Study of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)

FIB4 Score Values Over Time: Cohort 2

The FIB 4 score evaluates the degree of fibrosis in patients suspected of or already diagnosed with hepatic fibrosis. FIB-4 is calculated as (Age (years) \* aspartate aminotransferase) / (platelets \* √(ALT)). The result provided from the above equation is interpreted according to 2 cut off values: FIB 4 \<1.45 indicates absence of cirrhosis (with a negative predictive value of 90% for advanced fibrosis); FIB 4 between 1.45 - 3.25 are deemed inconclusive; FIB 4 \>3.25 indicates cirrhosis (with a positive predictive value of 65% for advanced fibrosis).

Time frame: Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 22, Week 28, Week 28 + 1 day, Week 34, Week 40, Week 48

Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b

The APRI suggests the level of hepatic fibrosis and possible liver disease. APRI is calculated as 100\*(aspartate aminotransferase/40) / platelets. Scores indicate the following: \< 0.5 = fibrosis is ruled out; 0.5 - 0.7 = associated with some kind of liver damage; 0.7 - 1 = significant fibrosis; \> 1 = associated with cirrhosis.

Time frame: Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 24

APRI Values Over Time: Cohort 2

The APRI suggests the level of hepatic fibrosis and possible liver disease. APRI is calculated as 100\*(aspartate aminotransferase/40) / platelets. Scores indicate the following: \< 0.5 = fibrosis is ruled out; 0.5 - 0.7 = associated with some kind of liver damage; 0.7 - 1 = significant fibrosis; \> 1 = associated with cirrhosis.

Time frame: Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 22, Week 28, Week 34, Week 40, Week 48

N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b

PRO-C3 may be a biomarker for the formation of fibrotic tissue in the liver. For serum, the normal range is 6.1 - 13.8 ng/mL (based on a study of human serum samples from healthy men and women). Due to ethnic, dietary and age variations, the reference limits given may not apply to all populations. A reduction in Pro-C3 over time may indicate a reduction in hepatic fibrogenesis.

Time frame: Baseline, Weeks 4, 16, 24

PRO-C3 Values Over Time: Cohort 2

PRO-C3 may be a biomarker for the formation of fibrotic tissue in the liver. For serum, the normal range is 6.1 - 13.8 ng/mL (based on a study of human serum samples from healthy men and women). Due to ethnic, dietary and age variations, the reference limits given may not apply to all populations. A reduction in Pro-C3 over time may indicate a reduction in hepatic fibrogenesis.

Time frame: Baseline, Weeks 4, 16, 28, 40, 48

FibroScan® Values Over Time: Cohorts 1/1b

FibroScan is a type of liver elastography. Normal results are usually between 2 and 7 kilopascals (kPa), with results higher than the normal range if liver disease is present. The highest possible result is 75 kPa.

Time frame: Baseline, Week 24

FibroScan® Values Over Time: Cohort 2

FibroScan is a type of liver elastography. Normal results are usually between 2 and 7 kilopascals (kPa), with results higher than the normal range if liver disease is present. The highest possible result is 75 kPa.

Time frame: Baseline, Week 24

Portal Inflammation Over Time: Cohorts 1/1b

Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of portal inflammation, which was scored on a scale from 0 (none) to 3 (severe). Participants with a baseline score of 0 were not included in any of the 3 categories for this analysis.

Time frame: Baseline, Week 24

Portal Inflammation Over Time: Cohort 2

Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of portal inflammation, which was scored on a scale from 0 (none) to 3 (severe). Participants with a baseline score of 0 were not included in any of the 3 categories for this analysis.

Time frame: Baseline, Week 48

Interface Hepatitis Over Time: Cohorts 1/1b

Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of interface hepatitis, which was scored on a scale from 0 (none) to 3 (severe). Participants with a baseline score of 0 were not included in any of the 3 categories for this analysis.

Time frame: Baseline, Week 24

Interface Hepatitis Over Time: Cohort 2

Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of interface hepatitis, which was scored on a scale from 0 (none) to 3 (severe). Participants with a baseline score of 0 were not included in any of the 3 categories for this analysis.

Time frame: Baseline, Week 48

Lobular Inflammation Over Time: Cohorts 1/1b

Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of lobular inflammation, which was scored on a scale from 0 (none) to 3 (severe). Participants with a baseline score of 0 were not included in any of the 3 categories for this analysis.

Time frame: Baseline, Week 24

Lobular Inflammation Over Time: Cohort 2

Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of lobular inflammation, which was scored on a scale from 0 (none) to 3 (severe). Participants with a baseline score of 0 were not included in any of the 3 categories for this analysis.

Time frame: Baseline, Week 48

Hepatocyte Cell Death Over Time: Cohorts 1/1b

Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1- point worsening from the baseline category in the liver biopsy parameter of hepatocyte cell death. Hepatocyte Cell Death Score: 0 = No acidophil bodies; 1 = Few acidophil bodies; 2 = Many acidophil. Participants with a baseline score of 0 were not included in any of the 3 categories for this analysis.

Time frame: Baseline, Week 24

Hepatocyte Cell Death Over Time: Cohort 2

Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of hepatocyte cell death. Hepatocyte Cell Death Score: 0 = No acidophil bodies; 1 = Few acidophil bodies; 2 = Many acidophil. Participants with a baseline score of 0 were not included in any of the 3 categories for this analysis.

Time frame: Baseline, Week 48

Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohorts 1/1b

Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1- point worsening from the baseline category in the METAVIR fibrosis stage score. The METAVIR scoring system is a system used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy of patients with hepatitis C. The stage represents the amount of fibrosis or scarring. Participants with a baseline score of 0 were not included in any of the 3 categories for this analysis. F0: no fibrosis F1: portal fibrosis without septa F2: portal fibrosis with few septa F3: numerous septa without cirrhosis F4: cirrhosis

Time frame: Baseline, Week 24

Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohort 2

Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1- point worsening from the baseline category in the METAVIR fibrosis stage score. The METAVIR scoring system is a system used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy of patients with hepatitis C. The stage represents the amount of fibrosis or scarring. Participants with a baseline score of 0 were not included in any of the 3 categories for this analysis. F0: no fibrosis F1: portal fibrosis without septa F2: portal fibrosis with few septa F3: numerous septa without cirrhosis F4: cirrhosis

Time frame: Baseline, Week 48

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

An Adverse Event (AE) is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. Serious Adverse Event (SAE) is an AE that results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability/incapacity, Is a congenital anomaly/birth defect, Is a medically important event or reaction. TEAEs are AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. Not related events include those reported as 'Not Related' to study drug. Related events include those reported as 'Possibly Related' or 'Probably Related' to study drug.

Time frame: From first dose of study drug up to a maximum duration of study follow-up of 202 weeks.