An Extension Study to Learn About the Long-Term Safety of Fazirsiran and if Fazirsiran Can Help People With Alpha-1 Antitrypsin Liver Disease

Open to people ages 18 years and up

• Participants must meet all of the following criteria to be eligible for inclusion in the study:
• The participant is willing and able to understand and fully comply with study procedures and requirements, in the opinion of the investigator.
• The participant is able to read, understand, and complete the study questionnaires electronically per investigator's judgment.
• The participant has provided informed consent (ICF) (that is, in writing, documented via a signed and dated ICF) and any required privacy authorization before the initiation of any study procedures.

Note: For participants who comprehend, can provide informed consent, and are unable to sign the ICF, an impartial witness may sign the ICF on behalf of the participant after the participant has orally consented to the participant's participation in the study.

• The participant enrolling in this open-label extension (OLE) study will have participated in a previously qualifying study, and will be considered for eligibility based on the following study-specific criteria:
• AROAAT2001:
  • Participants with fibrosis may roll over into this OLE study after they reach their next regularly scheduled, Q12W visit.
  • Participants with fibrosis who have completed the AROAAT2001 study may be enrolled into the OLE study.
• AROAAT2002:
  • Participants in Cohorts 1 and 1b may roll over after completing the 24-week primary study period.
  • Participants in Cohort 2 may roll over after completing the 48-week primary study period.
  • Participants who have completed the study may be enrolled into the OLE study.
• The participant is a nonsmoker (defined as: does not smoke cigarettes daily for at least 24 weeks) with current nonsmoking status confirmed by urine cotinine at Day 1.
  • E-cigarettes (vapor) are not permitted.
  • The participant may be on nicotine replacement (patch or gum). A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of the investigator.
• The participant must have suitable venous access for blood sampling.
• It must be confirmed that the participant does not have hepatocellular carcinoma (HCC). Participants will be screened for HCC with alpha-fetoprotein (AFP) and abdominal ultrasound. If the participant has any of the following, they will be required to have contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) imaging to exclude HCC before enrollment.
  • AFP >20 nanogram per milliliter (ng/mL).
  • AFP 15 to 19 ng/mL at enrollment if that is >2 times prestudy levels (if available).
  • Any liver lesion >10 millimeter (mm) (longest diameter) detected by ultrasound.
  • Poor visibility of liver on ultrasound.
• A person of childbearing potential (POCBP) must have a negative urine pregnancy test performed within 3 days prior to Day 1 dosing in this study (sensitive to 25 International Unit [IU] human chorionic gonadotropin [hCG]).
• 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. Participants who terminate early must use appropriate contraception methods for 6 months after the last dose of study intervention. Male participants who terminate early must not donate sperm for at least 6 months after the last dose of study intervention.
• Sexual abstinence, for the purposes of this study, is only considered a highly effective method of contraception when considered to align with the preferred and usual lifestyle of the participant. It will be employed for the entire duration of the study and the 6 months after last dose of study intervention.
• Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea methods are not considered "true" abstinence and are not acceptable methods of contraception.

• The participant will be excluded from the study if any of the following exclusion criteria are met:
• The participant is likely to require major surgery. Major surgery typically requires at least 1 night in the hospital. Examples include laparoscopic surgery (except cholecystectomy and tubal ligation); Gastrointestinal tract (GI) tract surgery including 1 or more segments of the colon or terminal ileum; open resection of organs; large joint replacements; mastectomy with reconstruction; and spine, thoracic, vascular, or intracranial surgery.
• The participant has evidence of other forms of chronic liver diseases, including viral hepatitis B or C, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, alcoholic hepatitis, hemochromatosis, liver cancer, history of biliary diversion, or autoimmune hepatitis.
• The participant has abnormal finding(s) of clinical relevance during the evaluation before the first study dosing that, in the opinion of the investigator, could adversely impact participant safety during the study or adversely impact study results.
• The participant had major protocol deviation(s) in AROAAT2001 or AROAAT2002 that would affect the conduct of this study.
• The participant permanently discontinued investigational product because of an AE, adjudicated as related to the study intervention, in AROAAT2001 or AROAAT2002.
• Female participants who became pregnant during Study AROAAT2001 or AROAAT2002, female participants who are lactating or planning to become pregnant during the study period; or males or female participants of childbearing potential not agreeing to continue using appropriate contraception methods through the conclusion of study participation.
• The participant has a Child-Turcotte-Pugh (CTP) score >=7 OR (Model for End-Stage Liver Disease) MELD score >14.

• The participant meets Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Creatinine criteria as per the protocol. All laboratory tests used as

  exclusion criteria may be repeated once and the repeat value may be used for study eligibility determination.

• Participants who have a newly-diagnosed malignancy or recurrence of malignancy (except for resected cutaneous basal cell carcinoma, squamous cell carcinoma, superficial bladder tumors, or carcinoma in situ of the uterine cervix that has been treated with no evidence of recurrence).
• The participant is experiencing a pulmonary exacerbation at the time of enrollment (participant enrollment may be temporarily delayed after the clinical resolution of an exacerbation).
• The participant has unstable, poorly controlled, or severe hypertension. Participants may be reevaluated once their blood pressure is successfully controlled.
• The participant has a history of more than moderate alcohol consumption within 12 months before the Day 1 visit.
• The participant has a history of hypersensitivity or allergies to fazirsiran or any associated excipients.
• The participant has any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or put the participant at additional safety risk.
• The participant has a history of clinically significant hematologic, renal, hepatic, cardiovascular, infectious, pulmonary, neurologic, psychiatric, GI, systemic inflammatory, metabolic, or endocrine disorder or any other condition that, in the opinion of the investigator, rendered the participant a poor candidate for inclusion into the study.
• The participant has a history of thromboembolic disease (including deep vein thrombosis or pulmonary embolism), within 24 weeks before enrollment; or is taking chronic anticoagulants. (Note: Participants taking stable doses of chronic anticoagulants may be allowed after consultation with the medical monitor, if they do not have cirrhosis or a history of liver decompensating events).
• The participant is unable to return for all scheduled study visits.
• The participant has known or suspected coronavirus disease 2019 (COVID-19) that in the opinion of the sponsor and investigator does not resolve during screening. Positive antibody testing for COVID-19 without other evidence of current or recent active infection does not exclude participation. Enrollment of participants who fail inclusion due to COVID-19 infection may be temporarily delayed at the discretion of the sponsor and investigator. If the participant has a positive polymerase chain reaction (PCR) with no other evidence of infection, a retest may be allowed; however, to enroll in the study the participant must have a negative PCR.
• The participant is a study site employee, an immediate family member (for example, spouse, parent, child, sibling), or is in a dependent relationship with a study site employee who is involved in conduct of this study, or may consent under duress.
• The participant who, in the opinion of the investigator or the sponsor, will be uncooperative or unable to comply with study procedures.
• The participant who participates in other studies involving an investigational product.