALN-AAT02<br>Participants will be administered a single dose of ALN-AAT02. | Drug: ALN-AAT02<br>* ALN-AAT02 will be administered subcutaneously (SC) at dose levels planned for Part A.<br>|
| Placebo Comparator: Part A: SAD: Placebo<br>Participants will be administered a single dose of matching placebo. | Drug: Placebo<br>* Sterile normal saline (0.9% NaCl) matching volume of ALN-AAT02 doses will be administered SC.<br>|
| Experimental: Part B: MAD: ALN-AAT02<br>Participants will be administered multiple doses of ALN-AAT02. | Drug: ALN-AAT02<br>* ALN-AAT02 will be administered subcutaneously (SC). Part B dose levels to be determined upon review of data from Part A.<br>|
| Placebo Comparator: Part B: MAD: Placebo<br>Participants will be administered multiple doses of matching placebo. | Drug: Placebo<br>* Sterile normal saline (0.9% NaCl) matching volume of ALN-AAT02 doses will be administered SC.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) |  | Part A: up to approximately 12 months; Part B: up to approximately 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Serum Levels of Alpha-1 Antitrypsin (AAT) |  | Part A: baseline up to Day 85 and every 84 days up to approximately 12 months; Part B: baseline up to Day 169 and every 84 days up to approximately 18 months | 
| Maximum Observed Plasma Concentration (Cmax) for ALN-AAT02 |  | Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87 | 
| Time to Reach Cmax (tmax) for ALN-AAT02 |  | Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87 | 
| Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ALN-AAT02 |  | Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87 | 
| Apparent Terminal Elimination Half-life (t1/2) for ALN-AAT02 |  | Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87 | 
| Fraction Eliminated in Urine (fe) of ALN-AAT02 |  | Part A: Day 1; Part B: Days 1 and 85 | 
| Amount of Full Length Drug Excreted in Urine (Ae) of ALN-AAT02 |  | Part A: Day 1; Part B: Days 1 and 85 |