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 liver produces a protein called alpha-1 antitrypsin (AAT). AAT is normally released into the bloodstream. In some people, the liver makes an abnormal version of the AAT protein, called Z-AAT. Making an abnormal version of the AAT protein can result in liver disease as Z-AAT builds up in liver cells, which leads to liver problems such as liver scarring (fibrosis), continuing liver damage (cirrhosis), and eventually end stage liver disease. Fazirsiran is a medicine that reduces the creation of the Z-AAT protein and thus the build-up of this abnormal protein in the liver. People with this type of liver disease who already have mild liver scarring will take part in the study. They will be treated with fazirsiran or a placebo for about 2 years. This study will check the long-term safety of fazirsiran, whether participants tolerate the treatment and if there are any effects on liver scarring. A liver biopsy, a way of collecting a small tissue sample from the liver, will be taken twice during the study.
• In the opinion of the investigator, the participant is capable of understanding and fully complying with the protocol requirements and adhering to the protocol schedule.
• The participant is able to read, understand, and complete the study questionnaires electronically per the investigator's judgment.
• The participant signs and dates a written Informed Consent Form (ICF). Any required privacy authorization should also be signed before the initiation of any study procedures.
• The participant, of any sex, is aged 18 to 75 years, inclusive.
• The participant must have a diagnosis of the protease inhibitor Z mutation (PiZZ) genotype AATD. A diagnosis of PiZZ from source-verifiable medical records is permitted. Otherwise, participants must undergo PiZZ confirmatory testing (genotyping for PiS and PiZ alleles) at screening. PiMZ or PiSZ genotypes are not permitted.
• The participant's liver biopsy core samples collected as per protocol requirements.
• The participant has evidence of METAVIR stage F1 liver fibrosis, evaluated by a centrally read baseline liver biopsy during the screening period; or confirmed as meeting all the entry criteria by central reading from a previous biopsy conducted within 1 year before the estimated enrollment date using an adequate liver biopsy and slides as defined in the study laboratory manual.
• The participant has a pulmonary status that meets the protocol requirements.
• It must be confirmed that the participant does not have hepatocellular carcinoma (HCC).
• Any participant who is taking statins, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or beta-1 selective adrenergic receptor inhibitors must have been receiving a stable dose of these medications for at least 8 weeks before randomization. All attempts are to be made for the participant to continue the same dose of the medication for the duration of study participation.
• An adult participant must have a body mass index (BMI) between 18 and 39 kilogram per meter square (kg/m\^2), inclusive.
• The participant has a 12-lead electrocardiogram at screening that, in the opinion of the investigator, has no abnormalities that could compromise the participant's safety in this study.
• The participant is a nonsmoker.
• If the participant was being treated with any respiratory medications including inhaled bronchodilators, inhaled anticholinergics, inhaled corticosteroids, or low-dose systemic corticosteroids (prednisone less than or equal to \[\<=10\] milligrams per day \[mg/d\] or its equivalent), the doses of the participant's medications must have remained unchanged for greater than or equal to (\>=) 4 weeks before screening.
• The participant must have suitable venous access for blood sampling.
• A person of childbearing potential (POCBP) must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1 before dosing.
• The participant must use appropriate contraception methods (that is, highly effective methods for female and medically appropriate methods for male study participants) for the entire duration of the study and for 6 months after the last dose of study medication. The participant must not donate sperm for at least 6 months after the last dose of study medication.