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

• Register: ClinicalTrials.gov
• Last refreshed on: 15 January 2024
• Main ID: NCT03945292
• Date of registration: 08/05/2019
• Prospective Registration: Yes
• Primary sponsor: Arrowhead Pharmaceuticals
• Public title: Safety, Tolerability and Pharmacodynamic Effect of Fazirsiran (TAK-999, ARO-AAT) SEQUOIA
• Scientific 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]
• Date of first enrolment: August 7, 2019
• Target sample size: 40
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/ct2/show/NCT03945292
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

Canada, Germany, Ireland, Italy, Netherlands, Portugal, Spain, Sweden, United States

Key inclusion & exclusion criteria

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



Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Alpha 1-Antitrypsin Deficiency

Intervention(s)

Drug: Fazisiran Injection

Other: Placebo

Primary Outcome(s)

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

Secondary Outcome(s)

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)]

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 [Time Frame: Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)]

Incidence of Anti-Drug Antibodies to Fazirsiran [Time Frame: 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)]

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)]

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)]

Absolute Change from Baseline in Liver Function Tests: Total Bilirubin, Direct Bilirubin at Week 16 and over time through EOS [Time Frame: Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)]

PK of Fazirsiran: Area Under the Plasma Concentration Versus Time Curve from Zero to Infinity (AUCinf) [Time Frame: 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)]

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)]

PK of Fazirsiran: Time to Maximum Observed Plasma Concentration (Tmax) [Time Frame: 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)]

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)]

Percent Change in Serum Z-AAT Over Time through EOS [Time Frame: Baseline, 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 [Time Frame: 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 [Time Frame: 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 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)]

Percent Change from Baseline in Liver Function Tests: Total Bilirubin, Direct Bilirubin at Week 16 and over time through EOS [Time Frame: 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 [Time Frame: Baseline, Week 16 (+/- 2 weeks) 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) [Time Frame: 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) [Time Frame: 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) [Time Frame: 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)]

Absolute Change in Serum Z-AAT Over Time through EOS [Time Frame: Baseline, through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)]

Change from Baseline in Metavir Fibrosis Stage at Post-Dose Biopsy for Participants with Fibrosis [Time Frame: Post-dose at Weeks 48 (+/- 2 weeks) or Week 72 (+/- 4 weeks) or Week 96 (+/- 4 weeks)]

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) at Week 16 and over time through End of Study (EOS) [Time Frame: Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis)]

Secondary ID(s)

AROAAT2001

2018-003385-14

Source(s) of Monetary Support

Please refer to primary and secondary sponsors