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

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

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.

Study Overview

• Status: Terminated
• Conditions: ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
• Intervention / Treatment: Drug: ALN-AAT02; Drug: ALN-AAT02; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome 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 Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 5, 2018
• Primary Completion (ACTUAL): June 25, 2020
• Study Completion (ACTUAL): June 25, 2020

Study Registration Dates

• First Submitted: December 5, 2018
• First Submitted That Met QC Criteria: December 5, 2018
• First Posted (ACTUAL): December 7, 2018

Study Record Updates

• Last Update Posted (ACTUAL): April 27, 2021
• Last Update Submitted That Met QC Criteria: April 26, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema; Liver Diseases; Alpha 1-Antitrypsin Deficiency
• Other Study ID Numbers: ALN-AAT02-001; 2018-001362-41 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No