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

Alnylam Pharmaceuticals1 site in 1 country32 target enrollmentDecember 5, 2018

ConditionsZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease

InterventionsPlacebo ALN-AAT02

DrugsALN-AAT02 Placebo

Overview

Phase: Phase 1
Intervention: Placebo
Conditions: ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
Sponsor: Alnylam Pharmaceuticals
Enrollment: 32
Locations: 1
Primary Endpoint: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)
Status: Terminated
Last Updated: 5 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

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.

Registry

clinicaltrials.gov

Start Date

December 5, 2018

End Date

June 25, 2020

Last Updated

5 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Alnylam Pharmaceuticals

Responsible Party

Sponsor

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;

Arms & Interventions

Part B: MAD: Placebo

Participants will be administered multiple doses of matching placebo.

Intervention: Placebo

Part A: SAD: ALN-AAT02

Participants will be administered a single dose of ALN-AAT02.

Intervention: ALN-AAT02

Part A: SAD: Placebo

Participants will be administered a single dose of matching placebo.

Intervention: Placebo

Part B: MAD: ALN-AAT02

Participants will be administered multiple doses of ALN-AAT02.

Intervention: ALN-AAT02

Outcomes

Primary Outcomes

Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)

Time Frame: Part A: up to approximately 12 months; Part B: up to approximately 18 months

Secondary Outcomes

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)
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)
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)
Amount of Full Length Drug Excreted in Urine (Ae) of ALN-AAT02(Part A: Day 1; Part B: Days 1 and 85)