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Completed

NCT Number: NCT03945292

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

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).

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Key information

Conditions

Alpha 1-Antitrypsin Deficiency Congenital, Hereditary, and Neonatal Diseases and Abnormalities Digestive System Diseases Emphysema Genetic Diseases, Inborn Liver Diseases Lung Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Respiratory Tract Diseases Subcutaneous Emphysema

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Research Site 27, Aachen, Germany

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Fazisiran Injection

Drug

solution for subcutaneous (sc) injection

Other names: ARO-AAT Injection, TAK-999 Injection

Placebo

Other

sterile normal saline (0.9% NaCl), calculated to match active comparator, for sc injection

Primary outcomes

  1. Percent Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) at Week 16

    Time frame: Baseline, Week 16 (+/- 2 weeks)

Secondary outcomes

  1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Phase

    Time frame: Double Blind Phase (up to Week 48): dose administration through end of study (EOS) or Early Termination or first dose of open-label phase fazirsiran.

    An adverse event (AE) is any untoward medical occurrence, which does not necessarily have to have a causal relationship with this treatment. A serious adverse event (SAE) is an AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction. TEAEs/TESAEs are defined as those AEs that first occurred or worsened in severity following dose administration through end of study (EOS) or Early Termination or first dose of open-label phase fazirsiran.

  2. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Phase

    Time frame: From dose administration of the first dose of open-label phase fazirsiran through EOS or Early Termination (up to Week 196).

    An adverse event (AE) is any untoward medical occurrence, which does not necessarily have to have a causal relationship with this treatment. A serious adverse event (SAE) is an AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction. TEAEs/TESAEs are defined as those AEs that first occurred or worsened in severity following dose administration through end of study (EOS) or Early Termination or first dose of open-label phase fazirsiran.

  3. Absolute Change From Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants With Fibrosis

    Time frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)

    Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.

  4. Percent Change From Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants With Fibrosis

    Time frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)

    Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.

  5. Absolute Change From Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants With Fibrosis

    Time frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)

    Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.

  6. Percent Change From Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants With Fibrosis

    Time frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)

    Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.

  7. Absolute Change From Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants With Fibrosis

    Time frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)

    Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.

  8. Percent Change From Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants With Fibrosis

    Time frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks)

    Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.

  9. Absolute Change From Baseline in Liver Function Tests: Alanine Aminotransferase (ALT) at Week 16 and Over Time Through End of Study (EOS)

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  10. Percent Change From Baseline in Liver Function Tests: ALT at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  11. Absolute Change From Baseline in Liver Function Tests: Aspartate Aminotransferase (AST) at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  12. Percent Change From Baseline in Liver Function Tests: AST at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  13. Absolute Change From Baseline in Liver Function Tests: Alkaline Phosphatase (ALP) at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  14. Percent Change From Baseline in Liver Function Tests: ALP at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  15. Absolute Change From Baseline in Liver Function Tests: Gamma Glutamyl Transferase (GGT) at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124,136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  16. Percent Change From Baseline in Liver Function Tests: GGT at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  17. Absolute Change From Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124,136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  18. Percent Change From Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  19. Absolute Change From Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  20. Percent Change From Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  21. Absolute Change From Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  22. Percent Change From Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and Over Time Through EOS

    Time frame: Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  23. Absolute Change in Serum Z-AAT Over Time Through EOS

    Time frame: Baseline, Weeks 2, 4, 6, 16, 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  24. Percent Change in Serum Z-AAT Over Time Through EOS

    Time frame: Baseline, Weeks 2, 4, 6, 16, 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination (up to 196 weeks), EOS (up to 208 weeks)

    PDLB=post-dose liver biopsy

  25. Pharmacokinetics (PK): ARO-AAT Plasma Concentration Summary for the Double-Blind Phase

    Time frame: Fazirsiran participants without fibrosis: Pre-dose, 1 hour, 2 hour, 24 hours post-dose on Day 1 (+/- 1 day). Fazirsiran participants with fibrosis: Pre-dose, 1 hour, 2 hours, 24 hours post-dose on Day 1 and Week 16 (+/- 1 day).

  26. Number of Participants Positive for Anti-Drug Antibodies to Fazirsiran

    Time frame: Baseline, Weeks 4, 16, 28, 40, 48, 52, 64, 76, 88, 96, 100, 112, 124, 136, 148 or Early Termination (up to 148 weeks)

    PDLB=post-dose liver biopsy

  27. Percentage of Participants With Shifts From Baseline in METAVIR Fibrosis Stage at Post-Dose Biopsy for Participants With Fibrosis

    Time frame: Baseline, Post-dose at Weeks 48 (+/- 2 weeks) or Week 72 (+/- 4 weeks) or Week 96 (+/- 4 weeks)

    The METAVIR scoring system is a system used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy. The stage represents the amount of fibrosis or scarring: 0= no fibrosis; 1=portal fibrosis without septa; 2=portal fibrosis with few septa; 3=numerous septa without cirrhosis; 4=cirrhosis. A higher score indicates a worse condition.

Sponsors and collaborators

Lead sponsor

Arrowhead Pharmaceuticals

Industry

Registry information

Official study title

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]

Acronym: SEQUOIA

Important dates

Study start
2019
Primary completion
2021
Study completion
2023
First posted
May 10, 2019
Registry last updated
Nov 4, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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