Clinical trial NCT03945292
Conditions: Alpha 1-Antitrypsin Deficiency
Sponsor: Arrowhead Pharmaceuticals
Start date: 2019-08-07; Completion date: 2023-09-18
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of AROAAT2001 (SEQUOIA) is to evaluate the safety, efficacy and tolerability of multiple doses of the investigational product, Fazirsiran Injection, administered subcutaneously to participants with alpha-1 antitrypsin deficiency (AATD).

Detailed description:
Participants will be enrolled to receive multiple subcutaneous injections of Fazirsiran Injection (also referred to as TAK-999 Injection or ARO-AAT Injection) or placebo. Eligible participants will require a pre-dose biopsy completed as part of the study within the screening window. However, any participant with a biopsy result within 1 year of screening showing no fibrosis does not require a pre-dose biopsy. Only participants who have liver fibrosis will undergo a post-dose biopsy and may continue treatment in an open-label phase.

Arms: arm 1: Double-blind (DB) Period: Participants with no fibrosis: Administered on Day 1 and Week 4. Participants with fibrosis: Administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Open-label (OL) Period: Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 25 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study. arm 2: DB Period: Participants with no fibrosis: Fazirsiran 100 mg administered on Day 1 and Week 4. Participants with fibrosis: Fazirsiran 100 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

OL Period: Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 100 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study. arm 3: DB Period: Participants with no fibrosis: Fazirsiran 200 mg administered on Day 1 and Week 4.

Participants with fibrosis: Fazirsiran 200 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

OL Period: Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 200 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study arm 4: DB Period: Participants with no fibrosis: Placebo administered on Day 1 and Week 4. Participants with fibrosis: Placebo administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

OL Period: Participants with fibrosis at Screening who received double-blind (DB) placebo and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.
Interventions: intervention 1: Fazisiran Injection intervention 2: Placebo
Intervention descriptions: intervention 1: solution for subcutaneous (sc) injection intervention 2: sterile normal saline (0.9% NaCl), calculated to match active comparator, for sc injection

Protocol documents:
Prot_000.pdf: 
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PROTOCOL 
NUMBER: 
AROAAT2001 
STUDY TITLE: 
A Placebo-Controlled, Multi-dose, Phase 2 Study to 
Determine the Safety, Tolerability and Pharmacodynamic 
Effect of Fazirsiran (TAK-999, ARO-AAT) in Patients with 
Alpha-1 Antitrypsin Deficiency (AATD) [SEQUOIA]  
 
DRUG (Active): 
Fazirsiran (TAK-999, also referred to as ARO-AAT) Injection 
 
ROUTE: 
Subcutaneous Injection  
 
STUDY DESIGN: 
A multi-center, multi-dose placebo-controlled Phase 2 study 
will be conducted to evaluate the safety, tolerability, and 
pharmacodynamic effect 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 Blvd., Suite 700 
Pasadena, CA 91105 
Telephone: +1 626 304-3400 
Facsimile: +1 626 304-3401 
 
 
EudraCT 
Number: 
2018-003385-14 
 
 
Version: 
6.0 Global, 29 August 2022 
 
 
 
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 Placebo-Controlled, Multi-dose Phase 2 Study to Determine the Safety, 
Tolerability and Pharmacodynamic Effect of Fazirsiran (TAK-999, ARO-AAT) in Patients with 
Alpha-1 Antitrypsin Deficiency (AATD) [SEQUOIA] 
Study Number: AROAAT2001 
Phase: Phase 2  
Location: Multiple sites in the United States and Europe.  
Study Treatments:  
There will be 2 study treatments; one active and one placebo. 
Active: Fazirsiran Injection (also referred to as ARO-AAT Injection or TAK-999 Injection) 
The active pharmaceutical ingredient (API) fazirsiran is a synthetic, double-stranded, small 
interfering RNA oligonucleotide (siRNA) duplex conjugated to an N-acetyl-galactosamine 
targeting ligand to facilitate hepatocyte delivery. 
Placebo (PBO) 
The placebo used in this study is normal saline (0.9%) administered subcutaneously, volume 
matched to the corresponding fazirsiran dose volume. 
Primary Objective: 
• To select a single dose for use in later stage development based on a combined 
evaluation of safety and pharmacodynamic (PD) effects of fazirsiran 
Primary Endpoint: 
• Percent change from baseline at Week 16 in serum Z-AAT 
Secondary Endpoints: 
• Subject incidence of treatment-emergent adverse events (AEs) 
• Absolute and percent change from baseline in total liver Z-AAT 
(insoluble + soluble) protein at post-dose biopsy visit 
• Absolute and percent change from baseline in liver Z-AAT soluble protein at 
post-dose biopsy visit 


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• Absolute and percent change from baseline in liver Z-AAT insoluble protein at 
post-dose biopsy visit 
• Absolute and percent change from baseline in liver function tests including alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, 
gamma glutamyl transferase (GGT), total bilirubin, direct bilirubin, and international 
normalized ratio (INR) at Week 16 and over time through End of Study (EOS) 
• Absolute and percent change in serum Z-AAT over time through EOS 
• Change over time in pharmacokinetic (PK) measurements of fazirsiran at timepoints 
specified in the Schedule of Assessments (SOA) 
• Incidence of anti-drug antibodies (ADAs) to fazirsiran 
• Change from baseline in Metavir fibrosis stage at post-dose biopsy  
Exploratory Endpoints: 
• Change from baseline in liver histology (e.g., globules, inflammation, steatosis) at 
post-dose biopsy 
• Change from baseline in hepatic SERPINA1 messenger RNA (mRNA) expression at 
post-dose biopsy 
• Change from baseline in liver fibrosis gene expression at post-biopsy  
• Absolute and percent change from baseline in serum PRO-C3 at Week 16 and over 
time through EOS 
• Change from baseline in noninvasive scoring systems for fibrosis, including 
aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 index 
(FIB-4), at Week 16 and over time through EOS 
• Changes from baseline in FibroScan® over time through EOS 
• Change from baseline in hepatic stiffness based on Magnetic Resonance 
Elastography (MRE) (if available) over time through EOS 
• Change from baseline in hepatic fat content based on magnetic resonance imaging 
(MRI) (MRI-proton density fat fraction [MRI-PDFF] if available) over time and 
through EOS  
• Change from baseline in hepatic iron content based on MRI (if available) over time 
and through EOS 


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• Change from baseline in markers of liver fibrosis, globules, and iron content using 
biomarkers (e.g., PRO-C6) and special stains and imaging (Masson’s Trichrome, 
Sirius Red, Iron, PAS-D), which may include histologic morphometric analysis (if 
scientifically feasible and sufficient sample available), over time and through EOS 
Study Population/Patient Number: This study will be conducted in patients homozygous for 
the Z mutation (PiZZ) with confirmed AATD. Both males and females are eligible, ages 18 to 
75 years. In total, the study will consist of approximately 36 patients. A minimum of 24 out of 
36 patients must have evidence of fibrosis on the liver biopsy at Screening. 
Study Key Inclusion/Exclusion Criteria: Patients must meet the following key eligibility 
criteria (per Sections 7.2 and 7.3) for study entry: no evidence of definitive cirrhosis; non-
smoking status (defined as does not smoke cigarettes daily for at least 12 months); platelet 
count ≥150 × 109/L; forced expiratory volume in one second (FEV1) ≥65%. 
Study Design/Methods: A multi-center, multi-dose placebo-controlled Phase 2 study will be 
conducted to evaluate the safety, efficacy, and tolerability of the investigational product, 
fazirsiran (TAK-999, ARO-AAT), administered subcutaneously to patients with AATD.  
Study Details 
The study will test 3 fazirsiran dose levels compared to placebo. Patients 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 assigned to one of 3 cohorts and 
randomized 2:1 (active: placebo) within each cohort. The 3 cohorts of the study are as follows: 
• Cohort 1: 25 mg dose of fazirsiran or placebo  
• Cohort 2: 100 mg dose of fazirsiran or placebo  
• Cohort 3: 200 mg dose of fazirsiran or placebo  
Within each cohort, requirements for biopsies, dosing schedules, and SOA will be determined 
based on the patient’s fibrosis score during Screening. 
Patients with no evidence of fibrosis 
Patients who have a documented biopsy showing no evidence of fibrosis within 1 year of the 
Screening visit will not require liver biopsy at any point during the study.  
Patients without fibrosis at Screening will receive 2 doses of fazirsiran or placebo on Day 1 and 
Week 4, as per the SOA. Following their Week 4 dose, these patients remain in the study with 
regular visits per the SOA until Week 64. 


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Patients with evidence of fibrosis 
Patients who have a pre-dose biopsy showing evidence of fibrosis (without definitive cirrhosis) 
during Screening will have a post-dose biopsy performed at Week 48. If a patient is beyond 
Week 48 at the time of IRB/EC approval of Protocol v4.0, then the post-dose biopsy will occur 
at Week 72 or 96. The study will end after the last patient with fibrosis receives their 10th dose 
(Week 100 visit) or until a long-term extension study is available at the subject’s study site, 
whichever comes first.   
Patients with evidence of fibrosis at Screening will receive a dose on Day 1, Week 4, and 
Week 16, then every 12 weeks for up to 18 doses total.   
Dose Evaluation and Selection 
After all enrolled patients completed the Week 16 visit, an Interim Analysis was performed to 
select a single dose level (25, 100, or 200 mg) for the open-label phase of the study. Based on 
cumulative safety, efficacy, and pharmacodynamic (PD) data from the fazirsiran clinical 
program (clinical studies AROAAT1001, AROAAT2001, and AROAAT2002), a fazirsiran 
dose (200 mg) was selected by the Sponsor. All patients with fibrosis at Screening who 
completed the post-dose biopsy visit will receive fazirsiran at the selected dose for the duration 
of the study (open-label phase) but will remain blinded to the randomized treatment assignment. 
Study Schema 
 
Number of Doses: The number of fazirsiran doses administered to each patient varies, but a 
minimum of 2 and a maximum of 18 total doses will be administered to each patient in the 
study. Patients without fibrosis will receive 2 doses (one at Day 1 and one at Week 4). 
Patients with fibrosis will receive up to 18 doses (Day 1, Week 4, Week 16 followed by a dose 
once every 12 weeks). All patients will discontinue dosing once the last enrolled patient with 
fibrosis receives their 10th dose (Week 100 visit) or until a long-term extension study is 
available at the subject’s study site, whichever comes first. 


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Study Duration: For patients without fibrosis, the duration of the study is approximately 
72 weeks, with an 8-week Screening period and a 64-week study follow-up period. For patients 
with fibrosis, the duration of the study is up to 216 weeks, with an 8-week Screening period, a 
196-week study dosing period (if all 18 doses are received), followed by a Study Completion 
visit performed within 4 to 12 weeks from the dosing visit. 
Study Assessments:  
Patients will undergo the following evaluations at regular intervals during the study (refer to the 
SOA): medical history, physical examinations, vital sign measurements (blood pressure [BP], 
temperature, heart rate [HR], respiratory rate [RR]), weight (at baseline), AE monitoring, 
electrocardiograms (ECGs), urine pregnancy test/follicle-stimulating hormone (FSH) (females), 
concurrent medication, pulmonary function testing (spirometry including vital capacity [VC], 
forced vital capacity (FVC), FEV1, FEV1/VC, FEV1/FVC, and diffusing capacity for carbon 
monoxide [DLCO]) and sample collection for hematology, coagulation, biochemistry, lipids, 
cardiac troponin, urinalysis, urine cotinine, ADAs, drug screens, serum alpha-1 antitrypsin 
levels, serum fibrosis biomarkers, liver biopsy, MRI (where feasible and available), and 
FibroScan® (where available). 
Study visits will occur during the Screening window (Day -60 to -1), and as per the SOA. A 
telephone follow-up will occur 90 days after the last dose (± 5) to verify compliance with 
contraceptive measures and absence of any known pregnancy. Clinically significant changes 
including AE will be followed until resolution is achieved, or until medically stable or the event 
is otherwise explained, or until the patient is lost to follow-up. 
Unless otherwise noted, baseline values will be those assessments obtained pre-dose within the 
closest proximity to the first dose. 
Safety Assessments will be performed at specified timepoints per the SOA and will include the 
following: 
• Vital signs: Resting HR, seated or semi-supine (same position each time is 
preferred) systolic/diastolic BP, RR, and temperature  
• Clinical laboratory measurements (e.g., biochemistry, hematology, cardiac troponin, 
lipids, coagulation, FSH, urine pregnancy test [women of childbearing potential 
{WOCBP}], urine cotinine, and urinalysis) 
• Resting ECG measurements (measured after patient is supine or semi-supine [same 
position each time is preferred] for at least 3 minutes) 
• At each visit, patients will be asked about concomitant medications/therapy and will 
be instructed to volunteer any information regarding AEs and serious adverse events 
(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 the Sponsor 


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• 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, 
FEV1/VC, and FEV1/FVC) and DLCO 
• Use of augmentation treatment at any time throughout the study 
• 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 in active versus placebo will be evaluated as an AE of special 
interest 
The AE reporting period for an enrolled patient will begin when the patient 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 
3 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. 
An independent Data Safety Monitoring Board (DSMB) will be established to review safety 
data at regular intervals. The safety of fazirsiran will be reviewed by the DSMB after at least 
18 enrolled patients have received at least one dose of study drug and completed the Week 16 
visit. An independent statistical center (ISC) will provide unblinded comparative safety 
summaries to the DSMB in a restricted manner. The Sponsor will not have access to the 
unblinded summaries. In addition to the routine safety summaries, the DSMB safety review will 
include evaluation of imbalances in clinically significant adverse changes in FEV1, DLCO, or 
pulmonary related AEs. The DSMB may be asked to review safety data at additional 
unscheduled meetings. The DSMB may also make recommendations regarding cessation of 
dosing in individual patients, modification of individual study cohorts, conduct of the study, 
and/or study design. The specific responsibilities and composition of the DSMB will be 
outlined in the DSMB Charter. 


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Pharmacodynamic and Efficacy 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 serum alpha-1 antitrypsin levels (using Z-specific 
and/or clinical assay) 
• Percent and absolute change in liver total (soluble plus insoluble) mutant AAT 
protein from Z allele (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 
• Percent change in expression of liver fibrosis associated genes 
• Percent change in SERPINA1 messenger RNA (mRNA) levels 
• Change in measures of fibrosis (Metavir fibrosis stage) 
• Change in liver histology (e.g., globules, inflammation, steatosis) 
• Measures of hepatic injury including ALT, GGT, and AST 
• Change in MRI (where available and if feasible) 
• Change in FibroScan® (where available) 
• Serum fibrosis biomarkers (PRO-C3/PRO-C6), FIB-4, APRI 
Pharmacokinetic Assessments: 
Blood samples will be collected from all enrolled patients for sparse sampling plasma 
pharmacokinetic (PK) analysis after dose 1 (all patients) and 3 (fibrosis subset) per the SOA. 
Immunogenicity Assessments: 
Emergence of ADAs will be evaluated with samples drawn per the SOA.  
Statistical Considerations: The objective of this Phase 2 study is to evaluate 3 dose levels 
relative to placebo and select a dose level to be used in the open-label phase of this study and in 
later stages of development based on the evaluation of safety, as well as percent change from 
baseline in serum Z-AAT levels. The primary efficacy analysis, executed after the last patient 
completes Week 16 visit, will evaluate the difference in mean percent change from baseline at 
Week 16 between each active dose group and the pooled placebo groups. The primary efficacy 
analysis, performed using the mixed model repeated measures (MMRM) approach, will be 


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executed in all randomized patients who receive at least one dose of study treatment (Full 
Analysis Set), regardless of the total number of received doses. With a total sample size of 
approximately 36, the study has 99% global power to declare at least one treatment dose group 
as different from placebo, assuming the treatment difference from placebo of at least 70 percent 
points (SD=35) and using a one-sided 2.5% level of significance with Hochberg’s adjustment 
for multiplicity of testing. Details of planned statistical analysis will be provided in the 
statistical analysis plan (SAP).  
Extended Efficacy Analysis will be performed after the last patient with fibrosis reaches the 
post-baseline biopsy visit. Patients will receive the treatment dose selected following the Week 
16 Interim Analysis, only after the patient has completed the post-baseline biopsy visit (Week 
48, 72, or 96). Final Analysis will be performed after all patients complete either an Early 
Termination or Study Completion visit and database lock. 
Treatment Stopping and Study Modification Rules: 
A decision to stop the trial early or discontinue drug in an individual patient or group of patients 
may be indicated based on any of the following:  
1. In the case of 2 or more similar SAEs both considered at least possibly related to 
fazirsiran, the DSMB will meet within 3 days of the DSMB being notified of the second 
event and within the timeframe of required regulatory agency notification. The DSMB 
will review available aggregated data to determine if the study remains safe to proceed, 
should be discontinued, or should continue but with amendments.  
2. Evaluation and fazirsiran study modification/discontinuation rules for elevated ALTs or 
worsening hepatic function (i.e., cirrhosis) and drug induced liver injury (DILI) are 
provided in Appendix 2. 
3. Evaluation and fazirsiran study modification/discontinuation rules for declines in 
pulmonary function are provided in Appendix 3. 










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1. 
Pulmonary function testing includes: Spirometry including VC, FVC, FEV1, FEV1/VC, FEV1/FVC, and DLCO. Pertinent study FEV1 will be based on post-bronchodilation 
value. Spirometry testing at Screening is to determine inclusion/exclusion. Spirometry and DLCO may be repeated once per timepoint. Spirometry and DLCO should also be 
conducted any time a patient experiences a COPD exacerbation. For dosing visits between Week 28 and Week 196, DLCO can occur once every 6 months. 
2. 
MRI hepatoscan will include magnetic resonance elastography (MRE), hepatic fat content by MRI-PDFF (or equivalent) and hepatic iron content. MRI should always be 
completed before biopsy (if performed on the same day) and after a 4-hour fast from food. 
3. 
A complete physical exam (PE) is to be performed at Screening and Study Completion/Early Termination. A symptom-directed PE is to be performed at all other designated 
visits. Genitourinary exam may be deferred. 
4. 
Patients should be fasting (water only) for a minimum of 2 hours prior to collection of the clinical labs. 
5. 
A post-dose biopsy visit will occur at Week 48 (± 2 weeks) for patients with evidence of fibrosis at Screening. For patients beyond Week 48 at the time of IRB/EC approval 
of Protocol v4.0, the post-dose liver biopsy will be performed at Week 72 (± 4 weeks) or Week 96 (± 4 weeks). 
6. 
The Study Completion visit can occur 4 to 12 weeks from the last study dose. 
7. 
For dosing visit between Week 28 and Week 196, ECG can be performed once every 6 months. 
8. 
Complete the Early Termination Visit within 30 days of decision to terminate a patient’s study participation. Liver biopsy does not need to be repeated in an Early 
Termination patient if a post-dose biopsy was performed at Week 48, 72, or 96. 
9. 
Negative urine pregnancy test must be confirmed pre-dose on dosing days in pre-menopausal females.  
 


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TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS .............................................................................................2 
2. 
STUDY INFORMATION AND SIGNATURES ......................................................19 
3. 
LIST OF ABBREVIATIONS AND TERMS.............................................................20 
4. 
INTRODUCTION ......................................................................................................23 
4.1. 
Background Information .............................................................................................23 
4.2. 
Development and Mechanism of Action of Fazirsiran ...............................................23 
4.3. 
Fazirsiran Preclinical Pharmacology and Studies .......................................................24 
4.4. 
Fazirsiran Preclinical Pharmacokinetic and Product Metabolism Studies .................25 
4.5. 
Fazirsiran Preclinical Toxicology Studies ..................................................................25 
4.6. 
Fazirsiran Clinical Pharmacology, Pharmacokinetic and Clinical Safety ..................25 
4.7. 
Rationale for the Study ...............................................................................................25 
4.8. 
Risk Assessment for Patients ......................................................................................26 
4.9. 
Justification for Dose Levels and Dose Intervals .......................................................29 
5. 
OBJECTIVES .............................................................................................................31 
5.1. 
Primary Objective .......................................................................................................31 
5.2. 
Primary Endpoint ........................................................................................................31 
5.3. 
Secondary Endpoints ..................................................................................................31 
5.4. 
Exploratory Endpoints ................................................................................................31 
6. 
STUDY PLAN............................................................................................................33 
6.1. 
Study Design ...............................................................................................................33 
6.2. 
Rationale for Study Design .........................................................................................34 
6.3. 
DSMB and Stopping Rules .........................................................................................35 
6.4. 
Duration of the Study ..................................................................................................36 
7. 
PATIENT SELECTION .............................................................................................37 
7.1. 
Number of Patients and Patient Demographics ..........................................................37 
7.2. 
Inclusion Criteria ........................................................................................................37 
7.3. 
Exclusion Criteria .......................................................................................................38 
7.4. 
Patient Withdrawal Criteria ........................................................................................40 
7.5. 
Restrictions and Concomitant Medications ................................................................41 
8. 
INVESTIGATIONAL PRODUCT ............................................................................43 
8.1. 
Description, Identification and Dosage ......................................................................43 


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8.2. 
Supply, Preparation, Storage and Labeling of Fazirsiran ...........................................43 
8.3. 
Study Drug Handling ..................................................................................................44 
8.4. 
Accountability of Study Supplies ...............................................................................44 
8.5. 
Retention of Investigational Product Vials .................................................................45 
8.6. 
Allocation to Treatment ..............................................................................................45 
8.7. 
Blinding and Code-break ............................................................................................46 
9. 
STUDY METHODS AND SCHEDULES .................................................................47 
9.1. 
Overview of Procedures .............................................................................................47 
9.2. 
Selection and Screening ..............................................................................................47 
9.3. 
On-Study Procedures/Assessments ............................................................................48 
9.3.1. 
Demographics/Medical History ..................................................................................48 
9.3.2. 
Physical Exam ............................................................................................................48 
9.3.3. 
Pulmonary Function Testing.......................................................................................48 
9.3.4. 
Electrocardiogram .......................................................................................................49 
9.3.5. 
Vital Sign Assessments...............................................................................................49 
9.3.6. 
Clinical Laboratory Tests ...........................................................................................49 
9.3.7. 
Pharmacokinetics ........................................................................................................50 
9.3.8. 
Pharmacodynamics .....................................................................................................51 
9.3.9. 
Concomitant Medications/Therapies ..........................................................................52 
9.3.10. 
Follow-Up Procedures: Telephone Call to Assess for Adverse Events .....................52 
9.3.11. 
Early Termination Procedures ....................................................................................52 
9.4. 
Allocation of Formulations .........................................................................................53 
9.5. 
Study Formulation Administration .............................................................................53 
9.6. 
Timing of Treatments and Procedures ........................................................................53 
9.7. 
Safety Endpoints .........................................................................................................54 
9.8. 
Sample Processing for Pharmacokinetics ...................................................................55 
9.9. 
Blood Sampling for Pharmacodynamic Analysis .......................................................55 
9.9.1. 
Sample Processing and Analysis for Pharmacodynamic Samples .............................55 
10. 
ADVERSE EVENTS..................................................................................................56 
10.1. 
Definitions ..................................................................................................................56 
10.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs .........57 
10.3. 
Timing, Frequency, and Method of Detecting AEs ....................................................57 


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10.4. 
Recording of AEs .......................................................................................................58 
10.5. 
Evaluating AEs ...........................................................................................................58 
10.5.1. 
Assessment of Intensity ..............................................................................................58 
10.5.2. 
Injection Site Reactions ..............................................................................................58 
10.5.3. 
AEs of COPD Exacerbation .......................................................................................59 
10.5.4. 
Assessment of Causality .............................................................................................59 
10.6. 
Follow-up of AEs .......................................................................................................60 
10.7. 
Prompt Reporting of SAEs .........................................................................................60 
10.7.1. 
Completion and Transmission of the SAE Reports ....................................................60 
10.7.2. 
Serious Adverse Event Reports to the IRB/EC ..........................................................61 
10.7.3. 
Pregnancy Reporting ..................................................................................................61 
10.8. 
Regulatory Requirements for Reporting of SAEs ......................................................61 
10.9. 
Post-study AEs............................................................................................................62 
10.10. 
SAEs Related to Study Participation ..........................................................................62 
11. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .............................63 
11.1. 
Study Populations .......................................................................................................63 
11.2. 
Sample Size Considerations .......................................................................................63 
11.3. 
Randomization and Stratification ...............................................................................64 
11.4. 
Screening Data ............................................................................................................64 
11.5. 
Safety/Tolerability Data ..............................................................................................64 
11.6. 
Immunogenicity Data .................................................................................................65 
11.7. 
Pharmacokinetic Data .................................................................................................65 
11.8. 
Pharmacodynamic Data ..............................................................................................65 
11.9. 
Pre-Specified Subgroup Analyses ..............................................................................66 
11.10. 
Analysis Methods .......................................................................................................66 
11.11. 
Interim and Planned Analyses ....................................................................................68 
11.12. 
Data Recording and Quality Control ..........................................................................69 
12. 
STUDY APPROVAL AND CONDUCT ...................................................................70 
12.1. 
Regulatory Approval ..................................................................................................70 
12.2. 
Institutional Review Board (IRB)/Ethics Committee (EC) Approval ........................70 
12.3. 
Ethical Considerations ................................................................................................70 
12.4. 
Written Informed Consent ..........................................................................................70 


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12.5. 
Emergency Contact with Principal Investigator .........................................................71 
12.6. 
Notification of General Practitioner ...........................................................................71 
12.7. 
Clinical Laboratory Certification and Reference Ranges ...........................................71 
12.8. 
Protocol Deviations ....................................................................................................71 
12.9. 
Termination of the Study ............................................................................................72 
13. 
STUDY ADMINISTRATION ...................................................................................73 
13.1. 
Study Monitoring ........................................................................................................73 
13.2. 
Quality Assurance .......................................................................................................74 
13.3. 
Records Retention .......................................................................................................74 
14. 
INFORMATION DISCLOSURE AND INVENTIONS ............................................76 
14.1. 
Ownership ...................................................................................................................76 
14.2. 
Confidentiality ............................................................................................................76 
14.3. 
Publication ..................................................................................................................76 
15. 
REFERENCES ...........................................................................................................78 
APPENDIX 1: METABOLIC SYNDROME CRITERIA ..........................................................80 
APPENDIX 2: ELEVATED ALT OR WORSENING HEPATIC FUNCTION STUDY 
MODIFICATION AND PATIENT DISCONTINUATION RULES ........................81 
APPENDIX 3: PULMONARY FUNCTION MONITORING ...................................................84 
APPENDIX 4: BIRTH CONTROL METHODS CONSIDERED HIGHLY 
EFFECTIVE ...............................................................................................................85 
APPENDIX 5: DISCUSSION OF RISKS ASSOCIATED WITH STUDY 
ASSESSMENTS.........................................................................................................86 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments for Patients Without Fibrosis at Screening ........................10 
Table 2: 
Schedule of Assessments – Patients With Evidence of Fibrosis ................................12 
Table 3: 
Injection Number and Volume per Cohort .................................................................53 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................34 
 


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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 patients. 
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 antibody 
ADS-001 
Drug substance (API, lyophilized powder) containing RNAi trigger 
(also referred to as fazirsiran, ARO-AAT, or TAK-999) 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
API 
Active Pharmaceutical Ingredient 
APRI 
Aspartate aminotransferase-to-platelet ratio index 
ARC-AAT 
Arrowhead previous clinical stage RNAi therapeutic candidate for 
AATD; discontinued 
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 aminotransferase 
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 
CRO 
Contract Research Organization 
CS 
Clinically significant 
CTN  
Clinical Trial Notification 
CV 
Coefficient of variation 
CVA 
Cerebrovascular accident 
DLCO 
Diffusing capacity for carbon monoxide 
DSMB  
Data Safety Monitoring Board 
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 
Forced expiratory volume in one second 


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FEV1/FVC 
Ratio of the forced expiratory volume in the first one second to the 
forced vital capacity of the lungs 
FEV1/VC 
Ratio of the forced expiratory volume in 1 second to vital capacity 
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 
HR 
Heart rate 
ICH 
International Council for Harmonisation  
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
IUD 
Intrauterine device 
IWRS 
Interactive Web Response System 
LD 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
MAR 
Missing at random 
MCH 
Mean cell hemoglobin 
MCHC 
Mean cell hemoglobin concentration 
MCV 
Mean cell volume 
MI 
Multiple imputation 
mmHg 
Millimeters of mercury 
MNAR 
Missing Not at Random 
MRE 
Magnetic resonance elastography 
MRI 
Magnetic resonance imaging 
MRI-PDFF 
Magnetic resonance imaging proton density fat fraction 
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 
PBO 
Placebo 
PD 
Pharmacodynamic 
PFT 
Pulmonary function test 
PI 
Principal Investigator 
PiZZ 
Homozygous Z allele individuals 


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PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
PTT 
Partial thromboplastin time 
Q28 
Once every 28 days 
Q4W 
Once every 4 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 
RR 
Respiratory rate 
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan  
SD 
Standard deviation 
siRNA 
Small interfering RNA oligonucleotides 
SOA 
Schedule of Assessments  
TIA 
Transient ischemic attack 
ULN 
Upper limit of normal 
VC 
Vital capacity 
WOCBP 
Women of childbearing potential 
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 from Z allele (Z-AAT) synthesized by 
PiZZ individuals contains a single point mutation that results in low secretion, polymer 
formation and accumulation 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 (De Serres et al., 
2012).  PiZZ adult patients may initially present with clinical signs of pulmonary disease such as 
dyspnea, cough, or 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.  
4.2. 
Development and Mechanism of Action of Fazirsiran 
Since Z-AAT protein accumulation is the underlying cause of hepatocyte injury in AATD, 
preventing Z-AAT synthesis is a rational step to prevent hepatic Z-AAT polymerization, 


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aggregate formation, and accumulation, and thus a logical approach 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 small 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 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 aggregates and fibrosis in the PiZZ 
transgenic mouse has been well demonstrated (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 Preclinical 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-AAT protein levels, which correlated with reduced 
liver Z-AAT mRNA levels. Multi-dose studies showed that mice treated with fazirsiran have less 
Z-AAT burden in their liver compared to saline-treated mice. Liver Z-AAT burden is determined 
by separating a liver homogenate into a soluble and insoluble fraction; the insoluble fraction 
represents aggregates of polymerized protein. 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 after receiving two once every 4 weeks (Q4W) 3 mg/kg doses of 
fazirsiran. Further information on the preclinical pharmacology studies is provided in the 
Investigator’s Brochure. 


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4.4. 
Fazirsiran Preclinical 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 Preclinical 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. Results of the AROAAT1001 study are available in the Investigator’s Brochure. 
Fazirsiran is also being evaluated in an ongoing, open-label pilot Phase 2 study in patients with 
AATD liver disease (AROAAT2002 study). Results of an Interim Analysis of the 
AROAAT2002 study are available in the Investigator’s Brochure.  
4.7. 
Rationale for the Study  
Intracellular mutant (Z-AAT) misfolded protein accumulation is the underlying cause of 
hepatocyte injury in AATD (Torres-Duran 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 upregulation 
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). This is supported by improvement in liver histology, reduced 
liver Z-AAT protein (soluble and insoluble aggregates) and reduced fibrosis associated gene 
expression seen in PiZ mice treated with siRNA targeting the SERPINA1 gene product 
(Wooddell et al., 2016). Treatment of patients with fazirsiran is expected to reduce hepatic 
production of Z-AAT, leading to reductions in intrahepatic misfolded soluble and insoluble 
aggregated Z-AAT protein and reduction in serum AAT 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-AAT 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 intrahepatic mutant protein while allowing 
endogenous clearance mechanisms to remove Z-AAT protein already accumulated. This removal 
of the offending agent should reduce/eliminate 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 


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injury including hepatitis B virus (HBV), hepatitis C virus (HCV), and nonalcoholic fatty liver 
disease (NAFLD)/ nonalcoholic steatohepatitis (NASH) (Ellis et al., 2012).  
The AROAAT2001 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. Accordingly, this study uses multiple 
doses of fazirsiran with each dose after the second dose administered approximately every 
3 months.  
Three different dose levels are being tested. The dosing regimen utilized in this study is 
supported by the PD effect and safety profile of three once every 28 days (Q28) doses of 
fazirsiran, which was evaluated in the AROAAT1001 study. 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 3 doses will be required to reduce insoluble aggregated liver Z-AAT 
sufficiently to reduce globule 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.  
The current study uses liver biopsy to obtain tissue samples to directly measure drug effect on 
hepatic Z-AAT protein and histopathology. Noninvasive measures (including serum biomarkers, 
FibroScan®, and magnetic resonance imaging [MRI]) of PD effect are also included. However, 
liver biopsy remains the gold standard for histological evaluation in clinical studies and is 
required to obtain tissue specimens for analysis of intrahepatic Z-AAT levels. 
4.8. 
Risk Assessment for Patients 
Based on the safety review of nonclinical and clinical trials, the following are considered as 
identified risks or potential risks: 


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Identified risks: 
• Injection Site AE Risk: Adverse events (AEs) at the injection site (e.g., erythema, pain, etc.) 
have been reported with administration of fazirsiran in clinical studies AROAAT1001, 
AROAAT2001, and AROAAT2002 and are therefore considered an identified risk. All were 
deemed to be non-serious and resolved without sequelae. The majority of the injection site 
reactions (ISRs) were mild in severity. Other siRNA antisense oligonucleotides (ASOs) in 
clinical trials have been associated with usually mild ISRs. This study includes directions for 
assessing injection site 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. 
Potential risks (monitored in this study using diagnostic evaluations, assessments, and study 
modification rules): 
• 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 some risk. See Appendix 5 for 
more information about risks associated with study assessments such as liver biopsy.  
• 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. The Sponsor anticipates an 
approximate 90% reduction of serum 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 consistent pattern of adverse changes in pulmonary function metrics 
seen in the AROAAT1001 study using siRNA to transiently reduce serum AAT levels, and 
the fact that the native Z-AAT has reduced inhibitory effect against neutrophil elastase, the 
reduction of serum Z-AAT should not significantly impact any protective effect. Pulmonary 
disease in PiZZ patients with very low serum AATD takes decades to develop. PiZZ patients 
already have very low serum AAT levels and a further reduction in already low AAT may 
not influence pulmonary function. Additionally, many of these patients are on AAT 
augmentation therapy or may be given augmentation therapy and will continue it during the 
trial. Steps will be taken in this study to mitigate this theoretical risk.  
1. Patients who smoke or with a significant smoking history will be excluded from this 
study and their non-smoking status will be confirmed by measuring urinary cotinine at 
Screening and with repeat confirmatory checks during the study. Patients with a positive 


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urine cotinine during the study (with positive result confirmed on repeat) will be 
counseled on the importance of not smoking during the study.  
2. Patients with severe and unavoidable exposure to inhaled environmental exposure will be 
excluded.  
3. Above standard of care pulmonary monitoring is implemented during the study with vital 
capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second 
(FEV1), ratio of the forced expiratory volume in the first one second to the forced vital 
capacity of the lungs (FEV1/FVC), and the ratio of the forced expiratory volume in 
1 second to vital capacity (FEV1/VC), measured pre-dose and at every dosing visit. 
Diffusing capacity for carbon monoxide (DLCO) is measured every dosing visit through 
Week 16 and then every other dosing visit. 
4. Patients without sufficient pulmonary reserve at baseline (e.g., post-bronchodilation 
FEV1 <65 % of predicted) are excluded. Patients with recent lower respiratory infections 
(such as pneumonia) are also excluded. 
5. Standard of care emphysema treatment (e.g., corticosteroids, bronchodilators) is 
permitted.  
6. Any patient developing pulmonary symptoms or worsening pulmonary function tests 
(PFTs) 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 3).  
7. Arrowhead will review all VC, FVC, FEV1, and DLCO test results on a weekly basis 
during Safety Review Team meetings. Pulmonary function test results will be exported 
directly from the clinical trial database and any resulting decreases >10% 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 follow up with sites will occur in order to 
obtain the pulmonologist evaluation.  
8. The AROAAT2001 study will have a Data Safety Monitoring Board (DSMB). The 
DSMB Members will review all pulmonary function data and, in particular, review the 
patient data holistically where a FEV1 >10% decline from baseline occurs. The Data 
Safety members will review those patients in an unblinded manner when deemed 
necessary to promptly identify if an imbalance in treatment groups occurs. It is the 
DSMB’s responsibility to make recommendations to Arrowhead regarding the study 
conduct (including patient discontinuation from the study per protocol) in a manner that 
preserves the study blind as appropriate.  
• 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 


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ascending doses/multiple ascending doses study. Others developing siRNA for AATD have 
seen evidence of mild to moderate elevations in transaminases using hepatocyte-targeted 
siRNA conjugates similar to those used by the Sponsor. It has been described that these 
alanine aminotransferase (ALT) changes were due to off-target effects of the siRNA seed 
region on microRNAs in the hepatocyte (Vaishnaw et al., 2017; Schlegel et al., 2017). 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. In chronic GLP toxicity 
studies in rats and monkeys, adverse liver findings were not identified, with the no-observed-
adverse-effect levels (NOAELs) of 120 mg/kg in rats and 180 mg/kg in monkeys, which in 
both cases were the highest doses tested. Given the very large safety margins based on the 
chronic GLP toxicity study NOAELs, liver toxicity in humans is not expected. However, to 
further mitigate this risk of adverse liver findings, the proposed study protocol has built in 
stopping 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. 
The DSMB will include hepatologists experienced in adjudication of drug induced liver 
events. Additionally, the planned doses used in this study of 25, 100, and 200 mg are 
approximately 1/336th, 1/84th, and 1/42nd, respectively (assuming weight-based conversion 
and a 70-kg subject) of the rat NOAEL of 120 mg/kg and 1/504th, 1/126th, and 1/63rd, 
respectively, of the 180 mg/kg monkey NOAEL from chronic GLP toxicity studies. 
Additionally, the doses used in this study are lower than the 300 mg dose level which was 
administered for 3 Q28 doses in the AROAAT1001 study and was well tolerated. 
Additional information about identified and potential risks is provided in the Investigator’s 
Brochure. 
4.9. 
Justification for Dose Levels and Dose Intervals 
The proposed dose levels of 25, 100, and 200 mg are each expected to produce PD effect. In the 
AROAAT1001 study, doses of 35, 100, and 200 mg yielded substantial serum AAT reductions, 
with both 100 and 200 mg reaching approximately 90% mean serum AAT reduction after 
multiple doses in the AROAAT1001 study. All proposed doses are below the top dose of 
300 mg, which was studied as both single and multiple (3) 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 to date and no pattern of adverse laboratory changes associated 
with fazirsiran. All 3 proposed dose levels are expected to provide varied and dose dependent PD 
effect and are well within a margin of safety based on previous human testing as well as rat and 
NHP GLP toxicity studies. A bracketing dose design was chosen based on doses and serum AAT 
activity observed in AROAAT1001 using the lowest dose expected to generate maximal 
intrahepatic reduction (100 mg) bracketed by one lower dose level (25 mg) and one higher dose 
level (200 mg). Serum AAT reductions with single and multiple doses of fazirsiran at the 100 
and 200 mg dose levels were similar in the AROAAT1001 study with both appearing to generate 
maximal serum reductions. Single 35 mg doses appear to be less active than 100 mg with regards 
to serum AAT reduction. It is presently unknown whether AATD patients will exhibit a similar 
sensitivity to ARO-AAT Injection, i.e., whether near full reduction in serum AAT in healthy 
volunteers correlates to patient liver reductions. However, data from other siRNA compounds 


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targeting AAT indicate that PiZZ patients respond to hepatocyte targeted siRNA silencing of 
AAT in a manner similar to healthy volunteers at equivalent dose levels (Turner et al., 2018). 
Finally, although similar serum AAT reduction, following multiple doses of 100 and 200 mg, 
were observed, there is less inter-subject variability in serum AAT reduction at the higher dose 
level and an apparent longer duration of effect. It is possible that 200 mg will produce greater 
suppression in liver Z-AAT production than the 100 mg dose. Arrowhead believes the greater the 
suppression of liver Z-AAT protein production, the greater potential for improvement in disease. 
This is based on other liver diseases such as HBV/HCV, where full or near full removal of the 
insulting agent has been observed to allow the liver to begin the regenerative process. 
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 
polymerized aggregates of Z-AAT as early and effectively as possible. Providing a dose on 
Day 1 followed by a dose on Day 29 (Week 4) 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 second dose on Day 113 (Week 16) and dosing approximately quarterly 
thereafter. This strategy of maximizing ablation of liver AAT early should yield the most benefit 
to patients in terms of liver PiZ 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 the third fazirsiran dose (and subsequent doses later in development) at 
Day 113 (Week 16) and quarterly dosing thereafter is based on 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.  
In chronic GLP toxicity studies in rats and monkeys, adverse findings were not identified, with 
the NOAELs of 120 mg/kg in rats and 180 mg/kg in monkeys, which in both cases were the 
highest doses tested. The planned doses used in this study of 25, 100, and 200 mg are 
approximately 1/336th, 1/84th, and 1/42nd, respectively, (assuming weight-based conversion and a 
70-kg subject) of the rat NOAEL of 120 mg/kg and 1/504th, 1/126th, and 1/63rd, respectively, of 
the 180 mg/kg monkey NOAEL from chronic GLP toxicity studies. Additionally, the doses used 
in this study are lower than the 300 mg dose level which was administered for 3 Q28 doses in the 
AROAAT1001 study and was well tolerated. 


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5. 
OBJECTIVES 
5.1. 
Primary Objective  
To select a single dose for use in later stage development based on a combined evaluation of 
safety and PD effects of fazirsiran 
5.2. 
Primary Endpoint 
• Percent change from baseline at Week 16 in serum Z-AAT 
5.3. 
Secondary Endpoints 
• Subject incidence of treatment-emergent AEs  
• Absolute and percent change from baseline in total liver Z-AAT (insoluble + soluble) 
protein at post-dose biopsy visit 
• Absolute and percent change from baseline in liver Z-AAT soluble protein at 
post-dose biopsy visit 
• Absolute and percent change from baseline in liver Z-AAT insoluble protein at 
post-dose biopsy visit 
• Absolute and percent change from baseline in liver function tests including ALT, 
aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl 
transferase (GGT), total bilirubin, direct bilirubin, and international normalized ratio 
(INR) at Week 16 and over time through End of Study (EOS) 
• Absolute and percent change in serum Z-AAT over time through EOS 
•  Change over time in PK measurements of fazirsiran at timepoints specified in the 
Schedule of Assessments (SOA) 
• Incidence of anti-drug antibodies (ADAs) to fazirsiran 
• Change from baseline in Metavir fibrosis stage at post-dose biopsy 
5.4. 
Exploratory Endpoints 
• Change from baseline in liver histology (e.g., globules, inflammation, steatosis) at 
post-dose biopsy 
• Change from baseline in hepatic SERPINA1 mRNA expression at post-dose biopsy 
• Change from baseline in liver fibrosis gene expression at post-dose biopsy 


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• Absolute and percent change from baseline in serum PRO-C3 at Week 16 and over 
time through EOS 
• Change from baseline in noninvasive scoring systems for fibrosis, including aspartate 
aminotransferase-to-platelet ratio index (APRI) and FIB-4, at Week 16 and over time 
through EOS 
• Change from baseline in FibroScan® over time through EOS 
• Change from baseline in hepatic stiffness based on magnetic resonance elastography 
(MRE) (if available) over time and through EOS 
• Change from baseline in hepatic fat content based on MRI (MRI) (MRI-proton 
density fat fraction [MRI-PDFF] if available) over time and through EOS 
• Change from baseline in hepatic iron content based on MRI (if available) over time 
and through EOS 
• Change from baseline in markers of liver fibrosis, globules, and iron content using 
biomarkers (e.g., PRO-C6) and special stains and imaging (Masson’s Trichrome, 
Sirius Red, Iron, PAS-D), which may include histologic morphometric analysis (if 
scientifically feasible and sufficient sample available), over time and through EOS  


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6. 
STUDY PLAN  
6.1. 
Study Design 
A multi-center, multi-dose placebo-controlled Phase 2 study will be conducted to evaluate the 
safety, efficacy, and tolerability of the investigational product, fazirsiran, administered 
subcutaneously to patients with AATD.  
Study Details 
The study will test 3 dose levels compared to placebo. Patients 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 assigned to one of 3 cohorts and randomized 
2:1 (active: placebo) within each cohort. The 3 cohorts of the study are as follows: 
• Cohort 1:  25 mg dose of fazirsiran or placebo  
• Cohort 2:  100 mg dose of fazirsiran or placebo  
• Cohort 3:  200 mg dose of fazirsiran or placebo  
Within each cohort, requirements for biopsies, dosing schedules, and SOA will be determined 
based on the patient’s fibrosis score during Screening. 
Patients With No Evidence of Fibrosis 
Patients who have a documented biopsy showing no evidence of fibrosis within 1 year of the 
Screening visit will not require liver biopsy at any point during the study.  
Patients without fibrosis at Screening will receive 2 doses of fazirsiran or placebo on Day 1 and 
Week 4, as per the SOA. Following their Week 4 dose, these patients remain in the study with 
regular visits per the SOA until Week 64. 
Patients With Evidence of Fibrosis 
Patients who have a pre-dose biopsy showing evidence of fibrosis (without definitive cirrhosis) 
during Screening will have a post-dose biopsy performed at Week 48. If a patient is beyond 
Week 48 at the time of IRB/EC approval of Protocol v4.0, then the post-dose biopsy will occur 
at Week 72 or 96. The study will end after the last patient with fibrosis receives their 10th dose 
(Week 100 visit) or until a long-term extension study is available at the subject’s study site, 
whichever comes first.  
Patients with evidence of fibrosis at Screening will receive a dose on Day 1, Week 4, and 
Week 16, then every 12 weeks for up to 18 doses total. A Study Completion visit will occur 
between 4 to 12 weeks after a patient’s last study treatment dose. 
Dose Evaluation and Selection 
After all enrolled patients completed the Week 16 visit, an Interim Analysis was performed to 
select a single dose level (25, 100, or 200 mg) for the open-label phase 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 


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by the Sponsor. All patients with fibrosis at Screening who completed the post-dose biopsy visit 
at Week 48 (or Week 72 or 96) will receive fazirsiran at the selected dose for the duration of the 
study (open-label phase) but will remain blinded to their randomized treatment assignment.  
Figure 1: 
Study Schema 
 
6.2. 
Rationale for Study Design  
The study is intended select a dose to be used in later stage development clinical studies and to 
collect noninvasive markers of liver disease alongside liver biopsy data to demonstrate the 
relationship of reduction of intrahepatic Z-AAT protein levels to improvement in biomarkers of 
liver disease. Tissue samples from percutaneous liver biopsy will be required. Other markers of 
liver injury such as fibrosis score will also be measured on biopsy. Biopsy will be conducted pre-
dose and post-dose for patients with evidence of fibrosis at Screening. The study will enroll PiZZ 
patients without definitive cirrhosis. Patients without evidence of fibrosis will be able to 
participate in a limited portion of the study. The study uses a placebo arm to help evaluate the 
safety of fazirsiran in an AATD patient population. The study is double-blind to limit the 
occurrence of conscious and unconscious bias in trial conduct and interpretation. Blinding will 
be achieved using a placebo (PBO) (0.9% normal saline) volume matched injection. Inclusion of 
patients receiving PBO will reduce bias in the assessment of drug safety and tolerability. 
In the study, 3 separate dose levels are used to test if there is a dose-response in safety and PD 
assessments. After all enrolled patients completed the Week 16 visit, an Interim Analysis was 
performed to facilitate the dose selection. As changes in serum Z-AAT levels in response to 
fazirsiran is the primary objective of the study, any patient who does not have cirrhosis is eligible 
to participate. Dose and PD response in patients with cirrhosis will be studied in a separate trial 
designed for a hepatic impairment population. 
Non-cirrhotic PiZZ AATD patients are an appropriate population to conduct dose-finding as 
serum Z-AAT is readily measured and levels are uninfluenced by fibrosis stage. Thus, all PiZZ 
patients (without definitive cirrhosis) can participate. Patients without evidence of fibrosis will 
only receive 2 doses and will not have a post-dose biopsy or continue into the open-label phase 
as they have no evidence of fibrosis and would be likely to have minimal to no histological 


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changes following treatment. Therefore, patients with a documented biopsy result showing no 
evidence of fibrosis within 1 year of screen, will not require a baseline biopsy. In order to 
maximize the available efficacy data and ensure sufficient samples for analysis of liver biopsies, 
a minimum of 24 patients with evidence of fibrosis will be enrolled. 
Fibrosis patients will have a screening liver biopsy and a second biopsy at Week 48. Changes in 
liver Z-AAT, adverse liver histological findings and liver injury biomarkers due to AATD liver 
disease are expected to require 6 months or longer of therapy to show improvement. Thus, a 
post-dose liver biopsy in patients with evidence of fibrosis at Screening will be taken at Week 48 
(if a patient is beyond Week 48 at the time of IRB/EC approval of Protocol v4.0, then the 
post-dose biopsy will occur at Week 72 or 96).  
The open-label phase of the study is intended to collect long-term safety of fazirsiran.  
6.3. 
DSMB and Stopping Rules 
An independent DSMB consisting of 2 hepatologists and a pulmonologist and aided by an 
unblinded biostatistician will review the unblinded data generated from this study after the first 
18 patients have received at least one dose of study drug and completed the Week 16 visit, or as 
needed in emergent safety related circumstances. An independent statistical center (ISC) will 
provide unblinded comparative safety summaries to the DSMB in a restricted manner. The 
Sponsor will not have access to the unblinded summaries. This planned safety review will 
include evaluations for imbalances between active and placebo groups for pulmonary AEs as 
well as clinically significant adverse changes in FEV1 and DLCO. The DSMB may be asked to 
review safety data at additional unscheduled meetings should a potential safety signal be 
detected. The DSMB will also be involved in decisions to evaluate individual patients for 
discontinuation (See study modification rules in Appendix 2 and Appendix 3). The DSMB may 
also make recommendations regarding modification of individual study cohorts and/or study 
design.  
A decision to stop the trial early or discontinue drug in an individual patient or group of patients 
may be indicated based on any of the following:  
1. In the case of 2 or more similar serious adverse events (SAEs) both considered at least 
possibly related to fazirsiran, the DSMB will meet within 3 days of the DSMB being 
notified of the second event and within the timeframe of required regulatory agency 
notification. The DSMB will review available aggregated data to determine if the study 
remains safe to proceed, should be discontinued, or should continue but with 
amendments. 
2. Evaluation and fazirsiran study modification/discontinuation rules for elevated liver tests 
signaling worsening AATD liver disease or drug induced liver injury (DILI) are provided 
in Appendix 2. 
3. Evaluation and fazirsiran study modification/discontinuation rules for declines in 
pulmonary function are provided in Appendix 3. 


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Any discontinued patient will be followed with appropriate assessments and monitoring 
(either per SOA or with more intensive evaluation) through EOS. Sponsor or Investigator 
can discontinue any patient at any time with or without DSMB consultation. If such events (as 
described in #1 through #3 above) occur and the patient is not discontinued from the study, the 
reason for not discontinuing the patient will be included in DSMB meeting minutes. Including, 
but not limited to the events listed above, the DSMB may pause the study 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 patient 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  
Arrowhead will notify the concerned regulatory agencies and ethics committees immediately and 
at least within 15 days from when the trial is temporarily halted or prematurely discontinued. A 
substantial protocol amendment will be submitted to the concerned regulatory agencies clearly 
explaining the reasons and scope, e.g., stopping recruitment and/or interrupting treatment of all 
patients already included. Furthermore, to restart the trial, the request will be submitted in form 
of a substantial amendment providing evidence that it is safe to restart the trial. If Arrowhead 
decides not to recommence a temporarily halted trial, the concerned regulatory agency(-ies) will 
be notified within 15 days of this decision, providing a brief explanation of the reasons for 
ending the trial. 
6.4. 
Duration of the Study 
The duration of the study is as follows: 
Patients without fibrosis: up to 72 weeks, as follows: 
Screening: up to 8 weeks 
Dosing and Follow-up: up to 64 weeks. Study treatment will be administered on Day 1 and 
Week 4. 
Patients with evidence of fibrosis: up to 216 weeks, as follows: 
Screening: up to 8 weeks 
Dosing through end of open-label phase: up to 196 weeks, followed by a Study Completion visit 
4 to 12 weeks after the last dose in the open-label phase. Up to 18 doses of study treatment will 
be administered (Day 1, Week 4, Week 16 followed by a dose once every 12 weeks up to 
Week 196). 


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7. 
PATIENT SELECTION 
7.1. 
Number of Patients and Patient Demographics 
This study will be conducted in PiZZ patients with confirmed alpha-1 antitrypsin deficiency. 
Both males and females are eligible, ages 18 to 75 years. In total, the study will consist of 
approximately 36 patients. A minimum of 24 out of 36 patients must have evidence of fibrosis 
on the liver biopsy at Screening. All eligible patients will require a pre-dose biopsy completed as 
part of the study.  
7.2. 
Inclusion Criteria 
To be eligible for enrollment, patients must meet all the following inclusion criteria: 
1. Male or non-nursing female patients 18 to 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. Liver biopsy indicating a liver fibrosis score less than F4 based on local pathologist read.  
a. A patient with no fibrosis may participate based in a previous biopsy conducted 
within one year if a source verifiable medical record specifies no evidence of fibrosis. 
4. A 12-lead electrocardiogram (ECG) at Screening that, in the opinion of the Investigator, 
has no new acute abnormalities (e.g., new onset atrial fibrillation) that compromise 
patient’s safety in this study. Stable disease (e.g., stable atrial fibrillation) is acceptable. 
5. 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 AND any previous smoking history prior to 12 months must be <15 pack years. 
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.  
6. Use highly effective contraception during the study and for 3 months following the last 
dose of fazirsiran. Males must not donate sperm for at least 3 months post last dose of 
study treatment. Women of childbearing potential (WOCBP) must have a negative urine 
pregnancy test at Screening and on Day 1 pre-dose. Women not of childbearing potential 
must be post-menopausal (defined as cessation of regular menstrual periods for at least 
12 months without an alternative medical cause), confirmed by follicle-stimulating 
hormone (FSH) consistent with post-menopausal state based on lab reference ranges.  


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• 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, 
intrauterine device (IUD), 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, is acceptable. 
• True 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 patient. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea methods are not 
considered “true” abstinence and are not acceptable methods of contraception. 
* All laboratory tests used as inclusion criteria may be repeated once and the repeat 
value may be used for inclusion purposes.  
7.3. 
Exclusion Criteria  
A potential patient will be excluded from the study if any of the following criteria apply: 
1. INR ≥1.2 at Screening (one retest permitted). 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 and if indicated a repeat INR 
within <1.2 would be acceptable. Vitamin K may be used for reversal. If INR is not 
indicated (direct thrombin inhibitors or Xa inhibitors) then appropriate washout period 
alone may be acceptable. (Note: Anti-platelet agents, aspirin, clopidogrel or nonsteroidal 
anti-inflammatory drugs [NSAIDs] are acceptable but must be held 7 days before and 
7 days after liver biopsy) 
2. Platelet count <150 × 109/L at Screening (one retest permitted) 
3. ALT and AST levels >250 U/L at Screening (one retest permitted) 
4. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 at Screening (one retest 
permitted) 
5. FEV1 <65% of predicted (preferentially post-bronchodilatory reading) at Screening (one 
retest permitted) 
6. Recent (last 3 months) pneumonia or lower respiratory infection (which must be 
verifiable from the medical record). Patient reported infection is not sufficient to meet 
this criterion.  
7. Unavoidable exposure to inhaled environmental toxins that in the clinical judgment of the 
Investigator could impair pulmonary function significantly over the course of the study. 


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8. Human immunodeficiency virus (HIV) 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 BP >170 and diastolic blood pressure [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), untreated heart block (excluding first-degree block, being PR 
interval prolongation only), congenital long QT syndrome or new acute ST segment 
elevation or depression or new acute Q wave on ECG. Stable atrial dysrhythmias 
(e.g., stable atrial fibrillation) are acceptable.  
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. Patients 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 
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 tetrahydrocannabinol is acceptable for enrollment at the 
discretion of the Investigator). The patient may still be eligible at discretion of Medical 
Monitor and Investigator if positive urine drug screen is due to a prescription medication.  
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 
who have participated in the ARCAAT-1001 study or observational studies are 
acceptable. Patients previously enrolled in but no longer enrolled in gene therapy studies 
are acceptable. 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.  


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19. Any concomitant medical or psychiatric condition or social situation that would make it 
difficult to comply with protocol requirements or put the patient 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 patient participation. Patients enrolled with NASH should 
have no plans to undergo bariatric surgery or have initiated or plan to initiate 
pharmaceutical therapy for NASH (such as Vitamin E or pioglitazone) during the course 
of the study.  
20. A history of thromboembolic disease (including deep vein thrombosis or pulmonary 
embolism), myocardial infarction, stroke within three (3) months of Screening. 
21. Any other condition or finding of clinical relevance at Screening that, in the opinion of 
the Investigator, would render the patient unsuitable for enrollment or could interfere 
with participating in and completing the study. 
22. Previous diagnosis of definitive liver cirrhosis based on biopsy or complications of 
cirrhosis (e.g., varices, ascites, hepatic encephalopathy) based on source verifiable 
medical record. 
23. Patients who have undergone lung or liver transplant for AATD are excluded. 
Note: Sponsor Medical Monitor has the option to exclude the enrollment of a patient if, based 
upon the patient’s medical history or Screening results, it is felt that a patient’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.  
7.4. 
Patient Withdrawal Criteria 
Patients 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 patient from the 
study, per the following criteria, to protect the patient’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 
• noncompliance of patient with protocol 
• patient unwilling to proceed and/or consent is withdrawn or 
• withdrawal from the study if, in the Investigator’s judgment, it is in the patient’s best 
interest 


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• pregnancy 
The reasons for withdrawal will be recorded on the electronic case report form (eCRF) and 
included in the final clinical study report, along with any AEs and any necessary medical 
treatment.  
If a patient 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 study’s Medical Monitor or 
medically qualified designee for consultation. No medical help, diagnosis, or advice will be 
withheld from the patient due to an inability to contact the Medical Monitor. The patient will be 
encouraged to remain available for follow-up medical monitoring. The Sponsor will be notified 
as soon as possible of any patient withdrawals. 
Patients who are withdrawn or discontinue prior to EOS visit, will not be replaced. 
7.5. 
Restrictions and Concomitant Medications 
1. Study Visit Duration: For each patient, clinic visits will last approximately 4 hours on 
dosing days. Patients will return to the clinical facility for outpatient visits as per the 
SOA. Patients will be observed post-dose for approximately 2 hours or as clinically 
indicated as per the Investigator. 
2. Fasting: On the day of dosing, patients will fast from food for at least 2 hours prior to study 
treatment administration. Fasting requirements prior to assessments include: 
a. Blood collection for study labs: patients should fast for a minimum of 2 hours (water 
only) 
b. MRI/magnetic resonance elastography (MRE): fast for a minimum of 4 hours 
c. Liver Biopsy: fast for a minimum of 6 hours 
3. Recreational Drugs, Smoking, and Alcohol: Patients 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, Patients 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. Patients must abstain from use 
of recreational drugs throughout the study. Patients must be non-smokers entering the 
study (as per Inclusion and Exclusion criteria) and abstain from smoking tobacco 
(including e-cigarettes) for the duration of the study. Nicotine patches or gum is 
acceptable. 
4. Concomitant Medications: Allowance of concomitant medications will be at the 
discretion of the study Investigator in consultation with the study’s Medical Monitor 
(when necessary). Augmentation therapy is permitted. Procedural sedation with 
benzodiazepines or equivalent during MRI or liver biopsy as needed is permitted. 


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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 Injection together 
with detailed instructions (in a Pharmacy Manual) describing preparation of Fazirsiran 
(TAK-999, ARO-AAT) Injection. The PBO (normal saline 0.9%) will be supplied by the clinical 
site. 
Accordingly, Fazirsiran Injection will be supplied as single sterile 2-mL vial containing the 
active pharmaceutical ingredient (API) fazirsiran, with the correct dose prepared by the 
pharmacy or designee prior to dosing patients. 
The PBO will be 0.9% normal saline (supplied by the clinical site) administered subcutaneously.  
Doses administered per Dose Level: 
Each single dose of either active drug (fazirsiran) or PBO (normal saline 0.9%), will be 
administered by subcutaneous injection. Injections will be made into the subcutaneous tissue at 
an appropriate site (e.g., abdomen, thigh, upper arm, etc.) using a 25 to 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, and alternating various locations on the abdomen is acceptable) and injection 
site location is to be recorded in the eCRF. Prior to dose administration, the Fazirsiran Injection 
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. 
Injection volume per injection site should not exceed approximately 1.0 mL. There will be no 
dose escalation within a cohort (i.e., the same drug dose will be administered to each patient 
within a cohort). The randomization schedule will be provided to each clinical site and will be 
maintained along with any other materials that could jeopardize the blind in a secured area of the 
pharmacy. 
8.2. 
Supply, Preparation, Storage and Labeling 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) with a fluorocarbon-lined butyl stopper and a red flip-off seal. The clinical drug product 
is labeled: ARO-AAT Injection. 
Strength:  
 
 
230 mg/mL (salt free basis) 
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, 2ºC to 8ºC 


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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.  
The investigational product vials will be labeled per current Good Manufacturing Practice 
(cGMP)/Good Clinical Practice (cGCP).  
Fazirsiran Injection will be stored at the clinical site’s pharmacy, or other Sponsor-approved 
storage facility, 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 unblinded personnel, 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 patients 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 authorized unblinded 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 Injection 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 the site pharmacy staff or designee on the day of dosing and recorded 
in the drug accountability records. A Pharmacy Manual is available to define the procedures for 
dispensing of study drug. 
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, 


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Inc., and the amount administered to patients. An unblinded Clinical Research Associate (CRA) 
will perform initial and ongoing study drug and placebo accountability. The unblinded CRA will 
protect the integrity of the assignment blind and will not participate in data review for study 
patients. Used vials of Fazirsiran Injection will be retained and sequestered per patient and 
cohort (where allowable by local policy) and made available to the unblinded CRA during study 
drug and placebo reconciliation.  
A Drug Dispensing Log must be kept current and will contain the following information: 
• the identification of the patient to whom the drug was dispensed; and 
• the date(s) and quantity of the drug dispensed to the patient. 
The date and time of dose preparation and release will be maintained to support administration of 
study drug/PBO. The authorized pharmacist or qualified staff will be unblinded to the doses. The 
pharmacy will dispense the study medication and the study center will administer the study 
medication only to patients included in this study following the procedures set out in the study 
protocol and Pharmacy Manual. Each patient will be given only the study medication carrying 
his/her study number. Study drug administration will be documented on the eCRFs and/or other 
study drug record. The inventory must be available for inspection by the unblinded CRA during 
the study. When requested in writing to 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 drug. 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 unblinded CRA. No additional study drug samples will be retained. 
8.6. 
Allocation to Treatment 
All potential patients 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 patient 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 patients permanent study ID number. 
Eligible patients will be allocated a unique randomization number, in accordance with the 
randomization schedule. In the double-blinded phase, each patient will be assigned to either 
active (fazirsiran) in one of the 3 dose groups or PBO treatment. The allocation of active 
treatment or PBO will be performed using a block randomization algorithm. In the open-label 


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phase, ongoing subjects will receive fazirsiran at the selected dose for the duration of the study 
(see Section 6.1). 
Patients who drop out prior to the end-of-study analysis may not be replaced. 
8.7. 
Blinding and Code-break 
Blinding of study drug/PBO assignment is critical to the integrity of this clinical trial. It is 
expected that in most cases, AEs can be properly managed without the need for unblinding. 
However, in the event of a medical emergency in which knowledge of an individual patient’s 
assignment is considered critical to the patient’s well-being and management, the Investigator or 
documented designated treating physician can unblind the treatment assignment. If the situation 
is not an immediate emergency, the Investigator should contact the responsible Medical Monitor 
to discuss the patient and circumstances requiring the unblinding. The blind will be broken only 
for the specific patient under discussion. The unblinding will be documented in the Electronic 
Data Capture system. The study monitor should be informed promptly. 
The randomization schedules will be maintained under controlled access. The personnel involved 
in the dispensing of investigational products will be accountable for ensuring compliance to 
randomization schedules. The non-blinded CRA will review the randomization schedule in 
comparison to the dispensing log to verify correct randomization.  
After all enrolled patients completed the Week 16 visit, an independent statistical center 
performed the Interim Analysis that facilitated dose selection. Unblinded results of the Interim 
Analysis were prepared and distributed to the select unblinded Sponsor representatives. 
Subsequent to the Interim Analysis, the fazirsiran dose for the open-label phase was selected (see 
Section 6.1). The Sponsor and Contract Research Organization (CRO) study operation team will 
remain blinded to the individual patient treatment assignment.  
Investigators and study patients will remain blinded to the randomized treatment assignment 
until all patients complete their post-baseline biopsy visit. Following dose selection and 
Extended Efficacy Analysis (performed after the last patient with fibrosis finishes their 
post-baseline biopsy visit), Investigators and study patients will be informed of the patient’s 
randomized treatment assignment from the double-blinded phase. 
A detailed Data Access Plan outlining which parties will have access to which data and at what 
time will be prepared. The plan will further indicate which study functions or parties have access 
to either individual patient or aggregate group treatment information, and/or the selected dose 
over the duration of the study.  
 


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9. 
STUDY METHODS AND SCHEDULES  
9.1. 
Overview of Procedures  
Patients will undergo the following evaluations at regular intervals during the study (refer to the 
SOA): medical history, physical examinations, vital sign measurements (BP, temperature, heart 
rate, respiratory rate), weight (at baseline), AE 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, lipids, cardiac troponin, urinalysis, urine cotinine, anti-drug antibodies, drug 
screens, serum alpha-1 antitrypsin levels (where applicable), serum fibrosis biomarkers, liver 
biopsy, MRI (where feasible and available), and FibroScan® (where available).  
Evaluations during Screening should be completed in the following order (if feasible): 
Within Day -60 to Day -1 Screening window: MRI and FibroScan®, followed by liver biopsy  
Within Day -30 to Day -1 Screening window: PFTs 
Study visits will occur during the Screening window (Days -60 to -1), and as per the SOA. The 
exception is pulmonary function testing, which must be done within the Day -30 to Day 1 
Screening window. 
Eligible patients will attend the Clinical Facility on Day 1. Note that study dose administration is 
on Day 1, which must occur within 60 days of Screening. 
On arrival at the clinical facility on Day 1, the Investigator, or designee, will meet with patients 
to reiterate all study procedures and encourage patients to ask any questions. Patients will fast 
from food for at least 2 hours pre-dose. Refer to the SOA for additional information. Patients will 
be confined to the clinical facility for approximately 4 hours on dosing days. 
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. Patients should refrain from strenuous physical activities, beyond their normal fitness 
level, throughout the study. 
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 patient is lost to follow-up. 
A telephone follow-up will occur 90 days after the last dose to assess for pregnancy occurrence. 
9.2. 
Selection and Screening 
Prior to commencement of any Screening procedures, the Investigator, or designee, will inform 
the patient 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 (ICF) for review. Each patient will acknowledge receipt of 
this information by giving written informed consent for their involvement in the study in the 


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presence of the Investigator, or designee, who will also sign and date the ICF. Time of consent 
will be recorded on the ICF or in the source documents for the patient. The original signed 
consent form will be retained by the Investigator and a copy of the original will be given to the 
patient. 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 patients will undergo procedures outlined in the SOA, 
to be performed within 60 days of the scheduled dosing date, to determine that they meet the 
inclusion/exclusion criteria specified in Sections 7.2 and 7.3.  
9.3. 
On-Study Procedures/Assessments 
9.3.1. 
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. 
9.3.2. 
Physical Exam 
A complete physical exam will be performed at Screening, Study Completion 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 timepoints outlined in the 
SOA, a symptom-directed physical exam will be performed if indicated.  
9.3.3. 
Pulmonary Function Testing  
Spirometry and DLCO will be conducted at timepoints outlined in the SOA for all patients. 
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: 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. 


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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. 
9.3.4. 
Electrocardiogram 
A single 12-lead ECG measurement will be obtained at timepoints outlined in the SOA after the 
patient is supine or semi-supine (same position each time is preferred) for at least 3 minutes. Any 
abnormal ECGs will be repeated in triplicate, with each measurement approximately 1 minute 
apart. ECGs will be performed prior to venipuncture and other invasive procedures. 
9.3.5. 
Vital Sign Assessments 
Systolic/diastolic BP, temperature, HR, and RR (breaths/min) will be obtained at timepoints 
outlined in the SOA after the patient 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.  
9.3.6. 
Clinical Laboratory Tests 
Blood and urine samples will be collected to perform clinical laboratory tests. Patients will be 
required to fast for at least 2 hours for the Screening sample collections. 
At the Screening visit, up to 60 days prior to the first dose of study medication, a fasting 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 patient or impact on the validity of 
the study results), will result in exclusion of that patient. Clinical laboratory tests will be 
performed on patients’ blood and urine at specified time-points listed in the SOA. 


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Biochemistry: Sodium, potassium, chloride, bicarbonate, glucose, urea, creatinine (including 
eGFR), creatine kinase, uric acid, phosphate, total calcium, anion gap, cholesterol, albumin, 
globulins, protein, total bilirubin, direct bilirubin, GGT, ALP, ALT, AST, lactate dehydrogenase 
(LD), triglycerides, C-reactive protein, low-density lipoprotein (LDL)-cholesterol, high-density 
lipoprotein (HDL)-cholesterol 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: Leukocytes, nitrites, urobilinogen, protein, pH, blood, specific gravity, ketone, 
bilirubin, and glucose. 
Urine Cotinine: urine cotinine levels (at Screening and during study) to confirm non-smoking 
status. 
Microscopic Urinalysis will be Performed if Indicated: White blood cells, RBCs, epithelial 
cells, bacteria. 
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, patients 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 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: Women 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. 
9.3.7. 
Pharmacokinetics 
Plasma samples for analysis of circulating fazirsiran will be obtained at timepoints following 
study drug administration as outlined in the SOA. Sparse sampling PK blood draws and analysis 
will be conducted per SOA on all patients enrolled in the study.  


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9.3.8. 
Pharmacodynamics  
Serum Alpha-1 Antitrypsin Level: Serum levels of alpha-1 antitrypsin will be obtained at 
Screening and on Day 1 prior to dose administration. Z-AAT serum levels will also be measured 
as per SOA. The Day 1 value will be used as each patient’s baseline value for data analysis 
purposes. Serum alpha-1 antitrypsin levels will be measured as per the SOA. Samples will be 
analyzed by standard clinical laboratory assay for serum alpha-1 antitrypsin levels and Z-AAT 
levels using a Z-specific assay. Z-AAT values will be used for final analysis. 
Liver Biopsy: Pre-dose (Screening) and post-dose (per the SOA) percutaneous liver biopsies will 
be conducted to obtain tissue samples for liver Z-AAT levels and histological evaluation. Per 
core sample, approximately 30 mm of tissue will be obtained containing at least 11 portal tracts 
using a 16-gauge needle. Procedure detail and tissue processing protocols are outlined in the 
Laboratory Manual. Left over tissue samples may be retained and stored for possible future 
additional analysis. Any retained samples will be deidentified and will not be labeled with 
patient identifying information. After 10 years from the end of the study, samples will be 
returned to the primary Institution or local repository or destroyed per local regulations. Tissue 
samples will be utilized for the following evaluations: 
• Soluble liver AAT protein levels 
• Insoluble liver AAT protein levels 
• Fibrosis gene expression 
• SERPINA1 mRNA expression 
• Total (soluble plus insoluble) liver AAT protein levels 
• Z-AAT protein PAS/D+ globules (globule size and number) 
• Metavir fibrosis stage 
• Liver histological evaluation 
• Iron content using biomarkers, special stains, and imaging (Masson’s Trichrome, 
Sirius Red, Iron, PAS-D, if scientifically feasible and sufficient sample available) 
Two liver biopsy passes will be made to obtain 2 core samples each consisting of approximately 
30 mm of tissue. In the event that only one core can be obtained, it should be used for histologic 
analysis. Additional details around performing biopsy and sample processing/logistics are 
present in a separate Laboratory Manual. 


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Serum Fibrosis Markers: 
PRO-C3 and PRO-C6 will be measured as a serum marker of liver fibrosis per SOA. Biomarkers 
of liver disease such as APRI and FIB-4 will be calculated using ALT, AST, age variables.  
Magnetic Resonance Imaging (completed if feasible for site): Pre-dose and post-dose (as per 
the SOA) liver stiffness will be evaluated using MRE. During the same MRI scan, liver fat 
content via MRI-PDFF (or equivalent methods for determining liver fat) and liver iron content 
will also be evaluated and quantified. MRE imaging will be conducted per QIBA standards 
(https://qibawiki.rsna.org/images/9/97/Draft-MRE-QIBAProfile-2017-07-06.pdf). Images will be 
obtained at the site using a standardized technique. Standardized image processing/interpretation 
to generate a quantitative MRE value in kilopascals (kPa), % liver fat and iron content will be 
centralized. Patients must fast from food for at least 4 hours prior to MRI.  
FibroScan®: Pre-dose (Screening) and post-dose (as per the SOA) liver stiffness will be 
evaluated using FibroScan® standard procedures (where available). 
9.3.9. 
Concomitant Medications/Therapies 
Patients 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 eCRF. 
Allowance of concomitant medications will be at the discretion of the study Investigator in 
consultation with Sponsor Medical Monitor (when necessary). Previous or current use of 
augmentation therapy is permitted. Sedation with benzodiazepines or alternatives is acceptable 
during MRI or liver biopsy. Continued use of medications to treat chronic conditions (including 
COPD) are acceptable.  
9.3.10. 
Follow-Up Procedures: Telephone Call to Assess for Adverse Events 
Documented telephone contact with each patient to verify the following: 
Adverse Events and Concomitant Medications: 24 to 48 hours after the following doses: 
Any dose given after Week 16 (Day 113) 
Compliance with contraceptive measures and absence of any known pregnancy: 
90 days after the last dose of study treatment 
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. Complete the Early Termination Visit 
within 30 days of decision to terminate a patient’s study participation. 


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9.4. 
Allocation of Formulations 
In each cohort, and across the study, patients will be randomized in a 2:1 ratio to receive active 
treatment or placebo in the double-blinded phase. Treatments will be administered per the 
randomized sequence generated by an Interactive Web Response System (IWRS). 
Randomizations will occur in parallel across the 3 cohorts.  
In the open-label phase, ongoing subjects will receive fazirsiran at the selected dose for the 
duration of the study (see Section 6.1). 
9.5. 
Study Formulation Administration 
Appropriately trained employees of the clinical site will administer the study treatment. There 
will be no patient self-administration in this study. 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 when administered in the clinical facility. The 
preferred site of injection is the abdomen. Optional additional sites are the upper arms and 
thighs. A fazirsiran dose of 200 mg was selected for the open-label phase of the study.  
Table 3: 
Injection Number and Volume per Cohort  
Cohort 
Dose 
Concentration 
Total Injection Volume 
# Injections per Planned Dose 
1 
25 mg 
230 mg/mL 
0.11 mL 
Single 
2 
100 mg 
230 mg/mL 
0.43 mL 
Single 
3 
200 mg 
230 mg/mL 
0.87 mL 
Single 
* Placebo injections of normal saline will be volume matched on a cohort-by-cohort basis.  
9.6. 
Timing of Treatments and Procedures 
Actual times of procedures for each patient will vary depending on scheduling and will be 
recorded in the eCRF. 
Post-dose timepoints will be determined from the end of the injection/administration.  
In the event of multiple procedures scheduled at the same time, noninvasive 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: 
Pre-dose:  
Within three (3) hours prior to dosing 
 
All other procedures through 2 hours:  
± 15 minutes 
Weeks 2, 4, and 6:  
See SOA 


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Week 16 and beyond:  
See SOA 
9.7. 
Safety Endpoints  
The safety of fazirsiran will be evaluated by collection of the following measurements performed 
at specified timepoints: 
• Monitoring of AEs/SAEs 
• Physical examinations 
• Vital signs  
• ECG measurements  
• Clinical laboratory tests (hematology, biochemistry, coagulation, urinalysis) 
• Concomitant medications/therapy  
• 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 patients receiving fazirsiran and patients receiving placebo will be analyzed 
and compared for statistical significance.  
• The number of patients receiving fazirsiran versus placebo that require augmentation 
treatment at any time throughout the study will be summarized. 
• Time until initiation of augmentation therapy in active versus placebo patients 
(Kaplan Meier) 
• Number and severity of COPD exacerbations based on Global Initiative for Chronic 
Obstructive Lung Disease (GOLD) criteria in active versus placebo will be evaluated 
as an AE of special interest. 
The AE/SAE reporting period for an enrolled patient will begin when the patient 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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9.8. 
Sample Processing for Pharmacokinetics 
Whole blood will be collected and processed per the Laboratory Manual. Plasma samples will be 
assayed by a validated hybridization-ligation method. The criteria for repeat analysis, as defined 
in the respective in-house procedure, will be followed. The validation study conducted by the 
appointed bioanalytical laboratory to establish validity including accuracy, precision, 
reproducibility, specificity, recovery, and frozen stability of the analytical method will be 
appended to the final report. 
9.9. 
Blood Sampling for Pharmacodynamic Analysis 
Blood samples will be collected from patients 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 timepoints outlined 
in the SOA.  
The target sample times will be printed in the eCRFs. The actual sample times (times samples 
taken) will be recorded alongside the nominal times in the eCRF 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. 
9.9.1. 
Sample Processing and Analysis for Pharmacodynamic Samples 
Pharmacodynamic (AAT): Serum alpha-1 antitrypsin samples will be drawn and analyzed per 
standard clinical laboratory specifications for serum alpha-1 antitrypsin levels using both a 
clinical quantitative assay for total AAT and a quantitative specific Z-AAT assay. Left over 
serum from AAT blood draws will be frozen and used to batch analyze serum Z-AAT levels. 
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 dose cohort and treatment group. 


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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 AEs 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. 
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 pre-existing 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 
• Is life-threatening, (NOTE: The term ‘life-threatening’ in the definition of ‘serious’ 
refers to an event/reaction in which the patient 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  


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• 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 patient 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 patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical/Surgical History.  
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. 


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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 eCRF. Additional reporting requirements for AEs 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 patient’s medical records to the 
Sponsor in lieu of completion of the appropriate AE eCRF pages. 
10.5. 
Evaluating AEs  
10.5.1. 
Assessment of Intensity 
The Investigator, or medically qualified designee, will assess intensity (also known as severity) 
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 patient, 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.  
10.5.2. 
Injection Site Reactions 
An ISR is defined as an adverse reaction (usually immunologic) developing at the site of study 
drug 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 


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For data analysis purposes, AEs at the injection site with reported terms of bruising or hematoma 
will not be considered ISRs. 
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 3 possible categories: Not Related, Possibly Related, and Probably Related. 
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). 


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• 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). 
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 patient and provide 
further information on the patient’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 patient is lost to follow-up. Once resolved, the appropriate AE 
eCRF 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 
CRO, and the IRB/EC. 
10.7.1. 
Completion and Transmission of the SAE Reports  
Once an Investigator becomes aware that an SAE has occurred in a study patient, 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. 


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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 report form 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 Investigator should report all pregnancies and pregnancies in partners of subjects within 
24 hours of awareness of the pregnancy using the Pregnancy Notification Form. 
The Sponsor will provide a list of project contacts for SAE and pregnancy report 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 patient’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 IRB/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 
IRB/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 the pregnancy reporting form to the designated Pharmacovigilance CRO 
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.  
Pregnancies are not 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.  


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The Sponsor will comply with all reporting requirements as stipulated in applicable 
regional/national regulations. The Sponsor is responsible for reporting all suspected unexpected 
serious adverse reactions to the Eudravigilance database. 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 EC, and in any case no later than 7 days after knowledge 
by the Sponsor of such a case, and that relevant follow-up information is subsequently 
communicated within an additional 8 days. All other suspected serious unexpected adverse 
reactions will be reported to the competent authorities concerned and to the EC concerned as 
soon as possible but within a maximum of 15 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 patients. However, if the 
Investigator learns of any SAE, including a death, at any time after a patient 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 provided. 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. Data will be analyzed by cohort and treatment groups of fazirsiran 25, 
100, and 200 mg versus pooled placebo. Data summarized in tables and figures will also be 
presented in patient listings.  
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. Patients will be included in the 
analyses according to the treatment they actually received. 
• Full Analysis Set (FAS): All randomized patients who receive at least one dose of 
study drug. The FAS will be used to analyze endpoints related to efficacy. Patients 
will be included in the analyses according to the treatment planned by randomization. 
• Modified Full Analysis Set (mFAS): All randomized patients who receive at least 
one dose of study drug who has pre-dose serum Z-AAT assessment and a Week 16 
post-dose assessment. 
• PK population: All FAS patients who have sufficient plasma concentration data to 
facilitate determination of PK parameters. Patients with major protocol violations will 
be assessed on a patient-by- patient basis for inclusion in the PK Analysis set. PK 
population will be used for PK analyses.  
11.2. 
Sample Size Considerations 
Approximately 36 patients will be enrolled and randomized in the study. The primary efficacy 
analysis based on serum AAT levels, will be executed after all enrolled patients complete 
Week 16 visit and will evaluate the difference in mean percent change from baseline at Week 16 
between each active dose group and the pooled placebo groups. Patients will be randomized in a 
2:1 (active:placebo) ratio within each of the 3 dose cohorts. With 8 patients in each of the 
3 active treatment dose groups and 12 patients in the pooled placebo group, the study has 99% 
global power to declare at least one treatment dose group as different from placebo, assuming the 
treatment difference from placebo of at least 70 percent points and using a one-sided 2.5% level 
of significance with Hochberg’s step-up adjustment for multiplicity of testing. Furthermore, the 
study has 97% conjunctive power to detect all dose groups that are truly different from placebo 
and 99% disjunctive power to detect at least one dose group that is truly different from placebo. 
The estimate of variability of the primary endpoint is calculated from prior studies to be 35%. 


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11.3. 
Randomization and Stratification 
Following Screening, eligible patients will be randomly allocated in a 2:1 ratio within each dose 
cohort, to receive one of 3 dose levels of fazirsiran (25, 100, or 200 mg) or placebo. 
Randomization will be performed within each dose cohort to maintain blinding due to different 
dose volumes in the double-blinded phase.  
Metabolic syndrome has been associated with increased risk of developing liver fibrosis in 
AATD (Clark et al., 2018). Randomization will be stratified by the presence of metabolic 
syndrome (defined as in Appendix 1) identified at Screening (Alberti et al., 2009). 
Randomization will also be stratified by presence of NASH (steatosis, inflammation, and 
ballooning) at Screening based on pre-dose study biopsy. Patients with both NASH and 
metabolic syndrome will be stratified based on the presence of NASH. 
11.4. 
Screening Data 
Demographics will be tabulated by patient and summarized by cohort and treatment group. 
Eligibility assessments at baseline, including medical/surgical history data and physical 
examination data (including height and weight), will be listed for each patient.  
11.5. 
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 and treatment group. All safety 
summaries will be accompanied by patient listings. 
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 percentage of patients 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 PT will also be summarized. Causality (relationship 
to study treatment) will be summarized separately. 
The incidence and frequency of AEs, SAEs, treatment-related AEs, treatment-related SAEs, and 
AEs leading to withdrawal, dose modification, or treatment discontinuation will be summarized 
by dose and treatment group per 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. Results for variables that are not 
coded will be presented in the listings as “below, within, and above” the normal limits of the 
laboratory. Pregnancy test results will be summarized separately by timepoint. 
Vital sign measurements will be summarized at each scheduled timepoint using descriptive 
statistics.  Physical examination findings will be summarized by timepoint and presented in 
patient listings.  


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ECG parameter changes overall, changes from baseline and qualitative assessments will be 
summarized.  
Change from baseline in VC, FVC, FEV1, and DLCO will be summarized by timepoint. For 
FEV1, summary measures will include change from baseline expressed in mL, as a percentage of 
baseline value, and in units of percent predicted normal and will also be summarized as upper 
95th percentiles with 95% confidence interval (CI). For DLCO summary measures will include 
change from baseline expressed as absolute change in values and as a percentage of baseline 
value. Number of patients requiring new initiation of augmentation therapy during the study and 
time from baseline until new initiation of augmentation therapy (Kaplan Meier analysis) will be 
evaluated.  
11.6. 
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. 
11.7. 
Pharmacokinetic Data 
The fazirsiran PK concentration data will be listed as appropriate.  
The plasma PK concentration will also be used for population PK analysis, combined with PK 
data from other clinical studies, using nonlinear mixed effect methods. The Population PK 
analysis will be supported with separate analysis plans and report. 
11.8. 
Pharmacodynamic Data 
Serum AAT Levels: The whole blood collected for PD analysis following multiple doses of 
fazirsiran or placebo will undergo analysis for PiZ protein and total alpha-1 antitrypsin levels 
using both a Z-AAT specific assay and a clinical assay. Results, including depth of knockdown 
as reported by percent change from baseline will be analyzed and summarized by dose cohort 
and treatment group. For data analysis, batched results using nephelometric assay may be used.  
MRI and FibroScan®: Noninvasive imaging using both FibroScan® and MRI (evaluation of 
liver stiffness with MRE, liver fat with MRI-PDFF (or equivalent MR based measure of liver fat) 
and liver iron content) will be completed pre-dose and post-dose per the SOA in a standardized 
fashion. Percent change in quantitative measure of liver stiffness, liver fat and liver iron content 
from pre-dose to post-dose will be analyzed and summarized by dose cohort and treatment 
group. MRI images will be collected in a standardized fashion with central image processing and 
analysis to determine quantitative elastography values. It is acknowledged that not all patients 
will be able to complete FibroScan® or MRI due to availability or individual medical conditions.  
Liver Biopsy Assessments: Liver biopsy will be completed pre-dose and post-dose per the SOA 
or Early Termination. Secondary and exploratory endpoints will be based on comparison of pre-
dose biopsy versus post-dose biopsy. The post-dose biopsy may include a biopsy completed at 


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Early Termination. Biopsy sample will be taken, prepped, and stored in a standardized manner 
with biopsy Histologic/IHC reads being completed by an independent blinded central 
pathologist. Percent change in intrahepatic Z-AAT, changes in PAS/D+ globules (size and 
number), mRNA, changes in Metavir fibrosis scale, fibrosis gene expression levels, 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 dose cohort and treatment group. A local reader at each site will be 
used during Screening to determine eligibility based on presence of fibrosis/cirrhosis per 
inclusion/exclusion criteria.  
11.9. 
Pre-Specified Subgroup Analyses 
Separate pre-specified analysis will be performed for the following subgroups.  
• Analysis of efficacy, PD, and safety based on pre-dose Metavir fibrosis Score 0-1 
versus 2-3. 
• Analysis of efficacy, PD, and safety based on the presence of NAFLD or NASH 
(defined as presence of hepatic steatosis, inflammation and hepatocyte ballooning on 
histology) versus no NAFLD and NASH.  
• Patients on AAT augmentation will be analyzed separately for changes from baseline 
in serum AAT levels.  
11.10. 
Analysis Methods 
The primary objective of the study is to evaluate the 3 doses of fazirsiran versus placebo and 
select a single active dose to be evaluated further in later stage studies and used in the open-label 
phase of this study. In addition to examination of safety, dose selection will be based on the 
evaluation of the mean percent change from baseline (Day 1, pre-dose) in serum Z-AAT levels 
through Week 16. The primary efficacy analysis, executed after all enrolled patients reach the 
Week 16 evaluation, will be performed using a MMRM approach. The repeated measures of the 
response are the values obtained at the scheduled study Weeks 2, 4, 6, and 16. The model will 
include fixed categorical effects for treatment, time, week, treatment by week interaction, and a 
baseline value of serum Z-AAT as a continuous covariate. Restricted maximum likelihood 
estimation (REML) with an unstructured within-patient covariance structure will be used. If the 
model fails to converge, alternative covariance structures will be considered. 
Based on the stated model, least squares (LS) estimates of the mean percent change from 
baseline for each treatment group, of the difference for each fazirsiran dose group and pooled 
placebo, and the corresponding 95% CIs will be reported for each timepoint. P-values from the 
Week 16 2-sided t-tests of each for each of the 3 dose groups vs placebo group will be evaluated 
for significance using Hochberg’s step-up procedure to adjust for multiplicity of testing. Placebo 
group will be pooled from placebo patients in 3 dose cohorts. The primary evaluation of interest 
is at Week 16 timepoint, to be completed in all randomized patients who receive at least one dose 


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of study treatment (FAS), regardless of the total number of received doses or any intercurrent 
events (hypothetical estimand).  
Secondary endpoints include: 
• Subject incidence of treatment-emergent AEs  
• Absolute and percent change from baseline in total liver Z-AAT (insoluble + soluble) 
protein at post-dose biopsy 
• Absolute and percent change from baseline in liver Z-AAT soluble protein at post-
dose biopsy 
• Absolute and percent change from baseline in liver Z-AAT insoluble protein at post-
dose biopsy 
• Absolute and percent change from baseline in liver function tests, including ALT, 
AST, ALP, GGT, total bilirubin, direct bilirubin and INR at Week 16 and over time 
through EOS  
• Absolute and percent change in serum Z-AAT overtime through EOS 
• Change over time in PK measurements of fazirsiran at timepoints specified in the 
SOA 
• Incidence of ADAs 
• Change from baseline in Metavir fibrosis stage at post-dose biopsy 
If the post-dose liver biopsy is not available, the biopsy completed at Early Termination may be 
used.  
For continuous secondary endpoints, analyses similar to the primary endpoint analysis will be 
performed. For all continuous longitudinal measures where data is collected at baseline and at 
more than one pre-scheduled post-baseline visits, a mixed-effects model repeated measures 
(MMRM) will be applied to evaluate the change from baseline at scheduled visits. 
Prior to each analysis of continuous endpoints, the endpoint variable will be evaluated for 
normality, and as a result, the original data may be transformed to achieve approximate 
normality. Results of analysis model from transformed data will be appropriately 
back-transformed to original scale for reporting purpose. 
Demographic, PK, 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). 
Sensitivity Analyses of Primary Efficacy Objective 


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The primary efficacy analysis method, MMRM, is based on the assumption of missing at random 
(MAR), where patients who discontinue the study prematurely are assumed to have behaved 
similarly to other patients in the same treatment group had they not dropped out. A sensitivity 
analysis, performed only if more than 5% of the patients discontinue from the study prematurely, 
will be performed to evaluate this assumption. The sensitivity analyses will be based on the 
multiple imputation (MI) control-based imputation method where placebo group is used to 
impute the missing values of the primary endpoint for the patients in the active treatment group. 
Specifically, the copy difference in reference method will be used which assumes that patients 
who withdraw from the active treatment group will have, following the dropout, their efficacy 
tend toward that of the placebo arm, but starting from the benefit already obtained. Missing 
endpoint values will be multiply imputed from their approximate posterior predictive 
distributions, obtained using multivariate imputation by chained equations algorithm. Details of 
the imputation model will be provided in the SAP. Multiply imputed datasets will be analyzed 
using the same methods as those in the primary analysis. Results from analysis of each imputed 
dataset, will be combined using Rubin’s combination rule, to produce, if appropriate, a pooled 
treatment difference and its 95% CI. 
A tipping point analysis will also be performed to evaluate the extent of departure from the 
observed treatment effect in order to arrive at a reversal of study inferences. These analyses will 
be performed under 2 scenarios regarding the assumptions around missing data mechanism: 
(1) MAR as applied in the primary analysis using the MMRM model, and (2) Missing Not at 
Random (MNAR) using the copy difference MI as described above.  
Exploratory Analyses 
The exploratory analyses are designed to investigate the association between treatment with 
fazirsiran or placebo and various biomarkers. These analyses will be exploratory, and data 
driven. Additional data, from other clinical trials, are often needed to confirm associations. Some 
of these exploratory analyses may be reported outside of the clinical study report. 
11.11. 
Interim and Planned Analyses 
A single Interim Analysis was performed by the ISC after all enrolled patients completed the 
Week 16 visit, the timepoint for the primary efficacy evaluation of interest. The unblinded results 
of the Interim Analysis were prepared for select Sponsor representatives, to facilitate the dose 
selection. The Sponsor and CRO’s study operational team will remain blinded to the individual 
patient treatment assignment. Investigators and study patients will remain blinded to the 
randomized treatment assignment until all patients complete their Week 48, post-baseline biopsy 
visit. Upon completion of the study, Investigators and study patients will be informed of the 
patient’s randomized treatment assignment from the double-blinded phase. 
In order to maintain a complete audit trail of activities related to the Interim Analysis and to 
secure a controlled access to interim results, the study will utilize a controlled access execution 
system for storage and distribution of Interim Analysis related documents.  


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A detailed Data Access Plan outlining which parties will have access to which data and at what 
time will be prepared. The plan will further indicate which study functions or parties have access 
to either individual patient or aggregate group treatment information, and/or the selected dose 
over the duration of the study. 
The Extended Efficacy Analysis will be performed after the last patient with fibrosis finish post-
baseline biopsy visit. The Final Analysis will be performed once all patients complete an Early 
Termination or Study Completion visit and database lock. 
11.12. 
Data Recording and Quality Control 
Source documents must be maintained for each patient in the study, consisting of all 
demographic and medical information, including clinical laboratory data, etc. A copy of the 
signed ICF must be retained. All information on the eCRFs must be traceable to these source 
documents in the patient's file. 
Data recorded in all patients’ 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. 
Institutional Review Board (IRB)/Ethics Committee (EC) Approval 
Prior to initiation of the study, written IRB/EC approval of the Protocol and ICFs, 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 IRB/EC prior to use. A list of the IRB/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 patient safety or the validity of the study will be 
approved by the IRB/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 IRB/EC, and written approval obtained before 
patients are enrolled. The composition of the IRB/EC will also be provided to the Sponsor. If 
approval is suspended or terminated by the IRB/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 patient 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 washout of 
excluded medications. 


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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 
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 patient will be required to provide written informed consent before 
participation in the study.  
All eligible patients 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 patient 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 ICF to retain. 
12.5. 
Emergency Contact with Principal Investigator 
Suitable arrangements will be made for patients 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 Principal Investigator (PI) or designee, to notify, where applicable, 
with the consent of the patient, the general practitioner of the patient’s participation in the trial, 
by sending a letter stating the nature of the trial, treatments, expected benefits or AEs 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 
the regulatory authorities and IRB/EC of an amendment, except where necessary to eliminate an 
immediate hazard to study patients. 


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Deviations may result from the action or inaction of the patient, 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, PK blood draws, 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 IRB/EC approvals for the 
protocol and ICF revisions 
Protocol deviations impacting patient safety or eligibility will be reported to the Sponsor or CRO 
within two (2) business days of occurrence and to the IRB/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 
patient’s eCRF. 
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 in the eCRFs. Patient 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 patient 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 enrollment 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 patients 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 
Because the study is blinded, an unblinded study monitor will be assigned to visit the site 
pharmacy during, and at Study Completion to review the randomization schedule in comparison 
to the dispensing log to verify correct randomization of study drug. 
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: 


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• Signed and dated copy of the final study protocol and any amendments 
• 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 IRB/EC or 
regulatory authorities 
• The IRB/EC approved ICF 
• Current curriculum vitae (signed and dated) of the PI and co-workers with major 
responsibilities in the trial 
• Site Signature and Delegation of Responsibility Log 
• Food and Drug Administration (FDA) Form 1572 (where applicable)  
• Financial Disclosure Form(s) 
• Blank case report form/eCRF 
• Signed patient ICFs 
• Laboratory reference ranges (signed and dated) 
• The completed Clinical Trial Notification (CTN) Application Form (where 
applicable) 
• The Final Study Report 
• Clinical raw data including the Source Data Forms, all clinical laboratory report 
forms, patient eCRFs, 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 
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the 
metabolic syndrome: a joint interim statement of the international Diabetes Federation Task 
Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American 
Heart Association; World Heart Federation; International Atherosclerosis Society and 
International Association for the Study of Obesity. Circulation 2009; 120(16): 1640-1645. 
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. 
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. 
De Serres FJ, 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. 
Ellis EL, Mann DA, Clinical evidence for the regression of liver fibrosis, Journal of Hepatology. 
2012;56:1171-1180. 
Feldman 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. 
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). 
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. 
Nelson DR, Teckman J, Di Bisceglie AM, Brenner DA. Diagnosis and management of patients 
with α1-antitrypsin (A1AT) Deficiency. Clin Gastroenterol Hepatol. 2012;10(6):575–580. 
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.  
Schlegel M, Janas M, Babu R, Blair L, Brown C, Castoreno A, et al. Improved Specificity and 
Therapeutic Index with ESC+ siRNA Conjugates Utilizing Seed-Pairing Destabilization via 
Novel Chemical Modifications. Presented as a poster at The 13th Annual Meeting of the 
Oligonucleotide Therapeutics Society; September 24-27, 2017, Bordeaux, France. 


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Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med 
2012;185:246-259. 
Teckman JH. Liver disease in alpha-1 antitrypsin deficiency: current understanding and future 
therapy. COPD;2013(10)S1:35-43. 
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. 
Turner AM, Stolk J, Bals R, Lickliter JD, Hamilton J, Christianson DR, et al. Hepatic-targeted 
RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in 
ZZ patients. J Hepatol. 2018 Aug;69(2):378-384.  
Vaishnaw A, Jadhav V, Janas M, Schlegel M. Platform Advances in RNAi Therapeutics, 
Alnylam Therapeutics Corporate Presentation, August 2017. 
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 
Wooddell CI, Peterson RM, Blomenkamp KS, Subbotin VM, Chu Q, Hamilton HL, et al. RNA 
interference therapeutic ARC-AAT prevents production of Z-alpha1 antitrypsin polymers and 
reverses liver disease phenotype in PiZ mouse model. Hepatology 2016; 64:68A. 


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APPENDIX 1: METABOLIC SYNDROME CRITERIA 
Metabolic syndrome in this study will be defined as having at least 3 of the identified risk factors 
(Alberti et al., 2009). 
 
 


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APPENDIX 2: ELEVATED ALT OR WORSENING HEPATIC FUNCTION 
STUDY MODIFICATION AND PATIENT 
DISCONTINUATION RULES 
Treatment-Emergent ALT 
Treatment-Emergent 
Total Bilirubin (TBL) 
Liver Symptoms 
Action 
Normal baseline: ALT >5× 
ULN 
Elevated baseline: ALT >3× 
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 >8× 
ULN 
Elevated baseline: ALT >5× 
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 >3× 
ULN 
Elevated baseline: ALT >2× 
baseline or >200 U/L 
(whichever occurs first) 
TBL >2× 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 >3× 
ULN 
Elevated baseline: ALT >2× 
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 
ALP=alkaline phosphatase; ALT= alanine aminotransferase; AST= aspartate aminotransferase; TBL=total bilirubin. 
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 (DILI): 
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 alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase 
(GGT), total bilirubin, direct bilirubin, and international normalized ratio (INR) 
• Ruling out acute viral hepatitis type A, B C D and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and 
biliary tract disease (abdominal ultrasound). 
• Consider gastroenterology or hepatology consultations 
Evaluate patients 2 or 3 times a week for signs and symptoms of clinical hepatitis and obtain 
liver biochemistries until biochemistries stabilize or the trial drug has been discontinued and the 
patient is asymptomatic. If biochemistries stabilize and the patient is asymptomatic, monitor liver 
biochemistries once a week until they return to baseline. Analysis of such biochemistries may 
occur at local lab.  
If the baseline liver enzymes are normal, follow the FDA guidance on “Drug- Induced Liver 
Injury: Premarketing Clinical Evaluation” for monitoring and managing patients if the patients 
experience elevations in liver enzymes during the clinical trial. 
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. 
Additional laboratory criteria to detect DILI: 
• Interrupt the treatment and initiate DILI evaluation if: 


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o Alkaline phosphatase (ALP)>2x ULN and direct bilirubin (DB) >2x ULN, if ALP 
and DB are normal at baseline 
o ALP >2x baseline and DB >2x baseline if they are elevated at baseline 
o ALP >2x baseline and DB >2x baseline and symptoms consistent with clinical 
hepatitis 
• In the event of liver enzyme elevation, perform a DILI evaluation. If a clear etiology is 
established to account for the liver enzyme abnormalities, and the liver enzymes return 
back to baseline, the study drug may be restarted. 
• If upon rechallenge, any magnitude of liver enzyme elevation recurs, the patient should 
cease the treatment drug and should be followed in the study. If a patient cannot be 
followed with laboratory or clinical monitoring, rechallenge should not be performed. 
Stopping rule for progression to cirrhosis during the study: 
APRI (using 40 U/L as ULN) will be calculated per SOA at baseline, Day 113 (Week 16), then 
every other dosing day (approximately every 168 days) or earlier if development of cirrhosis is 
suspected clinically, which may include development of varices, decompensating events or new 
thrombocytopenia and splenomegaly. Any increase from baseline to an APRI value >2.0 (must 
be confirmed on repeat) will trigger liver biopsy. For patients with baseline APRI >2.0 but who 
are eligible based on pre-dose biopsy, APRI will be calculated per SOA and a ≥50% increase 
from baseline (must be confirmed on repeat) will trigger liver biopsy. 
Investigator may elect to confirm an elevated APRI as a biomarker of cirrhosis with MRE if 
available PRIOR to proceeding to biopsy. If MRE is NOT consistent with cirrhosis then biopsy 
is not indicated and the patient may stay on study. Alternatively, the Investigator may elect to 
proceed directly from APRI to biopsy. 
If cirrhosis is detected on liver biopsy the patient will be discontinued from treatment and 
followed through EOS per SOA. This biopsy will represent EOS biopsy for purposes of endpoint 
determination. If cirrhosis is not confirmed on liver biopsy, patient may continue on treatment.  
 
 


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APPENDIX 3: PULMONARY FUNCTION MONITORING 
Pulmonary function will be monitored closely throughout the AROAAT2001 study using 
spirometry, DLCO, periodic DSMB reviews, weekly Sponsor reviews and medical monitoring 
for pulmonary AEs. 
If a patient in the AROAAT2001 study experiences an absolute 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 an absolute 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 an absolute 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 AROAAT2001 study while the patient is on fazirsiran (or 
placebo) and for up to an additional 6 months after the patient’s serum Z-AAT levels have 
returned to within 30% of their pre-dose Day 1 baseline serum 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 2 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 serum AAT may increase in frequency from SOA to monthly or every 
2 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, the Sponsor will work 
to make therapy available as part of the AROAAT2001 clinical study. 
Each patient newly started on augmentation therapy during the study due to declines in FEV1 
and/or DLCO as described above will be reviewed by the DSMB to assess if the patient should 
continue to receive treatment with fazirsiran or placebo. Additionally, the DSMB will evaluate 
for imbalances in adverse changes in FEV1, DLCO and pulmonary AEs in active versus placebo 
groups at each planned DSMB meeting.  
 


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APPENDIX 4: BIRTH CONTROL METHODS CONSIDERED HIGHLY 
EFFECTIVE 
Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective birth control methods. Such methods include: 
combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:  
oral  
intravaginal  
transdermal  
progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral  
injectable  
implantable 
intrauterine device (IUD) 
intrauterine hormone-releasing system (IUS) 
bilateral tubal occlusion 
vasectomized partner 
sexual abstinence, defined as refraining from heterosexual intercourse only when this method is 
in alignment with the normal lifestyle of the patient 
Birth control methods that result in a failure rate of more than 1% per year when used alone or in 
combination, thus are NOT considered highly effective include: 
progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action 
male or female condom with or without spermicide  
cap, diaphragm, or sponge with spermicide 
 
 
 


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APPENDIX 5: DISCUSSION OF RISKS ASSOCIATED WITH STUDY 
ASSESSMENTS 
Many of the assessments in the study i.e., liver biopsy, noninvasive hepatic imaging 
(FibroScan®), magnetic resonance imaging (MRI)/magnetic resonance elastography (MRE) and 
laboratory measurements are often part of a standard evaluation for liver disease severity made 
by a consulting physician treating a patient with AATD liver disease. Risk Assessments for 
patients are described in Section 4.8 of the study protocol. Assessments such as pulmonary 
function tests (PFTs), FibroScan® and MRE are noninvasive and involve minimal risk. Liver 
biopsy is an invasive assessment but is of critical importance in this study. AROAAT2001 is an 
innovative clinical study that requires liver biopsy to assess the novel histological primary 
endpoint and rating scale. Further assessment of the risk/benefit of the study assessments are 
summarized below: 
• PFTs as used in the study (spirometry and DLCO) are standardly used to evaluate 
lung function in alpha-1 patients. A key benefit of this assessment is to track lung 
function during the study to evaluate for lung toxicity. There is very minimal risk 
associated with pulmonary function testing.  
• FibroScan® and Magnetic Resonance Elastography (MRE) are noninvasive imaging 
modalities commonly used to evaluate liver disease in AATD and are of minimal risk 
for patients. The key clinical research benefit of these noninvasive imaging 
procedures is to track changes in liver stiffness related which in this study is being 
explored as markers for liver fibrosis and liver disease severity in patients with 
AATD-associated liver disease.  
• Liver biopsy is the most invasive assessment in the study. 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 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 BP) 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. The following 
risk mitigations are implemented in the protocol: 
− Liver biopsies are being performed by experienced physicians with appropriate 
local procedural credentials, in the setting of a hospital facility experienced with 
such procedures.  
Measures of hemostatic function (e.g., platelets, international normalized ratio [INR]) will be 
conducted prior to biopsy, and may be used to exclude any patient at increased risk for 
procedural complications. 


Arrowhead Pharmaceuticals, Inc.  
Protocol No.: AROAAT2001 
 
Global Version 6.0, 29-AUG-2022  
Confidential 
Page 87 of 87 
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. Liver biopsy is the only method for obtaining the tissue 
specimens needed to evaluate the primary endpoint of the study.  
Demonstration of an intrahepatic reduction of the disease-causing Z-AAT protein in response to 
fazirsiran is the pharmacologic and efficacy assessment which is most clinically relevant to 
patients with AATD-associated liver disease. Thus, the minimal risk of liver biopsy is justified in 
light of its use to obtain tissue samples required to assess clinically meaningful changes in 
intrahepatic Z-AAT protein and histology as represented by multiple key secondary study 
endpoints.  
 



SAP_001.pdf: 
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Statistical Analysis Plan Addendum 
 
 
Investigational Product: 
Fazirsiran (TAK-999, ARO-AAT) 
Protocol Title: 
A Placebo-Controlled, Multi-dose, Phase 2 Study to 
Determine the Safety, Tolerability and 
Pharmacodynamic Effect of Fazirsiran in Patients 
with Alpha-1 Antitrypsin Deficiency (AATD) 
[SEQUOIA] 
Study Number: 
AROAAT-2001 
Sponsor: 
Arrowhead Pharmaceuticals, Inc. 
177 East Colorado Boulevard, Suite 700 
Pasadena, CA 91105 USA 
 
Protocol Version: 
Version 6.0 
 
SAP Addendum Version: 
Version 1.0  
 
SAP Approval Date: 
30JAN2024 
 
 
 
 




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Version Number 
Date (DDMMYYYY) 
Summary of Changes 
Original (v1.0) 
30JAN2024 
N/A 
 
 
 


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TABLE OF CONTENTS 
1.
INTRODUCTION AND OBJECTIVES OF ANALYSIS............................................7
1.1. 
Introduction .......................................................................................................... 7 
1.2. 
Objectives and Endpoints .................................................................................... 7 
2. 
STUDY DESIGN .............................................................................................................. 8 
3. 
SUBJECT POPULATIONS ............................................................................................ 9 
3.1. 
Population Definitions ......................................................................................... 9 
4. 
DEFINITIONS AND DATA HANDLING .................................................................. 10 
5. 
PLANNED ANALYSIS ................................................................................................. 11 
6. 
STATISTICAL METHODS OF ANALYSIS .............................................................. 12 
6.1. 
General Considerations ..................................................................................... 12 
6.2. 
Efficacy Evaluation ............................................................................................ 12 
6.3. 
Pharmacodynamic Evaluations ........................................................................ 12 
6.4. 
Immunogenicity Summaries ................................. Error! Bookmark not defined. 
6.5. 
Safety Analyses ................................................................................................... 12 
6.5.1. 
Adverse Events ..................................................................................... 12 
6.5.2. 
Laboratory Data .................................................................................... 13 
6.5.3. 
Prior and Concomitant Medication ....................................................... 13 
6.5.4. 
Electrocardiogram (12-Lead ECG) ....................................................... 13 
6.5.5. 
Vital Signs and Physical Measurements ............................................... 14 
6.5.6. 
Pulmonary Function .............................................................................. 14 
 
 
 


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ABBREVIATIONS
Abbreviation 
Definition 
AAT 
Alpha-1 antitrypsin 
AATD 
Alpha-1 antitrypsin deficiency 
ALT 
Alanine aminotransferase  
AST 
Aspartate transaminase 
ARO 
Arrowhead Pharmaceuticals, Inc 
ARO-AAT Injection 
Clinical drug product solution ready for SC injection 
ARO-AAT 
Short name for ARO-AAT Injection 
BP 
Blood Pressure 
CRF 
Case Report Form 
DLCO 
Carbon Monoxide Diffusing Capacity 
DSMB  
Data Safety Monitoring Board 
EC  
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FEV1 
1 second Forced Expiratory Volume 
FSH 
Follicle-Stimulating Hormone 
GGT 
Gamma glutamyl transferase 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
ISR 
Injection Site Reaction 
LD 
Lactate Dehydrogenase 
LISR 
Local Injection Site Reaction 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
mmHg 
millimeters of mercury 
MRE 
Magnetic Resonance Elastography 
MRI 
Magnetic Resonance Imaging 
MRI-PDFF 
Magnetic Resonance Imaging Proton Density Fat Fraction 
PD 
Pharmacodynamic 
PBO 
Placebo 
PI 
Principal Investigator 
PiZZ 
Homozygous Z allele individuals 
PK 
Pharmacokinetic 
PT 
Prothrombin Time 
PTT 
Partial thromboplastin time 


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Abbreviation
Definition
RNAi 
RNA interference 
SAE 
Serious Adverse Event  
SD 
Standard Deviation 
siRNA 
Short interfering RNA oligonucleotides  
SOA 
Schedule of Assessments 
TIA 
Transient Ischemic Attack 
ULN 
Upper Limit of Normal 
Z-AAT 
Mutant AAT protein from Z allele  
 
 
 
 
 
 


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1.
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
This document presents the statistical analysis plan (SAP) addendum for Arrowhead Pharmaceuticals, Protocol 
AROAAT2001: A Placebo-Controlled, Multi-dose, Phase 2 Study to Determine the Safety, Tolerability and 
Pharmacodynamic Effect of Fazirsiran in Patients with Alpha-1 Antitrypsin Deficiency (AATD) [SEQUOIA]. 
This SAP Addendum is based on the AROAAT2001, V6.0, protocol dated 29 August 2022. Per the final SAPv3.0 
purpose of this SAP Addendum is to provide further detail on these open-label phase descriptive statistics. 
Analyses that were described in the final SAPv3.0 will not be described again in this document. 
The formats for the tables, figures, and listings (TFLs) described in this SAP are provided in a companion 
document. A table of contents for the TFLs will be included in the companion document. 
1.2. 
Objectives and Endpoints 
Refer to SAPv3.0. 
 
 


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2.
STUDY DESIGN 
Refer to SAPv3.0. 
 


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3.
SUBJECT POPULATIONS 
Refer to SAPv3.0. 
3.1. 
Population Definitions 
The following population samples for analyses will be evaluated and used for presentation and analysis of data 
captured during the open-label phase:   
 
Open-label Phase Set: All subjects who receive at least one dose of Fazirsiran in the open-label phase.  




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5.
PLANNED ANALYSIS 
Refer to SAPv3.0 


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6.
STATISTICAL METHODS OF ANALYSIS 
6.1. 
General Considerations 
Refer to SAPv3.0. 
As indicated in the protocol Schedule of Assessments, select assessments continue into the open-label phase. 
Generally, data collected in the open-label phase will by descriptively summarized in separate summaries from 
those pertaining to data collected in the double-blind phase. 
No separate open-label phase listings will be generated. 
6.2. 
Efficacy Evaluation 
No separate efficacy analyses will be performed. 
6.3. 
Pharmacodynamic Evaluations 
Serum Z-AAT value and derived change/percent change from baseline at each open-label visit will be 
summarized.   
Serum Fibrosis Markers 
A descriptive statistics summary of serum Pro-C3, Pro-C6, APRI and FIB-4 by open-label visit will be provided 
by fibrosis status at Screening. Derived changes from baseline and percent changes from baseline will be 
included. Subgroup analysis based on central read Metavir score will be done.  
FIB-4: FIB-4 is calculated as  
 
APRI: APRI is calculated as  
 
6.4. 
Safety Analyses 
Refer to SAPv3.0 
6.4.1. 
Adverse Events 
Adverse events analyses described in the SAPv3.0 will be repeated for adverse events captured during open-label 
phase. Overall summaries of TEAEs occurring during the double-blind phase and open-label phase will be 
provided. The overall summaries will include the number and percentage of subjects reporting at least one: 
TEAE; TESAE; TEAE by severity; treatment related TEAE; TEAE leading to study drug discontinuation; TEAE 
leading to study termination; inject site reaction and deaths. 
Descriptive statistics summaries of subject incidence of AEs will be summarized for all TEAEs, treatment-related 
TEAEs, TESAEs, treatment-related TESAEs, TEAEs resulting in study drug discontinuation, TEAE with an 
outcome of death, TEAE at injection site, TEAE relevant to COPD exacerbation, TEAE 
 by 
SOC in alphabetical order and PT in descending order of frequency. Subject incidence of TEAEs will also be 


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summarized by PT in descending order of frequency. TEAE will be summarized by fibrosis status at Screening.
Number of TEAEs will be summarized by SOC in alphabetical order and PT in descending order of frequency. 
Descriptive statistics summaries of subject incidence of TEAE, TEAE at injection site, by SOC, PT, severity will 
be provided. Subjects will be counted once under the worst severity reported within each SOC and PT.  
Descriptive statistics summaries of subject incidence of TEAEs by SOC, PT and relationship to investigation 
product will be provided. Subjects will be counted once under the closest relationship reported within each SOC 
and PT.  
Descriptive statistics of exposure-adjusted incidence rate of TEAES by PT will be provided. The definition of 
exposure-adjusted incidence rate is the number of subjects experiencing the TEAE divided by the total exposure-
-year is calculated as (date of last dose of study 
drug  date of first dose of study drug +1) / 365.25. 
6.4.2. 
Laboratory Data 
Laboratory data (details refer to Protocol section 9.2.6), including biochemistry, hematology, and coagulation will 
be summarized using descriptive statistics at each open-label visit. For continuous parameters, a summary of the 
change from baseline and percent change from baseline to each post dose laboratory assessment in the open-label 
phase will be produced. Shifts in selected laboratory parameters between baseline and the worst open-label 
assessment value will be summarized according NCI CTCAE toxicity grades. The number and percent of subjects 
will be reported in each shift category. 
Separate summary table will be generated for ALT, AST, alkaline phosphatase, CK, GGT, total bilirubin, direct 
bilirubin and INR. An evaluation of drug-induced serious hepatotoxicity (eDISH) scatter plot will be produced for 
the open-label phase. 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 
 
6.4.3. 
Prior and Concomitant Medication 
Refer to SAPv3.0 for prior and concomitant medications. 
No separate concomitant medications summaries will be generated. 
6.4.4. 
Electrocardiogram (12-Lead ECG)  
ECG parameters will include heart rate (beats/min), PR interval, QRS interval, QT interval, and QTc interval. 
The observed value and change from baseline in ECG parameters will be summarized as continuous variables at 
baseline and each open-label stage visit.  
ECG interpretation shift from baseline to each open-label timepoint will be summarized as the number and 
percentage of subjects with normal, clinically insignificant abnormal, and clinically significant abnormal 
interpretations. 


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6.4.5. 
Vital Signs and Physical Measurements 
Vital signs include body temperature (°C), pulse 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 open-label stage visit. 
6.4.6. 
Pulmonary Function 
Refer to SAPv3.0 for additional details related to pulmonary function assessments. 
Change from baseline in pulmonary function test parameters (PFT) will be summarized by time point for open-
label phase visits.  Additional plots of PFT parameters and change from baseline trend will be generated.