Safety, Tolerability and Pharmacodynamic Effect of Fazirsiran (TAK-999, ARO-AAT) (SEQUOIA)

A Placebo-Controlled, Multi-dose, Phase 2 Study to Determine the Safety, Tolerability and Pharmacodynamic Effect of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency (AATD) [SEQUOIA]

The purpose of AROAAT2001 (SEQUOIA) is to evaluate the safety, efficacy and tolerability of multiple doses of the investigational product, Fazirsiran Injection, administered subcutaneously to participants with alpha-1 antitrypsin deficiency (AATD).

Study Overview

• Status: Completed
• Conditions: Alpha 1-Antitrypsin Deficiency
• Intervention / Treatment: Drug: Fazisiran Injection; Other: Placebo

Detailed Description

Participants will be enrolled to receive multiple subcutaneous injections of Fazirsiran Injection (also referred to as TAK-999 Injection or ARO-AAT Injection) or placebo. Eligible participants will require a pre-dose biopsy completed as part of the study within the screening window. However, any participant with a biopsy result within 1 year of screening showing no fibrosis does not require a pre-dose biopsy. Only participants who have liver fibrosis will undergo a post-dose biopsy and may continue treatment in an open-label phase.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52074
    • Universitatsklinikum Aachen, Anstalt des offentlich
• Italy
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico S. Matteo
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center
• Portugal
  • Funchal, Portugal, 9004-514
    • Hospital Central Do Funchal (Hospital Nelio Mendoca)
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham Medical Center
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • California
    • La Jolla, California, United States, 92037
      • University of California San Diego Altman Clinical and Translational Research Institute
    • Los Angeles, California, United States, 90095
      • UCLA David Geffen School of Medicine, Center for Health Sciences
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • San Francisco, California, United States, 94158
      • UCSF Medical Center Benioff Children's Hospital
    • Stanford, California, United States, 94305
      • Stanford Health Care
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Hepatology Research at CTRB
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health University Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • SSM-Health Cardinal Glennon Children's Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina (MUSC)
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of AATD
• Liver biopsy at Screening indicating liver fibrosis (score less than F4); a patient with no fibrosis may participate based on a previous biopsy conducted within one year
• Women of childbearing potential must have a negative pregnancy test, cannot be breastfeeding, 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
• Previous lung or liver transplant due to AATD
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fazirsiran (also referred to as TAK-999 or ARO-AAT); Participants with no fibrosis: Administered on Day 1 and Week 4 Participants with fibrosis: Administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.	Drug: Fazisiran Injection; solution for subcutaneous (sc) injection; Other Names: ARO-AAT Injection; TAK-999 Injection
Placebo Comparator: Placebo; Participants with no fibrosis: Administered on Day 1 and Week 4 Participants with fibrosis: Administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.	Other: Placebo; sterile normal saline (0.9% NaCl), calculated to match active comparator, for sc injection
Experimental: Open-Label Fazisiran (also referred to as TAK-999 or ARO-AAT); After all enrolled participants completed the Week 16 visit, an interim analysis was performed to select a single dose level (25, 100 or 200 mg) for the open-label phase of the study. Fazirsiran 200 mg was the selected dose and all participants with fibrosis at Screening who completed the post-dose liver biopsy at Week 48 (or Week 72 or 96) receive this dose every 12 weeks for the duration of the study (open-label phase).	Drug: Fazisiran Injection; solution for subcutaneous (sc) injection; Other Names: ARO-AAT Injection; TAK-999 Injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT)	Baseline, Week 16 (+/- 2 weeks)

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) at Week 16 and over time through End of Study (EOS)	Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)
Absolute Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis	Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)
Percent Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis	Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)
Absolute Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis	Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)
Percent Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis	Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)
Absolute Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis	Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)
Percent Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis	Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)
Absolute Change from Baseline in Liver Function Tests: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP), Gamma-Glutamyl Transferase (GGT) at Week 16 and over time through EOS	Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)
Percent Change from Baseline in Liver Function Tests: ALT, AST, ALP, GGT at Week 16 and over time through EOS	Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)
Absolute Change from Baseline in Liver Function Tests: Total Bilirubin, Direct Bilirubin at Week 16 and over time through EOS	Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)
Percent Change from Baseline in Liver Function Tests: Total Bilirubin, Direct Bilirubin at Week 16 and over time through EOS	Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)
Absolute Change from Baseline in Liver Function Tests: International Normalized Ratio (INR) at Week 16 and over time through EOS	Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)
Percent Change from Baseline in Liver Function Tests: INR at Week 16 and over time through EOS	Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)
Absolute Change in Serum Z-AAT Over Time through EOS	Baseline, through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)
Percent Change in Serum Z-AAT Over Time through EOS	Baseline, through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)
Pharmacokinetics (PK) of Fazirsiran: Maximum Observed Plasma Concentration (Cmax)	Participants without fibrosis: Pre-dose, 1 hour, 2 hour & 24 or 48 hours post-dose on Day 1 (+/- 1 day). Participants with fibrosis: Pre-dose, 1 hour, 2 hours & 24 or 48 hours post-dose on Days 1 and 113 (+/- 1 day)
PK of Fazirsiran: Time to Maximum Observed Plasma Concentration (Tmax)	Participants without fibrosis: Pre-dose, 1 hour, 2 hour & 24 or 48 hours post-dose on Day 1 (+/- 1 day). Participants with fibrosis: Pre-dose, 1 hour, 2 hours & 24 or 48 hours post-dose on Days 1 and 113 (+/- 1 day)
PK of Fazirsiran: Terminal Elimination Half-Life (t1/2)	Participants without fibrosis: Pre-dose, 1 hour, 2 hour & 24 or 48 hours post-dose on Day 1 (+/- 1 day). Participants with fibrosis: Pre-dose, 1 hour, 2 hours & 24 or 48 hours post-dose on Days 1 and 113 (+/- 1 day)
PK of Fazirsiran: Area Under the Plasma Concentration Versus Time Curve from Zero to the Last Time Point with a Quantifiable Concentration (AUC0-t)	Participants without fibrosis: Pre-dose, 1 hour, 2 hour & 24 or 48 hours post-dose on Day 1 (+/- 1 day). Participants with fibrosis: Pre-dose, 1 hour, 2 hours & 24 or 48 hours post-dose on Days 1 and 113 (+/- 1 day)
PK of Fazirsiran: Area Under the Plasma Concentration Versus Time Curve from Zero to Infinity (AUCinf)	Participants without fibrosis: Pre-dose, 1 hour, 2 hour & 24 or 48 hours post-dose on Day 1 (+/- 1 day). Participants with fibrosis: Pre-dose, 1 hour, 2 hours & 24 or 48 hours post-dose on Days 1 and 113 (+/- 1 day)
Incidence of Anti-Drug Antibodies to Fazirsiran	Participants Without Fibrosis: Pre-dose on Days 1 & 29, and on Days 113, 197 and 281; Participants With Fibrosis: Pre-dose on all dosing visits (Days 1, 29, 113, and every 12 weeks up to Week 196)
Change from Baseline in Metavir Fibrosis Stage at Post-Dose Biopsy for Participants with Fibrosis	Post-dose at Weeks 48 (+/- 2 weeks) or Week 72 (+/- 4 weeks) or Week 96 (+/- 4 weeks)

Collaborators and Investigators

• Sponsor: Arrowhead Pharmaceuticals

Publications and helpful links

General Publications

• Remih K, Amzou S, Strnad P. Alpha1-antitrypsin deficiency: New therapies on the horizon. Curr Opin Pharmacol. 2021 Aug;59:149-156. doi: 10.1016/j.coph.2021.06.001. Epub 2021 Jul 10.

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2019
• Primary Completion (Actual): November 8, 2021
• Study Completion (Actual): September 18, 2023

Study Registration Dates

• First Submitted: May 8, 2019
• First Submitted That Met QC Criteria: May 8, 2019
• First Posted (Actual): May 10, 2019

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 5, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Liver Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema; Alpha 1-Antitrypsin Deficiency
• Other Study ID Numbers: AROAAT2001; 2018-003385-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes