A Randomized, Double-blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Fazirsiran in the Treatment of Alpha-1 Antitrypsin Deficiency–Associated Liver Disease With METAVIR Stage F2 to F4 Fibrosis

The primary objective of this study is to evaluate the **efficacy** of fazirsiran compared with placebo in improving measures of histologic fibrosis in **Alpha-1 Antitrypsin Deficiency-Associated Liver Disease** (AATD-LD). This is clinically relevant as it aims to address the progression of liver fibrosis, a critical factor in the management and prognosis of AATD-LD.

Secondary objectives include:

• Evaluating the pharmacodynamic effect of fazirsiran via measurement of intrahepatic Z-alpha-1 antitrypsin (Z-AAT) protein and serum Z-AAT.
• Assessing the impact of fazirsiran versus placebo on modulating disease progression, specifically progression to cirrhosis or decompensating liver-related clinical events.
• Evaluating the safety and tolerability of fazirsiran compared with placebo, with an emphasis on monitoring lung function, lung injury, and associated symptoms.
• Assessing the efficacy of fazirsiran in reducing histologic evidence of portal inflammation and Z-AAT polymer burden in the liver.
• Using noninvasive measures of liver fibrosis, including biomarkers, to evaluate the efficacy of fazirsiran compared with placebo.
• Evaluating the pharmacokinetics of fazirsiran.

The clinical trial involves a total of **53 participants** diagnosed with **Alpha-1 Antitrypsin Deficiency-Associated Liver Disease**. The study population includes both male and female subjects, aged between 18 to 75 years. Participants were selected based on specific criteria, including a confirmed diagnosis of the PiZZ genotype of Alpha-1 Antitrypsin Deficiency (AATD) and evidence of METAVIR stage F2, F3, or F4 liver fibrosis. The trial population is not restricted by gender, and both sexes are represented. The study also considers individuals with a vulnerable health status, as indicated by the inclusion of a vulnerable population. Participants' general health status includes those with a pulmonary condition that meets the protocol's criteria. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, Phase 3 study** to evaluate the efficacy and safety of **fazirsiran** in the treatment of **Alpha-1 Antitrypsin Deficiency-Associated Liver Disease** with METAVIR stage F2 to F4 fibrosis. The trial aims to assess the improvement in histologic fibrosis compared to placebo. The study will involve the administration of **fazirsiran** or saline as a placebo, both delivered via **subcutaneous injection**. The trial is expected to last until June 30, 2030, with recruitment starting on May 1, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of the PiZZ genotype and evidence of METAVIR stage F2, F3, or F4 liver fibrosis. Follow-up visits will occur at specified intervals to monitor the primary and secondary endpoints, including changes in histologic fibrosis and intrahepatic Z-AAT protein levels. The primary endpoint will be assessed at Week 106, with additional evaluations at Week 202. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

The expected length of participant involvement is approximately 202 weeks, with conditions for early termination including non-compliance with the study protocol, adverse events, or withdrawal of consent. The study will adhere to rigorous scientific standards to ensure the validity and reliability of the results, contributing valuable insights into the treatment of this rare liver disease.

The clinical trial involves the administration of **Fazirsiran**, an experimental medication designed for the treatment of **Alpha-1 Antitrypsin Deficiency-Associated Liver Disease**. Fazirsiran is a **solution for injection** and is administered via **subcutaneous injection**. The active substance in Fazirsiran is a **nucleic acid** known as a **N-acetylgalactosamine-conjugated synthetic double-stranded oligomer** specific to the **serpin family A member 1 gene**. The pharmaceutical form is a solution for injection, with a maximum daily dose of 200 mg and a total maximum dose of 3600 mg over a treatment period of 196 days. The medication is provided by Takeda Development Center Americas, Inc., and is identified by the sponsor product code TAK-999. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.

In addition to the experimental treatment, a **placebo** is used as a comparator in the study. The placebo is a **saline solution for injection**, also administered via subcutaneous injection. The saline solution serves as a control to evaluate the efficacy and safety of Fazirsiran. The placebo is administered with the same dosing schedule as the experimental medication, with a maximum daily dose of 200 mg and a total maximum dose of 3600 mg over the same treatment period of 196 days. The use of a placebo allows for a double-blind, placebo-controlled study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thus minimizing bias in the assessment of the treatment's efficacy and safety.

The efficacy of Fazirsiran in the treatment of **Alpha-1 Antitrypsin Deficiency-Associated Liver Disease (AATD-LD)** will be assessed through a randomized, double-blind, placebo-controlled, Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the decrease from baseline of at least one stage of histologic fibrosis, as determined by the Meta-Analysis of Histological Data in Viral Hepatitis (METAVIR) staging system. This assessment will be conducted through a centrally read liver biopsy at Week 106 for participants with METAVIR stage F2 and F3 fibrosis.

Secondary endpoints include several measures: the percent change from baseline in intrahepatic Z-AAT protein at Week 106 for METAVIR stage F2 to F3 fibrosis, and a decrease from baseline of at least one stage of histologic fibrosis at Week 202 for METAVIR stage F2 to F4 fibrosis. Additional secondary endpoints involve assessing disease progression to cirrhosis or other liver-related clinical events by Week 202, changes from baseline in serum Z-AAT protein, intrahepatic Z-AAT protein polymer burden, intrahepatic portal inflammation, and liver stiffness as measured by vibration-controlled transient elastography (VCTE) at Week 202. Pharmacokinetic endpoints will also be evaluated, including observed plasma concentrations of Fazirsiran at specified time points throughout the study duration.