Conditions: Alpha 1-Antitrypsin Deficiency
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

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.

Arms:
arm 1: 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 AROAAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. arm 2: 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 AROAAT Q12W. Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. arm 3: 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 AROAAT Q12W. Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W.

Interventions: intervention 1: ARO-AAT
Intervention descriptions: intervention 1: solution for subcutaneous injection

Protocol document:
Prot_000.pdf: 
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PROTOCOL 
NUMBER: 
AROAAT2002 
 
STUDY TITLE: 
A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the Safety 
and Efficacy of Fazirsiran (TAK-999, ARO-AAT) in Patients with 
Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)  
DRUG (Active): 
Fazirsiran (TAK-999, also referred to as ARO-AAT) Injection 
 
ROUTE: 
Subcutaneous Injection  
 
STUDY DESIGN: 
A multi-center, multi-dose, open-label phase 2 study will be 
conducted to evaluate the safety and efficacy of the investigational 
product, fazirsiran (TAK-999, ARO-AAT), administered 
subcutaneously to patients with Alpha-1 Antitrypsin Deficiency.   
 
SPONSOR: 
Arrowhead Pharmaceuticals, Inc. 
177 East Colorado Boulevard  
Suite 700 
Pasadena, CA 91105 
 
Telephone: +1 626 304 3400     Facsimile: +1 626 304 3401 
 
 
EudraCT Number: 
2019-000068-86 
 
Version: 
7.0  
 
 
 
 
Confidential 
Information contained in this protocol should not be disclosed, other than to those directly involved in the execution 
or ethical review of the study, without written authorization from Arrowhead Pharmaceuticals, Inc. It is, however, 
permissible to provide information to a volunteer to obtain consent.  
 


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1. 
PROTOCOL SYNOPSIS 
Study Title:  A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the Safety and Efficacy 
of Fazirsiran (TAK-999, ARO-AAT) in Patients with Alpha-1 Antitrypsin Deficiency 
Associated Liver Disease (AATD) 
Study Number:  AROAAT2002 
Phase:  Phase 2 
Location:  Multiple sites in Europe and United Kingdom  
Study Treatments:   
The study treatment is Fazirsiran (TAK-999, also referred to as ARO-AAT) Injection.  
The active pharmaceutical ingredient (API) fazirsiran is a synthetic, double-stranded, small 
interfering RNA (siRNA) duplex conjugated to an N-acetyl-galactosamine targeting ligand to 
facilitate hepatocyte delivery. 
Primary Endpoint: 
• To evaluate change from baseline over time in total, soluble, and insoluble Z-AAT 
concentrations in the liver of patients with AAT-associated liver disease. 
Secondary Endpoints: 
• To determine the effect of multiple doses of fazirsiran on circulating levels of 
Z-AAT alpha-1 antitrypsin over time versus baseline.  
• To evaluate the effect of fazirsiran on changes in ALT over time.  
• To evaluate the effect of fazirsiran on changes in GGT over time. 
• To evaluate the effect of fazirsiran on changes in FIB-4 and APRI over time.  
• To evaluate the effect of fazirsiran on changes in PRO-C3 over time.  
• To evaluate the effect of fazirsiran on changes in hepatic stiffness based on 
FibroScan® over time versus baseline (when available). 
• To evaluate effect of fazirsiran on histological metrics of liver disease in patients 
with AAT-associated liver disease over time. 
• To evaluate change from baseline in Metavir fibrosis score over time in fazirsiran 
treated patients. 


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• To determine the incidence and severity of treatment-emergent adverse events as a 
measure of the safety and tolerability of fazirsiran.  
• To determine the incidence and titers of anti-drug antibodies (ADAs) to fazirsiran. 
Exploratory Endpoints: 
• To evaluate the effect of fazirsiran on changes in hepatic stiffness based on magnetic 
resonance elastography (MRE) over time versus baseline (optional). 
• To evaluate changes in hepatic SERPINA1 mRNA expression over time versus 
baseline in response to multiple doses of fazirsiran (if sufficient sample available). 
• To evaluate changes in liver disease related gene expression over time versus 
baseline (if scientifically feasible and sufficient sample available). 
• To evaluate change in liver PAS+D stained globule size and number over time 
versus baseline. 
• To evaluate the effect of fazirsiran on changes in liver collagen using biomarkers 
(e.g., PRO-C6), special stains and imaging [Masson’s Trichrome, Sirius Red, Iron] 
(if scientifically feasible and sufficient sample available) over time versus baseline. 
• To determine the effect of multiple doses of fazirsiran on circulating levels of total 
alpha-1 antitrypsin at multiple post-dose time points versus baseline (patients on 
and not on AAT augmentation therapy will be evaluated separately). 
Study Population/Subject Number:  This study will be conducted in PiZZ patients with 
Alpha-1 Antitrypsin Deficiency. Both males and females are eligible, ages 18-75. In total, the 
study will consist of up to approximately 16 participants in three cohorts.  Cohort 1 consists of 
4 patients, Cohort 1b consists of 4 patients and Cohort 2 consists of 8 patients. Patients who 
complete any cohort may elect to participate in the treatment extension periods which would 
include an additional 12 doses as well as an optional repeat liver biopsy (performed following 
the fourth dose). 
All eligible patients will require a pre-dose biopsy completed as part of the study within the 
screening window. Participants will consist of male and female adult PiZZ (based on genotype 
completed at Screening or from a source verifiable document) alpha-1 antitrypsin patients.  
Patients previously, currently, or never receiving AAT augmentation therapy are eligible for 
enrollment.  
Number of Doses:  Doses will be 100 or 200 mg of fazirsiran.  A minimum of three 200 mg 
doses will be administered to patients in Cohort 1. Patients in Cohort 1b will receive a 
minimum of three 100 mg doses, and a minimum of five 200 mg doses will be administered to 
patients in Cohort 2.  The maximum number of doses for patients completing the treatment 


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extension periods will be 15 doses for Cohort 1 and 1b patients and 17 doses for Cohort 2 
patients.   
Study Duration:  For Cohort 1 and 1b, the duration of the study is approximately 36 weeks, 
from beginning of the Screening period to the phone call after the End-of-Study (EOS) visit. 
For Cohort 2, the duration of the study is approximately 60 weeks, from beginning of the 
Screening period to the phone call after the EOS visit. All patients will be invited to continue 
dosing with fazirsiran beyond the planned EOS visit as part of the treatment extension periods.  
As a participant in the treatment extensions, they will receive a total of twelve additional doses 
of fazirsiran at 12-week intervals.  The expected total duration of the treatment extensions 
(Extension I, 12 months; and Extension II, up to 24 months) is up to 36 months (144 weeks), 
i.e., 3 years.   
Study Visit Duration:  For each participant, clinic visits for drug administration will last 
approximately up to 3 hours total, 2 hours pre-dose and 1-hour post-dose on dosing days. 
Shorter or longer visits on dosing days are acceptable and are per Investigator judgement.  
Clinic visits on non-dosing days are expected to last 1-2 hours.   
Study Design/Methods:  A multi-center, multi-dose, open-label, Phase 2 study will be 
conducted to evaluate the safety and efficacy of the investigational product, fazirsiran 
(TAK-999, ARO-AAT), administered subcutaneously to patients with Alpha-1 Antitrypsin 
Deficiency.  
The study will include 3 study periods: 1) a Primary Study Period, 2) an optional Treatment 
Extension I, and 3) an optional Treatment Extension II, which are described below.  
Primary Study Period (6-12 Months) 
Participants who have signed an Institutional Review Board (IRB)/Ethics Committee (EC) 
approved informed consent and have met all the protocol eligibility criteria during Screening, 
will be enrolled in one of three cohorts: 
• Cohort 1: 200 mg dose of subcutaneous fazirsiran  
• Cohort 1b: 100 mg dose of subcutaneous fazirsiran 
• Cohort 2: 200 mg dose of subcutaneous fazirsiran 
Cohorts 1 and 1b will receive a minimum of 3 doses and Cohort 2 will be receiving a minimum 
of 5 doses. All subjects will have a baseline biopsy and post-baseline biopsy at Week 24 
(Cohorts 1 and 1b) OR at Week 48 (Cohort 2) per the Schedule of Assessments (SOA), OR at 
Early Termination. At the end of the Primary Study Period, subjects will be offered the 
opportunity to continue treatment in the open-label Treatment Extension I. Participants who 
drop out prior to biopsy at the end of the Primary Study Period for reasons other than an AE 
considered at least possibly related to drug, may be replaced. 


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Treatment Extension I (12 Months) 
Subjects who opt to continue in Treatment Extension I will receive the same dose level of 
fazirsiran as administered in their assigned initial cohort every 12 weeks (Q12W). Dosing with 
fazirsiran may continue approximately 12 weeks from the previous dose in the Primary Study 
Period. All subjects who opted to continue will have an optional biopsy at Week 44 of 
Treatment Extension I. At the end of this study period, subjects may opt to continue treatment 
for up to an additional 24 months in Treatment Extension II. 
Treatment Extension II (up to 24 Months)  
Subjects will continue to receive fazirsiran Q12W for up to an additional 24 months or until 
they roll over into another long-term Extension study, whichever comes first. Dosing with 
fazirsiran may continue approximately 12 weeks from the previous dose in Treatment 
Extension I. No biopsies will be collected in Treatment Extension II. 
Study Schema 
Primary Study Period 
Treatment Extension I 
Treatment Extension II 
 
Subjects who proceed into Treatment Extension I and/or II will continue to receive the dose to 
which they were assigned at the start of the study. Based on cumulative safety, efficacy, and 
pharmacodynamics (PD) data from the fazirsiran clinical program (clinical studies 
AROAAT1001, AROAAT2001, and AROAAT2002), a fazirsiran dose (200 mg) was selected 
by the Sponsor. Following the respective country regulatory and ethics committees’ approvals 
(including local approvals as necessary) of AROAAT2002 protocol amendment v7.0, all 
ongoing subjects will be consented and informed of the selected dose and subjects in Cohort 1b 
(100 mg) will begin receiving the selected dose at their next scheduled dosing timepoint. 
Study Assessments:  
Participants will undergo the following evaluations at regular intervals during the study (refer to 
SOA): medical history, physical examinations, vital sign measurements (blood pressure, 
temperature, heart rate, respiratory rate), weight, adverse events monitoring, electrocardiograms 


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(ECGs), urine pregnancy test/FSH (females), concurrent medication, pulmonary function 
testing (spirometry including vital capacity [VC], forced vital capacity [FVC], 1 second forced 
expiratory volume [FEV1], FEV1/VC, FEV1/FVC, and diffusing capacity for carbon monoxide 
[DLCO]) and sample collection for hematology, coagulation, biochemistry, cardiac troponin, 
urinalysis, urine cotinine, anti-drug antibodies, drug screens, serum alpha-1 antitrypsin levels 
(where applicable), serum fibrosis biomarkers, liver biopsy, MRE (where feasible and 
available) and FibroScan® (where available).   
Study visits will occur during the Screening window (Day -56 to -1), and as per the SOA. A 
telephone follow-up will occur 12 weeks (± 5 days) after the last dose to verify compliance with 
contraceptive measures and absence of any known pregnancy.  Clinically significant changes 
including AEs will be followed until resolution is achieved, or until medically stable or the 
event is otherwise explained, or until the participant is lost to follow-up. 
Baseline values will be those assessments obtained pre-dose within the closest proximity to the 
first dose of the study.  
Histologic Assessments:  
A liver biopsy will be collected at screening and at the end of the Primary Study Period (or at 
early termination). At the end of an additional 12 months of treatment for those subjects 
entering into and completing Treatment Extension I, an optional third liver biopsy may be 
collected based on each subject’s consent. The biopsy will assess the following: 
• Changes in AATD related histological metrics (e.g., steatosis, inflammation) 
• Measure of size and number of PAS/D + globules (percent change and absolute 
change) 
• Changes in Metavir fibrosis score 
Additional PD assessments from the liver biopsy are listed under Other Pharmacodynamic 
Assessments. 
Safety Assessments: 
Safety assessments will be performed at specified time points per the SOA and will include the 
following:  
• Vital signs: Resting heart rate, seated or semi-supine (same position each time is 
preferred) systolic/diastolic blood pressure, respiratory rate and temperature  
• Clinical laboratory measurements (e.g., biochemistry, hematology, cardiac troponin, 
coagulation, urine cotinine and urinalysis) 
• Resting ECG measurements (measured after participant is supine or semi-supine 
[same position each time is preferred] for at least 3 minutes) 


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• At each visit, participants will be asked about concomitant medications/therapy and 
will be instructed to volunteer any information regarding AEs and SAEs that they 
may have experienced. Any known untoward event that occurs beyond the AE 
reporting period that the Investigator(s) considers an SAE and possibly related to 
study treatment will be reported to Arrowhead. 
• Injection site reactions (ISRs): Injection site reactions will be defined and graded as 
mild, moderate or severe based on clinical findings 
• 90-day, post-last dose follow-up phone call to assess for pregnancy occurrence  
• Physical examination (symptom directed as described in the SOA)  
• Pulmonary Function Testing including spirometry (including VC, FVC, FEV1) and 
DLCO 
• Use of augmentation treatment at any time throughout the study and date when last 
augmentation was administered prior to each fazirsiran dose 
• Time from baseline to initiation of augmentation therapy  
• Number and severity of chronic obstructive pulmonary disease (COPD) 
exacerbations based on Global Initiative for Chronic Obstructive Lung Disease 
(GOLD) criteria will be evaluated as an AE of special interest 
The AE reporting period for an enrolled participant will begin when the participant provides 
informed consent. Treatment-emergent AEs will be those defined as following dose 
administration, or in the event onset preceded dose administration, those AEs with severity or 
frequency increasing post-dose. All AEs that occur during the AE reporting period specified in 
the protocol must be reported, regardless of the relationship of the AE to study treatment.  For 
this trial, the Investigator should evaluate the relatedness of an AE to investigational product 
using three categories:  Not Related, Possibly Related and Probably Related. Laboratory 
abnormalities will be reported as an AE if considered clinically significant by the Investigator 
or if there are clinical sequelae. Any known SAE that occurs beyond the AE reporting period 
that the Investigator considers possibly or probably related to study treatment will be reported. 
Other Pharmacodynamic Assessments:  
The following PD measures and diagnostic studies will be collected for each dose and treatment 
group as per the SOA: 
• Quantitative and/or % change in alpha-1 antitrypsin levels and mutant AAT protein 
(Z-AAT) levels 
• Change in FibroScan® (where available) 


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• Change in magnetic resonance elastography (optional) 
• Percent and absolute change in liver total (soluble plus insoluble) Z-AAT protein 
levels 
• Percent and absolute change in liver Z-AAT soluble protein levels 
• Percent and absolute change in liver Z-AAT insoluble protein levels 
• Quantified and percent change in liver expression of liver fibrosis associated genes 
• Percent and absolute change in SERPINA1 mRNA levels 
• Measures of hepatic function including prothrombin time, partial thromboplastin 
time (PTT), international normalized ratio (INR), albumin, ALT, AST, gamma 
glutamyl transferase (GGT), platelet count, total bilirubin, and alkaline phosphatase 
• Collagen content measurement (Masson’s Trichrome, Sirius Red, morphometric 
analysis) 
• Serum fibrosis biomarkers (e.g. PRO-C3) 
• Calculated values indicative of liver disease (Fibrosis-4 index [FIB-4], aspartate 
aminotransferase-to-platelet ratio index [APRI]) 
Immunogenicity Assessments:  
Emergence of anti-drug antibodies will be evaluated with serum samples collected as per the 
SOA. 
Data Analysis:  
Descriptive summaries will be presented for primary, secondary and exploratory endpoints 
using appropriate methods. A detailed statistical analysis plan (SAP) will be prepared and 
finalized prior to database lock.  
Study Populations 
• Safety Population: All patients who receive at least one dose of study drug. The 
Safety Population will be used for safety analyses. 
• Full Analysis Set (FAS): All patients who receive at least one dose of study drug 
and have baseline and post-dose liver biopsy histology results available. FAS 
population will be used for all efficacy analyses. 


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• Per Protocol (PP) population: All FAS patients who did not violate the protocol in a 
substantial manner, such determination to be made prior to database lock.  
Sample Size  
There were no formal sample size calculations made in this open-label exploratory study.  
Screening, Tolerability and Safety Data: 
In general, safety analyses will be performed, and the results summarized. Baseline safety 
assessments will be compared with measurements recorded post-baseline.   
• Treatment-emergent AEs will be summarized using the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) by System Organ Class (SOC) and 
Preferred Term (PT), classified from verbatim terms.  
• The incidence and frequency of AEs, SAEs, related AEs, related SAEs, and AEs 
leading to withdrawal, dose modification, or treatment discontinuation will be 
summarized by dose according to SOC and PT.  
• AEs will also be summarized in listings. The duration of AEs will be determined 
and included in listings, along with the action taken and outcome.   
• The incidence of laboratory abnormalities will be summarized.  
• Vital sign measurements will be summarized at each scheduled time point using 
descriptive statistics.  
• Physical examination findings will be summarized by time point and presented in 
participant listings.   
• Clinically significant changes on ECG and changes in spirometry (including VC, 
FVC, FEV1), and DLCO will be summarized.  
• Pregnancy test/FSH results will be summarized separately by time point.  
• The number of patients that require augmentation treatment at any time throughout 
the study will be summarized. Time from baseline to initiation of augmentation 
therapy will be summarized using Kaplan Meier estimates.   
• The percentage of patients experiencing an ISR (see definition of ISR in protocol) 
will be summarized using descriptive statistics. 
• The number and percentage of patients with ADA positive by time will be 
summarized.  


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Treatment Stopping and Study Modification Rules: 
A decision to stop the trial early or discontinue drug in an individual subject or group of 
patients may be indicated based on any of the following:  
• In the case of two or more similar Serious Adverse Events both considered at least 
possibly related to fazirsiran, the trial will be put on halt even if the subject(s) is/are 
not discontinued from the study drug/study. The Principal Investigator and Sponsor 
will meet within 3 days of the Sponsor being notified of the 2nd event and within the 
timeframe of required regulatory agency notification. Available aggregated data will 
be reviewed to determine if the study remains safe to proceed, should be 
discontinued or should continue but with amendments. Restart of the trial will 
require approval of a substantial amendment from the competent authorities. 
• Evaluation and fazirsiran discontinuation/dosing modification rules for elevated 
ALTs are provided in Appendix 1. 
• Evaluation and fazirsiran study modification/discontinuation rules for declines in 
pulmonary function are provided in Appendix 2. 
• Subject who becomes pregnant while in the study. 
Sponsor or Investigator can discontinue any subject at any time. If such events (as described in 
#1, #2, or #3 above) occur and the subject is not discontinued from the study, the reason for not 
discontinuing the subject will be documented. Including, but not limited to the events listed 
above, the study may be paused to additional dosing to provide time to evaluate safety data and 
recommend the action to be taken, which may include, but is not limited to, one of the 
following: 
• Discontinuation of a subject or group of patients from the study 
• The study is stopped immediately with no further dosing 
• The study will continue, but using a lower dose 
• The study will continue as planned 
− Inclusion Criteria 
            To be eligible for enrollment, participants must meet all the following inclusion criteria: 
• Male or non-nursing female patients 18-75 years of age, inclusive, at the time of 
Screening with previous diagnosis of PiZZ genotype Alpha-1 Antitrypsin 
Deficiency. PiZZ diagnosis from source verifiable medical records is permitted. 


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Otherwise, patients must undergo PiZZ confirmatory testing at Screening. PiMZ or 
PiSZ genotypes are not permitted.  
• Able and willing to provide written informed consent prior to the performance of 
any study specific procedures. 
• A 12-lead ECG at Screening that, in the opinion of the Investigator, has no 
abnormalities that compromise participant’s safety in this study. 
• Non-smoker (defined as does not smoke cigarettes daily for at least 12 months) with 
current non-smoking status confirmed by urine cotinine at screening and throughout 
the study.  Patients may be on nicotine replacement (patch or gum). E-cigarettes 
(vapor) are not permitted. A positive urine cotinine result due to nicotine 
replacement is acceptable for enrollment at the discretion of the Investigator.  
• Participants using highly effective contraception during the study and for 12 weeks 
following the last dose of fazirsiran.  Males must not donate sperm for at least 
12 weeks post last dose of study treatment. Females of childbearing potential must 
have a negative urine pregnancy test at Screening and on Day 1 pre-dose. Females 
not of childbearing potential must be post-menopausal (defined as cessation of 
regular menstrual periods for at least 12 months), confirmed by follicle-stimulating 
hormone (FSH) consistent with post-menopausal state based on lab reference 
ranges.  
• Using twice the normal protection of birth control by using a condom AND one 
other form of either birth control pills (The Pill), depot or injectable birth control, 
IUD (Intrauterine Device), birth control patch (e.g., Ortho Evra), NuvaRing®, OR 
Surgical sterilization as a single form of birth control: i.e., tubal ligation, 
hysterectomy, bilateral oophorectomy, vasectomy or equivalently effective surgical 
form of birth control. 
− True subject abstinence for the duration of the study and 12 weeks after the dose 
of fazirsiran is acceptable only when in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea methods are not considered “true” abstinence and are not 
acceptable methods of contraception.  
• Participants who are willing and able to comply with all study assessments and 
adhere to the protocol schedule. 
• Must have suitable venous access for blood sampling. 


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• No abnormal finding of clinical relevance at the Screening evaluation that in the 
opinion of the Investigator could adversely impact subject safety during the study or 
adversely impact study results.  
• Liver biopsy indicating Metavir F1- F3 (or equivalent on other grading scales, see 
Appendix 3) liver fibrosis based on local pathologist read. All patients will require a 
liver biopsy during the screen period except for prior screened patients who now 
meet the fibrosis criteria as long as there is sufficient material for a baseline 
assessment as per specifications in the laboratory manual.   
All laboratory tests used as inclusion criteria may be repeated once and the repeat 
value may be used for inclusion purposes. Central labs will be utilized for the study, 
however local labs may be utilized as necessary due to emergent situations. 
− Exclusion Criteria  
A potential participant will be excluded from the study if any of the following criteria apply:       
• INR ≥1.5 at Screening. If based on opinion of Investigator and/or prescribing 
physician patient is appropriate for anticoagulant holiday, patient may stop taking 
anticoagulant for an appropriate washout period or reversal with vitamin K and if 
indicated a repeat INR within <1.5 would be acceptable. If INR is not indicated 
(direct thrombin inhibitors or Xa inhibitors) then appropriate washout period alone 
may be acceptable. (Note: Anti-platelet agents such as aspirin, clopidogrel or 
nonsteroidal anti-inflammatory drugs [NSAIDs] are acceptable but must be held 
7 days before and 7 days after liver biopsy) 
• ALT and AST levels >250 U/L at Screening (one retest permitted) 
• Estimated glomerular filtration rate (eGFR) <60 ml/min at Screening (one retest 
permitted) 
• Post-bronchodilation (if available) FEV1 <65% of predicted at Screening in any 
subject not receiving AAT augmentation therapy.  
• Post-bronchodilation (if available) FEV1 <45% of predicted at Screening in any 
subject currently receiving AAT augmentation therapy on a regular basis and 
planning to continue AAT augmentation therapy for the duration of the study.  
• Patients expected to have severe and unavoidable high-level exposure to inhaled 
pulmonary toxins during the study.  
• Patients with recent (last 3 months) diagnosis of pneumonia are also excluded. 


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• Human immunodeficiency virus infection, as shown by the presence of anti-HIV 
antibody (sero-positive) 
• Seropositive for HBV (HBsAg positive at Screening) or HCV (detectable HCV 
RNA at Screening). Cured HCV (positive antibody test without detectable HCV 
RNA is acceptable). 
• Uncontrolled hypertension (systolic blood pressure [BP] >170 and diastolic BP 
>100 mmHg at Screening). Patients may rescreen once BP is successfully 
controlled. 
• A history of torsades de pointes, ventricular rhythm disturbances (e.g., ventricular 
tachycardia or fibrillation), heart block (excluding first-degree block, being PR 
interval prolongation only), congenital long QT syndrome or new ST segment 
elevation or depression or new Q wave on ECG. Participants with a history of atrial 
arrhythmias should be discussed with the Medical Monitor 
• Symptomatic heart failure (per New York Heart Association guidelines), unstable 
angina, myocardial infarction, severe cardiovascular disease (ejection fraction 
<20%, transient ischemic attack (TIA) or cerebrovascular accident (CVA) within 
6 months prior to Screening 
• History of malignancy within the last 1 year except for adequately treated basal cell 
carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical 
cancer. Participants with other curatively treated malignancies who have no 
evidence of metastatic disease and >1-year disease-free interval may be entered 
following approval by the Medical Monitor. 
• History of major surgery within the prior 1 month prior to Screening 
• Regular use of alcohol within one month prior to the Screening visit (i.e., more than 
14 units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 
40% alcohol])  
• Use of illicit drugs (such as cocaine, phencyclidine [PCP]) within 1 year prior to the 
Screening visit or positive urine drug screen at Screening (a urine drug screen 
positive for benzodiazepines, opioids or marijuana is acceptable for enrollment at 
the discretion of the Investigator if the positive test is due to a substance used for 
medical reasons).  
• Use of an investigational agent or device within 30 days prior to dosing or current 
participation in an investigational study involving a therapeutic intervention. 
Patients receiving AAT augmentation therapy as part of a post-marketing study or 
other access program for approved therapies are acceptable.   


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• Blood donation (≥500 mL) within 7 days prior to study treatment administration.  
• 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. Patients with nonalcoholic steatohepatitis (NASH), 
nonalcoholic fatty liver disease (NAFLD), metabolic syndrome, well controlled 
diabetes mellitus (even if on insulin) or hemochromatosis are acceptable if disease is 
stable and does not pose a significant threat to subject participation. Patients 
enrolled with NASH should have no plans to undergo bariatric surgery or initiate 
pharmaceutical therapy for NASH (such as Vitamin E or pioglitazone) during the 
course of the study. If already on such treatment, regimen must be stable for at least 
12 weeks.  
• A history of thromboembolic disease (including deep vein thrombosis or pulmonary 
embolism), myocardial infarction, stroke within six (6) months of screening. 
• Participants who are unable to return for all scheduled study visits. 
• Females of childbearing potential who are breastfeeding. 
• Any other condition, that in the opinion of the Investigator would render the 
participant unsuitable for enrollment or could interfere with participating in and 
completing the study. 
• Previous diagnosis of decompensated liver cirrhosis or complications of cirrhosis 
(e.g., varices, ascites, hepatic encephalopathy) based on source verifiable medical 
record. 
• Diagnosis of F4 (Metavir) or similar grading scale equivalent indicating definitive 
cirrhosis on pre-dose liver biopsy completed as part of the AROAAT2002 study 
based on local pathologist read or based on historical liver biopsy (last 6 months 
from consent) with a source verifiable pathologist read of definitive liver cirrhosis. 
Note: Sponsor Medical Monitor has the option to exclude the enrollment of a participant if, 
based upon the participant’s medical history or Screening results, it is felt that a participant’s 
safety may be at risk.  
All laboratory tests used as exclusion criteria may be repeated once and the repeat value may be 
used for exclusion purposes. Central labs will be utilized for the study, however local labs may 
be utilized as necessary due to emergent situations. 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 15 of 89 
Table 1: 
Cohort 1 & 1b Schedule of Assessments 
Assessment visit 
Baseline / 
Screen1 
 
ENROLLMENT 
Day 1 
Dosing 
day 
24-48 
hr post-
dose  
Wk 2  
 
Wk 4 
Dosing 
day 
24-48 
hr post-
dose  
Wk 6 
 
Wk 16 
Dosing 
day 
24-48 
hr post-
dose  
Wk 24 
visit  
12 Wks 
post last 
dose 
Early 
Term 
Window in days 
-56 to 
Day -1 
 
 
± 5 
± 5 
 
± 5 
± 14 
 
± 14 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight (Optional) 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
Urine Cotinine 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis/HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
FSH in post-menopausal 
females 
X 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function 
Testing2 
X 
X 
 
 
X 
 
 
X 
 
X10 
 
X10 
FibroScan®  
X 
 
 
 
 
 
 
 
 
X10 
 
X10 
Magnetic Resonance 
Elastography (Optional) 
   X11 
 
 
 
 
 
 
 
 
X 
 
X 
Liver Biopsy 
X 
 
 
 
 
 
 
 
 
X10 
 
X10 
PiZZ Genotype 
 X3 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X 
 
X 
Urine Pregnancy Test 
X 
X5 
 
 
X5 
 
 
X5 
 
X 
 
X 
ECG 
X 
X6 
 
 
X6 
 
 
X6 
 
X 
 
X 
Vital Signs (BP, temp, heart 
rate, respiratory rate) 
X 
X7 
X 
X 
X7 
X 
X 
X7 
X 
X 
 
X  
Clinical Labs (chem, heme, 
coag, UA) 
 X8 
X8 
X 
X 
X8 
X 
X 
X8 
X 
X8 
 
X8 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 16 of 89 
Table 1: 
Cohort 1 & 1b Schedule of Assessments (Continued) 
Assessment visit 
Baseline /  
Screen1 
ENROLLMENT 
Day 1 
Dosing 
day  
24-48 
hr post-
dose  
Wk 2  
 
Wk 4 
Dosing 
day 
24-48 
hr post-
dose  
Wk 6 
 
Wk 16 
Dosing 
day 
24-48 
hr post-
dose  
Wk 24 
visit  
12 Wks 
post last 
dose 
Early 
Term 
Window in days 
-56 to 
Day -1 
 
 
± 5 
± 5 
 
± 5 
± 14 
 
± 14 
 
 
Alpha-1 Antitrypsin Level 
X 
X9 
 
X 
X9 
 
X 
X9 
 
X 
 
X 
PRO-C3 
 
X9 
 
 
X9 
 
 
X9 
 
X 
 
X 
Anti-drug Antibodies 
 
X9 
 
 
 
 
X 
 
 
X 
 
X 
Concomitant 
Meds/Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Fazirsiran Administration 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Pregnancy Follow Up  
 
 
 
 
 
 
 
 
 
 
X 
 
Calculate FIB-4, APRI 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
1. 
Screen visit may be split into separate days per site discretion. 
2. 
Pulmonary function testing includes VC, FVC, FEV1, FEV1/VC, FEV1/FVC, and DLCO. Pertinent study FEV1 will be based on post-bronchodilation value. If FEV1 at 
screen does not meet inclusion/exclusion, there is no need to perform DLCO. 
3. 
Only if genotype not already confirmed and documented in medical record. 
4. 
Symptom-directed PEs to be performed by visit as necessary. 
5. 
Negative urine pregnancy test must be confirmed pre-dose on dosing days in pre-menopausal females.  
6. 
On dosing days, ECGs will be performed at pre-dose, and post dose only if clinically warranted based on reported AEs. A clinically significant abnormal result will be 
repeated in triplicate. 
7. 
On dosing days vital sign assessment will be performed pre-dose, and 1-hour post-dose; more frequently per hour if necessary. 
8. 
Participants should be fasting (water only) for a minimum of two hours prior to the collection of the clinical labs. 
9. 
On dosing days, samples will be drawn pre-dose.  
10. Evaluations of VC, FVC, FEV1, DLCO, liver biopsy and FibroScan® should be completed in the following order: VC, FVC, FEV1 and DLCO on same day, then 
FibroScan® prior to liver biopsy. FibroScan should not occur after liver biopsy. 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 17 of 89 
11. Magnetic resonance elastography performed at the screen/baseline visit and/or prior to this visit, but within the screening period (Day -56 to Day -1), should be collected 
at the screen/baseline visit and/or retrospectively (if applicable) for analysis. 
A visit specified as Week X has a target date of Day 1+X number of weeks, for example, the Week 4 visit ideally occurs 28 days after 
Day 1 (on Day 29).  In Treatment Extension I, the calendar resets and Day 1 will be the first dose received during the treatment 
extension periods (approximately 12 weeks after the last dose in either Cohort 1, 1b, or 2) although the subject may have received 
previous doses while participating in Cohort 1, 1b, or 2. 
 
 
 
 
 
 
 
 
 
 
 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 18 of 89 
Table 2: 
Cohort 2 Schedule of Assessments 
Assessment visit 
Baseline 
/ 
Screen1 
 
ENROLLMENT 
Day 1 
Dosing 
day 
 
24-48 
hr 
post-
dose  
Wk 2  
 
Wk 4 
Dosing 
day 
 
24-48 
hr 
post-
dose  
Wk 6 
 
Wk 16 
Dosing 
day 
 
24-48 
hr 
post-
dose  
Wk 
22 
 
Wk 28 
Dosing 
day  
 
Wk 
34 
 
Wk 40 
Dosing 
day 
 
Wk 
48 
visit  
 
12 
Wks 
post 
last 
dose 
Early 
Term 
Window in days 
-56 to 
Day -1 
 
 
± 5 
± 5 
 
± 5 
± 14 
 
± 14 
± 14 
± 14 
± 14 
± 14 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (Optional) 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Urine Cotinine 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis/HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH in post-
menopausal females 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function 
Testing2 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X10 
 
X  
FibroScan®  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X10 
 
X  
Magnetic Resonance 
Elastography 
(Optional) 
   X11 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Liver Biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X10 
 
X  
PiZZ Genotype 
 X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 19 of 89 
Table 2: 
Cohort 2 Schedule of Assessments (Continued) 
Assessment visit 
Baseline 
/ 
Screen1 
 
ENROLLMENT 
Day 1 
Dosing 
day  
 
24-48 
hr post-
dose  
Wk 2  
 
Wk 4 
Dosing 
day 
 
24-48 
hr 
post-
dose  
Wk 6 
 
Wk 16 
Dosing 
day 
 
24-48 
hr 
post-
dose  
Wk 
22 
 
Wk 28 
Dosing 
day  
 
Wk 
34 
 
Wk 40 
Dosing 
day 
 
Wk 
48 
visit  
 
12 
Wks 
post 
last 
dose 
Early 
Term 
Window in days 
-56 to 
Day -1 
 
 
± 5 
± 5 
 
± 5 
± 14 
 
± 14 
± 14 
± 14 
± 14 
± 14 
 
 
Physical Exam 
X 
X 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X 
 
X 
Urine Pregnancy 
Test 
X 
X5 
 
 
X5 
 
 
X5 
 
 
X5 
 
X5 
X 
 
X 
ECG 
X 
X6 
 
 
X6 
 
 
X6 
 
 
X6 
 
X6 
X 
 
X 
Vital Signs (BP, 
temp, heart rate, 
respiratory rate) 
X 
X7 
X 
X 
X7 
X 
X 
X7 
X 
X 
X7 
X 
X7 
X 
 
X  
Clinical Labs 
(chem, heme, coag, 
UA) 
 X8 
X8 
X 
X 
X8 
X 
X 
X8 
X 
X 
X8 
X 
X8 
X8 
 
X 
Alpha-1 
Antitrypsin Level 
X 
X9 
 
X 
X9 
 
X 
X9 
 
X 
X9 
X 
X9 
X 
 
X 
PRO-C3 
 
X9 
 
 
X9 
 
 
X9 
 
 
X9 
 
X9 
X 
 
X 
Anti-drug 
Antibodies 
 
X9 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Concomitant 
Meds/Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Fazirsiran 
Administration 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
Pregnancy Follow 
Up  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Calculate FIB-4, 
APRI 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 20 of 89 
1. 
 Screen visit may be split into separate days per site discretion. 
2. 
Pulmonary function testing includes VC, FVC, FEV1, FEV1/VC, FEV1/FVC, and DLCO. Pertinent study FEV1 will be based on post-bronchodilation value. If FEV1 at 
screen does not meet inclusion/exclusion, there is no need to perform DLCO. 
3. 
Only if genotype not already confirmed and documented in medical record.  
4. 
Symptom-directed PEs to be performed by visit as necessary. 
5. 
Negative urine pregnancy test must be confirmed pre-dose on dosing days in pre-menopausal females.  
6. 
On dosing days, ECGs will be performed at pre-dose, and post dose only if clinically warranted based on reported AEs. A clinically significant abnormal result will be 
repeated in triplicate. 
7. 
On dosing days vital sign assessment will be performed pre-dose, and 1-hour post-dose; more frequently per hour if necessary. 
8. 
Participants should be fasting (water only) for a minimum of two hours prior to the collection of the clinical labs.   
9. 
On dosing days, samples will be drawn pre-dose. 
10. Evaluations of VC, FVC, FEV1, DLCO, liver biopsy and FibroScan® should be completed in the following order: VC, FVC, FEV1 and DLCO on same day, then 
FibroScan® prior to liver biopsy. FibroScan should not occur after liver biopsy. 
11. Magnetic resonance elastography performed at the screen/baseline visit and/or prior to this visit, but within the screening period (Day -56 to Day -1), should be collected 
at the screen/baseline visit and/or retrospectively (if applicable) for analysis. 
A visit specified as Week X has a target date of Day 1+X number of weeks, for example, the Week 4 visit ideally occurs 28 days 
after Day 1 (on Day 29).  In Treatment Extension I, the calendar resets and Day 1 will be the first dose received during the 
treatment extension periods (approximately 12 weeks after the last dose in either Cohort 1, 1b, or 2) although the subject may have 
received previous doses while participating in Cohort 1, 1b, or 2. 
 
 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 21 of 89 
Table 3: 
Treatment Extension I Schedule of Assessments 
Assessment visit 
TREATMENT EXTENSION I 
Day 1 Dosing day 
(12 weeks after 
last dose in 
Cohort 1, 1b, or 2) 
Wk 6   
Wk 12 
Dosing 
day 
Wk 
18 
 
Wk 24 
Dosing 
day 
Wk 
30  
Wk 36 
Dosing day 
Wk 44 
Biopsy 
visit 
Early 
Term 
Window in days 
± 14 
± 14 
± 5 
± 14 
± 5 
± 14 
± 5 
± 14 
 
Fazirsiran Administration 
X 
 
X 
 
X 
 
X 
 
 
Pulmonary Function Testing1 
X 
 
X 
 
X 
 
X 
X8 
X  
FibroScan®  
 
 
 
 
 
 
 
X8 
X  
Magnetic Resonance Elastography (Optional) 
 
 
 
 
 
 
 
X 
X 
Liver Biopsy (Optional) 
 
 
 
 
 
 
 
X8 
X  
Physical Exam 
X 
 
X2 
 
X2 
 
X2 
X 
X 
Urine Pregnancy Test 
X3 
 
X3 
 
X3 
 
X3 
X 
X 
ECG  
X4 
 
X4 
 
X4 
 
X4 
X 
X 
Vital Signs (BP, temp, heart rate, respiratory rate) 
X5 
 
X5 
 
X5 
 
X5 
X 
X  
Urine Cotinine 
 
 
 
 
 
 
 
X 
X 
Clinical Labs (chem, heme, coag, UA) 
X6 
 
X6 
 
X6 
 
X6 
X 
X 
Alpha-1 Antitrypsin Level 
X7 
 
X7 
 
X7 
 
X7 
X 
 
PRO-C3 
X7 
 
X7 
 
X7 
 
X7 
X 
X 
Anti-drug Antibodies 
 
 
 
 
X7 
 
 
X 
X 
Concomitant Meds/Therapies 
X 
 
X 
 
X 
 
X 
X 
X 
Adverse Events 
X 
 
X 
 
X 
 
X 
X 
X 
Calculate FIB-4, APRI 
X 
 
X 
 
X 
 
X 
X 
X 
Weight (optional) 
 
 
X 
 
X 
 
X 
X 
X 
Telephone Contact to Evaluate for AEs 
 
X 
 
X 
 
X 
 
 
 
1. 
Pulmonary function testing includes VC, FVC, FEV1, FEV1/VC, FEV1/FVC, and DLCO. Pertinent study FEV1 will be based on post-bronchodilation value. 
2. 
Symptom-directed PEs to be performed by visit as necessary. 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 22 of 89 
3. 
Negative urine pregnancy test must be confirmed pre-dose on dosing days in pre-menopausal females.  
4. 
On dosing days, ECGs will be performed at pre-dose, and post dose only if clinically warranted based on reported AEs. A clinically significant abnormal result will be 
repeated in triplicate. 
5. 
On dosing days vital sign assessment will be performed pre-dose, and 1-hour post-dose; more frequently per hour if necessary. 
6. 
Participants should be fasting (water only) for a minimum of two hours prior to the collection of the clinical labs.   
7. 
On dosing days, samples will be drawn pre-dose.  
8. 
Evaluations of VC, FVC, FEV1, DLCO, optional liver biopsy and FibroScan® should be completed in the following order: VC, FVC, FEV1 and DLCO on same day, 
then FibroScan® prior to optional liver biopsy. FibroScan should not occur after optional liver biopsy. 
A visit specified as Week X has a target date of Day 1+X number of weeks, for example, the Week 4 visit ideally occurs 28 days after 
Day 1 (on Day 29).  In Treatment Extension I, the calendar resets and Day 1 will be the first dose received during the treatment 
extension periods (approximately 12 weeks after the last dose in either Cohort 1, 1b, or 2) although the subject may have received 
previous doses while participating in Cohort 1, 1b, or 2. 
 
 
 
 
 
 
 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 23 of 89 
Table 4: 
Treatment Extension II Schedule of Assessments 
Assessment visit 
TREATMENT EXTENSION II 
Wk 48 
Dosing day 
(12 weeks 
after last 
dose in 
Treatment 
Extension I) 
Wk 
54  
Wk 60 
Dosing 
day 
Wk 
66  
Wk 72 
Dosing 
day 
Wk 
78  
Wk 84 
Dosing 
day 
Wk 
90 
Wk 96 
Dosing 
day 
Wk 
102 
Wk 
108 
Dosing 
day 
Wk 
114 
Wk 
120 
Dosing 
day 
Wk 
126 
Wk 
132 
Dosing 
day 
Wk 
140 
EOS 
visit 
12 
Wks 
post 
last 
dose 
Early 
Term 
Window in days 
± 5 
± 
14 
± 5 
± 
14 
± 5 
± 
14 
± 5 
± 
14 
± 5 
± 
14 
± 5 
± 
14 
± 5 
± 
14 
± 5 
± 14 
± 14 
 
Fazirsiran 
Administration 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Pulmonary Function 
Testing1 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X  
FibroScan®  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X  
Magnetic Resonance 
Elastography 
(Optional) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Physical Exam 
X 
 
X2 
 
X2 
 
X2 
 
X2 
 
X2 
 
X2 
 
X2 
X 
 
X 
Urine Pregnancy 
Test 
X3 
 
X3 
 
X3 
 
X3 
 
X3 
 
X3 
 
X3 
 
X3 
X 
 
X 
ECG  
X4 
 
X4 
 
X4 
 
X4 
 
X4 
 
X4 
 
X4 
 
X4 
X 
 
X 
Vital Signs (BP, 
temp, heart rate, 
respiratory rate) 
X5 
 
X5 
 
X5 
 
X5 
 
X5 
 
X5 
 
X5 
 
X5 
X 
 
X  
Urine Cotinine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Clinical Labs (chem, 
heme, coag, UA) 
X6 
 
X6 
 
X6 
 
X6 
 
X6 
 
X6 
 
X6 
 
X6 
X 
 
X 
Alpha-1 Antitrypsin 
Level 
X7 
 
X7 
 
X7 
 
X7 
 
X7 
 
X7 
 
X7 
 
X7 
X 
 
 
PRO-C3 
X7 
 
X7 
 
X7 
 
X7 
 
X7 
 
X7 
 
X7 
 
X7 
X 
 
X 
Concomitant 
Meds/Therapies 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
Adverse Events 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 24 of 89 
Pregnancy Follow 
Up  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Calculate FIB-4, 
APRI 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
Weight (optional) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
Telephone Contact 
to Evaluate for AEs 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
 
 
 
 
1. 
Pulmonary function testing includes VC, FVC, FEV1, FEV1/VC, FEV1/FVC, and DLCO. Pertinent study FEV1 will be based on post-bronchodilation value.   
2. 
Symptom-directed PEs to be performed by visit as necessary. 
3. 
Negative urine pregnancy test must be confirmed pre-dose on dosing days in pre-menopausal females.  
4. 
On dosing days, ECGs will be performed at pre-dose, and post dose only if clinically warranted based on reported AEs. A clinically significant abnormal result will be 
repeated in triplicate. 
5. 
On dosing days vital sign assessment will be performed pre-dose, and 1-hour post-dose; more frequently per hour if necessary. 
6. 
Participants should be fasting (water only) for a minimum of two hours prior to the collection of the clinical labs.   
7. 
On dosing days, samples will be drawn pre-dose.  
A visit specified as Week X has a target date of Day 1+X number of weeks, for example, the Week 4 visit ideally occurs 28 days after 
Day 1 (on Day 29).  
 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 25 of 89 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS .............................................................................................2 
2. 
STUDY INFORMATION AND SIGNATURES ......................................................29 
3. 
LIST OF ABBREVIATIONS AND TERMS.............................................................30 
4. 
INTRODUCTION ......................................................................................................34 
4.1. 
Background Information .............................................................................................34 
4.2. 
Development and Mechanism of Action of Fazirsiran ...............................................35 
4.3. 
Fazirsiran Pre-Clinical Pharmacology and Studies ....................................................35 
4.4. 
Fazirsiran Pre-Clinical Pharmacokinetic and Product Metabolism Studies ...............36 
4.5. 
Fazirsiran Pre-Clinical Toxicology Studies ................................................................36 
4.6. 
Fazirsiran Clinical Pharmacology, Pharmacokinetic and Clinical Safety ..................36 
4.7. 
Rationale for the Study ...............................................................................................36 
4.8. 
Risk Assessment for Participants ................................................................................37 
4.9. 
Justification for Dose Levels and Dose Intervals .......................................................40 
5. 
OBJECTIVE AND STUDY ENDPOINTS ................................................................42 
5.1. 
Study Objective ..........................................................................................................42 
5.2. 
Primary Endpoint ........................................................................................................42 
5.3. 
Secondary Endpoints ..................................................................................................42 
5.4. 
Exploratory Endpoints ................................................................................................42 
6. 
STUDY PLAN............................................................................................................44 
6.1. 
Study Design ...............................................................................................................44 
6.2. 
Rationale for Study Design .........................................................................................44 
6.3. 
Stopping Rules ............................................................................................................45 
6.4. 
Duration of the Study ..................................................................................................46 
7. 
SUBJECT SELECTION .............................................................................................47 
7.1. 
Number of Patients & Patient Demographics .............................................................47 
7.2. 
Inclusion Criteria ........................................................................................................47 
7.3. 
Exclusion Criteria .......................................................................................................48 
7.4. 
Participant Withdrawal Criteria ..................................................................................51 
7.5. 
Restrictions and Concomitant Medications ................................................................52 
8. 
INVESTIGATIONAL PRODUCT ............................................................................53 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 26 of 89 
8.1. 
Description, Identification and Dosage ......................................................................53 
8.2. 
Supply, Preparation, Storage and Labelling of Fazirsiran ..........................................53 
8.3. 
Study Drug Handling ..................................................................................................54 
8.4. 
Accountability of Study Supplies ...............................................................................54 
8.5. 
Retention of Investigational Product Vials .................................................................55 
8.6. 
Allocation to Treatment ..............................................................................................55 
9. 
STUDY METHODS AND SCHEDULES .................................................................56 
9.1. 
Overview of Procedures .............................................................................................56 
9.2. 
Selection and Screening ..............................................................................................56 
9.3. 
On-Study Procedures/Assessments ............................................................................57 
9.3.1. 
Study Procedures: Clinical Facility Confinement ......................................................57 
9.3.2. 
Demographics/Medical History ..................................................................................57 
9.3.3. 
Physical Exam ............................................................................................................57 
9.3.4. 
Pulmonary Function Testing.......................................................................................58 
9.3.5. 
Electrocardiogram .......................................................................................................58 
9.3.6. 
Vital Sign Assessments...............................................................................................59 
9.3.7. 
Clinical Laboratory Tests ...........................................................................................59 
9.3.8. 
Pharmacodynamics .....................................................................................................60 
9.3.9. 
Concomitant Medications/Therapies ..........................................................................60 
9.3.10. 
Follow-Up Procedures: 12 Week Post Last Dose Telephone Call .............................61 
9.3.11. 
Early Termination Procedures ....................................................................................61 
9.4. 
Study Formulation Administration .............................................................................61 
9.5. 
Timing of Treatments and Procedures ........................................................................61 
9.6. 
Safety Assessments .....................................................................................................62 
9.7. 
Blood Sampling for Pharmacodynamic Analysis .......................................................63 
9.7.1. 
Sample Processing and Analysis for Pharmacodynamic Samples .............................63 
10. 
ADVERSE EVENTS..................................................................................................64 
10.1. 
Definitions ..................................................................................................................64 
10.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs .........65 
10.3. 
Timing, Frequency, and Method of Detecting AEs ....................................................65 
10.4. 
Recording of AEs .......................................................................................................66 
10.5. 
Evaluating AEs ...........................................................................................................66 


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10.5.1. 
Assessment of Intensity ..............................................................................................66 
10.5.2. 
AEs at the Injection Site .............................................................................................67 
10.5.3. 
AEs of COPD Exacerbation .......................................................................................67 
10.5.4. 
Assessment of Causality .............................................................................................67 
10.6. 
Follow-up of AEs .......................................................................................................68 
10.7. 
Prompt Reporting of SAEs .........................................................................................68 
10.7.1. 
Completion and Transmission of the SAE Reports ....................................................69 
10.7.2. 
Serious Adverse Event Reports to the EC ..................................................................69 
10.7.3. 
Pregnancy Reporting ..................................................................................................69 
10.8. 
Regulatory Requirements for Reporting of SAEs ......................................................70 
10.9. 
Post-study AEs............................................................................................................70 
10.10. 
SAEs Related to Study Participation ..........................................................................70 
11. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .............................71 
11.1. 
Study Populations .......................................................................................................71 
11.2. 
Sample Size Considerations .......................................................................................71 
11.3. 
Screening Data ............................................................................................................71 
11.4. 
Safety/Tolerability Data ..............................................................................................71 
11.5. 
Immunogenicity Data .................................................................................................72 
11.6. 
Pharmacodynamic Data ..............................................................................................72 
11.7. 
Analysis Methods .......................................................................................................73 
11.8. 
Data Recording and Quality Control ..........................................................................73 
12. 
STUDY APPROVAL AND CONDUCT ...................................................................74 
12.1. 
Regulatory Approval ..................................................................................................74 
12.2. 
Ethics Committee (EC) Approval ...............................................................................74 
12.3. 
Ethical Considerations ................................................................................................74 
12.4. 
Written Informed Consent ..........................................................................................74 
12.5. 
Emergency Contact with Principal Investigator .........................................................75 
12.6. 
Notification of General Practitioner ...........................................................................75 
12.7. 
Clinical Laboratory Certification and Reference Ranges ...........................................75 
12.8. 
Protocol Deviations ....................................................................................................75 
12.9. 
Termination of the Study ............................................................................................76 
13. 
STUDY ADMINISTRATION ...................................................................................77 


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13.1. 
Study Monitoring ........................................................................................................77 
13.2. 
Quality Assurance .......................................................................................................78 
13.3. 
Records Retention .......................................................................................................78 
14. 
INFORMATION DISCLOSURE AND INVENTIONS ............................................80 
14.1. 
Ownership ...................................................................................................................80 
14.2. 
Confidentiality ............................................................................................................80 
14.3. 
Publication ..................................................................................................................80 
15. 
REFERENCES ...........................................................................................................82 
APPENDIX 1. Elevated Alt Study Modification and Patient Discontinuation Rules ...................84 
APPENDIX 2.  Pulmonary Function Monitoring ..........................................................................86 
APPENDIX 3.  Fibrosis Staging Systems Guidance .....................................................................87 
 
LIST OF TABLES 
Table 1: 
Cohort 1 & 1b Schedule of Assessments ....................................................................15 
Table 2: 
Cohort 2 Schedule of Assessments .............................................................................18 
Table 3: 
Treatment Extension I Schedule of Assessments .......................................................21 
Table 4: 
Treatment Extension II Schedule of Assessments ......................................................23 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................44 
 


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2. 
STUDY INFORMATION AND SIGNATURES 
Investigator’s Statement: 
I have read and understood the information in this protocol and agree to conduct the trial 
according to the protocol (subject to any amendments) and in accordance with the 
principles of Good Clinical Practice. I have read and agree to comply with the 
Investigator obligations stated in this protocol. Any changes in procedure will only be 
made if necessary to protect the safety, rights or welfare of participants. 
I agree to conduct in person or to supervise the trial. 
I agree to ensure that all that assist me in the conduct of the study are aware of their 
obligations. 
 
 
 
 
Principal Investigator: 
 
 
 
 _____________________________  
 _____________________________ 
 
 Signature 
Date 
 
 
 
 
 
 
 
 _____________________________  
 
 
 Printed Name 
 
 
 
 
 


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3. 
LIST OF ABBREVIATIONS AND TERMS 
AAT 
Alpha-1 antitrypsin 
AATD 
Alpha-1 antitrypsin deficiency 
ADA 
Anti-drug antibodies 
ADS-001 
Drug substance (API, lyophilized powder) containing RNAi 
trigger (also referred to as fazirsiran, ARO-AAT, or TAK-999) 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
API 
Active Pharmaceutical Ingredient 
APRI 
Aspartate aminotransferase-to-platelet ratio index 
ARO 
Arrowhead Pharmaceuticals, Inc 
ARO-AAT 
Short name for ARO-AAT Injection 
ARO-AAT Injection 
Clinical drug product solution ready for SC injection (also referred 
to as Fazirsiran Injection or TAK-999 Injection) 
AST 
Aspartate transaminase 
ATS-ERS 
American Thoracic Society and European Respiratory Society 
BMI 
Body mass index 
BP 
Blood pressure 
cGCP 
Current Good Clinical Practice 
cGMP 
Current Good Manufacturing Practice 
COPD 
Chronic obstructive pulmonary disease 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically significant 
CTN  
Clinical Trial Notification 
CV 
Coefficient of variation 
CVA 
Cerebrovascular accident 


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DLCO 
Diffusing capacity for carbon monoxide 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of Study 
FAS 
Full Analysis Set 
Fazirsiran 
Drug substance (API, lyophilized powder) containing RNAi 
trigger (also referred to as ADS-001, ARO-AAT, or TAK-999) 
Fazirsiran Injection 
Clinical drug product solution ready for subcutaneous injection 
(also referred to as ARO-AAT Injection or TAK-999 Injection) 
FDA 
Food and Drug Administration 
FEV1 
1 second forced expiratory volume 
FIB-4 
Fibrosis-4 index 
FSH 
Follicle-stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
ICH 
International Council for Harmonisation  
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 


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IUD 
Intrauterine device 
LD 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
Mean cell hemoglobin 
MCHC 
Mean cell hemoglobin concentration 
MCV 
Mean cell volume 
mmHg 
Millimeters of mercury 
MRE 
Magnetic resonance elastography 
mRNA 
Messenger RNA 
NAFLD 
Nonalcoholic fatty liver disease 
NASH 
Nonalcoholic steatohepatitis 
NHP 
Non-human primate 
NOAEL 
No observed adverse effect level 
NSAID 
Nonsteroidal anti-inflammatory drug 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PiZZ 
Homozygous Z allele individuals 
PP 
Per Protocol 
PK 
Pharmacokinetic 
PT 
Preferred term 
PTT 
Partial thromboplastin time 
Q4W 
Once every four weeks 
Q12W 
Once every twelve weeks 
QT 
QT interval - a measure of the time between the start of the 
Q wave and the end of the T wave in the heart's electrical cycle 
RBC 
Red blood cell 
RNAi 
RNA interference 


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SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SD 
Standard deviation 
siRNA 
Short interfering RNA oligonucleotides  
SOA 
Schedule of Assessments 
SOC 
System Organ Class 
TIA 
Transient ischemic attack 
ULN 
Upper limit of normal 
VC 
Vital capacity 
Z-AAT 
Mutant AAT protein from Z allele  


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4. 
INTRODUCTION 
4.1. 
Background Information 
Alpha-1 antitrypsin deficiency is an autosomal co-dominant genetic disorder with a prevalence 
range of 1/1500-1/5000 that causes early pulmonary disease in adults and liver disease in 
children and adults (Nelson et al., 2012). Alpha-1-antitrypsin (AAT) is a 52 kDa circulating 
glycoprotein protease inhibitor of the serpin family. The primary function of AAT is to inhibit 
neutrophil elastase to prevent excessive elastase-induced tissue damage. Normally, AAT is 
synthesized primarily in hepatocytes and several grams daily are secreted directly into the serum. 
In lung parenchyma, AAT is critical for protection of alveolar interstitial elastin from 
degradation by neutrophil elastase. A lack of adequate levels of functional AAT leads to damage 
of lung elastin by neutrophil elastase and the development of early emphysema.  It generally 
takes decades for lung disease to manifest and usually requires additional environmental insult, 
usually cigarette smoking. Low plasma AAT levels that lead to pulmonary disease in individuals 
homozygous for the Z mutation (PiZZ) are not from a lack of synthesis (except in null/null 
patients) but from a disruption of its processing and secretion by hepatocytes. AAT is normally 
secreted in monomeric form, but the mutant AAT protein (Z-AAT) synthesized by PiZZ 
individuals contains a single point mutation that results in low secretion, accumulation and 
polymer formation in hepatocytes leading to liver disease. Lung disease is frequently treated with 
AAT replacement therapy, and fewer than 10,000 patients are on replacement or “augmentation” 
therapy in the U.S. (Stoller et al., 2012). However, augmentation therapy does nothing to treat 
liver disease, and no specific therapy is available for alpha-1 antitrypsin deficiency (AATD)-
associated liver disease.   
In clinical practice, over 90% of AAT deficiency is due to the PiZZ genotype (DeSerres et al., 
2012).  PiZZ adult patients may initially present with clinical signs of pulmonary disease such as 
dyspnea, cough, chronic bronchitis, or they may initially present with signs of liver disease such 
as elevated transaminases or bilirubin, hepatitis, or cirrhosis (American Thoracic 
Society/European Respiratory Society 2003). Pediatric patients typically present with clinical 
symptoms of liver disease, which may include asymptomatic chronic hepatitis, failure to thrive, 
poor feeding or hepatomegaly and splenomegaly. However, disease natural history in both 
pediatric and adult patients is variable. 
A 2018 publication by Clark et al., examined 94 PiZZ adults using liver biopsy and various other 
noninvasive measures of liver disease (e.g., transient elastography, Fibrosis-4 index [FIB-4]) 
(Clark et al., 2018). In this cohort, the prevalence of clinically significant liver disease (≥F2) was 
35.1%. The presence of accumulated Z-AAT globules, portal inflammation, and hepatocellular 
degeneration were associated with clinically significant fibrosis. Similarly, accumulation of 
Z-AAT globules, portal inflammation, and hepatocellular degeneration are seen on histologic 
evaluation of the PiZ mouse model liver.  


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4.2. 
Development and Mechanism of Action of Fazirsiran 
Since Z-AAT protein accumulation is the underlying cause of hepatocyte injury in AATD, 
preventing monomer accumulation and polymer formation is a logical step for treating AATD-
associated liver disease. This is supported by the lack of liver disease in AATD patients with 
null/null genotypes. These rare patients completely lack AAT synthesis. They present clinically 
with pulmonary disease, but since they have no hepatocyte production or accumulation of mutant 
AAT protein, they are devoid of liver disease.  
One mechanism of preventing Z-AAT accumulation is through RNA interference (RNAi)-
mediated gene silencing of Z-AAT protein production. RNA interference (RNAi)-based 
therapeutics have the potential to silence the expression of any disease gene. RNAi is a naturally 
occurring process by which short interfering RNA oligonucleotides (siRNAs) trigger a sequence-
specific down-modulation of gene expression. By delivering siRNAs targeting AAT sequences 
to the liver, it is possible to knock down expression of AAT messenger RNAs (mRNAs) in 
hepatocytes. This reduces the synthesis of Z-AAT proteins that are responsible for hepatic 
disease in AATD. Reductions in levels of Z-AAT protein production should allow for 
degradation or secretion of Z-AAT proteins already present, prevent further hepatocyte injury, 
reduce inflammation and fibrosis and allow for hepatic healing. Knocking down Z-AAT protein 
production with resulting reduction of both mutant protein globules and fibrosis in the PiZZ 
transgenic mouse has been well demonstrated by Teckman et al., 2013 (Teckman et al., 2013). 
Based on findings in mouse models of AATD-associated liver disease and effective treatment of 
other hepatic diseases such as viral hepatitis, it is also expected that with effective reduction in 
necro-inflammation, fibrosis and early cirrhosis should reverse, as well, with effective, chronic 
treatment.  
Arrowhead Pharmaceuticals, Inc. has developed a drug candidate, fazirsiran (TAK-999, also 
referred to as ARO-AAT) to treat AATD-associated liver disease through an RNAi-mediated 
mechanism. Fazirsiran is a novel hepatocyte targeted RNAi trigger molecule which is conjugated 
to N-acetyl-galactosamine to facilitate hepatocyte endocytosis. Fazirsiran is highly effective at 
knocking down the AAT mRNA gene transcript and reducing the production of hepatic Z-AAT 
protein.   
4.3. 
Fazirsiran Pre-Clinical Pharmacology and Studies 
Preclinical pharmacology of fazirsiran was evaluated in the PiZ transgenic mouse model of 
AATD liver disease and in cynomolgus monkeys. In the mouse model, treatment with fazirsiran 
resulted in dramatically reduced serum Z-hAAT protein levels, which correlated with reduced 
liver Z-hAAT mRNA levels. Multi-dose studies showed that mice treated with fazirsiran have 
less Z-hAAT monomer and a reduced burden of Z-hAAT polymer in the liver compared to 
saline-treated mice. As expected, these mice also showed reductions in hepatocyte necrosis, liver 
inflammation and down-regulation of fibrosis-related genes. Importantly, hepatocyte necrosis 
and liver inflammation are also seen on histologic evaluation of human PiZZ patient livers. 
Fazirsiran treatment in cynomolgus monkeys resulted in a maximum reduction in circulating 
AAT of approximately 93% with 80% or greater knockdown sustained for more than 8 weeks 


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after receiving two once every four weeks (Q4W) 3 mg/kg doses of fazirsiran. Further 
information on the pre-clinical pharmacology studies is provided in the Investigator’s Brochure. 
4.4. 
Fazirsiran Pre-Clinical Pharmacokinetic and Product Metabolism 
Studies 
Pharmacokinetic (PK) parameters for fazirsiran have been evaluated in both rats and monkeys. 
Results of these studies can be found in the Investigator’s Brochure. 
4.5. 
Fazirsiran Pre-Clinical Toxicology Studies 
Fazirsiran has been clinically well tolerated in rats and in non-human primate (NHP) toxicology 
studies. Details regarding Good Laboratory Practice (GLP) and non-GLP toxicology results are 
provided in the Investigator’s Brochure. 
4.6. 
Fazirsiran Clinical Pharmacology, Pharmacokinetic and Clinical 
Safety 
Fazirsiran has been evaluated in the AROAAT1001 study which investigated the safety and 
pharmacodynamic (PD) effects of single and multiple doses of fazirsiran in a healthy volunteer 
population. Full results of the completed AROAAT1001 study, interim results of the ongoing 
AROAAT2002, and preliminary (blinded safety data) from the ongoing AROAAT2001 study are 
available in the Investigator’s Brochure.  
4.7. 
Rationale for the Study  
This study is intended to explore differences in histological and PD responses with different 
durations of treatment (e.g., biopsy at approximately 6, 12, 18 and 24 months post-dose) versus 
pre-dose baseline. This will inform on duration of treatment required to show therapeutic effect. 
Intracellular mutant (Z-AAT) misfolded protein accumulation is the underlying cause of 
hepatocyte injury in AATD (Torres-Durán et al., 2018). Preventing hepatic accumulation of 
misfolded protein by silencing Z-AAT synthesis is a logical intervention for treating AATD-
associated liver disease. This is supported by the development of liver tumors and upregulating 
of fibrosis associated genes in the PiZ transgenic mouse model and by the lack of liver disease in 
AATD patients with null/null genotypes versus the presence of liver disease in PiZZ genotype 
patients (Feldman et al., 1975). Treatment of patients with fazirsiran is expected to reduce 
hepatic production of AAT, leading to reductions in intra-hepatic misfolded monomer, polymer 
and reduction in AAT serum levels. Data obtained from nonclinical pharmacology studies in the 
PiZ mouse model have demonstrated that multiple doses of fazirsiran administered every other 
week for 4 doses can prevent the accumulation of, and even reduce the burden of already present 
Z-hAAT protein in the livers of PiZ mice (Wooddell et al., 2020).  Based on this animal data, it 
is expected that multi-dose treatment with fazirsiran in AATD patients will prevent further 
accumulation of intra-hepatic mutant protein while allowing endogenous clearance mechanisms 
to remove Z-AAT protein already accumulated. This removal of the offending agent should 


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reduce/eliminate necro-inflammation, which should prevent further liver injury while allowing 
fibrosis due to earlier injury to remodel.  The ability of the liver to heal with removal of an 
inciting insult has been demonstrated with treatment of other causes of liver injury including 
hepatitis B virus (HBV), hepatitis C virus (HCV) and nonalcoholic fatty liver disease 
(NAFLD)/nonalcoholic steatohepatitis (NASH) (Ellis et al., 2012). 
The AROAAT2002 design and conduct is supported by existing nonclinical pharmacology and 
toxicology data as well as data from a Phase 1 clinical study AROAAT1001 in healthy 
volunteers which evaluated safety, PK, and PD effect of single and multiple escalating doses of 
fazirsiran. AATD patients with AATD associated liver disease will require multiple doses of 
fazirsiran to sustain hepatic silencing of AAT production. This study will assess effects after 
three doses of fazirsiran compared with five doses, with each dose after the second dose 
administered approximately every 12 weeks. Dose levels of 100 mg or 200 mg were planned in 
this study based on PD results seen at these dose levels in the AROAAT1001 study which 
supports PD effect and high potential for Z-AAT silencing at both dose levels. Single dose PD 
effect from the AROAAT1001 study indicates that AAT serum protein levels generally reach 
nadir, but not always full suppression to below lower limit of quantitation around Week 6 to 8 
and start to rebound by approximately Week 12 after a single dose. This observed time until 
rebound supports quarterly dosing. This study also demonstrated that a second dose at Day 29 (4 
weeks after initial dose) resulted in complete suppression of circulating AAT levels that was 
sustained. (See Investigator’s Brochure for details.) Based on these results, it was determined 
that 2 doses administered 28 days apart would quickly lead to maximal and sustained reduction 
in hepatic AAT production but thereafter dosing could be quarterly. Hence, this was viewed as 
the best approach to achieve the fullest level of hepatic reduction of the insulting agent while 
minimizing overall patient exposure by moving to quarterly dosing. 
Based on non-clinical studies in the PiZ mouse model and experience with liver recovery from 
other necro-inflammatory diseases such as viral hepatitis, it is highly likely that dose 
administration beyond a single dose will be required to reduce liver polymer sufficiently to 
reduce globule levels, necro-inflammation and hopefully allow repair of hepatic architecture. 
Based on other precedents as discussed above, improvement of fibrosis or other adverse liver 
histologic findings due to AATD liver disease may require long term therapy to show 
improvement. Two cohorts of differing treatment durations will assess the time until liver 
histological improvements may be observed. 
The current study uses liver biopsy to obtain tissue samples for the histological measurement of 
drug effect at the end of the study. Non-invasive measures (including FibroScan®) of PD effect 
are also included. However, liver biopsy remains the gold standard for histological evaluation in 
clinical studies. 
4.8. 
Risk Assessment for Participants 
• Liver Biopsy Risk: Performance of liver biopsies is commonly part of the standard 
of care in patients with liver disease related to AATD as well as other adult liver 
diseases. While it is a common procedure, like any procedure it is associated with 


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some risk. The risk of bleeding associated with biopsies requiring blood transfusion 
or hospitalization is 0.04% or less and the risk of less severe but clinically significant 
events (causing pain, tachycardia or lower blood pressure) is estimated at 0.2% 
(Rockey et al., 2009). Several larger studies show that complications and serious 
bleeding related to liver biopsy are overwhelmingly more likely in patients with 
serious clotting disorders, malignancy, and other serious health conditions that are 
described in the exclusion criteria for this study. Measures of hemostatic function 
(e.g., platelets, international normalized ratio [INR]) will be conducted prior to 
biopsy, and may be used to exclude any participant at increased risk for procedural 
complications. Thrombocytopenia and elevated INR are exclusionary for this study. 
Therefore, the risk of liver biopsy related complications in this study is acceptable 
and similar to other studies using liver histology as an endpoint. Monitoring and 
recovery of the patient following the procedure will be consistent with locally 
accepted standards of clinical practice. 
• Pulmonary Risk: AATD may manifest as pulmonary disease in adult patients. 
AATD pulmonary disease is often treated with AAT augmentation therapy in 
countries where this therapy has been approved and is available. Fazirsiran is 
intended to reduce hepatic production of AAT and will, by extension, reduce serum 
levels of AAT protein. In AATD patients, this protein is poorly functional in its 
capacity to inhibit neutrophil elastase relative to wild type protein. Pulmonary disease 
in AATD requires decades to develop, especially in the absence of smoking, and it is 
extremely unlikely that short-term reduction in serum AAT will worsen pulmonary 
disease, particularly in non-smokers. Sponsor anticipates an approximate 90% 
reduction of serum Z-AAT to represent near maximum reduction possible with a 
hepatocyte targeted RNAi mechanism based on previous experience. Extra-hepatic 
production, including locally in the lung, is not expected to be reduced by fazirsiran.  
Based on the lack of a statistically significant difference between active and placebo 
adverse changes in pulmonary function metrics seen in the AROAAT1001 study 
using siRNA to transiently reduce serum AAT levels, and the fact that pulmonary 
disease in PiZZ patients with very low and already dysfunctional serum AAT takes 
decades to develop (if it develops at all), we do not believe that transient lower AAT 
serum levels represents a significant pulmonary risk to AATD patients, many of 
whom may already have lung disease and who may be on AAT augmentation 
therapy. This is also the opinion of key pulmonology opinion leaders who manage 
AATD patients. Steps will be taken in this study to mitigate this theoretical risk.  
▪ Patients who smoke or with a significant smoking history will be excluded 
from this study, at least initially, and their non-smoking status will be 
confirmed by measuring urinary cotinine at Screening and throughout the 
study.  
▪ Patients expected to have severe and unavoidable exposure to inhaled 
environmental exposure during the study will be excluded.  


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▪ Above standard of care pulmonary monitoring is implemented during the 
study with vital capacity (VC), forced vital capacity (FVC), 1 second forced 
expiratory volume (FEV1), FEV1/FVC, FEV1/VC, and diffusing capacity for 
carbon monoxide (DLCO) measured pre-dose and at every dosing visit.  
▪ Patients without sufficient pulmonary reserve at baseline (e.g., post-
bronchodilation FEV1 <65 % of predicted) are excluded unless using AAT 
augmentation therapy. Patients with recent lower respiratory infections (such 
as pneumonia) are also excluded. 
▪ Standard of care emphysema treatment (e.g., corticosteroids, bronchodilators) 
is permitted.  
▪ Any patient developing pulmonary symptoms or worsening pulmonary 
function tests while on study will be referred to a pulmonologist for 
consideration of AAT augmentation therapy, which will be provided by the 
Sponsor if not otherwise available locally and if indicated in the opinion of the 
treating pulmonologist (See Pulmonary Study Modification Rules in 
Appendix 2).  
▪ Arrowhead will review all VC, FVC, FEV1, and DLCO test results on a 
weekly basis during our Safety Review Team meetings. Pulmonary function 
test results will be exported directly from the clinical trial database and any 
resulting decreases consistent with study modification rules (Appendix 2) 
from baseline will be identified. A query will be sent to the investigator to 
confirm a pulmonary consultation has been requested and further dosing will 
be suspended for this patient until the consultation has occurred. Arrowhead’s 
follow up with sites will occur in order to obtain the pulmonologist 
evaluation.  
• Hepatic Risk: Fazirsiran targets the hepatic synthesis of AAT. Arrowhead has not 
seen a pattern of adverse transaminase changes in the AROAAT1001 healthy 
volunteer single ascending doses/multiple ascending doses study. However, others 
developing an siRNA for AATD has seen evidence of mild to moderate elevations in 
transaminases using hepatocyte targeted siRNA conjugates. The cause of these 
alanine aminotransferase (ALT) changes has been reported as due to off target effects 
of the siRNA seed region on microRNAs in the hepatocyte. The siRNA sequence of 
the fazirsiran sense and antisense molecules have been screened for potential mRNA 
and microRNA homology and sequences with homology were excluded from 
consideration. Thus, no such off-target effects are anticipated. Multi-dose (3 weekly 
doses) GLP toxicity studies with fazirsiran in rats demonstrated minimal to slight 
hepatocellular necrosis at doses of 30, 60, 120, and 300 mg/kg with associated 
elevations in ALT and aspartate aminotransferase (AST) of <3X control animals. 
However, there were no such findings in NHPs which are thought to be more 
representative of human subjects. In addition, these findings were not found in the 


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chronic toxicology studies (6-month rat study and the 9-month monkey), which 
administered monthly doses suggesting the longer interval between administration of 
doses helped prevent this effect. The chronic toxicology study no observed adverse 
effect levels (NOAELs) are the highest doses tested; 120 mg/kg in rats and 180 mg/kg 
in NHPs. To mitigate this risk of adverse ALT changes, the proposed study protocol 
has built in stopping/study modification rules for ALT elevation applicable to patients 
who may have elevated ALT at baseline. Blood samples will be drawn frequently to 
evaluate liver injury and liver function. Additionally, the highest planned dose used in 
this study of 200 mg is approximately 1/42nd (assuming weight-based conversion and 
a 70-kg subject) of the rat NOAEL of 120 mg/kg and 1/63rd of the monkey NOAEL 
from chronic GLP toxicology studies. 
• Injection Site AE Risk: Fazirsiran and other subcutaneously administered modified 
siRNA drug candidates evaluated in clinical studies have been associated with mild to 
moderate injection site reactions (ISRs) (e.g., pain, induration, erythema). Adverse 
events at the injection site (e.g., erythema, pain, etc.) have been reported with 
administration of fazirsiran in clinical studies and are therefore considered an 
identified risk. All were deemed to be nonserious and resolved without sequelae. The 
majority of the ISRs were mild in severity. Other siRNA antisense oligonucleotides in 
clinical trials have bene associated with usually mild ISRs. This study includes 
directions for assessing injection site adverse event (AE) intensity based on pre-
defined criteria (see Section 10.5.2).  Additionally, steps will be taken to minimize 
ISRs such as rotating injection sites and allowing the fazirsiran solution to come to 
room temperature prior to injecting. 
4.9. 
Justification for Dose Levels and Dose Intervals 
The proposed doses of 100 mg for up to 3 doses and 200 mg for up to 5 total doses is expected to 
produce substantial PD effect. In the AROAAT1001 healthy volunteer study, doses of 35, 100, 
and 200 mg yielded substantial serum AAT reductions, with both 100 mg and 200 mg reaching 
approximately 90% mean serum AAT reduction after multiple doses.  Both the 100 mg and 
200 mg dose are below the top dose of 300 mg, which was studied as both single and multiple 
(three) doses in AROAAT1001. In the Phase 1 study, dose levels up to the top dose of 300 mg 
were well tolerated with no serious or severe AEs reported in the study and no pattern of adverse 
laboratory changes associated with fazirsiran.  
The rationale for the proposed dosing interval is based on the goal of targeting AATD patients 
exhibiting liver fibrosis with the aim of halting the liver insult and damage produced by 
polymers as early and effectively as possible. Providing a dose on Day 1 followed by a dose on 
Day 29 is likely to more rapidly drive hepatic AAT levels to maximally reduced levels (similar 
to a loading dose strategy) followed by a maintenance dose 12 weeks after the 2nd dose, and 
dosing approximately quarterly thereafter. This strategy of maximizing ablation of liver AAT 
early should yield the most benefit to participants in terms of liver Z-AAT protein reduction over 
the course of the study, while then moving to quarterly dosing should maximize safety by 
limiting patient exposure to drug. The administration of quarterly dosing thereafter is based on 


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AROAAT1001 single dose data showing duration of PD activity with rebound in serum AAT 
levels beginning approximately 12 weeks after dose administration. Approximate quarterly 
dosing should minimize additional unnecessary dosing and minimize safety risk.  
Using a weight-based conversion, 200 mg, the highest dose level planned for this study provides 
a safety margin of approximately 63-fold and 42-fold (assuming a 70 kg individual) from the 
respective NOAELs of 180 mg/kg in a 9-month GLP monkey toxicology study and 120 mg/kg in 
a GLP 6-month rat toxicology study. 


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5. 
OBJECTIVE AND STUDY ENDPOINTS 
5.1. 
Study Objective 
To evaluate safety and changes in serum and liver Z-AAT levels, changes in liver disease related 
biomarkers and changes in liver histology in response to fazirsiran in patients with alpha-1 
antitrypsin deficiency associated liver disease (AATD). 
5.2. 
Primary Endpoint 
• To evaluate change from baseline over time in total, soluble, and insoluble Z-AAT 
concentrations in the liver of patients with AAT-associated liver disease. 
5.3. 
Secondary Endpoints  
• To determine the effect of multiple doses of fazirsiran on circulating levels of Z-AAT 
alpha-1 antitrypsin over time versus baseline.  
• To evaluate the effect of fazirsiran on changes in ALT over time.  
• To evaluate the effect of fazirsiran on changes in GGT over time.  
• To evaluate the effect of fazirsiran on changes in FIB-4 and APRI over time.  
• To evaluate the effect of fazirsiran on changes in PRO-C3 over time.  
• To evaluate the effect of fazirsiran on changes in hepatic stiffness based on 
FibroScan® over time versus baseline (when available). 
• To evaluate effect of fazirsiran on histological metrics of liver disease in patients with 
AAT-associated liver disease over time. 
• To evaluate change from baseline in Metavir fibrosis score over time in fazirsiran 
treated patients. 
• To determine the incidence and severity of treatment-emergent adverse events as a 
measure of the safety and tolerability of fazirsiran.  
• To determine the incidence and titers of anti-drug antibodies (ADAs) to fazirsiran. 
5.4. 
Exploratory Endpoints 
• To evaluate the effect of fazirsiran on changes in hepatic stiffness based on magnetic 
resonance elastography (MRE) over time versus baseline (optional). 


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• To evaluate changes in hepatic SERPINA1 mRNA expression over time versus 
baseline in response to multiple doses of fazirsiran (if sufficient sample available). 
• To evaluate changes in liver disease related gene expression over time versus baseline 
(if scientifically feasible and sufficient sample available). 
• To evaluate change in liver PAS+D stained globule size and number over time versus 
baseline 
• To evaluate the effect of fazirsiran on changes in liver collagen using biomarkers 
(e.g., PRO-C6), special stains and imaging [Masson’s Trichrome, Sirius Red, Iron] (if 
scientifically feasible and sufficient sample available) over time versus baseline. 
• To determine the effect of multiple doses of fazirsiran on circulating levels of total 
alpha-1 antitrypsin at multiple post-dose time points versus baseline (patients on and 
not on AAT augmentation therapy will be evaluated separately). 
 


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6. 
STUDY PLAN 
6.1. 
Study Design 
A multi-center, multi-dose, open-label, Phase 2 study will be conducted to evaluate the safety 
and efficacy of the investigational product, fazirsiran, administered subcutaneously to patients 
with Alpha-1 Antitrypsin Deficiency. Participants who have signed an Institutional Review 
Board (IRB)/Ethics Committee (EC) approved informed consent and have met all the protocol 
eligibility criteria during Screening, will be enrolled in one of three cohorts.  All patients will 
receive a minimum of three 100 mg or 200 mg doses of fazirsiran, depending on the cohort. At 
the end of the cohort specified treatment period, subjects will be offered the opportunity to 
continue treatment in the open-label treatment extension periods.  Dosing with fazirsiran may 
continue a minimum of 12 weeks from the previous dose.  Subjects who proceed into Treatment 
Extension I and/or II will continue to receive the dose to which they were assigned at the start of 
the study. Based on cumulative safety, efficacy, and PD data from the fazirsiran clinical program 
(clinical studies AROAAT1001, AROAAT2001, and AROAAT2002), a fazirsiran dose 
(200 mg) was selected by the Sponsor. Following the respective country regulatory and ethics 
committees’ approvals (including local approvals as necessary) of AROAAT2002 protocol 
amendment v7.0, all ongoing subjects will be consented and informed of the selected dose and 
subjects in Cohort 1b (100 mg) will begin receiving the selected dose at their next scheduled 
dosing timepoint. 
All patients will undergo liver biopsies per Schedule of Assessments (SOA) or at Early 
Termination. 
Cohort 1, 1b, or 2 participants who drop out for reasons other than an AE considered at least 
possibly related to drug may be replaced.  
Figure 1: 
Study Design 
 
6.2. 
Rationale for Study Design  
The study is intended to demonstrate that fazirsiran can safely and effectively improve liver 
histologic parameters as well as other biomarkers of liver disease by reducing intra-hepatic 
Z-AAT protein levels through an RNAi mechanism in patients with AATD. Cohort 1 and 1b will 


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assess histologic changes after 3 doses of fazirsiran and Cohort 2, after 5 doses. Tissue samples 
from liver biopsy will be required to achieve this. Other markers of liver injury such as Metavir 
(or equivalent fibrosis staging system, see Appendix 3) fibrosis score will also be measured on 
biopsy. Biopsy will be conducted pre-dose and post-last dose. Participants who finish Cohort 1, 
1b, or 2 may elect to enroll in the treatment extension periods.  This treatment extension would 
continue open-label treatment every 12 weeks for twelve additional doses with an optional liver 
biopsy, following the fourth dose, at Week 44. 
The study will enroll PiZZ patients without F4 (or equivalent by other grading scales) cirrhosis 
but with evidence of F1-F3 (by Metavir or equivalent) liver disease. The PiZZ genotype 
represents the majority of AATD patients at risk for the development of liver disease and all 
PiZZ patients should have measurable intra-hepatic Z-AAT protein in biopsy samples.  
6.3. 
Stopping Rules 
A decision to stop the trial early or discontinue drug in an individual subject or group of patients 
may be indicated based on any of the following:  
1. In the case of two or more similar (defined as serious adverse events (SAEs) within same 
System organ Class [SOC]) Serious Adverse Events both considered at least possibly 
related to fazirsiran, the trial will be put on halt even if the subject(s) is/are not 
discontinued from the study drug/study.  The Principal Investigator and Sponsor will 
discuss within 3 days of the Sponsor being notified of the 2nd event and within the 
timeframe of required regulatory agency notification. Available aggregated data will be 
reviewed to determine if the study remains safe to proceed, should be discontinued or 
should continue but with amendments. Restart of the trial will require approval of a 
substantial amendment from the competent authorities.  
2. Evaluation and fazirsiran discontinuation rules for elevated ALTs are provided in 
Appendix 1. 
3. Evaluation and fazirsiran study modification/discontinuation rules for declines in 
pulmonary function are provided in Appendix 2. 
4. Subject who becomes pregnant while in the study. 
Sponsor or Investigator can discontinue any subject at any time. If such events (as described in 
#1, #2, or #3 above) occur and the subject is not discontinued from the study, the reason for not 
discontinuing the subject will be documented. Including, but not limited to the events listed 
above, the study may be paused to additional dosing to provide time to evaluate safety data and 
recommend the action to be taken, which may include, but is not limited to, one of the following: 
• Discontinuation of a subject or group of patients from the study 
• The study is stopped immediately with no further dosing 


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• The study will continue, but using a lower dose 
• The study will continue as planned  
6.4. 
Duration of the Study 
For Cohort 1 and 1b, the duration of the study is approximately 36 weeks, from beginning of the 
Screening period to the End-of-Study (EOS) visit. For Cohort 2, the duration of the study is 
approximately 60 weeks, from beginning of the Screening period to the EOS visit.  
All patients will be invited to continue dosing with fazirsiran beyond the planned EOS visit as 
part of the treatment extension periods.  The total duration of the treatment extension is 
approximately 144 weeks (36 months, i.e., 3 years). The duration of the study for Cohort 1, 1b 
and Cohort 2 patients entering the treatment extension is 180 and 204 weeks respectively. In that 
case, they will receive a total of twelve additional doses of fazirsiran at 12-week intervals.  There 
will be a follow-up telephone call to assess for pregnancy occurrence 12 weeks post-last dose. 


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7. 
SUBJECT SELECTION 
7.1. 
Number of Patients & Patient Demographics 
This study will be conducted in PiZZ patients with Alpha-1 Antitrypsin Deficiency. Both males 
and females are eligible, ages 18-75. In total, the study will consist of up to approximately 
16 participants. Patients with a history of PiZZ AATD in Cohort 1 will receive three 200 mg 
doses of fazirsiran, in Cohort 1b will receive three 100 mg doses of fazirsiran and Cohort 2 will 
receive five 200 mg doses of fazirsiran.  At the conclusion of Cohort 1, 1b, or 2, patients who 
elect to participate in the treatment extension periods will receive twelve additional doses of 
fazirsiran every 12-weeks. 
All eligible patients will require a pre-dose biopsy completed as part of the study within the 
screening window. Participants will consist of male and female adult PiZZ (based on genotype 
completed at baseline or from a source verifiable document) alpha-1 antitrypsin patients.  
Patients previously, currently or never receiving AAT augmentation therapy are eligible for 
enrollment. 
7.2. 
Inclusion Criteria 
To be eligible for enrollment, participants must meet all the following inclusion criteria: 
1. Male or non-nursing female patients 18-75 years of age, inclusive, at the time of 
Screening with previous diagnosis of PiZZ genotype Alpha-1 Antitrypsin Deficiency. 
PiZZ diagnosis from source verifiable medical records is permitted. Otherwise, patients 
must undergo PiZZ confirmatory testing at Screening. PiMZ or PiSZ genotypes are not 
permitted. 
2. Able and willing to provide written informed consent prior to the performance of any 
study specific procedures.  
3. A 12-lead electrocardiogram (ECG) at Screening that, in the opinion of the Investigator, 
has no abnormalities that compromise participant’s safety in this study. 
4. Non-smoker (defined as does not smoke cigarettes daily for at least 12 months) with 
current non-smoking status confirmed by urine cotinine at screening and throughout the 
study. Patients may be on nicotine replacement (patch or gum). E-cigarettes (vapor) are 
not permitted. A positive urine cotinine result due to nicotine replacement is acceptable 
for enrollment at the discretion of the Investigator.  
5. Participants using highly effective contraception during the study and for 12 weeks 
following the last dose of fazirsiran.  Males must not donate sperm for at least 12 weeks 
post last dose of study treatment. Females of childbearing potential must have a negative 
urine pregnancy test at Screening and on Day 1 pre-dose. Females not of childbearing 
potential must be post-menopausal (defined as cessation of regular menstrual periods for 


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at least 12 months), confirmed by follicle-stimulating hormone (FSH) consistent with 
post-menopausal state based on lab reference ranges.  
• Using twice the normal protection of birth control by using a condom AND one 
other form of either birth control pills (The Pill), depot or injectable birth control, 
IUD (Intrauterine Device), birth control patch (e.g., Ortho Evra), NuvaRing®, OR 
Surgical sterilization as a single form of birth control: i.e., tubal ligation, 
hysterectomy, bilateral oophorectomy, vasectomy or equivalently effective 
surgical form of birth control. 
• True subject abstinence for the duration of the study and 12 weeks after the dose 
of fazirsiran is acceptable only when in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea methods are not considered “true” abstinence and are not acceptable 
methods of contraception.  
6. Participants who are willing and able to comply with all study assessments and adhere to 
the protocol schedule 
7. Must have suitable venous access for blood sampling 
8. No abnormal finding of clinical relevance at the Screening evaluation that in the opinion 
of the Investigator could adversely impact subject safety during the study or adversely 
impact study results.  
9. Liver biopsy indicating Metavir F1- F3 (or equivalent on other grading scales, see 
Appendix 3) liver fibrosis based on local pathologist read. All patients will require a liver 
biopsy during the screen period except for prior screened patients who now meet the 
fibrosis criteria as long as there is sufficient material for a baseline assessment as per 
specifications in the laboratory manual.   
All laboratory tests used as inclusion criteria may be repeated once and the repeat value may be 
used for inclusion purposes.  Central labs will be utilized for the study, however local labs may 
be utilized as necessary due to emergent situations. 
7.3. 
Exclusion Criteria  
A potential participant will be excluded from the study if any of the following criteria apply: 
1. INR ≥1.5 at Screening. If based on opinion of Investigator and/or prescribing physician 
patient is appropriate for anticoagulant holiday, patient may stop taking anticoagulant for 
an appropriate washout period or reversal with vitamin K and if indicated a repeat INR 
within <1.5 would be acceptable. If INR is not indicated (direct thrombin inhibitors or Xa 
inhibitors) then appropriate washout period alone may be acceptable. (Note: Anti-platelet 


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agents such as aspirin, clopidogrel or nonsteroidal anti-inflammatory drugs [NSAIDs] are 
acceptable but must be held 7 days before and 7 days after liver biopsy) 
2. ALT and AST levels >250 U/L at Screening (one retest permitted) 
3. Estimated glomerular filtration rate (eGFR) <60 ml/min at Screening (one retest 
permitted) 
4. Post-bronchodilation (if available) FEV1 <65% of predicted at Screening in any subject 
not receiving AAT augmentation therapy.   
5. Post-bronchodilation (if available) FEV1 <45% of predicted at Screening in any subject 
currently receiving AAT augmentation therapy on a regular basis and planning to 
continue AAT augmentation therapy for the duration of the study. 
6. Patients expected to have severe and unavoidable high-level exposure to inhaled 
pulmonary toxins during the study.  
7. Patients with recent (last 3 months) diagnosis of pneumonia are also excluded. 
8. Human immunodeficiency virus infection, as shown by the presence of anti-HIV 
antibody (sero-positive) 
9. Seropositive for HBV (HBsAg positive at Screening) or HCV (detectable HCV RNA at 
Screening). Cured HCV (positive antibody test without detectable HCV RNA is 
acceptable). 
10. Uncontrolled hypertension (systolic blood pressure [BP] >170 and diastolic BP 
>100 mmHg at Screening). Patients may rescreen once BP is successfully controlled. 
11. A history of torsades de pointes, ventricular rhythm disturbances (e.g., ventricular 
tachycardia or fibrillation), heart block (excluding first-degree block, being PR interval 
prolongation only), congenital long QT syndrome or new ST segment elevation or 
depression or new Q wave on ECG. Participants with a history of atrial arrhythmias 
should be discussed with the Medical Monitor 
12. Symptomatic heart failure (per New York Heart Association guidelines), unstable angina, 
myocardial infarction, severe cardiovascular disease (ejection fraction <20%, transient 
ischemic attack (TIA) or cerebrovascular accident (CVA) within 6 months prior to 
Screening 
13. History of malignancy within the last 1 year except for adequately treated basal cell 
carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical 
cancer. Participants with other curatively treated malignancies who have no evidence of 
metastatic disease and >1-year disease-free interval may be entered following approval 
by the Medical Monitor 


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14. History of major surgery within the prior 1 month prior to Screening 
15. Regular use of alcohol within one month prior to the Screening visit (i.e., more than 
14 units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 
40% alcohol])  
16. Use of illicit drugs (such as cocaine, phencyclidine [PCP]) within 1 year prior to the 
Screening visit or positive urine drug screen at Screening (a urine drug screen positive for 
benzodiazepines, opioids or marijuana is acceptable for enrollment at the discretion of the 
Investigator if the positive test is due to a substance used for medical reasons).  
17. Use of an investigational agent or device within 30 days prior to dosing or current 
participation in an investigational study involving a therapeutic intervention. Patients 
receiving AAT augmentation therapy as part of a post-marketing study or other access 
program for approved therapies are acceptable.   
18. Blood donation (≥500 mL) within 7 days prior to study treatment administration.  
19. 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. Patients with NASH, NAFLD, metabolic syndrome, well controlled diabetes 
mellitus (even if on insulin) or hemochromatosis are acceptable if disease is stable and 
does not pose a significant threat to subject participation. Patients enrolled with NASH 
should have no plans to undergo bariatric surgery or initiated pharmaceutical therapy for 
NASH (such as Vitamin E or pioglitazone) during the course of the study. If already on 
such treatment, regimen must be stable for at least 12 weeks.  
20. A history of thromboembolic disease (including deep vein thrombosis or pulmonary 
embolism), myocardial infarction, stroke within six (6) months of screening. 
21. Participants who are unable to return for all scheduled study visits. 
22. Females of childbearing potential who are breastfeeding. 
23. Any other condition, that in the opinion of the Investigator would render the participant 
unsuitable for enrollment or could interfere with participating in and completing the 
study. 
24. Previous diagnosis of decompensated liver cirrhosis or complications of cirrhosis (e.g., 
varices, ascites, hepatic encephalopathy) based on source verifiable medical record. 
25. Diagnosis of F4 (Metavir) or similar grading scale equivalent indicating definitive 
cirrhosis on pre-dose liver biopsy completed as part of the AROAAT2002 study based on 
local pathologist read or based on historical liver biopsy (last 6 months from consent) 
with a source verifiable pathologist read of definitive liver cirrhosis. 


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Note: Sponsor Medical Monitor has the option to exclude the enrollment of a participant if, 
based upon the participant’s medical history or Screening results, it is felt that a participant’s 
safety may be at risk.  
All laboratory tests used as exclusion criteria may be repeated once and the repeat value may be 
used for exclusion purposes.  Central labs will be utilized for the study, however local labs may 
be utilized as necessary due to emergent situations. 
7.4. 
Participant Withdrawal Criteria 
Participants will be advised that they are free to withdraw from the study at any time for any 
reason or, if necessary, the Investigator, or medically trained designee, may withdraw a 
participant from the study, per the following criteria, to protect the participant's health: 
• the need to take medication which may interfere with study measurements; 
• intolerable/unacceptable adverse experiences; 
• major violation of or deviation from study protocol procedures; 
• non-compliance of participant with protocol; 
• participant unwilling to proceed and/or consent is withdrawn; or 
• withdrawal from the study if, in the Investigator’s judgement, it is in the participant’s 
best interest. 
• pregnancy 
The reasons for withdrawal will be recorded on the case report form (CRF) and included in the 
final clinical study report, along with any adverse events and any necessary medical treatment.  
If a participant is withdrawn from the study due to significant AE or SAE, the Investigator, or 
medically trained designee, will evaluate the urgency of the event. If the situation warrants, the 
Investigator, or medically trained designee, will take appropriate diagnostic and therapeutic 
measures. If the situation is not an immediate emergency, the Investigator, or medically trained 
designee, at the clinical study facility will attempt to contact the Arrowhead Pharmaceuticals, 
Inc. Medical Monitor or medically qualified designee for consultation. No medical help, 
diagnosis, or advice will be withheld from the participant due to an inability to contact the 
Medical Monitor. The participant will be encouraged to remain available for follow-up medical 
monitoring. The Sponsor will be notified as soon as possible of any participant withdrawals. The 
Investigator should report all pregnancies and pregnancies in partners of subjects within 24 hours 
of awareness of the pregnancy using the Pregnancy Notification Form.  This completed form 
should be emailed to Labcorp, the pharmacovigilance vendor for this study at: 
Arrowhead.Safety@Labcorp.com or fax to: 1-626-628-1882 


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Participants who are withdrawn or discontinue prior to EOS visit for reasons other than an AE 
considered at least possibly related to drug, may be replaced. 
7.5. 
Restrictions and Concomitant Medications 
1. Study Visit Duration: For each participant, clinic visits will last approximately 3 hours 
total, 2 hours pre-dose and 1hour post-dose on dosing days. Participants will return to the 
clinical facility for out-patient visits as per SOA. Participants will be observed post-dose 
for approximately 2 hours or as clinically indicated as per the Investigator. Fasting: On 
the day of dosing, participants will fast from food for at least 2 hours prior to study 
treatment administration and 2 hours post dose. Duration of site stay for days when liver 
biopsy is completed is site dependent.  
2. Recreational Drugs, Smoking & Alcohol:  Participants will be instructed to abstain from 
consuming alcohol for at least 48 hours prior to their clinic visit on dosing days, and 
during the clinic visit. In addition, participants will be instructed to refrain from regular 
use of alcohol (i.e., more than 14 units of alcohol per week [1 Unit = 150 mL of wine, 
360 mL of beer, or 45 mL of 40% alcohol]) for the study duration. Participants must 
abstain from use of recreational drugs throughout the study. Participants must be non-
smokers entering the study (as per Inclusion & Exclusion criteria) and abstain from 
smoking tobacco (including e-cigarettes) for the duration of the study. Nicotine patches 
or gum is acceptable. 
3. Concomitant Medications:  Continuation of medications, vitamins and supplements 
deemed medically indicated is acceptable. Otherwise, allowance of concomitant 
medications will be at the discretion of the study Investigator in consultation with 
Sponsor Medical Monitor (when necessary). Augmentation therapy is permitted. 
Procedural sedation with benzodiazepines or equivalent during liver biopsy as needed is 
permitted. Standard of care for chronic obstructive pulmonary disease (COPD) including 
bronchodilators, corticosteroids and other modalities are permitted. 


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8. 
INVESTIGATIONAL PRODUCT 
8.1. 
Description, Identification and Dosage 
Arrowhead Pharmaceuticals, Inc. is responsible for the supply of fazirsiran together with detailed 
instructions (in a Pharmacy Manual) describing preparation of fazirsiran (TAK-999, also referred 
to as ARO-AAT). 
Accordingly, fazirsiran will be supplied as single sterile 2-mL vials containing fazirsiran, with 
the correct dose of fazirsiran prepared by the Pharmacy prior to dosing participants. 
Each dose of fazirsiran will be administered by subcutaneous injection. The injection volume is 
0.43 mL for 100 mg and 0.87 mL for 200 mg and should be administered as a single injection. 
Injections will be made into the subcutaneous tissue at an appropriate site (e.g., abdomen, thigh, 
upper arm, etc.) using a 25-30 Gauge, ½ inch needle. The abdomen is the preferred site. The 
injection site is to be varied (no multiple injections into the same exact site. Alternating various 
locations on the abdomen is acceptable) and injection site location is to be recorded in the 
electronic Case Report Form (eCRF). Prior to dose administration, the fazirsiran vial must be 
allowed sufficient time to come to room temperature. Do not inject into areas of active skin 
disease or injury such as sunburns, skin rashes, inflammation or skin infections. 
8.2. 
Supply, Preparation, Storage and Labelling of Fazirsiran 
Fazirsiran Injection is a ready to use injection preparation for subcutaneous administration and is 
supplied as a sterile Type-1 glass 2-mL vial (1.1 mL nominal volume, 1.0 mL withdrawable 
volume). The clinical drug product is labeled:  ARO-AAT Injection. 
Strength:   
230 mg/mL 
Appearance:   Clear, colorless to yellow solution 
Inactive ingredients:  0.5 mM sodium phosphate monobasic, 0.5 mM sodium phosphate dibasic 
in water for injection 
Shipment and Storage:  
Refrigerated, 2 to 8 °C 
The fazirsiran dose will be prepared, per the Pharmacy Manual instructions, by a Pharmacist or 
qualified staff at the clinical sites. Aseptic technique will be used throughout dose preparation 
ensuring sterility of the solution. Because the fazirsiran vial must come to room temperature 
before administration, the time the vial is removed from the refrigerator and the time of 
administration must be documented to demonstrate administration within drug stability 
boundaries.  
Fazirsiran has been shown to be stable and compatible with the clinical administration 
components.  Please refer to the Pharmacy Manual for more detailed instructions. 


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The investigational product vials will be labeled per current Good Manufacturing Practice 
(cGMP)/Good Clinical Practice (cGCP).  
Fazirsiran will be stored at clinical sites securely under the appropriate conditions. 
8.3. 
Study Drug Handling  
The Sponsor will provide the Investigator with a sufficient quantity of clinical drug supplies. The 
Investigator must ensure that deliveries of investigational product from the Sponsor are correctly 
received by a responsible person, that all receipts of drug shipments are recorded on the 
appropriate Drug Accountability forms prepared by the pharmacy at the clinical site and that the 
products are stored in a secure area under recommended storage conditions.  It is also the 
responsibility of the Investigator to ensure that the integrity of packaged study product is not 
jeopardized prior to dispensing.   
Only participants enrolled in the study may receive study drug, in accordance with all applicable 
regulatory requirements. Only authorized site staff may supply or administer study drug. The 
study drug must be stored in a secure area with access limited to the Investigator and authorized 
staff and under the physical conditions that are consistent with the study drug-specific 
requirements.  
An authorized and trained staff member at each clinical trial site will dispense the study drug per 
pre-defined drug dispensing requirements. The dispensing and administration will be verified by 
a second member of site staff.  
Fazirsiran will be supplied by Arrowhead Pharmaceuticals, Inc. and labeled with the drug name, 
batch number, expiration date (as applicable) and storage conditions. Individual doses will be 
dispensed by clinical trial site staff members on the morning of dosing and recorded in the drug 
accountability records. A Pharmacy Manual will be prepared to define the procedures for 
dispensing. 
Standard Operating Procedures will be followed for the receipt, handling and accountability of 
the study formulations. 
8.4. 
Accountability of Study Supplies 
All material supplied is for use only in this clinical study and should not be used for any other 
purpose. The Investigator is responsible for the investigational product accountability, 
reconciliation and record maintenance at the investigational site. In accordance with all 
applicable regulatory requirements, the Investigator or designated site staff must maintain 
investigational product accountability records throughout the course of the study. This person 
will document the amount of investigational product received from Arrowhead Pharmaceuticals, 
Inc. and the amount administered to participants.  A Clinical Research Associate (CRA) will 
perform initial and ongoing study drug accountability. Used vials of fazirsiran will be retained 
sequestered per participant (where allowable by local policy) and made available to the CRA 
during study drug reconciliation.  


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A Drug Dispensing Log must be kept current and will contain the following information: 
• the identification of the participant to whom the drug was dispensed; and 
• the date(s) and quantity of the drug dispensed to the participant. 
The date and time of dose preparation and release will be maintained to support administration of 
study drug. The Pharmacy will dispense the study medication and the study center will 
administer the study medication only to participants included in this study following the 
procedures set out in the study protocol and Pharmacy Manual. Each participant will be given 
only the study medication carrying his/her study number.  Study drug administration will be 
documented on the CRFs and/or other study drug record. The inventory must be available for 
inspection by the monitor during the study. Drug supplies, excluding partially used or empty 
containers, will either be collected at the end of the study by the study monitor or returned by the 
Investigator or designee to Arrowhead Pharmaceuticals, Inc. When requested in writing by the 
Sponsor, following drug accountability and reconciliation, unused drug supplies may be 
destroyed by the Investigator or designee provided such disposition does not expose humans to 
risks from the drug and is permitted per the site’s Standard Operating Procedures. Records shall 
be maintained by the Investigator of any such alternate disposition of the test drug. These records 
must show the identification and quantity of each unit disposed of, the method of destruction 
(considering the requirements of local law), and the person who disposed of the test substance. 
Such records must be submitted to the Sponsor. 
8.5. 
Retention of Investigational Product Vials 
For this study, used and partially used drug vials will be retained for an adequate period to allow 
accountability by the CRA. No additional study drug samples will be retained. 
8.6. 
Allocation to Treatment 
All potential participants who sign an informed consent at Screening will receive a unique 6-digit 
number (i.e., a Screening Number).  The first 3 digits will represent the assigned site number and 
will be the same for each participant that screens at an individual site.  The next 3 digits will be 
assigned sequentially (starting with 001).  For patients who are deemed eligible, this 6-digit 
screening number will become the subject’s permanent study ID number. 
Participants who drop out for reasons other than an AE considered at least possibly related to 
drug may be replaced. 


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9. 
STUDY METHODS AND SCHEDULES  
9.1. 
Overview of Procedures  
A multi-center, multi-dose, open-label study will be conducted to evaluate the safety, tolerability 
and effect on liver histology of the investigational product, fazirsiran, administered 
subcutaneously to patients with Alpha-1 Antitrypsin Deficiency. Participants who have signed an 
IRB/EC approved informed consent and have met all the protocol eligibility criteria during 
Screening, will receive multiple subcutaneous doses of fazirsiran.  
Participants will undergo the following evaluations at regular intervals during the study (refer to 
the SOA): medical history, physical examinations, vital sign measurements (blood pressure, 
temperature, heart rate, respiratory rate), weight (at baseline), adverse events monitoring, ECGs, 
urine pregnancy test/FSH (females), concurrent medication, pulmonary function testing 
(spirometry including VC, FVC, FEV1, FEV1/VC, FEV1/FVC, and DLCO) and sample 
collection for hematology, coagulation, biochemistry, cardiac troponin, urinalysis, urine cotinine, 
anti-drug antibodies, drug screens, serum alpha-1 antitrypsin levels (where applicable), serum 
fibrosis biomarkers, liver biopsy, MRE (where feasible and available) and FibroScan® (where 
available).  
Study visits will occur during the Screening window (Day -56 to -1), and as per the SOA. A 
telephone follow-up will occur 12 weeks after the last dose to assess for pregnancy occurrence.  
Clinically significant changes including adverse events will be followed until resolution is 
achieved, or until medically stable or the event is otherwise explained, or until the participant is 
lost to follow-up. 
Baseline values will be those assessments obtained pre-dose and in the closest proximity to the 
first dose.  
Participants will fast from food for at least 2 hours pre-dose and 2 hours post-dose.  Refer to the 
SOA for additional information.  
The Investigator (or medically qualified designee) will be required to remain within the clinical 
study facility for 2 hours after dosing on Day 1 and will remain on call for the duration of the 
study.   
9.2. 
Selection and Screening  
Prior to commencement of any screening procedures, the Investigator, or designee, will inform 
the participant about the nature and purpose of the study, including the risks and benefits 
involved, possible AEs, the fact that their participation is voluntary and provide a copy of the 
IRB/EC-approved Informed Consent Form for review. Each participant will acknowledge receipt 
of this information by giving written informed consent for their involvement in the study in the 
presence of the Investigator, or designee, who will also sign and date the Informed Consent 
Form. Time of consent will be recorded on the Informed Consent Form or in the source 
documents for the subject. The original signed consent form will be retained by the Investigator 


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and a copy of the original will be given to the participant. Informed consent will be performed 
per the Principles of the International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) procedures. 
Having given Informed Consent, potential participants will undergo procedures outlined in the 
SOA, to be performed within 56 days of the scheduled dosing date, to determine that they meet 
the inclusion/exclusion criteria specified in Section 7.2 and Section 7.3.  
9.3. 
On-Study Procedures/Assessments 
9.3.1. 
Study Procedures: Clinical Facility Confinement 
Eligible participants will attend the Clinical Facility on Day 1.  Note that study dose 
administration is on Day 1, which must occur within 56 days of Screening.  Participants will be 
confined to the clinical facility for approximately 2 hours pre-dose and 1hour post-dose.   
On arrival at the clinical facility on Day 1, the Investigator, or designee, will meet with the 
patient to reiterate all study procedures and encourage the patient to ask any questions. All 
participants shall undergo a check-in procedure during which questions will be asked regarding 
protocol compliance and safety monitoring.  
Documentation of the participant’s fulfillment of the entry criteria, for all participants considered 
for the study and subsequently included or excluded, is to be completed by the Investigator, or 
medically qualified designee. Documentation of screening failure details will be recorded using 
eligibility screening forms or a participant screen failure log. Procedures outlined in the SOA 
will be performed. Timing will abide by fasting restrictions outlined Section 7.5. 
On days when biopsy is completed, duration of confinement at the site is dependent on-site 
specific policies and procedures related to monitoring post-procedure. If such policies or 
procedures do not exist, timing for post-biopsy monitoring is at the discretion of the Investigator.  
9.3.2. 
Demographics/Medical History 
Medical History will include medication use over the previous 30 days, including vitamins, over-
the-counter, prescription drugs, recreational drugs or supplements (such as protein powder or 
creatine) and alcohol and tobacco use. 
9.3.3. 
Physical Exam 
A complete physical exam will be performed at Screening and as per the SOA. At Screening, 
height (centimetres, without shoes) and weight (kilograms, without shoes) will be obtained to 
determine body mass index (BMI).  At all other time-points outlined in the SOA, a symptom-
directed physical exam will be performed if indicated.  


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9.3.4. 
Pulmonary Function Testing  
Spirometry and DLCO will be conducted at time-points outlined in the SOA for all participants.  
When conducted on dosing days, spirometry and DLCO are to be conducted pre-dose. 
Spirometry will be conducted in a pulmonology laboratory or at the clinical site in accordance 
with American Thoracic Society and European Respiratory Society (ATS-ERS) guidelines 
(Graham et al., 2019) and each patient will undergo pulmonary function testing at the same 
location throughout the study. DLCO assessment will be conducted in accordance with ATS-
ERS guidelines (Graham et al., 2017).  All spirometry and DLCO values collected and recorded 
will include both pre- and post-bronchodilation measurements (unless contraindicated or 
unavailable). Spirometry and DLCO should also be conducted at any time a patient experiences a 
COPD exacerbation. 
Spirometry: Spirometry will include VC, FVC, FEV1, FEV1/VC, and FEV1/FVC, all of which 
will be recorded in the eCRF. 
Bronchodilator: At least 3 pre-bronchodilator maneuvers will be performed, followed by 
administration of a bronchodilator (generally 90 μg albuterol per puff or 100 μg salbutamol per 
puff), unless contraindicated or unavailable. A site may elect to not perform bronchodilation on 
certain study subjects if that is in accordance with the site’s standard of practice. Following the 
administration of the bronchodilator, at least 3 post-bronchodilator maneuvers will be performed. 
The best pre- and post-bronchodilation measurements should be documented in an eCRF as 
follows: 
• The best FEV1 is the largest volume FEV1 from an acceptable maneuver 
• The best FVC is the largest volume FVC from an acceptable maneuver 
• The best FEV1/FVC is the best FEV1 divided by the best FVC, even if these values 
come from different maneuvers 
The number of puffs of bronchodilator administered should be documented, as this information 
will be captured on the pulmonary function testing eCRF. If administration of bronchodilator 
during spirometry is not aligned with the institution’s practice, the CRA will be notified to 
ensure Sponsor notification and appropriate study file documentation. 
DLCO: The DLCO assessment may be performed either pre- or post-bronchodilation. At least 
2 maneuvers should be attempted. The DLCO value recorded in the eCRF should be the average 
of 2 or more acceptable, repeatable maneuvers. 
9.3.5. 
Electrocardiogram 
A single 12-lead ECG measurement will be obtained at time-points outlined in the SOA after the 
participant is supine or semi-supine (same position each time is preferred) for at least 3 minutes. 
Any clinically significant abnormal ECGs will be repeated in triplicate, with each measurement 


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approximately 1 minute apart. ECGs will be performed prior to venepuncture and other invasive 
procedures. 
9.3.6. 
Vital Sign Assessments 
Systolic/diastolic blood pressure, temperature, heart rate, respiratory rate (breaths/min) will be 
obtained at time-points outlined in the SOA after the participant is seated or semi-supine (same 
position each time is preferred) for at least 3 minutes. Vitals signs will be obtained prior to 
venepuncture and other invasive procedures.  
9.3.7. 
Clinical Laboratory Tests 
Blood and urine samples will be collected to perform clinical laboratory tests. Participants will 
be required to fast for at least 2 hours for the screening sample collections. 
At the screening visit, up to 56 days prior to the first dose of study medication, a blood and urine 
sample will be collected for the laboratory tests detailed below, to establish baseline data and 
eligibility for enrolment. The results will be assessed by the Investigator, or medically qualified 
designee, before study enrolment. Any abnormality in laboratory values (that are confirmed on 
repeat) deemed clinically significant by the Investigator, or medically qualified designee (i.e., 
those that would jeopardize the safety of the participant or impact on the validity of the study 
results), will result in exclusion of that participant. Clinical laboratory tests will be performed on 
participants’ blood and urine at specified time-points listed in the SOA. 
Biochemistry: Sodium, potassium, chloride, bicarbonate, glucose, urea, creatinine, eGFR, 
creatine kinase, uric acid, phosphate, total calcium, anion gap, total cholesterol, albumin, 
globulins, protein, total bilirubin, conjugated bilirubin, gamma glutamyltransferase (GGT), 
alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate transaminase (AST), 
lactate dehydrogenase (LD), triglycerides, C-reactive protein, low-density lipoprotein (LDL)-
cholesterol, high-density lipoprotein (HDL)-cholesterol, Triglycerides and Troponin I. 
Hematology: Hemoglobin, red blood cell (RBC) count, hematocrit, mean cell volume (MCV), 
mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), platelets, white 
cell count, neutrophils, lymphocytes, monocytes, eosinophils and basophils.  
Coagulation: Partial thromboplastin time (PTT), Prothrombin time with INR and Fibrinogen. 
Urinalysis: Leucocytes, nitrites, urobilinogen, protein, pH, blood, specific gravity, ketone, 
bilirubin and glucose. 
Urine Cotinine: Urine cotinine levels (at Screening and throughout the study) to confirm non-
smoking status. 
Microscopic Urinalysis will be Performed if Indicated: White Blood Cells, RBCs, Epithelial 
cells, Bacteria. 


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Serology: Hepatitis B surface antigen, Hepatitis C antibody (with HCV RNA as confirmatory 
test if needed for positive antibody test) and HIV antibody screen. If necessary, participants will 
be counseled by the Investigator, or medically trained designee, concerning the blood tests for 
Hepatitis B surface antigen, Hepatitis C and HIV antibodies, and their subsequent results.   
FSH: Post-menopausal status will be confirmed by follicle-stimulating hormone (FSH) level 
consistent with post-menopausal state. 
Drugs Screen: Urine drug screen for Benzodiazepines, Amphetamines, Barbiturates, 
Methamphetamines, Methadone, Opiates, Phencyclidine, Cannabinoids, Ecstasy and Cocaine.  
Pregnancy: Females of childbearing potential will have a urine pregnancy test.  If the urine 
pregnancy test is positive, the patient will not be dosed and will be referred to their primary care 
provider for follow up.  
Anti-drug Antibody (ADA): Serum will be collected to assess for presence of fazirsiran 
antibodies. 
9.3.8. 
Pharmacodynamics  
Alpha-1 Antitrypsin Level: Alpha-1 antitrypsin levels will be measured as per the SOA and per 
Laboratory Manual. Samples will be analyzed by standard clinical laboratory assay for alpha-1 
antitrypsin levels and Z-AAT levels using a Z-specific assay. 
Liver Biopsy: Pre-dose and post-dose percutaneous liver biopsies will be conducted to obtain 
tissue samples for liver Z-AAT levels and histological evaluation. Procedure detail and tissue 
processing protocols are outlined in the Laboratory Manual. 
Fibrosis Markers: Markers of liver fibrosis including PRO-C3, PRO-C6 (if feasible) as well as 
calculated values for aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 will be 
assessed.  
Magnetic Resonance Elastography (MRE): Pre-dose and post-dose per the SOA liver stiffness 
using will be evaluated using MRE standard procedures (optional). 
FibroScan®: Pre-dose and post-dose per the SOA liver stiffness will be evaluated using 
FibroScan® standard procedures (if available at site). 
9.3.9. 
Concomitant Medications/Therapies 
Participants will be instructed to inform the Investigator of the details (indication, dose and dates 
of administration) if they do take any medication, and these details will be recorded in the CRF.  
Allowance of concomitant medications will be at the discretion of the study Investigator in 
consultation with Sponsor Medical Monitor (when necessary). Augmentation therapy is 
permitted. Start date and dose of augmentation therapy should be captured. Sedation with 
benzodiazepines or alternatives is acceptable during liver biopsy. Continued use of medications to 
treat chronic conditions (including COPD) are acceptable. 


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9.3.10. 
Follow-Up Procedures: 12 Week Post Last Dose Telephone Call   
Document telephone contact with each participant to verify compliance with contraceptive 
measures and absence of any known pregnancy. 
9.3.11. 
Early Termination Procedures 
The reason for Early Termination will be documented in source documents and eCRF. 
Procedures as outlined in the SOA will be completed.  
9.4. 
Study Formulation Administration 
Appropriately trained employees of the clinical site will administer the study treatment. Each 
dose will be administered as a single subcutaneous injection. The date, time, and location of 
administration will be recorded in the source notes and witnessed by a second person from the 
clinical facility.  The preferred site of injection is the abdomen. Optional additional sites are the 
upper arms and thighs.  
Table 5: 
Injection Volume per Dose Level 
Dose 
Concentration 
Total Injection Volume 
# Injections per planned dose 
100 mg 
230 mg/mL 
0.43 mL 
 One 
200 mg 
230 mg/mL 
0.87 mL 
 One 
 
9.5. 
Timing of Treatments and Procedures 
The visits following Day 1 are listed in the SOA.  A post-dose visit is to be conducted 24 to 
48 hours after the first three fazirsiran administrations.  A visit specified as Week X has a target 
date of Day 1+X number of weeks, for example, the Week 4 visit ideally occurs 28 days after 
Day 1 (on Day 29).  In Treatment Extension I, the calendar resets and Day 1 will be the first dose 
received during the treatment extension periods (approximately 12 weeks after the last dose in 
either Cohort 1, 1b, or 2) although the subject may have received previous doses while 
participating in Cohort 1, 1b, or 2. 
Actual times of procedures for each participant will vary depending on scheduling and will be 
recorded in the CRF. 
Post-dose time-points will be determined from the end of the injection/administration.  
In the event of multiple procedures scheduled at the same time, non-invasive procedures 
(i.e., ECGs, AE assessment) will be conducted prior to invasive procedures (i.e., blood sample 
collection). Timing of activities may be adjusted slightly to accommodate all procedures. 
The following windows are allowed for study assessments/visits: 


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Pre-dose:  
 
 
 
 
Within three (3) hours prior to dosing  
All other procedures through 2 hours:  
±15 minutes 
See the SOA for treatment windows.  
9.6. 
Safety Assessments  
The safety of fazirsiran will be evaluated by collection of the following measurements performed 
at specified time-points: 
• Monitoring of AEs/SAEs 
• Physical examinations 
• Vital signs  
• ECG measurements  
• Injection Site Reactions  
• Clinical laboratory tests (hematology, biochemistry, cardiac troponin, coagulation, 
urine cotinine and urinalysis) 
• Concomitant medications/therapy, and  
• Reasons for treatment or study discontinuation due to toxicity 
• Pulmonary Function Testing including spirometry (including VC, FVC, FEV1, 
FEV1/VC, and FEV1/FVC,) and DLCO. Changes in VC, FVC, FEV1, and DLCO 
between pre-dose and all post-dose evaluations will be analyzed.  
• Number and severity of COPD exacerbations based on Global Initiative for Chronic 
Obstructive Lung Disease (GOLD) criteria will be evaluated as an AE of special 
interest.  
The AE/SAE reporting period for an enrolled participant will begin when the participant 
provides informed consent. Treatment-Emergent AEs/SAEs will be those defined as following 
dose administration through EOS or Early Termination. All AEs/SAEs that occur during the AE 
reporting period specified in the protocol must be reported to Arrowhead Pharmaceuticals, Inc., 
regardless of the relationship of the AE to study treatment.  Any known untoward event that 
occurs beyond the AE reporting period that the Investigator considers an SAE and possibly 
related to study treatment will be reported to Arrowhead.  


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9.7. 
Blood Sampling for Pharmacodynamic Analysis 
Blood samples will be collected from participants through an indwelling cannula or through a 
fresh vein puncture.  The actual blood collection time will be recorded in the source documents. 
All deviations outside the range allowed above will be documented as protocol deviations. In all 
such cases, appropriate time corrections, for the actual time of sample collection will be 
incorporated at the time of data analysis. Blood samples will be collected at time-points outlined 
in the SOA.  
The target sample times will be printed in the CRFs. The actual sample times (times samples 
taken) will be recorded alongside the nominal times in the CRF and will be entered at the time of 
or as soon as possible after sampling. All times must be recorded in the 24-hour format. An 
explanation must be given for any blood sample taken outside of the set sampling times. 
9.7.1. 
Sample Processing and Analysis for Pharmacodynamic Samples 
Pharmacodynamic (AAT): 
Serum alpha-1 antitrypsin samples will be drawn and analyzed by standard clinical laboratory 
assay for alpha-1 antitrypsin levels and Z-AAT levels using a Z-specific assay. Left over serum 
from AAT blood draws will be frozen as back up samples. 
Whole blood will be collected and processed per the Laboratory Manual.   
Results, percent change, and duration of response from baseline to timepoints specified in the 
SOA will be analyzed and summarized by cohort and whether or not on augmentation. 


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10. 
ADVERSE EVENTS 
The Investigator and clinical facility staff are responsible for detection, recording and reporting 
of events that meet the criteria and definition of various adverse events as listed below. Adverse 
events will be recorded from time of signed consent through to end of study; only AEs that occur 
post-dose will be considered treatment-emergent.  The Investigator and clinical facility staff are 
responsible for detection, recording and reporting of pregnancy and appropriate follow up.  The 
Investigator should report all pregnancies and pregnancies in partners of subjects within 24 hours 
of awareness of the pregnancy using the Pregnancy Notification Form.  This completed form 
should be emailed to Labcorp, the pharmacovigilance vendor for this study at: 
Arrowhead.Safety@Labcorp.com or fax to: 1-626-628-1882 
10.1. 
Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding or diagnostic test), symptom, or 
disease temporally associated with the use of a medicinal (investigational/experimental) product, 
whether related to this product or not. (Refer to ICH E2a: Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, 27 October 1994). 
Treatment emergent AEs will be defined as AEs with onset after administration of the study 
drug, or when a preexisting medical condition increases in severity or frequency after study drug 
administration.  
AEs will not include: 
• A medical or surgical procedure such as surgery, endoscopy, tooth extraction, or 
transfusion (although the condition that leads to the procedure may be an AE) 
• A pre-existing disease or condition present at the start of the study that does not 
worsen during the study 
• Any situation where an untoward medical occurrence has not occurred (for example, 
hospitalizations for cosmetic elective surgery or “social” admissions) 
• An overdose of either the investigational product or a concurrent medication without 
any resulting signs or symptoms. 
A Serious Adverse Event (SAE) is an AE that: 
• Results in death, 


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• Is life-threatening, (NOTE: The term ‘life-threatening’ in the definition of ‘serious’ 
refers to an event/reaction in which the participant was at immediate risk of death at 
the time of the event/reaction; it does not refer to an event/reaction which 
hypothetically might have caused death, if it were more severe) 
• 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.  
Medical and scientific judgment should be exercised in deciding whether other situations, should 
be considered serious such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but might jeopardize the participant or might 
require medical or surgical intervention to prevent one of the other serious outcomes listed in the 
above definition. These should also be considered serious. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse. 
10.2. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as AEs 
Abnormal assessments (e.g., ECGs and vital signs) that are judged by the Investigator as 
clinically significant or result in clinical sequelae will be recorded as AEs. Laboratory 
abnormalities will be reported by the Investigator as AEs if the abnormality is considered 
clinically significant or result in clinical sequelae.  Laboratory abnormalities not reported as AEs 
are not to be reported as clinically significant (CS) in the study database. 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen following the start 
of the study will be reported as AEs.  
The Investigator (or medically qualified designee) will exercise his or her medical and scientific 
judgment in deciding whether an abnormal laboratory result or other abnormal assessment is 
clinically significant.   
10.3. 
Timing, Frequency, and Method of Detecting AEs 
Any pre-existing conditions or signs and/or symptoms present in a participant prior to the start of 
the study (i.e., before informed consent) should be recorded as Medical/Surgical History.  


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All AEs occurring after informed consent and on or before the final visit must be reported as 
AEs; only AEs that occur post-dose will be considered treatment-emergent.  All AEs must be 
recorded irrespective of whether they are considered drug-related. 
At each visit/assessment in the period defined above, AEs will be evaluated by the Investigator 
(or medically qualified designee) and recorded in the medical notes and eCRF. 
10.4. 
Recording of AEs  
When an AE occurs, it is the responsibility of the Investigator or medically qualified designee to 
review all documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event. The Investigator or medically qualified designee will then record the AE on 
the AE CRF. Additional reporting requirements for an AE meeting serious criteria are discussed 
in Section 10.7 below. 
The Investigator or medically qualified designee will attempt to establish a diagnosis of the event 
based on signs, symptoms, and/or other clinical information. In all cases, when available, the 
diagnosis should be reported as the event and not the individual signs/symptoms.  It is not 
acceptable for the Investigator to send photocopies of the subject’s medical records to the 
Sponsor in lieu of completion of the appropriate AE CRF pages. 
10.5. 
Evaluating AEs  
10.5.1. 
Assessment of Intensity 
The Investigator, or medically qualified designee, will assess intensity for each AE reported 
during the study. The assessment will be based on the Investigator’s (or medically qualified 
designee’s) clinical judgment. The intensity should be assigned to one of the following 
categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. 
An AE that is assessed as severe should not be confused with a SAE. Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as described in 
Section 10.1.  


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10.5.2. 
AEs at the Injection Site 
AEs at the injection site (or ISRs) only include AEs at the site of Fazirsiran Injection. AEs at the 
injection site will be assessed as either Mild, Moderate or Severe: 
• Mild: Tenderness with or without associated symptoms (e.g., warmth, erythema, 
itching), mild pain or mild edema.  
• Moderate: Moderate to significant pain or lipodystrophy.  
• Severe: Tissue ulceration or necrosis with associated severe tissue damage or if 
operative intervention is indicated 
10.5.3. 
AEs of COPD Exacerbation 
AEs reported as an exacerbation of COPD will be assessed as either Mild, Moderate or Severe 
according to the GOLD criteria provided below: 
• Mild: Treated with short acting bronchodilators only 
• Moderate: Treated with short acting bronchodilators plus antibiotics and/or oral 
corticosteroids 
• Severe: Patient requires hospitalization or visits the emergency room. Severe 
exacerbations may also be associated with acute respiratory failure. 
10.5.4. 
Assessment of Causality 
The Investigator (or medically qualified designee) is obligated to assess the relationship between 
investigational product and the occurrence of each AE. The Investigator (or medically qualified 
designee) will use clinical judgment to determine the relationship. Alternative causes, such as 
natural history of the underlying diseases, concomitant therapy, other risk factors, and the 
temporal relationship of the event to the investigational product will be considered and 
investigated. The Investigator (or medically qualified designee) will also consult the 
Investigator’s Brochure in the determination of his/her assessment. 
There may be situations when an SAE has occurred, and the Investigator has minimal 
information to include in the initial SAE report. However, it is very important that the 
Investigator (or medically qualified designee) always assess causality for every event prior to 
transmission of the SAE report form. The Investigator (or medically qualified designee) may 
change his/her opinion of causality considering follow-up information, amending the SAE report 
form accordingly. The causality assessment is one of the criteria used when determining global 
regulatory reporting requirements. 
The Investigator (or medically qualified designee) will provide the assessment of causality 
utilizing three possible categories:  Not Related, Possibly Related and Probably Related. 


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An AE will be considered “Not Related” to the use of the product if any of the following tests 
are met: 
• An unreasonable temporal relationship between administration of the product and the 
onset of the AE (e.g., the event occurred either before, or too long after administration 
of the product for it to be considered product-related). 
• A causal relationship between the product and the AE is biologically implausible 
(e.g., death as a passenger in an automobile accident). 
• A clearly more likely alternative explanation for the AE is present (e.g., typical 
adverse reaction to a concomitant drug and/or typical disease-related event). 
• AE is more likely related to and temporally associated with a procedure (such as liver 
biopsy). 
An AE will be considered “Possibly Related” when there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the product under investigation. 
An AE will be considered “Probably Related” when there are facts, evidence, or arguments to 
suggest that the event is related to the product under investigation. 
10.6. 
Follow-up of AEs 
After the initial AE, the Investigator is required to proactively follow each participant and 
provide further information on the participant’s condition as deemed appropriate.  
All AEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up. Once resolved, the appropriate 
AE CRF page and SAE report form (if event is serious) will be updated. The Investigator, or 
medically qualified designee, will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.  In the event of a fatal outcome in an SAE, the 
Investigator, or medically qualified designee, will attempt to obtain postmortem findings, 
including histopathology, and provide all additional information in a follow up SAE report. 
New or updated information regarding an SAE will be recorded on a new SAE report form 
marked as follow-up with the appropriate follow-up number added to the report. The follow-up 
report will be signed and dated by the Investigator.  
10.7. 
Prompt Reporting of SAEs  
AEs meeting serious criteria MUST be reported promptly to the designated Pharmacovigilance 
Contract Research Organization (CRO), and the EC. 


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10.7.1. 
Completion and Transmission of the SAE Reports 
Once an Investigator becomes aware that an SAE has occurred in a study participant, she/he will 
report the information on an SAE report form to the designated Pharmacovigilance CRO within 
24 hours. The SAE report form will always be completed as thoroughly as possible with all 
available details of the event and signed by the Investigator (or medically qualified designee). If 
the Investigator does not have all information regarding an SAE, he/she will not wait to receive 
additional information before reporting the event. The SAE report form will be updated when 
additional information is received. 
The Investigator (or medically qualified designee) will always provide an assessment of causality 
at the time of the initial report as described in Section 10.5.4. 
Facsimile or email transmission of the SAE report form are the preferred methods to transmit 
this information to the designated Pharmacovigilance CRO. In rare circumstances, notification 
by telephone is acceptable, with a copy of the SAE CRF sent by overnight mail. Initial 
notification via the telephone does not replace the need for the Investigator, or medically 
qualified designee, to complete and sign the SAE report form within the outlined time frames. 
The Sponsor will provide a list of project contacts for SAE receipt, fax numbers, telephone 
numbers, and mailing addresses. Any event that in the opinion of the Investigator may be of 
immediate or potential concern for the participant’s health or well-being will be reported to the 
Sponsor emergency contact listed below.  
Sponsor Emergency Contact 
 
 
 
10.7.2. 
Serious Adverse Event Reports to the EC 
The Investigator, or responsible person per local requirements, will comply with the applicable 
local regulatory requirements related to the reporting of SAEs to regulatory authorities and the 
EC. 
10.7.3. 
Pregnancy Reporting 
Pregnancy occurring in a subject or in the female partner of a male subject during the study must 
be reported on a pregnancy reporting form to Labcorp, the pharmacovigilance vendor for this 
study immediately and not later than 24 hours of initially becoming aware of the pregnancy by 
the Investigator.  
Pregnancy data will be collected at the initial notification, birth/termination of pregnancy, and 
for up to 1 year after birth or until the end of the pregnancy. 


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Pregnancies are not considered SAEs. However, any SAE that occurs during pregnancy (e.g., 
serious maternal complications, therapeutic or spontaneous abortion, ectopic pregnancy, 
stillbirth, etc.) must be reported in accordance with the procedure for reporting SAEs. 
10.8. 
Regulatory Requirements for Reporting of SAEs  
The Investigator (or medically qualified designee) will promptly report all SAEs in accordance 
with the procedures detailed in Section 10.7.  Prompt notification of SAEs by the Investigator (or 
medically qualified designee) is essential so that the Sponsor may comply with its regulatory 
obligations.  
The Sponsor will comply with all reporting requirements as stipulated in European Directive 
2001/20/EC and in accordance with other national regulations outside the EU as appropriate. The 
Sponsor is responsible for reporting all suspected unexpected serious adverse reactions to the 
Eudravigilance database. An adverse reaction, in contrast to an adverse event, is characterized 
by the fact that a causal relationship between a medicinal product and an occurrence is suspected. 
The Sponsor will ensure that all relevant information about suspected serious unexpected adverse 
reactions that are fatal or life-threatening is recorded and reported as soon as possible to the 
competent authorities in all the Member States concerned, and to the Ethics Committee, and in 
any case no later than seven days after knowledge by the Sponsor of such a case, and that 
relevant follow-up information is subsequently communicated within an additional eight days. 
All other suspected serious unexpected adverse reactions will be reported to the competent 
authorities concerned and to the Ethics Committee concerned as soon as possible but within a 
maximum of fifteen days of first knowledge by the Sponsor. 
10.9. 
Post-study AEs 
A post-study AE is defined as any event that occurs outside of the AE detection period defined in 
Section 10.3. 
Investigators are not obligated to actively seek AEs in former study participants. However, if the 
Investigator learns of any SAE, including a death, at any time after a participant has been 
discharged from the study, and he/she considers the event reasonably related to the 
investigational product, the Investigator will promptly notify Arrowhead.  
10.10. 
SAEs Related to Study Participation 
An SAE considered related to study participation (e.g., procedures, invasive tests, a change in 
existing therapy), even if it occurs during the pre- or post-treatment period, will be reported 
promptly (refer Section 10.7).  


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11. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
Statistical analyses and descriptive summaries will be presented for primary, secondary and 
exploratory endpoints using appropriate methods. A detailed statistical analysis plan (SAP) will 
be prepared and finalized prior to submission of the initial protocol to regulatory authorities prior 
to database lock. Descriptive statistics will be presented for all analyses unless otherwise 
specified. For continuous variables, data will be presented as number (n), mean, median, 
standard deviation, minimum, and maximum. Discrete variables will be presented as frequencies 
and proportions or percent. 
11.1. 
Study Populations 
Four study populations will be defined and evaluated in this study.   
• Safety Population: All patients who receive at least one dose of study drug. The 
Safety Population will be used for safety analyses. 
• Full Analysis Set (FAS): All patients who receive at least one dose of study drug and 
have baseline and post-dose liver biopsy histology results available. FAS population 
will be used for all efficacy analyses. 
• Per Protocol (PP) population: All FAS patients who did not violate the protocol in a 
substantial manner, such determination to be made prior to database lock.  
11.2. 
Sample Size Considerations 
There were no formal sample size calculations made in this open-label exploratory study. 
11.3. 
Screening Data 
Demographics will be tabulated by participant and summarized. Eligibility assessments at 
baseline, including medical/surgical history data and physical examination data (including height 
and weight), will be listed for each participant.  
11.4. 
Safety/Tolerability Data 
All safety analyses will be performed using the Safety Population. In general, safety analyses 
will be performed, and the results summarized by cohort. All safety summaries will be 
accompanied by patient listings. Baseline safety assessments will be compared with 
measurements recorded post-baseline.   
• Treatment-emergent AEs will be summarized using the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) by SOC and Preferred Term (PT), 
classified from verbatim terms. The incidence and percentage of participants with at 
least 1 occurrence of a PT will be included, per the most severe grade using a 3-point 
scale (mild, moderate, severe). The number of events per Preferred Term will also be 


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summarized. Causality (relationship to study treatment) will be summarized 
separately. The incidence and frequency of AEs, SAEs, related AEs, related SAEs, 
and AEs leading to withdrawal, dose modification, or treatment discontinuation will 
be summarized by dose according to SOC and PT.  
• AEs will also be summarized in listings. The duration of AEs will be determined and 
included in listings, along with the action taken and outcome.   
• The incidence of laboratory abnormalities will be summarized.  
• Vital sign measurements will be summarized at each scheduled time point using 
descriptive statistics.  
• Physical examination findings will be summarized by time point and presented in 
participant listings.   
• Clinically significant changes on ECG and changes in spirometry (including VC, 
FVC, FEV1), and DLCO will be summarized.  
• Pregnancy test/FSH results will be summarized separately by time point.  
• The number of patients that require augmentation treatment at any time throughout 
the study will be summarized. Time from baseline to initiation of augmentation 
therapy will be summarized using Kaplan Meier estimates.   
• The percentage of patients experiencing an ISR (see definition of ISR in protocol) 
will be summarized using descriptive statistics. 
• Number and severity of COPD exacerbations based on GOLD criteria will be 
evaluated as an AE of special interest. 
11.5. 
Immunogenicity Data 
The number and percentage of patients who are ADA positive at baseline and at any post-
baseline visit will be summarized. A listing of patients with positive ADA assay results will be 
provided.  
11.6. 
Pharmacodynamic Data 
AAT Levels: The whole blood collected for PD analysis following multiple doses of fazirsiran 
will undergo analysis for alpha-1 antitrypsin levels using both a Z-AAT specific assay and a 
clinical assay for total AAT. Results, including depth of knockdown as reported by percent 
change from baseline will be analyzed and summarized.  


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FibroScan®: Non-invasive imaging using FibroScan® will be completed pre-dose and post-
dose per the SOA in a standardized fashion. Percent change in quantitative measure of liver 
stiffness from pre-dose to post-dose will be analyzed and summarized.  
Liver Biopsy Assessments: Liver biopsy will be completed pre-dose and post-dose per the SOA 
or early termination. Primary, Secondary and exploratory endpoints will be based on comparison 
of pre-dose biopsy versus end of study biopsy unless otherwise specified and between cohort 
comparison conducted. Biopsy sample will be taken, prepped and stored in a standardized 
manner with biopsy. Histologic/IHC reads being completed by an independent central 
pathologist. Percent change in intra-hepatic Z-AAT, changes in PAS/D+ globules (size and 
number), change in a liver disease severity grading scale, mRNA, changes in Metavir fibrosis 
scale, fibrosis gene expression levels and Liver collagen and iron content using biomarkers, 
special stains and imaging [Masson’s Trichrome, Sirius Red, Iron] (if scientifically feasible and 
sufficient sample available) from pre-dose to post-dose sample will be analyzed and summarized 
by cohort and between cohorts. A local reader at each site will be used during Screening to 
identify and exclude patients with pre-dose liver cirrhosis.  
11.7. 
Analysis Methods 
Demographic, PD and safety parameters will be summarized using descriptive statistics (n, 
mean, SD, % coefficient of variation (CV), geometric mean, geometric %CV, minimum, median, 
and maximum for continuous parameters; frequency and percentage for categorical parameters). 
Detailed statistical considerations, such as biopsy derived measures analysis methods, missing 
data handling, study population definitions, and other important analysis issues will be described 
in a separate SAP. The SAP will be finalized prior to database lock.  
Exploratory Analyses 
The exploratory analyses are designed to investigate the association between treatment with 
fazirsiran and various biomarkers, liver proteins, gene and mRNA expression, FibroScan. These 
analyses will be exploratory, and data driven.  
11.8. 
Data Recording and Quality Control 
Source documents must be maintained for each participant in the study, consisting of all 
demographic and medical information, including clinical laboratory data, etc.  A copy of the 
signed informed consent form must be retained.  All information on the eCRFs must be traceable 
to these source documents in the participant's file.   
Data recorded in all participants’ eCRFs will be subjected to a quality control review.  


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12. 
STUDY APPROVAL AND CONDUCT 
The following conditions will be met. 
12.1. 
Regulatory Approval 
The requirements for the conduct of clinical trials in accordance with local applicable regulations 
will be met before commencement of this study. 
12.2. 
Ethics Committee (EC) Approval 
Prior to initiation of the study, written EC approval of the Protocol and Informed Consent Forms, 
based on the principles of ICH cGCP procedures, will be received. A copy of the signed and 
dated letter of approval will be provided to the clinical site and Arrowhead Pharmaceuticals, Inc. 
prior to study commencement. Any written information and/or advertisements to be used for 
volunteer recruitment will be approved by the EC prior to use. A list of the EC voting members, 
their titles or occupations, Federalwide Assurance number (where applicable) and their 
institutional affiliations will be requested before study initiation.  
Protocol modifications that may impact subject safety or the validity of the study will be 
approved by the EC, following written agreement from the Sponsor. 
12.3. 
Ethical Considerations 
This study will be carried out per the Declaration of Helsinki 1964, as modified by the 64th 
World Medical Assembly, Fortaleza, Brazil, October 2013, the Notes for Guidance on Good 
Clinical Practice (cGCP) (2000) (CPMP/ICH/135/95), and the Principles of the ICH cGCP. The 
protocol will be submitted for approval to the EC, and written approval obtained before patients 
are enrolled. The composition of the EC will also be provided to the Sponsor. If approval is 
suspended or terminated by the EC, the Investigator will notify the Sponsor immediately 
Where applicable, the clinical site and Arrowhead Pharmaceuticals, Inc. agree to abide by the 
local compensation guidelines for injury resulting from participating in a company-sponsored 
research project. Compensation will only be provided on the understanding that the provision of 
compensation does not amount to an admission of legal liability and is subject to the proposed 
recipient signing a full and complete release of the company from all claims, damages and costs. 
12.4. 
Written Informed Consent 
Informed consent will be obtained before the subject can participate in the study. The contents 
and process of obtaining informed consent will be in accordance with all applicable regulatory 
requirements. Study participation includes all screening procedures, as well as any wash-out of 
excluded medications. 
It is the responsibility of the Investigator (or medically qualified designee) to obtain a written 
informed consent from everyone participating in this study after adequate explanation of the 


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aims, methods, objectives, and potential hazards of the study. The Investigator (or medically 
qualified designee) must also explain to the patients that they are completely free to refuse to 
enter the study or to withdraw from it at any time. Appropriate forms for documenting a written 
consent will be provided by the Investigator or by Arrowhead Pharmaceuticals, Inc. 
For this study, each eligible participant will be required to provide written informed consent 
before participation in the study.  
All eligible participants will have the study explained by the Investigator or designee. They will 
receive a full explanation, in lay terms, of the aims of the study, the discomforts, risks and 
benefits in taking part as well as of insurance and other procedures for compensation in case of 
injury. It will be explained that the study is for research purposes only and is not expected to 
provide any therapeutic benefit to the individual. It will be pointed out that they can withdraw 
from the study at any time without prejudice. Each participant will acknowledge receipt of this 
information by giving written informed consent for participation in the study. The volunteer will 
be given a copy of the signed Informed Consent Form to retain. 
Patients will undergo reconsent in the period between the last dose in either Cohort 1, 1b, or 2 
and before initiating participation in the treatment extension periods.  
12.5. 
Emergency Contact with Principal Investigator 
Suitable arrangements will be made for participants to contact the Investigator or medically 
trained designee in the event of an emergency. 
12.6. 
Notification of General Practitioner 
It is the responsibility of the PI or designee, to notify, where applicable, with the consent of the 
participant, the general practitioner of the subject’s participation in the trial, by sending a letter 
stating the nature of the trial, treatments, expected benefits or adverse events and concomitant 
drugs to be avoided. 
12.7. 
Clinical Laboratory Certification and Reference Ranges 
Before the initiation of this study, the PI, or designee, will obtain a copy of the certification form, 
with certification number and expiration date for all clinical laboratories (excluding central 
laboratories) used in the study. Reference ranges for each clinical laboratory test used in this 
study will be obtained from the appropriate laboratory, which will perform the test for the study. 
12.8. 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. The PI will conduct the study in 
compliance with the approved protocol and will not implement any deviation from or changes to 
the protocol without prior agreement by the Sponsor and review and documented approval from 


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the regulatory authorities and IRB/EC of an amendment, except where necessary to eliminate an 
immediate hazard to study patients. 
Deviations may result from the action or inaction of the participant, PI, or site staff. Examples of 
deviations include, but are not limited to: 
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications, food, drink, herbal remedies, or supplements that are specifically 
prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, medical history, etc. – either tests not done, incorrect tests done, or not 
done within the time frame specified in the protocol 
• Procedural deviations such as incorrect storage of study drug, failure to update the 
ICF when new risks become known, failure to obtain EC approvals for the protocol 
and ICF revisions 
Protocol deviations impacting subject safety or eligibility will be reported to the Sponsor or CRO 
within 2 business days of occurrence and to the EC/competent regulatory authority per local 
regulatory requirements.  
The Investigator is responsible for ensuring that any known protocol deviations are recorded and 
reported as agreed. The nature and reasons for protocol deviations will be recorded in each 
participant’s CRF. 
12.9. 
Termination of the Study 
The Sponsor reserves the right to discontinue the trial at any time. Reasons will be provided in 
the event of this happening. The Investigator reserves the right to discontinue the study for safety 
reasons at any time in collaboration with the Sponsor. 


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13. 
STUDY ADMINISTRATION 
13.1. 
Study Monitoring 
Arrowhead Pharmaceuticals, Inc. is responsible for assuring the proper conduct of the study 
about protocol adherence and validity of the data recorded on the CRFs. Participant 
confidentiality will be maintained. 
In accordance with applicable regulations, cGCP, and Arrowhead Pharmaceuticals, Inc. 
procedures, Arrowhead Pharmaceuticals, Inc. will be responsible for assigning a study monitor 
(CRA) who will contact the site to organize a visit prior to participant enrolment to review the 
protocol and data collection procedures with site staff. In addition, the assigned study monitor 
will periodically contact the site, including conducting on-site visits. The extent, nature and 
frequency of on-site visits will be based on such considerations as the study objective and/or 
endpoints, the purpose of the study, study design complexity, and enrolment rate. 
During these site visits, the study monitor will: 
• Check the progress of the study. 
• Review study data collected. 
• Conduct source document verification. 
• Identify any issues and address their resolution. 
• Check investigational product accountability 
• Review blood and urine samples and ensure they are labeled and stored correctly. 
This will be done to verify that the: 
• Data are authentic, accurate and complete. 
• Safety and rights of participants are being protected. 
• Study is conducted in accordance with the currently approved protocol (and any 
amendments), cGCP and all applicable regulatory requirements. 
The PI agrees to allow the monitor direct access to all relevant documents and to allocate his/her 
time and the time of his/her staff to the monitor to discuss findings and any relevant issues. 
At study closure, a study monitor will conduct the following activities in conjunction with the PI 
or site staff as appropriate: 
• Return of all study data to Arrowhead Pharmaceuticals, Inc. 


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• Data queries. 
• Accountability, reconciliation and arrangements for unused investigational 
product(s). 
• Inventory and final disposition (e.g., destruction, shipping to repository, etc.). 
• Review of site study records for completeness. 
13.2. 
Quality Assurance 
To ensure compliance with cGCP and all applicable regulatory requirements, Arrowhead 
Pharmaceuticals, Inc. may conduct a quality assurance audit of the study site. Regulatory 
agencies may also conduct a regulatory inspection of this study. Such audits/inspections can 
occur at any time during or after completion of the study. If an audit or inspection occurs, the PI 
and clinical site agree to notify Sponsor as soon as possible following awareness of an 
impending regulatory inspection.  The PI and clinical site agree to allow the auditor/inspector 
direct access to all relevant documents and allocate his/her time and the time of his/her staff to 
the auditor/inspector to discuss findings and any relevant issues. 
13.3. 
Records Retention 
Following closure of the study, the PI must maintain all site study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., 
audit or inspection) and whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems and staff. When permitted by 
local laws/regulations or institutional policy, some of these records can be maintained in a format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The PI must assure that all reproductions are legible and 
are a true and accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required. Furthermore, the PI must ensure there is an 
acceptable back-up of these reproductions and that an acceptable quality control process exists 
for making these reproductions. 
Arrowhead Pharmaceuticals, Inc. will inform the PI of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, or Arrowhead Pharmaceuticals, Inc. 
standards/procedures; otherwise, the retention period will default to 15 years. 
The material to be stored shall include, but is not limited to, the following: 
• Signed and dated copy of the final study protocol and any amendments. 


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• Signed and dated letter of IRB/EC approval, letter of constitution of the IRB/EC and 
copies of any other correspondence relevant to the study with the IBR/EC or 
regulatory authorities. 
• The IRB/EC approved Informed Consent Form. 
• Current curriculum vitae (signed and dated) of the Principal Investigator and co-
workers with major responsibilities in the trial. 
• Site Signature and Delegation of Responsibility Log 
• FDA Form 1572 (where applicable)  
• Financial Disclosure Form(s) 
• Blank CRF/eCRF. 
• Signed participant informed consent forms. 
• Laboratory reference ranges (signed and dated). 
• The completed CTN Application Form (where applicable). 
• The Final Study Report. 
• Clinical raw data including the Source Data Forms, all clinical laboratory report 
forms, subject CRFs, drug accountability forms, and dispensing records, etc. 


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14. 
INFORMATION DISCLOSURE AND INVENTIONS 
14.1. 
Ownership 
 
 
 
 
 
 
 
 
 
 
14.2. 
Confidentiality 
 
 
 
 
 
 
 
 
 
 
 
14.3. 
Publication 
 
 
 
 
 
 
 
  
 
 


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15. 
REFERENCES 
1. American Thoracic Society/European Respiratory Society Statement. Standards for the 
diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J 
Respir Crit Care Med. 2003; 168 (7):818–900. 
2. Clark V, Marek G, Liu C, Collinsworth A, Shuster J, Kurtz T, et al. Clinical and 
Histologic Features of Adults with Alpha-1 Antitrypsin Deficiency in a Non-Cirrhotic 
Cohort. J Hepatol. 2018; Dec;69(6):1357-1364.  
3. De Serres, Blanco I. Prevalence of alpha-1-antitrypsin deficiency alleles PI*S and PI*Z 
worldwide and effective screening for each of the five phenotypic classes PI*MS, 
PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review. Ther Adv Respir Dis, 2012 
6(5) 277-295. 
4. Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis, Journal of 
Hepatology (2012) vol 56, 1171-1180. 
5. Feldmann G, Martin JP, Sesboue R, Ropartz C, Perelman R, Nathanson M, et al. The 
ultrastructure of hepatocytes in alpha-1 antitrypsin deficiency with the genotype Pi_ _. 
Gut (1975), 16, 796-799. 
6. Graham BL, Brusasco V, Burgos F, Cooper BG, Jensen R, Kendrick A, et al. 2017 
ERS/ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 
2017 Jan 3;49(1):1600016. Erratum in: Eur Respir J. 2018 Nov 22;52(5). 
7. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. 
Standardization of Spirometry 2019 Update. An Official American Thoracic Society and 
European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019 
Oct 15;200(8):e70-e88. 
8. Nelson DR, Teckman J, Di Bisceglie AM, Brenner DA. Diagnosis and Management of 
Patients with a1-Antitrypsin (A1AT) Deficiency. Clin Gastroenterol Hepatol (2012) 
10(6): 575–580. 
9. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association 
for the Study of Liver Diseases. Liver biopsy. Hepatology. 2009 Mar;49(3):1017-44. 
10. Stoller JK, Aboussouan LS. A Review of α1-Antitrypsin Deficiency. Am J Respir Crit 
Care Med 2012;185: 246-259. 
11. Teckman JH. Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Understanding 
and Future Therapy. COPD 2013 (10)S1:35-43. 


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12. Torres-Durán M, Lopez-Campos JL, Barrecheguren M, Miravitlles M, Martinez-Delgado 
B, Castillo S, et al. Alpha-1 antitrypsin deficiency: outstanding questions and future 
directions. Orphanet Journal of Rare Diseases (2018) 13:114. 
13. Wooddell CI, Blomenkamp K, Peterson RM, Subbotin VM, Schwabe C, Hamilton J, et 
al. Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease. JCI Insight. 
2020 Jun 18;5(12):e135348. 
 


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APPENDIX 1. Elevated ALT Study Modification and Patient 
Discontinuation Rules 
Treatment-Emergent 
ALT 
Treatment-Emergent Total 
Bilirubin(TBL) 
Liver Symptoms 
Action 
Normal baseline: ALT 
>5x ULN 
Elevated baseline: ALT 
>3x baseline or >300 U/L 
(whichever occurs first) 
Normal 
None 
Repeat ALT, AST, ALP, 
TBL, in 2–3 
days 
Follow-up for symptoms. 
Normal baseline: ALT 
>8x ULN 
Elevated baseline: ALT 
>5x baseline or >500 U/L 
(whichever occurs first) 
Normal 
None 
Interrupt study drug. 
Initiate close observation 
and workup for 
competing etiologies. (see 
below) 
Study drug can be 
restarted only if an 
alternative etiology is 
identified and liver 
enzymes return to 
baseline. 
Normal baseline: ALT 
>3x ULN 
Elevated baseline: ALT 
>2x baseline or >200 U/L 
(whichever occurs first) 
TBL >2x ULN 
None 
Interrupt study drug. 
Initiate close observation 
and workup for 
competing etiologies. 
Study drug can be 
restarted only if an 
alternative etiology is 
identified and liver 
enzymes return to 
baseline. 
Normal baseline: ALT 
>3x ULN 
Elevated baseline: ALT 
>2x baseline or >200 U/L 
(whichever occurs first) 
Normal or elevated 
Symptoms of 
clinical hepatitis - 
severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
Interrupt study drug. 
Initiate close observation 
and workup for 
competing etiologies. 
Study drug should not be 
restarted 
Source: Adapted from Chalasani, Naga and Regev, Arie et al. Drug-Induced Liver Injury in Subjects with 
Preexisting Chronic Liver Disease in Drug Development: How to Identify and Manage? Gastroenterology, Volume 
151, Issue 6, 1046 – 1051 


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Close observation for potential drug induced liver injury: 
Within 72 hours, perform a complete history, physical, and liver biochemistries, including 
evaluation of: 
• New or worsening signs and symptoms of clinical hepatitis such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia 
• Concomitant medications, including acetaminophen, dietary supplements, herbal 
remedies, over-the-counter medications, recreational drug use, and special diets 
• Alcohol consumption 
• Exposure to environmental chemical agents 
• Past medical history 
• Complete review of systems 
• Liver biochemistries including ALT, AST, alkaline phosphatase, total bilirubin, and 
INR. 
Evaluate patients two or three times a week for signs and symptoms of clinical hepatitis and 
obtain liver biochemistries until biochemistries stabilize. 
If biochemistries stabilize and the subject is asymptomatic, monitor liver biochemistries once a 
week until they return to baseline. 
Patients who live far from study sites may be evaluated locally for history, physical exam, and 
laboratories, if the results are communicated promptly to the site investigator. 


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APPENDIX 2. Pulmonary Function Monitoring 
Pulmonary function will be monitored closely throughout the AROAAT2002 study using 
spirometry, DLCO, weekly sponsor reviews and medical monitoring for pulmonary AEs. 
• If a patient in the AROAAT2002 study experiences a decline of 10% or more in percent 
of predicted FEV1 (must be confirmed on repeat within 30 days) from baseline with 
symptoms of chronic obstructive pulmonary disease (COPD) exacerbation, 
• OR experiences a decline in percent of predicted FEV1 by 10% (must be confirmed on 
repeat within 30 days) AND a decline in percent of predicted DLCO of at least 10%, 
• OR a decline of percent of predicted FEV1 of 20% or more (must be confirmed on repeat 
within 30 days), regardless of concurrent symptoms and regardless of any drop in percent 
of predicted DLCO,  
they will be referred to a pulmonologist for possible initiation of augmentation therapy. 
Arrowhead will provide the therapy in any instance where the patient cannot access it through 
normal channels. Additionally, pulmonary monitoring visits for spirometry will be increased to 
approximately monthly.  
If deemed necessary by the treating pulmonologist, AAT augmentation therapy may be initiated 
per locally approved package insert (typically weekly infusions at 60 mg/kg per dose) or 
equivalent for the duration of the AROAAT2002 study while the subject is on fazirsiran and for 
up to an additional six months after the subject’s Z-AAT levels have returned to within 30% of 
their pre-dose Day 1 baseline AAT value OR until AAT levels have returned to within 30% of 
pre-dose Day 1 baseline and pulmonary function parameters (either DLCO or FEV1) have 
stabilized (defined as two sequential measurements that are not declining) OR until cessation of 
augmentation therapy is deemed appropriate by treating pulmonologist. In the circumstance of 
patients in the study newly started on AAT augmentation therapy, measurement of AAT may 
increase in frequency from SOA to monthly or every two weeks. This measurement may be done 
with a Z-AAT specific assay or may require occasional AAT augmentation washout for 
measurement of endogenous production using the clinical AAT assay. In countries where 
augmentation is not available or not reimbursed, Sponsor will work to make therapy available as 
part of the AROAAT2002 clinical study. 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 87 of 89 
APPENDIX 3. FIBROSIS STAGING SYSTEMS GUIDANCE 
Guidance on the acceptable fibrosis scores based on different fibrosis staging systems for 
purposes of determining eligibility for the AROAAT2002 clinical trial. 
The study relies on local pathologists for histological inclusion/exclusion evaluation. As such, 
Table 1 provides the numerical scores for commonly used fibrosis staging systems and highlights 
the scores accepted for liver fibrosis eligibility in AROAAT2002.  The below figures and tables 
from published sources provide further reference for the staging system description and 
representative histological images. Sponsor recommends use of Ishak, Metavir or Scheuer 
Systems. 
Table A1. Commonly used systems for fibrosis and general numerical comparison (yellow 
highlight represents stages eligible AROAAT2002 study) 
Ishak 
 
Metavir 
Kleiner 
Scheuer 
Batts and 
Ludwig 
2002 STUDY 
ELLIGIBILITY 
0 
 
0 
0 
0 
0 
NO 
1 
 
1 
1a  
1 
1 
YES 
1b 
 
2 
 
2 
1c 
2 
2 
YES 
3 
2 
YES 
4 
 
3 
3 
3 
3 
YES 
5 
YES 
6 
 
4 
4 
4 
4 
NO 
 
Figure A1. Illustrative numerical comparison for common fibrosis staging (Fiel, MI. Clin Liver 
Dis. 14 [2010] 555-575) 
 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 88 of 89 
Table A2 Descriptive terms and corresponding fibrosis scores for common fibrosis staging 
systems (Fiel, MI. Clin Liver Dis. 14 [2010] 555-575) 
 
Table A3 Kleiner system descriptive terminology (adapted from Kleiner et al., Hepatology 41 
[2005] 1313-1321. 
Kleiner 
Score 
None 
0 
Perisinusoidal or periportal 
1 
Mild, zone 3, perisinusoidal 
1a 
Moderate, zone 3, perisinusoidal 
1b 
Portal/periportal 
1c 
Perisinusoidal and portal/periportal 
2 
Bridging fibrosis 
3 
Cirrhosis 
4 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2002 
 
Version 7.0, 21 July 2022  
Confidential 
Page 89 of 89 
 
 
Referenced protocol language 
Inclusion 9: 
Liver biopsy indicating Metavir F1- F3 (or equivalent on other grading scales) liver fibrosis 
based on local pathologist read within 6 months of consent.  All patients will still require a liver 
biopsy during the screen period except for prior screened patients who now meet the fibrosis 
criteria as long as there is sufficient material for a baseline assessment.   
 
Exclusion 25: 
Diagnosis of F4 (Metavir) or similar grading scale equivalent indicating definitive cirrhosis on 
pre-dose liver biopsy completed as part of the AROAAT2002 study based on local pathologist 
read or based on historical liver biopsy (last 6 months from consent) with a source verifiable 
pathologist read of definitive liver cirrhosis. 
 
 
 
 
 


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Approval
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Approval


Confidential and Proprietary 
DO NOT COPY or DISTRIBUTE without Written Permission from Arrowhead Pharmaceuticals, Inc. 
Clinical Trial Protocol Approval Form 
Protocol Title/ID: A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the Safety and 
Efficacy of Fazirsiran (TAK-999, ARO-AAT) in Patients with Alpha-1 Antitrypsin Deficiency 
Associated Liver Disease (AATD) / AROAAT2002 
Protocol/Amendment Version: AROAAT2002 Global Protocol Amendment v7.0 
Version Number/Date:  Version 7.0, 21 July 2022 
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Approved by: 
Clinical Development Medical Monitor: 
 
 Date 
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 Date 
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SAP_001.pdf: 
ARO-AAT 
 
 
Statistical Analysis Plan v2.1 
 
AROAAT2002 
 
CONFIDENTIAL 
1 
Arrowhead Pharmaceuticals, Inc. 
 
 
 
 
Statistical Analysis Plan 
 
Investigational Product: 
ARO-AAT 
Protocol Title: 
A Pilot Open Label, Multi-dose, Phase 2 Study to 
Assess the Safety and Efficacy of ARO-AAT in 
Patients with Alpha-1 Antitrypsin Deficiency 
Associated Liver Disease (AATD) 
Study Number: 
AROAAT-2002 
Sponsor: 
Arrowhead Pharmaceuticals, Inc. 
177 East Colorado Boulevard, Suite 700 
Pasadena, CA 91105 USA 
 
Author: 
 
Manager, Statistical Programming 
Arrowhead Pharmaceuticals, Inc. 
 
 
Protocol Version: 
7.0 
 
SAP Version: 
2.1  
 
SAP Approval Date: 
28 OCT 2024 
 
 
 


ARO-AAT 
 
 
Statistical Analysis Plan v2.1 
 
AROAAT2002 
 
CONFIDENTIAL 
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Arrowhead Pharmaceuticals, Inc. 
 
Signature Page 
 
Protocol Title: 
A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the 
Safety and Efficacy of ARO-AAT in Patients with Alpha-1 
Antitrypsin Deficiency Associated Liver Disease (AATD) 
Protocol Number: 
AROAAT2002 
SAP Version/Date: 
Version 2.1 / 28OCT2024 
 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
 
  
Signature 
 Date 
Manager, Statistical Programming  
Arrowhead Pharmaceuticals, Inc. 
Director Alliances Management 
Arrowhead Pharmaceuticals, Inc. 
 
  
Chief Medical Scientist 
Arrowhead Pharmaceuticals, Inc. 
 
 


ARO-AAT 
 
 
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Version Number 
Date (DDMMYYYY) Summary of Changes 
Original (v1.0) 
03MAY2022 
NA 
Amendment 7 (v2.0) 
08FEB2024 
• Updated from Protocol Amendment 6 
to Amendment 7 
• Update section 3.7.5 related to PFT 
data to clarify the Protocol 
Amendment 6 to 7  pre- and post-
bronchodilation for spirometry 
assessments 
• Appendix A filled out for completion 
of entire study scope 
Amendment 7 (v2.1) 
28OCT2024 
Additional liver biopsy parameters are added 
for consistency with the histology manual. 
 


ARO-AAT 
 
 
Statistical Analysis Plan v2.1 
 
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Table of Contents 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...................................................................... 1 
1. 
INTRODUCTION ............................................................................................................... 2 
2. 
STUDY OVERVIEW .......................................................................................................... 2 
2.1 
ENDPOINTS ........................................................................................................................... 2 
2.2 
STUDY DESIGN ..................................................................................................................... 3 
2.2.1 
Overview .......................................................................................................................... 3 
2.2.2 
Randomization and Blinding ............................................................................................ 4 
3. 
STATISTICAL METHODOLOGY .................................................................................... 5 
3.1 
GENERAL CONSIDERATIONS ................................................................................................. 5 
3.1.1 
Hypothesis testing ............................................................................................................ 5 
3.1.2 
Definitions ........................................................................................................................ 5 
3.1.3 
Handling of Missing and Incomplete Data ...................................................................... 6 
3.1.4 
Outliers ............................................................................................................................. 7 
3.2 
ANALYSIS SETS ..................................................................................................................... 7 
3.3 
COVARIATES AND SUBGROUPS ............................................................................................. 8 
3.4 
SUBJECT DATA AND STUDY CONDUCT ................................................................................. 8 
3.4.1 
Subject Disposition .......................................................................................................... 8 
3.4.2 
Protocol Deviations .......................................................................................................... 8 
3.4.3 
Demographic and Baseline Characteristics ...................................................................... 8 
3.4.4 
Medical History ................................................................................................................ 9 
3.4.5 
Concomitant Medication .................................................................................................. 9 
3.4.6 
Investigational Product Exposure .................................................................................... 9 
3.5 
EFFICACY ANALYSES ............................................................................................................ 9 
3.5.1 
Liver Z-AAT protein ........................................................................................................ 9 
3.5.2 
Liver Biopsy ................................................................................................................... 10 
3.6 
ANALYSES OF PHARMACODYNAMIC ENDPOINTS ................................................................ 11 
3.7 
SAFETY ANALYSES ............................................................................................................. 11 
3.7.1 
Adverse Events ............................................................................................................... 11 
3.7.2 
Laboratory Test Results ................................................................................................. 12 


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3.7.3 
Vital Signs and Physical Measurements ........................................................................ 13 
3.7.4 
Electrocardiogram .......................................................................................................... 13 
3.7.5 
Pulmonary Function ....................................................................................................... 13 
3.8 
ANALYSIS OF IMMUNOGENICITY ......................................................................................... 14 
4. 
SAMPLE SIZE DETERMINATION ................................................................................ 14 
5. 
PLANNED ANALYSES ................................................................................................... 14 
5.1 
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES ..................................................... 14 
5.2 
FINAL ANALYSIS ................................................................................................................. 14 
6. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ........................................... 15 
7. 
LITERATURE CITATIONS/REFERENCES................................................................... 15 
8. 
APPENDIX ........................................................................................................................ 15 
8.1 
APPENDIX A: ANALYTICAL DAY ........................................................................................ 15 
 
 
 


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List of abbreviations and definitions of terms 
 
Abbreviation or Term 
Definition/Explanation  
AAT  
Alpha-1 antitrypsin  
AATD  
Alpha-1 antitrypsin deficiency  
ALT  
Alanine aminotransferase  
APRI 
AST to Platelet Ratio Index 
AST  
Aspartate transaminase  
CRF  
Case Report Form  
DLCO  
Carbon Monoxide Diffusing Capacity  
FEV1  
1 second Forced Expiratory Volume  
FIB4 
Fibrosis-4 score 
GGT  
Gamma glutamyl transferase  
ICH  
International Conference on Harmonisation  
ISR  
Injection Site Reaction  
mmHg  
millimeters of mercury  
MRE  
Magnetic Resonance Elastography  
MRI  
Magnetic Resonance Imaging  
MRI-PDFF  
Magnetic Resonance Imaging Proton Density Fat Fraction  
PD  
Pharmacodynamic  
RNAi  
RNA interference  
siRNA  
Short interfering RNA oligonucleotides  
TEAE 
Treatment emergent adverse event 
TESAE  
Treatment emergent serious adverse event 
ULN  
Upper Limit of Normal  
Z-AAT  
Mutant AAT protein from Z allele  
 
 
 
 
 
 
 
 
 
 
 


ARO-AAT 
 
 
Statistical Analysis Plan v2.1 
 
AROAAT2002 
 
CONFIDENTIAL 
2 
Arrowhead Pharmaceuticals, Inc. 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) is designed in compliance with ICH E9 to outline the 
methods to be used in the analysis of study data in order to evaluate the study objective(s) from 
Arrowhead Pharmaceuticals, Inc. (Sponsor) protocol AROAAT-2002 Version 7.0, dated 21 Jul 
2022. Populations for analysis, data handling rules, statistical methods, and formats for data 
presentation are provided. The statistical analyses and summary tabulations described in this 
SAP will provide the basis for the results sections of the clinical study report (CSR) for this trial. 
An approved and signed SAP is required prior to database lock. 
The formats for the tables, figures, listings (TFLs) described in this SAP are provided in a 
companion document. A table of contents for the TFLs will be included. 
2. 
STUDY OVERVIEW 
2.1 
Endpoints 
Primary Endpoint: 
• To evaluate change from baseline over time in total, soluble, and insoluble Z-AAT 
concentrations in the liver of patients with AAT-associated liver disease. 
Secondary Endpoints: 
• To determine the effect of multiple doses of ARO-AAT on circulating levels of Z-
AAT alpha-1 antitrypsin over time versus baseline.  
• To evaluate the effect of ARO-AAT on changes in ALT over time.  
• To evaluate the effect of ARO-AAT on changes in GGT over time. 
• To evaluate the effect of ARO-AAT on changes in FIB4 and APRI over time.  
• To evaluate the effect of ARO-AAT on changes in PRO-C3 over time.  
• To evaluate the effect of ARO-AAT on changes in hepatic stiffness based on 
FibroScan® over time versus baseline (when available). 
• To evaluate effect of ARO-AAT on histological metrics of liver disease in patients 
with AAT-associated liver disease over time. 
• To evaluate change from baseline in Metavir fibrosis score over time in ARO-AAT 
treated patients. 
• To determine the incidence and severity of adverse events as a measure of the safety 
and tolerability of ARO-AAT.  
• Incidence of anti-drug antibodies to ARO-AAT 
 
Exploratory Endpoints: 


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• To evaluate the effect of ARO-AAT on changes in hepatic stiffness based on 
Magnetic Resonance Elastography (MRE) over time versus baseline (optional). 
• To evaluate changes in hepatic SERPINA1 mRNA expression over time versus 
baseline in response to multiple doses of ARO-AAT (if sufficient sample available). 
• To evaluate changes in liver disease related gene expression over time versus baseline 
(if scientifically feasible and sufficient sample available). 
• To evaluate change in liver PAS+D stained globule size and number over time versus 
baseline. 
• To evaluate the effect of ARO-AAT on changes in liver collagen using biomarkers 
(e.g. Pro-C6), special stains and imaging [Masson’s Trichrome, Sirius Red, Iron] (if 
scientifically feasible and sufficient sample available) over time versus baseline. 
• To determine the effect of multiple doses of ARO-AAT on circulating levels of total 
alpha-1 antitrypsin at multiple post-dose time points versus baseline (patients on and 
not on AAT augmentation therapy will be evaluated separately). 
• Any data-driven exploratory endpoint 
 
2.2 
Study Design 
2.2.1 Overview 
This is a multi-center, multi-dose, open-label, Phase 2 study conducted to evaluate the safety and 
efficacy of the investigational product, ARO-AAT, administered subcutaneously to patients with 
Alpha-1 Antitrypsin Deficiency.  
The study will include 3 study periods: 1) a Primary Study Period, 2) an optional Treatment 
Extension I, and 3) an optional Treatment Extension II, which are described below.  
Primary Study Period (6-12 Months) 
Participants who have signed an IRB/EC approved informed consent and have met all the 
protocol eligibility criteria during Screening, will be enrolled in one of three cohorts: 
• Cohort 1: 200 mg dose of subcutaneous ARO-AAT  
• Cohort 1b: 100 mg dose of subcutaneous ARO-AAT  
• Cohort 2: 200 mg dose of subcutaneous ARO-AAT  
Cohorts 1 and 1b will receive a minimum of 3 doses and Cohort 2 will be receiving a minimum 
of 5 doses. All subjects will have a baseline biopsy and post-baseline biopsy at Week 24 
(Cohorts 1 and 1b) OR at Week 48 (Cohort 2) per the Schedule of Assessments, OR at Early 
Termination. At the end of the Primary Study Period, subjects will be offered the opportunity to 
continue treatment in the open-label Treatment Extension I. Participants who drop out prior to 
biopsy at the end of the Primary Study Period for reasons other than an AE considered at least 
possibly related to drug, may be replaced. 
Treatment Extension I (12 Months) 


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Subjects who opt to continue in Treatment Extension I will receive the same dose level of ARO-
AAT as administered in their assigned initial cohort every 12 weeks (Q12W). Dosing with ARO-
AAT may continue approximately 12 weeks from the previous dose in the Primary Study Period. 
All subjects who opted to continue will have a biopsy at Week 44 of Treatment Extension I. At 
the end of this study period, subjects may opt to continue treatment for up to an additional 24 
months in Treatment Extension II. 
Treatment Extension II (up to 24 Months) 
Subjects will continue to receive the same dose level of ARO-AAT Q12W for up to an additional 
24 months or until they roll over into another long-term Extension study, whichever comes first. 
Dosing with ARO-AAT may continue approximately 12 weeks from the previous dose in 
Treatment Extension I. No biopsies will be collected in Treatment Extension II. 
 
Primary Study Period 
Treatment Extension I 
Treatment Extension II 
 
 
2.2.2 Randomization and Blinding 
This is an open label study, and no randomization is conducted. 


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3. 
STATISTICAL METHODOLOGY 
 
3.1 
General Considerations 
Tabulations will be produced for appropriate demographic, baseline, efficacy, 
pharmacodynamics, and safety parameters. 
Descriptive statistics on categorical variables will be reported using frequencies and percentages. 
All percentages will be presented with one-decimal point. For categorical variables, summary 
tabulations of the number and percentage within each category (with a category for missing data) 
of the parameter will be presented. Percentages equal to 100 will be presented as 100% and 
percentages will not be presented for zero frequencies, but the categories whose counts are zero 
will be displayed for the sake of completeness.  
Descriptive statistics on continuous variables will be summarized using the mean, median, 
standard deviation, minimum and maximum values. The same number of decimal places as in 
the raw data will be presented when reporting min and max, 1 more decimal place than in the 
raw data will be presented when reporting mean and median, and 2 more decimal places than in 
the raw data will be presented when reporting SD.  
Considering subjects from cohort 1 and cohort 2 will receive 200 mg dose of AROAAT but 
different schedule of assessment and subjects from cohort 1b will receive 100 mg dose of 
AROAAT, analyses will be broadly displayed by cohorts (cohort 1b, cohort 1, cohort 2) and dose 
level (100 mg and 200 mg) without specification. All data will be summarized as observed 
except specify otherwise 
3.1.1 Hypothesis testing 
No formal hypothesis is considered for this open label study. The analysis will be descriptive in 
nature.  
3.1.2 Definitions 
Baseline: Baseline value is defined as the latest non-missing value measured prior to the first 
dose of investigational product.  
TEAE: treatment emergent adverse event is defined as adverse event first occurred or worsened 
in severity following IP administration through EOS or early termination whichever is earlier. 
TESAE: treatment emergent serious adverse event is defined as adverse event first occurred or 
worsened in severity following IP administration through EOS or early termination whichever is 
earlier. 
Analytical Day: Since each cohort has different schedule of assessment and there are multiple 
treatment periods involved in this study. By visit analyses will be displayed using analytical day 
described in Appendix A.  
FIB-4: FIB-4 is calculated as  


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𝐹𝐼𝐵4 =
𝐴𝑔𝑒 (𝑦𝑟) ∗𝐴𝑆𝑇(𝑈/𝐿)
𝑃𝑙𝑎𝑡𝑒𝑙𝑒𝑡 𝐶𝑜𝑢𝑛𝑡(109/𝐿) ∗√𝐴𝐿𝑇(𝑈/𝐿)
 
APRI: APRI is calculated as  
𝐴𝑃𝑅𝐼=
𝐴𝑆𝑇(𝑈/𝐿)
𝐴𝑆𝑇(𝑢𝑝𝑝𝑒𝑟 𝑙𝑖𝑚𝑖𝑡 𝑜𝑓 𝑛𝑜𝑟𝑚𝑎𝑙 𝑈/𝐿)
𝑃𝑙𝑎𝑡𝑒𝑙𝑒𝑡 𝐶𝑜𝑢𝑛𝑡(109/𝐿)
 
Injection site reaction (IRS): AEs at the injection site is captured in eCRF. 
3.1.3 Handling of Missing and Incomplete Data 
Subjects maybe missing specific data points for various reasons. In general, data may be missing 
due to a subject’s early withdrawal from study, a missed visit or non-evaluability of a data point 
or an endpoint at a particular point in time. Queries will be made to the sites to distinguish true 
missing values from other unknown values (due to measurement or sample processing error). All 
attempts will be made to capture missing or partial data for this trial before planned analyses and 
database lock.  
Adverse event, prior and concomitant mediation, and medical history with completely or partial 
missing start dates will be queried. After the issue is queried, if the date is still incomplete, the 
start date will be imputed as described in Table below. 
 Missing 
Imputation 
Exception 
Day 
01 
Default to Study Day 1 if an 
AE, medication/procedure 
starts the same year and 
month as Study Day 1 and 
the end date has same year 
and month as Study Day 1 
or later.  
 
Day / Month  
 
01 / Jan  
 
Default to Study Day 1 if an 
AE, medication/procedure 
starts the same year as Study 
Day 1 and the end date has 
same year as Study Day 1 or 
later.  
 
Day / Month / Year  
 
To calculate a missing 
start date:  
1. If a partial or complete 
stop date is present:  
 


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a. Stop date < first dosing 
date: impute January 1 of 
the stop year  
b. Stop date ≥ first dosing 
date: impute the date of 
first dose  
2. If it is unknown whether 
the stop date is < or ≥ first 
dosing date due to a 
missing or partial stop 
date, or if a stop date is not 
collected: impute date of 
first dose.  
 
Medications and procedures with missing or partial end dates will be assumed to be concomitant 
unless a partial end date documents it as ending prior to treatment. 
The original missing or partial date, the imputed complete date, and an indicator variable that 
indicates which dates were imputed will be retained in the database. Dates will be presented as 
collected in all listings. Imputed dates will not be presented in listings but may be used for 
summary tables. 
3.1.4 Outliers 
Descriptive statistics may be used to identify outliers of key variables. However, no statistical 
analysis or adjustment for outliers is planned; outliers will not be omitted from summaries. 
 
3.2 
Analysis Sets 
Safety Analysis Set 
Safety Analysis Set includes all subjects who receive at least one dose of study drug. The Safety 
Analysis Set will be used for safety endpoints, pharmacodynamics endpoints and efficacy 
endpoints.  
Full Analysis Set (FAS):  
Full Analysis Set includes all subjects who receive at least one dose of study drug and have 
baseline and post-dose liver biopsy histology results available. FAS population will be used for 
all efficacy analyses. 
Per Protocol (PP) Set:  
Per Protocol (PP) Set includes all FAS patients who did not violate the protocol in a substantial 
manner, such determination to be made prior to database lock.  


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3.3 
Covariates and Subgroups 
Not applicable 
3.4 
Subject Data and Study Conduct 
3.4.1 Subject Disposition 
The number and percentage of subjects received investigational product, completed study and 
discontinued study (primary reasons for early termination) will be summarized using Safety 
Analysis Set. Key study dates for the first subject enrolled, last subject enrolled, and last 
subject’s end of study will be presented.  
3.4.2 Protocol Deviations 
The number and percentage of randomized subjects with important protocol deviations will be 
summarized by deviation category and by as-randomized treatment group and overall. Deviation 
categories will be presented in descending order of overall frequency.  
A by-subject listing of protocol deviations will be provided for enrolled subjects. The Safety 
Analysis Set will be used to summarize protocol deviations.  
3.4.3 Demographic and Baseline Characteristics 
Demographics data will include:  
• Age (in years), also categorized as < 50, 50-65, ≥ 65  
• Sex (male, female)  
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino)  
• Race (American Indian or Alaska Native, Asian, Black, Native Hawaiian or Other Pacific 
Islander, White, Other, Not Reported, Unknown)  
Baseline characteristics and disease history include:  
• Weight (kg)  
• Height (cm)  
• BMI (kg/m2)  
• Subject has past medical conditions (yes, no)  
• Subject has smoking history (yes, no)  
• Subject smoked cigarettes/e-cigarettes within the past 12 months (yes, no)  
• Fibrosis score at baseline (central reading) 
• FEV1 at baseline 
• Percent predicted FEV1 at baseline 
• PiZZ genotype confirmed (yes, no)  
• On AAT augmentation therapy (yes, no)  
• Gilbert’s Syndrome (yes, no)  


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3.4.4 Medical History 
Medical history will be summarized by system organ class (SOC) and preferred term (PT), and 
displayed in descending order of overall frequency within SOC and PT.  
A by-subject listing of medical history will be provided based on Safety Analysis Set.  
3.4.5 Concomitant Medication 
Concomitant medications will be defined as all medications taken by the patient any time on-
study treatment or within 28 days after the last administration date of investigational product. 
Prior medications will be defined as all medications taken by the patient before the first injection 
of the study drug.  
Prior and concomitant medications will be coded using the WHO-DD. Results will be tabulated 
alphabetically by Anatomic Therapeutic Class (ATC) and Preferred Name. For each subject, 
multiple records of the same medication will be counted only once within each ATC and/or 
Preferred Name.  
In case the date value does not allow allocation of a medication to prior or concomitant category, 
the medication will be considered as concomitant.  
Concomitant and prior medications will be summarized using data recorded in the “Concomitant 
Medications/Therapies” eCRF pages.  
A by-subject listing of concomitant medications/therapies will be provided. Prior and 
concomitant medications will be flagged. 
3.4.6 Investigational Product Exposure 
Study drug exposure will be summarized descriptively by treatment group for treated subjects, 
and will include the following parameters:  
• Total number of injections received  
• Duration of study follow-up (weeks)  
• Number and percentage of subjects in the following duration of study follow-up 
categories: 0 to 24 weeks, >24 to 48 weeks, >48 to 72 weeks, >72 weeks  
3.5 
Efficacy Analyses 
Analysis of efficacy endpoints will be based on Full Analysis Set.  
3.5.1 Liver Z-AAT protein 
Descriptive statistics and derived change from baseline and percent change from baseline in 
insoluble Z-AAT protein, soluble Z-AAT protein and total Z-AAT protein will be summarized. 
Owing to the limited sample size of each cohort, changes from baseline may be tested using non-
parametric Wilcoxon signed-rank test for significance due to data availability.  
For measurement of intra-hepatic Z-AAT below the detection limit, half of the lower limit value 
will be imputed for summaries.  


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A by-subject liver Z-AAT listing will be provided. Listing won’t include imputed values. 
3.5.2 Liver Biopsy 
For METAVIR fibrosis score, a descriptive statistics summary displaying the number and 
percent of subjects having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 
1-point worsening from each of the baseline category will be generated. A shift table of 
METAVIR fibrosis score (F0–F4) from baseline to post-baseline (F0-F4) score will be 
presented.  
Similarly, percent of subjects having improvement from baseline, no change from baseline and 
worsening from each of the baseline category in following liver biopsy parameters will be 
summarized. 
• PAS+D Globule Burden (0-9) (Sum of Globule Portal Tract Involvement, Periportal 
Hepatocyte Involvement, and Zonal Location).  
• Globule Portal Tract Involvement (0-3) 
• PAS+D Zonal Location (0-3) 
• Zone 1 Globule Periportal Involvement (0-3) 
• Globule Burden of Globules > RBC (0-3) 
• Globule Size (0-3) 
• Portal Inflammation (0-3) 
• Interface Hepatitis (0-3) 
• Lobular Inflammation (0-3) 
• Hepatocyte Cell Death (0-2) 
• Steatosis (0-3) 
• Brunt Macrovascular Steatosis Score (0-3) 
• Hepatocellular Ballooning (0-3) 
• NASH Diagnosis (0-3) 
• ISHAK Fibrosis (0-6) 
• Ductular Reaction (0-2) 
• Iron Deposition (0-4) 
• Periportal Lipofuscin (0-1) 
• AATD Liver Disease Severity (0-3) 
 
PAS+D Globule Burden includes portal tract involvement, periportal hepatocyte involvement 
and zonal location. Each give a score 0-3, equal weight will be assigned and calculated the total 
aggregate score 0-9. Descriptive statistics and change from baseline in PAS+D Globule Burden 
will be also summarized.  
In addition, overall shift table of METAVIR score, PAS+D globule burden, portal inflammation, 
interface hepatitis, hepatocyte cell death and lobular inflammation will be provided. The number 
and percent of subjects having ≥ 1-point improvement from baseline, no change from baseline, 
and ≥ 1-point worsening from baseline will be summarized based on eligible baseline scores. For 
example, if 3 out of 4 subjects have portal inflammation improve and only these 3 subjects have 


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baseline scores more than 0 and the other subject has baseline score as 0, the percent of 
improvement will be calculated as 3 out of 3, which is 100%. The denominator of this overall 
summary will be the number of subjects who are eligible to meet the improvement or worsening 
condition. 
A by-subject listing will be provided to present liver biopsy data. 
3.6 
Analyses of Pharmacodynamic Endpoints 
Analyses of pharmacodynamic endpoints will be based on Safety Analysis Set. 
Serum ZAAT protein 
Descriptive statistics and derived change from baseline and percent change from baseline in 
serum ZAAT will be summarized. The change from baseline in serum Z-AAT may be tested by 
non-parametric Wilcoxon signed-rank test at scheduled visit. 
A by-subject serum Z-AAT listing will be included. 
Longitudinal plots of serum Z-AAT and percent change in serum Z-AAT will be generated.  
Serum Fibrosis and Imaging Markers 
Descriptive statistics and derived change from baseline and percent change from baseline in 
following PD parameters will be provided 
• FIB4 and APRI 
• PRO-C3 
• Hepatic stiffness (FibroScan) 
The derivation of FIB4 and APRI refer to Section 3.1.2 Definition. 
Descriptive statistics and change from baseline of MRE may be summarized based on data 
availability. 
3.7 
Safety Analyses 
Safety data will be summarized using Safety Analysis Set. 
3.7.1 Adverse Events 
All AEs and SAEs will be collected and reported in the patient’s eCRF throughout study 
duration, i.e., from the first trial related activity after the subject signs the informed consent and 
until EOS. 
The Medical Dictionary for Regulatory Activities (MedDRA) version 21.1 or later will be used 
to code all events categorized as adverse events to a system organ class and a preferred term. 
An overall summary of AEs will be provided. The overall summary will include the number and 
percentage of subjects reporting at least one: TEAE; mild TEAE; moderate TEAE; severe 


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TEAE; TEAE possibly related to study drug; TEAE probably related to study drug; TESAE; 
TEAE leading to study drug discontinuation; TEAE leading to study termination; and deaths. 
Subject incidence of all treatment-emergent adverse events, treatment-emergent serious adverse 
events, treatment-emergent treatment related adverse events, treatment-emergent adverse events 
leading to discontinuation of investigational product, fatal adverse events and injection site 
reaction will be tabulated by system organ class and preferred term in alphabetical order.  
Subject incidence of all treatment-emergent adverse events, treatment-emergent serious adverse 
events will be tabulated by preferred term in descending order of frequency. 
Summaries of treatment-emergent and serious adverse events will be tabulated by system organ 
class, preferred term, and grade. 
A by-subject listing of all AEs reported in the eCRF will be provided. Duration of AE (i.e., AE 
end date – AE start date + 1) will be included in the listing. Separate listings will be presented for 
all SAEs, deaths, and injection site reaction AEs.  
3.7.2 Laboratory Test Results 
Laboratory data including biochemistry, hematology, coagulation and urinalysis will be 
summarized using descriptive statistics at each scheduled timepoint in study. For continuous 
parameters, a summary of the change from baseline and percent change from baseline to each 
post dose laboratory assessment will be produced. Shifts in selected laboratory parameters 
including ALT, AST, alkaline phosphatase, CK, GGT, total bilirubin, and INR between baseline 
and the worst on-study value will be summarized by NCI CTCAE toxicity grades. The number 
and percent of subjects will be reported in each shift category.  
Separate summary table will be generated for lab parameters of interests, but not limited to, 
ALT, AST, alkaline phosphatase, CK, GGT, total bilirubin. Longitudinal plots of these 
laboratory parameters by visit and treatment group will be generated as well. An evaluation of 
drug-induced serious hepatotoxicity (eDISH) scatter plot will be produced. Maximum total 
bilirubin (presented as xULN) will be plotted on a log scale on the y-axis and maximum ALT 
(presented as xULN) will be plotted on a log scale on the x-axis. A horizontal reference line will 
be placed at 2x ULN for maximum total bilirubin, and a vertical reference line will be placed at 
3x ULN for maximum ALT. The lower left quadrant will be labeled “Normal Range”. The upper 
left quadrant will be labeled “Cholestasis Quadrant”. The lower right quadrant will be labeled 
“Temple’s Corollary Quadrant”. The upper right quadrant will be labeled “Hy’s Law Quadrant”.  
All laboratory data will be provided in data listings. A subset listing will be presented for all 
clinically significant abnormal laboratory values. This listing will present all lab values for any 
parameter with at least one clinically significant abnormal value so that a time course for that lab 
parameter can be presented. 


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3.7.3 Vital Signs and Physical Measurements 
Vital signs include body temperature (°C), heart rate (beats/min), respiratory rate (breaths/min), 
systolic and diastolic blood pressures (mmHg). Physical measurements include height (cm, 
measured only at baseline), weight (kg), and BMI (kg/m2).  
The observed value and change from baseline in vital signs and physical measurements will be 
summarized at each visit. A by-subject listing will be provided as well.  
3.7.4 Electrocardiogram 
ECG parameters will include heart rate (beats/min), PR interval, QRS interval, QT interval, and 
QTcF interval.  
The observed value and change from baseline in ECG parameters will be summarized as 
continuous variables at baseline and each post-baseline visit.  
ECG interpretation shift from baseline to each post-baseline timepoint will be summarized as the 
number and percentage of subjects with normal, clinically insignificant abnormal, and clinically 
significant abnormal interpretations.  
By-subject listing of ECG data will be provided and repeat ECGs will be flagged.  
3.7.5 Pulmonary Function 
Descriptive statistics and the derived change from baseline and percent change from baseline in 
FEV1(L), VC(L), FVC (L), DLCO (mL/min/mmHg) and DLCO adjusted for 
hemoglobin(mL/min/mmHg) will be provided by the scheduled study visit. Descriptive statistics 
and the derived change from baseline in percent predicted FEV1, percent predicted VC, percent 
predicted FVC, percent predicted DLCO and percent predicted DLCO adjusted for hemoglobin 
will be provided by the scheduled study visit. 
DLCO adjusted for hemoglobin is defined as below  
𝐷𝐿𝐶𝑂ℎ𝑔𝑏(𝑀𝑎𝑙𝑒 𝑎𝑛𝑑 𝑎𝑔𝑒≥15 𝑦𝑟) = 𝐷𝐿𝐶𝑂 (10.22 + 𝐻𝑔𝑏)/(1.7 ∗𝐻𝑔𝑏) 
𝐷𝐿𝐶𝑂ℎ𝑔𝑏(𝐹𝑒𝑚𝑎𝑏𝑙𝑒 𝑜𝑟 𝑎𝑔𝑒< 15 𝑦𝑟) = 𝐷𝐿𝐶𝑂(9.38 + 𝐻𝑔𝑏)/(1.7 ∗𝐻𝑔𝑏)  
where Hgb is the value of hemoglobin collected same day as measurement of DLCO. 
Proportion of subject who meet following pulmonary function decline will be summarized by 
each schedule visit.  
• Decline from baseline in FEV1 ≥ 200 ml, ≥ 300ml, ≥10%, ≥ 15% 
• Decline from baseline in FVC ≥ 200 ml, ≥ 300ml, ≥10%, ≥ 15% 
• Decline from baseline in DCLO ≥ 6.5 ml/(min*mmHg), ≥10%, ≥ 15% 
• Decline from baseline in DCLO adjusted for hemoglobin ≥ 6.5 ml/(min*mmHg), ≥10%, 
≥ 15% 
PFT data will be summarized by baseline augmentation status Yes vs No and overall. 


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Longitudinal plots of PFT parameters (FEV1, FVC and DLCO adjusted and unadjusted for 
hemoglobin) and change from baseline in percent predicted PFT parameters will be generated.  
A by-subject listing of pulmonary function test results will be provided. 
The number of patients that require augmentation treatment at any time throughout the study will 
be summarized. Time from baseline to initiation of augmentation therapy maybe summarized 
using Kaplan Meier estimates due to data availability.   
After Protocol Amendment 7, PFT text was updated to clarify instructions for performing 
spirometry, to acknowledge acceptability of following bronchodilator administration as per site 
practice. See protocol section 9.3.4 from Amendment 6 “All spirometry and DLCO values 
recorded will be those completed post-bronchodilation (unless contraindicated or unavailable).” 
vs. Amendment 7 “All spirometry and DLCO values collected and recorded will include both 
pre- and post-bronchodilation measurements [unless contraindicated or unavailable].”.  Thus, 
for spirometry assessments (FEV1, VC, FVC), in addition to summarizing pre- and post-
bronchodilation measurements separately, additional summaries will be provided where post-
bronchodilation measurements are used when available and pre-bronchodilation measurements 
are used in the absence.  
3.8 
Analysis of Immunogenicity 
Immunogenicity will be assessed for anti-drug antibodies. Results will be described by frequency 
tables on patients with presence of anti-drug antibodies, by time of assessment using Safety 
Analysis Set.  
Summary statistics for changes from baseline in detected levels of anti-drug antibodies will be 
calculated and presented.  
Immunogenicity data will be provided in a by-subject listing. 
4. 
SAMPLE SIZE DETERMINATION 
No formal sample size calculations were conducted in this open label exploratory study. 
5. 
PLANNED ANALYSES 
 
5.1 
Interim Analysis and Early Stopping Guidelines 
No formal interim analysis is planned for this study. Since this is an open label study, ad hoc 
interim analyses maybe performed depending on business need. Ad hoc interim analyses will be 
descriptive in nature. 
5.2 
Final Analysis 
The Final Analysis will be performed once all subjects complete the last visit or early 
termination whichever is earlier and after database lock. Data will be cleaned, and all queries 
will be addressed before database lock. 


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6. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
There have been no changes between the Protocol AROAAT2002 V7.0 defined statistical 
analyses and those presented in this statistical plan. 
7. 
LITERATURE CITATIONS/REFERENCES 
Conover, W. J. (1999). Practical nonparametric statistics (3rd ed.). John Wiley & Sons, 
Inc. ISBN 0-471-16068-7., p. 350 
Macintyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath determination of 
carbon monoxide uptake in the lung. Eur Respir J 2005; 26:720. 
Sterling RK, Lissen E, Clumeck N, et. al. Hepatology: Official Journal of the American 
Association for the Study of Liver Diseases 2006, 43 (6): 1317-25 
Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate aminotransferase-to-platelet ratio 
index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 
2011;53:726-36. 
Teckman J, Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Understanding and Future 
Therapy. COPD 2013 (10)S1:35-43.  
 
 
 
 
8. 
APPENDIX 
8.1 Appendix A: Analytical Day 
Analytical Day for cohort 1 and cohort 1b 
Study Period 
Visit 
Analytical Day 
Primary (3 DOSES) 
Screening 
Screening 
Day 1 * 
Day 1 * 
Day 2 (24-48 hr) PSD 
Day 2 (24-48 hr) PSD 
Wk 2 
Wk 2 
Wk 4 * 
Wk 4 * 
Wk 4 (24-48 hr) PSD 
Wk 4 (24-48 hr) PSD 


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Wk 6 
Wk 6 
Wk 16 * 
Wk 16 * 
Wk 16 (24-48 hr) PSD 
Wk 16 (24-48 hr) PSD 
Wk 24  
Wk 24  
12 Wk Post Last Dose 
Wk 28 
Extension I (4 DOSES) 
Day 1 * 
Wk 28 + 1 day * 
Wk 6 
Wk 34 
Wk 12 * 
Wk 40 * 
Wk 18 
Wk 46 
Wk 24 * 
Wk 52 * 
Wk 30 
Wk 58 
Wk 36 * 
Wk 64 * 
Wk 44 
Wk 72 
Extension II (8 DOSES) 
Wk 48 * 
Wk 76 * 
Wk 54 
Wk 82 
Wk 60 * 
Wk 88 * 
Wk 66 
Wk 94 
Wk 72 * 
Wk 100 * 
Wk 78 
Wk 106 
Wk 84 * 
Wk 112 * 
Wk 92  
Wk 120 
 
Wk 96 * 
Wk 124 * 
 
Wk 104 
Wk 132 
 
Wk 108 * 
Wk 136 * 
 
Wk 116 
Wk 144 
 
Wk 120 * 
Wk 148 * 
 
Wk 128 
Wk 154 
 
Wk 132 * 
Wk 160 * 


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Wk 140 
Wk 168 
 
Analytical Day for cohort 2 
Study Period 
Visit 
Analytical Day 
Primary (5 DOSES) 
Screening 
Screening 
Day 1 * 
Day 1 * 
Day 2 (24-48 hr) PSD 
Day 2 (24-48 hr) PSD 
Wk 2 
Wk 2 
Wk 4 * 
Wk 4 * 
Wk 4 (24-48 hr) PSD 
Wk 4 (24-48 hr) PSD 
Wk 6 
Wk 6 
Wk 16 * 
Wk 16 * 
Wk 16 (24-48 hr) PSD 
Wk 16 (24-48 hr) PSD 
Wk 22 
Wk 22 
Wk 28 * 
Wk 28 * 
Wk 34  
Wk 34  
Wk 40 * 
Wk 40 * 
Wk 48  
Wk 48  
12 Wk Post Last Dose 
Wk 52 
Extension I (4 DOSES) 
Day 1 * 
Wk 52 + 1 day * 
Wk 6 
Wk 58 
Wk 12 * 
Wk 64 * 
Wk 18 
Wk 70 
Wk 24 * 
Wk 76 * 
Wk 30 
Wk 82 
Wk 36 * 
Wk 88 * 
Wk 44 
Wk 96 
Extension II (8 DOSES) 


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Wk 48 * 
Wk 100 * 
Wk 54 
Wk 106 
Wk 60 * 
Wk 112 * 
Wk 66 
Wk 118 
Wk 72 * 
Wk 124 * 
Wk 78 
Wk 130 
Wk 84 * 
Wk 136 * 
Wk 92  
Wk 144 
Wk 96 * 
Wk 148 * 
 
Wk 104 
Wk 154 
 
Wk 108 * 
Wk 160 * 
 
Wk 116 
Wk 168 
 
Wk 120 * 
Wk 172 * 
 
Wk 124 
Wk 176 
 
Wk 132 * 
Wk 184 * 
“*” denotes dosing day.