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 has evidence of >= F2 fibrosis based on liver biopsy during the screening period.
The participant has a history of liver decompensating events.
The participant has a history of varices based on a previous esophagogastroduodenoscopy.
The participant has portal vein thrombosis.
Parallel
Fazirsiran Injection
DrugFazirsiran will be injected subcutaneously.
Placebo
DrugFazirsiran matching placebo.
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of the study intervention, whether or not it is considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study intervention. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect, suspected transmission of any infectious agent, an important medical event. AEs and SAEs including any pulmonary AEs or SAEs indicative of worsening pulmonary condition (example, pulmonary exacerbation, respiratory infection, significant pulmonary function test decline) will be reported.
Number of Participants With Clinically Significant Change From Baseline in Pulmonary Function Parameters
Standard pulmonary function parameters will be used to study lung function. Clinical significance of pulmonary function parameters will be determined at the investigator's discretion.
Change From Baseline in Whole Lung 15th Percentile Density as Measured by Computed Tomography (CT) Lung Densitometry
Change from baseline in whole lung 15th percentile density as measured by CT lung densitometry will be assessed.
Number of Participants With Clinically Significant Changes in Vital Signs
Vital signs include body temperature, respiratory rate, blood pressure (systolic and diastolic), pulse (beats per minute) and pulse oximetry. Clinical significance of vital signs will be determined at the investigator's discretion.
Change From Baseline in Serum Z-AAT Protein Over Time to Week 106
Change From Baseline in Serum Z-AAT Protein will be assessed.
Percent Change From Baseline in Intrahepatic Liver Z-AAT Protein at Week 106
Percent change from baseline in intrahepatic liver Z-AAT protein will be assessed.
Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining in Liver Biopsy at Week 106
Change from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining in liver biopsy will be assessed.
Number of Participants with No Change or Decrease From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by PAS+D staining at Week 106
Number of participants with no change or decrease from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining will be reported.
