ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
Conditions
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.
Interventions
DRUGALN-AAT02
ALN-AAT02 will be administered subcutaneously (SC) at dose levels planned for Part A.
DRUGPlacebo
Sterile normal saline (0.9% NaCl) matching volume of ALN-AAT02 doses will be administered SC.
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | 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
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
Countries
United Kingdom
Outcome results
None listed