A Phase 2, Randomized, Double-blind, Placebo-Controlled Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Dose Levels of Belcesiran in Patients With Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
Phase: PHASE2
Conditions: Alpha 1-Antitrypsin Deficiency
Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04764448 
Sponsor trial ID: 
DCR-A1AT-201 
Official title of study: 
A Phase 2, Randomized, Double-blind, Placebo-controlled 
Study Investigating Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Two Dose Levels of Belcesiran in 
Patients with Alpha-1 Antitrypsin Deficiency-Associated Liver 
Disease 
Document date: 
02-May-2023 
*Document date refers to the date on which the document was most recently updated. 

CERNATITLE PAGE
Protocol Title: 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study
Investigating Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Two Dose Levels of Belcesiran in Patients 
with Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
Protocol Number:
DCR-A1AT-201
Compound:
Belcesiran, also known as DCR-A1AT
Study Phase:
2
Short Title: 
A Phase 2 Study of Belcesiran in Patients with AATLD
Study Name:
ESTRELLA
EudraCT Number: 2020-003313-35
NCT Number:
NCT04764448
Sponsor Name:
Dicerna Pharmaceuticals, Inc.
75 Hayden Ave
Lexington, MA 02421 US
(617) 621-8097
Version History:
Original Protocol (version 1.0)
03-Sep-2020
Amendment 1 (version 2.0)
04-Feb-2021
Amendment 2 (version 3.0)     
24-May-2022
Amendment 3 (version 4.0)     
02-May-2023
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Redacted protocol 
Includes redaction of personal identifiable information only. 

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Medical Monitor and Pharmacovigilance Contact Information 
SAE Submission:  
Novo Nordisk Safety Operations:  
Email: soclin@novonordisk.com   
24-hour Safety Fax: +45 44427787  
Clinical Research Organization Medical Monitor: 
, 
, 
, 
 
, 
 
 
24-hour Emergency Telephone:  
 
Email: 
 
 
, 
, 
 
, 
 
, 
 
Emergency Telephone:  
 
Email: 
 
Sponsor Medical Monitor: 
Dicerna Pharmaceuticals, Inc. 
, 
 
, 
 
Telephone: 
 
Email:  
  
 
 
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Protocol Amendment 3, Summary of Changes 
DOCUMENT HISTORY 
Document 
Date 
Amendment 3 
02-May-2023 
Amendment 2 
24-May-2022 
Amendment 1 
04-Feb-2021 
Original Protocol 
03-Sep-2020 
 
Amendment 3, 02-May-2023 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
As the duration of this study will extend beyond January 2025, the protocol was updated to prepare for 
compliance with EU Clinical Trial Regulation 536/2014 (EU-CTR). The protocol has been 
harmonized across country-specific versions in the EU Member States, to the extent possible. Where 
not feasible, country-specific requirements are now located in Section 10.5. Additionally, the protocol 
has been updated to correct inconsistencies among the 3 study cohorts. Additional updates and 
clarifications were also included. A summary of all changes follows in the table below. 
Description of Change 
Brief Rationale 
Affected Sections 
Re-instate close monitoring rules for 
DILI 
Close monitoring rules were 
initially added to address 
HPRA concerns. These rules 
will now apply across all 
countries. 
7.1.1.2 Drug-Induced Liver Injury  
 
 
 
Monitoring 
Study stopping rules were added 
Study stopping rules were 
initially added to address 
HPRA concerns. These rules 
will now apply across all 
countries. 
7.1.2 
Study Stopping Rules 
Stopping rules were updated and 
guidance on electrocardiogram 
findings are provided 
To include electrocardiogram 
findings as judges by the 
investigator as a stopping rule 
for individual participants 
7.1.1 
Stopping Rules for Individual   
 
 
Participants 
10.5 
Electrocardiogram Findings 
Added PFTs to the schedule of 
events 
To harmonize schedule of 
activities with the US version 
of the protocol 
1.3  
Schedule of Activities 
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Made changes to the timing of 
collection of serum AFP, urinalysis, 
anti-drug antibodies, and blood 
biomarkers in Cohort 1 SoA 
To harmonize schedule of 
activities between cohorts 
1.3  
Schedule of Activities 
Made changes to the timing of 
collection of anti-drug antibodies, 
injection site inspection, hematology, 
chemistry, and coagulation, DLCO 
and spirometry, pregnancy test for 
WOCBP, weight, and serum and 
CRP in Cohort 2 SoA 
To harmonize schedule of 
activities between cohorts 
1.3  
Schedule of Activities 
Made changes to the timing of 
collection of urinalysis, anti-drug 
antibodies, SRGQ, and CLDQ, and 
added complement collection to 
Cohort 3 SoA 
To harmonize schedule of 
activities between cohorts 
1.3  
Schedule of Activities 
Specified the duration in which 
WOCBP must use contraception for 
at least 12 weeks after last dose of 
study drug 
Was not clearly defined in 
previous versions 
5.1  
Inclusion Criteria 
10.4 
Contraceptive Guidance and   
 
 
Collection of Pregnancy Information 
Clarified the definition of 
“pulmonary exacerbation” 
To ensure consistency of 
reporting of exacerbations 
between sites  
8.2.6 
Other Pulmonary Information 
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TABLE OF CONTENTS 
CERNATITLE PAGE .....................................................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
MEDICAL MONITOR AND PHARMACOVIGILANCE CONTACT INFORMATION ............3 
PROTOCOL AMENDMENT 3, SUMMARY OF CHANGES ......................................................4 
TABLE OF CONTENTS .................................................................................................................6 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis ......................................................................................................................11 
1.2. 
Schema ........................................................................................................................15 
1.3. 
Schedules of Activities ...............................................................................................17 
2. 
INTRODUCTION ......................................................................................................30 
2.1. 
Study Rationale ...........................................................................................................30 
2.2. 
Background .................................................................................................................31 
2.2.1. 
Alpha-1 Antitrypsin Deficiency .................................................................................31 
2.2.2. 
Pharmacology of Belcesiran .......................................................................................32 
2.2.3. 
Nonclinical Pharmacokinetics and Toxicokinetics of Belcesiran ..............................32 
2.2.4. 
Clinical Overview .......................................................................................................35 
2.2.5. 
Summary .....................................................................................................................36 
2.3. 
Benefit/Risk Assessment ............................................................................................36 
2.3.1. 
Potential Risks Associated with Belcesiran ................................................................36 
2.3.2. 
Risks Associated with Liver Biopsy and Study-Specific Evaluations .......................38 
2.3.3. 
Risk Assessment .........................................................................................................40 
2.3.4. 
Overall Benefit: Risk Conclusion ...............................................................................43 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................44 
4. 
STUDY DESIGN .......................................................................................................45 
4.1. 
Overall Study Design ..................................................................................................45 
4.2. 
Scientific Rationale for Study Design ........................................................................46 
4.3. 
Justification for Dose ..................................................................................................46 
4.4. 
End of Study Definition ..............................................................................................48 
5. 
STUDY POPULATION .............................................................................................48 
5.1. 
Inclusion Criteria ........................................................................................................48 
5.2. 
Exclusion Criteria .......................................................................................................49 
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5.3. 
Lifestyle Considerations .............................................................................................51 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................51 
5.3.2. 
Activity .......................................................................................................................51 
5.4. 
Screen Failures ............................................................................................................51 
5.4.1. 
Screening Tests Required during the Rescreening Period ..........................................52 
6. 
STUDY INTERVENTION ........................................................................................52 
6.1. 
Study Intervention Administered ................................................................................52 
6.1.1. 
Dose Level ..................................................................................................................53 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................53 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................54 
6.4. 
Study Intervention Compliance ..................................................................................54 
6.5. 
Concomitant Therapy .................................................................................................54 
6.5.1. 
Augmentation Therapy ...............................................................................................55 
6.5.2. 
Vaccinations ...............................................................................................................55 
6.6. 
Dose Modification ......................................................................................................55 
6.7. 
Intervention after the End of the Study .......................................................................55 
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................56 
7.1. 
Discontinuation of Study Intervention........................................................................56 
7.1.1. 
Stopping Rules for Individual Participants .................................................................56 
7.1.2. 
Study Stopping Rules .................................................................................................58 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................58 
7.3. 
Lost to Follow up ........................................................................................................59 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................60 
8.1. 
Efficacy Assessments .................................................................................................60 
8.1.1. 
Serum Z-AAT Protein Concentration .........................................................................60 
8.1.2. 
Assessment of Fibrosis and Hepatic Z-AAT Content via Percutaneous Liver 
Biopsy .........................................................................................................................60 
8.1.3. 
Noninvasive Measures of Liver Fibrosis ....................................................................62 
8.1.4. 
Assessment of Liver Stiffness ....................................................................................63 
8.1.5. 
Omics Analyses ..........................................................................................................64 
8.1.6. 
St. George’s Respiratory Questionnaire .....................................................................64 
8.1.7. 
Chronic Liver Disease Questionnaire .........................................................................64 
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8.1.8. 
Covid-19 Testing ........................................................................................................65 
8.2. 
Safety and Other Assessments ....................................................................................65 
8.2.1. 
Screening Assessments ...............................................................................................65 
8.2.2. 
Physical Examinations ................................................................................................66 
8.2.3. 
Vital Sign Measurements ............................................................................................66 
8.2.4. 
Electrocardiograms .....................................................................................................66 
8.2.5. 
Pulmonary Function Tests ..........................................................................................66 
8.2.6. 
Other Pulmonary Information .....................................................................................68 
8.2.7. 
Clinical Safety Laboratory Assessments ....................................................................68 
8.3. 
Adverse Events and Serious Adverse Events .............................................................69 
8.3.1. 
Time Period and Frequency for Event Assessment ....................................................69 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................69 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................69 
8.3.4. 
Serious Adverse Event Reporting ...............................................................................70 
8.3.5. 
Reporting of Pregnancy ..............................................................................................70 
8.3.6. 
Adverse Events of Special Interest .............................................................................70 
8.4. 
Treatment of Overdose ...............................................................................................71 
8.5. 
Pharmacokinetics ........................................................................................................71 
8.5.1. 
Metabolite Identification ............................................................................................71 
8.6. 
Pharmacodynamics .....................................................................................................71 
8.7. 
Genetics ......................................................................................................................72 
8.8. 
Immunogenicity Assessments ....................................................................................72 
8.9. 
Medical Resource Utilization and Health Economics ................................................72 
9. 
STATISTICAL METHODS .......................................................................................73 
9.1. 
Randomization and Sample Size ................................................................................73 
9.2. 
Study Populations .......................................................................................................74 
9.3. 
Statistical Analyses .....................................................................................................74 
9.3.1. 
Analyses of Primary Endpoints ..................................................................................74 
9.3.2. 
Analyses of Secondary Endpoints ..............................................................................75 
9.3.3. 
Exploratory Analyses ..................................................................................................75 
9.4. 
Interim Analyses .........................................................................................................75 
9.4.1. 
Data Safety Monitoring Committee ............................................................................76 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................77 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................77 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................77 
10.1.2. 
Financial Disclosure ...................................................................................................77 
10.1.3. 
Informed Consent Process ..........................................................................................77 
10.1.4. 
Data Protection ...........................................................................................................78 
10.1.5. 
Committee Structure ...................................................................................................78 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................78 
10.1.7. 
Data Quality Assurance ..............................................................................................79 
10.1.8. 
Source Documents ......................................................................................................79 
10.1.9. 
Study and Site Closure................................................................................................79 
10.1.10. 
Publication Policy .......................................................................................................80 
10.2. 
Clinical Laboratory Tests ...........................................................................................80 
10.2.1. 
Samples for Future Analysis .......................................................................................82 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow 
up, and Reporting ........................................................................................................82 
10.3.1. 
Definition of AE .........................................................................................................82 
10.3.2. 
Definition of SAE .......................................................................................................83 
10.3.3. 
Definition of Adverse Event of Special Interest .........................................................84 
10.3.4. 
Recording and Follow-Up of AE and/or SAE ............................................................84 
10.3.5. 
Reporting of SAEs ......................................................................................................86 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information ...........................86 
10.4.1. 
Definitions ..................................................................................................................86 
10.4.2. 
Contraception Guidance .............................................................................................87 
10.4.3. 
Pregnancy Testing ......................................................................................................88 
10.4.4. 
Collection of Pregnancy Information .........................................................................89 
10.5. 
Country-specific Requirements ..................................................................................90 
10.6. 
Abbreviations ..............................................................................................................91 
10.7. 
Investigator Signature Page ........................................................................................95 
10.8. 
Protocol Amendment History .....................................................................................96 
11. 
REFERENCES .........................................................................................................109 
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LIST OF TABLESTable 1: ................................................................... Screening Period Schedule of 
Activities .....................................................................................................................17 
Table 2: 
Treatment Period Schedule of Activities – Cohort 1 ..................................................19 
Table 3: 
Treatment Period Schedule of Activities – Cohort 2 ..................................................22 
Table 4: Treatment Period Schedule of Activities – Cohort 3 .................................................25 
Table 5: 
Ishak Fibrosis Staging.................................................................................................61 
Table 6 
METAVIR Scoring System ........................................................................................62 
Table 7: 
Minimum Timing of the Data Safety Monitoring Committee Data Reviews ............76 
Table 8: 
Protocol-Required Laboratory Assessments...............................................................80 
Table 9: 
Grading of Injection Site Reactions, CTCAE v 5.0 ....................................................84 
Table 10: Highly Effective Contraceptive Methods ...................................................................88 
LIST OF FIGURESFigure 1 .................................................................................... Dose Regimens by 
Cohort .........................................................................................................................15 
Figure 2: 
Study Schematic .........................................................................................................16 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 2, Randomized, Double-blind, Placebo-controlled Study Investigating 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Dose 
Levels of Belcesiran in Patients with Alpha-1 Antitrypsin -Associated Liver 
Disease 
 
Short Title: 
A Phase 2 Study of Belcesiran in Patients with AATLD 
Rationale: 
 
Alpha-1 antitrypsin deficiency (AATD) is caused by inherited autosomal mutations in SERPINA1, the 
gene that encodes the alpha-1 antitrypsin (AAT) protein. The resultant mutant AAT protein (Z-AAT) 
is prone to misfolding and aggregation as homopolymers in hepatocytes. In individuals homozygous 
for the autosomal mutant AAT Z-allele (known as PiZZ patients), impaired degradation of the 
aggregated protein leads to putatively toxic accumulation of Z-AAT in the liver (toxic gain-of-
function) and exerts continuous stress on the hepatocytes. Over time, this constant stress can lead to 
liver fibrosis, cirrhosis, and hepatocellular cancer. Currently, there is no treatment for this severe liver 
disease, aside from liver transplantation. 
Dicerna Pharmaceuticals, Inc. is developing belcesiran, also known as DCR-A1AT, as a treatment for 
alpha-1 antitrypsin associated liver disease (AATLD) using an RNAi strategy to silence SERPINA1. 
This knockdown may lead to a reduction of total Z-AAT expression in the liver and, in turn, reduce 
the accumulation of toxic Z-AAT. Without the continuous putative toxic stimulus, the progression of 
AATLD in affected individuals may be halted, or potentially even reversed. 
Belcesiran sodium (DCR-S1459, the drug substance for belcesiran), has been shown to significantly 
reduce AAT mRNA and AAT protein levels in transgenic mice and cynomolgus monkeys. 
Additionally, in the transgenic mouse model of AATLD, belcesiran sodium substantially reduced 
hepatic globules, indicating reduced accumulation of aggregated human Z-AAT protein. 
The initial safety, tolerability, PK, and PD of belcesiran are being evaluated in an ongoing single-
ascending-dose study in healthy volunteers (DCR-A1AT-101). To date, single doses of belcesiran 
have been well tolerated, with no SAEs or dose-limiting toxicities (DLT) reported. Study DCR-A1AT-
201 is the first study of belcesiran in adults with AATLD. The overall goals of this study are to:  
o demonstrate that belcesiran is safe and well-tolerated in adult PiZZ patients with liver 
fibrosis; 
o investigate the effect of 2 dose levels of belcesiran on reduction of Z-AAT production in 
the liver, reflected by a reduction in circulating Z-AAT levels; and 
o evaluate the effect of belcesiran on AATLD as assessed by liver biopsy and non-invasive 
markers of liver disease 
Overall Design: 
This study is a multiple dose, randomized, placebo-controlled, double-blind study to evaluate the 
safety, tolerability, PK, and PD of 2 belcesiran doses in adult patients with PiZZ AATLD (liver 
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fibrosis stage 1-4, METAVIR scoring system). Administration of the first dose of study intervention 
will occur on Day 1. Participants will return to the site for administration of study intervention and 
safety, tolerability, PK, and PD monitoring at specified time points as per the SoA through the End of 
Treatment (EOT) visit. 
Intervention Groups and Duration: 
The study will be conducted in 3 separate cohorts. Participants will be randomized in a 1:1 fashion to 
either Cohort 1 or 2. Once Cohort 1 and 2 have enrolled, enrollment of Cohort 3 will be initiated. 
Randomization will be stratified based on fibrosis stage (METAVIR Score F1, F2, F3, or F4) in all 
cohorts.   
x Participants in Cohort 1 (N=8) will be randomized 3:1 to either belcesiran 210 mg or placebo 
and a liver biopsy will be performed at week 24 to assess the effect of belcesiran. In addition, 
participants will have the option to continue treatment for an additional 72 weeks so that the 
total treatment duration will be 96 weeks. 
x Participants in Cohort 2 (N=8) will be randomized 3:1 to either belcesiran 210 mg or placebo 
and a liver biopsy will be performed at week 48 to assess the effect of belcesiran. In addition, 
participants will have the option to continue treatment for an additional 48 weeks so that the 
total treatment duration will be 96 weeks. 
x Participants in Cohort 3 (N=30) will be randomized 2:1:2:1 to belcesiran 210 mg, the 
equivalent amount of placebo for belcesiran 210 mg, belcesiran 50 mg or the equivalent 
amount of placebo for belcesiran 50 mg. Participants will be blinded within each dose level. 
Participants will have a liver biopsy performed at week 24 to assess the effect of belcesiran and 
thereafter continue treatment until 96 weeks of treatment have been completed.  
All participants in Cohorts 1 to 3 will have the option to undergo a liver biopsy at EOT/week 96. 
Biopsy findings will be correlated with changes in non-invasive markers of liver disease and liver 
stiffness.  
In all cohorts, a follow up period of 48 weeks will follow EOT. In addition, Cohorts 1 and 2 will be 
followed for an additional 48 weeks to inform about the duration of potential treatment effects.   
Study Population: 
Key Inclusion Criteria: 
1. Male or female age 18 to 75 years inclusive, at the time of signing the ICF.  
2. Documented diagnosis of PiZZ-type AATD, confirmed by genotyping. Historical genotyping data 
may be used, if available. 
3. AATLD, with a liver fibrosis score categorized as F1, F2, F3, or F4 in the METAVIR scoring 
system, documented by liver biopsy during Screening.  
4. Post-bronchodilator FEV1 > 45% of predicted at Screening. Participants receiving augmentation 
therapy on a regular basis and intending to continue augmentation therapy during the study are 
eligible to participate. 
5. eGFR at Screening ≥ 60 mL/min normalized to 1.73 m2 BSA. 
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6. Non-smokers (defined as having not smoked cigarettes daily for at least the preceding 12 months) 
with current non-smoking status confirmed by urine cotinine at Screening AND any previous 
smoking history prior to 12 months must be < 15 pack years, including use of 
e-cigarettes. Participants may be on nicotine replacement (patch or gum). A positive urine cotinine 
result due to nicotine replacement is acceptable for enrollment at the discretion of the Investigator. 
Key Exclusion Criteria: 
1. History of chronic liver disease other than non-alcoholic fatty liver disease from any cause other 
than PiZZ-type AATD.  
2. Child-Pugh Score B or C or a previous hepatic decompensation event. 
3. History of one single severe exacerbation of underlying lung disease in the year prior to 
randomization.  
A severe exacerbation is defined as an exacerbation that requires hospitalization or a visit 
to the emergency room. 
4. History of rapid decline in pulmonary function, as assessed by the Investigator. 
Disclosure Statement:  
This is a parallel-cohort, placebo-controlled, treatment study investigating belcesiran in patients with 
AATLD. Participants and Investigators will be blinded to treatment. Complete details, including any 
Sponsor team members who are planned to be unblinded, will be presented in the Study Specific 
Blinding Plan.  
Number of Participants: 
Up to a total number of 16 participants will be enrolled in Cohorts 1 and 2. A total of 30 participants 
will be enrolled in Cohort 3.  
Data Safety Monitoring Committee: 
A DSMC will be convened to review safety data at predefined intervals, including at the time of a 
planned interim analysis, to ensure the safety of the participants in all cohorts. The timing and scope of 
the review meetings will be defined in the DSMC charter.  
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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary (Cohorts 1 and 2) 
1. To evaluate the safety and tolerability of multiple 
doses of belcesiran in patients with AATLD 
1. The incidence and nature of TEAEs, and the 
change from Baseline in PFTs, 12 -lead ECGs, 
physical examination findings, vital signs, and 
clinical laboratory tests 
2. To characterize the PD of belcesiran in patients 
with AATLD 
2. Changes from baseline to weeks 24 (Cohort 1)/48 
(Cohort 2) in serum AAT protein concentrations  
Primary (Cohort 3) 
1. To characterize the PD of belcesiran in patients 
with AATLD 
1. 
Change from baseline to week 24 in serum 
Z-AAT protein levels 
2. 
Change from baseline to week 24 in liver 
Z-AAT protein levels 
Secondary 
1. To characterize the PK of belcesiran in the plasma 
of patients with AATLD  
1. PK profile of belcesiran 
2. To assess the effect of belcesiran on liver 
histology in patients with AATLD 
2. Change from Baseline up until week 96 in liver 
fibrosis 
3. Change from Baseline up until week 96 in 
diastase-resistant PAS-positive AAT globules 
Exploratory 
1. To assess the effect of belcesiran on liver stiffness 
in patients with AATLD 
1. Change from Baseline up until week 96 in 
FibroScan® score 
2. To assess the effect of belcesiran on liver fibrosis 
and/or inflammation in patients with AATLD 
2. Change from Baseline up until week 96 in ELF 
score  
3. Change from Baseline up until week 96 in CK-18 
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1.2. 
Schema 
Figure 11 
Dose Regimens by Cohort 
 
 
 
 
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Figure 22: 
Study Schematic 
        
    
              
                
        
         
                
        
         
        
      
 belcesiran or
placebo 
      
       
  
      
 egen 
        
      
 belcesiran or 
placebo 
        
         
                
                 
        
             
  
 belcesiran or 
placebo 
        
         
                
                 
 
          
      
    
              
                
 
 
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1.3. 
Schedules of Activities 
Table 11: 
Screening Period Schedule of Activities 
Study Week a 
−6 
−4 
Visit Window  
±2 weeks 
±1 week 
Procedure/Assessment 
 
Informed consent b 
X 
 
Assess I/E criteria 
X 
PiZZ genotyping c 
X 
 
Demographics 
X 
 
General medical history 
X 
 
Medication history 
X 
 
Smoking history  
X 
 
Pulmonary X-ray d 
X 
 
Vital signs  
X 
 
Complete physical examination e  
X 
 
Height and Weight 
X 
 
12-lead ECG  
X 
 
Screening labs f 
X 
 
Hematology/ chemistry/ coagulation g 
X 
 
Serum AFP  
X 
 
Blood biomarkers of fibrosis h 
X 
 
Blood biomarkers of inflammation 
X 
 
Samples for future analysis i 
X 
 
Serum pregnancy test for WOCBP 
X 
 
Urinalysis  
X 
 
Urine cotinine  
X 
 
FibroScan® j 
X 
 
MRE j 
X 
 
DLCO & Spirometry k, l 
X 
 
Serum AAT & CRP  
X 
 
Liver biopsy m 
 
X 
Record AEs & SAEs  
X 
X 
Abbreviations: AAT: alpha-1 antitrypsin; AE: adverse event; AFP: alpha fetoprotein; CRP: C-reactive protein; DLCO: diffusion 
capacity of the lungs for carbon monoxide; ECG: electrocardiogram; FSH: follicle stimulating hormone; I/E: inclusion/exclusion; 
MRE: magnetic resonance elastography; PiZZ: autosomal homozygous mutant AAT Z allele genotype; SAE: serious adverse event; 
WOCBP: women of childbearing potential. 
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Page 18 
a 
The screening period may take up to 6 weeks (±2 weeks) but can be condensed into a shorter time period if possible.  
b 
Potential participants will provide informed consent prior to the initiation of any study-related screening assessment. 
The signing of the ICF will initiate the screening window.  
c 
If a participant has been previously genotyped, historical data may be used if documentation is available. 
d 
If the participant has undergone x-ray imaging in a stable condition within the prior 4 weeks, that x-ray may be used if 
the images are available. 
e 
A complete physical examination is defined in Section 8.2.2. 
f 
To include viral serology, urine drug screen, HbA1c, FSH (as needed to confirm post-menopausal status), 
antimitochondrial antibodies (if primary biliary cholangitis is suspected) and testing to rule out autoimmune hepatitis 
(may include total IgG or gamma-globulin levels and/or serologic markers), and cotinine as needed. If a participant has 
documented screening for the hepatitis B virus, hepatitis C virus, and human immunodeficiency virus in the past 3 
months, historical data may be used. See Section 10.2 for details. 
g 
See Section 10.2 for a detailed list of clinical laboratory parameters.  
h 
To include biochemical fibrosis index, APRI, Fib-4, Enhanced Liver Fibrosis Score, and other serum biomarkers of 
liver fibrosis (see Section 8.1.3). 
i 
Samples for future analysis will be collected at selected visits only if a participant has consented to future analysis.  
j 
Participants must be fasting for a minimum of 3 hours prior to the FibroScan and 6 hours prior to the MRE (Cohorts 1 
& 2 only) being performed. Please ensure fasting begins at the site after the participant has signed the ICF. If the 
clinical site does not have access to the required equipment or technology, MRE assessments would be optional. 
k 
Spirometry (FEV1 and FVC) will be performed pre-bronchodilator and post-bronchodilator. The order of testing for 
recorded values should be 1) administer bronchodilator, 2) immediately perform DLCO, 3) perform spirometry. 
l 
When screening pulmonary function tests are being performed, historical information including the number and 
severity of pulmonary exacerbations, resting peripheral oxygen saturation, smoking status including number of 
cigarettes per day, and use of AAT replacement therapy should be collected from the participant. The Modified 
Medical Research Council dyspnea scale should also be assessed. 
m 
Liver biopsy to be performed only after all other screening assessments are completed.  
 
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Page 19 
Table 22: 
Treatment Period Schedule of Activities – Cohort 1 
Dose # 
1 
 
 
 
2 
 
3 
4 
5 
6 
EOT/ 
7 
 
8 a 
 
9 a 
10 a 
11 a 
12 a 
13/ 
ET a1,b 
Study day 
1 
2 
3 
15  
29 30 c 
57 
85 
113 
141 
169 
211 
253 
295 
337 
421 
505 
589 
673 
Visit 
V1 V2 V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
P12d V13 P14d 
V15 
V16 
V17 
V18 
V19 
Visit window (days) 
− 
− 
− 
±2 
±2 
− 
±5 
±5 
±5 
±5 
±5 
±5 
±7 
±5 
±7 
±7 
±7 
±7 
±7 
Confirm I/E criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention 
Xe 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Injection Site Inspection 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
DLCO & Spirometry f 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Pulmonary Information g 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Hematology/chemistry/ 
coagulation h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy test for WOCBP i 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Complement j 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum AFP k 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis l 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
UACR & UPCR l 
X 
 
 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
Serum AAT & CRP m 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Antidrug antibodies n  
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
Blood biomarkers of fibrosis o 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
Blood biomarkers of 
inflammation 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
Samples for future analysis p 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
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Page 20 
Dose # 
1 
 
 
 
2 
 
3 
4 
5 
6 
EOT/ 
7 
 
8 a 
 
9 a 
10 a 
11 a 
12 a 
13/ 
ET a1,b 
Study day 
1 
2 
3 
15  
29 30 c 
57 
85 
113 
141 
169 
211 
253 
295 
337 
421 
505 
589 
673 
Visit 
V1 V2 V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
P12d V13 P14d 
V15 
V16 
V17 
V18 
V19 
Visit window (days) 
− 
− 
− 
±2 
±2 
− 
±5 
±5 
±5 
±5 
±5 
±5 
±7 
±5 
±7 
±7 
±7 
±7 
±7 
Plasma PK q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Vital signs r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Physical examination  
X 
Xs 
Xs 
Xs 
Xs 
Xs 
X 
Xs 
Xs 
Xs 
X 
 
Xs 
 
Xs 
Xs 
Xs 
Xs 
X 
Weight 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
12-lead ECG t 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
X 
CLDQ u 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
SGRQ u 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
FibroScan v 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
MRE v 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Liver biopsy  
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X w 
Record AEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record SAEs x 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Attend visit fasting y 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Abbreviations: AAT: alpha-1 antitrypsin; AE: adverse event; AFP: alpha fetoprotein; BMI: body mass index; CLDQ: Chronic Liver Disease Questionnaire; COVID-19: corona 
virus disease 2019; CRP: C-reactive protein; DLCO: diffusion capacity of the lungs for carbon monoxide; DSMC: Data Safety Monitoring Committee; ECG: electrocardiogram; 
EOT: end of treatment; ET: early termination; FEV1: forced expiratory volume in one second; F/U: follow-up; I/E: Inclusion/Exclusion; FVC: forced vital capacity; MRE: 
magnetic resonance elastography; PK: pharmacokinetics; SAE: serious adverse event; SGRQ: St. George’s Respiratory Questionnaire; UACR: urine albumin-creatinine ratio; 
UPCR: urine protein-creatinine ratio; WOCBP: women of childbearing potential. 
a 
Visits indicated are optional dosing visits that can be performed if the participant consents. If the participant does not want to continue with the optional dosing, they will 
receive their final dose at EOT/D169 and then continue into follow up.  
b 
Participants who terminate the stu y prematurely  early termination “ET”  will un ergo all activities as  escribe  un er D673 with the exception of dosing.  
c 
Day 30 will always be the day after Day 29, regardless of when Day 29 occurs within the ± 2-day visit window 
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Page 21 
d 
Any visit marke  with a “P” in the “Visit” row can be complete  as a phone visit. The Investigator can choose to have site visits on these days if deemed necessary. 
e 
The first dose of study intervention must be administered at the clinical site. 
f 
Post-bronchodilator values for DLCO and spirometry (FEV1 and FVC) will be recorded. The order of testing for recorded values should be 1) administer bronchodilator, 2) 
immediately perform DLCO, and 3) perform spirometry. On dosing days, DLCO and spirometry will be performed predose. 
g 
Collect and record the number and severity of pulmonary exacerbations since the last PFT assessment, resting peripheral oxygen saturation, smoking status including number 
of cigarettes per day, and use of AAT replacement therapy since the last visit. Assess and record the Modified Medical Research Council dyspnea scale. 
h 
For Dose 1 only, blood samples for hematology, clinical chemistry, and coagulation studies will be collected predose and at 6 hours (± 30 minutes) postdose. At other dosing 
visits, these samples will only be collected predose. See Section 10.2 for a detailed list of clinical laboratory parameters. 
i 
A urine pregnancy test will be performed prior to dosing. If the result is positive, a confirmatory serum pregnancy test will be performed. Dosing should not occur unless a 
negative result is obtained with the confirmatory serum pregnancy test in consultation with the Sponsor. 
j 
Samples for complement analysis will be collected surrounding Dose 1 only. For Dose 1, samples will be collected predose, at 2 and 6 hours (±30 minutes), and 24 hours 
(± 1 hour) postdose. At EOT, samples will be collected at the same time as all other sample collections.  
k 
The AFP sample should be collected predose.  
l 
Urine sample will be collected predose.  
m 
The serum AAT and CRP samples should be collected predose. Blood samples for determination of CRP will be collected at the same time as those for determination of 
serum AAT. 
n 
At all visits, the blood sample for antidrug antibodies will be collected predose.  
o 
Blood samples for biomarkers of fibrosis will be collected predose on dosing days.  
p 
Samples for future analysis will be collected at selected visits only if a participant has consented to future analysis.  
q 
Plasma samples for PK analysis will be collected predose and at 5, 15, 30, and 60 minutes and 2, 4, 6, 8, 12, and 24 hours postdose for Doses 1 and 2 only. Single samples 
will be collected predose for other doses and at other visits as indicated. The following windows are allowed: 
• 
Predose  
• 
5 and 15 minutes postdose: ± 3 minutes 
• 
30 and 60 minutes postdose: ± 5 minutes 
• 
2, 4, 6, and 8 hours postdose: ± 15 minutes 
• 
12 and 24 hours postdose: ± 1 hour 
r 
Vital sign measurements will include blood pressure, pulse rate, respiratory rate, and temperature (collected per local standard of care). For Dose 1 and 2, vital sign 
measurements will be performed predose, at the end of injection, at 30 (± 10) and 60 (± 15) minutes, at 2 (± 30 minutes), 6 (± 30 minutes), and 24 hours (± 1 hour) postdose. 
At other dosing visits, vital signs will be measured predose. If multiple assessments are due at the same time, the order of priority should be ECG, vitals, PK, and then other 
assessments; with PK sampling being performed at the nominal time point.  
s 
A focused physical examination will be performed (see Section 8.2.2) for Dose 1 and 2 only, ECG will be performed predose and at 30 minutes and 6 hours postdose. For 
other doses, a single ECG will be performed predose. If multiple assessments are due at the same time, the order of priority should be ECG, vitals, PK, and then other 
assessments, with PK sampling being performed at the nominal time point.  
t 
At Dose 1, the required questionnaires will be performed predose. See Section 8.1.6 and 8.1.7. 
u 
The EOT FibroScan and MRE will be performed prior to the EOT liver biopsy. Participants must be fasting for a minimum of 3 hours prior to the FibroScan and 6 hours 
prior to the MRE being performed. If Screening MRE is done, it is expected that an MRE is done at EOT. If a clinical site does not have access to the required equipment or 
technology, MRE assessments would be optional.  
v 
At ET, a liver biopsy will be optional.  
w 
Serious AEs and treatment-emergent SAEs will be assessed until 30 days after the last day of study participation. Ongoing SAEs will be followed until resolution or until 
resolved with sequalae. 
x 
Participants should be fasting for a minimum of 8 hours prior to selected visits. 
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Table 33: 
Treatment Period Schedule of Activities – Cohort 2  
Dose No. 
1 
 
 
 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EOT/ 
13 
14a 
15a 
16a 
17/  
ET a1,b 
Study Day 
1 
2 
3 
15 
29 
30 c 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
421 
505 
589 
673 
Visit window (days) 
− 
− 
− 
±2 
±2 
− 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±7 
±7 
±7 
±7 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
Confirm I/E criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention 
Xd 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection Site Inspection 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLCO & Spirometry e 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulmonary Information f 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/chemistry/ 
coagulation g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test for WOCBP h 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complement i 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Serum AFP j 
X 
 
 
 
X 
 
 
X 
 
 
 X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Urinalysis k 
X 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
UACR & UPCR k 
X 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Serum AAT & CRP l 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Antidrug antibodies m 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Blood biomarkers of fibrosis n X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Blood biomarkers of 
inflammation 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
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Page 23 
Dose No. 
1 
 
 
 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EOT/ 
13 
14a 
15a 
16a 
17/  
ET a1,b 
Study Day 
1 
2 
3 
15 
29 
30 c 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
421 
505 
589 
673 
Visit window (days) 
− 
− 
− 
±2 
±2 
− 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±7 
±7 
±7 
±7 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
Samples for future analysis o 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Plasma PK p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
X 
Xr 
Xr 
Xr 
Xr 
Xr 
Xr 
X 
Xr 
Xr 
X 
Xr 
Xr 
Xr 
Xr 
Xr 
X 
Xr  
Xr 
Xr 
X 
Weight 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
12-lead ECG s 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
CLDQ t 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
SGRQ t 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
FibroScan® u 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
MRE u 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Liver biopsy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X v 
Record AEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record SAEs w 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/ 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Attend visit fasting x 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Abbreviations: AAT: alpha-1 antitrypsin; AE: adverse event; AFP: alpha fetoprotein; F/U: follow-up; CLDQ: Quality of Life Index for Patients with Chronic Liver Disease; CRP: 
C-reactive protein; DLCO: diffusion capacity of the lungs for carbon monoxide; DSMC: Data Safety Monitoring Committee; ECG: electrocardiogram; EOT: end of treatment; ET: 
early termination; I/E: Inclusion/Exclusion; MRE: magnetic resonance elastography; PE: physical examination; PK: pharmacokinetics; SAE: serious adverse event; SGRQ: St. 
George’s Respiratory Questionnaire; UACR: urine albumin-creatinine ratio; UPCR: urine protein-creatinine ratio; WOCBP: women of childbearing potential; Z-AAT: the mutant 
AAT protein. 
a 
Visit indicated are optional dosing visits that can be performed if the participant consents. If the participant does not want to continue with the optional dosing, they will 
receive their final dose at EOT/ D337 and then continue into follow up.  
b 
Participants who terminate the stu y prematurely  early termination “ET”  will un ergo all activities as described under D673, with the exception of dosing.  
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Page 24 
c 
Day 30 will always be the day after Day 29, regardless of when Day 29 occurs within the ± 2-day visit window. 
d 
The first dose of study intervention must be administered at the clinical site. 
e 
Post-bronchodilator values for DLCO and spirometry (FEV1 and FVC) will be recorded. The order of testing for recorded values should be 1) administer bronchodilator, 2) 
immediately perform DLCO, and 3) perform spirometry. On dosing days, DLCO and spirometry will be performed predose. 
f 
Collect and record the number and severity of pulmonary exacerbations since the last PFT assessment, resting peripheral oxygen saturation, smoking status including number 
of cigarettes per day, and use of AAT replacement therapy since the last visit. Assess and record the Modified Medical Research Council dyspnea scale. 
g 
For Dose 1 only, blood samples for hematology, clinical chemistry, and coagulation studies will be collected predose and at 6 hours (± 30 minutes) postdose. At other dosing 
visits, these samples will be collected predose only. See Section 10.2 for a detailed list of clinical laboratory parameters. 
h 
A urine pregnancy test will be performed. If the result is positive, a confirmatory serum pregnancy test will be performed. Dosing should not occur unless a negative result is 
obtained with the confirmatory serum pregnancy test in consultation with the Sponsor. 
i 
Samples for complement analysis will be collected surrounding Dose 1 only. For Dose 1, samples will be collected predose, at 2 and 6 hours (± 30 minutes), and 24 hours 
(± 1 hour) postdose. At EOT, samples will be collected at the same time as all other sample collections. 
j 
The AFP sample should be collected predose.  
k 
Urine sample will be collected predose.  
l 
The serum AAT and CRP sample should be collected predose. Blood samples for determination of CRP will be collected at the same time as those for determination of 
serum AAT.  
m 
At all visits, the blood sample for antidrug antibodies will be collected predose.  
n 
Blood samples for biomarkers or fibrosis will be collected predose on dosing days.  
o 
Samples for future analysis will be collected at selected visits only if a participant has consented to future analysis.  
p 
Plasma samples for PK analysis will be collected predose and at 5, 15, 30, and 60 minutes and 2, 4, 6, 8, 12, and 24 hours postdose for Doses 1 and 2 only. Single samples 
will be collected predose for other doses and at other visits as indicated. The following windows are allowed: 
• 
Predose 
• 
5 and 15minutes postdose: ± 3 minutes 
• 
30 and 60 minutes postdose: ± 5 minutes 
• 
2, 4, 6, and 8 postdose: ± 15 minutes 
• 
12 and 24 hours postdose: ± 1 hour 
q 
Vital sign measurements will include blood pressure, pulse rate, respiratory rate, and temperature (collected per local standard of care). For Dose 1 and 2, vital sign 
measurements will be performed predose, at the end of injection, at 30 (± 10) and 60 (± 15) minutes, at 2 (± 30 minutes), 6 (± 30 minutes), and 24 hours (± 1 hour) postdose 
for Dose 1 only. At other dosing visits, vital signs will be measured predose. If multiple assessments are due at the same time, the order of priority should be ECG, vitals, 
PK, and then other assessments; with PK sampling being performed at the nominal time point. 
r 
Focused physical examination (see section 8.2.2).  
s 
For Dose 1 and 2 only, ECG will be performed predose and at 30 minutes and 6 hours postdose. For other doses, a single ECG will be performed predose. If multiple 
assessments are due at the same time, the order of priority should be ECG, vitals, PK, and then other assessments, with PK sampling being performed at the nominal time 
point.  
t 
At Dose 1, the required questionnaires will be performed predose.  
u 
The EOT FibroScan and MRE will be performed prior to the EOT liver biopsy. Participants must be fasting for a minimum of 3 hours prior to the FibroScan and 6 hours 
prior to the MRE being performed. If Screening MRE is done, it is expected that an MRE is done at EOT. If a clinical site does not have access to the required equipment or 
technology, MRE assessments would be optional. 
v 
Liver biopsy is optional at V21. 
w 
Serious AEs and treatment-emergent SAEs will be assessed until 30 days after the last day of study participation, ongoing SAEs will be followed until resolution or until 
resolved with sequalae. 
x 
Participants should be fasting for a minimum of 8 hours prior to selected visits. 
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Table 44: Treatment Period Schedule of Activities – Cohort 3 
Dose No. 
1 
 
 
 
2 
 
3 
4 
5 
6 
7 
 
8 
 
9 
10 
11  
12 
EOT/
ET a1 
13 
Study Day 
1 
2 
3 
15  
29 
30 b 
57 
85 
113 
141 
169 
211 
253 
295 
337 
421 
505 
589 
673 
Visit  
V1 
V2 
P3c 
P4c 
V5 
P6c 
V7 
V8 
V9 
V10 
V11 
P12c 
V13 
P14c 
V15 V16 
V17 
V18 
V19 
Visit window (days) 
− 
− 
− 
± 3 
± 5 
− 
± 5 
± 5 
± 5 
± 5 
± 5 
± 5 
± 7 
± 5 
± 7 
± 7 
± 7 
± 7 
± 7 
Confirm I/E criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention 
Xd 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Injection Site Inspection 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
DLCO & Spirometry e 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Pulmonary Information f 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/chemistry/ 
coagulation g 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy test for WOCBP h 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Complement i 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Serum AFP j 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis k 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
UACR & UPCR k 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
Serum AAT & CRP l 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Antidrug antibodies m 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
Blood biomarkers of fibrosis n 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
Blood biomarkers of inflammation 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
Samples for future analysis o 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Plasma PK p 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Vital signs q 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
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Dose No. 
1 
 
 
 
2 
 
3 
4 
5 
6 
7 
 
8 
 
9 
10 
11  
12 
EOT/
ET a1 
13 
Study Day 
1 
2 
3 
15  
29 
30 b 
57 
85 
113 
141 
169 
211 
253 
295 
337 
421 
505 
589 
673 
Visit  
V1 
V2 
P3c 
P4c 
V5 
P6c 
V7 
V8 
V9 
V10 
V11 
P12c 
V13 
P14c 
V15 V16 
V17 
V18 
V19 
Visit window (days) 
− 
− 
− 
± 3 
± 5 
− 
± 5 
± 5 
± 5 
± 5 
± 5 
± 5 
± 7 
± 5 
± 7 
± 7 
± 7 
± 7 
± 7 
Physical examination 
X 
X r 
 
 
Xr  
 
Xr  
X 
Xr  
Xr  
X  
 
X r 
 
X 
Xr  
X r 
Xr  
X 
Weight 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
12-lead ECG s 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
CLDQ t 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
SGRQ t 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
FibroScan® u 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Liver biopsy  
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Xv 
Record AEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record SAEs w 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/ 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Attend visit fasting x 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Abbreviations: AAT: alpha-1 antitrypsin; AE: adverse event; AFP: alpha fetoprotein; F/U: follow-up; CLDQ: Quality of Life Index for Patients with Chronic Liver Disease; CRP: 
C-reactive protein; DLCO: diffusion capacity of the lungs for carbon monoxide; DSMC: Data Safety Monitoring Committee; ECG: electrocardiogram; EOT: end of treatment; ET: 
early termination; I/E: Inclusion/Exclusion; PE: physical examination; PK: pharmacokinetics; SAE: serious adverse event; SGRQ: St. George’s Respiratory Questionnaire; UACR: 
urine albumin-creatinine ratio; UPCR: urine protein-creatinine ratio; WOCBP: women of childbearing potential; Z-AAT: the mutant AAT protein. 
a 
Participants who terminate the stu y prematurely  early termination “ET”  will un ergo all activities as  escribe  un er EOT (Note: ± 14-day window does not apply to 
ET).  
b 
Day 30 will always be the day after Day 29, regardless of when Day 29 occurs within the ± 2-day visit window. 
c 
Any visit marke  with a “P” in the “Visit” row can be completed as a phone visit. Investigator can choose to have site visits on these days if deemed necessary. 
d 
The first dose of study intervention must be administered at the clinical site. 
e 
Post-bronchodilator values for DLCO and spirometry (FEV1 and FVC) will be recorded. The order of testing for recorded values should be 1) administer bronchodilator, 2) 
immediately perform DLCO, and 3) perform spirometry. On dosing days, DLCO and spirometry will be performed predose. 
f 
Collect and record the number and severity of pulmonary exacerbations since the last PFT assessment, resting peripheral oxygen saturation, smoking status including number 
of cigarettes per day, and use of AAT replacement therapy since the last visit. Assess and record the Modified Medical Research Council dyspnea scale. 
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g 
For Dose 1 only, blood samples for hematology, clinical chemistry, and coagulation studies will be collected predose and at 6 hours (± 30 minutes) postdose. At other dosing 
visits, these samples will be collected predose. See Section 10.2 for a detailed list of clinical laboratory parameters. 
h 
A urine pregnancy test will be performed. If the result is positive, a confirmatory serum pregnancy test will be performed. Dosing should not occur unless a negative result is 
obtained with the confirmatory serum pregnancy test in consultation with the Sponsor. 
i 
Samples for complement analysis will be collected surrounding Dose 1 only. For Dose 1, samples will be collected predose, at 2 and 6 hours (± 30 minutes), and 24 hours (± 
1 hour) postdose. At D169, D337, and EOT, samples will be collected at the same time as all other sample collections. 
j 
The AFP sample should be collected predose.  
k 
Urine sample will be collected predose.  
l 
The serum AAT and CRP sample should be collected predose. Blood samples for determination of CRP will be collected at the same time as those for determination of 
serum AAT.  
m 
At all visits, the blood sample for antidrug antibodies will be collected predose.  
n 
Blood samples for biomarkers or fibrosis will be collected predose on dosing days.  
o 
Samples for future analysis will be collected at selected visits only if a participant has consented to future analysis.  
p 
Plasma samples for PK analysis will be collected predose and at 5, 15, 30, and 60 minutes and 2, 4, 6, 8, and 12 hours postdose for Doses 1 and 2 only; and at 24 hours for 
postdose for Dose 1 only. Single samples will be collected predose for other doses and at other visits as indicated. The following windows are allowed: 
• 
Predose 
• 
5 and 15minutes postdose: ± 3 minutes 
• 
30 and 60 minutes postdose: ± 5 minutes 
• 
2, 4, 6, and 8 postdose: ± 15 minutes 
• 
12 and 24 hours postdose: ± 1 hour 
q 
Vital sign measurements will include blood pressure, pulse rate, respiratory rate, and temperature (collected per local standard of care). For Dose 1 and 2, vital sign 
measurements will be performed predose, at the end of injection, at 30 (± 10) and 60 (± 15) minutes, at 2 (± 30 minutes), 6 (± 30 minutes), and 24 hours (± 1 hour) postdose 
for Dose 1 only. At other dosing visits, vital signs will be measured predose. If multiple assessments are due at the same time, the order of priority should be ECG, vitals, 
PK, and then other assessments; with PK sampling being performed at the nominal time point. 
r 
Focused physical examination (see Section 8.2.2) 
s 
For Dose 1 and 2 only, ECG will be performed predose and at 30 minutes and 6 hours postdose. For other doses, a single ECG will be performed predose. If multiple 
assessments are due at the same time, the order of priority should be ECG, vitals, PK, and then other assessments, with PK sampling being performed at the nominal time 
point.  
t 
At Dose 1, the required questionnaires will be performed predose.  
u 
The D169 and EOT FibroScans will be performed prior to the liver biopsies. Participants must be fasting for a minimum of 3 hours prior to the FibroScan being performed. 
v 
Liver biopsy is optional at V19. 
w 
Serious AEs and treatment-emergent SAEs will be assessed until 30 days after the last day of study participation, ongoing SAEs will be followed until resolution or until 
resolved with sequalae. 
x 
Participants should be fasting for a minimum of 8 hours prior to selected visits. 
 
 
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Table 5: Follow-up Period Schedule of Activities  
Post-EOT Week 
12 
24 
36 
48a 
72 
96 b 
ET 
Window (Days) 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
N/A 
Procedure/Assessment 
 
 
 
 
 
 
 
DLCO & Spirometry c 
X 
X 
X 
X 
X 
X 
X 
Pulmonary Information d 
X 
X 
X 
X 
X 
X 
X 
Blood biomarkers of fibrosis  
 
X 
 
X 
X 
X 
X 
Blood biomarkers of inflammation 
 
X 
 
X 
X 
X 
X 
Serum AAT & CRP  
X 
X 
X 
X 
X 
X 
X 
Hematology/chemistry/coagulation 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy test for WOCBP 
X 
X 
 
 
 
 
X 
UACR & UPCR 
 
X 
 
X 
 
X 
X 
Serum AFP  
 
X 
 
X 
X 
X 
X 
Antidrug antibodies 
X 
 
 
X 
 
X 
X 
Samples for future analysis  
 
 
 
X 
 
X 
X 
MRE e 
 
X 
 
X 
 
X 
X 
FibroScan® e 
 
X 
 
X 
 
X 
X 
Record AEs/SAEs f 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Attend visit fasting g 
 
 
 
X 
 
X 
X 
Abbreviations: AAT: alpha1 antitrypsin; AFP: alpha fetoprotein; F/U: follow-up; CRP: C-reactive protein; DLCO: diffusion capacity of the lungs for carbon monoxide; EOT: end 
of treatment; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; MRE: magnetic resonance elastography; SAE: serious adverse event; WOCBP: 
women of childbearing potential; Z-AAT: the mutant AAT protein. 
a 
The follow-up period for Cohort 3 will terminate at the Week 48 Post-EOT visit. Week 72 and 96 Post-EOT visits will be performed for Cohort 1 and Cohort 2 only. 
b 
If possible, participants prematurely discontinuing from the F/U period will undergo all activities indicated for Week 48 F/U visit. 
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c 
Post-bronchodilator values for DLCO and spirometry (FEV1 and FVC) will be recorded. The order of testing for recorded values should be 1) administer bronchodilator, 2) 
immediately perform DLCO, 3) perform spirometry.  
d 
Collect and record number and severity of pulmonary exacerbations since the last PFT assessment, resting peripheral oxygen saturation, smoking status including number of 
cigarettes per day, and use of AAT replacement therapy since the last visit. Assess and record the Modified Medical Research Council dyspnea scale. 
e 
If a clinical site does not have access to the required equipment or technology, MRE assessments would be optional. Participants must be fasting for a minimum of 3 hours 
prior to the FibroScan or MRE being performed. MRE will only be performed for participants in Cohorts 1 & 2. 
f 
Adverse events/SAEs will be assessed until 30 days after the last day of participation in this study. Ongoing SAEs will be followed until resolution or resolved with 
sequalae. 
g 
Participants should be fasting for a minimum of 8 hours prior to selected visits. 
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2. 
INTRODUCTION 
AATD is a rare genetic disease resulting from the abnormal production of the serine protease 
inhibitor AAT. Normal human AAT is a 52-kDa acute-phase protein that is produced in liver 
cells. It is released into the plasma in response to inflammatory stimuli. Inherited autosomal 
mutations in SERPINA1, the gene that encodes the AAT protein, leads to the production of a 
misfolded insoluble protein (Z-AAT) that aggregates in hepatocytes rather than being secreted 
into the blood (Lomas & Parker, 2006). 
AATD is a proteinopathy that affects the lungs and the liver by two different mechanisms. In the 
lungs, emphysema and COPD are the results of a loss-of-function mechanism, where AAT is not 
present in adequate amounts to inhibit neutrophil elastase, resulting in the destruction of lung 
tissue. The liver disease associated with AATD is by a gain-of-toxic function mechanism. The 
misfolded Z-AAT protein accumulates in the endoplasmic reticulum, leading to hepatocyte cell 
death and liver inflammation, progressive fibrosis, and, in some cases, hepatocellular cancer 
(HCC). 
More than 100 variants of SERPINA1 have been described. Approximately 95% of the 
population of patients with AATD and liver disease express the autosomal homozygous mutant 
Z-allele (i.e., PiZZ), containing a Glu342Lys missense mutation caused by a GAG to AAG 
transition mutation in SERPINA1. The predicted homozygous PiZZ mutant frequency is 
approximately 1 in 2000 within northwestern European populations (Blanco et al., 2017; Blanco 
et al., 2006). 
Dicerna Pharmaceuticals, Inc. is developing belcesiran as a treatment for AATLD using an 
RNAi strategy (McManus and Sharp, 2002). Belcesiran is a sterile solution of the drug substance 
belcesiran sodium, a synthetic double-stranded RNA oligonucleotide conjugated to GalNAc 
aminosugar residues, in WFI. The antisense strand of belcesiran sodium is designed to silence 
the expression of SERPINA1. This gene knockdown may lead to a reduction of total Z-AAT 
expression in the liver and, in turn, reduce the accumulation of the toxic Z-AAT. Without the 
continuous putative toxic stimulus, the progression of liver disease in affected individuals may 
be halted, or potentially even reversed.  
2.1. 
Study Rationale 
AATLD is a progressive condition resulting in liver fibrosis, and, in some patients, cirrhosis and 
even HCC. There is no effective treatment for patients with the toxic gain-of-function liver 
disease associated with AATD, other than standard supportive care, and, in those who progress 
to end-stage liver disease, organ transplantation. Given the substantial morbidity and mortality of 
AATLD and the burden of liver transplantation, there is a significant unmet need for a safe and 
efficacious treatment. 
In nonclinical studies, belcesiran sodium (the drug substance for belcesiran) has been shown to 
significantly reduce target mRNA and AAT protein levels in transgenic mice expressing multiple 
copies of the human Z-mutant allele of SERPINA1 and in cynomolgus monkeys expressing wild-
type SERPINA1 at doses of 0.1 mg/kg or greater. Additionally, in the transgenic mouse model of 
AATLD, belcesiran sodium significantly reduced hepatic globule levels, which is indicative of 
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reduced accumulation of aggregated human Z-AAT protein. Decreased cellular proliferation and 
hepatic fibrosis were also observed upon repeated administration of belcesiran sodium. These 
findings suggest that, by eliminating the toxic protein, belcesiran may prevent and reverse liver 
disease progression, eliminating the need for liver transplantation. These nonclinical 
pharmacology studies support the clinical evaluation of belcesiran to treat patients with AATLD. 
DCR-A1AT-101 is an ongoing, Phase 1, single-ascending-dose (SAD) study of belcesiran in 
healthy volunteers. Participants in Study DCR-A1AT-101 received a single dose of DCR-A1AT 
(0.1, 1.0, 3.0, 6.0, or 12 mg/kg) or placebo and were followed for 56 days (treatment period) 
thereafter. At the end of the 56 day treatment period, any participant whose serum AAT protein 
concentration had not returned to ≥ 80% of baseline (or was not within the normal range) 
returned for PD monitoring visits (conditional follow-up) every 4 (±1) weeks for 2 months, then 
every 8 (±2) weeks for the next 4 months, and then every 12 (± 3) weeks for an additional 
6 months or until AAT returned to ≥ 80% of baseline, whichever is shorter. Currently, all 
participants have completed the 56-day treatment period and follow-up continues for participants 
who met the criteria for conditional follow-up.  
An interim analysis of PK, PD, and safety data from this single ascending-dose study was used to 
inform the selection of the dose and dosing interval in this study. 
This study is the first evaluation of belcesiran in adults with AATLD.  
The overall goals of this study are to:  
o demonstrate that belcesiran is safe and well-tolerated in adult PiZZ patients with liver 
fibrosis; 
o investigate the effect of two dose levels of belcesiran on reduction of Z-AAT 
production in the liver, reflected by a reduction in circulating Z-AAT levels; and 
o evaluate the effect of belcesiran on liver disease as assessed by liver biopsy and non-
invasive markers of liver disease 
2.2. 
Background 
2.2.1. 
Alpha-1 Antitrypsin Deficiency 
Carl-Bertil Laurell and Sten Eriksson first described severe AATD as a condition in which low 
serum levels of AAT are associated with pulmonary emphysema (Laurell & Eriksson, 1963). 
The lack of functional AAT in individuals with the PiZZ genotype, in conjunction with other 
precipitating factors, can lead to unchecked activity of neutrophil elastases in the alveoli, causing 
emphysema and COPD. In 1969, Harvey Sharp and associates first described cirrhosis in 
10 children with AATD (Sharp et al., 1969). In 1971, Sharp described the intrahepatocyte 
PASD-resistant globules or inclusions, resulting from polymer formation by Z-AAT in the 
endoplasmic reticulum (Sharp, 1971). In some patients, polymers of Z-AAT can also be detected 
in the serum using polymer-specific antibodies. Polymers of Z-AAT in serum have been 
associated with inflammation and pulmonary symptoms and/or more rapid progression of liver 
disease (Lomas & Parker, 2006; Teckman, 2017).  
The natural history of AATD is not well defined. The emergence of clinical liver disease may 
occur at any age but appears to increase with increasing age in adulthood (Townsend et al., 
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2018). Risk factors for the development of liver disease in adulthood include male gender, age 
over 50 years, repeated elevation in LFTs, hepatitis virus infection, obesity, and metabolic 
syndrome; although not all factors have been identified in all studies (Elzouki and Eriksson, 
1996; Bowlus et al., 2005; Townsend et al., 2018). 
The reported prevalence of the clinical liver disease in individuals with AATD varies widely and 
is likely under-reported. A longitudinal study of 1595 individuals with PiZZ from the Swedish 
National Patient Register reported a 10% prevalence of the liver disease in adults with PiZZ, 
with a mean age of liver-disease onset in adults of 61 years (Tanash & Piitulainen, 2019). A 
1996 analysis of autopsy data from Sweden detailed that 43% of PiZZ homozygotes had 
developed cirrhosis, and 28% had HCC (Elzouki and Eriksson, 1996). In the UK, Dawwas et al. 
reported that 63% of 57 PiZZ homozygotes had a history or clinical findings suggestive of liver 
disease; or had one or more abnormalities of liver function or liver ultrasound; 17.5% had 
evidence of severe fibrosis or cirrhosis on biopsy (Dawwas et al., 2013). In a prospective study 
of liver biopsy data from 94 PiZZ homozygotes in the US and Canada, Clark et al. described that 
the prevalence of clinically significant liver fibrosis (≥ F2) was 35.1% (Clark et al., 2018). 
Despite the variability in the reported prevalence of the liver disease in AATD, it is clear that 
adults with AATD are at significant risk for the development of liver fibrosis, cirrhosis, and 
HCC.  
2.2.2. 
Pharmacology of Belcesiran 
Belcesiran sodium (DCR-S1459, the drug substance for belcesiran) was developed to inhibit the 
mRNA that encodes the mutated AAT protein. Belcesiran sodium consists of a chemically 
synthesized double-stranded duplex RNA oligonucleotide conjugated to GalNAc aminosugar 
residues. After cellular internalization of belcesiran sodium, Dicer protein binds the double-
stranded belcesiran sodium molecule and introduces the 22-mer antisense strand into the RNAi 
pathway in a manner similar to that used by natural miRNAs. The introduction of the belcesiran 
sodium antisense strand, complementary to SERPINA1 mRNA, causes selective reduction of 
SERPINA1 mRNA and AAT protein expression.  
Belcesiran sodium has been shown to significantly reduce target mRNA and AAT protein levels 
in transgenic mice expressing multiple copies of the human Z-mutant allele of SERPINA1 and in 
cynomolgus monkeys expressing wild-type SERPINA1 at doses of 0.1 mg/kg or greater. 
Additionally, in the transgenic mouse model of AATLD, belcesiran sodium substantially reduced 
hepatic globule levels, indicating reduced accumulation of aggregated human Z-AAT protein. 
Repeated administration of belcesiran sodium in the transgenic mice also demonstrated a 
decrease in cellular proliferation and hepatic fibrosis. 
2.2.3. 
Nonclinical Pharmacokinetics and Toxicokinetics of Belcesiran 
Plasma PK and TK were determined in CD-1 mice, NZW rabbits, and cynomolgus monkeys 
after SC administration of belcesiran. After a single SC administration, belcesiran was rapidly 
absorbed into the bloodstream, with a Tmax of approximately 1 to 2 hours in mice and rabbits and 
a Tmax ranging from approximately 2 to 24 hours in monkeys. In mice dosed at 3 mg/kg, Cmax 
and AUClast were 115 ng/mL and 155 hr*ng/mL, respectively. In pregnant rabbits dosed at 2 or 
6 mg/kg in the definitive EFD study, Cmax was 252 and 591 ng/mL respectively and AUC0-48hr 
was 761 and 2180 hr*ng/mL respectively. In monkeys dosed at 1 mg/kg, Cmax and AUClast were 
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122 ng/mL and 1340 hr*ng/mL, respectively, and bioavailability was approximately 30%. In 
toxicity studies, in mice and monkeys, plasma exposure (Cmax and AUClast) increased with 
increasing dose (20 to 300 mg/kg). No sex-related differences were observed in either species 
and no accumulation in plasma was apparent after up to 7 doses (mice) or 10 doses (monkeys) 
administered 4 weeks apart in repeat dose toxicity studies. The elimination phase could not be 
accurately determined in mice. In pregnant rabbits, the estimated t½ values ranged from 1.57 to 
2.02 hours in the definitive EFD study. In monkeys, mean plasma t½ was estimated as 3.2 hours 
at a dose of 1 mg/kg.  
Belcesiran plasma protein binding ranged from 40% to 56% at a concentration of 20 μg/mL in 
mouse, monkey, and human plasma, with no apparent differences between species.  
Distribution of belcesiran following SC administration was primarily to the liver. This finding is 
consistent with the profile expected for GalNAc-conjugated siRNA that target the hepatocytes 
via the ASGPR (D’Souza & Devarajan, 2015). In mice, at 24 and 168 hours after a single 
3 mg/kg SC dose, belcesiran concentrations in the kidney, which were the next highest 
concentration, were less than 4% of those in liver. At dose levels of 100 and 300 mg/kg, 
concentrations in kidney were 7% to 11% of those in liver, and in other organs were less than 2% 
of those in liver. The mean elimination t½ in liver ranged from 3.6 to 4.9 days in mice and was 
12 to 17 days in individual monkeys. In toxicity studies, in both CD-1 mice and cynomolgus 
monkeys, tissue concentrations of belcesiran were consistently higher in the liver than in the 
kidney 24 hours postdose (mouse) and 48 hours postdose (monkey). In mice and monkeys, the 
increase in tissue concentrations was less-than-dose proportional in the liver and greater-than-
dose proportional in the kidney across the dose range of 20 to 300 mg/kg. Thus, the liver-to-
kidney ratio decreased with increasing dose. These results are hypothesized to reflect a dose-
related trend toward saturation of hepatocellular uptake via the ASGPR, which in turn increases 
excretion of the molecule in urine through the kidneys. The greater-than-dose proportional 
increases in mean Cmax observed in urine in mice also support this hypothesis. 
In pregnant mice, distribution to liver and kidney was similar to that observed in non-pregnant 
animals. Distribution to fetal liver was observed in mice in the EFD study with doses of 250 to 
1000 mg/kg every other day. The concentrations of belcesiran observed in mouse fetal liver were 
0.13% or less than that of the dams, indicating limited placental transfer. In pregnant rabbits, 
distribution to maternal liver and kidney was observed. Belcesiran was observed in fetal plasma 
and liver, but levels were a fraction of maternal concentrations (< 20% and < 0.0014%, 
respectively). 
Qualitative metabolic profiling was conducted on urine and liver from mice and on urine from 
monkeys. In mouse liver, the most prevalent antisense strand-related species were FLP and 
3′N-1, and the most prevalent sense strand-related species was FLP with the removal of all 
4 GalNAc sugars. In mouse and monkey urine, the primary species were FLP and 3′N-1 
antisense strand and FLP sense strand. 
The interaction of belcesiran with human CYP metabolic enzymes, human ABC (efflux) 
transporters, and the human SLC (uptake) transporters was evaluated in vitro using human 
hepatocytes in culture. Data suggest clinically relevant DDI due to transporter inhibition seem 
unlikely at plasma concentrations up to 37.5 μg/mL and DDI due to CYP enzyme inhibition or 
induction seem unlikely at plasma concentrations up to 75 μg/mL. 
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The safety of belcesiran sodium has been characterized in a program of nonclinical studies. 
Repeat-dose SC toxicity studies of up to 6 months (7 doses) in mice, and up to 9 months 
(10 doses) in monkeys have been conducted. The 9-month study in monkeys specifically 
included FDA-requested pulmonary function. Belcesiran sodium has been evaluated for potential 
genotoxicity in in vitro tests in bacteria and mammalian cells and in vivo in a mouse 
micronucleus assay. Developmental and reproductive toxicity was assessed in a mouse FEED 
study and EFD studies in mice and rabbits. The potential for platelet activation by belcesiran 
sodium was assessed in vitro. In addition, a comprehensive safety pharmacology study was 
conducted.  
Overall, belcesiran is well tolerated following chronic administration to mice and monkeys at 
dose levels up to 300 mg/kg. In monkeys, no adverse on-target effects were observed despite the 
persistent and almost complete knockdown of SERPINA1 mRNA in the liver. No toxicity 
indicative of off-target hybridization was evident in mice or monkeys. Non-adverse test article 
related effects were limited primarily to those reported with other oligonucleotides including 
those that are GalNAc conjugated (e.g., basophilic granules in hepatocytes and vacuolated 
macrophages) and were not degenerative in nature (Henry et al., 1999; Janas et al., 2018; 
EMA/70703/2020; EMA/568312/2020). Of note, minimal vascular inflammation of the 
pulmonary arteries and other tissues observed in the 3-month study was not recapitulated in the 
9-month monkey study. Further, in the 9-month monkey study, there were no belcesiran-related 
effects on pulmonary function testing (lung diffusion capacity for carbon monoxide, quasi-static 
lung compliance, and various indices derived from the flow-volume loop, including FVC and 
FEVt, and flow rates [FEFv]) and no histologic evidence of adverse pulmonary effects such as 
those reported in PiZZ patients. 
Belcesiran was negative in the bacterial reverse mutation assay and did not induce micronuclei in 
mammalian cells in vitro. There were no adverse effects on CV, respiratory, and neurological 
function in in vitro or in vivo studies with belcesiran. Administration of belcesiran was not 
associated with any effects typically attributable to oligonucleotide chemical modifications. 
Belcesiran was not associated with adverse injection site reactions in either species. 
Belcesiran and its active mouse analog (DCR-m0641) did not affect maternal viability or 
reproductive function in a mouse FEED study (NOAEL was 1000 mg/kg, the highest dose of 
belcesiran administered). In the mouse EFD study, modest (~5% to 6%) reductions of embryo-
fetal weights were observed. There were no increases in malformations in any dose group. The 
fetal weight effect was observed in both belcesiran and mouse-active analog groups and occurred 
in the absence of on-target pharmacologic activity, as there was no Serpina1 mRNA reduction in 
the fetuses from dams administered the active analog. Belcesiran was detected in mouse fetal 
liver at 0.13% or less than that of the dams, indicating limited placental transfer. The 
developmental NOAEL was 500 mg/kg/dose (total dose 2500 mg/kg), which is > 65 x greater 
than the monthly human dose (3 mg/kg) on a mg/kg basis. The human relevance of the decreased 
fetal weights is unclear, especially in the absence of target mRNA reduction and negligible fetal 
exposure. 
In the rabbit EFD studies, repeat and single dose (DRF EFD study) administration of belcesiran 
during organogenesis resulted in maternal weight loss and lower food consumption that began 
within 24 hours of the first dose and was of particular note throughout the first few doses. Higher 
post-implantation loss and lower numbers of live fetuses, and increased external, visceral, and/or 
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skeletal malformations were observed after repeat or single doses of belcesiran. Belcesiran 
exposure in fetal plasma after repeated dosing of 10 or 50 mg/kg/dose (DRF study) and in fetal 
liver at 50 mg/kg/dose was observed but were a fraction of maternal concentrations and 
belcesiran was not detectable after repeat-dosing of 0.2 to ≤6 mg/kg. These data suggest that 
placental transfer is negligible at dose levels similar to those administered in human clinical 
trials. In the definitive EFD study, a dose level of 2 mg/kg/dose was considered to be the 
NOAEL for maternal toxicity and based on postimplantation loss noted at 6 mg/kg/dose and 
visceral malformations of the heart and major blood vessels noted at ≥ 0.6 mg/kg/dose, a dose 
level of 0.2 mg/kg/dose was considered to be the NOAEL for embryo-fetal development. 
Of note, belcesiran does not have complete homology with the rabbit A1AT mRNA sequence 
(7 mismatches) and therefore is not predicted to be pharmacologically active in the rabbit. In an 
exploratory EFD study (data available upon request), single and repeat dosing of a 
pharmacologically inactive but chemically comparable GalNAc-conjugated siRNA demonstrated 
similar maternal effects on food consumption, body weights, and post-implantation loss (skeletal 
and visceral effects not characterized). A lack of pharmacologic activity of belcesiran in rabbits 
and similar effects with the inactive but chemically comparable GalNAc-conjugated siRNA 
demonstrate that the belcesiran-related EFD effects are associated with the bulk chemical and 
physical properties (e.g., high molecular weight, polyanionic polymer) of the molecule rather 
than pharmacology (i.e., RNAi). The maternal body weight loss and decreased food consumption 
in conjunction with no measurable fetal exposure, are evidence of maternal effects driving the 
EFD effects rather than a direct effect on the fetus. The human relevance of the EFD effects in 
rabbits is unclear, as similar toxicities were not observed in mice with belcesiran nor the 
pharmacologically active mouse analog. 
2.2.4. 
Clinical Overview 
Belcesiran is currently being evaluated in one ongoing, Phase 1 study in healthy volunteers. 
Study DCR-A1AT-101 is a multi-cohort, randomized, placebo-controlled, SAD study evaluating 
the safety, tolerability, PK, and PD of belcesiran at doses ranging from 0.1 to 12.0 mg/kg 
(sodium salt). Participants are followed for at least 56 days after single dose administration on 
Day 1. Participants whose serum AAT protein concentration has not returned to ≥ 80% of 
baseline (or is not within normal range) at Day 57 every 4 (± 1) weeks for 2 months, then every 8 
(± 2) weeks for the next 4 months, and then every 12 (± 3) weeks for an additional 6 months or 
until AAT has returned to ≥ 80% of baseline, whichever is shorter.  
All cohorts (0.1, 1.0, 3.0, 6.0, and 12.0 mg/kg) in Study DCR-A1AT-101 are complete through 
Day 57 (the EOT visit), and all eligible participants are in C-F/U.   
No SAEs, severe TEAEs, or DLTs have been reported. All TEAEs were mild in severity except 
for 3 events of moderate severity reported for 2 participants: nasopharyngitis (1 participant in 
Cohort 1, 0.1 mg/kg belcesiran), gastroenteritis and staphylococcal skin infection (1 participant 
in Cohort 4, 6.0 mg/kg belcesiran). 
Thus far, the medical monitor and SRC have not identified any safety concerns. 
Belcesiran, at single doses of 1.0 mg/kg, 3.0, 6.0 and 12.0 mg/kg, resulted in robust reductions in 
serum AAT concentrations. The mean reduction in serum AAT concentration at the EOT visit 
ranged from approximately 48% for the 1.0 mg/kg cohort to 78% for the 12.0 mg/kg cohort. 
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2.2.5. 
Summary 
Adults with AATD are at significant risk for the development of progressive liver disease. Due 
to the variable natural progression of the disease, it is currently not possible to predict which 
adults with AATD will remain stable, and which will develop life-threatening liver disease over 
time. Some patients with progressive liver fibrosis or compensated liver cirrhosis can remain 
stable for many years with little need for intervention, while others may progress to fulminant 
liver failure and death. 
While augmentation therapy may address the loss of AAT in the lungs, no treatment yet exists 
for the toxic gain-of-function-mediated liver disease. The knockdown of SERPINA1 mRNA 
should lead to a reduction of total Z-AAT expression in the liver, which in turn reduces the 
accumulation of the toxic Z-AAT protein. Without the continuous putative toxic stimulus, the 
progression of liver disease in affected individuals may be halted, or potentially even reversed. 
Nonclinical studies of belcesiran sodium in transgenic mice and cynomolgus monkeys have 
shown a significant reduction of target mRNA and AAT protein levels. In transgenic mice, 
belcesiran sodium substantially reduced hepatic globule levels, indicating reduced accumulation 
of aggregated human Z-AAT protein. 
The clinical evaluation of belcesiran is ongoing. The initial safety, tolerability, PK, and PD of 
belcesiran are being evaluated in a Phase 1 SAD study in healthy volunteers (DCR-A1AT-101). 
To date, belcesiran administration in healthy volunteers appears to be safe and well-tolerated, 
with no SAEs or DLTs reported. The SRC for Study DCR-A1AT-101 and the DSMC from this 
study have reviewed all available safety data from all cohorts and have affirmed that it is safe to 
advance the proposed dosing regimens in this study. Two belcesiran dose levels (210 mg and 
50 mg) will be assessed in this study. The doses selected span a range of expected serum AAT 
reduction, allowing for assessment of the dose-exposure-response relationship of belcesiran and 
its safety profile with different levels of AAT knockdown (see Section 4.3 for further details). 
Study DCR-A1AT-201 is designed to demonstrate the safety and tolerability of belcesiran in 
adults with AATLD and to establish proof-of-concept that belcesiran can reduce Z-AAT 
production, as reflected by a reduction in circulating Z-AAT levels. Paired liver biopsies will be 
employed to evaluate levels of the mutated Z-AAT protein and its polymers in the liver and the 
degree of liver fibrosis over time.  
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Potential Risks Associated with Belcesiran 
The summary of potential risks provided below is based on an in-depth review of literature 
relating to the proposed approach, and insights from the nonclinical pharmacology, toxicology 
studies and human Phase 1 data. 
Potential safety issues that may be associated with belcesiran can be characterized into 3 broad 
categories: risks associated with the siRNA molecule, risks associated with the knockdown of 
AAT, and risks associated with potential off-target effects. 
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2.3.1.1. 
Risks Related to the siRNA Molecule 
Due to the lack of excipients in the drug product, the potential risks associated with belcesiran 
are limited to the risks associated with the siRNA oligonucleotide portion of the drug product 
(belcesiran sodium).  
To date, belcesiran sodium has been associated with little-to-no toxicity in the nonclinical studies 
and no toxicity in a Phase 1 study in healthy volunteers. Results of nonclinical toxicity studies of 
belcesiran sodium conducted to date are presented in Section 2.2.3. 
Clinical experience with modern GalNAc siRNA platforms, including the Sponsor’s GalXC 
platform, suggest an enhanced safety profile with no evidence for systemic immune stimulation 
or toxicities observed in more than 150 humans dosed with GalNAc siRNAs (Dicerna data on 
file).  
Nevertheless, all study participants will be monitored for signs or symptoms of systemic toxicity, 
decline in liver or kidney function, abnormalities on hematologic parameters (including platelets 
and abnormalities in coagulation parameters), and abnormalities in vital signs, ECGs, or other 
relevant safety parameters. 
2.3.1.2. 
Risks Related to AAT Knockdown 
There is currently little experience with AAT knockdown in patients with PiZZ AATLD. 
However, the knockdown of AAT could potentially worsen the related loss-of-function effects in 
the lungs, since it has been shown that subjects with Null mutations of the SERPINA1 gene and 
thereby no Z-AAT production, are at a particularly high risk of emphysema. It is however 
important to note that the pulmonary manifestations in the Null mutation population usually 
develop after decades of total absence of the AAT protein (Fregonese et al, 2008).  
In the DCR-A1AT-101 study, a mean knockdown of 78% was achieved and no clinically 
significant changes in lung function were noted on spirometry or DLCO, no dose‐dependent 
changes were noted in repeat measurements of any spirometry parameter, and all Percent 
Predicted DLCO measurements remained within normal limits across all cohorts.  
In addition, others have reported that no clinically meaningful changes in spirometry were 
observed after 40 weeks (N=16) or 72 weeks (N=4) of Z-AAT knockdown in patients with 
AATLD (Strnad et al., 2021).  
To mitigate this risk, serial measurements of PFTs will be conducted throughout the study, and 
whenever applicable augmentation therapy will be able to restore absent serum AAT protein 
concentrations and anti-neutrophil elastase capacity to levels at the lower limit of normal 
(Wewers, 1987; Sandhaus et al., 2016; Chapman et al., 2015; Sorrells et al., 2015).  
In study participants already on augmentation therapy at the initiation of the study, the risk of 
worsening the loss-of-function disease mechanism in the lungs is reduced because these study 
participants have non-mutated M-AAT levels restored to the lower limit of normal and this 
would not be affected by the Z-AAT knockdown (Chapman KR, Chorostowska-Wynimko J, 
Koczulla AR, Ferrarotti I, McElvany NG. Alpha 1 antitrypsin to treat lung disease in alpha 1 
antitrypsin deficiency recent developments and clinical implications. Int J Chron Obstruct 
Pulmon Dis. 2018;13:419-432. 
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). 
2.3.1.3. 
Risks Related to Potential Off-Target Effects  
In silico analysis for the potential for off-target activity of belcesiran was assessed via thorough 
bioinformatics analysis that suggests it has minimal potential for off-target effects via siRNA 
hybridization to the human genome. Potential off-target homologies at the levels > 15 contiguous 
NTs were completely absent from the human transcripts analyzed other than SERPINA1. Such a 
gap suggests excellent specificity for the intended target SERPINA1. Only four genes (KLKB1, 
DAPK1, CAMLG, and KATNAL1) with seed region complementarity and moderate to high 
expression in the liver were identified. Additionally, in an in vitro assay in a human 
hepatocellular carcinoma cell line, the IC50 for belcesiran against its target transcript SERPINA1 
was approximately 0.09 pM, which is > 18,000-fold lower than the genes identified with partial 
complementarity to the antisense strand of belcesiran (KLKB1, DAPK1, CAMLG, and 
KATNAL1) that would be expressed in normal liver. This indicates that none of the selected 
genes with partial complementarity to the antisense strand of belcesiran are likely to be 
functionally reduced in expression by treatment with belcesiran. These findings, combined with 
the high specificity of GalNAc conjugates for the delivery of belcesiran to the liver suggest a low 
likelihood of hybridization based off-target effects for belcesiran. Overall, these results suggest 
that the belcesiran sequence has a high degree of specificity for the intended SERPINA1 mRNA 
target with minimal potential to exert unintended RNAi effects against nontarget genes. The 
potential risks associated with off-target effects remain only hypothetical because of the lack of 
complementarity, and the results of the in vitro studies demonstrate that belcesiran has extremely 
low activity with the genes tested. Additionally, in the Phase 1 study of belcesiran in healthy 
volunteers, there was no evidence of a patient safety signal associated with these genes. Overall, 
there is no evidence of patient risk from these potential off-target effects.  
2.3.2. 
Risks Associated with Liver Biopsy and Study-Specific Evaluations  
To be eligible for participation in the study, prospective participants must agree to undergo 2 
liver biopsies.  
The Screening liver biopsy will only be conducted once the prospective participant has met all 
other eligibility criteria. 
Percutaneous liver biopsy is a standard diagnostic procedure that bears several risks. Milder and 
more common risks include pain and bruising at the biopsy or incision site. More serious 
complications include prolonged bleeding from the biopsy or incision site or internal bleeding 
(which may require hospitalization, transfusions, and sometimes surgery or another procedure to 
stop the bleeding), infection of the biopsy site or incision site that may cause sepsis, and 
pneumothorax, hemothorax, or puncture of other organs (Liver Biopsy-NIDDK). The overall risk 
of serious complications following liver biopsy is approximately 1% (Boyum et al., 2016), and 
the risk of death directly related to the liver biopsy is approximately 1 in 
10,000 (West & Card, 2010). 
Liver biopsy may be conducted under procedural sedation and analgesia (PSA) to reduce 
potential pain and anxiety for the study participant. PSA bears a low risk of complications but 
may include respiratory compromise with resultant hypoxia or hypercarbia, vomiting, aspiration, 
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hypotension, bradycardia, and drug reaction. The overall incidence of SAEs during PSA, such as 
laryngospasm, aspiration, and intubation, is rare (Bellolio et al., 2016).  
The risks associated with the liver biopsies are minimized through the selection of suitable study 
participants through eligibility criteria and safety precautions outlined in detail in the Liver 
Biopsy Manual. 
Study-specific evaluations and sampling procedures, e.g., blood-pressure measurements using a 
blood pressure cuff and frequent blood-sampling, may cause transient discomfort and carry a low 
risk of bleeding, hematoma formation, peripheral nerve damage, or infection. 
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2.3.3. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 
Study Intervention 
AEs and SAEs 
This is the first multiple dose study of belcesiran in 
humans and the first evaluation of belcesiran in adults with 
AATLD. All AEs are considered to be unexpected. 
In the ongoing first-in-human study (DCR-A1AT-101), 
belcesiran has been well tolerated. No SAEs or dose-
limiting toxicities have been reported. Thus far, the 
medical monitor and SRC have identified no safety 
concerns. The SRC has endorsed the expansion of each 
cohort beyond the sentinel pair and each proposed dose 
escalation. The DSMC reviewed all available data from 
DCR-A1AT-101 prior to dosing of the first participant in 
this study (DCR-A1AT-201) and found no safety 
concerns. 
Both proposed belcesiran fixed doses (210 mg and 50 mg) 
are within the dose range tested in the DCR-A1AT-101 
study (with 210 mg corresponding approximately to a 
3 mg/kg dose level) and are expected to be safe and well-
tolerated. The highest dose tested in DCR-A1AT-101 is 
12 mg/kg. 
The DSMC has reviewed a minimum of 3 weeks of data 
from a sentinel pair of participants in this DCR-A1AT-201 
and allowed for continued enrollment of participants. The 
DSMC will continue to review data throughout the study, 
as per the DSMC charter. 
Oligonucleotide class risks, 
including stimulation of pattern 
recognition receptors leading to 
cytokine release, inflammation, 
injection site reactions, low 
elevations of LFTs, and a 
prolonged aPTT 
The various RNA and DNA chemical modifications 
studied over 3 decades of clinical trials of ASOs, with and 
without phosphorothioates, suggest these class toxicities 
are highly dependent on phosphorothioate modifications.  
Single- or double-stranded oligonucleotides delivered in 
lipid nanoparticles, major adverse reactions include 
infusion reaction symptoms typical of other lipid-particle-
based drugs. 
 
GalNAc-siRNA conjugates have chemical modifications 
to resist enzymatic degradation, reduce or eliminate 
cytokine responses, reduce non-specific protein binding 
(the source of coagulopathies), and target the siRNAs to 
the hepatocytes, thus eliminating the need for any lipid 
nanoparticle formulation. 
Participants will be monitored for signs or symptoms of 
systemic toxicity, decline in liver or kidney function, 
abnormalities in hematologic parameters (including 
platelets and abnormalities in coagulation parameters), and 
abnormalities in vital signs, ECGs, or other relevant safety 
parameters 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 
AAT knockdown 
 
An average of approximately 80% reduction from baseline 
Z-AAT could potentially worsen the loss-of-function 
disease mechanism in the lungs in patients who are not 
receiving augmentation. In this patient population, an 
average of approximately 80% reduction from baseline Z-
AAT knockdown of Z-AAT in the liver would result in a 
nearly complete absence of Z-AAT protein in the blood. 
Subjects with Null mutations, which are also devoid of 
AAT production, are at a particularly high risk of 
emphysema; however, these pulmonary manifestations 
usually develop after decades of total absence of the AAT 
protein (Fregonese et al, 2008).  
Only participants with stable lung function are eligible for 
enrollment, including participants who may be on 
augmentation therapy. 
Serial measurements of PFTs will be conducted 
throughout the study. 
Augmentation therapy to restore serum AAT protein 
concentrations can be provided.  
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 
Study Procedures 
SC injection 
The study drug is administered via SC injection in the 
abdomen or thigh. Subcutaneous injection is associated 
with pain and may cause vasovagal reactions, allergic 
reactions, infections, and bleeding.  
The risk/burden associated with the SC injection of the 
study drug is minimal and will be controlled by close 
monitoring of the events. Therefore, SC injections are 
assessed as a minimal risk/burden to patients. 
Blood sampling, including 
cannulation 
 
Risks include acute pain, bleeding, vessel injury, and, in 
rare instances, arterial vessel blockage, potentially leading 
to infection. 
The risk/burden is minimal and not over and above the 
risk/burden associated with blood sampling as part of the 
standard treatment for AATLD. Due to the increased 
frequency of blood sampling in the trial to ensure patient 
safety, the likelihood of patients experiencing minor 
effects from blood sampling may be higher during the 
study. 
Biopsy 
Percutaneous liver biopsy is a standard invasive diagnostic 
procedure that bears several risks. Milder and more 
common risks include pain and bruising at the biopsy or 
incision site. More serious complications include 
prolonged bleeding from the biopsy or incision site, 
internal bleeding (which may require hospitalization, 
transfusion, and sometimes surgery or another procedure 
to stop the bleeding), infection of the biopsy site or 
incision site that may cause sepsis, and pneumothorax, 
hemothorax, or puncture of other organs. 
The overall risk of serious complications following liver 
biopsy is approximately 1% (Boyum et al., 2016).  
The risks associated with the liver biopsies are minimized 
through the selection of suitable study participants through 
eligibility criteria and safety precautions outlined in detail 
in the Liver Biopsy Manual. Safety precautions include 
monitoring of the patient during the procedure and post 
procedure per local standard of care. The low risk of 
respiratory compromise in the elective setting of PSA is 
minimized through the standard-of-care monitoring and 
the presence of a healthcare provider with the knowledge 
and skills to recognize and treat airway complications. 
Abbreviations: AAT: alpha 1 anti-trypsin; AATLD: Alpha-1 Antitrypsin Deficiency-Associated Liver Disease; AE: adverse event; aPTT: activated partial 
thromboplastin time; ASO: antisense oligonucleotide; DNA: deoxyribonucleic acid; DSMC: Data Safety Monitoring Committee; ECG: electrocardiogram; 
GalNAc: N-acetylgalactosamine; LFT: liver function tests; PFT: pulmonary function test; PSA: procedural sedation and anesthesia; RNA: ribonucleic acid; 
SAE: serious adverse event; SC: subcutaneous; siRNA: small interfering ribonucleic acid; SERPINA1: the mutant AAT protein; SRC: Safety Review Committee; 
Z-AAT: the mutant AAT protein. 
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2.3.4. 
Overall Benefit: Risk Conclusion 
At present, no pharmacological therapies are approved for the treatment of patients with 
AATLD. These patients are at increased risk of developing cirrhosis and portal hypertension 
(PHT). Complications associated with PHT include gastrointestinal bleeding, ascites, 
encephalopathy, and reduced levels of platelets, or decreased white blood cell count. The 
standard-of-care includes the use of vasoactive drugs, endoscopic band ligation, and antibiotic 
prophylaxis. Patients failing standard-of-care treatment may undergo transjugular intra hepatic 
portosystemic shunt (TIPS) placement. Ultimately, the only cure for AATLD is liver 
transplantation. 
Belcesiran has been shown to decrease serum AAT protein concentrations in healthy volunteers. 
In Study DCR-A1AT-101, the mean reduction in serum AAT concentration at EOT visit ranged 
from approximately 48% for the 1.0 mg/kg cohort to 78% for the 12.0 mg/kg cohort. Belcesiran 
treatment has the potential benefit to reduce the production and, hence, the accumulation of the 
misfolded Z-AAT protein in the liver. By eliminating the toxic protein, belcesiran may prevent 
liver disease progression, which ultimately may eliminate the need for liver transplantation.  
Participants with AATLD could potentially benefit from the investigational drug. This potential 
benefit has not been proven and may be limited in duration to the treatment period of this trial.  
The key potential risks associated with belcesiran include exacerbation of emphysema, a decline 
in lung function, elevations of LFTs, and injection site reactions. All these risks are monitorable 
and should be reversible over time after drug discontinuation or could potentially be treated with 
intravenous augmentation therapy in the case of knockdown-mediated lung function decline. In 
DCR-A1AT-101, single doses of belcesiran in healthy volunteers (up to and including 12 mg/kg) 
appeared to be safe and well tolerated. Repeat measurements of spirometry and DLCO indicated 
that normal lung function was preserved. No clinically significant or apparent dose‐dependent 
increases in AST or ALT levels were observed. 
In study participants already on augmentation therapy at the initiation of the study, the risk of 
lung function decline due to reduction of Z-AAT serum levels would be reduced because these 
study participants have non-mutated M-AAT levels restored to the lower limit of normal. 
The primary potential risk associated with percutaneous liver biopsy in participants with AATLD 
is bleeding. This risk is minimized through the selection of suitable participants through 
eligibility criteria that exclude participants with decompensated cirrhosis (Child Pugh Score B or 
C) and by the safety precautions outlined in the Liver Biopsy Manual. The low risk of respiratory 
compromise in the elective setting of PSA is minimized through the standard of care monitoring 
and the presence of a healthcare provider with the knowledge and skills to recognize and treat 
airway complications. 
In summary, the Sponsor believes the Benefit to Risk ratio to be favorable. Ongoing risk-benefit 
assessments will be conducted throughout the trial by the independent DSMC. 
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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary (Cohorts 1 and 2) 
1. To evaluate the safety and tolerability of multiple 
doses of belcesiran in patients with AATLD 
1. The incidence and nature of TEAEs, and the 
change from Baseline in PFTs, 12 -lead ECGs, 
physical examination findings, vital signs, and 
clinical laboratory tests 
2. To characterize the PD of belcesiran in patients 
with AATLD 
2.  Changes from baseline to weeks 24 (Cohort 1)/48 
(Cohort 2) in serum AAT protein concentrations  
Primary (Cohort 3) 
3. To characterize the PD of belcesiran in patients 
with AATLD 
3. Change from baseline to week 24 in serum Z-AAT 
protein levels 
4. Change from baseline to week 24 in liver Z-AAT 
protein levels 
Secondary 
1. To characterize the PK of belcesiran in the plasma 
of patients with AATLD  
1. PK profile of belcesiran 
2. To assess the effect of belcesiran on liver 
histology in patients with AATLD 
2. Change from Baseline up until week 96 in liver 
fibrosis 
3. Change from Baseline up until week 96 in 
diastase-resistant PAS-positive AAT globules 
Exploratory 
1. To assess the effect of belcesiran on liver stiffness 
in patients with AATLD 
1. Change from Baseline up until week 96 in 
FibroScan® score 
2. To assess the effect of belcesiran on liver fibrosis 
and/or inflammation in patients with AATLD 
2. Change from Baseline up until week 96 in ELF 
score  
3. Change from Baseline up until week 96 in CK-18 
 
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4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
This study is a multiple dose, randomized, placebo-controlled, double-blind study to evaluate the 
safety, tolerability, PK, and PD of 2 doses of belcesiran in adult patients with PiZZ AATLD 
(liver fibrosis F1, F2, F3, or F4, METAVIR scoring system). 
After the screening period, participants will be randomized, and administration of IMP 
(investigational medicinal product) will be initiated. Participants will return to the site for 
administration of IMP and safety, tolerability, PK, and PD monitoring at specified time points as 
per the SoA through the EOT visit. If participants are not able to return to the site for 
assessments or procedures, visits may be conducted by qualified medical professionals as 
at-home telemedicine and/or home nursing visits, at the discretion of the Investigator.  
The study will be conducted in 3 separate cohorts. Participants will be randomized in a 1:1 
fashion to either Cohort 1 and 2. Once Cohort 1 and 2 have enrolled, enrollment of Cohort 3 will 
be initiated.  
x Participants in Cohort 1 (N=8) will be randomized 3:1 to either belcesiran 210 mg or 
placebo and a liver biopsy will be performed at week 24 to assess the effect of belcesiran. 
In addition, participants will have the option to continue treatment for an additional 
72 weeks so that the total treatment duration will be 96 weeks. 
x Participants in Cohort 2 (N=8) will be randomized 3:1 to either belcesiran 210 mg or 
placebo and a liver biopsy will be performed at week 48 to assess the effect of belcesiran. 
In addition, participants will have the option to continue treatment for an additional 
48 weeks so that the total treatment duration will be 96 weeks. 
x Participants in Cohort 3 (N=30) will be randomized 2:1:2:1 to belcesiran 210 mg, the 
equivalent amount of placebo for belcesiran 210 mg, belcesiran 50 mg or the equivalent 
amount of placebo for belcesiran 50 mg. Participants will be blinded within each dose 
level. Participants will have a liver biopsy performed at week 24 to assess the effect of 
belcesiran and thereafter continue treatment until 96 weeks of treatment have been 
completed.  
Randomization will be stratified based on fibrosis stage (METAVIR Score F1/F2, F3, or F4) in 
all cohorts.   
Participants in Cohort 1 and 3 will receive monthly dosing for the first 24 weeks and then shift to 
quarterly dosing thereafter until week 96. Participants in Cohort 2 will receive monthly dosing 
for the first 48 weeks and then shift to quarterly dosing thereafter until week 96. Participants will 
continue the IMP throughout the study, unless the participant or investigator decide to 
discontinue IMP, or the participant withdraws from the trial or a discontinuation criterion is met.  
All Participants in Cohorts 1 to 3 will have the option to undergo a liver biopsy at EOT/week 96. 
The biopsy at 96 weeks will inform about Z-AAT levels and provide further information about 
possible improvements in liver histology. Biopsy findings will be correlated with changes in 
non-invasive markers of liver disease and liver stiffness.  
After the EOT visit, all participants will be followed up for 48 weeks. In addition, Cohorts 1 and 
2 will be followed for an additional 48 weeks to inform about the duration of potential treatment 
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effects.  If a participant in Cohorts 1 or 2 does not wish to extend the treatment period to 96 
weeks, follow-up will stop after the 48-week follow-up period.   
There are 3 interim analyses planned for this trial. Interim analyses for Cohorts 1 and 2 will take 
place after all participants in Cohorts 1 and 2 complete 24 weeks and 48 weeks of treatment, 
respectively. The third interim analysis will be performed when all the participants in Cohort 3 
have completed 24 weeks of treatment. The third interim analysis will evaluate the dose-response 
relationship on efficacy and safety assessments of the two doses of belcesiran. If based on the 
interim analysis it is concluded that one dose is more favorable with respect to effect while 
showing no overall difference in safety – the least favorable dose-arm can be stopped. 
The trial will be monitored by an independent external DSMC. The DSMC will review 
accumulating data from the trial in an unblinded fashion to ensure adequate monitoring of safety. 
The timing and scope of the review meetings will be defined in the DSMC charter. 
4.2. 
Scientific Rationale for Study Design 
As this is the first evaluation of belcesiran in patients with AATLD, safety and tolerability are 
best assessed via a double-blind, placebo-controlled study. Because AATLD is a rare disease, the 
use of an unbalanced randomization ratio will minimize exposure of participants to placebo 
whilst still allowing for an unbiased assessment of safety and maximizing the amount of PD data 
to be collected. 
It is expected that the knockdown of SERPINA1 mRNA will result in decreased production of 
Z-AAT in the liver, and hence decreased levels of circulating AAT in serum.  
The effect of belcesiran on AATLD will be assessed via changes in the levels of Z-AAT in the 
liver and serum, as well as by changes in liver histology. Liver biopsy is regarded as the gold 
standard for the direct assessment of the progression of liver disease over time. The use of 3 
parallel cohorts with biopsies scheduled at either weeks 24 or 48 as well as the optional biopsy at 
week 96 will allow for the evaluation of treatment effect at different timepoints especially since 
change in liver histology might require a longer treatment period. Biopsy findings will be 
correlated with changes in non-invasive markers of liver disease and will potentially be 
supported by “omics” analyses, such as proteomics.  
The targeted population includes patients with fibrotic liver disease who are most likely to 
benefit from a future therapy with belcesiran, and excludes patients with liver impairment or 
decompensated cirrhosis, as these patients are at higher risk for complications, including those 
associated with liver biopsy. WOCBP are eligible if they agree to follow the contraception 
guidelines provided in Section 10.4.2. 
4.3. 
Justification for Dose 
Two doses of belcesiran will be evaluated in this study: 210 mg and 50 mg. No safety concerns 
have been identified by the SRC or DSMC who reviewed all available DCR-A1AT-101 data 
prior to dosing the first patient in DCR-A1AT-201. Both doses selected for this study are within 
the dose range tested in DCR-A1AT-101 and are expected to be safe and well-tolerated. In 
addition, the NOAEL plasma exposure observed in the pivotal repeat-dose toxicity studies 
provides adequate safety margin for the expected exposure at these doses (at least 23-fold to the 
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high dose proposed in this study). Details on clinical safety data from DCR-A1AT-101 and 
nonclinical toxicology studies are provided in the DCR‑A1AT Investigator Brochure. 
A PK/PD modeling and simulation analysis was performed using all available PK and PD (serum 
AAT protein levels) data from DCR-A1AT-101 including data up to EOT for 12 mg/kg dose and 
all available data from C-F/U period. The adequacy of models in describing the available data 
and the predictive performance of the final model were assessed using pre-specified goodness-
of-fit criteria. Based on the final PK/PD model, simulations of serum AAT profiles were 
performed to inform the dosing regimen for this study. A dataset of 1000 virtual adult subjects 
was created by sampling the demographics for these virtual subjects from the National Health 
and Nutrition Examination Survey (NHANES; http://wwwn.cdc.gov/nchs/nhanes/search/
nhanes_continuous.aspx.), with age range of 18 to 65 years and weight range of 41 to 199 kg 
(median weight of 77.5 kg). Various dosing regimens, including weight-based dose and fixed 
dose with different dosing intervals, were evaluated. The simulations over the wide range of 
weight indicated that weight-based and equivalent fixed-dose regimens would result in similar 
reductions in serum AAT. Given similar predicted PD responses, a fixed-dose regimen is 
preferred over the weight-based regimen for ease in dose administration.  
The 210 mg q4w dosing regimen was selected to target a near-maximal PD response. From the 
simulations, the mean reduction in serum AAT was predicted to be approximately 82% by 
Week 24 (90% prediction interval [PI]: -59.1% to -98.8%). A lower dose of 50 mg q4w was 
included to better characterize the dose-exposure-response relationship of belcesiran and its 
safety profile over a range of serum AAT reduction. Following the administration of 50 mg q4w, 
the mean reduction in serum AAT was predicted to be approximately 65% (90% PI: -44.5% 
to -82.4%) by Week 24. Simulations predicted a serum AAT reduction of at least 50% by Week 
24 in about 90% of the participants receiving 50 mg q4w dose, suggesting a 50% reduction in 
hepatic AAT production. It has been shown that adults with the SERPINA1 PiMZ genotype, 
which leads to an approximately 50% reduction in hepatic Z-AAT production, have lower levels 
of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with 
the PiZZ genotype, although higher than adults without the PiZ variant (Schneider et al, 2020). 
Therefore, the 50 mg q4w dose, which is predicted to reduce hepatic Z-AAT production (and 
hence the downstream serum Z-AAT) by at least 50% in the majority of study participants with 
AATLD, may offer some clinical benefits to most of the participants receiving this dose while 
expanding the range of PD response for dose-exposure-response characterization.  
Monthly dose frequency has been selected for Cohorts 1 and 2 to maximize potential PD 
response. The first 6 months dosing in Cohort 3 will also be monthly after which patients will 
shift to quarterly dosing. The rationale for exploring an alternative dosing regime is out of 
consideration for patient burden. For the high dose explored, simulations suggest that reducing 
dose frequency after steady state would only have a minor effect on the PD response.  
In summary, the two belcesiran doses included in the clinical protocol (210 mg and 50 mg) are 
predicted to result in a range of PD response that would allow for adequate characterization of 
belcesiran dose-exposure-response in patients with AATLD. 
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4.4. 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of 
the study (including F/U), including the last visit or the final scheduled procedure shown in the 
SoAs (Section 1.3).  
The end of the study is defined as the completion of the final database lock. 
5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Age 18 to 75 years, inclusive, at the time of signing the ICF. 
Type of Participant and Disease Characteristics 
2. Documented diagnosis of PiZZ-type AATD, confirmed by genotyping. Historical genotyping 
data may be used, if available. 
3. AATLD, with a liver fibrosis score categorized as F1, F2, F3, or F4 in the METAVIR scoring 
system, documented by liver biopsy during Screening.  
4. Post-bronchodilator FEV1 > 45% of predicted at Screening.  
5. Participants receiving augmentation therapy on a regular basis and intending to continue 
augmentation therapy during the study are eligible to participate. 
6. eGFR at Screening ≥ 60 mL/min normalized to 1.73 m2 BSA.  
7. Non-smokers (defined as having not smoked cigarettes daily for at least the preceding 
12 months) with current non-smoking status confirmed by urine cotinine at Screening AND 
any previous smoking history prior to 12 months must be < 15 pack years, including use of 
e-cigarettes. Participants may be on nicotine replacement (patch or gum). A positive urine 
cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of 
the Investigator. 
Sex 
8. Male or female 
Male participants: 
A male participant with a partner of childbearing potential must agree to use 
contraception, as detailed in Section 10.4.2, during the treatment period and for at 
least 12 weeks after the last dose of study intervention and refrain from donating 
sperm during this period. 
Female participants:  
A female participant is eligible to participate if she is not pregnant (see Section 
10.4.2), not breastfeeding, and at least one of the following conditions applies: 
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Not a woman of childbearing potential (WOCBP) as defined in Section 10.4.1 
OR 
A WOCBP who agrees to follow the contraceptive guidance in Section 10.4.2 during 
the treatment period and for at least 12 weeks after the last dose of study intervention. 
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
Informed Consent 
9. 
Capable of giving signed informed consent, which includes compliance with the 
requirements (including consent to undergo paired liver biopsies) and restrictions listed in 
the ICF and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. 
Any condition which, in the investigator's opinion might jeopardize participant's safety or 
compliance with the protocol. 
2. History of chronic liver disease other than non-alcoholic fatty liver disease from any cause 
other than PiZZ-type AATD. Diagnostic testing exclusions are defined in the Diagnostic 
Assessments section below. 
3. Child-Pugh Score B or C or a previous hepatic decompensation event. 
4. History of one single severe exacerbation of underlying lung disease in the year prior to 
randomization.  
A severe exacerbation is defined as an exacerbation that requires hospitalization or a 
visit to the emergency room. 
5. History of rapid decline in pulmonary function, as assessed by the Investigator. 
6. Known or suspected abuse of drugs in the opinion of the Investigator. 
7. Known or suspected excessive consumption of alcohol (≥ 21 units of alcohol per week in 
men and ≥ 14 units of alcohol per week in women; where a "unit" of alcohol is equivalent to 
a 12-ounce beer, 4-ounce glass of wine, or 1 ounce shot of hard liquor as defined by the 
World Health Organization). 
8. Any of the following: myocardial infarction, stroke, classification of heart failure New York 
Heart Association (NYHA) Class IV, hospitalization for unstable angina pectoris or transient 
ischemic attack within the past 90 days prior to the day of screening (V2A) and between 
screening and randomization. 
9. History of malignancy, unless the malignancy (other than hepatocellular or lung cancer) has 
been in complete remission off chemotherapy and without additional medical or surgical 
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interventions within the preceding 5 years, or unless the malignancy has been an adequately 
treated skin cancer (other than melanoma) or, superficial bladder tumor, or in situ cervical 
cancer in the preceding 1 year.  
Prior/Concomitant Therapy 
5. Use of an RNAi drug at any time. 
6. History of one or more of the following reactions to an oligonucleotide-based therapy: 
a. severe thrombocytopenia (platelet count < 100,000/ mm3) 
b. hepatotoxicity, defined as ALT or AST > 3 × ULN and total bilirubin > 2 × ULN 
or INR > 1.5 
c. severe flu-like symptoms leading to discontinuation of therapy 
d. localized skin reaction from the injection (graded severe) leading to 
discontinuation of therapy 
e. coagulopathy/clinically significant prolongation of clotting time 
Prior/Concurrent Clinical Study Experience 
7. Participation in any clinical study in which they received an IMP within 4 months (or 5 times 
the half-life, whichever is longer) before Screening. 
Diagnostic assessments 
8. AST and ALT > 5 × ULN at Screening 
For individuals with any serum aminotransferase elevation > 2 × ULN, autoimmune 
hepatitis should be ruled out through the appropriate screening tests, which may 
include total IgG or gamma-globulin levels and/or serologic markers (i.e., antinuclear 
antibodies, anti-smooth-muscle antibodies at a titer of at least 1:40, anti-liver/kidney 
microsomal-1 antibodies, anti-liver cytosol antibody [anti-LC 1], or antisoluble 
liver/liver pancreas [anti-SLA/LP] antibodies). 
9. ALP 2 × ULN at Screening. 
10. Serum AFP value > 100 ng/mL at Screening. 
If AFP at screening is > ULN but < 100 ng/mL, the participant is still eligible if an 
appropriate hepatic imaging study reveals no lesions. 
11. Positive screening for antimitochondrial antibodies (only required if primary biliary 
cholangitis is suspected). 
12. Platelets < 100,000/mm3 at Screening 
13. INR > 1.6 × ULN at Screening 
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14. Positive screening for HBsAg, HCV antibodies, or HIV1 and 2 antibodies. If a participant 
has been tested in the past 3 months, medical record documentation of this testing can be 
used for eligibility. 
NOTE: In participants with previous treatment for hepatitis C with direct-acting HCV 
medication and seropositivity for HCV, or in participants with prior infection and 
spontaneous resolution, HCV RNA must be undetectable (at least 2 negative HCV 
RNA tests at least 12 weeks apart), and the HCV infection must have been resolved 
or cured > 3 years prior to enrollment. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
During this study, participants will be asked to: 
o Abstain from heavy drinking throughout the study period, for example, no more than 
≥ 21 units of alcohol per week in men and ≥ 14 units of alcohol per week in women 
(4 units per day for men and 3 units per day for women); where a "unit" of alcohol is 
equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1 ounce shot of hard liquor 
as defined by the World Health Organization. Social drinking is allowed. 
5.3.2. 
Activity 
During this study, participants will be asked to: 
o Abstain from strenuous exercise for 48 hours before each blood collection for clinical 
laboratory tests. Participants may participate in light recreational activities 
(e.g., walking at a pace < 3 miles per hour, shopping, watering plants) in that 48-hour 
time period. 
o Plan to undertake no significant changes in exercise levels from the 48 hours prior to 
Day 1 until completion of the study, including F/U. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to the study intervention/entered in the study. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the CONSORT publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information includes, but are not limited to, demography, screen 
failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened once, at the discretion of the Investigator. 
Rescreened participants will be assigned the same participant number as originally assigned 
preceded by the number “9.” 
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5.4.1. 
Screening Tests Required during the Rescreening Period 
If a participant undergoes rescreening after being deemed a screen failure, the following 
screening assessments do not need to be repeated as part of the rescreening visit.  
x Liver biopsy performed within 180 days (if the participant screen failed before a 
biopsy was performed, the liver biopsy must be collected as part of rescreening)  
x PiZZ genotyping 
x Viral serology (documented results within 3 months) 
x Pulmonary X-ray (initial Screening pulmonary X-ray within 3 months of 
rescreening) 
x FibroScan (initial Screening FibroScan within 30 days of the start of rescreening) 
x MRE (initial Screening MRE within 30 days of the start of rescreening) (Cohort 1 & 
2 only) 
x Spirometry (initial Screening Spirometry within 30 days of the start of rescreening) 
x DLCO (initial Screening DLCO within 30 days of the start of rescreening) 
x Serum biomarkers (initial Screening serum biomarkers collected within 30 days of 
rescreening) 
Any assessment not listed above must be performed again as part of the rescreening procedures.  
6. 
STUDY INTERVENTION 
Study intervention is defined as the investigational intervention, or placebo, intended to be 
administered to a study participant according to the study protocol. 
6.1. 
Study Intervention Administered 
Belcesiran is supplied as a solution of the drug substance (belcesiran sodium) in water for 
injection. The molecular mass of the sodium salt and free acid of the drug substance is 
22286.2 Da and 21033.3 Da, respectively. The manufactured drug substance can be isolated only 
as a salt. As such, nonclinical and early clinical doses were expressed in terms of the sodium salt 
form of the drug substance. However, the United States Pharmacopeia 2013 “Salt Policy” 
specifies that when the active ingredient in a drug product is a salt, the strength should be 
expressed in terms of the active moiety rather than salt strength equivalent. For belcesiran, the 
sodium salt provides an additional 5.6% mass to the free acid. As such, the table below provides 
drug product concentrations and doses expressed in both the sodium salt and equivalent free acid 
(“active moiety”) weights.  
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Arm Name 
Active  
Placebo 
Intervention name 
belcesiran  
0.9% saline for injection 
Intervention type 
Drug 
Drug 
Dose formulation 
solution for injection 
solution for injection 
 
Sodium salt 
Free acid 
 
Drug product concentration 
185 mg/mL 
175 mg/mL 
n/a 
Route of administration 
SC injection  
(thigh or abdomen) 
SC injection  
(thigh or abdomen) 
IMP or NIMP 
IMP 
n/a 
Sourcing 
Provided centrally by the Sponsor or 
designee 
Provided locally by the trial 
site 
Packaging and labeling 
Belcesiran will be provided in vials. 
Each vial will be labeled as required per 
country. 
n/a 
Abbreviations: IMP: investigational medicinal product; n/a: not applicable; NIMP: non-investigational 
medicinal product; SC: subcutaneous. 
6.1.1. 
Dose Level 
Participants will receive belcesiran (or matching placebo) at a fixed dose of 210 mg in Cohorts 1 
and 2 or a fixed dose of either 50 mg or 210 mg in Cohort 3. Cohorts 1 and 2 will be dosed 
monthly and Cohort 3 will be dosed monthly for the first 6 months and then quarterly thereafter. 
Participants in Cohort 1 will receive up to 13 doses, participants in Cohort 2 will receive up to 17 
doses, and participants in Cohort 3 will receive 13 doses.  
6.2. 
Preparation/Handling/Storage/Accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit and storage at the site for all study intervention received, and any 
discrepancies are reported and approved by the Sponsor before the administration of the study 
intervention. 
Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may prepare or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area per the labeled 
storage conditions with access limited to authorized site staff. 
The authorized site staff are responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
Belcesiran is to be stored at 2°C to 8°C (inclusive). Belcesiran should be allowed to warm to 
room temperature for approximately 1 hour (but no more than 4 hours) before administration. 
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Further guidance and information regarding study interventions are provided in the Pharmacy 
Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
The study is a randomized, placebo-controlled, double-blind study, where the Investigator and 
the study participants are blinded to IMP and placebo. All sites will have unblinded staff 
responsible for preparing IMP. A subset of the Sponsor’s study team will be unblinded. Details 
of unblinding, including the list of unblinded Sponsor team members, will be captured in the 
Study Specific Blinding Plan.  
All participants will be centrally assigned to randomized study intervention using an 
IVRS/IWRS. Before the study is initiated, directions for the IWRS will be provided to each site. 
Investigators will remain blinded to each participant’s assigned study intervention throughout the 
course of the study. In order to maintain this blind, the unblinded site staff will be responsible for 
the preparation and dispensation of all study intervention and will endeavor to ensure that there 
are no differences in the time taken to dispense the study intervention following randomization. 
Additionally, the unblinded site staff will affix a translucent label over the syringe(s) to mask the 
contents. 
The unblinded study monitor and any auditors present in the event of a Quality Assurance or a 
competent authority audit will be allowed access to unblinded study intervention records at the 
site(s) to verify that randomization/dispensing has been done accurately and per protocol and the 
Pharmacy Manual. 
In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a participant’s treatment assignment is warranted. Participant safety must always 
be the first consideration in making such a determination. If a participant’s treatment assignment 
is unblinded, the Medical Monitor must be notified within 24 hours after breaking the blind. The 
date and reason that the blind was broken must be recorded in the source documentation. 
Potentially unblinding study results, such as the serum AAT protein concentrations, will not be 
shared with blinded study participants and site personnel during the treatment period.  
6.4. 
Study Intervention Compliance 
Study intervention will be administered at the investigational site or home (after the first dose) if 
the participant is unable to come to the study site. The planned dose, actual administered dose, 
and injection date and time will be recorded in the source documentation.  
6.5. 
Concomitant Therapy 
Any medication or vaccine (including OTC or prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving within 30 days prior to Screening or receives 
during the study treatment period must be recorded along with: 
o Reason for use 
o Dates of administration including start and end dates 
o Dosage information including dose and frequency 
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The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1. 
Augmentation Therapy 
Study participants who are receiving augmentation therapy prior to study entry should continue 
their augmentation therapy on a regular basis for the duration of the study.  
For study participants who are not receiving augmentation therapy prior to study entry, 
augmentation therapy is available in case of a clinically significant worsening in lung function at 
the discretion of the investigator during the entire trial. Only doctors with augmentation therapy 
experience should make the decision to initiate the treatment. The date, time, and dosage 
regimen of intravenous purified AAT administration must be recorded. 
6.5.2. 
Vaccinations 
Where possible, to allow discernment of AEs related to the administration of a vaccine from 
those related to administration of study intervention, vaccines should not be administered in the 
7 days prior to or following scheduled administration of study intervention.  
6.6. 
Dose Modification 
No dose modifications for individual participants will be allowed.  
6.7. 
Intervention after the End of the Study 
 Upon completion of the study, Investigators will discuss care options with participants.  
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7. 
STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
Treatment of a participant may be discontinued at any time during the trial at the discretion of 
the investigator for safety, behavioral, compliance or administrative reasons. Efforts must be 
made to have participants, who discontinue trial product, continue in the trial to evaluate safety 
and serum AAT protein concentrations. Participants must be educated about the continued 
scientific importance of their data, even if they discontinue trial product. Data to be collected at 
the time of intervention discontinuation and follow-up and for any further evaluations that need 
to be completed are outlined in the SoA (Section 1.3). Only participants who withdraw consent 
will be considered as withdrawn from the trial. 
7.1.1. 
Stopping Rules for Individual Participants 
Discontinuation of treatment can be decided by either the Investigator or the participant. 
Participants who discontinue trial product should continue with the scheduled visits and 
assessments. If the participant does not wish to attend the scheduled clinic visits, efforts should 
be made to have visits converted to phone contacts. However, all efforts should be made to have 
the participant attend the visits at week 24, 48 and 96, as applicable.  
The trial product must be discontinued, if any of the following applies for the participant: 
1. Decline in Pulmonary Function (see Section 7.1.1.1) 
2. Abnormal liver blood parameters indicating DILI (see Section 7.1.1.2) 
3. Pregnancy/ Intention of becoming pregnant 
4. Simultaneous use of an approved or non-approved investigational medicinal product in 
another clinical trial 
5. Safety concerns as judged by the Investigator 
Participants meeting any of the above treatment discontinuation criteria are allowed to resume 
trial product, if the criterion is no longer met. 
For Germany: please also see country-specific requirements in Section 10.5. 
7.1.1.1. 
Decline in Pulmonary Function 
For participants not on augmentation therapy, the occurrence of the events detailed as A and B 
below will result in temporary discontinuation of study intervention in the affected participant. 
These events will necessitate review and adjudication by the DSMC. If, in the opinion of the 
DSMC, the decline in pulmonary function (as defined by events A or B, below) is likely related 
to something other than the study drug, e.g., a common cold, dosing in that participant may 
continue, otherwise, dosing of the participant can be permanently discontinued at the discretion 
of the Investigator.  
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A. FEV1: At least 2 pulmonary function tests showing relative decrease from baseline of 
≥ 15% AND an absolute decrease from baseline of > 200 mL in FEV1 following 
administration of bronchodilators over a period of at least 3 months.  
B. DLCO: At least 2 pulmonary function tests showing a relative decrease from baseline 
of ≥ 15% in Hb-corrected DLCO AND an absolute decrease from baseline of 
> 6.5 mL/min/mmHg in Hb-corrected DLCO, following administration of 
bronchodilators over a period of at least 3 months.  
7.1.1.2. 
Drug-Induced Liver Injury Monitoring 
For Participants with Normal Liver Biochemistries at Baseline 
Study intervention will be discontinued when a participant meets one of the conditions outlined 
below (from Guidance for Industry-Drug Induced Liver Injury: Premarketing Clinical Evaluation 
[FDA, 2009]) or if the Investigator believes that it is in the best interest of the participant. Safety 
laboratories will be monitored by a central laboratory in real time with potential drug-induced 
liver injury (DILI) alerts sent to the Investigator.  
o ALT or AST > 8 × ULN 
o ALT or AST > 5 × ULN for more than 2 weeks 
o ALT or AST > 3 × ULN and (total bilirubin >2 × ULN or INR >1.5) 
o ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
Participants should be monitored at each study visit and instructed to call the Investigator for 
new or worsening symptoms of clinical hepatitis. Both symptoms and calls should be 
documented in source notes. 
NOTE: Any elevation in an LFT leading to discontinuation of study intervention must be at least 
possibly related to the investigational drug, and other potential causes (e.g., strenuous exercise, 
use of concomitant medication) must have been excluded. 
Alternative DILI Monitoring Algorithm for Participants with Elevated Transaminases at 
Baseline 
The following alternative DILI monitoring algorithm should be used in participants with elevated 
transaminases above ULN at baseline.  
o Close Monitoring: If participants develop elevations of AST or ALT > 2 times the 
screening value or total bilirubin > 1.5 times the screening value while on the study, 
testing should be repeated within 48 to 72 hours. Persistent elevations should be 
followed by repeat testing and physical examinations 2 to 3 times per week with or 
without drug discontinuation. 
o Study Intervention Discontinuation: Study intervention will be discontinued if a 
participant meets one of the following abnormal liver function conditions:  
 ALT or AST > 5 × the screening value in participants with a screening value 
< 2 × ULN 
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 ALT or AST > 3 × the screening value in participants with a screening value 
≥ 2 × ULN but < 5 × ULN 
 ALT or AST increase > 2 × the screening value accompanied by a concomitant 
total bilirubin increase to > 2 × the screening value OR an INR increase of > 0.2 
 Elevations of liver enzymes accompanied by symptoms consistent with hepatic 
injury (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia [> 5%]) 
Assessments in Case of Increased Levels of Liver Blood Parameters 
For all such events listed above repeated testing must occur within 48 to 72 hours and work up 
for competing etiologies must be performed including: 
x Complete liver profile including ALT, AST, alkaline phosphatase, conjugated 
bilirubin, total bilirubin and INR. Hereafter repeat testing should be done 2 to 3 times 
weekly. If close monitoring is not possible the trial product should be discontinued. 
The frequency of repeat testing can decrease to once a week or less if abnormalities 
stabilize and the participant is asymptomatic. 
x A detailed history of symptoms and prior or concurrent diseases. 
x History of concomitant drug use (including non-prescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets. 
x Ruling out acute viral hepatitis (including hepatitis A, B, C and E); autoimmune or 
alcoholic hepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease. 
x Obtaining a history of exposure to environmental chemical agents. 
Trial product can be restarted if an alternative etiology is definitively identified, and liver blood 
parameters have returned to pre-event levels. 
7.1.2. 
Study Stopping Rules 
All further enrollment and dosing in the study will be stopped if any of the stopping rules defined 
in the DSMC charter are met and the DSMC recommends stopping the study. 
The Sponsor will promptly notify all sites if stopping rules are triggered.  
NOTE: In the event that a study stopping rule is triggered, all ongoing participants will continue 
to be followed for safety assessments as indicated in the SoA (Section 1.3). 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons (i.e., ET). This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early termination visit should be 
conducted, as shown in the SoA (Section 1.3). Data to be collected at the time of study 
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discontinuation, during follow-up, and for any further evaluations that need to be completed, 
provided the participant did not withdraw consent, are outlined in the SoA. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request the destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
CRF.  
Participants who sign the ICF, are randomized and subsequently withdraw or are withdrawn or 
discontinued from the study, may be replaced to meet the minimum requirements of sample size 
described in the study design (Section 4.1). 
7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she fails to return for 3 consecutive 
visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
o The site will attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
o Before a participant is deemed lost to follow-up, the Investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls, and if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record or study file.  
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of study procedures is summarized in the SoAs (Section 1.3). Protocol waivers or 
exemptions are not allowed. 
Immediate safety concerns should be discussed with the Medical Monitor upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoAs (Section 1.3), 
is essential and required for study conduct. 
Informed consent must be obtained before any trial related activity (Section 10.1.3) 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
The maximum amount of blood drawn from each participant at any visit (including PK, PD, and 
safety laboratory testing) will not exceed: 
o 132 mL  
The total amount of blood collected (including PK, PD, and safety laboratory testing) will not 
exceed: 
o 480 mL in 28 days or 
o 550 mL in 8 weeks 
8.1. 
Efficacy Assessments 
x The following sections describe the assessments and procedures while their timing is 
specified in the SoAs (Section 1.3).  
x Phone visits may be replaced by a site visit at the discretion of the Investigator. 
x Repeat samples may be taken for technical issues and additional samples or assessments 
may be taken for safety reasons. Please refer to Appendix 2, Section 10.2 for further 
details on laboratory samples. 
x Laboratory tests may be analyzed on either an on-going basis, at end-of-treatment or at 
end-of-trial, depending on the test. 
8.1.1. 
Serum Z-AAT Protein Concentration 
Venous blood samples of approximately 16 mL will be collected for the measurement of serum 
Z-AAT protein concentrations at time points specified in the SoA (Section 1.3). Instructions for 
the collection and handling of samples will be provided in the Lab Manual. 
8.1.2. 
 Assessment of Fibrosis and Hepatic Z-AAT Content via Percutaneous Liver 
Biopsy 
Percutaneous non-targeted liver biopsies will be performed to assess eligibility to the study and 
quantify the change in hepatic Z-AAT protein content and histology.  
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Liver biopsy will be performed according to the study-specific Liver Biopsy Manual. The first 
biopsy will be performed at Screening once all other eligibility criteria are met, and the 
participant is qualified for enrollment. The second liver biopsy will be at either 24 weeks (Cohort 
1 and 3) or 48 weeks (Cohort 2) after administration of the first dose of the study intervention. 
Finally, there will be an optional liver biopsy at week 96.  
The participant’s vital signs will be monitored during the biopsy procedure per local standard of 
care. As post-biopsy care, the participant will be observed per local standards of care for any 
signs or symptoms of bleeding, hematoma, and pain.  
Liver tissue will be processed on-site, in accordance with the study-specific Liver Biopsy 
Manual (e.g., snap frozen or formalin-fixed) and sent to a central laboratory for pathology. A 
clinical report will be generated and sent to the Principal Investigator. In addition, the histology 
assessment might be supplemented by digital pathology evaluation. 
8.1.2.1. 
Liver Histology: Ishak Fibrosis Staging 
The Ishak staging system for liver fibrosis is a 1995 update to the algorithm initially developed 
by De Groote et al. (Ishak et al., 1995; De Groote et al., 1968). Ishak scores range from 0 (no 
fibrosis) to 6 (cirrhosis) as summarized in Table 55. 
Table 55: 
Ishak Fibrosis Staging 
Stage 
Description 
0 
No fibrosis  
1 
Fibrous expansion of some portal areas, with or without short fibrous septa  
2 
Fibrous expansion of most portal areas, with or without short fibrous septa  
3 
Fibrous expansion of most portal areas with occasional portal-to-portal bridging  
4 
Fibrous expansion of portal areas with marked bridging (portal to portal as well as portal 
to central)  
5 
Marked bridging (portal–portal and/or portal–central) with occasional nodules 
(incomplete cirrhosis)  
6 
Cirrhosis, probable or definite  
8.1.2.2. 
Liver Histology: METAVIR Scoring System 
In 1996, The METAVIR Cooperative Study Group developed an algorithm to generate a single 
score of necroinflammatory liver activity based on basic histological features (Bedossa & 
Poynard, 1996). The resultant score is composed of a 2-letter and 2-number coding system that 
describes activity (A) and fibrosis (F), as displayed in Table 66. 
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Table 66 
METAVIR Scoring System 
Fibrosis score:  
Activity score: 
F0 = no fibrosis 
A0 = no activity 
F0 – F1 
A0 – A1 
F1 = portal fibrosis without septa 
A1 = mild activity 
F1 – F2 
A1 – A2 
F2 = portal fibrosis with few septa  
A2 = moderate activity 
F3 = numerous septa without cirrhosis 
A2 – A3 
F3 – F4 
A3 = severe activity 
F4 = cirrhosis 
 
8.1.2.3. 
Liver Histology: Additional Parameters 
In relation to the liver histology evaluation, additional histology parameters, such as presence of 
liver globules, are assessed. Further details can be found in the Liver Biopsy Manual.  
8.1.2.4. 
Hepatic Z-AAT Content 
Measurements of Z-AAT in liver tissues will be performed. Instructions for the collection and 
handling of samples will be provided in the Lab Manual. 
8.1.3. 
Noninvasive Measures of Liver Fibrosis 
Noninvasive measures of liver fibrosis will be measured at time points specified in the SoA 
(Section 1.3). The blood biomarkers to be assessed are detailed in Sections 8.1.3.1 
through 8.1.3.5. Full details regarding the collection, preparation, and handling of samples will 
be provided in the laboratory manual. Note that the list of blood biomarkers detailed is not 
comprehensive, and biomarkers may be added or deleted as deemed appropriate.  
8.1.3.1. 
Biochemical Fibrosis Index 
The FibroSure fibrosis index was first developed as a non-invasive alternative to liver biopsy for 
staging of fibrosis in patients with chronic hepatitis C (Imbert-Bismut et al., 2001). Multiple 
studies have since demonstrated that the diagnostic value of the index is comparable to that of 
liver biopsy in assessing fibrosis across a range of liver diseases (Ratziu et al., 2006; 
Zeremski et al., 2014; Lurie et al., 2015). The fibrosis index utilizes 10 biochemical markers (α-2 
macroglobulin, haptoglobin, GGT, ALT, AST, total bilirubin, apolipoprotein A1, total 
cholesterol, triglycerides, and serum glucose) plus age and gender to provide fibrosis staging. 
8.1.3.2. 
Aspartate Aminotransferase to Platelet Ratio Index  
The APRI is calculated using the AST level (corrected for the ULN) and platelet count: 
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A meta-analysis of 40 studies found that an APRI cutoff of ≥ 0.7 had an estimated sensitivity of 
77% and specificity of 72% for detection of significant hepatic fibrosis (≥ F2 by METAVIR; 
Lin et al., 2011). 
8.1.3.3. 
FIB-4 
The FIB-4 is an index based on age, AST, ALT, and platelet count: 
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In patients with HCV infection, a FIB-4 index < 1.45 was shown to have a negative predictive 
value of 94.7% to exclude severe fibrosis with a sensitivity of 74.3%. A FIB-4 index > 3.25 had 
a positive predictive value to confirm the existence of significant fibrosis (F3-F4) of 82.1% with 
a specificity of 98.2%. The FIB-4 was found to correlate strongly (P < 0.001) with FibroTest 
results (Vallet-Pichard et al., 2007). 
8.1.3.4. 
Enhanced Liver Fibrosis Score 
The ELF score is an extracellular matrix marker set consisting of tissue inhibitor of 
metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP), and 
hyaluronic acid (HA). Lichtinghagen et al. identified three cut-off values for the ELF Score in 
predicting fibrosis: 7.7 for a high sensitivity exclusion of fibrosis, 9.8 for a high specificity 
identification of fibrosis (sensitivity 69%, specificity 98% for moderate fibrosis), and 11.3 to 
discriminate cirrhosis (sensitivity 83%, specificity 97%), but noted that age and gender must be 
taken into account (Lichtinghagen et al., 2013). 
8.1.3.5. 
Other Markers of Fibrosis or Liver Inflammation 
Other blood biomarkers to be measured may include:  
o Pro-C3, tenascin, CK-18, M30, and M65 
8.1.4. 
Assessment of Liver Stiffness 
Assessment of liver stiffness via MRE (only Cohorts 1 and 2) and/or FibroScan will be measured 
at time points specified in the SoAs (Section 1.3).  
8.1.4.1. 
FibroScan 
Liver stiffness measurement (LSM) is evaluated by measuring the velocity of a vibration wave 
generated on the skin by the FibroScan (Echosens, Paris, France) device at sites where the 
equipment is available. The LSE is the median of the successful stiffness measurements and has 
a range of 2.5 kPa (lowest stiffness) to 75 kPa (highest stiffness). At sites where FibroScan® 
equipment with Controlled Attenuation Parameter (CAP) option is available, measurements of 
liver steatosis must also be performed. 
The liver stiffness and CAP measurements must be performed in a fasting state (fasting for at 
least 3 hours) and according to site standard procedures.  
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8.1.4.2. 
Magnetic Resonance Elastography (Cohorts 1 and 2 only) 
MRE is a non-invasive technique that uses propagating mechanical shear waves ranging from 20 
to 200 Hz, to determine liver stiffness. The MRE hardware typically consists of an active 
acoustic driver coupled with a disc-shaped non-metallic passive driver that is placed against the 
right anterior chest wall overlying the liver. Usually, a continuous acoustic vibration of 60 Hz is 
transmitted into the abdomen via the passive driver. Shear waves propagate more rapidly through 
stiffer liver tissue (longer wavelength) indication of liver fibrosis than the softer healthy liver 
tissue (shorter wavelength). The imaging process is accomplished in one or more breath-holds, 
and the images are processed with MRE specialized software to generate quantitative cross-
sectional elastograms depicting the liver stiffness (Venkatesh et al., 2013). 
The technique is useful for differentiating patients with clinically important hepatic fibrosis 
(F1 to F4) from those without (Yin et al., 2007; Kim et al., 2016).  
Central overread of MRE will be performed to ensure consistency of findings across sites. Full 
details regarding the conduct and central overread of the MRE will be provided in a separate 
manual. 
All participants in Cohorts 1 and 2 should have the MRE assessment completed unless access to 
the equipment and technology is not available. The MRE hardware and software must be locally 
approved for diagnostic medical imaging. If the site does not have MRE hardware and software 
that is locally approved for diagnostic medical imaging, MRE assessments will be optional. 
8.1.5. 
Omics Analyses 
In order for further characterize and quantify the effect of belcesiran on biological molecules, 
such as proteins (proteomics) or RNA molecules (transcriptomics), omics analyses may be 
performed using validated methods such as the Somalogic Platform. 
8.1.6. 
St. George’s Respiratory Questionnaire  
The SGRQ is designed to measure health impairment in patients with asthma and COPD and is 
comprehensive, covering a range of aspects of COPD (Cazzola et al, 2008). This instrument has 
3 domains: symptoms; activity; and impacts. A total score is also calculated. It was designed for 
supervised self-administration. 
This assessment will be conducted as indicated in the SoA (Section 1.3). 
8.1.7. 
Chronic Liver Disease Questionnaire 
The Chronic Liver Disease Questionnaire (CLDQ) was developed as an evaluative instrument to 
measure longitudinal change in health status within individuals with chronic liver disease 
(Chawla et al, 2016). In addition to measuring both physical and mental health, the instrument 
was designed to be a disease-specific tool for assessing areas of function important to patients 
with chronic liver disease. 
This assessment will be conducted as indicated in the SoA (Section 1.3). 
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8.1.8. 
Covid-19 Testing  
No routine COVID-19 testing is planned during the trial. COVID-19 testing may be performed at 
any time during the study as required by local requirements or deemed necessary by the 
investigator or by Sponsor. Laboratory results will not be transferred to the study database, but 
COVID-19 infection should be registered as concomitant illness or AEs. 
8.2. 
Safety and Other Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). Unless 
otherwise specified, a ± 10-minute window around each time point is allowed if multiple 
assessments are due at the same time. In such cases, the order of priority should be ECG, vital 
signs, PK, and then other assessments, with the PK sampling preferably at the nominal time 
point. Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
Investigators are able to schedule visits if needed and to convert phone visits to site visits if 
needed.  
8.2.1. 
Screening Assessments 
A chest x-ray must be performed during Screening to establish a baseline for comparison. If the 
participant had been imaged in a stable condition within the prior 4 weeks, that x-ray may be 
used if the images are available. 
In addition to diagnostic testing performed throughout the treatment period (and F/U, as 
applicable), the following laboratory testing will be performed during the Screening Period: 
o HbA1c 
o Viral serology: HBsAg, HCV antibodies, or HIV1 and 2 antibodies. If a participant 
has been tested in the past 3 months, medical record documentation of this testing can 
be used for screening. 
o Urine drug screen (to include at a minimum: amphetamines, barbiturates, cocaine, 
opiates, and benzodiazepines) 
o Amount of cotinine in urine to assess smoking status at Screening. 
Additionally, as indicated: 
o Follicle stimulating hormone (FSH), to confirm postmenopausal status 
o Suspected primary biliary cholangitis should be ruled out via antimitochondrial 
antibody testing 
o Suspected autoimmune hepatitis should be ruled out through the appropriate 
screening tests, which may include total IgG or gamma-globulin levels and/or 
serologic markers (antinuclear antibodies, anti-smooth-muscle antibodies at a titer of 
at least 1:40, anti-liver/kidney microsomal-1 antibodies, anti-liver cytosol antibody 
[anti-LC 1], or anti-soluble liver/liver pancreas [anti-SLA/LP] antibodies). 
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8.2.2. 
Physical Examinations 
A complete physical examination will be required at visits as indicated in the SoA (Section 1.3) 
and will include, at a minimum, assessments of the eyes, ears, nose, throat, thyroid/neck, lymph 
nodes, as well as cardiovascular, respiratory, gastrointestinal, musculoskeletal, dermatological, 
and neurological systems. Height (in cm, only at Screening), weight (in kg), and body mass 
index will also be measured and recorded. Height and weight should be measured without shoes. 
In lieu of a complete physical examination, a focused physical examination will be performed at 
other visits indicated in the SoA (Section 1.3). It will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen). 
Investigators should note any pre-existing clinical signs related to previous illnesses. 
For at-home visits (whenever applicable), the home-health nurse will provide in-person support 
to the Investigator in assessing the participant. 
Study intervention injection sites should be inspected at each visit. 
8.2.3. 
Vital Sign Measurements 
Temperature (per local standard of care), pulse rate, respiratory rate, and blood pressure will be 
assessed. 
Blood pressure and pulse measurements will be assessed in the sitting position with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones).  
Temperature will be obtained in degrees Celsius. The pulse rate should be counted for a full 
minute and recorded in beats per minute. Respirations should be counted for a full minute and 
recorded in breaths per minute.  
8.2.4. 
Electrocardiograms 
Standard 12-lead ECGs will be performed after the participant has rested comfortably for 5 
minutes. Where feasible, ECGs will be obtained using a machine that automatically calculates 
the heart rate and ventricular rate and measures RR, PR, QRS, QT, and corrected QT interval 
(QTcF, Fridericia correction). The Investigator or their qualified designee is responsible for 
reviewing the ECG(s) to assess whether the results are within normal limits and to determine the 
clinical significance of the results.  
8.2.5. 
Pulmonary Function Tests 
8.2.5.1. 
Spirometry 
Definitions: 
o FVC is the maximal volume of air exhaled with maximally forced effort from a 
maximal inspiration, i.e., VC performed with a maximally forced expiratory effort, 
expressed in liters. 
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o FEV1 is the maximal volume of air exhaled in the first second of a forced expiration 
from a position of full inspiration, expressed in liters. 
Procedure: 
o Spirometry will be performed per the ATS/ERS standards (Miller et al., 2005). A 
nose clip should be used for spirometry testing. Spirometry will be performed 
postadministration of bronchodilators. At screening, spirometry will also be 
performed pre-bronchodilator administration. 
There are 3 distinct phases to the FVC maneuver: 
o maximal inspiration  
o a blast of exhalation; and  
o continued complete exhalation to the end of the test  
The participant should inhale rapidly and completely. The breathing tube should be inserted into 
the participant’s mouth (if this has not already been done), making sure the lips are sealed around 
the mouthpiece and that the tongue does not occlude it. Then the FVC maneuver should begin 
immediately.  
It is important that the participant takes a complete inhalation before beginning the maneuver. 
The participant should be prompted to “blast,” not just “blow,” the air from their lungs, and then 
be encouraged to exhale fully. 
An adequate test requires at least 3 acceptable FVC maneuvers. If acceptability criteria are not 
met in 3 attempts, additional trials should be attempted, up to not more than 8 total attempts.  
Full details regarding the conduct of and the criteria for acceptability of spirometry testing will 
be provided in a separate manual. 
8.2.5.2. 
Diffusion Capacity of the Lungs for Carbon Monoxide 
Definition: 
o DLCO is a measure of the quantity of CO transferred per minute from alveolar gas to 
red blood cells (specifically hemoglobin) in pulmonary capillaries. DLCO is 
expressed as mL/min/mmHg, that is, the milliliters of CO transferred per minute for 
each millimeter of mercury in pressure difference across the total available 
functioning lung gas exchange surface. 
Procedure: 
o DLCO will be performed per the ATS/ERS standards (Graham et al., 2017). The 
same calibrated equipment must be utilized throughout the study. 
o DLCO will be performed prior to spirometry testing. 
o Participants should be seated throughout the procedure and should be allowed several 
minutes of quiet breathing prior to testing to become accustomed to the mouthpiece 
and nose clip. A minimum of 2 acceptable maneuvers should be completed, with 
values within 2.00 mL/min/mmHg (0.67 mmol/min/kPa) of each other. Participants 
should be given a 4-minute window between maneuvers to allow for adequate 
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elimination of the test gas from the lungs. Not more than 5 maneuvers should be 
attempted. 
Full details regarding the conduct of and the criteria for acceptability of DLCO will be provided 
in a separate manual. 
8.2.6. 
Other Pulmonary Information 
As indicated in the SoA (Section 1.3), at each timepoint for which PFTs are performed, the 
following information should be collected and noted in the eCRF: 
x Number and severity of pulmonary exacerbations (characterized by dyspnea and/or 
cough and sputum that worsen over ≤14 days) since the last visit; 
o Mild exacerbation: Worsening of symptoms that can be self-managed and resolved 
without systemic corticosteroids or antibiotics. 
o Moderate exacerbation: Increase in symptoms that requires treatment with 
antibiotics and/or corticosteroids 
o Severe exacerbation: Need for hospitalization 
x Smoking status, including number of cigarettes (or equivalent) per day 
x Use of AAT replacement therapy (yes/no) since the last visit 
x Modified Medical Research Council dyspnea score (adapted from Fletcher et al., 
1959) 
o Grade 0: The patient only gets breathless with strenuous exercise 
o Grade 1: The patient gets short of breath when hurrying on level ground or walking 
up a slight hill 
o Grade 2: On level ground, the patient walks slower than people of the same age 
because of breathlessness, or have to stop for breath when walking at their own 
pace 
o Grade 3: The patient stops for breath after walking about 100 yards or after a few 
minutes on level ground  
o Grade 4: The patient is too breathless to leave the house or is breathlessness when 
dressing 
x Resting peripheral oxygen saturation 
8.2.7. 
Clinical Safety Laboratory Assessments 
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA (Section 1.3) 
for the timing and frequency. Participants should be fasting for a minimum of 8 hours prior to the 
collection of blood samples as indicated in the SoA. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.  
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All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or Medical Monitor. 
o If such values do not return to normal/baseline within a time judged reasonable by the 
Investigator, the etiology should be identified, and the Sponsor notified. 
o If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE) they must be 
recorded in the eCRF. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs are located in Section 10.3. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain accountable for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7.1). 
8.3.1. 
Time Period and Frequency for Event Assessment 
All AEs/SAEs will be collected from the signing of the ICF until the last day of study 
participation, including F/U. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline medical history and not reported as an AE. However, if the study 
participant’s condition deteriorates after having received the first dose of Investigational Product 
during the study, it will be recorded as a TEAE.  
Investigators are not obligated to actively seek AE or SAE after the conclusion of the study 
participation. However, if the Investigator learns of any SAE, including death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must notify the Sponsor 
promptly. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
AE or SAEs will be reported by the participant or observed by the study staff. Care will be taken 
not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal 
questioning of the participant is the preferred method to inquire about AE occurrences, for 
example, “Have you noticed anything different since you started the study?”. The occurrence of 
an AE or SAE may also be detected upon review by a study monitor. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious AESI; as defined in 
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Section 10.3.3) will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). Further information on 
follow-up procedures is given in Section 10.3. 
8.3.4. 
Serious Adverse Event Reporting 
All SAEs will be recorded and reported to the Sponsor or designee immediately; under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3.5. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of the 
study intervention under clinical investigation are met.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators. 
Investigator safety reports will be prepared for SUSAR according to local regulatory 
requirements and Sponsor or Sponsor’s designee’s policy and will be forwarded to Investigators 
as necessary. 
8.3.5. 
Reporting of Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until 24 weeks after the last dose.  
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4.4.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
The participant or pregnant partner will be followed to determine the outcome of the pregnancy. 
The Investigator will collect follow-up information on the participant or pregnant partner and the 
neonate, and the information will be forwarded to the Sponsor. 
Any post-study pregnancy-related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. 
8.3.6. 
Adverse Events of Special Interest  
AEs of special interest (AESI; as defined in Section 10.3.3), will be followed until resolution or 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3). 
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8.4. 
Treatment of Overdose 
For this study, any dose of study intervention greater than the protocol-specified dose will be 
considered an overdose. 
In the event of an overdose, the Investigator should: 
1. Immediately contact the Medical Monitor. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities for at 
least 14 days. 
3. Obtain a plasma sample for PK analysis within 14 days from the date of the last dose 
of study intervention if requested by the Medical Monitor (determined on a case-by-
case basis). 
4. Document the quantity of the total dose as well as the number of injections over time. 
Decisions regarding dose interruptions will be made by the Investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
Pharmacokinetics 
Blood samples of approximately 2.0 mL will be collected for the measurement of plasma 
concentrations of belcesiran, as specified in the SoA (Section 1.3).  
Instructions for the collection and handling of biological samples will be provided by in the 
laboratory manual. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Samples collected for analyses of belcesiran concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study. 
Pharmacokinetic parameters to be determined include apparent clearance (CL/F) and apparent 
volume of distribution (Vz/F), AUC, Cmax, Tmax, and t1/2, as data permit to determine the PK 
profile of belcesiran. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel. 
8.5.1. 
Metabolite Identification 
Plasma metabolite identification studies may be performed by nuclear magnetic resonance, mass 
spectrometry, liquid chromatography-mass spectrometry, gas chromatography-mass 
spectrometry, Fourier transform mass spectrometry, and/or equivalent methods. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters, other than serum Z-AAT protein concentrations (as described in 
Section 8.1.1), are not evaluated in this study. 
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8.7. 
Genetics 
Genetics are not evaluated in this study. Genotyping will be performed locally at screening if 
historical data are not available for determination of study eligibility for the participants. 
8.8. 
Immunogenicity Assessments 
Antibodies to belcesiran will be evaluated in serum samples collected from all participants, 
according to the SoA (Section 1.3). Additionally, serum samples should also be collected at the 
final visit from participants who discontinued study intervention or were withdrawn from the 
study. These samples will be tested by the Sponsor or Sponsor's designee. 
Samples for the detection and characterization of antibodies to belcesiran will be stored until a 
validated assay method is available. 
8.9. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics will not be evaluated in this study. 
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9. 
STATISTICAL METHODS 
In general, summary statistics (n, mean, standard deviation, median, minimum and maximum 
values for continuous variables, and number and percentage of participants in each category for 
categorical variables) will be provided by treatment group and cohort for all variables.  
Baseline value is defined as the last non-missing assessment prior to the first dose of study drug, 
except for serum AAT where baseline is defined as the mean from all predose AAT 
measurements. 
Source data for the summary tables will be presented as by-subject data listings. 
All statistical tests will be 1-sided with a type I error rate of 5%, unless otherwise specified. 
Complete details of the statistical analysis will be outlined in the SAP and finalized before the 
interim analysis database lock.  
9.1. 
Randomization and Sample Size 
The study will include 3 cohorts. In Cohorts 1 and 2 there will be up to 8 participants in each 
cohort (randomization scheme ratio of 3:1 active:placebo). The sample size for Cohort 1 and 
Cohort 2 is based on clinical consideration rather than statistical power calculation. 
The primary endpoint for Cohort 3 of this study is the percentage change from baseline in serum 
and liver Z-AAT protein concentration at week 24. Assuming the percentage change from 
baseline is 80%, 60% and 10% in the active high dose group, active low dose group and placebo 
group respectively, and the standard deviation is 0.5 for all three groups, a sample size of 
10 participants per treatment group will provide at least 80% power to detect a statistically 
significant difference between active high dose group and placebo, and between active low dose 
group and placebo, at an overall 1-sided significance level of 0.05. 
The F1, F2, F3, and F4 fibrosis types will be used as randomization stratification factors for all 
3 cohorts. 
  
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9.2. 
Study Populations 
For purposes of analysis, the following populations are defined: 
x Enrolled: All participants who sign the informed consent 
x Safety: All participants randomly assigned to study intervention and who received at 
least 1 dose of belcesiran/placebo. Participants will be analyzed according to initial dose 
received. 
x Pharmacokinetic: All participants randomly assigned to study intervention and who 
received at least 1 dose of belcesiran and have at least 1 postdose PK assessment 
x Pharmacodynamic: All participants randomly assigned to study intervention and who 
received at least 1 dose of belcesiran/placebo and have at least 1 postdose PD assessment 
x Evaluable: All participants randomly assigned to study intervention and who received at 
least 50% of planned doses of belcesiran/placebo 
Additional subpopulations may be included for sensitivity analysis. These will be detailed in the 
SAP. 
9.3. 
Statistical Analyses 
9.3.1. 
Analyses of Primary Endpoints 
9.3.1.1. 
Safety Analysis 
All safety analyses will be performed on the Safety Population. Adverse events will be defined 
as TEAEs if they have a start date on or after the administration of study drug during the 
treatment period, or if they occur prior to the administration of study drug and worsen in 
severity/grade or relationship to the study intervention after the administration of study 
intervention during the treatment period. Frequency and percentages will be used to summarize 
TEAEs, SAEs, and AEs of special interest by relationship. Laboratory values will be reported by 
grade and summarized, if applicable. 
Change from baseline and observed values will be summarized where applicable. Laboratory 
analytes will be presented by a shift from baseline and graphically represented in mean values 
over time where applicable. Vital signs, ECG, and PFTs (i.e., FEV1, FVC, FEV1/FVC, and 
DLCO) will be summarized as continuous parameters. 
9.3.1.2. 
Analysis of Serum and Liver Z-AAT Concentrations  
The primary endpoint for Cohort 3 of this study is the percentage change from baseline in serum 
and liver Z-AAT protein concentration at week 24.  
The primary endpoint for Cohort 3 will be analyzed by using a linear log-normal regression 
model. Statistical testing for the primary endpoint of Cohort 3 will be carried out using the 
Hocheberg testing procedure for the following comparisons: (active high dose vs. placebo) and 
(active low dose vs. placebo). The linear log-normal regression model will include treatment, 
baseline value (log transformed) and randomization stratification factor of fibrosis types (F1, F2, 
F3, and F4) as covariates. 
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9.3.2. 
Analyses of Secondary Endpoints  
9.3.2.1. 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be performed on all participants who received at least 1 dose of 
belcesiran and have sufficient data for at least one evaluable postdose PK assessment. Actual 
sampling times will be used for all parameter estimations.  
Plasma concentrations and PK parameters will be listed and summarized by group and by time 
point with descriptive statistics. The arithmetic mean, SD, CV%, geometric mean, geometric 
CV%, minimum, median, and maximum will be presented.  
Additional PK parameters may be estimated if deemed appropriate. Details will be provided in 
the PK Analysis Plan. Analysis of PK parameters may be reported in a supplement to the CSR. 
9.3.2.2. 
Analyses of Fibrosis, Steatosis, and Inflammation 
Changes from Baseline in liver histology including METAVIR and Ishak scores will be analyzed 
by descriptive statistical methods. METAVIR and Ishak scores will summarized and, if 
applicable, analyzed using modeling techniques, which will be described in the SAP.  
9.3.3. 
Exploratory Analyses 
Exploratory analyses will be conducted as deemed appropriate and will be detailed in the SAP.  
Descriptive summaries will be provided for the following exploratory endpoints: FibroScan® 
score, ELF score, and CK-8. Values, changes, and percent change for each parameter will be 
analyzed, when applicable.  
Further supporting analyses such as correlation analyses between biomarkers and/or liver 
histology parameters might be performed to better understand the effect of belcesiran, if 
applicable.  
9.4. 
Interim Analyses  
There are 3 interim analyses (IAs) planned for this study. The first interim analysis (IA1) will be 
conducted when all participants in Cohort 1 have completed 24 weeks of treatment. The second 
interim analysis (IA2) will be performed when all participants in Cohort 2 have completed 
48 weeks of treatment. The third interim analysis (IA3) will be performed when all the participants 
in Cohort 3 have completed 24 weeks of treatment. As part of the IAs, all study site personnel will 
remain blinded, but the Sponsor will be unblinded. Details of unblinding including the list of 
unblinded Sponsor team members, will be described in the Study Specific Unblinding Plan. 
Additional interim analyses may be performed as needed. 
The unblinded IA results will be reviewed and assessed by the DSMC while the participant, 
Investigator, and Outcome assessor will remain blinded. In addition, a small group of Sponsor 
personnel will be unblinded to participant level data as well to prepare and support regulatory 
interactions. Personnel who are unblinded to a critical fraction of the participant level data will 
subsequently not be allowed to participate in any aspects of the continued trial conduct. 
Based on IA3 results, DSMC will make recommendation whether one dose is more favorable with 
respect to effect while showing no overall difference in safety. The Sponsor will make the final 
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decision whether to stop the least favorable dose-arm based on DSMC’s recommendation and IA 
results. 
Details of the analysis will be included in the SAP, which will be approved prior to the IAs. 
9.4.1. 
Data Safety Monitoring Committee 
Table 77 shows the minimal required timing of reviews by the DSMC. Ongoing risk-benefit 
assessments will be conducted throughout the trial by the independent DSMC. In addition, 
DSMC will provide a comprehensive review of study safety, tolerability, and PK/PD data, along 
with a summary of cohort reviews across all cohorts and provide decisions. Further operational 
details will be prespecified in the DSMC charter. 
Table 77: 
Minimum Timing of the Data Safety Monitoring Committee Data Reviews 
Review of data from 
Study DCR-A1AT-101 
The DSMC reviewed all available safety data from the first 3 cohorts of Study 
DCR-A1AT-101 and affirmed that it is safe to advance the dose level selected by 
M&S into a multiple dose regimen. 
Review of sentinel pair 
dosing 
The DSMC must review the available safety data collected on a sentinel pair of 
participants, through at least 3 weeks postdose before the remaining participants 
can be randomized and dosed. The data to be reviewed will be specified in the 
DSMC charter. 
Review of first 
10 participants 
randomized and dosed 
The DSMC will review the available safety data collected on the first 
10 participants to receive study intervention, through Day 29. The data to be 
reviewed will be specified in the DSMC charter. 
After completion of 
Cohort 1 (IA1) 
The DSMC will review the safety and efficacy data collected through the EOT 
(Week 24) visit for all participants in Cohort 1. 
Occurrence of a 
potential stopping rule 
The DSMC will review and adjudicate all AEs that constitute potential stopping 
rules, in addition to the cumulative safety data collected on all participants 
previously dosed. The DSMC will determine whether dosing and enrollment may 
resume as detailed in Section 7.1. 
After completion of 
Cohort 2 (IA2) 
The DSMC will review the safety and efficacy data collected through the EOT 
(Week 48) visit for all participants in Cohort 2. 
Interim Analysis 3 (IA3)  The DSMC will review the safety and efficacy data collected through the Week 24 
visit for all participants in Cohort 3. 
Additional IA if 
performed 
The DSMC will review the safety and efficacy data collected through additional IA 
if performed. 
 
Abbreviations: AE: adverse event; DSMC: Data Safety Monitoring Committee; EOT: end of treatment; IA: interim 
analysis; M&S: modeling and simulation. 
 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) 
must be submitted to an IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC 
before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit a complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the study and for 1 year after 
completion of the study. 
10.1.3. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the participant 
and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, and the IRB/IEC or study center.  
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The source document must include a statement that written informed consent was obtained 
before the participant was enrolled in the study, and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the participant.  
A participant who is rescreened is required to sign another ICF. 
10.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or Sponsor’s designee will contain the identifier only; 
participant names or any information which would make the participant identifiable will not be 
transferred.  
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committee Structure 
The external DSMC will be comprised of an independent hepatologist and an independent 
pulmonologist, both of whom have experience in caring for patients with AATD, and a 
biostatistician who is also not involved in the study. The DSMC will provide a comprehensive 
review of study safety and tolerability data, along with a summary of cohort reviews and 
decisions. Further operational details will be prespecified in the DSMC charter. 
The internal Novo Nordisk safety committee will perform ongoing safety surveillance. If new 
safety signals are identified, these will be evaluated by an internal safety committee. The safety 
committee may recommend unblinding of any data for further analysis, and in this case an 
internal trial independent ad hoc group will be established in order to maintain the blinding of the 
trial personnel. 
10.1.6. 
Dissemination of Clinical Study Data 
After de-identification, individual data collected during the trial may be shared with investigators 
whose proposed use of the data has been approved by the sponsor. 
All trial results will be posted to www.clinicaltrials.gov and www.clinicaltrialsregister.eu within 
1 year of study completion. 
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10.1.7. 
Data Quality Assurance 
All participant data relating to the study will be recorded on electronic CRF unless transmitted to 
the Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the CRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide access to source data documents.  
Monitoring details describing methods, responsibilities, and requirements, including handling of 
non-compliance issues and monitoring techniques (central, remote, or on-site monitoring) are 
provided in the Monitoring Plan. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
The Sponsor or designee is responsible for the data management of this study, including the 
quality checking of the data.  
The Sponsor assumes accountability for actions delegated to other individuals (i.e., Contract 
Research Organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for at least 15 years after study completion unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor.  
10.1.8. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data entered in the eCRF must be consistent with the source documents, or the discrepancies 
must be explained. The Investigator may need to request previous medical records or transfer 
records. Current medical records must be available. 
10.1.9. 
Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Please see Section 7.1 for study stopping 
rules relating to participant safety. Study sites will be closed upon study completion. A study site 
is considered closed when all required documents and study supplies have been collected, and a 
study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause, 
and sufficient notice is given in advance of the intended termination. 
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Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
1. Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
2. Inadequate recruitment of participants by the Investigator 
3. Discontinuation of further study intervention development 
10.1.10. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments.  
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support the publication of 
multi-center studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with the International Committee 
of Medical Journal Editors' authorship requirements. 
10.2. 
Clinical Laboratory Tests 
The tests detailed in Table 88 will be performed by the central laboratory, with the exception of 
pregnancy testing and cotinine testing which will be performed locally. Laboratory testing 
required for immediate safety concerns may also be performed locally at the discretion of the 
Investigator. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests that are required for clinical management of the participant may be performed at 
any time during the study as determined necessary by the Investigator or required by local 
regulations. 
Investigators must document their review of each laboratory report. 
Table 88: 
Protocol-Required Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Red blood cell count 
hemoglobin 
hematocrit 
platelet count 
reticulocytes 
mean corpuscular volume (MCV) 
mean corpuscular hemoglobin (MCH) 
mean corpuscular hemoglobin concentration (MCHC) 
White blood cell count: 
lymphocytes, abs and % 
monocytes, abs and % 
eosinophils, abs and % 
basophils, abs and % 
neutrophils, abs and % 
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Laboratory 
Assessments 
Parameters 
Clinical Chemistry 
alanine aminotransferase (ALT) 
aspartate aminotransferase (AST) 
glutamate dehydrogenase (GLDH) 
gamma glutamyl transferase (GGT) 
alkaline phosphatase (ALP) 
bilirubin; total and direct 
lactate dehydrogenase (LDH) 
total cholesterol 
triglycerides 
total protein 
albumin 
creatine kinase (CK) 
sodium 
chloride 
potassium 
creatinine 
urea (BUN) 
glucose 
Routine Urinalysis 
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
Urine protein-to-creatinine ratio (UPCR) 
Urine albumin-to-creatinine ratio (UACR) 
Microscopic examination (if blood or protein is abnormal) 
Other safety tests 
x 
Total complement hemolytic activity (CH50): C3a, C5a, and Bb 
x 
Serum alpha fetoprotein (AFP) 
x 
Coagulation parameters: aPTT, PT, INR 
x 
Antidrug antibodies 
x 
C-reactive protein 
x 
Urine pregnancy test 
Pregnancy testing 
Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as needed) (see 
Schedule of Activities in Section 1.3  
Other Screening 
Tests 
x 
FSH (as needed in postmenopausal women only) 
x 
Urine drug screen (to include, at a minimum: amphetamines, barbiturates, cocaine, 
opiates, and benzodiazepines) 
x 
Serology (HIV antibody, HBsAg, and HCV antibody) 
x 
Antimitochondrial antibodies (if suspected for PBC) 
x 
HbA1c 
x 
Urine cotinine 
Other Tests 
x 
α-2 macroglobulin, haptoglobin, and apolipoprotein A1 (components of non-invasive 
fibrosis index) 
x 
Biomarkers of liver fibrosis (ELF, Pro-C3, tenascin) 
x 
Biomarkers of inflammation and liver apoptosis (CK-18, M30, and M65) 
x 
Samples for future analyses 
x 
Serum AAT (total and Z-AAT) 
x 
Liver Z-AAT, PAS-positive AAT globules 
x 
Liver histology, including fibrosis 
Abbreviations: aPTT: activated partial thromboplastin time; EGF: epidermal growth factor; FSH: follicle-stimulating hormone; 
HbA1c: hemoglobin A1c; HBsAg: hepatitis surface antigen; HCV: hepatitis C virus; HIV: human immunodeficiency virus; 
IFN: interferon; IL: interleukin; INR: international normalized ratio; PBC: primary biliary cholangitis; PT: prothrombin time; 
SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TNF-α: tumor necrosis factor-alpha. 
 
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10.2.1. 
Samples for Future Analysis 
The trial will involve collection of samples to be stored in a central archive for future use. 
Participants who do not wish to contribute samples for storage may still participate in the trial. 
Participants must consent before samples are collected to be stored for future analysis.  
The material to be collected is blood (whole blood, plasma and serum) and liver tissue. Blood 
samples will be collected as indicated in the SoA (Section 1.3).  
Liver tissue will be collected from the liver biopsy at week 24, 48 and 96 as applicable.  
Samples will be used to improve knowledge and understanding of the biology of the trial disease 
and related diseases, such as mechanism of action or treatment effect. The biosamples may be 
transferred to other countries and third parties including commercial vendors such as diagnostics 
developers for analysis. In case the participant withdraws his/her informed consent for 
biosamples for future analysis, the monitor must contact the Sponsor trial manager as soon as 
possible in order to have the samples withdrawn from storage. If the collected biosamples 
(serum, plasma, liver biopsy samples) will be used in the future, the participant and investigator 
will not become directly informed by Sponsor about the results. 
 
10.3. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow up, and Reporting 
10.3.1. 
Definition of AE 
AE/TEAE Definition 
An AE/TEAE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related to the 
study intervention. Therefore, an AE/TEAE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
Events Meeting the AE/TEAE Definition  
o Any abnormal laboratory test results or other safety assessments (e.g., ECG, 
radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of 
the Investigator (i.e., not related to the progression of underlying disease). 
o Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
o New conditions detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study. 
o Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
o Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or concomitant medication. Overdose per se will not be reported as an 
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AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.  
10.3.2. 
Definition of SAE 
If an event is not an AE per the definition above, it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of the disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death had it been more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
4. Results in persistent disability/incapacity 
The term “disability” means a substantial disruption of a person’s ability to conduct normal 
life functions. 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle) that may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, 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. 
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10.3.3. 
Definition of Adverse Event of Special Interest 
An AESI is a noteworthy event for the particular product or class of products that a Sponsor may 
wish to monitor carefully (CIOMS, 2005). 
Events Meeting the AESI Definition: 
Injection site reaction (ISR): 
An ISR is a disorder characterized by an intense adverse reaction (usually immunologic) 
developing at the site of injection. Potential ISRs will be graded as indicated in Table 99. 
Individual signs or symptoms at the injection site (e.g., erythema, swelling, etc.) with an onset of 
less than 4 hours from the time of study intervention administration will be recorded as AEs (not 
as ISRs). 
Signs or symptoms at the injection site with an onset time of greater than 4 hours postdose will 
be evaluated according to the CTCAE v. 5.0 criteria for ISR, detailed below. If any of the 
CTCAE criteria for ISR are met, the event will be recorded as an ISR and graded in accordance 
with Table 99. If the criteria are not met, individual signs or symptoms will be recorded as AEs 
and graded in accordance with the intensity categories detailed Section 10.3.4. 
Table 99: 
Grading of Injection Site Reactions, CTCAE v 5.0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Tenderness with 
or without 
associated 
symptoms (e.g., 
warmth, 
erythema, itching) 
Pain; 
lipodystrophy; 
edema; phlebitis 
Ulceration or 
necrosis; severe 
tissue damage; 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
10.3.4. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
The Investigator or designee will then record all relevant AE/SAE information in the CRF. 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records 
in lieu of completion of the AE/SAE eCRF page. 
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor. In this case, all participant identifiers, with the exception of the participant number, will 
be redacted on the copies of the medical records before submission. 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. The Investigator will attempt to establish a 
diagnosis of the event based on signs, symptoms, and/or other clinical information. Whenever 
possible, the diagnosis (not the individual signs/symptoms) will be documented as the AE/SAE. 
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Assessment of Intensity 
The intensity of AEs and SAEs will be graded in accordance with CTCAE v. 5.0 grading scale. 
Assessment of Causality 
The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. A “reasonable possibility” of a relationship conveys that there are 
facts, evidence, and/or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out.  
The Investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration, will be considered and 
investigated. The Investigator will also consult the Investigator’s Brochure and/or Product 
Information for marketed products in his/her assessment. 
For each AE/SAE, the site personnel must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report. However, it is very important that the Investigator 
always make an assessment of causality for every event before the initial transmission of 
the SAE data to the SAE Coordinator. The Investigator may change his/her opinion of 
causality in light of follow-up information and send a SAE follow-up report with the updated 
causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The following definitions will be used in assessing causality: 
o Not Related: Event for which sufficient evidence exists to conclude that the etiology 
is unrelated to study intervention. 
o Possibly Related: There is some temporal relationship between the event and the 
administration of the study intervention, and the event is unlikely to be explained by 
the participant’s medical condition or other therapies.  
o Probably Related: The temporal relationship between the event and administration 
of the study intervention is suggestive, and the event is unlikely explained by the 
participants’ medical condition or other therapies.  
o Definitely Related: The event follows reasonable temporal sequence from the 
administration of the study intervention, follows a known or suspected response 
pattern to the study intervention, is confirmed by improvement upon stopping the 
study intervention, and reappears upon repeated exposure if that occurs.  
Follow-up of AEs and SAEs 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
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additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide the Sponsor with a copy of any post-mortem findings, including 
histopathology. 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of 
the information. 
10.3.5. 
Reporting of SAEs 
Facsimile or electronic transmission of the SAE Report Form is the preferred method to transmit 
SAE information to the SAE coordinator; however, the SAE Report Form may also be 
transmitted via email. Appropriate measures such as encryption or leaving out certain identifiers 
will be enforced to protect the identity of participants as required by local, regional, and national 
requirements. In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight mail or 
courier service. 
Initial notification via telephone does not replace the need for the Investigator to complete and 
sign the SAE Report Form within the designated reporting time frames. 
Contacts for SAE reporting can be found on Page 3 of this document. 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). If fertility is unclear (e.g., amenorrhea in athletes) and a 
menstrual cycle cannot be confirmed before the first dose of study intervention, additional 
evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal with one of the following: 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (e.g., müllerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
NOTE: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
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3. Postmenopausal 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
o Female participants on HRT and whose menopausal status is in doubt will be required 
to use one of the non-estrogen hormonal highly effective contraception methods if 
they wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception Guidance 
Female participants 
Women of childbearing potential must agree to use a highly effective method of contraception 
consistently and correctly as described in Table 1010 during the protocol-defined time frames, as 
outlined in Section 5.1. 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during the protocol-defined time frames, as outlined in 
Section 5.1. 
o Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
o Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 1010 when having penile-vaginal 
intercourse with a WOCBP who is not currently pregnant. 
o In addition, male participants must refrain from donating sperm for the duration of the 
study and for 12 weeks after the last dose of the study intervention. 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the protocol-defined time frame. 
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Table 1010: Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly.  
x 
Combined (estrogen- and progesterone-containing) hormonal contraception associated with 
inhibition of ovulation 
x 
Oral  
x 
Intravaginal  
x 
Transdermal  
x 
Injectable 
x 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
x 
Oral  
x 
Injectable  
x 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
Highly Effective Methods That Are User Independent a1 
x 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
x 
Intrauterine device (IUD) 
x 
Intrauterine hormone-releasing system (IUS) 
x 
Bilateral tubal occlusion 
x 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method, provided that the partner is the 
sole male sexual partner of the WOCBP, and the absence of sperm has been confirmed. If not, an 
additional, highly effective method of contraception should be used.  
 Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
10.4.3. 
Pregnancy Testing 
Pregnancy testing will be conducted approximately every 4 weeks during the study, including 
F/U.  
Pregnancy tests must be performed monthly, at the timepoints specified in the Schedule of 
Activities (Section 1.3). Home pregnancy tests will be issued to WOCBP for months when no 
clinic visit is scheduled. Participants will be instructed to contact the clinic staff in case of a 
positive test. 
In addition, a pregnancy test must be performed whenever a menstruation is late or missed, or 
when pregnancy is otherwise suspected. Home pregnancy tests will be provided to participants 
and can be resupplied as needed throughout the trial. 
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10.4.4. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant  
o The Investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. 
o After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
o The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy.  
o The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate, and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
o While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy-related SAE considered reasonably related to the 
study intervention by the Investigator will be reported to the Sponsor as described in 
Section 10.3.2. While the Investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
o Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
 
 
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10.5. 
Country-specific Requirements 
For Germany only: 
In addition to the stopping rules detailed in Section 7.1, the following rule will also apply to sites 
in Germany: 
o 7.1.1.3 Electrocardiogram Findings (Applicable to Germany only) 
If QT interval changes as listed below or other clinically significant findings are identified after 
enrollment, the Investigator or qualified designee will determine if the participant can continue in 
the study and if any change in participant management is needed.  
x Absolute QTc or QTcF > 500 msec and/or  
x QTc or QTcF change of > 60 msec from baseline 
This review of the ECG printed at the time of collection must be documented. Any new, 
clinically relevant finding should be reported as an AE. 
o 7.1.1.4 CTCAE Grade 4 Adverse Events (Applicable to Germany only) 
This study will use NCI CTCAE v. 5.0 to grade AEs, with modifications given for the medical 
characteristics of the population under investigation. 
Study intervention for an individual participant will be permanently discontinued for the 
occurrence of any Grade 4 AE, regardless of attribution to study intervention, provided that the 
participant had no signs/symptoms or the signs/symptoms of a Grade 1 or Grade 2 event at 
baseline. 
 
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10.6. 
Abbreviations 
Abbreviation 
Description 
AAT 
alpha-1 antitrypsin 
AATD 
AAT deficiency 
AATLD 
Alpha-1 Antitrypsin Deficiency-Associated Liver Disease 
AE 
adverse event 
AESI 
AE of special interest 
AFP 
alpha fetoprotein 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
APRI 
aspartate aminotransferase to platelet ratio index 
Anti-LC 
anti-liver cytosol antibody 
Anti-SLA/LP 
anti-soluble liver/liver pancreas 
ASGPR 
asialoglycoprotein receptor 
ARDS 
acute respiratory distress syndrome 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under the curve 
AUClast 
area under the concentration time curve at the time of last observation 
BMI 
body mass index 
BP 
blood pressure 
BSA 
body surface area 
°C 
degrees Celsius 
C-F/U 
CK-18 
Conditional Follow-up 
cytokeratin 18 
CIOMS 
Council for International Organizations of Medical Sciences 
CLDQ 
Chronic Liver Disease Questionnaire 
CL/F 
apparent clearance 
Cmax 
maximum observed concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
corona virus disease 2019 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
coefficient of variation (percent) 
DCR-S1459 
drug substance for this IMP, also known as belcesiran sodium 
DCR-A1AT 
drug product for this IMP, also known as belcesiran 
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Abbreviation 
Description 
DDI 
drug-drug interaction 
DILI 
drug induced liver injury 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
DLT 
dose-limiting toxicity 
DRF 
dose-range-finding 
DSMC 
Data Safety Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EFD 
embryo-fetal development (study) 
e.g. 
for example (exempli gratia) 
EGF 
epidermal growth factor 
EGFR 
epidermal growth factor receptor 
eGFR 
ELF 
estimated glomerular filtration rate 
enhanced liver fibrosis 
EOS 
End of Study 
EOT 
End of Treatment 
ERS 
European Respiratory Society 
ET 
early termination 
FDA 
Food and Drug Administration 
FEED 
fertility and early embryonic development (study) 
FEFv 
flow rates 
FEV1 
forced expiratory volume in one second 
FSH 
follicle stimulating hormone 
F/U 
follow-up 
FVC 
forced vital capacity 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
HA 
Hydrochloric acid 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
hr 
hour(s) 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (formerly International Conference on Harmonisation) 
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Abbreviation 
Description 
i.e. 
that is (id est) 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IFN-α 
interferon alpha 
IFN-γ 
interferon gamma 
IgG 
immunoglobulin G 
IL-6 
interleukin 6 
IL-10 
interleukin 10 
IL-12 
interleukin 12 
IMP 
Investigational Medicinal Product  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IVRS/IWRS 
interactive voice/web response system 
kg 
kilogram(s) 
kPa 
kilopascal(s) 
LFT 
liver function test 
LSE 
liver stiffness evaluation 
mg 
milligram(s) 
min 
minute(s) 
mL 
milliliter(s) 
MRE 
magnetic resonance elastography 
mRNA 
messenger ribonucleic acid 
M&S 
modeling and simulation 
NAAT 
nucleic acid amplification test 
NOAEL 
no observed adverse effect level 
NSAID(s) 
nonsteroidal anti-inflammatory drug(s) 
OTC 
over the counter 
PD 
pharmacodynamic(s) 
PFT 
pulmonary function test(s) 
PHT 
portal hypertension 
PI 
prediction interval 
PIIINP 
amino-terminal propeptide of type III procollagen 
PiZZ 
autosomal homozygous mutant AAT Z-allele genotype 
PK 
pharmacokinetic(s) 
Pro-C3  
N-terminal type III collagen propeptide 
PSA 
procedural sedation and anesthesia 
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Abbreviation 
Description 
PT 
prothrombin time 
q4w 
every 4 weeks 
QTcF 
QT interval (Fridericia correction) 
RNA 
ribonucleic acid 
RNAi 
RNA interference 
RT-PCR 
reverse transcription polymerase chain reaction 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SD 
standard deviation 
SERPINA1 
the gene that encodes the AAT protein 
SGRQ 
St. Georges Respiratory Questionnaire 
siRNA 
small interfering RNA 
SNP 
single nucleotide polymorphism 
SoA 
Schedule of Activities 
SOC 
system organ class 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TIMP-1 
tissue inhibitor of metalloproteinases 1 
TIPS 
transjugular intra hepatic portosystemic shunt 
TK 
toxicokinetic(s) 
Tmax 
time to maximum observed concentration 
TNF-α 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
VC 
vital capacity 
Vz/F 
apparent volume of distribution 
WFI 
water for injection 
WOCBP 
woman(en) of childbearing potential 
Z-AAT 
the mutant AAT protein 
 
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10.7. 
Investigator Signature Page 
A Phase 2, Randomized, Double-blind, Placebo--controlled Study Investigating Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of Two Dose Levels of Belcesiran 
in Patients with Alpha-1 Antitrypsin -Associated Liver Disease 
 
 
Protocol Number: DCR-A1AT-201 
Version: 4.0  
Date: 02-May-2023 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with Good Clinical Practice (GCP) guidelines, the Declaration of 
Helsinki, and local regulations (as applicable). 
 
 
Signature: 
 
Date: 
Name: 
 
Title: 
Institution: 
 
Site Number: 
 
 
 
 
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10.8. 
Protocol Amendment History 
The Protocol Amendment Summary of Changes table for the current amendment is located 
directly before the Table of Contents.  
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Description of Change 
Brief Rationale 
Affected Sections 
Study design was updated to include a third cohort, 
which utilizes a new dose of 50 mg. 
The two belcesiran doses included in the clinical protocol (210 mg 
and 50 mg) are predicted to result in a range of PD response that 
would allow for adequate characterization of belcesiran dose-
exposure-response in patients with AATLD. 
Section 1.1 
Section 1.2 
Section 1.3 
Section 2.1 
Section 2.2.5 
Section 3 
Section 4.1 
Section 4.3 
Section 6.1 
Section 9.1 
Section 9.3 
Section 9.4 
An optional extended treatment period of quarterly 
dosing is added for Cohorts 1 and 2. 
The rationale for exploring an alternative dosing regime is out of 
consideration for patient burden. For the high dose explored, 
simulations suggest that reducing dose frequency after steady state 
would only have a minor effect on the PD response. 
Section 1.2 
Section 1.3 
Section 4.1 
Section 7.1.1 
The follow-up period is no longer conditional. Each 
cohort will have a fixed follow-up period. 
This update ensures that blinded personnel remain blinded to 
subject treatment assignments throughout the follow-up period.  
Section 1.1 
Section 1.2 
Section 1.3 
Section 4.1 
Section 4.2 
Section 4.4 
Section 6.3 
Section 8.1  
The number of subjects to be enrolled decreased to 46 
subjects. 
Updates based on the revised study design. 
Section 1.1 
Section 4.1 
Section 9.1 
DocuSign Envelope ID: 

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Description of Change 
Brief Rationale 
Affected Sections 
Baseline serum AAT will now be the predose value at 
D1 instead of the mean of the values from screening 
and D1 
To simplify the serum AAT baseline calculation algorithm. 
Section 8.1.1 
Section 9.1 
The maximum age for inclusion in the study is 
changed from 70 years to 75 years 
To include subjects aged 70 through 75.  
Section 1.1 
Section 5.1 
Participants with liver fibrosis score of F1 on the 
METAVIR scoring system now included  
To facilitate recruitment and to explore the effects of belcesiran in 
this patient population 
Section 1.1 
Section 4.1 
Section 5.1 
Section 8.1 
Section 9.3.1 
Inclusion criteria for serum AAT protein 
concentration > 10 mg/dL during screening is 
removed. 
Since PiZZ confirmed AATLD patients are expected to have a 
protein concentration > 10mg/dL, the criterion was removed to 
decrease patient burden and facilitate recruitment. 
Section 1.1 
Section 5.1 
Post-bronchodilator inclusion criteria updated to 
include participants with FEV1 >45% of predicted at 
screening instead of the previous FEV1 >60% 
The inclusion of patients on augmentation therapy requires 
bronchodilator inclusion criteria to be lowered.  
Section 1.1 
Section 5.1 
Participants on augmentation therapy are now allowed 
to enroll 
To include subjects that are prescribed augmentation therapy to 
facilitate recruitment and assess the effects of belcesiran in this 
patient population 
Section 1.1 
Section 2.3.1.2 
Section 2.3.3 
Section 5.1 
Section 5.2 
Section 6.5.1 
Section 7.1.1 
Removed augmentation therapy as a treatment related 
to exacerbations of pre-existing emphysema. 
Investigators who start a participant on augmentation 
therapy must have experience with the therapy. 
Updated to provide further detail and clarification. 
Section 2.3.4 
Section 6.5.1  
Section 7.1.1.1 
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Smoking inclusion criteria updated, and cotinine 
testing a  e  at Investigator’s  iscretion 
To ensure adequate confirmation that patient is not smoking. 
Section 1.1 
Section 1.3 
Section 5.1 
Section 8.2.1 
Section 10.2 
WOCBP are now allowed to enroll 
• 
Pregnancy testing is added to all Cohorts  
• 
At home pregnancy testing allowed for 
months where participants do not come to 
site  
• 
Contraception wording updated 
To include WOCBP. Inclusion of WOCBP will require more 
pregnancy testing. We are allowing for home pregnancy tests in 
between site visits to ensure that monthly pregnancy testing takes 
place. 
Section 1.1 
Section 1.3 
Section 4.2 
Section 5.1 
Section 8.3.5 
Section 10.2 
Section 10.4 
Exclusion criteria was clarified to further define 
history of chronic liver disease and history of a severe 
exacerbation 
Updated for clarity.  
Section 1.1 
Section 5.2 
Risks related to potential off-target effects was 
updated.  
 
Updated based on additional data. 
Section 2.3.1.3 
Exclusion criteria around alcohol consumption and 
drug abuse were clarified  
Updated for clarity.  
Section 5.2 
Section 5.3 
Section 7.1 
Section 8.5 
Cytokines and some complement tests are removed. 
Cytokines and complements were reviewed by an independent 
rheumatologist for the DCR-PHXC program. This review revealed 
no interpretable signal. In addition, there have been no AEs 
suggestive of system immune activation across the Dicerna 
program. 
Section 1.3 
Section 2.2.5 
Section 9.3.1 
Section 10.2 
History of rapid decline in pulmonary function as 
assessed by Investigator was added as an exclusion. 
Exclusion was added to allow for investigator discretion when 
determining eligibility.  
Section 1.1 
Section 5.2 
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Added exclusions for specific heart related conditions 
and malignancy within the last 90 days 
Exclusion was a  e  to ensure the patient’s health is stable when 
determining eligibility.  
Section 5.2 
Removed the restrictions around 
acetaminophen/paracetamol, steroid, and NSAID use 
Exclusion was removed to allow for investigator discretion when 
determining eligibility.  
Section 5.2 
Section 6.5 
Exclusion criteria around HbA1c, triglycerides, white 
blood cells, and neutrophils lab tests and blood 
pressure were removed  
Exclusion was removed to allow for investigator discretion when 
determining eligibility.  
Section 5.2 
Physical examination assessments further defined and 
allowed to be focused at many visits. Height and 
weight were also separated into their own assessment 
in the schedule of assessments.  
For clarity and to decrease site/patient burden 
Section 1.3 
Section 8.2.2 
CLDQ and SGRQ added  
Added to collect quality of life data on enrolled subjects.  
Section 1.3 
Section 5.2 
Section 8.1.6 
Section 8.1.7 
Blood biomarker assessments further defined  
For clarity between blood biomarkers of inflammation and fibrosis  
Section 1.3 
Section 8.1.3 
Section 10.2 
Samples for future research assessments further 
defined. 
Revised to include details around collection of future use samples 
for clarity.  
Section 1.3 
Section 4.2 
Section 8.1.5 
Section 10.2 
Additional parameters were added to the liver 
histology evaluation 
Updated for clarity.  
Section 8.1.2.3 
Section 10.2 
Measures of liver fibrosis were clarified  
Updated for clarity.  
Section 8.1 
Section 10.2 
An optional liver biopsy is added at 96 weeks. 
Added based on updated study design.  
Section 1.1 
Section 1.2 
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Section 1.3 
Section 4.1 
Section 4.2 
Section 5.1 
Section 8.1.2 
Section 10.2.1  
Fasting requirements were clarified 
Updated for clarity.  
Section 1.3 
Section 8.1 
Section 8.2.6 
Definition of clinically significant abnormal 
laboratory findings is removed 
Updated for clarity. 
Section 8.2.6 
FibroScan expectations were updated and are only to 
be conducted if sites have access to the technology.  
Up ate  for clarity an  to account for site’s that  o not have access 
to FibroScan equipment. 
Section 1.3 
Section 8.1.4.1 
MRE assessments are only to be conducted if sites 
have access to the technology. 
To harmonize country specific amendments and to account for 
site’s that  o not have access to MRE equipment or technology. 
Section 1.3 
Section 8.1.4.2 
Some visits can be conducted via phone rather than 
in-clinic. 
Updated to lessen patient burden.  
Section 1.3 
Section 8.1 
Section 8.2  
The primary endpoint was updated from change from 
baseline in serum AAT protein concentration over 
time to changes from baseline to Week 24 (Cohort 1) 
and Week 48 (Cohort 2) in serum AAT protein 
concentrations.  
Updated to define the time over which the primary endpoint would 
be analyzed. 
Section 1.1 
Section 3 
Section 9.1 
A primary objective/endpoint is added (for cohort 3 
only) to characterize the PD of belcesiran in patients 
with AATLD as measured by change from baseline to 
Week 24 in serum and liver Z-AAT protein levels. 
Added based on updated study design.  
Section 1.1 
Section 3 
Section 9.1 
Secondary and exploratory endpoints are amended to 
include the change from baseline up to Week 96 and 
include clarity around assessments being done. 
Added based on updated study design.  
Section 1.1 
Section 3 
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Section 9.1 
The exploratory endpoint of change from baseline in 
blood-based biomarkers of inflammation is removed. 
Removed based on updated study design.  
Section 1.1 
Section 3 
Section 9.1 
Injection Site Inspection added to all Treatment 
Period SOAs 
To clarify that this is expected after every dosing  
Section 1.3 
Statistical analyses are changed to accommodate 
changes to the study design and endpoints. 
To reflect the changes of study design and ensure sample size for 
Cohort 3 is powered and primary analysis model is pre-specified. 
Section 4.1 
Section 9 
Added F1 fibrosis type to the randomization 
stratification factor. 
To include patients with F1 fibrosis type in this study. 
Section 9.1 
COVID testing is removed as a requirement. 
COVID testing was updated to be performed as necessary.  
Section 1.3 
Section 6.5.2 
Section 8.1.8 
Section 10.2 
Screening windows are updated. 
To decrease site and patient burden when scheduling screening 
assessments.  
Section 1.3 
Nonclinical background updated 
• 
Includes updates to off-target effects 
To reflect changes to the Investigator Brochure v5.0 made with 
more recent information  
Section 2.2.3 
Section 2.3 
Clinical background updated  
• 
Includes updates to AAT knockdown  
To reflect changes to the Investigator Brochure v5.0 made with 
more recent data from the DCR-A1AT-101 study 
Section 2.2.4 
Section 2.3.1.1 
Section 2.3.1.2 
Section 4.3 
Language regarding risks related to knockdown was 
revised 
To include more recent data from the DCR-A1AT-101 study 
Section 2.3.1.2 
AE/SAE risks updated  
To include more recent data from the DCR-A1AT-101 study 
Section 2.3.3 
Section 2.3.1.1 
Clinical data from DCR-A1AT-101 study was 
updated 
To include more recent data from the DCR-A1AT-101 study 
Section 2.2.4 
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Affected Sections 
TEAE defined 
Updated for clarity  
Section 10.3.1 
Reporting of AEs/SAEs was updated 
Updated for clarity 
Section 8.3.1 
Instructions on changes in PK timepoints were 
removed 
Updated for clarity 
Section 8.5 
Rescreening of screen failed patients was clarified  
Updated for clarity.  
Section 5.4 
Home dosing was included as an option if the 
participant is unable to come to the study site 
Updated to lessen patient burden.  
Section 6.4 
Stopping rules were updated  
Updated to provide further detail and clarification. 
Section 7 
Maximum blood volume limits were updated 
To reflect changes in laboratory assessments. 
Section 8 
Editorial changes for clarity. 
Updates made for clarity  
Throughout  
Mention of the long term, open label extension study 
has been removed from the protocol 
Administrative update.  
Section 6.7 
Protocol title updated 
To reflect changes made throughout the protocol 
Title page 
Sponsor Signature Page  
Section 1.1 
Section 10.6 
Study phase updated to 2 from 2a 
To reflect that the data from this study will be used for both safety 
and efficacy parameters 
Title page 
Updated Sponsor and CRO contacts 
Administrative Changes in Sponsor/CRO personnel. 
Sponsor Signature Page 
Medical Monitor and 
Pharmacovigilance Contact 
Information 
 
 
 
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Amendment 1 (version 2.0), 04-Feb-2021 
The 03-Sep-2020 amendment was principally undertaken to include the dosing regimen, to 
specify that C-reactive protein will be measured at the same time as serum AAT, and to clarify 
procedures affected by and/or implemented to address the COVID-19 pandemic.  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
The table below summarizes all changes in Version 2.0 from Version 1.0. 
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Affected Sections 
Updated dosage and other information relating to the 
IMP 
• 
Replace  “DCR-A1AT” with the a opte  
name “belcesiran” 
• 
Specified the dosage of belcesiran to be 
administered in the study (210 mg [1.2 mL 
injection volume] once every 4 weeks).  
 
• 
Clarified that the dosage of belcesiran is 
expressed in terms of the free-acid form of the 
drug substance. 
 
• 
Removed lot number of IMP from table of 
study interventions 
 
 
• 
The INN was recently adopted 
 
• 
The dosage was determined by modeling and 
simulation of PK/PD data from an interim 
analysis of Study DCR-A1AT-101 and was 
affirmed by the SRC and DSMC.  
• 
The US Pharmacopeia states that when the active 
ingredient in a drug product is a salt, the strength 
should be expressed in terms of the active moiety 
rather than salt strength equivalent. 
• 
More than one lot number may be used in the 
study 
1.1 
Synopsis 
1.2 
Schema 
2.2.5 
Summary 
2.3.3 
Risk Assessment 
4.1 
Overall Study Design 
4.3 
Justification for Dose 
6.1 
Study Intervention(s) 
Administered 
6.1.1 
Dose Level 
6.2 
Preparation/Handling/ 
Storage/Accountability 
Belcesiran name change - throughout the 
protocol 
Provided separate Schedules of Activities for Cohort 1 
and Cohort 2 
Ease of interpretation 
1.3 
Schedules of Activities 
Specified that C-reactive protein will be measured at 
the same time as all serum AAT protein concentrations, 
and that any AAT concertation that is accompanied by a 
CRP value above the upper limit of normal will be 
repeated. 
C-reactive protein and A1AT are both acute-phase 
proteins released into the plasma in response to 
inflammatory stimuli. Concomitant assessment of CRP 
and A1AT will allow discern between elevations in 
A1AT due to inflammatory stimuli or to study 
intervention. 
1.3 
Schedules of Activities 
5.4.1 
Repeated Screening Tests 
8.1.1.1 Calculation of Baseline Serum 
A1AT Concentration 
8.1.1.2 Conditional Follow-up 
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Addressed the impact of COVID-19: 
• 
All prospective participants must have a 
negative test for SARS-CoV-2 at the time of 
randomization 
• 
Any participant testing positive for 
SARS-CoV-2 will be discontinued from study 
intervention 
• 
Telehealth and/or home nursing visits may be 
employed if participants are unable to return to 
the site due to COVID-19 restrictions 
• 
Vaccine administration should be separated by 
7 days from administration of study 
intervention 
 
• 
To ensure that randomized participants do not 
have COVID-19 
 
• 
To decrease the risk for decline in pulmonary 
function that could arise from concomitant 
infection with SARS-CoV-2 
• 
To enable participant to continue study 
participant during the pandemic 
 
• 
To enable differentiation of potential AEs due 
to the vaccine from those due to study 
intervention 
1.3 
Schedules of Activities 
4.1 
Overall Study Design 
5.2 
Exclusion Criteria 
6.5.1 
Rescue Medication 
6.5.2 
COVID-19 Vaccine 
7.1.1.2 Positive SARS-CoV-2 Test 
7.2 
Participant 
Discontinuation/Withdrawal 
from Study 
10.2 
Clinical Laboratory Tests 
10.5 
Abbreviations 
Added a statement to note that any participant with a 
serum AAT protein concentration that has not returned 
to ≥ 80% of Baseline by Week 48 of con itional 
follow-up will be followed in a separate study. 
To ensure that long-term follow-up of participants 
occurs within a sponsored study protocol. 
1.1 
Synopsis 
1.3 
Schedules of Activities 
2.2.4 
Clinical Overview 
4.1 
Overall Study Design 
4.4 
End of Study Definition 
8.1.1.2 Conditional Follow-up 
8.3.1 
Time Period and Frequency for 
Event Assessment 
Updated clinical laboratory tests to be performed during 
• 
the conditional follow-up period 
• 
Screening 
 
• 
Increased participant safety 
• 
Removed tests that are now scheduled to be 
assessed on an ongoing basis and corrected 
typographical errors in version 1.0 
1.3 
Schedules of Activities 
8.1.1.2 Conditional Follow-up 
8.2.1 
Screening Assessments 
10.2 
Clinical Laboratory Tests 
Updated description of indirect, noninvasive fibrosis 
blood biomarker panel, and added 3 analytes to be 
collected. 
The trademarked LabCorp FibroSure test will not be 
performed as previously specified. The Sponsor will 
calculate the fibrosis score from the individual 
components of the panel. 
8.1.3.1 Biochemical Fibrosis Index 
10.2 
Clinical Laboratory Tests 
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Affected Sections 
Added section describing the determination of hepatic 
Z-AAT protein content 
Not previously included 
8.1.2.4 Hepatic Z-AAT Content 
Stated that SAEs will be collected until 30 days after 
the last day of study participation or until serum AAT 
protein concentration is ≥ 80% of baseline on 
2 consecutive visits, whichever is longer. 
To ensure that participants are followed for occurrence 
of SAEs for a sufficient period of time. 
1.3 
Schedules of Activities 
8.3.1 
Time Period and Frequency for 
Event Assessment 
Updated DLCO criteria in the individual participant 
stopping rules. The absolute change in DLCO was 
lowere  to ≥ 6.5 m /min/mmHg from 
≥ 8 mL/min/mmHg 
Increased participant safety 
7.1.1.3 Decline in Pulmonary Function 
Clarified that the duration of the conditional follow-up 
period is up to 48 weeks, not 12 months 
Greater accuracy 
1.1 
Synopsis 
1.3 
Schedules of Activities 
2.2.4 
Clinical Overview 
4.1 
Overall Study Design 
4.4 
End of Study Definition 
8.1.1.2 Conditional Follow-up 
Clarified that the intensity of all AEs will be graded in 
accordance with CTCAE v 5.0 
A “mil /mo erate/severe” rating scale is not needed in 
addition to CTCAE grading 
10.3.4. Recording and Follow-Up of AE 
and/or SAE 
Added a statement of statistical power 
Previously not included 
1.1 
Synopsis 
9.1 
Randomization and Sample Size 
Updated language to specify the nature, number, and 
timing of the interim analyses 
To clarify that one interim futility analysis will be 
performed and that additional analyses to support 
composite endpoint determination may be performed. 
9.4 
Interim Analyses 
 
Added steatosis scores as an endpoint 
Previously missing in the tables of Objectives and 
Endpoints  
1.1 
Synopsis 
3 
Objectives and Endpoints 
Removed determination of PK in urine 
No longer needed in Phase 2 
1.1 
Synopsis 
1.3 
Schedules of Activities 
3 
Objectives and Endpoints 
4.1 
Overall Study Design 
8.5 
Pharmacokinetics 
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Affected Sections 
8.5.1 
Metabolite Identification 
9.3.2.1 Pharmacokinetic Analyses 
Specified that blood pressure and ECG readings are to 
be conducted in the sitting rather supine position and 
that only 5 minutes of rest (not 10 minutes) are required 
Consistency with clinical practice 
5.2  
Exclusion Criteria 
8.2.3 
Vital Signs Measurements 
8.2.4 
Electrocardiograms 
Removed clarification that heart rate will be taken from 
the ECG when the ECG and vital signs are recorded at 
the same time and added ventricular rate and RR to the 
list of parameters to be recorded via ECG. 
To better align with electronic data outputs 
1.3 
Schedules of Activities 
8.2.3 
Vital Signs Measurements 
8.2.4 
Electrocardiograms 
Updated interval for rescreening due to exacerbations of 
underlying lung disease from 2 to 3 months 
To ensure that participants have stable lung function at 
the time of enrollment.  
5.2 
Exclusion Criteria 
5.4 
Screen Failures 
Removed Medical Monitor approval of restricted 
concomitant medications 
Ad hoc approval is inconsistent with intent of 
restrictions 
6.5 
Concomitant Medications 
Updated units of measure for DLCO to mL/min/mmHg 
Consistency across protocol 
8.2.5.2 Diffusion Capacity of the Lungs 
for Carbon Monoxide 
Removed language requesting that the Investigator to 
make every effort to contact the medical monitor prior 
to unblinding in case of medical emergency. 
The decision to unblind in an emergency belongs solely 
to the Investigator.  
6.3 
Measures to Minimize Bias: 
Randomization and Blinding 
Deleted Heading 8.8 Biomarkers. Promoted Heading 
8.8.1 Immunogenicity Assessments to 8.8 
Consistency with protocol template 
8.8 
Biomarkers Immunogenicity 
Assessments 
Updated the acronyms for alpha-1 antitrypsin 
deficiency and alpha-1 antitrypsin deficiency-associated 
liver disease 
To conform with new style guide 
Throughout the protocol 
Administrative updates 
Updated personnel, updated Sponsor corporate address, 
updated reference and abbreviation lists, and other 
minor corrections 
Cover Page, Sponsor Signature Page, 
References, Abbreviations, and 
throughout the protocol 
 
 
 
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11. 
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