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

Phase 2

Completed

• Conditions: Alpha 1-Antitrypsin Deficiency
• Interventions: Drug: Fazirsiran Injection (TAK-999, ARO-AAT)

• Registration Number: NCT03946449
• Lead Sponsor: Arrowhead Pharmaceuticals

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2019-05-08
• Study First Submitted QC: 2019-05-09
• Study First Posted: 2019-05-10
• Study Start: 2019-10-31
• Primary Completion: 2022-04-28
• Study Completion: 2023-12-14
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-28
• Last Update Posted: 2024-10-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fazirsiran (TAK-999, ARO-AAT) Cohort 1	Fazirsiran Injection (TAK-999, ARO-AAT)	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.
Fazirsiran (TAK-999, ARO-AAT) Cohort 1b	Fazirsiran Injection (TAK-999, ARO-AAT)	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.
Fazirsiran (TAK-999, ARO-AAT) Cohort 2	Fazirsiran Injection (TAK-999, ARO-AAT)	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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 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 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 Histological Metrics of Liver Disease: Inflammation Score	Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44	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.
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 Histological Metrics of Liver Disease: Steatosis Score	Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44	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.
Change From Baseline Over Time in Histological Metrics of Liver Disease: Hepatocyte Cell Death Score	Baseline and Week 24 (Cohort 1 &1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44	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.
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
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
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
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 Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Score	Baseline and Week 24 (Cohort 1 & 1b) or Week 48 (Cohort 2); Extension Cohort: Extension Week 44	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.
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

Trial Locations

Locations (4)

Royal Infirmary of Edinburgh, NHS Lothian; 🇬🇧 Edinburgh, United Kingdom

Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust; 🇬🇧 Cambridge, United Kingdom

Universitatsklinikum Aachen, Anstalt des offentlich; 🇩🇪 Aachen, Germany

Medical University of Vienna Division of Gastroenterology and Hepatology; 🇦🇹 Vienna, Austria