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

Alpha 1-Antitrypsin Deficiency Clinical Trial

— SEQUOIA  

Official 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]

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03945292
• Other study ID #: AROAAT2001
• Secondary ID: 2018-003385-14
• Status: Completed
• Phase: Phase 2
• Start date: August 7, 2019
• Est. completion date: September 18, 2023

Study information

• Verified date: January 2024
• Source: Arrowhead Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: September 18, 2023
• Est. primary completion date: November 8, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Alpha 1-Antitrypsin Deficiency

Intervention

Drug:
• Fazisiran Injection
solution for subcutaneous (sc) injection

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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Arrowhead Pharmaceuticals

Countries where clinical trial is conducted

United States,  Germany,  Italy,  Netherlands,  Portugal,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT)		Baseline, Week 16 (+/- 2 weeks)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)