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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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]

Conditions
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Alpha 1-Antitrypsin Deficiency

Intervention / Treatment
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* Drug: Fazisiran Injection
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fazirsiran (also referred to as TAK-999 or ARO-AAT)<br>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<br>* solution for subcutaneous (sc) injection<br>* Other names: TAK-999 Injection;|
| Placebo Comparator: Placebo<br>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<br>* sterile normal saline (0.9% NaCl), calculated to match active comparator, for sc injection<br>|
| Experimental: Open-Label Fazisiran (also referred to as TAK-999 or ARO-AAT)<br>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<br>* solution for subcutaneous (sc) injection<br>* Other names: TAK-999 Injection;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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) |