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
    • Research Site 27
• Italy
  • Pavia, Italy, 27100
    • Research Site 22
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Research Site 23
• Portugal
  • Funchal, Portugal, 9004-514
    • Research Site 24
• Spain
  • Barcelona, Spain, 08035
    • Research Site 20
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Research Site 5
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Research Site 9
  • California
    • La Jolla, California, United States, 92037
      • Research Site 14
    • Los Angeles, California, United States, 90095
      • Research Site 17
    • Sacramento, California, United States, 95817
      • Research Site 11
    • San Francisco, California, United States, 94158
      • Research Site 15
    • Stanford, California, United States, 94305
      • Research Site 13
  • Florida
    • Gainesville, Florida, United States, 32610
      • Research Site 2
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Research Site 7
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Research Site 3
  • Missouri
    • St Louis, Missouri, United States, 63104
      • Research Site 10
  • New York
    • New York, New York, United States, 10032
      • Research Site 12
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Research Site 1
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Research Site 4
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site 19
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Research Site 16

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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fazirsiran 25 mg DB/200 mg OL; Double-blind (DB) Period: 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. Open-label (OL) Period: Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 25 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.	Drug: Fazisiran Injection; solution for subcutaneous (sc) injection; Other Names: ARO-AAT Injection; TAK-999 Injection
Experimental: Fazirsiran 100 mg DB/200 mg OL; DB Period: Participants with no fibrosis: Fazirsiran 100 mg administered on Day 1 and Week 4. Participants with fibrosis: Fazirsiran 100 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses. OL Period: Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 100 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.	Drug: Fazisiran Injection; solution for subcutaneous (sc) injection; Other Names: ARO-AAT Injection; TAK-999 Injection
Experimental: Fazirsiran 200 mg DB/200 mg OL; DB Period: Participants with no fibrosis: Fazirsiran 200 mg administered on Day 1 and Week 4. Participants with fibrosis: Fazirsiran 200 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses. OL Period: Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 200 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study	Drug: Fazisiran Injection; solution for subcutaneous (sc) injection; Other Names: ARO-AAT Injection; TAK-999 Injection
Placebo Comparator: Placebo DB / Fazirsiran 200 mg OL; DB Period: Participants with no fibrosis: Placebo administered on Day 1 and Week 4. Participants with fibrosis: Placebo administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses. OL Period: Participants with fibrosis at Screening who received double-blind (DB) placebo and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.	Drug: Fazisiran Injection; solution for subcutaneous (sc) injection; Other Names: ARO-AAT Injection; TAK-999 Injection; Other: Placebo; sterile normal saline (0.9% NaCl), calculated to match active comparator, for sc injection

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Phase	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.	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.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Open-Label Phase	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.	From dose administration of the first dose of open-label phase fazirsiran through EOS or Early Termination (up to Week 196).
Absolute Change From Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants With Fibrosis	Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.	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	Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.	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	Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.	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	Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.	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	Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.	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	Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96.	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) at Week 16 and Over Time Through End of Study (EOS)	PDLB=post-dose liver biopsy	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)
Percent Change From Baseline in Liver Function Tests: ALT at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Absolute Change From Baseline in Liver Function Tests: Aspartate Aminotransferase (AST) at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Percent Change From Baseline in Liver Function Tests: AST at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Absolute Change From Baseline in Liver Function Tests: Alkaline Phosphatase (ALP) at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Percent Change From Baseline in Liver Function Tests: ALP at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Absolute Change From Baseline in Liver Function Tests: Gamma Glutamyl Transferase (GGT) at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Percent Change From Baseline in Liver Function Tests: GGT at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Absolute Change From Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Percent Change From Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Absolute Change From Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Percent Change From Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Absolute Change From Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Percent Change From Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Absolute Change in Serum Z-AAT Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Percent Change in Serum Z-AAT Over Time Through EOS	PDLB=post-dose liver biopsy	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)
Pharmacokinetics (PK): ARO-AAT Plasma Concentration Summary for the Double-Blind Phase		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).
Number of Participants Positive for Anti-Drug Antibodies to Fazirsiran	PDLB=post-dose liver biopsy	Baseline, Weeks 4, 16, 28, 40, 48, 52, 64, 76, 88, 96, 100, 112, 124, 136, 148 or Early Termination (up to 148 weeks)
Percentage of Participants With Shifts From Baseline in METAVIR Fibrosis Stage at Post-Dose Biopsy for Participants With Fibrosis	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.	Baseline, 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.
• Clark VC, Strange C, Strnad P, Sanchez AJ, Kwo P, Pereira VM, van Hoek B, Barjaktarevic I, Corsico AG, Pons M, Goldklang M, Gray M, Kuhn B, Vargas HE, Vierling JM, Vuppalanchi R, Brantly M, Kappe N, Chang T, Schluep T, Zhou R, Hamilton J, San Martin J, Loomba R. Fazirsiran for Adults With Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA). Gastroenterology. 2024 Oct;167(5):1008-1018.e5. doi: 10.1053/j.gastro.2024.06.028. Epub 2024 Jul 2.

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 (Estimated): November 4, 2025
• Last Update Submitted That Met QC Criteria: October 30, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Liver Diseases; Subcutaneous Emphysema; Emphysema; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; 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