Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Fazirsiran in Alpha-1 Antitrypsin Deficiency-Associated Liver Disease with METAVIR F1 Fibrosis

The primary objective of this study is to evaluate the long-term **safety** and tolerability of fazirsiran compared with placebo, with a particular focus on lung safety, including measures of pulmonary function. This is clinically relevant as it addresses the potential respiratory implications of fazirsiran in patients with Alpha-1 Antitrypsin Deficiency-Associated Liver Disease, ensuring that the treatment does not adversely affect lung function, which is a critical concern in this patient population.

Secondary objectives include:

• Evaluating the pharmacodynamic effect of fazirsiran via measurement of serum Z-Alpha-1 Antitrypsin (Z-AAT).
• Assessing the efficacy of fazirsiran compared with placebo in reducing liver Z-AAT levels.
• Determining the efficacy of fazirsiran compared with placebo in reducing histologic evidence of Z-AAT polymer burden and portal inflammation in the liver.
• Evaluating the efficacy of fazirsiran compared with placebo at modulating the progression of liver fibrosis, assessed by liver biopsy at Week 106.
• Assessing the efficacy of fazirsiran compared with placebo using noninvasive measures of liver injury and fibrosis, including imaging tests and biomarkers.

The clinical trial involves a total of **25 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 1 liver fibrosis. The trial also considers the pulmonary status of participants, ensuring it meets protocol requirements. The selection process included a centrally-read baseline liver biopsy or confirmation from a previous biopsy conducted within a year before the screening period. The trial population is not limited by gender, and it includes individuals from a vulnerable population. 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 safety and efficacy of **fazirsiran** in the treatment of **Alpha-1 Antitrypsin Deficiency-Associated Liver Disease** with METAVIR stage F1 fibrosis. The trial aims to assess the long-term safety and tolerability of fazirsiran compared with placebo, with a particular focus on lung safety, including measures of pulmonary function. The study will involve participants aged 18 to 75 years who have a confirmed diagnosis of the PiZZ genotype of Alpha-1 Antitrypsin Deficiency (AATD) and evidence of METAVIR stage 1 liver fibrosis. The trial is expected to commence recruitment in May 2024 and conclude by October 2028.

Participants will be involved in the study for a maximum treatment period of 100 weeks. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The primary endpoints include the assessment of adverse events (AEs) and serious adverse events (SAEs), changes in pulmonary function parameters, and various clinical laboratory values. Secondary endpoints focus on changes in serum and intrahepatic Z-AAT protein levels, liver stiffness, and markers of liver injury.

Participants will receive either fazirsiran or a saline placebo via subcutaneous injection. The maximum daily dose is set at 200 mg, with a total maximum dose of 2000 mg over the treatment period. Conditions that may lead to early termination from the study include significant adverse events or failure to adhere to the study protocol. The trial is not categorized as low intervention and is conducted under the sponsorship of Takeda Development Center Americas, Inc. The study is structured to ensure rigorous monitoring and data collection to evaluate the therapeutic potential of fazirsiran in this patient population.

The clinical trial involves the administration of **Fazirsiran**, an experimental medication designed for the treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease with METAVIR Stage F1 Fibrosis. Fazirsiran is a **solution for injection** and is administered via **subcutaneous injection**. The active substance in Fazirsiran is a synthetic, double-stranded, hepatocyte-targeted, GalNAc-conjugated RNAi, specifically targeting the serpin family A member 1 gene. The maximum daily dose of Fazirsiran is 200 mg, with a total maximum dose of 2000 mg over a treatment period of up to 100 days. The medication is provided by Takeda Development Center Americas, Inc., and is identified by the sponsor product code TAK-999. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo consists of **saline**, which is also a solution for injection. The saline is administered in the same manner as Fazirsiran, via subcutaneous injection, to maintain the study's blinding. The dosing schedule for the placebo mirrors that of the experimental treatment, with a maximum daily dose of 200 mg and a total maximum dose of 2000 mg over the same treatment period of up to 100 days. The use of saline as a placebo ensures that any observed effects can be attributed to the active treatment, Fazirsiran, rather than the administration process itself.

The efficacy of Fazirsiran in the treatment of **Alpha-1 Antitrypsin Deficiency-Associated Liver Disease** with METAVIR Stage F1 Fibrosis will be assessed through a series of primary and secondary endpoints. Primary endpoints include the evaluation of adverse events (AEs) and serious adverse events (SAEs), particularly those related to pulmonary conditions, changes in pulmonary function parameters from baseline to the end of the study (EOS), and changes in whole lung 15th percentile density as measured by computed tomography (CT) lung densitometry up to Week 100. Additionally, vital signs, electrocardiogram (ECG) measurements, and clinical laboratory values, including hematology, biochemistry, liver tests, coagulation, and urinalysis results, will be monitored.

Secondary endpoints focus on changes from baseline in serum Z-AAT protein levels over time to Week 106, percent change in intrahepatic liver Z-AAT protein at Week 106, and changes in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining. The study will also assess changes in intrahepatic portal inflammation and histologic fibrosis score (METAVIR staging) at Week 106, as well as changes in VCTE-derived liver stiffness and markers of liver injury, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (GGT), over time to Week 106.