Alpha 1-Antitrypsin Deficiency
Conditions
Brief summary
The purpose of this study is to evaluate the the safety and efficacy of the investigational product, fazirsiran (TAK-999, ARO-AAT), administered subcutaneously to patients with alpha-1 antitrypsin deficiency associated liver disease (AATD).
Detailed description
Participants will be enrolled to receive multiple subcutaneous injections of fazirsiran (TAK-999, ARO-AAT). All eligible participants will require a pre-dose biopsy completed as part of the study within the screening window. All participants will undergo an end of study (EOS) biopsy. Treated participants will be offered the opportunity to continue treatment in an open label extension during which they will undergo a final biopsy.
Interventions
DRUGARO-AAT
solution for subcutaneous injection
Sponsors
Arrowhead Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of AATD * Liver biopsy indicating Metavir F1-F3 liver fibrosis based on local pathology read. * Women of childbearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use contraception * Willing to provide written informed consent and to comply with study requirements * Non-smoker for at least 1 year * No abnormal finding of clinical relevance at screening
Exclusion criteria
* Clinically significant health concerns other than AATD * Previous diagnosis or diagnosis at Screening of definitive liver cirrhosis * Regular use of alcohol within one month prior to Screening * Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving therapeutic intervention * Use of illicit drugs within 1 year prior to Screening Note: additional inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b | Baseline, Week 24 |
| Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 48: Cohort 2 | Baseline, Week 48 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 24 | — |
| ALT Values Over Time: Cohort 2 | Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 22, Week 28, Week 34, Week 40, Week 48 | — |
| Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 24 | — |
| GGT Values Over Time: Cohort 2 | Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 22, Week 28, Week 34, Week 40, Week 48 | — |
| Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | 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 | 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). |
| FIB4 Score Values Over Time: Cohort 2 | 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 | 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). |
| Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | 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 | 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. |
| APRI Values Over Time: Cohort 2 | 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 | 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. |
| N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b | Baseline, Weeks 4, 16, 24 | 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. |
| PRO-C3 Values Over Time: Cohort 2 | Baseline, Weeks 4, 16, 28, 40, 48 | 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. |
| FibroScan® Values Over Time: Cohorts 1/1b | Baseline, Week 24 | 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. |
| Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Baseline, Weeks 2, 4, 6, 16, 24 | — |
| Portal Inflammation Over Time: Cohorts 1/1b | Baseline, Week 24 | 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. |
| Portal Inflammation Over Time: Cohort 2 | Baseline, Week 48 | 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. |
| Interface Hepatitis Over Time: Cohorts 1/1b | Baseline, Week 24 | 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. |
| Interface Hepatitis Over Time: Cohort 2 | Baseline, Week 48 | 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. |
| Lobular Inflammation Over Time: Cohorts 1/1b | Baseline, Week 24 | 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. |
| Lobular Inflammation Over Time: Cohort 2 | Baseline, Week 48 | 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. |
| Hepatocyte Cell Death Over Time: Cohorts 1/1b | Baseline, Week 24 | 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. |
| Hepatocyte Cell Death Over Time: Cohort 2 | Baseline, Week 48 | 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. |
| Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohorts 1/1b | Baseline, Week 24 | 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 |
| Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohort 2 | Baseline, Week 48 | 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 |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From first dose of study drug up to a maximum duration of study follow-up of 202 weeks. | 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. |
| FibroScan® Values Over Time: Cohort 2 | Baseline, Week 24 | 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. |
| Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2 | Baseline, Weeks 2, 4, 6, 16, 22, 28, 34, 40, 48 | — |
Countries
Austria, Germany, United Kingdom
Participant flow
Pre-assignment details
All eligible subjects required a pre-dose biopsy completed as part of the study within the screening window. Participants consisted of male and female adult homozygous Z allele individuals (PiZZ; based on genotype completed at Screening or from a source verifiable document) alpha-1 antitrypsin patients.
Participants by arm
| Arm | Count |
|---|---|
| ARO-AAT 100 mg Cohort 1b Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. As of global protocol version 7.0 (21-Jul-2022) / German protocol version 2.6 (29-Jul-2022) and after applicable regulatory, Ethics Committee and local approval, participants in Cohort 1b switched from 100 mg to 200 mg while maintaining their dosing schedule.
The maximum number of doses for participants completing the treatment extension periods was 15 doses. | 4 |
| ARO-AAT 200 mg Cohort 1 Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT Q12W. Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W.
The maximum number of doses for participants completing the treatment extension periods was 15 doses. | 4 |
| ARO-AAT 200 mg Cohort 2 Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT Q12W. Treatment Extension II (up to 24 months): 200 mg dose of subcutaneous ARO-AAT Q12W.
The maximum number of doses for participants completing the treatment extension periods was 17 doses. | 8 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Treatment Extension II | Rolled over to another study | 0 | 0 | 2 |
| Treatment Extension II | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | ARO-AAT 200 mg Cohort 2 | Total | ARO-AAT 100 mg Cohort 1b | ARO-AAT 200 mg Cohort 1 |
|---|---|---|---|---|
| Age, Continuous | 54.6 years STANDARD_DEVIATION 13.68 | 52.1 years STANDARD_DEVIATION 14.92 | 54.8 years STANDARD_DEVIATION 10.01 | 44.5 years STANDARD_DEVIATION 17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 16 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Insoluble Z-Alpha 1 Antitrypsin (Z-AAT) | 37.4500 nmol/g STANDARD_DEVIATION 27.73075 | 36.0375 nmol/g STANDARD_DEVIATION 31.38345 | 35.9750 nmol/g STANDARD_DEVIATION 16.51694 | 33.2750 nmol/g STANDARD_DEVIATION 53.31019 |
| Race/Ethnicity, Customized White | 8 Participants | 16 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 14 Participants | 3 Participants | 4 Participants |
| Soluble Z-AAT | 23.3125 nmol/g STANDARD_DEVIATION 7.59914 | 24.3188 nmol/g STANDARD_DEVIATION 7.50984 | 26.3500 nmol/g STANDARD_DEVIATION 5.18813 | 24.3000 nmol/g STANDARD_DEVIATION 10.58899 |
| Total Z-AAT | 60.7625 nmol/g STANDARD_DEVIATION 34.04199 | 60.3563 nmol/g STANDARD_DEVIATION 36.13456 | 62.3250 nmol/g STANDARD_DEVIATION 15.8121 | 57.5750 nmol/g STANDARD_DEVIATION 59.65391 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 | 0 / 8 |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 8 / 8 |
| serious Total, serious adverse events | 0 / 4 | 4 / 4 | 5 / 8 |
Outcome results
Primary
Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b
Time frame: Baseline, Week 24
Population: Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b | Total Liver Z-AAT | -83.07 percent change | Standard Deviation 5.83 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b | Insoluble Liver-ZAAT | -81.58 percent change | Standard Deviation 6.947 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b | Soluble Liver Z-AAT | -85.36 percent change | Standard Deviation 4.835 |
| ARO-AAT 200 mg Cohort 1 | Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b | Total Liver Z-AAT | -79.84 percent change | Standard Deviation 10.519 |
| ARO-AAT 200 mg Cohort 1 | Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b | Insoluble Liver-ZAAT | -12.91 percent change | Standard Deviation 131.702 |
| ARO-AAT 200 mg Cohort 1 | Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b | Soluble Liver Z-AAT | -88.18 percent change | Standard Deviation 5.718 |
Primary
Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 48: Cohort 2
Time frame: Baseline, Week 48
Population: Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 48: Cohort 2 | Total Liver Z-AAT | -90.26 percent change | Standard Deviation 9.029 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 48: Cohort 2 | Insoluble Liver-ZAAT | -84.83 percent change | Standard Deviation 19.92 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 48: Cohort 2 | Soluble Liver Z-AAT | -92.64 percent change | Standard Deviation 7.482 |
Secondary
Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b
Time frame: Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 24
Population: Safety Analysis Set: all participants who received at least one dose of study drug. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Day 2 (24-48 hr post-dose) | 58.5 U/L | Standard Deviation 42.68 |
| ARO-AAT 100 mg Cohort 1b | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 16 (24-48 hr post-dose) | 31.5 U/L | Standard Deviation 8.85 |
| ARO-AAT 100 mg Cohort 1b | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 2 | 76.5 U/L | Standard Deviation 55.24 |
| ARO-AAT 100 mg Cohort 1b | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 6 | 49.8 U/L | Standard Deviation 25.16 |
| ARO-AAT 100 mg Cohort 1b | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 4 | 62.3 U/L | Standard Deviation 35.77 |
| ARO-AAT 100 mg Cohort 1b | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 24 | 27.8 U/L | Standard Deviation 9.29 |
| ARO-AAT 100 mg Cohort 1b | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 4 (24-48 hr post-dose) | 60.3 U/L | Standard Deviation 33.97 |
| ARO-AAT 100 mg Cohort 1b | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Baseline (Day 1) | 58.5 U/L | Standard Deviation 41.36 |
| ARO-AAT 100 mg Cohort 1b | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 16 | 35.7 U/L | Standard Deviation 8.5 |
| ARO-AAT 200 mg Cohort 1 | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 24 | 39.5 U/L | Standard Deviation 3.11 |
| ARO-AAT 200 mg Cohort 1 | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 6 | 77.0 U/L | Standard Deviation 20.85 |
| ARO-AAT 200 mg Cohort 1 | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 16 (24-48 hr post-dose) | 42.7 U/L | Standard Deviation 3.06 |
| ARO-AAT 200 mg Cohort 1 | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Baseline (Day 1) | 87.8 U/L | Standard Deviation 30.42 |
| ARO-AAT 200 mg Cohort 1 | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Day 2 (24-48 hr post-dose) | 88.3 U/L | Standard Deviation 32.72 |
| ARO-AAT 200 mg Cohort 1 | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 2 | 99.8 U/L | Standard Deviation 53.89 |
| ARO-AAT 200 mg Cohort 1 | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 4 | 106.5 U/L | Standard Deviation 42.57 |
| ARO-AAT 200 mg Cohort 1 | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 4 (24-48 hr post-dose) | 99.0 U/L | Standard Deviation 38.58 |
| ARO-AAT 200 mg Cohort 1 | Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b | Week 16 | 49.8 U/L | Standard Deviation 5.25 |
Secondary
ALT Values Over Time: Cohort 2
Time frame: Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 22, Week 28, Week 34, Week 40, Week 48
Population: Safety Analysis Set: all participants who received at least one dose of study drug. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Baseline (Day 1) | 62.1 U/L | Standard Deviation 14.98 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Day 2 (24-48 hr post-dose) | 58.6 U/L | Standard Deviation 15.59 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 2 | 61.9 U/L | Standard Deviation 20.17 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 4 | 55.3 U/L | Standard Deviation 14.09 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 4 (24-48 hr post-dose) | 53.0 U/L | Standard Deviation 14.83 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 6 | 54.9 U/L | Standard Deviation 9.79 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 16 | 39.6 U/L | Standard Deviation 13.13 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 16 (24-48 hr post-dose) | 37.5 U/L | Standard Deviation 11.61 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 22 | 41.0 U/L | Standard Deviation 14.58 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 28 | 36.7 U/L | Standard Deviation 15.76 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 34 | 39.4 U/L | Standard Deviation 11.13 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 40 | 33.4 U/L | Standard Deviation 10.08 |
| ARO-AAT 100 mg Cohort 1b | ALT Values Over Time: Cohort 2 | Week 48 | 34.5 U/L | Standard Deviation 10.54 |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 2 | 0.486 numerical score | Standard Deviation 0.1551 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Baseline (Day 1) | 0.500 numerical score | Standard Deviation 0.2102 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Day 2 (24-48 hr post-dose) | 0.515 numerical score | Standard Deviation 0.2023 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 4 | 0.479 numerical score | Standard Deviation 0.2226 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 4 (24-48 hr post-dose) | 0.454 numerical score | Standard Deviation 0.2127 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 6 | 0.463 numerical score | Standard Deviation 0.1678 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 16 | 0.372 numerical score | Standard Deviation 0.1812 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 16 (24-48 hr post-dose) | 0.358 numerical score | Standard Deviation 0.216 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 22 | 0.386 numerical score | Standard Deviation 0.2011 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 28 | 0.387 numerical score | Standard Deviation 0.2642 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 34 | 0.379 numerical score | Standard Deviation 0.2449 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 40 | 0.349 numerical score | Standard Deviation 0.1768 |
| ARO-AAT 100 mg Cohort 1b | APRI Values Over Time: Cohort 2 | Week 48 | 0.440 numerical score | Standard Deviation 0.231 |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Day 2 (24-48 hr post-dose) | 0.463 numerical score | Standard Deviation 0.2133 |
| ARO-AAT 100 mg Cohort 1b | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 6 | 0.433 numerical score | Standard Deviation 0.1688 |
| ARO-AAT 100 mg Cohort 1b | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 4 | 0.463 numerical score | Standard Deviation 0.2185 |
| ARO-AAT 100 mg Cohort 1b | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 16 | 0.343 numerical score | Standard Deviation 0.0404 |
| ARO-AAT 100 mg Cohort 1b | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 2 | 0.633 numerical score | Standard Deviation 0.3349 |
| ARO-AAT 100 mg Cohort 1b | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 16 (24-48 hr post-dose) | 0.330 numerical score | Standard Deviation 0.07 |
| ARO-AAT 100 mg Cohort 1b | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 4 (24-48 hr post-dose) | 0.468 numerical score | Standard Deviation 0.1921 |
| ARO-AAT 100 mg Cohort 1b | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 24 | 0.310 numerical score | Standard Deviation 0.097 |
| ARO-AAT 100 mg Cohort 1b | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Baseline (Day 1) | 0.485 numerical score | Standard Deviation 0.2249 |
| ARO-AAT 200 mg Cohort 1 | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 24 | 0.513 numerical score | Standard Deviation 0.2892 |
| ARO-AAT 200 mg Cohort 1 | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Baseline (Day 1) | 0.745 numerical score | Standard Deviation 0.3877 |
| ARO-AAT 200 mg Cohort 1 | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Day 2 (24-48 hr post-dose) | 0.753 numerical score | Standard Deviation 0.3923 |
| ARO-AAT 200 mg Cohort 1 | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 2 | 0.910 numerical score | Standard Deviation 0.5231 |
| ARO-AAT 200 mg Cohort 1 | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 4 | 0.810 numerical score | Standard Deviation 0.4031 |
| ARO-AAT 200 mg Cohort 1 | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 4 (24-48 hr post-dose) | 0.785 numerical score | Standard Deviation 0.4171 |
| ARO-AAT 200 mg Cohort 1 | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 6 | 0.918 numerical score | Standard Deviation 0.1834 |
| ARO-AAT 200 mg Cohort 1 | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 16 | 0.555 numerical score | Standard Deviation 0.3008 |
| ARO-AAT 200 mg Cohort 1 | Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b | Week 16 (24-48 hr post-dose) | 0.603 numerical score | Standard Deviation 0.4203 |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 6 | 1.367 numerical score | Standard Deviation 0.6419 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Baseline (Day 1) | 1.395 numerical score | Standard Deviation 0.6634 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Day 2 (24-48 hr post-dose) | 1.543 numerical score | Standard Deviation 0.8209 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 2 | 1.383 numerical score | Standard Deviation 0.6358 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 4 | 1.420 numerical score | Standard Deviation 0.7054 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 4 (24-48 hr post-dose) | 1.356 numerical score | Standard Deviation 0.6344 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 16 | 1.299 numerical score | Standard Deviation 0.5636 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 16 (24-48 hr post-dose) | 1.271 numerical score | Standard Deviation 0.6521 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 22 | 1.336 numerical score | Standard Deviation 0.6269 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 28 | 1.377 numerical score | Standard Deviation 0.7152 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 34 | 1.239 numerical score | Standard Deviation 0.7527 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 40 | 1.319 numerical score | Standard Deviation 0.5782 |
| ARO-AAT 100 mg Cohort 1b | FIB4 Score Values Over Time: Cohort 2 | Week 48 | 1.502 numerical score | Standard Deviation 0.768 |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | FibroScan® Values Over Time: Cohort 2 | Baseline | 9.89 kPa | Standard Deviation 3.205 |
| ARO-AAT 100 mg Cohort 1b | FibroScan® Values Over Time: Cohort 2 | Week 48 | 8.67 kPa | Standard Deviation 3.263 |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | FibroScan® Values Over Time: Cohorts 1/1b | Baseline | 7.28 kPa | Standard Deviation 2.632 |
| ARO-AAT 100 mg Cohort 1b | FibroScan® Values Over Time: Cohorts 1/1b | Week 24 | 7.30 kPa | Standard Deviation 3.73 |
| ARO-AAT 200 mg Cohort 1 | FibroScan® Values Over Time: Cohorts 1/1b | Baseline | 12.70 kPa | Standard Deviation 6.988 |
| ARO-AAT 200 mg Cohort 1 | FibroScan® Values Over Time: Cohorts 1/1b | Week 24 | 10.55 kPa | Standard Deviation 5.802 |
Secondary
Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b
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 24
Population: Safety Analysis Set: all participants who received at least one dose of study drug. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Day 2 (24-48 hr post-dose) | 1.353 numerical score | Standard Deviation 0.2699 |
| ARO-AAT 100 mg Cohort 1b | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 6 | 1.355 numerical score | Standard Deviation 0.4612 |
| ARO-AAT 100 mg Cohort 1b | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 4 | 1.260 numerical score | Standard Deviation 0.384 |
| ARO-AAT 100 mg Cohort 1b | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 16 | 1.257 numerical score | Standard Deviation 0.3326 |
| ARO-AAT 100 mg Cohort 1b | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 2 | 1.580 numerical score | Standard Deviation 0.5806 |
| ARO-AAT 100 mg Cohort 1b | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 16 (24-48 hr post-dose) | 1.227 numerical score | Standard Deviation 0.223 |
| ARO-AAT 100 mg Cohort 1b | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 4 (24-48 hr post-dose) | 1.333 numerical score | Standard Deviation 0.4194 |
| ARO-AAT 100 mg Cohort 1b | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 24 | 1.265 numerical score | Standard Deviation 0.3196 |
| ARO-AAT 100 mg Cohort 1b | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Baseline (Day 1) | 1.425 numerical score | Standard Deviation 0.3613 |
| ARO-AAT 200 mg Cohort 1 | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 24 | 1.688 numerical score | Standard Deviation 1.2563 |
| ARO-AAT 200 mg Cohort 1 | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Baseline (Day 1) | 1.583 numerical score | Standard Deviation 0.9085 |
| ARO-AAT 200 mg Cohort 1 | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Day 2 (24-48 hr post-dose) | 1.618 numerical score | Standard Deviation 0.9668 |
| ARO-AAT 200 mg Cohort 1 | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 2 | 1.900 numerical score | Standard Deviation 1.3056 |
| ARO-AAT 200 mg Cohort 1 | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 4 | 1.750 numerical score | Standard Deviation 1.3273 |
| ARO-AAT 200 mg Cohort 1 | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 4 (24-48 hr post-dose) | 1.760 numerical score | Standard Deviation 1.3867 |
| ARO-AAT 200 mg Cohort 1 | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 6 | 2.013 numerical score | Standard Deviation 1.1073 |
| ARO-AAT 200 mg Cohort 1 | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 16 | 1.605 numerical score | Standard Deviation 1.221 |
| ARO-AAT 200 mg Cohort 1 | Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b | Week 16 (24-48 hr post-dose) | 1.940 numerical score | Standard Deviation 1.621 |
Secondary
Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b
Time frame: Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 24
Population: Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 4 (24-48 hr post-dose) | 70.0 U/L | Standard Deviation 45.19 |
| ARO-AAT 100 mg Cohort 1b | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 2 | 66.0 U/L | Standard Deviation 37.15 |
| ARO-AAT 100 mg Cohort 1b | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 6 | 64.0 U/L | Standard Deviation 35.62 |
| ARO-AAT 100 mg Cohort 1b | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Day 2 (24-48 hr post-dose) | 70.5 U/L | Standard Deviation 39.07 |
| ARO-AAT 100 mg Cohort 1b | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 16 | 48.0 U/L | Standard Deviation 23.25 |
| ARO-AAT 100 mg Cohort 1b | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 16 (24-48 hr post-dose) | 48.0 U/L | Standard Deviation 22.38 |
| ARO-AAT 100 mg Cohort 1b | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 4 | 73.0 U/L | Standard Deviation 43.37 |
| ARO-AAT 100 mg Cohort 1b | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 24 | 52.3 U/L | Standard Deviation 28.31 |
| ARO-AAT 100 mg Cohort 1b | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Baseline (Day 1) | 70.8 U/L | Standard Deviation 35.3 |
| ARO-AAT 200 mg Cohort 1 | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 24 | 112.0 U/L | Standard Deviation 156.92 |
| ARO-AAT 200 mg Cohort 1 | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Baseline (Day 1) | 244.8 U/L | Standard Deviation 355.68 |
| ARO-AAT 200 mg Cohort 1 | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Day 2 (24-48 hr post-dose) | 247.3 U/L | Standard Deviation 358.01 |
| ARO-AAT 200 mg Cohort 1 | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 2 | 210.8 U/L | Standard Deviation 304.4 |
| ARO-AAT 200 mg Cohort 1 | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 4 | 222.0 U/L | Standard Deviation 334.85 |
| ARO-AAT 200 mg Cohort 1 | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 4 (24-48 hr post-dose) | 210.3 U/L | Standard Deviation 312 |
| ARO-AAT 200 mg Cohort 1 | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 6 | 199.3 U/L | Standard Deviation 292.28 |
| ARO-AAT 200 mg Cohort 1 | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 16 (24-48 hr post-dose) | 161.7 U/L | Standard Deviation 212.17 |
| ARO-AAT 200 mg Cohort 1 | Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b | Week 16 | 135.3 U/L | Standard Deviation 190.31 |
Secondary
GGT Values Over Time: Cohort 2
Time frame: Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 22, Week 28, Week 34, Week 40, Week 48
Population: Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point. Participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Baseline (Day 1) | 62.5 U/L | Standard Deviation 31.09 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Day 2 (24-48 hr post-dose) | 62.1 U/L | Standard Deviation 33.21 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 2 | 60.6 U/L | Standard Deviation 33.14 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 4 | 59.1 U/L | Standard Deviation 49.82 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 4 (24-48 hr post-dose) | 57.6 U/L | Standard Deviation 46.91 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 6 | 58.0 U/L | Standard Deviation 36.21 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 16 | 49.1 U/L | Standard Deviation 36.84 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 16 (24-48 hr post-dose) | 48.3 U/L | Standard Deviation 38.68 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 22 | 48.5 U/L | Standard Deviation 34.85 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 28 | 44.5 U/L | Standard Deviation 34.62 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 34 | 45.3 U/L | Standard Deviation 31.37 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 40 | 45.3 U/L | Standard Deviation 38.2 |
| ARO-AAT 100 mg Cohort 1b | GGT Values Over Time: Cohort 2 | Week 48 | 48.5 U/L | Standard Deviation 45.05 |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Hepatocyte Cell Death Over Time: Cohort 2 | ≥ 1-point worsening | 0.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Hepatocyte Cell Death Over Time: Cohort 2 | Baseline score = 0 | 37.5 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Hepatocyte Cell Death Over Time: Cohort 2 | ≥ 1-point improvement | 0.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Hepatocyte Cell Death Over Time: Cohort 2 | no change | 62.5 percentage of participants |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Hepatocyte Cell Death Over Time: Cohorts 1/1b | ≥ 1-point improvement | 0.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Hepatocyte Cell Death Over Time: Cohorts 1/1b | no change | 25.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Hepatocyte Cell Death Over Time: Cohorts 1/1b | ≥ 1-point worsening | 25.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Hepatocyte Cell Death Over Time: Cohorts 1/1b | Baseline score = 0 | 50.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Hepatocyte Cell Death Over Time: Cohorts 1/1b | Baseline score = 0 | 75.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Hepatocyte Cell Death Over Time: Cohorts 1/1b | ≥ 1-point improvement | 0.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Hepatocyte Cell Death Over Time: Cohorts 1/1b | ≥ 1-point worsening | 25.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Hepatocyte Cell Death Over Time: Cohorts 1/1b | no change | 0.0 percentage of participants |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Interface Hepatitis Over Time: Cohort 2 | ≥ 1-point improvement | 25.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Interface Hepatitis Over Time: Cohort 2 | no change | 25.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Interface Hepatitis Over Time: Cohort 2 | ≥ 1-point worsening | 0.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Interface Hepatitis Over Time: Cohort 2 | Baseline score = 0 | 50.0 percentage of participants |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Interface Hepatitis Over Time: Cohorts 1/1b | ≥ 1-point improvement | 50.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Interface Hepatitis Over Time: Cohorts 1/1b | no change | 0.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Interface Hepatitis Over Time: Cohorts 1/1b | ≥ 1-point worsening | 25.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Interface Hepatitis Over Time: Cohorts 1/1b | Baseline score = 0 | 25.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Interface Hepatitis Over Time: Cohorts 1/1b | Baseline score = 0 | 0.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Interface Hepatitis Over Time: Cohorts 1/1b | ≥ 1-point improvement | 0.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Interface Hepatitis Over Time: Cohorts 1/1b | ≥ 1-point worsening | 0.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Interface Hepatitis Over Time: Cohorts 1/1b | no change | 100.0 percentage of participants |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Lobular Inflammation Over Time: Cohort 2 | ≥ 1-point improvement | 0.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Lobular Inflammation Over Time: Cohort 2 | no change | 62.5 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Lobular Inflammation Over Time: Cohort 2 | ≥ 1-point worsening | 12.5 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Lobular Inflammation Over Time: Cohort 2 | Baseline score = 0 | 25.0 percentage of participants |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Lobular Inflammation Over Time: Cohorts 1/1b | ≥ 1-point improvement | 0.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Lobular Inflammation Over Time: Cohorts 1/1b | no change | 25.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Lobular Inflammation Over Time: Cohorts 1/1b | ≥ 1-point worsening | 50.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Lobular Inflammation Over Time: Cohorts 1/1b | Baseline score = 0 | 25.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Lobular Inflammation Over Time: Cohorts 1/1b | Baseline score = 0 | 0.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Lobular Inflammation Over Time: Cohorts 1/1b | ≥ 1-point improvement | 0.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Lobular Inflammation Over Time: Cohorts 1/1b | ≥ 1-point worsening | 50.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Lobular Inflammation Over Time: Cohorts 1/1b | no change | 50.0 percentage of participants |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohort 2 | ≥ 1-point improvement | 50.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohort 2 | no change | 12.5 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohort 2 | ≥ 1-point worsening | 25.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohort 2 | Baseline score = 0 | 12.5 percentage of participants |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug. Participants with an assessment at the given time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohorts 1/1b | ≥ 1-point improvement | 0.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohorts 1/1b | no change | 100.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohorts 1/1b | ≥ 1-point worsening | 0.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohorts 1/1b | ≥ 1-point improvement | 50.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohorts 1/1b | no change | 50.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohorts 1/1b | ≥ 1-point worsening | 0.0 percentage of participants |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b | Week 16 | 15.60 μg/L | Standard Deviation 1.818 |
| ARO-AAT 100 mg Cohort 1b | N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b | Week 4 | 16.90 μg/L | Standard Deviation 3.539 |
| ARO-AAT 100 mg Cohort 1b | N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b | Week 24 | 18.08 μg/L | Standard Deviation 2.159 |
| ARO-AAT 100 mg Cohort 1b | N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b | Baseline | 16.78 μg/L | Standard Deviation 2.96 |
| ARO-AAT 200 mg Cohort 1 | N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b | Week 24 | 16.63 μg/L | Standard Deviation 1.621 |
| ARO-AAT 200 mg Cohort 1 | N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b | Week 4 | 22.10 μg/L | Standard Deviation 7.202 |
| ARO-AAT 200 mg Cohort 1 | N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b | Week 16 | 19.30 μg/L | Standard Deviation 0.245 |
| ARO-AAT 200 mg Cohort 1 | N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b | Baseline | 25.15 μg/L | Standard Deviation 9.31 |
Secondary
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.
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Causing Death | 0 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE ISR Severity = Severe | 0 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE = Not Related to Study Drug (SD) | 1 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Requiring Dose Interruption of SD | 0 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE ISR Severity = Moderate | 0 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE = Related to SD | 3 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥ 1 Serious TEAE | 0 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Injection Site Reaction (ISR) Severity = Mild | 2 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Leading to PRemature Withdrawal From Study | 0 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Severity = Moderate | 1 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Severity = Mild | 3 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥ 1 TEAE | 4 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Leading to SD Discontinuation | 0 participants |
| ARO-AAT 100 mg Cohort 1b | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Severity = Severe | 0 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Leading to SD Discontinuation | 0 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Severity = Moderate | 3 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥ 1 TEAE | 4 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥ 1 Serious TEAE | 3 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Severity = Mild | 1 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Severity = Severe | 0 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE = Not Related to Study Drug (SD) | 2 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE = Related to SD | 2 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Injection Site Reaction (ISR) Severity = Mild | 1 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE ISR Severity = Moderate | 0 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE ISR Severity = Severe | 0 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Requiring Dose Interruption of SD | 1 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Leading to PRemature Withdrawal From Study | 0 participants |
| ARO-AAT 200 mg Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Causing Death | 0 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Severity = Severe | 2 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Leading to PRemature Withdrawal From Study | 0 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Severity = Moderate | 4 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥ 1 Serious TEAE | 5 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Leading to SD Discontinuation | 0 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥ 1 TEAE | 8 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE ISR Severity = Severe | 0 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Requiring Dose Interruption of SD | 3 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE = Related to SD | 5 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Severity = Mild | 2 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Injection Site Reaction (ISR) Severity = Mild | 3 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE = Not Related to Study Drug (SD) | 3 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE Causing Death | 0 participants |
| ARO-AAT 200 mg Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAE ISR Severity = Moderate | 1 participants |
Secondary
Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2
Time frame: Baseline, Weeks 2, 4, 6, 16, 22, 28, 34, 40, 48
Population: Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2 | Week 2 | -72.08 percent change | Standard Deviation 8.645 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2 | Week 4 | -82.22 percent change | Standard Deviation 7.476 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2 | Week 6 | -89.92 percent change | Standard Deviation 4.024 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2 | Week 16 | -85.76 percent change | Standard Deviation 6.106 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2 | Week 22 | -90.87 percent change | Standard Deviation 4.246 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2 | Week 28 | -85.06 percent change | Standard Deviation 7.847 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2 | Week 34 | -89.54 percent change | Standard Deviation 5.434 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2 | Week 40 | -84.12 percent change | Standard Deviation 12.433 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2 | Week 48 | -89.58 percent change | Standard Deviation 5.419 |
Secondary
Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b
Time frame: Baseline, Weeks 2, 4, 6, 16, 24
Population: Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Week 4 | -80.24 percent change | Standard Deviation 8.88 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Week 16 | -78.61 percent change | Standard Deviation 9.186 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Week 6 | -87.27 percent change | Standard Deviation 6.14 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Week 24 | -83.85 percent change | Standard Deviation 5.426 |
| ARO-AAT 100 mg Cohort 1b | Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Week 2 | -69.12 percent change | Standard Deviation 12.381 |
| ARO-AAT 200 mg Cohort 1 | Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Week 24 | -89.47 percent change | Standard Deviation 3.738 |
| ARO-AAT 200 mg Cohort 1 | Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Week 2 | -77.28 percent change | Standard Deviation 7.394 |
| ARO-AAT 200 mg Cohort 1 | Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Week 4 | -88.07 percent change | Standard Deviation 4.931 |
| ARO-AAT 200 mg Cohort 1 | Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Week 6 | -91.79 percent change | Standard Deviation 3.795 |
| ARO-AAT 200 mg Cohort 1 | Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b | Week 16 | -83.08 percent change | Standard Deviation 6.269 |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Portal Inflammation Over Time: Cohort 2 | ≥ 1-point improvement | 12.5 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Portal Inflammation Over Time: Cohort 2 | no change | 37.5 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Portal Inflammation Over Time: Cohort 2 | ≥ 1-point worsening | 0.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Portal Inflammation Over Time: Cohort 2 | Baseline score = 0 | 50.0 percentage of participants |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | Portal Inflammation Over Time: Cohorts 1/1b | ≥ 1-point improvement | 25.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Portal Inflammation Over Time: Cohorts 1/1b | no change | 50.0 percentage of participants |
| ARO-AAT 100 mg Cohort 1b | Portal Inflammation Over Time: Cohorts 1/1b | ≥ 1-point worsening | 25.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Portal Inflammation Over Time: Cohorts 1/1b | ≥ 1-point improvement | 50.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Portal Inflammation Over Time: Cohorts 1/1b | no change | 50.0 percentage of participants |
| ARO-AAT 200 mg Cohort 1 | Portal Inflammation Over Time: Cohorts 1/1b | ≥ 1-point worsening | 0.0 percentage of participants |
Secondary
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
Population: Safety Analysis Set: all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARO-AAT 100 mg Cohort 1b | PRO-C3 Values Over Time: Cohort 2 | Week 28 | 14.31 μg/L | Standard Deviation 2.362 |
| ARO-AAT 100 mg Cohort 1b | PRO-C3 Values Over Time: Cohort 2 | Baseline | 18.21 μg/L | Standard Deviation 3.002 |
| ARO-AAT 100 mg Cohort 1b | PRO-C3 Values Over Time: Cohort 2 | Week 4 | 15.81 μg/L | Standard Deviation 2.948 |
| ARO-AAT 100 mg Cohort 1b | PRO-C3 Values Over Time: Cohort 2 | Week 16 | 17.03 μg/L | Standard Deviation 2.463 |
| ARO-AAT 100 mg Cohort 1b | PRO-C3 Values Over Time: Cohort 2 | Week 40 | 15.10 μg/L | Standard Deviation 2.989 |
| ARO-AAT 100 mg Cohort 1b | PRO-C3 Values Over Time: Cohort 2 | Week 48 | 17.09 μg/L | Standard Deviation 7.967 |