Study of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the the safety and efficacy of the investigational product, fazirsiran (TAK-999, ARO-AAT), administered subcutaneously to patients with Alpha-1 Antitrypsin Deficiency.

Detailed Description
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Participants will be enrolled to receive multiple subcutaneous injections of fazirsiran (TAK-999, ARO-AAT). All eligible participants will require a pre-dose biopsy completed as part of the study within the screening window. All participants will undergo an End of Study (EOS) biopsy. Treated participants will be offered the opportunity to continue treatment in an open label extension during which they will undergo a final biopsy.

Official Title
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A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the Safety and Efficacy of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)

Conditions
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Alpha 1-Antitrypsin Deficiency

Intervention / Treatment
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* Drug: Fazirsiran Injection (TAK-999, ARO-AAT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of AATD Women of childbearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use contraception Willing to provide written informed consent and to comply with study requirements Non-smoker for at least 1 year No abnormal finding of clinical relevance at screening Exclusion Criteria: Clinically significant health concerns other than AATD Previous diagnosis or diagnosis at Screening of definitive liver cirrhosis Regular use of alcohol within one month prior to Screening Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving therapeutic intervention Use of illicit drugs within 1 year prior to Screening Note: additional inclusion/exclusion criteria may apply, per protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fazirsiran (TAK-999, ARO-AAT) Cohort 1<br>Administered on Day 1, Weeks 4 and 16 for a minimum of 3 doses. Treatment Extension (optional enrollment): Administered every 12 weeks for 12 additional doses. | Drug: Fazirsiran Injection (TAK-999, ARO-AAT)<br>* solution for subcutaneous (sc) injection<br>|
| Experimental: Fazirsiran (TAK-999, ARO-AAT) Cohort 1b<br>Administered on Day 1, Weeks 4 and 16, for a minimum of 3 doses. Treatment Extension (optional enrollment): Administered every 12 weeks for 12 additional doses. | Drug: Fazirsiran Injection (TAK-999, ARO-AAT)<br>* solution for subcutaneous (sc) injection<br>|
| Experimental: Fazirsiran (TAK-999, ARO-AAT) Cohort 2<br>Administered on Day 1, Weeks 4, 16, 28 and 40 for a minimum of 5 doses. Treatment Extension (optional enrollment): Administered every 12 weeks for 12 additional doses. | Drug: Fazirsiran Injection (TAK-999, ARO-AAT)<br>* solution for subcutaneous (sc) injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Over Time in Total, Soluble, and Insoluble Z-Alpha 1 Antitrypsin (Z-AAT) Liver Concentrations |  | Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Over Time in Circulating Levels of Z-AAT |  | Baseline through Week 24 (Cohort 1 & 1b) or through Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140 | 
| Change From Baseline Over Time in Alanine Transaminase (ALT) |  | Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140 | 
| Change From Baseline Over Time in Gamma-Glutamyl Transferase (GGT) |  | Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline and Extension Weeks 44 and 140 | 
| Change From Baseline Over Time in Fibrosis-4 Index (FIB4) |  | Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140 | 
| Change From Baseline Over Time in Aspartate Transaminase (AST) to Platelet Ratio Index (APRI) |  | Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140 | 
| Change From Baseline Over Time in Plasma Collagen Type 3 (PRO-C3) |  | Baseline through Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Baseline through Extension Weeks 44 and 140 | 
| Change From Baseline Over Time in Hepatic Stiffness based on FibroScan (when available) |  | Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 44 and 140 | 
| Change From Baseline Over Time in Histological Metrics of Liver Disease: Inflammation Score | Change in inflammation score, based on pathology slide reads. Inflammation was assessed on a scale of 0-3, with higher scores showing more severe inflammation. | Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44 | 
| Change From Baseline Over Time in Histological Metrics of Liver Disease: Steatosis Score | Change in steatosis score, based on pathology slide reads. Steatosis was assessed on a scale of 0-3, with higher scores showing more severe steatosis. | Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44 | 
| Change From Baseline Over Time in Histological Metrics of Liver Disease: Hepatocyte Cell Death Score | Change in hepatocyte cell death score, based on pathology slide reads. Hepatocyte cell death was assessed on a scale of 0-2, with higher scores showing more severe hepatocyte cell death. | Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44 | 
| Change From Baseline Over Time in Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Score | METAVIR scores range from F0 to F4 (F0=No Fibrosis, F1=Mild Fibrosis, F2= Significant Fibrosis, F3=Severe Fibrosis, F4=Cirrhosis). Higher scores indicate more severe fibrosis. | Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44 | 
| Number of Participants with Adverse Events (AEs) Possibly or Probably Related to Treatment |  | Up to Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: up to Extension Week 140 | 
| Incidence of Anti-Drug Antibodies (ADAs) to Fazirsiran |  | Day 1, Week 6, and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 24 and 44 | 
| Titers of Anti-Drug Antibodies (ADAs) to Fazirsiran |  | Day 1, Week 6, and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Weeks 24 and 44 |