Clinical trial NCT04820686
Conditions: Chronic Hepatitis B
Keywords: cHBV HBV hepatitis B vebicorvir VBR AB-729
Sponsor: Assembly Biosciences
Start date: 2021-05-07; Completion date: 2023-03-30
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if vebicorvir (VBR, ABI-H0731) in combination with AB-729 is safe and effective in participants with chronic hepatitis B infection (cHBV) receiving a standard of care nucleos(t)ide/reverse transcriptase inhibitor (SOC NrtI).

Detailed description:
The initial cohort of participants will be enrolled in 3 treatment groups receiving 1) VBR + AB-729 + SOC NrtI, 2) VBR + SOC NrtI, or 3) AB-729 + SOC NrtI for up to 48 weeks. At Week 48, all participants will have an assessment of Treatment Stopping Criteria. Any participant who meets the Treatment Stopping Criteria, will discontinue their assigned treatment including NrtI and will remain in follow-up through Week 96. The participants who do not meet the Treatment Stopping Criteria will continue treatment with NrtI alone and will remain in follow-up through Week 96. Up to an additional 2 cohorts may be added to the study in future protocol amendments.

Arms: arm 1: Participants with cHBV received VBR + AB-729 + SOC NrtI for 48 weeks followed by 48 weeks in follow-up. arm 2: Participants with cHBV received VBR + SOC NrtI for 48 weeks followed by 48 weeks in follow-up. This treatment was used as a reference regimen. arm 3: Participants with cHBV received AB-729 + SOC NrtI for 48 weeks followed by 48 weeks in follow-up. This treatment was used as a reference regimen.
Interventions: intervention 1: VBR intervention 2: AB-729 intervention 3: SOC NrtI
Intervention descriptions: intervention 1: VBR is an HBV core protein inhibitor. Participants will receive VBR 300 mg tablets orally once daily (QD). intervention 2: AB-729 is a small interfering ribonucleic acid (siRNA) inhibitor of HBV. Participants will receive a 60-mg subcutaneous injection of AB-729 once every 8 weeks. intervention 3: Participants will receive their SOC NrtI (ETV, TDF or TAF) tablet orally as per approved package insert.

Protocol documents:
Prot_SAP_000.pdf: 
Study Title: A Randomized Phase 2a, Multicenter, Open-Label, Multiple-Cohort Study 
Evaluating Regimens Containing Vebicorvir in Subjects with Chronic Hepatitis B Virus 
Infection 
NCT Number: NCT04820686 
Date of Document: 27 October 2021 


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CLINICAL STUDY PROTOCOL 
PROTOCOL TITLE  
A Randomized Phase 2a, Multicenter, Open-Label, 
Multiple-Cohort Study Evaluating Regimens Containing 
Vebicorvir in Subjects with Chronic Hepatitis B Virus 
Infection  
PROTOCOL NUMBER  
ABI-H0731-204 
DRUG NAME  
Vebicorvir (VBR; formerly ABI-H0731) 
AB-729 
REGULATORY AGENCY 
IDENTIFIER NUMBER(S) 
US IND 136780  
SPONSOR 
Assembly Biosciences, Inc. 
331 Oyster Point Boulevard, 4th Floor 
South San Francisco, California 94080, USA 
(833) 509-4583 
PROTOCOL VERSION – 
DATE 
Amendment 1 – 27 October 2021  
PROTOCOL HISTORY  
Original – 20 November 2020 
CONFIDENTIALITY STATEMENT  
The information contained in this document and all other information relevant to Assembly 
Biosciences are the confidential and proprietary information of Assembly Biosciences and, 
except as may be required by federal, state, or local laws or regulation, may not be disclosed to 
others without prior written permission of Assembly Biosciences. 


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CLINICAL STUDY PROTOCOL SPONSOR APPROVAL FORM  
Protocol Title  
A Randomized Phase 2a, Multicenter, Open-Label, Multiple-Cohort 
Study Evaluating Regimens Containing Vebicorvir in Subjects with 
Chronic Hepatitis B Virus Infection 
Protocol Number  
ABI-H0731-204  
Protocol Version and 
Date  
Amendment 1 – 27 October 2021 
 
This clinical study protocol was subject to critical review and has been approved by the appropriate 
protocol review personnel of the Sponsor. The information contained in this protocol is consistent 
with: 
 The current risk-benefit evaluation of the investigational products. 
 The ethical and scientific standards governing clinical research that are set out in the 
current International Council for Harmonisation (ICH) guideline (E6) on Good Clinical 
Practice (GCP), US Title 21 of the Code of Federal Regulations (CFR) Parts 50, 54, 56, 
and 312, and other applicable local requirements. 
The Principal Investigator will be supplied with details of any significant or new findings, 
including adverse events, relating to treatment with the investigational product. 
Sponsor Signatory: 
 
 
Assembly Biosciences 
Approval Signature and Date 
 
 
 


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INVESTIGATOR STATEMENT 
Protocol Title  
A Randomized Phase 2a, Multicenter, Open-Label, Multiple-Cohort 
Study Evaluating Regimens Containing Vebicorvir in Subjects with 
Chronic Hepatitis B Virus Infection 
Protocol Number  
ABI-H0731-204  
Protocol Version and 
Date  
 Amendment 1 – 27 October 2021 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
described herein, in accordance with Good Clinical Practice (GCP) as set out in the current 
International Council for Harmonisation (ICH) guidelines (E6) and other applicable national or 
local requirements, and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Assembly Biosciences or specified 
designees. I will discuss the material with them to ensure that they are fully informed about 
Assembly Biosciences and the study. 
Principal Investigator Signature:  
Print Name:  
Date:  
Please keep the original, signed copy of this Investigator signature page in your records and email 
a copy to your site monitor for archival in the Trial Master File (TMF). 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................. 4 
ABBREVIATIONS AND TERMS ............................................................................................ 10 
1 
SYNOPSIS ............................................................................................................................ 13 
2 
INTRODUCTION ............................................................................................................... 22 
 
Chronic Hepatitis B Virus Infection ........................................................................... 22 
 
Vebicorvir ..................................................................................................................... 23 
2.2.1 
Description ............................................................................................................. 23 
2.2.2 
Nonclinical Studies ................................................................................................ 24 
2.2.3 
Clinical Studies ...................................................................................................... 24 
 
AB-729 ........................................................................................................................... 34 
2.3.1 
Description ............................................................................................................. 34 
2.3.2 
Nonclinical Studies ................................................................................................ 35 
2.3.3 
Clinical Studies ...................................................................................................... 35 
 
Study Rationale ............................................................................................................ 36 
2.4.1 
Rationale for Combination Treatment of Vebicorvir and AB-729 .................. 36 
2.4.2 
Rationale for Dose Selection ................................................................................ 37 
3 
Study Objectives and Endpoints ........................................................................................ 39 
 
Study Objectives ........................................................................................................... 39 
3.1.1 
Primary Objective ................................................................................................. 39 
3.1.2 
Secondary Objectives............................................................................................ 39 
3.1.3 
Exploratory Objectives ......................................................................................... 39 
 
Study Endpoints ........................................................................................................... 40 
3.2.1 
Primary Endpoint ................................................................................................. 40 
3.2.2 
Secondary Endpoints ............................................................................................ 40 
3.2.3 
Exploratory Endpoints ......................................................................................... 40 
4 
Study Design ......................................................................................................................... 42 
 
Overview ....................................................................................................................... 42 
4.1.1 
Treatment Stopping Criteria ............................................................................... 42 
4.1.2 
NrtI-Restart Criteria ............................................................................................ 43 
 
Study Treatments ......................................................................................................... 43 
 
Duration of Treatment ................................................................................................. 44 


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End of Study Definition ............................................................................................... 44 
5 
Study Population ................................................................................................................. 45 
 
Number of Subjects ...................................................................................................... 45 
 
Inclusion Criteria ......................................................................................................... 45 
 
Exclusion Criteria ........................................................................................................ 46 
 
Screen Failures ............................................................................................................. 48 
6 
Study Drugs .......................................................................................................................... 49 
 
Investigational Medicinal Product(s) (IMPs) ............................................................ 49 
6.1.1 
Vebicorvir .............................................................................................................. 49 
6.1.2 
AB-729 .................................................................................................................... 49 
6.1.3 
Accountability of IMP .......................................................................................... 50 
 
Non-Investigational Medicinal Products(s) (NIMPs) ................................................ 51 
6.2.1 
Nucleos(t)ide/Reverse Transcriptase Inhibitor (NrtI) ....................................... 51 
6.2.2 
Accountability for NIMPs .................................................................................... 51 
 
Concomitant Medications ............................................................................................ 51 
6.3.1 
Prohibited Concomitant Therapy ....................................................................... 52 
 
Randomization, Blinding, and Treatment Codes ...................................................... 53 
6.4.1 
Randomization ...................................................................................................... 53 
6.4.2 
Blinding .................................................................................................................. 53 
7 
Discontinuation of Study Treatment and Subject Discontinuation/Withdrawal .......... 54 
 
Discontinuation of Study Treatment .......................................................................... 54 
 
Criteria for Discontinuation of Study Treatment ..................................................... 54 
 
Subject Discontinuation/Withdrawal from the Study .............................................. 55 
7.3.1 
Subject Lost to Follow-Up .................................................................................... 55 
8 
Study Procedures and Assessments ................................................................................... 56 
 
Schedule of Assessments .............................................................................................. 56 
 
Study Visit Assessments ............................................................................................... 63 
 
Subject Enrollment and Treatment Assignment ....................................................... 63 
8.3.1 
Screening Visits ..................................................................................................... 63 
8.3.2 
Day 1 Visit .............................................................................................................. 64 
8.3.3 
Week 2 Through Week 48 Visits (±3 Days) ........................................................ 65 
8.3.4 
Week 50 Through Week 96 Off-Treatment Follow-Up Visits for Subjects 
Meeting Treatment Stopping Criteria (±5 Days) .............................................................. 67 


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8.3.5 
Week 52 Through Week 96 Follow-Up Visits for Rest of the Subjects (±5 
Days) 
68 
 
Unscheduled Visit ......................................................................................................... 70 
 
Premature Termination Visit ...................................................................................... 71 
 
Assessment of Efficacy ................................................................................................. 72 
8.6.1 
Quantification of HBV Total Nucleic Acids (TNA) ........................................... 72 
8.6.2 
Quantification of HBV DNA ................................................................................ 72 
8.6.3 
Quantification of HBV RNA ................................................................................ 72 
8.6.4 
Quantification of HBV Antigens and Antibodies ............................................... 73 
 
Resistance Monitoring ................................................................................................. 73 
 
Assessment of Safety .................................................................................................... 73 
8.8.1 
Physical Examination ........................................................................................... 73 
8.8.2 
Vital Signs .............................................................................................................. 74 
8.8.3 
Electrocardiograms............................................................................................... 74 
8.8.4 
Clinical Safety Laboratory Assessments ............................................................. 74 
8.8.5 
Injection Site Reaction Diary ............................................................................... 76 
 
Assessment of Pharmacokinetics ................................................................................ 76 
 Exploratory Biomarkers .............................................................................................. 76 
 Use of Residual Samples for Optional Future Research .......................................... 77 
9 
Adverse Events and Toxicity Management ....................................................................... 78 
 
Definition of Adverse Event ........................................................................................ 78 
 
Documenting Adverse Events ..................................................................................... 78 
 
Assessment of Intensity ................................................................................................ 78 
 
Assessment of Causality ............................................................................................... 79 
 
Adverse Event Follow-up ............................................................................................. 79 
 
Serious Adverse Events ................................................................................................ 79 
9.6.1 
Definition of Serious Adverse Event ................................................................... 79 
9.6.2 
Definition of Terms ............................................................................................... 80 
9.6.3 
Reporting Serious Adverse Events ...................................................................... 81 
 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs or 
SAEs 81 
 
Overdose ........................................................................................................................ 81 
 
Pregnancy ...................................................................................................................... 82 


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9.9.1 
Female Subjects Who Become Pregnant ............................................................ 82 
9.9.2 
Male Subjects With Partners Who Become Pregnant ....................................... 82 
 Toxicity Management .................................................................................................. 82 
9.10.1 
Grades 1 and 2 Clinical Event or Laboratory Abnormality ............................. 83 
9.10.2 
Grade 3 Clinical Event or Laboratory Abnormality ......................................... 83 
9.10.3 
Grade 4 Clinical Event or Laboratory Abnormality ......................................... 83 
9.10.4 
Management of Alanine Aminotransferase (ALT) Elevations ......................... 83 
10 Statistical Considerations.................................................................................................... 87 
 General Considerations ............................................................................................... 87 
 Determination of Sample Size ..................................................................................... 87 
 Analysis Populations .................................................................................................... 87 
 Planned Analyses .......................................................................................................... 88 
10.4.1 
Disposition of the Study Subjects ........................................................................ 88 
10.4.2 
Demographic and Baseline Characteristics ........................................................ 88 
10.4.3 
Extent of Exposure ................................................................................................ 88 
10.4.4 
Analysis of Efficacy Endpoint(s).......................................................................... 88 
10.4.5 
Analysis of Safety Endpoints................................................................................ 89 
10.4.6 
Analysis of Pharmacokinetic Endpoints ............................................................. 89 
 Interim Analysis ........................................................................................................... 90 
 Handling of Missing Data ............................................................................................ 90 
 Multiplicity Adjustment .............................................................................................. 90 
11 Responsibilities..................................................................................................................... 91 
 Investigator Responsibilities ........................................................................................ 91 
11.1.1 
Good Clinical Practice .......................................................................................... 91 
11.1.2 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ....... 91 
11.1.3 
Informed Consent ................................................................................................. 91 
11.1.4 
Confidentiality ....................................................................................................... 92 
11.1.5 
Study Files and Retention of Records ................................................................. 92 
11.1.6 
Audits and Inspections ......................................................................................... 92 
11.1.7 
Protocol Compliance ............................................................................................. 93 
 Sponsor Responsibilities .............................................................................................. 93 
11.2.1 
Protocol Amendments and Modifications .......................................................... 93 


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11.2.2 
Data Management ................................................................................................. 93 
11.2.3 
Study Report and Publications ............................................................................ 93 
REFERENCES ............................................................................................................................ 95 
APPENDICES ............................................................................................................................. 97 
APPENDIX 1. TOXICITY GRADING SCALE FOR ADVERSE EVENTS AND 
LABORATORY ABNORMALITIES ...................................................................................... 97 
APPENDIX 2. PREGNANCY PRECAUTIONS AND THE DEFINITION OF 
CHILD-BEARING POTENTIAL AND CONTRACEPTIVE REQUIREMENTS ........... 114 
APPENDIX 3. PROTOCOL AMENDMENT SUMMARY OF CHANGES ...................... 116 
 
LIST OF TABLES  
Table 1. 
Overall Summary of Treatment-Emergent Adverse Events Through Week 24 
(Study 211) ........................................................................................................... 25 
Table 2. 
HBV DNA and pgRNA for Treatment-Naïve Subjects with cHBV by Week of 
Treatment with Vebicorvir+ETV (Study 202/211) .......................................... 28 
Table 3. 
HBV Antigens for Treatment-Naïve Subjects with cHBV by Week of 
Treatment with Vebicorvir+ETV (Study 202/211) .......................................... 30 
Table 4. 
Alanine Aminotransferase for Treatment-Naïve Subjects with cHBV by 
Week of Treatment with Vebicorvir+ETV (Study 202/211) ........................... 30 
Table 5. 
HBV DNA for Virologically-Suppressed Subjects with cHBV by Week of 
Treatment with Vebicorvir+NrtI (Study 201/211) ........................................... 32 
Table 6. 
HBV pgRNA for Virologically-Suppressed Subjects with cHBV by Week of 
Treatment with Vebicorvir+NrtI (Study 201/211) ........................................... 33 
Table 7. 
Subject Treatment Assignment for Study ABI-H0731-204 Cohort 1 ............ 43 
Table 8. 
Prohibited Concomitant Therapies ................................................................... 52 
Table 9. 
Schedule of Assessments (Cohort 1) – On-Treatment for All Subjects ......... 57 
Table 10. 
Schedule of Assessments (Cohort 1) – Off-treatment Follow-Up for Subjects 
Meeting Treatment Stopping Criteria .............................................................. 60 
Table 11. 
Schedule of Assessments (Cohort 1) – Follow-up for Rest of the Subjects .... 61 
Table 12. 
Clinical Laboratory Tests................................................................................... 75 
Table 13. 
Pharmacokinetic Parameters and Definitions .................................................. 90 
 
LIST OF FIGURES  
Figure 1. 
Mean Log10 HBV DNA for Treatment-Naïve Subjects with cHBV 
(Study 202/211) .................................................................................................... 26 
Figure 2. 
Mean Log10 HBV pgRNA for Treatment-Naïve Subjects with cHBV 
(Study 202/211) .................................................................................................... 27 


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Figure 3. 
Proportions of Treatment-Naïve Subjects with HBV DNA <LLOQ and HBV 
pgRNA Decrease ≥ 3 log10 U/mL from Baseline or HBV pgRNA <LLOQ by 
Week of Treatment with Vebicorvir+ETV (Study 202/211) ........................... 29 
Figure 4. 
Proportion of Virologically-Suppressed Subjects With HBV DNA TND and 
HBV pgRNA <LLOQ by Week of Treatment with Vebicorvir+ETV 
(Study 201/211) .................................................................................................... 34 
Figure 5. 
Mean (±SEM) Log10 HBsAg Declines up to 12 Weeks Post Single Dose of 
AB-729 60 mg or AB-729 60 mg Administered Every 4 Weeks ..................... 38 
Figure 6.  
Study Design Schematic for Study ABI-H0731-204 ........................................ 42 
Figure 7. 
Schematic for Safety Management of ALT Elevation ..................................... 86 


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ABBREVIATIONS AND TERMS  
Abbreviation  
Definition  
AASLD 
American Association for the Study of Liver Diseases 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APRI 
AST to platelet ratio index 
AST 
Aspartate aminotransferase 
cccDNA 
Covalently closed circular DNA 
cHBV 
Chronic hepatitis B virus infection 
CMV 
Cytomegalovirus  
CRO 
Clinical research organization 
CSR 
Clinical Study Report 
DAIDS 
Division of AIDS 
DNA 
Deoxyribonucleic acid 
EBV 
Epstein-Barr virus  
eCRF 
Electronic Case Report Form 
EOT 
End of treatment  
EOS 
End of study  
ETV 
Entecavir 
EU 
European Union 
FDA 
Food and Drug Administration 
GalNAc 
N-Acetylgalactosamine 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBcAb 
Antibody to the HBV core protein 
HBcrAg 
Hepatitis B core-related antigen 
HBeAb 
Anti-hepatitis B e antigen antibody 


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Abbreviation  
Definition  
HBeAg 
Hepatitis B e antigen 
HBsAb 
Anti-hepatitis B surface antigen antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus  
HCC 
Hepatocellular carcinoma 
HIV 
Human immunodeficiency virus 
HSV 
Herpes simplex virus  
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LLOQ 
Lower limit of quantitation 
NrtI  
Nucleos(t)ide/reverse transcriptase inhibitor 
PBO 
Placebo 
PCR 
Polymerase chain reaction 
Peg-IFNα 
Pegylated-interferon alpha 
pgRNA 
Pregenomic ribonucleic acid 
PK 
Pharmacokinetic(s) 
RNA 
Ribonucleic acid 
RNAi 
Ribonucleic acid interference 
RT-qPCR 
Quantitative reverse transcription PCR 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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Abbreviation  
Definition  
siRNA 
Small interfering ribonucleic acid 
SOC 
Standard-of-care 
SVR 
Sustained virologic response 
TD 
Target detected 
TDF 
Tenofovir disoproxil fumarate 
TNA 
Total nucleic acids 
TND 
Target not detected 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal  
US 
United States 
VBR 
Vebicorvir  
WHO 
World Health Organization 
 
 
 


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1 SYNOPSIS  
Protocol Title  
A Randomized Phase 2a, Multicenter, Open-Label, Multiple-Cohort Study 
Evaluating Regimens Containing Vebicorvir in Subjects with Chronic Hepatitis B 
Virus Infection 
Protocol 
Number  
ABI-H0731-204 
Test Product, 
Dose, and Mode 
of 
Administration  
Cohort 1 
300 mg vebicorvir (VBR; formerly ABI-H0731) (100 mg tablets), oral, once daily 
+ 60 mg AB-729 (180 mg/mL solution), subcutaneous, once every 8 weeks + 
nucleos(t)ide/reverse transcriptase inhibitor (NrtI) tablets, oral, once daily 
Reference 
Therapy, Dose, 
and Mode of 
Administration  
Cohort 1 
• 
300 mg VBR (100 mg tablets) + NrtI tablets; both oral, once daily 
• 
60 mg AB-729 (180 mg/mL solution), subcutaneous, once every 8 weeks 
+ NrtI tablets, oral, once daily 
Target 
Population  
Male or female subjects with chronic hepatitis B virus (HBV) infection (cHBV), 
aged 18 to 50 years (inclusive), with no evidence of cirrhosis or end-stage liver 
disease.  
Virologically-suppressed subjects on NrtI therapy with HBeAg negative cHBV 
will be enrolled in Cohort 1. Additional cohorts may be added in future protocol 
amendments to evaluate other populations and/or treatment regimens. 
Phase  
2a 
Number of 
Subjects 
Planned  
Approximately 60 in Cohort 1 
Up to 2 additional cohorts, with approximately 60 subjects per cohort, may be 
added in future protocol amendments, for a maximum sample size of 
approximately 180 subjects. 
Study Sites  
Approximately 25 study sites worldwide 
Treatment 
Duration  
Cohort 1: 48 Weeks  
Study Duration  
Cohort 1: Up to 45 days for Screening, 48 weeks of treatment, and 48 weeks of 
follow-up. 
Rationale  
Chronic hepatitis B virus infection is a major cause of liver-related morbidity and 
mortality affecting >250 million people worldwide. While standard-of-care (SOC) 
therapy with NrtIs is able to achieve adequate viral suppression in most HBeAg 
negative patients and three quarters of HBeAg positive patients, sustained 
virologic response (SVR) off treatment, and loss of hepatitis B surface antigen 
(HBsAg) are rare (<5%). Compared to NrtIs, finite treatment with pegylated 


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interferon alpha (Peg-IFNα) leads to lower rates of viral suppression, although 
small increases in the rate of HBsAg loss (5-10%) have been observed. However, 
any advantages associated with immunomodulation are offset by poor tolerability 
of Peg-IFNα. New therapeutic modalities are required to improve the depth of 
suppression and provide the potential for cure. Combination regimens utilizing 
agents with complementary mechanisms of action and resistance profiles may be 
required to support finite treatment durations. 
Vebicorvir is an orally administered, potent and selective small molecule inhibitor 
of the HBV core protein. Through this mechanism, VBR interferes with multiple 
steps in the viral lifecycle including capsid disassembly and deoxyribonucleic acid 
(DNA) delivery to the nucleus, pregenomic ribonucleic acid (pgRNA) 
encapsidation, capsid assembly, and DNA recirculation, preventing de novo 
establishment of covalently closed circular DNA (cccDNA).  
AB-729 is a subcutaneously administered novel N-Acetylgalactosamine (GalNAc) 
conjugated small interfering ribonucleic acid (siRNA), which cleaves and degrades 
HBV ribonucleic acid (RNA), inhibiting production of all viral proteins, including 
HBsAg. Suppression of HBsAg production by AB-729 may contribute to breaking 
immune tolerance to HBV and restoring T-cell activity directed toward HBV, 
thereby promoting functional cure. The addition of VBR and AB-729 to other 
treatments for cHBV will provide multiple complementary antiviral mechanisms, 
with potential collateral immunological consequences, that may act synergistically 
to increase cure rates. This Phase 2a study will explore the safety and antiviral 
activity of VBR and AB-729 in combination with other cHBV treatments (NrtIs). 
Objectives  
Primary Objective 
The primary objective of Cohort 1 is:  
• 
To evaluate the safety and tolerability of combination treatment with VBR, 
AB-729, and NrtI 
Secondary Objectives  
The secondary objectives of Cohort 1 are: 
• 
To evaluate the effect of adding VBR and AB-729 to NrtI on reduction in 
and loss of HBsAg 
• 
To evaluate the effect of adding VBR and AB-729 to NrtI in reducing 
HBV DNA levels 
• 
To evaluate the effect of adding VBR and AB-729 to NrtI in reducing 
HBV RNA levels 
• 
To evaluate the effect of adding VBR and AB-729 to NrtI in reducing 
other HBV antigens (ie, hepatitis B core-related antigen [HBcrAg]) 


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• 
To evaluate the effect of adding VBR and AB-729 to NrtI on HBsAg 
seroconversion 
• 
To evaluate the effect of adding VBR and AB-729 to NrtI on 
normalization of alanine aminotransferase (ALT) 
• 
To evaluate the off-treatment durability of response to treatment with VBR 
and AB-729 
• 
To evaluate the pharmacokinetics (PK) of VBR and AB-729 when 
coadministered with NrtI 
Exploratory Objectives 
The exploratory objectives of Cohort 1 are: 
• 
To evaluate the emergence of resistance to VBR and AB-729 when 
coadministered with NrtI 
• 
To evaluate the effect of VBR, AB-729, and NrtI on immunological 
biomarkers, where applicable 
• 
To evaluate the effect of VBR, AB-729, and NrtI on HBsAg isoforms and 
immune complexes, where applicable 
• 
To evaluate the effect of AB-729 on an HBV-derived RNA interference 
biomarker, where applicable 
Endpoints  
Primary Endpoint  
The primary endpoint of Cohort 1 is: 
• 
Proportion of subjects with adverse events (AEs), premature treatment 
discontinuation due to AEs, and abnormal laboratory results 
Secondary Endpoints 
The secondary endpoints of Cohort 1 are: 
• 
Mean change in log10 HBsAg from Baseline at each timepoint 
• 
Proportion of subjects with HBsAg <LLOQ at each timepoint 
• 
Proportion of subjects with HBV DNA target not detected (TND; 
<5 IU/mL) at Week 48 
• 
Proportion of subjects with HBV RNA <LLOQ at Week 48 
• 
Mean change in log10 HBV RNA from Baseline at each timepoint 


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• 
Mean change in log10 HBcrAg from Baseline at each timepoint 
• 
Proportion of subjects with HBsAg seroconversion at Week 48 
• 
Proportion of subjects with abnormal ALT at Baseline who have normal 
ALT (by central laboratory and American Association for the Study of 
Liver Diseases [AASLD] criteria) at each timepoint 
• 
Proportion of subjects achieving Treatment Stopping Criteria at end of 
treatment (EOT) 
• 
Proportion of subjects who remain off-treatment at end of study (EOS) 
• 
Analysis of VBR and AB-729 drug concentrations. NrtI concentrations 
may be analyzed, as needed  
 
Exploratory Endpoints 
The exploratory endpoints of Cohort 1 are: 
• 
Proportion of subjects who continued NrtI after Week 48 and subsequently 
met the Treatment Stopping Criteria  
• 
The incidence of HBV variants with reduced susceptibility to VBR and 
AB-729 
• 
The evaluation of immune response markers, where applicable  
• 
The evaluation of the effect on HBsAg isoforms, where applicable  
• 
The evaluation of the effect on HBsAg immune complexes, where 
applicable 
• 
The evaluation of the effect on an HBV-derived RNA interference 
biomarker over time, where applicable 
Study Design  
This is a randomized Phase 2a, multicenter, open-label, multiple-cohort study 
evaluating the safety and antiviral activity of VBR and AB-729 in combination 
with other cHBV treatments in subjects with cHBV. 
Cohort 1 is prespecified and will enroll virologically-suppressed subjects on NrtI 
therapy with HBeAg negative cHBV. Approximately 60 eligible subjects will be 
randomized 2:1:1 in 1 of 3 treatment groups as shown in the following figure. Up 
to 2 additional cohorts may be added in future protocol amendments to 
evaluate other populations and/or treatment regimens. 


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Study Design Schematic  
 
Abbreviations: VBR=vebicorvir; NrtI=nucleos(t)ide /reverse transcriptase inhibitor; Wk=week 
Treatment with VBR and NrtI will be administered orally, once daily; treatment 
with AB-729 will be administered subcutaneously, once every 8 weeks, for a total 
of 6 doses. 
Treatment assignments will be stratified by HBsAg level (ie, HBsAg ≤1000 IU/mL 
vs >1000 IU/mL) during the Screening visit. 
Treatment Stopping Criteria:  
At Week 48, all subjects will have an assessment of Treatment Stopping Criteria. 
Any subjects who meet the below Treatment Stopping Criteria, will discontinue their 
assigned treatment including NrtI, and continue with off-treatment follow-up 
through Week 96, unless they meet the NrtI-restart criteria specified below. 
Decisions to discontinue assigned treatment and undergo off-treatment follow-up 
will be based on laboratory results from blood samples collected at the Week 48 
visit. Subjects will remain on their assigned oral agents (ie, VBR+NrtI for Groups 1 
and 2; NrtI for Group 3) until Week 48 laboratory results required for Treatment 
Stopping Criteria assessment are available. 
Treatment Stopping Criteria are:  
• 
ALT < 2 × ULN, and 
• 
HBV DNA < LLOQ, and 
• 
HBsAg < 100 IU/mL 
Subjects who do not meet the Treatment Stopping Criteria with Week 48 laboratory 
results will continue treatment with NrtI alone and will remain in follow-up through 
Week 96. 
NrtI-Restart Criteria:  
Subjects who meet the Treatment Stopping Criteria at the Week 48 assessment but 
subsequently meet ANY of the below NrtI-Restart Criteria, will restart treatment 
with NrtI and remain in follow-up through Week 96.  
NrtI-Restart Criteria are:  
• 
Alanine aminotransferase (ALT) > 10 × upper limit of normal (ULN), 
confirmed by repeat 


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• 
ALT > Baseline and > ULN, confirmed by repeat, and  
o Direct bilirubin > 2.0 × ULN, confirmed by repeat, or 
o International Normalized Ratio > 1.5, confirmed by repeat 
• 
ALT ≥ 2 – 5 × ULN AND HBV DNA > 2000 IU/mL for 12 weeks 
• 
ALT elevations ≥ 5 – 10 × ULN AND HBV DNA > 2000 IU/mL for 4 
weeks 
• 
Any clinical decompensation, regardless of HBV DNA level 
• 
Investigator discretion 
Study 
Population  
Key Inclusion Criteria for Cohort 1  
Subjects must meet all the following key inclusion criteria in order to be eligible 
for Cohort 1 of the study: 
1. Willing and able to provide Informed Consent 
2. Male or female between the ages 18 and 50 years (inclusive) at Screening 
3. Body mass index (BMI) 18 to 36 kg/m2 and a minimum body weight of 
45 kg (inclusive) at Screening 
4. Female subjects of child-bearing potential (Appendix 2) must be 
non-pregnant and have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test at Day 1 predose 
5. cHBV defined as HBV infection documented for ≥6 months prior to 
Screening 
6. Must be HBeAg negative at least 3 months prior to the Screening Visit 
(historical documentation) AND at the Screening Visit to be eligible for 
Cohort 1 
7. Virologically suppressed on NrtI therapy with nonquantifiable HBV DNA 
for at least 6 months prior to and including Screening 
8. On a stable NrtI regimen of entecavir, tenofovir disoproxil fumarate or 
tenofovir alafenamide for >12 months 
9. HBsAg ≥100 IU/mL at Screening 
10. Lack of bridging fibrosis or cirrhosis as documented by the following: 
• 
Fasting FibroScan® ≤8 kPa within 3 months prior to Screening 
(including the Screening visit) or other Sponsor-approved hepatic 


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imaging method within 6 months of Screening (eg, Meta-analysis of 
Histological Data in Viral Hepatitis [METAVIR] F0-F2 or equivalent) 
OR 
• 
Liver biopsy results (eg, METAVIR F0-F2 or equivalent) within 1 
year prior to Screening 
If results from liver biopsy and FibroScan® are available, then the 
diagnostic method reporting the most advanced liver disease will be 
used to determine eligibility for the study 
11. Agreement to comply with protocol-specified contraceptive requirements 
(Appendix 2) 
12. In good general health, except for cHBV, in the opinion of the Investigator 
13. Able to take oral medication, be willing to receive subcutaneous injections 
of AB-729, and in the opinion of the Investigator, be willing to adhere to 
study treatment and procedures 
 
Key Exclusion Criteria for Cohort 1  
Subjects who meet any of the following key exclusion criteria will not be eligible 
for the study: 
1. Co-infection with human immunodeficiency virus, hepatitis C virus, 
hepatitis D virus, acute hepatitis A virus or acute hepatitis E virus 
2. Females who are lactating or wish to become pregnant during the course of 
the study 
3. History of liver transplant or evidence of advanced liver disease, cirrhosis, 
or hepatic decompensation (including jaundice, ascites, portal 
hypertension, gastrointestinal bleeding esophageal varices, hepatic 
encephalopathy) at any time prior to, or at the time of Screening 
4. History of persistent alcohol abuse (alcohol consumption exceeding 
2 standard drinks per day on average [1 standard drink=14 grams of 
alcohol]) or illicit drug abuse within 3 years prior to Screening 
5. Clinically significant diseases or conditions, such as cardiac disease, 
including poorly-controlled or unstable hypertension; pulmonary disease; 
chronic or recurrent renal or urinary tract disease; liver disease other than 
cHBV; endocrine disorder; autoimmune disorder; poorly controlled 
diabetes mellitus; neuromuscular, musculoskeletal, or mucocutaneous 
conditions requiring frequent treatment, seizure disorders requiring 
treatment; ongoing infection or other medical conditions requiring frequent 
medical management or pharmacologic or surgical treatment that, in the 


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opinion of the Investigator or the Sponsor, makes the subject unsuitable for 
study participation 
6. History of hepatocellular carcinoma (HCC) 
7. History of malignancy other than HCC unless the subject’s malignancy has 
been in complete remission off chemotherapy and without additional 
medical or surgical interventions during the 3 years before Screening 
8. History or presence at Screening of electrocardiogram abnormalities 
deemed clinically significant, in the opinion of the Investigator 
9. History of hypersensitivity or idiosyncratic reaction to any components or 
excipients of the investigational drugs 
10. History of any significant food or drug-related allergic reactions such as 
anaphylaxis or Stevens-Johnson syndrome 
11. The following are exclusionary laboratory results at Screening: 
a. Platelet count <100,000/mm3 
b. Albumin <3 g/dL  
c. Direct bilirubin >1.2× upper limit of normal (ULN)  
d. ALT ≥5× ULN 
e. Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is 
>ULN but <100 ng/mL, the subject is eligible if hepatic imaging prior 
to initiation of study drug reveals no lesions indicative of possible 
HCC 
f. International Normalized Ratio (INR) >1.5× ULN  
g. Estimated creatinine clearance <50 mL/min (using the 
Cockcroft-Gault method) based on serum creatinine and actual body 
weight at Screening  
h. Any other laboratory abnormality deemed clinically significant by the 
Investigator 
12. Current or prior use of prohibited concomitant medications from 28 days 
prior to Day 1 (Section 6.3.1) 
13. Current or prior treatment for cHBV with: 
• 
Lamivudine, telbivudine or adefovir (any duration) 


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• 
HBV core inhibitor (any duration) 
• 
siRNA or other oligonucleotide therapeutic (any duration) 
• 
Interferon in the 6 months prior to Screening 
• 
Any investigational agent for cHBV in the 6 months prior to Screening 
14. Participation in another clinical study of a drug or device whereby the last 
investigational drug/device administration is within 60 days or 5 half-lives 
prior to the first study drug administration, whichever is longer 
Statistical 
Methods  
This is a proof-of-concept study. The sample size is similar to that previously 
utilized for this type of study and is not based upon statistical considerations. 
All safety, PK, and antiviral activity endpoints will be summarized using 
descriptive statistics by treatment groups. Continuous endpoints will be 
summarized using the mean, standard deviation, median, minimum, and 
maximum. Categorical endpoints will be described using the number and percent 
of subjects who meet the endpoint criterion.  
Due to sample size limitations, no formal statistical inference is planned.  
 


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2 INTRODUCTION 
 
Chronic Hepatitis B Virus Infection 
Worldwide >250 million people are chronically infected with the hepatitis B virus (HBV), and 
chronic hepatitis B virus infection (cHBV) is a major cause of severe liver morbidity and liver-
related mortality (WHO 2019). An estimated 600,000 to 1 million people die each year due to 
cirrhosis and hepatocellular carcinoma (HCC), the end-stage complications of cHBV (Colvin 
2010, El-Serag 2012, EASL 2017, Terrault 2018, WHO 2019). The global prevalence of chronic 
HBV infection shows wide geographic variation, with a prevalence of more than 8% of people in 
highly endemic regions (eg, East Asia and equatorial Africa), 2% to 7% of people in moderately 
endemic regions (eg, the Middle East and the Indian subcontinent), and less than 2% in locales of 
low endemicity (eg, North America and Europe) (Schweitzer 2015). Despite broad implementation 
of HBV vaccination programs, new cases of HBV infection are still common. The World Health 
Organization (WHO) estimates that there are greater than 4 million acute HBV infections 
worldwide each year (WHO 2019).  
The clinical stages of cHBV represent different risks for ongoing liver injury depending on the 
degree of HBV replication and individuals’ concurrent immune responses (Yim 2006, Hoofnagle 
2007, Lok 2009, Sorrell 2009, Pungpapong 2013, Gish 2015, EASL 2017). The standard virologic 
and serologic markers for HBV infection include HBV deoxyribonucleic acid (DNA), hepatitis B 
surface antigen (HBsAg), anti-hepatitis B surface antigen antibody (HBsAb), hepatitis B e antigen 
(HBeAg), anti-hepatitis B e antigen antibody (HBeAb), and in almost all patients, antibody to the 
HBV core protein (HBcAb). More recently, HBV pregenomic ribonucleic acid (pgRNA) and HBV 
core-related antigen (HBcrAg) have also been used as markers of infection. In particular, HBV 
pgRNA is recognized as a direct measure of covalently closed circular DNA (cccDNA) 
transcriptional activity, and the number of infected cells (Fanning 2019). Historically, treatment 
goals include prevention of HBV-related liver injury through suppression of HBV DNA, 
achievement of HBeAg loss and seroconversion, and loss of HBsAg and seroconversion. The 
secretion of viral antigens, especially HBsAg, may play a key role in modulating the host immune 
response to infection by promoting T cell exhaustion, suppressing innate immune responses and 
cytokine production, and altering adaptive immune function (Yuen 2018). A transition to an 
HBsAg negative, minimally replicative state is rare (occurring spontaneously in only 1-3% of 
patients per year, and <5% per year in [nucleos(t)ide reverse transcriptase inhibitors] NrtI-treated 
patients) but usually durable and, if it precedes the development of cirrhosis and HCC, is associated 
with improved long-term clinical outcomes (EASL 2017). As such, HBsAg seroconversion is 
considered a “functional cure” and a potential endpoint for cHBV therapy. However, as HBsAg is 
derived from both cccDNA as well as integrated HBV DNA, sustained undetectable HBV DNA 
with or without HBsAg loss after stopping treatment (“off-therapy sustained virologic response 
[SVR]”) is considered an intermediate goal (EASL 2017, Cornberg 2019). 
Currently, there are 2 clinically accepted treatment options for cHBV, interferon alfa (IFNα) and 
NrtIs of the HBV polymerase. Of these agents, oral NrtIs are the more broadly used, and have 
demonstrated success in achieving and maintaining viral suppression in most patients (Lampertico 


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2012). However, there is a sizable number of individuals who do not achieve viral suppression to 
levels below quantitation on commercial assays following an adequate course of NrtI therapy. In 
the Phase 3 studies with entecavir (ETV), 33% of HBeAg positive patients and 10% of HBeAg 
negative patients did not achieve HBV DNA <lower limit of quantitation (LLOQ; 300 copies/mL) 
after 48 weeks of treatment, and 2% or less achieved HBsAg loss (Chang 2006, Lai 2006). 
Similarly, in a Phase 3 study in HBeAg positive patients, 36% of tenofovir alafenamide (TAF) 
recipients and 33% of tenofovir disoproxil fumarate (TDF) recipients had HBV DNA >LLOQ (29 
IU/mL) at Week 48, and 1% or less achieved HBsAg loss (Chan 2016). In the complementary 
Phase 3 study in HBeAg negative patients, 6% of TAF recipients and 7% of those receiving TDF 
had HBV DNA >LLOQ (29 IU/mL) at Week 48, and no subjects experienced HBsAg loss (Buti 
2016). Importantly, the level of HBV replication as measured by HBV DNA and HBsAg 
production in those treated with and without complete virologic response (ie, achieving/not 
achieving HBV DNA <LLOQ with or without HBsAg loss) has been predictive of progression of 
liver disease and risk of HCC (Papatheodoridis 2015, EASL 2017, Yip 2019). Further, despite 
suppression of HBV DNA for extended periods of time with NrtIs, the template for ongoing viral 
replication, cccDNA, is not eliminated in most patients. Patients with HBV DNA below the limit 
of quantification using commercial assays continue to have low levels of viral replication even 
after many years of NrtI therapy (Marcellin 2014, Burdette 2019). As a result, off therapy SVR 
with currently approved agents is rare, necessitating long-term chronic suppressive treatment 
approaches. There is a need for improved, novel HBV therapies that further reduce HBV 
replication and result in a higher proportion of patients achieving SVR (HBV DNA <LLOQ with 
or without HBsAg loss) with a subsequent improvement in long-term patient outcomes, ie, 
reduction of HBV associated hepatic inflammation leading to reduced morbidity and mortality 
from end-stage liver disease and HCC (FDA 2018). Additionally, such deeper virologic responses 
may enable patients to achieve durable virologic and clinical outcomes following finite treatment 
duration. 
 
Vebicorvir  
2.2.1 
Description  
Vebicorvir (VBR; formerly ABI-H0731) is an orally administered, potent and selective small 
molecule inhibitor of the HBV core protein discovered by Assembly Biosciences (Assembly), 
which is being developed as a therapeutic agent for the treatment of cHBV. Vebicorvir inhibits 
HBV replication by interfering with essential functions of the HBV core protein, and therefore 
inhibits HBV replication by different mechanisms than NrtIs. Thus, inhibition of HBV core protein 
functions by VBR, when used in combination with currently approved HBV antivirals has the 
potential to immediately improve current therapy for chronic HBV infection and in combination 
with additional agents, ultimately provide patients with enhanced rates of SVR following a finite 
treatment period. 
General information concerning VBR is described in the VBR Investigator’s Brochure (IB). 


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2.2.2 
Nonclinical Studies  
Refer to the VBR IB for a complete summary of the nonclinical and toxicology studies performed 
to date. 
2.2.3 
Clinical Studies  
A complete summary of all clinical studies performed to date is provided in the VBR IB. The VBR 
IB also includes preliminary safety and efficacy information for the ongoing Phase 2 studies, 
Study ABI-H0731-201 (Study 201) and Study ABI-H0731-202 (Study 202), for which the study 
conduct has been completed. Following completion of treatment in Study 202 and Study 201, 
eligible subjects were able to participate in Study ABI-H0731-211 (Study 211), a long-term 
extension study and receive open-label, 300 mg VBR+NrtI for up to an additional 100 weeks. In 
Study 211, treatment with VBR is ongoing and the overall summary of exposure is based on a data 
cut-off date of 12 March 2020. The available preliminary efficacy and safety results from 
Study 211 are provided in Sections 2.2.3.1, 2.2.3.2, and 2.2.3.3. 
2.2.3.1 
Study 211 Preliminary Disposition  
In the open-label treatment extension Study 211, 92 subjects, who participated in Studies 201 and 
202 (ie, 23 subjects from Study 202 [12 subjects from the VBR+ETV group; 11 subjects from the 
Placebo (PBO)+ETV group] and 69 subjects from Study 201 [43 subjects from the VBR+NrtI 
group; 26 subjects from the PBO+NrtI group]), were enrolled to receive 300 mg VBR for up to 
100 additional weeks. Through the first 24 weeks of Study 211, 90 (98%) subjects who enrolled 
continued on study treatment, one subject discontinued study drug due to a Grade 1 adverse event 
(AE) of rash and one subject discontinued study drug due to virologic resistance in the setting of 
noncompliance with study drug. 
2.2.3.2 
Study 211 Preliminary Safety  
In Study 211, preliminary safety data are available for all subjects through 24 weeks of treatment 
with VBR+NrtI and demonstrate that 300 mg VBR daily continues to be generally well-tolerated 
in the open-label treatment extension study (Table 1). No subjects discontinued treatment due to 
treatment-emergent adverse events (TEAEs) in Study 211. One subject discontinued treatment due 
to a Grade 1 AE of rash which began in Study 201. Overall, 42 of 92 subjects (46%) have 
experienced TEAEs, the majority of which were Grade 1. The only AEs reported by >5% of 
subjects in the first 24 weeks of Study 211 are rash (5/92, 5%) and upper respiratory tract infection 
(5/92, 5%). All the AEs of rash were Grade 1 and 2 AEs were considered not related to study drug. 
Two subjects have reported Grade 3 AEs. One subject experienced Grade 3 elevations in alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST), which were reported as Grade 3 
AEs not considered related to study drug and resolved on continued treatment. Another subject 
experienced a Grade 3 elevation in ALT, which was reported as a Grade 3 AE and considered 
possibly related to study drug by the Investigator who noted increased alcohol use by the subject 
at the time; this was associated with a Grade 2 elevation in AST and improved to Grade 2 on 
continued treatment. No Grade 4 AEs or serious adverse events (SAEs) have been reported and no 


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deaths have occurred. Most treatment-emergent laboratory abnormalities which occurred have 
been Grade 1. In addition to the Grade 3 elevations in ALT and AST reported as AEs, one subject 
had a Grade 3 prolonged prothrombin time and another subject had a Grade 3 elevation in AST 
(not reported as an AE). There have been no Grade 4 laboratory abnormalities. 
Table 1. 
Overall Summary of Treatment-Emergent Adverse Events Through Week 24 
(Study 211) 
Characteristic [n, (%)] 
Vebicorvir+NrtI 
(N=92) 
Any Treatment-Emergent AE a 
42 (46) 
Grade 1 
26 (28) 
Grade 2 
14 (15) 
Grade 3 or 4 
2 (2) 
Serious adverse events 
0 
TEAEs leading to study drug discontinuation b 
0 
Abbreviations: AE=adverse event; n=number of subjects with event; N=Number of subjects in the Safety population; 
NrtI=nucleos(t)ide analog reverse transcriptase inhibitor; TEAE=treatment-emergent adverse event. 
Source: Study 211 Table 6.1.1.1. 
Data cut through 12 March 2020 including AE data for the first 6 months of exposure in Study 211. 
Adverse events were graded according to Division of AIDS (DAIDS) criteria. 
a 
Subjects with more than 1 TEAE were reported in the highest TEAE grade. 
b 
One non-TEAE (began in Study 201) led to study drug discontinuation in Study 211. 
2.2.3.3 
Study 211 Preliminary Efficacy  
This section summarizes the antiviral activity for subjects continuing treatment from Study 202 or 
Study 201 into Study 211. During Study 202 and Study 201, subjects received either VBR+NrtI 
or PBO+NrtI for 24 weeks in a blinded fashion, and, during Study 211, all subjects received 
open-label treatment with VBR+NrtI. The analyses for Study 211 reported below are based on the 
subject’s characteristics and the initial study into which they enrolled, with treatment naïve 
subjects with HBeAg positive cHBV originating from Study 202 and virologically-suppressed 
subjects with HBeAg positive or HBeAg negative cHBV originating from Study 201. 
2.2.3.3.1 
Treatment-Naïve Subjects with HBeAg Positive cHBV (Originating from 
Study 202) 
The changes in HBV DNA and HBV pgRNA from the beginning of Study 202 through Week 24 
in Study 211 are presented in graphical form in Figure 1 and Figure 2. In both figures, each line 
represents a treatment group originating in Study 202 (either VBR+ETV or PBO+ETV) with green 
representing VBR+ETV and blue representing PBO+ETV. The numbers of subjects contributing 
data at each timepoint are presented below the x-axes. These figures demonstrate the different 
declines in HBV nucleic acids over time in the treatment groups. At Week 24 in Study 202, the 


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VBR+ETV group had statistically significant lower levels of HBV DNA and pgRNA compared 
to group receiving PBO+ETV (p=0.048 and p=0.002, respectively). In addition, there is a change 
in trajectory of HBV DNA and HBV pgRNA following the addition of VBR to ETV at the end of 
Study 202 in the group who were initially assigned to PBO+ETV. Of note, there is a clear 2-phase 
decline in pgRNA observed in both treatment groups observed upon initiation of VBR treatment. 
The initial rapid phase decline of pgRNA is thought to be primary mechanism-based inhibition (ie, 
core inhibition preventing encapsidation of pgRNA and secretion into serum), while the second 
slower phase decline of pgRNA is believed to reflect reduction in the cccDNA pool over time. 
Although all subjects receive VBR+ETV in Study 211, pooling of data in this study is not 
appropriate given the differing treatments received during Study 202. The Study 202 treatment 
assignments (VBR+ETV and PBO+ETV) lead to different starting points for markers of HBV 
infection at the beginning of Study 211. Consequently, the remainder of this section will focus on 
the subjects who received 48 weeks of VBR+ETV from the beginning of Study 202 through 
Week 24 in Study 211. 
Figure 1. 
Mean Log10 HBV DNA for Treatment-Naïve Subjects with cHBV 
(Study 202/211) 
 
Abbreviations: 731=vebicorvir; cHBV=chronic hepatitis B virus infection; ETV=entecavir; HBV=hepatitis B virus; 
IU=international units; PBO=placebo. 
Includes subjects in the Intent-to-Treat population. HBV DNA lower limit of quantitation=20 IU/mL (1.30 log10 IU/mL). 


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Figure 2. 
Mean Log10 HBV pgRNA for Treatment-Naïve Subjects with cHBV 
(Study 202/211) 
  
Abbreviations: 731=vebicorvir; cHBV=chronic hepatitis B virus infection; ETV = entecavir; HBV=hepatitis B virus;  
PBO=placebo; pgRNA=pregenomic RNA; U=units. 
Includes subjects in the Intent-to-Treat population. HBV pgRNA lower limit of quantitation=135 U/mL (2.13 log10 U/mL).  
For subjects who have received 48 cumulative weeks of VBR+ETV in Study 202/211, Table 2 
summarizes the absolute value and change from Baseline in HBV DNA (COBAS® TaqMan®; 
LLOQ=20 IU/mL) and HBV pgRNA (Assembly quantitative reverse transcription PCR 
[RT-qPCR]; LLOQ=135 U/mL) by week of treatment. In these subjects, the mean (minimum, 
maximum) Baseline HBV DNA was 7.9 (5.5, 8.7) log10 IU/mL which declined to 1.6 (1.0, 2.7) 
log10 IU/mL after 48 weeks of treatment with VBR+ETV, representing a mean (minimum, 
maximum) change of -6.3 (-7.2, -4.2) log10 IU/mL. Further, the proportion of subjects in this group 
who had HBV DNA <LLOQ increased from 0% at Baseline to 42% (5/12) at Week 48. The mean 
(minimum, maximum) HBV pgRNA at Baseline was 7.1 (4.8, 8.6) log10 U/mL which declined to 
4.3 (2.1, 5.8) log10 U/mL after 48 weeks of treatment with VBR+ETV, representing a mean 
(minimum, maximum) change of -2.8 (-4.9, -1.9) log10 U/mL. 


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Table 2. 
HBV DNA and pgRNA for Treatment-Naïve Subjects with cHBV by Week of 
Treatment with Vebicorvir+ETV (Study 202/211) 
Week of Treatment 
HBV DNAa 
Log10 IU/mL 
(N=12) 
HBV pgRNAa 
Log10 U/mL 
(N=12) 
Baseline 
   n 
  Mean (Min, Max) 
 
12 
7.9 (5.5, 8.7) 
 
12 
7.1 (4.8, 8.6) 
Week 12 
   n 
   Mean (Min, Max) 
   Change from Baseline (Min, Max) 
 
12 
3.4 (1.3, 5.3) 
-4.5 (-6.2, -3.2) 
 
12 
4.7 (2.5, 6.3) 
-2.4 (-4.2, -1.6) 
Week 24 
   n 
   Mean (Min, Max) 
   Change from Baseline (Min, Max) 
 
12 
2.2 (1.3, 3.4) 
-5.7 (-6.8, -4.2) 
 
12 
4.6 (2.6, 6.2) 
-2.5 (-4.3, -1.6) 
Week 36 
   n 
  Mean (Min, Max) 
  Change from Baseline (Min, Max) 
 
11 
1.8 (1.3, 3.4) 
-6.1 (-7.3, -4.2) 
 
11 
4.3 (2.1, 5.8) 
-2.7 (-4.5, -1.8) 
Week 48 
   n 
   Mean (Min, Max) 
   Change from Baseline (Min, Max) 
 
12 
1.6 (1.0, 2.7) 
-6.3 (-7.2, -4.2) 
 
12 
4.3 (2.1, 5.8) 
-2.8 (-4.9, -1.9) 
Abbreviations: ETV=entecavir; HBV=hepatitis B virus; IU=international units; Max=maximum; Min=minimum; n=number of 
subjects at each visit; N=Number of subjects in the Intent-to-Treat population; pgRNA=pregenomic RNA; U=units.  
Source: Study 211 Trends Analysis Table 4.1.1, 4.2. 
HBV DNA lower limit of quantitation (LLOQ)=20 IU/mL (1.30 log10 IU/mL); HBV pgRNA LLOQ=135 U/mL 
(2.13 log10 U/mL). 
a 
Subjects who received vebicorvir+ETV in Study 202 
The addition of VBR to NrtI has the potential to more effectively inhibit HBV replication than 
NrtI alone. In addition to reductions in HBV DNA, VBR also reduces HBV pgRNA which is 
considered to be a direct assessment of cccDNA transcription (Wang 2016). The measurement of 
a combined meaningful reduction in both HBV DNA and HBV pgRNA is therefore important in 
assessing the overall treatment effect on HBV replication. Figure 3 summarizes the proportions of 
subjects who attained both HBV DNA <LLOQ and either HBV pgRNA ≥3 log10 reduction from 
Baseline or HBV pgRNA <LLOQ (considered responders) at key study visits through 48 weeks 
of treatment with VBR+ETV. 
In these subjects, 17% (2/12) attained the combined endpoint of HBV DNA <LLOQ and either 
HBV pgRNA >3 log10 reduction from Baseline or HBV pgRNA <LLOQ. While the number of 
subjects in this subgroup is relatively low and there is no direct comparator of ETV alone for the 
full treatment duration, Figure 1 and Figure 2 provide context for estimated reductions in HBV 
DNA and HBV pgRNA that would likely be observed with ETV monotherapy. 


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Figure 3. 
Proportions of Treatment-Naïve Subjects with HBV DNA <LLOQ and HBV 
pgRNA Decrease ≥ 3 log10 U/mL from Baseline or HBV pgRNA <LLOQ by 
Week of Treatment with Vebicorvir+ETV (Study 202/211) 
 
Abbreviations: ETV=entecavir; HBV=hepatitis B virus; LLOQ=lower limit of quantitation; pgRNA=pregenomic ribonucleic 
acid; TND=target not detected. 
As HBV DNA and HBV pgRNA decline over time, it is anticipated that reductions in HBV 
antigens may be observed reflective of a lower viral replicative state. Table 3 summarizes the 
absolute and change from Baseline in HBeAg, HBcrAg and HBsAg by week of treatment. The 
Baseline values for HBeAg, HBcrAg and HBsAg were 2.5 log10 IU/mL, 5.5 log10 kU/mL and 4.5 
log10 IU/mL, respectively. The change from Baseline at Week 48 was -0.4 log10 IU/mL, -0.8 log10 
kU/mL and -0.2 log10 IU/mL for HBeAg, HBcrAg and HBsAg, respectively. 


Vebicorvir 
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Table 3. 
HBV Antigens for Treatment-Naïve Subjects with cHBV by Week of 
Treatment with Vebicorvir+ETV (Study 202/211) 
Week of Treatment 
HBeAga 
Log10 IU/mL 
(N=12) 
HBcrAga 
Log10 kU/mL 
(N=12) 
HBsAga 
Log10 IU/mL 
(N=12) 
Baseline 
  n 
  Mean (Min, Max) 
 
12 
2.5 (0.6, 3.1) 
 
12 
5.5 (3.6, 6.2) 
 
12 
4.5 (3.3, 4.9) 
Week 12 
  n 
 Mean (Min, Max) 
 Change from Baseline (Min, Max) 
 
12 
2.2 (0.2, 3.1) 
-0.3 (-1.5, 0.1) 
 
12 
5.1 (3.1, 5.9) 
-0.4 (-2.0, 0.0) 
 
12 
4.3 (3.4, 4.9) 
-0.1 (-1.5, 0.5) 
Week 24 
  n 
 Mean (Min, Max) 
 Change from Baseline (Min, Max) 
 
12 
2.1 (0.1, 3.1) 
-0.4 (-1.1, 0.0) 
 
11 
4.9 (3.0, 6.0) 
-0.5 (-2.1, -0.1) 
 
12 
4.3 (3.3, 4.8) 
-0.2 (-1.6, 0.7) 
Week 36 
  n 
  Mean (Min, Max) 
 Change from Baseline (Min, Max) 
 
11 
2.0 (0.1, 3.1) 
-0.4 (-1.1, 0.1) 
 
11 
4.6 (2.6, 5.7) 
-0.8 (-2.5, -0.1) 
 
11 
4.2 (3.4, 4.8) 
-0.20 (-1.5, 0.7) 
Week 48 
  n 
  Mean (Min, Max) 
 Change from Baseline (Min, Max) 
 
12 
2.1 (0.0, 3.1) 
-0.4 (-1.2, 0.1) 
 
12 
4.7 (2.5, 5.8) 
-0.8 (-2.6, 0.0) 
 
12 
4.2 (3.3, 4.8) 
-0.2 (-1.5, 0.7) 
Abbreviations: cHBV=chronic hepatitis B virus infection; ETV=entecavir; HBcrAg=hepatitis B core-related antigen; 
HBeAg=hepatitis B e antigen; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; IU=international units; kU=kilounits; 
Max=maximum; Min=minimum; n=number of subjects at each visit; N=Number of subjects in the Intent to Treat population.  
Source: Trends Analysis Tables 4.3, 4.4, 4.5  
Lower limit of quantitation (LLOQ) HBeAg=0.11 IU/mL (-0.96 log10 IU/mL); LLOQ for HBcrAg=1 kU/mL (0 log10 kU/mL); 
LLOQ for HBsAg=0.05 IU/mL (-1.30 log10 IU/mL). 
a 
Subjects who received vebicorvir+ETV in Study 202. 
Table 4 summarizes the absolute and change from Baseline in serum ALT and proportions of 
subjects who were >ULN of ALT at key study visits. Treatment with VBR+NrtI led to rapid and 
sustained normalization of ALT with a mean (minimum, maximum) change from Baseline at 
Week 48 of -40.8 (-286.0, 148.0). 
Table 4. 
Alanine Aminotransferase for Treatment-Naïve Subjects with cHBV by Week 
of Treatment with Vebicorvir+ETV (Study 202/211) 
Week of Treatment 
Vebicorvir+ETV a 
(N=12) 
U/L 
Baseline 
 
n 
12 
Mean (Min, Max) 
70.3 (17, 295) 
>ULN, n (%) 
7 (58) 
Week 12 
 
n 
12 
Mean (Min, Max) 
22.3 (13.0, 33.0) 
Change from Baseline (Min, Max) 
-48.1 (-272.0, 6.0) 


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Week of Treatment 
Vebicorvir+ETV a 
(N=12) 
U/L 
>ULN, n (%) 
0 
Week 24 
 
n 
12 
Mean (Min, Max) 
19.2 (10.0, 37.0) 
Change from Baseline (Min, Max) 
-51.2 (-282.0, 17.0) 
>ULN, n (%) 
1 (8) 
Week 36 
 
n 
11 
Mean (Min, Max) 
26.5 (9.0, 128.0) 
Change from Baseline (Min, Max) 
-48.6 (-286.0, 108.0) 
>ULN, n (%) 
1 (9) 
Week 48 
 
n 
12 
Mean (Min, Max) 
29.6 (9.0, 168.0) 
Change from Baseline (Min, Max) 
-40.8 (-286.0, 148.0) 
>ULN, n (%) 
1(8) 
Abbreviations: cHBV=chronic hepatitis B virus infection; ETV=entecavir; Max=maximum; Min minimum; n=number of subjects 
at each visit; N=number of subjects in the Intent-to-Treat population.; U=units; ULN = upper limit of normal. 
Source: Study 211 Trends Analysis Table 4.6  
ULN (Covance)=34 U/L for females and 43 U/L for males. 
No subjects in Study 202/211 have had evidence of treatment-emergent resistance. 
a 
Subjects who received vebicorvir+ETV in Study 202. 
2.2.3.3.2 
Virologically-Suppressed Subjects with HBeAg Positive or HBeAg Negative 
cHBV (Originating from Study 201) 
The virologically-suppressed subjects with cHBV who enrolled in Study 201 had low HBV DNA 
at Baseline, thus HBV DNA in this population is reported in Study 201 and Study 211 by a 
sensitive Assembly semi-quantitative polymerase chain reaction (PCR) assay with a Limit of 
detection=5 IU/mL. Table 5 summarizes the proportions of HBeAg positive and HBeAg negative 
subjects with undetectable HBV DNA (target not detected; [TND]) at Baseline, Week 24, and 
Week 48 of treatment with VBR+NrtI in Study 201/211. 
To be eligible for participation in the Study 201, subjects must have had HBV DNA ≤20 IU/mL 
on NrtI treatment for at least 6 months before screening. As shown in Table 5, despite this 
eligibility criterion, only 7% (2/27) HBeAg positive and 63% (10/16) HBeAg negative subjects 
had HBV DNA TND (LOD=5 IU/mL) at Baseline by the high sensitivity Assembly assay. This is 
consistent with prior reports in which virologically-suppressed individuals with cHBV on 
standard-of-care NrtI treatment who had HBV DNA <20 IU/mL still harbored low levels of 
infectious virus (Marcellin 2014, Burdette 2019). Following 48 weeks of treatment with 
VBR+NrtI, 81% (21/26) HBeAg positive subjects and 93% (13/14) of HBeAg negative subjects 
had achieved HBV DNA TND by the high sensitivity Assembly assay. These data provide 
evidence that the addition of VBR to NrtI results in deeper virologic suppression in virologically-
suppressed subjects with HBeAg positive or HBeAg negative cHBV who have received chronic 
NrtI therapy for some time. 


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Table 5. 
HBV DNA for Virologically-Suppressed Subjects with cHBV by Week of 
Treatment with Vebicorvir+NrtI (Study 201/211) 
Week of Treatment 
HBV DNA  
Patients with TND 
[n/N, (%)] 
HBeAg Positivea 
(N=27) 
HBeAg Negativea 
(N=16) 
Baseline 
2/27 (7) 
10/16 (63) 
Week 24 
22/27 (81) 
15/16 (94) 
Week 48 
21/26 (81) 
13/14 (93) 
Abbreviations: HBeAg=hepatitis B e antigen; HBV=hepatitis B virus; N=number of subjects in the intent-to-treat population; 
n=number of patients at each visit; TND=target not detected. 
HBV DNA LOD=5 IU/mL.  
 a Subjects who received ABI-H0731+NrtI in Study 201 
As described above, the virologically-suppressed subjects with cHBV who enrolled in Study 201 
had low HBV pgRNA at Baseline and so HBV pgRNA in this population is reported in Study 201 
and Study 211 by a sensitive Assembly RT-qPCR assay with LLOQ <35 U/mL. Table 6 
summarizes the absolute value and change from Baseline in HBV pgRNA by week of treatment. 
In HBeAg positive subjects, the mean (minimum, maximum) Baseline HBV pgRNA was 3.6 (1.5, 
6.1) log10 U/mL which decreased to 1.9 (1.5, 4.6) log10 U/mL after 48 weeks of treatment, 
representing a mean (minimum, maximum) change of -1.7 (-3.7, 0) log10 U/mL. Compared to 
HBeAg positive subjects, pgRNA was lower in HBeAg negative subjects and showed less change 
over 48 weeks of treatment with VBR+NrtI. In HBeAg negative subjects, the mean (minimum, 
maximum) Baseline HBV pgRNA was 1.7 (1.5, 2.6) log10 U/mL which decreased to 1.5 (1.5, 1.6) 
log10 U/mL at Week 48. 


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Table 6. 
HBV pgRNA for Virologically-Suppressed Subjects with cHBV by Week of 
Treatment with Vebicorvir+NrtI (Study 201/211) 
Week of Treatment 
HBV pgRNA 
Log10 U/mL 
HBeAg Positivea 
(N=27) 
HBeAg Negativea 
(N=16) 
Baseline 
 n 
 Mean (Min, Max) 
 
27 
3.6 (1.5, 6.1) 
 
16 
1.7 (1.5, 2.6) 
Week 12 
 n 
 Mean (Min, Max) 
 Change from Baseline (Min, Max) 
 
27 
1.9 (1.5, 3.7) 
-1.7 (-3.5, 0.0) 
 
16 
1.5 (1.5, 1.5) 
-0.1 (-1.0, 0.0) 
Week 24 
 n 
 Mean (Min, Max) 
 Change from Baseline (Min, Max) 
 
27 
1.9 (1.5, 3.4) 
-1.7 (-3.1, 0.0) 
 
16 
1.5 (1.5, 1.7) 
-0.1 (-1.0, 0.0) 
Week 36 
 n 
 Mean (Min, Max) 
 Change from Baseline (Min, Max) 
 
27 
1.9 (1.5, 3.6) 
-1.7 (-3.6, 0.0) 
 
14 
1.6 (1.5, 1.9) 
-0.1 (-1.0, 0.3) 
Week 48 
 n 
 Mean (Min, Max) 
 Change from Baseline (Min, Max) 
 
26 
1.9 (1.5, 4.6) 
-1.7 (-3.7, 0.0) 
 
14 
1.5 (1.5, 1.6) 
-0.1 (-1.0, 0.1) 
Abbreviations: HBeAg=hepatitis B e antigen; HBV=hepatitis B virus; Max=maximum; Min=minimum; n=number of subjects at 
each visit; N=number of subjects in the Intent-to-Treat population; NrtI=Nucleos(t)ide/reverse transcriptase inhibitor; 
pgRNA=pregenomic ribonucleic acid.  
Source: Trends Analysis Table 4.2  
pgRNA LLOQ=35 U/mL.  
a 
Subjects who received vebicorvir+NrtI in Study 201. 
The measurement of combined reduction in both HBV DNA and HBV pgRNA is important in 
assessing the overall treatment effect of VBR+NrtI on HBV replication. Figure 4 summarizes the 
proportions of virologically-suppressed subjects originally enrolled in Study 201 who attained 
both HBV DNA TND and HBV pgRNA <LLOQ (considered responders) through 48 weeks of 
treatment with VBR+NrtI. In HBeAg positive subjects, 4% (1/27) attained the combined endpoint 
of HBV DNA TND and HBV pgRNA <LLOQ at Baseline which increased to 73% (19/26) at 
Week 48. In HBeAg negative subjects, 63% (10/16) attained the combined endpoint of HBV DNA 
TND and HBV pgRNA <LLOQ at Baseline which increased to 86% (12/14) at Week 48. Together, 
these results suggest that treatment with VBR+NrtI leads to deeper virologic suppression through 
more effective inhibition HBV replication. 


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Figure 4. 
Proportion of Virologically-Suppressed Subjects With HBV DNA TND and 
HBV pgRNA <LLOQ by Week of Treatment with Vebicorvir+ETV 
(Study 201/211) 
 
Abbreviations: ETV=entecavir; HBV=hepatitis B virus; LLOQ=lower limit of quantitation; pgRNA=pregenomic ribonucleic 
acid; TND=target not detected. 
Subjects in Study 201 had low mean serum ALT was at Baseline (25.0-26.7 U/L) as would be 
expected for virologically-suppressed individuals on chronic NrtI therapy. Analyses of ALT over 
the 48 weeks of treatment with VBR+NrtI in this patient population are not included in this 
summary since it is not meaningful to show change or normalization. 
One subject in Study 201/211 experienced virologic rebound and had evidence of 
treatment-emergent resistance. This subject had been virologically-suppressed with HBV DNA 
<LLOQ through Week 12 in Study 201 but had low-level viremia with HBV DNA 22-74 IU/mL 
between Week 16 and Week 24. In Study 211, the subject reported noncompliance with study drug 
which began around Week 12, intermittently taking NrtI (tenofovir) with continuous VBR, and 
then intermittently taking VBR. The subject experienced virologic rebound with HBV DNA levels 
of 4.68 log10 IU/mL at Week 16 at which time the resistance-associated substitution T109I was 
observed in 100% of the circulating viral population. Per protocol, the subject discontinued VBR 
treatment, and restarted NrtI treatment. The subject’s HBV DNA declined to <20 IU/mL at the 
first follow-up visit 1 month later and HBV DNA was not detected at a follow-up visit 3 months 
later. 
 
AB-729 
2.3.1 
Description 
AB-729 is a novel subcutaneously administered small interfering ribonucleic acid (siRNA) 
inhibitor of HBV that induces cleavage and degradation of HBV ribonucleic acid (RNA) through 


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the mechanism of RNA interference (RNAi). The AB-729 drug substance is a 
N-Acetylgalactosamine (GalNAc)-conjugated siRNA duplex composed of single antisense 
(AB-729-AS) and sense (AB-729-S) strands. In each duplex, the AB-729-AS and AB-729-S 
strands are present at a nominal 0.49:0.51 (weight:weight) ratio and are bound together by 
Watson-Crick base pairing over a 17-base region of complementarity. 
General information concerning AB-729 is described in the AB-729 IB. 
2.3.2 
Nonclinical Studies  
Refer to the AB-729 IB for a complete summary of the nonclinical and toxicology studies 
performed to date. 
2.3.3 
Clinical Studies  
Preliminary data from the ongoing first-in-human Study AB-729-001 (A Single and Multiple Dose 
Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
AB-729 Administered by Subcutaneous Injection to Healthy Subjects and Subjects with Chronic 
Hepatitis B Infection), including Part 1 healthy subject safety and PK, are available in the AB-729 
IB. Additional preliminary safety and efficacy data from fully enrolled cohorts in Part 2 (single 
doses of 60 mg, 90 mg, or 180 mg in virologically-suppressed cHBV subjects) and Part 3 (repeat 
doses of 60 mg administered every 4 weeks or every 8 weeks in cHBV subjects) are described in 
Sections 2.3.3.1, 2.3.3.2, and 2.3.3.3. The summary of preliminary safety and efficacy data is based 
on a data cut-off date of 23 September 2020. 
2.3.3.1 
Study AB-729-001 Preliminary Disposition  
To date, 22 subjects have been dosed amongst 4 cohorts in Part 2 (single doses of AB-729 at either 
60 mg [n=6], 90 mg [n=6], or 180 mg [n=4]), and 16 subjects have been dosed amongst 4 cohorts 
in Part 3 (repeat doses of AB-729 at either 60 mg administered every 4 or 8 weeks [n=7 per cohort], 
or 90 mg administered every 8 or 12 weeks [n=1 per cohort]) of the study. Cohort A (180 mg 
single dose) has been completed, but the remainder of the cohorts are ongoing. No subjects have 
discontinued due to AEs, but 2 subjects (Cohort C, 90 mg single dose) withdrew consent after the 
Week 12 follow-up visit for personal reasons. 
2.3.3.2 
Study AB-729-001 Preliminary Safety  
In Part 2 of Study AB-729-001, preliminary safety data are available for Cohort A (180 mg single 
dose), Cohort B (60 mg single dose), and Cohort C (90 mg single dose). There have been no deaths, 
SAEs, or AEs leading to discontinuation. In Cohort A, 8 TEAEs were observed in 4 subjects 
including 5 related AEs (Grade 1 ALT [n=2] and AST; Grade 2 headache [n=2]). One subject had 
an unrelated Grade 2 foodborne toxic illness that was accompanied by Grade 3 ALT and AST 
changes (without bilirubin changes or changes in markers of liver synthetic function), which 
returned to baseline levels. In Cohort B, 6 Grade 1 TEAEs have been observed in 3 subjects, 
including 2 related AEs of Grade 1 injection site redness and injection site pruritis, both transient. 


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In Cohort C, 8 Grade 1 or 2 TEAEs have been observed in 6 subjects, including 5 related AEs of 
Grade 1 or 2 injection site pain lasting less than 1 hour (including 2 subjects whose doses were 
split into 2 injections erroneously). There were no other clinically significant changes in laboratory 
parameters, ECGs, vital signs, or physical exam findings. 
In Part 3 of Study AB-729-001, preliminary safety data are available for Cohort E (60 mg 
administered every 4 weeks) and Cohort F (60 mg administered every 8 weeks). There have been 
no deaths, SAEs, or AEs leading to discontinuation. In Cohort E, 7 Grade 1 or 2 TEAEs have been 
observed in 4 subjects, including 4 related Grade 1 injection site AEs (bruising and transient 
redness) and 2 related Grade 1 ALT elevations. In Cohort F, 2 Grade 1 TEAEs have been observed 
in 2 subjects, both related (fatigue and injection site redness). There were no other clinically 
significant changes in laboratory parameters, ECGs, vital signs, or physical exam findings. 
2.3.3.3 
Study AB-729-001 Preliminary Efficacy  
While clinical efficacy is not an objective of Study AB-729-001, preliminary pharmacodynamic 
data are available from 4 subjects in Part 2, Cohort A (180 mg single dose), 6 subjects in Part 2, 
Cohort B (60 mg single dose), 6 subjects in Part 2, Cohort C (90 mg single dose), and 6 subjects 
in Part 3, Cohort E (60 mg every 4 weeks). 
After administration of single subcutaneous doses of 60 mg, 90 mg, or 180 mg of AB-729, all 
subjects demonstrated >0.5 log10 IU/mL declines in HBsAg by the follow-up Week 12 visit: mean 
(SEM) HBsAg declines were similar at -0.989 (0.238) log10 IU/mL, -1.23 (0.180) log10 IU/mL, 
and 0.980 (0.217) log10 IU/mL and 3/6, 5/6, and 3/4 subjects achieved ≥1 log10 decline in HBsAg, 
respectively.  
In Part 3, HBV DNA negative cHBV subjects are currently receiving AB-729 60 mg every 
4 weeks. At Week 12 (4 weeks after the third dose of AB-729), mean (SEM) HBsAg decline 
was -1.10 (0.154) log10 IU/mL, similar to that observed at Week 12 following single subcutaneous 
doses of 60 mg to 180 mg. 
 
Study Rationale  
2.4.1 
Rationale for Combination Treatment of Vebicorvir and AB-729  
Chronic hepatitis B virus infection is a major cause of liver-related morbidity and mortality 
affecting >250 million people worldwide. While SOC therapy with NrtIs is able to achieve 
adequate viral suppression in most HBeAg negative patients and three quarters of HBeAg positive 
patients, SVR off-treatment and loss of HBsAg are rare (<5%). Compared to NrtIs, finite treatment 
with Peg-IFNα leads to lower rates of viral suppression although small increases in the rate of 
HBsAg loss (5-10%) have been observed. However, any advantages associated with 
immunomodulation are offset by poor tolerability of Peg-IFNα. New therapeutic modalities are 
required to improve the depth of suppression and provide the potential for cure. Combination 
regimens utilizing agents with complementary mechanisms of action and resistance profiles will 
likely be required to support finite treatment durations. 


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Vebicorvir is an orally administered, potent and selective small molecule inhibitor of the HBV 
core protein. Through this mechanism, VBR interferes with multiple steps in the viral lifecycle 
including capsid disassembly and DNA delivery to the nucleus, pgRNA encapsidation, capsid 
assembly, and DNA recirculation preventing de novo establishment of cccDNA.  
AB-729 is a subcutaneously administered novel GalNAc-conjugated siRNA, which cleaves and 
degrades HBV RNA, inhibiting production of all viral proteins including HBsAg. Suppression of 
HBsAg production by AB-729 may contribute to breaking immune tolerance to HBV and restoring 
T-cell activity directed toward HBV, thereby promoting functional cure. The addition of VBR and 
AB-729 to other treatments for cHBV will provide multiple complementary antiviral mechanisms, 
with potential collateral immunological consequences, that may act synergistically to increase cure 
rates. This Phase 2a study will explore the safety and antiviral activity of VBR and AB-729 in 
combination with other cHBV treatments (NrtIs). 
2.4.2 
Rationale for Dose Selection  
In the Phase 1 clinical studies, VBR was well-tolerated in healthy subjects at single doses of up to 
1000 mg daily, at twice daily doses of 800 mg for 7 days, and at single daily doses of up to 300 mg 
for 14 days. All TEAEs were considered mild (Grade 1) and reversible. In subjects with cHBV, 
VBR was well tolerated at doses of up to 300 mg daily for 28 days. Final data indicate that there 
is a dose dependent decrease in viral load at doses of 100 mg, 200 mg, and 300 mg daily in subjects 
with cHBV. Phase 2 studies (Studies 201, 202, and 211) demonstrate that 300 mg VBR 
administered once daily in combination with NrtI for 48 weeks is well-tolerated and leads to 
continued reductions in HBV DNA and HBV pgRNA (see Section 2.2.3). It is expected that this 
regimen will be safe, well-tolerated, and demonstrate improved HBV suppression in subjects with 
cHBV compared to SOC NrtI therapy.  
In the AB-729 Phase 1 clinical study (Study AB-729-001), single and repeat 60 mg subcutaneous 
doses administered every 4 weeks were well tolerated in healthy subjects and subjects with cHBV. 
In subjects with cHBV, there were no SAEs or AEs leading to discontinuation; all AEs were 
considered mild (Grade 1). As described previously and displayed in Figure 5, preliminary 
pharmacodynamic data from this study showed similar mean HBsAg declines at Week 12 
following administration of AB-729 60 mg every 4 weeks as that following a single dose of 
AB-729 60 mg. Furthermore, the slopes of mean HBsAg decline appear similar between single 
and multiple doses of AB-729 60 mg and taken together, these data suggest that dosing AB-729 
as frequently as every 4 weeks is not necessary to achieve substantial HBsAg decline. Thus, 
AB-729 60 mg will be administered every 8 weeks in this study. 


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Figure 5. 
Mean (±SEM) Log10 HBsAg Declines up to 12 Weeks Post Single Dose of 
AB-729 60 mg or AB-729 60 mg Administered Every 4 Weeks 
 
Abbreviations: HBsAg=hepatitis B surface antigen; Q4weeks=every 4 weeks. 
The cumulative safety, tolerability, and antiviral activity data generated to date with both VBR 
and AB-729 support the conduct of the proposed study. 


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3 STUDY OBJECTIVES AND ENDPOINTS  
 
Study Objectives  
3.1.1 
Primary Objective 
The primary objective of Cohort 1 is:  
• To evaluate the safety and tolerability of combination treatment with VBR, AB-729, and 
NrtI 
3.1.2 
Secondary Objectives  
The secondary objectives of Cohort 1 are:  
• To evaluate the effect of adding VBR and AB-729 to NrtI on reduction in and loss of 
HBsAg 
• To evaluate the effect of adding VBR and AB-729 to NrtI in reducing HBV DNA levels  
• To evaluate the effect of adding VBR and AB-729 to NrtI in reducing HBV RNA levels  
• To evaluate the effect of adding VBR and AB-729 to NrtI in reducing other HBV 
antigens (ie, HBcrAg)  
• To evaluate the effect of adding VBR and AB-729 to NrtI on HBsAg seroconversion 
• To evaluate the effect of adding VBR and AB-729 to NrtI on normalization of ALT 
• To evaluate the off-treatment durability of response to treatment with VBR and AB-729 
• To evaluate the PK of VBR and AB-729 when coadministered with NrtI 
3.1.3 
Exploratory Objectives  
The exploratory objectives of Cohort 1 are:  
• To evaluate the emergence of resistance to VBR and AB-729 when coadministered with 
NrtI 
• To evaluate the effect of VBR, AB-729, and NrtI on immunological biomarkers, where 
applicable 
• To evaluate the effect of VBR, AB-729, and NrtI on HBsAg isoforms and immune 
complexes, where applicable 


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• To evaluate the effect of AB-729 on an HBV-derived RNA interference biomarker, 
where applicable 
 
Study Endpoints  
3.2.1 
Primary Endpoint 
The primary endpoint of Cohort 1 is: 
• Proportion of subjects with AEs, premature treatment discontinuation due to AEs, and 
abnormal laboratory results 
3.2.2 
Secondary Endpoints 
The secondary endpoints of Cohort 1 are:  
• Mean change in log10 HBsAg from Baseline at each timepoint 
• Proportion of subjects with HBsAg <LLOQ at each timepoint 
• Proportion of subjects with HBV DNA TND (<5 IU/mL) at Week 48 
• Proportion of subjects with HBV RNA <LLOQ at Week 48 
• Mean change in log10 HBV RNA from Baseline at each timepoint 
• Mean change in log10 HBcrAg from Baseline at each timepoint 
• Proportion of subjects with HBsAg seroconversion at Week 48 
• Proportion of subjects with abnormal ALT at Baseline who have normal ALT (by central 
laboratory and American Association for the Study of Liver Diseases [AASLD] criteria) 
at each timepoint 
• Proportion of subjects achieving Treatment Stopping Criteria at end of treatment (EOT) 
• Proportion of subjects who remain off-treatment at end of study (EOS) 
• Analysis of VBR and AB-729 drug concentrations.  NrtI concentrations may be analyzed, 
as needed 
3.2.3 
Exploratory Endpoints  
The exploratory endpoints of Cohort 1 are:  
• Proportion of subjects who continued NrtI after Week 48 and subsequently met the 
Treatment Stopping Criteria  


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• The incidence of HBV variants with reduced susceptibility to VBR and AB-729 
• The evaluation of immune response markers, where applicable 
• The evaluation of the effect on HBsAg isoforms, where applicable  
• The evaluation of the effect on HBsAg immune complexes, where applicable 
• The evaluation of the effect on an HBV-derived RNAi biomarker over time, where 
applicable 


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4 STUDY DESIGN  
 
Overview  
This is a randomized Phase 2a, multicenter, open-label, multiple-cohort study evaluating the safety 
and antiviral activity of VBR and AB-729 in combination with other cHBV treatments in subjects 
with cHBV. 
Cohort 1 is prespecified and will enroll virologically-suppressed subjects on NrtI therapy with 
HBeAg negative cHBV. Approximately 60 eligible subjects will be randomized 2:1:1 in 1 of 
3 treatment groups as shown in Figure 6. Up to 2 additional cohorts may be added in future 
protocol amendments to evaluate other populations and/or treatment regimens. 
Figure 6.  
Study Design Schematic for Study ABI-H0731-204 
Abbreviations: VBR=vebicorvir; NrtI= nucleos(t)ide /reverse transcriptase inhibitor; Wk=week. 
Treatment assignments will be stratified by HBsAg level (ie, HBsAg ≤1000 IU/mL vs 
>1000 IU/mL) during the Screening visit. 
Treatment with VBR and NrtI will be administered orally, once daily; treatment with AB-729 will 
be administered subcutaneously, once every 8 weeks, for a total of 6 doses (Figure 6). 
4.1.1 
Treatment Stopping Criteria 
At Week 48, all subjects will have an assessment of Treatment Stopping Criteria. Any subjects 
who meet the below Treatment Stopping Criteria, will discontinue their assigned treatment 
including NrtI, and continue with off-treatment follow-up through Week 96, unless they meet the 
NrtI-restart criteria (see Section 4.1.2). Decisions to discontinue assigned treatment and undergo 
off-treatment follow-up will be based on laboratory results from blood samples collected at the 
Week 48 visit. Subjects will remain on their assigned oral agents (ie, VBR+NrtI for Groups 1 and 
2; NrtI for Group 3) until Week 48 laboratory results required for Treatment Stopping Criteria 
assessment are available. 
Treatment Stopping Criteria are:  
• ALT < 2 × ULN, and 


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• HBV DNA < LLOQ, and 
• HBsAg < 100 IU/mL 
Subjects who do not meet the Treatment Stopping Criteria with Week 48 laboratory results will 
continue treatment with NrtI alone and will remain in follow-up through Week 96. 
4.1.2 
NrtI-Restart Criteria  
Subjects who meet the Treatment Stopping Criteria at the Week 48 assessment but subsequently 
meet ANY of the below NrtI-Restart Criteria, will restart treatment with NrtI and remain in follow-
up through Week 96.  
NrtI-Restart Criteria are:  
• ALT > 10 ×ULN, confirmed by repeat 
• ALT > Baseline and > ULN, confirmed by repeat, and  
o Direct bilirubin > 2.0 × ULN, confirmed by repeat, or 
o International Normalized Ratio > 1.5, confirmed by repeat 
• ALT ≥ 2 – 5 × ULN AND HBV DNA > 2000 IU/mL for 12 weeks 
• ALT elevations ≥ 5 – 10 ×ULN AND HBV DNA > 2000 IU/mL for 4 weeks 
• Any clinical decompensation, regardless of HBV DNA level 
• Investigator discretion 
 
Study Treatments 
Approximately 60 subjects will be randomized in Cohort 1 as shown in Table 7. Up to 2 additional 
cohorts may be subsequently enrolled by future protocol amendments. 
Table 7. 
Subject Treatment Assignment for Study ABI-H0731-204 Cohort 1 
Treatment Group  
Study Treatment  
Mode of Delivery  
Number of Subjects per 
Group 
1 
VBR+AB-729+NrtI 
VBR and NrtI: Oral; 
AB-729: Subcutaneous 
30 
2 
VBR+NrtI 
Oral 
15 
3 
AB-729+NrtI 
AB-729: Subcutaneous; 
NrtI: Oral 
15 


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Treatment Group  
Study Treatment  
Mode of Delivery  
Number of Subjects per 
Group 
Total Subjects Planned: 
60 
Abbreviations: NrtI=nucleos(t)ide/reverse transcriptase inhibitor; VBR=vebicorvir. 
For detailed information regarding dosing and administration, refer to Sections 6.1.1.4 and 6.1.2.4. 
 
Duration of Treatment  
All subjects will receive their assigned treatment for 48 weeks. Subjects will continue to receive 
assigned oral agents (ie, VBR+NrtI for Groups 1 and 2, and NrtI for Group 3) until all laboratory 
results from the Week 48 visit are available to determine each individual subject treatment action, 
based on Treatment Stopping Criteria (discontinuation of all treatment or continuation of NrtI; see 
Section 4.1.1). 
 
End of Study Definition  
The study will end when the last subject completes the last visit of the follow-up period or is 
considered “lost to follow-up,” whichever is later.  


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5 STUDY POPULATION  
 
Number of Subjects  
Approximately 60 subjects will be enrolled in Cohort 1 of this study. Up to 2 additional cohorts, 
with approximately 60 subjects per cohort, may be added in future protocol amendments, for a 
maximum sample size of approximately 180 subjects. 
 
Inclusion Criteria  
Subjects must meet all of the following inclusion criteria in order to be eligible for enrollment into 
Cohort 1: 
1. Willing and able to provide Informed Consent 
2. Male or female between the ages 18 and 50 years (inclusive) at Screening 
3. Body mass index (BMI) 18 to 36 kg/m2 and a minimum body weight of 45 kg (inclusive) 
at Screening 
4. Female subjects of child-bearing potential (Appendix 2) must be non-pregnant and have a 
negative serum pregnancy test at Screening and a negative urine pregnancy test at Day 1 
predose  
5. cHBV defined as HBV infection documented for ≥6 months prior to Screening 
6. Must be HBeAg negative at least 3 months prior to the Screening Visit (historical 
documentation) AND at the Screening Visit to be eligible  
7. Virologically suppressed on NrtI therapy with nonquantifiable HBV DNA for at least 
6 months prior to and including Screening 
8. On a stable NrtI regimen of entecavir (ETV), tenofovir disoproxil fumarate (TDF), or 
tenofovir alafenamide (TAF) for >12 months 
9. HBsAg ≥100 IU/mL at Screening 
10. Lack of bridging fibrosis or cirrhosis as documented by the following: 
• Fasting FibroScan® ≤8 kPa within 3 months prior to Screening (including the 
Screening visit) or other Sponsor-approved hepatic imaging method within 6 months 
prior to Screening (eg, Meta-analysis of Histological Data in Viral Hepatitis 
[METAVIR] F0-F2 or equivalent) 
OR 


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• Liver biopsy results (eg, METAVIR F0-F2 or equivalent) within 1 year prior to 
Screening 
If results from liver biopsy and FibroScan® are available, then the diagnostic method 
reporting the most advanced liver disease will be used to determine eligibility for the 
study 
11. Agreement to comply with protocol-specified contraceptive requirements (Appendix 2)  
12. In good general health, except for cHBV, in the opinion of the Investigator 
13. Able to take oral medication, be willing to receive subcutaneous injections of AB-729, 
and in the opinion of the Investigator, be willing to adhere to study treatment and 
procedures 
 
Exclusion Criteria  
Subjects who meet any of the following exclusion criteria will not be eligible for Cohort 1 of the 
study: 
1. Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), 
hepatitis D virus (HDV), acute hepatitis A virus (HAV), or acute hepatitis E virus (HEV)  
2. Females who are lactating or wish to become pregnant during the course of the study 
3. History of liver transplant or evidence of advanced liver disease, cirrhosis, or hepatic 
decompensation (including jaundice, ascites, portal hypertension, gastrointestinal 
bleeding esophageal varices, hepatic encephalopathy) at any time prior to, or at the time 
of Screening 
4. History of persistent alcohol abuse (alcohol consumption exceeding 2 standard drinks per 
day on average [1 standard drink=14 grams of alcohol]) or illicit drug abuse within 
3 years prior to Screening 
5. Clinically significant diseases or conditions, such as cardiac disease, including 
poorly-controlled or unstable hypertension; pulmonary disease; chronic or recurrent renal 
or urinary tract disease; liver disease other than cHBV; endocrine disorder; autoimmune 
disorder; poorly controlled diabetes mellitus; neuromuscular, musculoskeletal, or 
mucocutaneous conditions requiring frequent treatment, seizure disorders requiring 
treatment; ongoing infection or other medical conditions requiring frequent medical 
management or pharmacologic or surgical treatment that, in the opinion of the 
Investigator or the Sponsor, makes the subject unsuitable for study participation 
6. History of hepatocellular carcinoma (HCC) 


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7. History of malignancy other than HCC unless the subject’s malignancy has been in 
complete remission off chemotherapy and without additional medical or surgical 
interventions during the 3 years before Screening 
8. History or presence at Screening of electrocardiogram (ECG) abnormalities deemed 
clinically significant, in the opinion of the Investigator 
9. History of hypersensitivity or idiosyncratic reaction to any components or excipients of 
the investigational drugs 
10. History of any significant food or drug-related allergic reactions such as anaphylaxis or 
Stevens-Johnson syndrome 
11. The following are exclusionary laboratory results at Screening: 
a. Platelet count <100,000/mm3 
b. Albumin <3 g/dL  
c. Direct bilirubin >1.2× ULN  
d. ALT ≥5× ULN 
e. Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is > ULN but 
<100 ng/mL, the subject is eligible if hepatic imaging prior to initiation of study drug 
reveals no lesions indicative of possible HCC 
f. INR >1.5× ULN  
g. Estimated creatinine clearance (CrCl) <50 mL/min (using the Cockcroft-Gault 
method) based on serum creatinine and actual body weight at Screening  
h. Any other laboratory abnormality deemed clinically significant by the Investigator 
12. Current or prior use of prohibited concomitant medications from 28 days prior to Day 1 
(Section 6.3.1) 
13. Current or prior treatment for cHBV with: 
• Lamivudine, telbivudine or adefovir (any duration) 
• HBV core inhibitor (any duration) 
• siRNA or other oligonucleotide therapeutic (any duration) 
• Interferon in the 6 months prior to Screening 


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• Any investigational agent for cHBV in the 6 months prior to Screening 
14. Participation in another clinical study of a drug or device whereby the last investigational 
drug/device administration is within 60 days or 5 half-lives prior to the first study drug 
administration, whichever is longer 
 
Screen Failures  
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomized to study treatment. Minimal information to be retained on all screen 
failures includes demography, screen failure details, eligibility criteria, and any SAE information. 
Data regarding HBV genotype and HBV viral variants, if generated, will also be retained to further 
our understanding of the epidemiology of HBV and the natural frequency of polymorphisms 
present in the HBV sequences around the core and polymerase regions and the AB-729 target site.  
Individuals who do not meet the protocol eligibility criteria for participation in this study (screen 
failure) may be allowed to rescreen (once). Rescreening may occur following resolution of acute 
exclusionary conditions or stabilization of conditions that were exclusionary and reversible (eg, 
unstable hypothyroidism, electrolyte abnormalities) and with the approval of the study Medical 
Monitor. 
A single retest for a laboratory parameter(s) is permitted if there is a specific issue related to the 
collection, shipping, processing or analysis of a sample (eg, receipt of a hemolyzed sample at the 
testing laboratory, or samples received by the testing laboratory outside of the acceptable 
temperature range, or resolved intercurrent illness). If more than 45 days are required to obtain a 
result of a screening procedure and/or test conducted within the permitted window, the screening 
period may be extended until results are obtained. However, the clinical safety laboratory tests 
may need to be repeated under the instruction of the study Medical Monitor if the screening period 
is beyond 45 days.  
 


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6 STUDY DRUGS  
 
Investigational Medicinal Product(s) (IMPs) 
The investigational medicinal products (IMPs) to be used in this study are VBR and AB-729. 
6.1.1 
Vebicorvir  
6.1.1.1 
Formulation  
 
 
 
 
 
 
6.1.1.2 
Packaging and Labeling  
 
 
 
 
 
6.1.1.3 
Storage and Handling  
 
 
6.1.1.4 
Dosage and Administration  
Vebicorvir is administered once daily as a 300 mg oral dose (3×100 mg tablets); VBR and the NrtI 
(Groups 1 and 2 in Figure 6) should be taken together at approximately the same time each day.  
Additional information concerning VBR dosing and the management of missed or incorrect doses 
of VBR is provided in the Pharmacy Manual. 
6.1.2 
AB-729 
6.1.2.1 
Formulation  
 
 
 
 


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6.1.2.2 
Packaging and Labeling  
 
 
 
 
6.1.2.3 
Storage and Handling  
 
 
6.1.2.4 
Dosage and Administration  
AB-729 is administered once every 8 weeks as a 60 mg subcutaneous injection at specified clinic 
visits. 
Additional information concerning AB-729 dosing and the management of missed or incorrect 
doses is provided in the Pharmacy Manual. 
6.1.3 
Accountability of IMP  
Regulatory requirements stipulate accounting of all IMPs received by the study site. Records of 
drug disposition must include the date received by the site, date administered, quantity 
administered, and the subject to whom IMP was administered. The Investigator is responsible for 
the accountability of all IMPs at their site. The study site is to use an IMP accountability record to 
document IMP disposition. All items on this form are to be fully completed. The Sponsor or the 
Clinical Research Organization (CRO) will confirm if the method of recording IMP accountability 
by the site and the location of IMP records at the site is appropriate. 
Each time designated site personnel dispense IMP (ie, VBR and AB-729) for a subject, he or she 
is to record the date dispensed, the quantity of IMP dispensed, and his or her initials. Study site 
personnel are to monitor the inventory of clinical supplies and maintain a count of all used and 
unused IMP. The site monitor will review the IMP accountability records during the monitoring 
visits. The site pharmacist or designated staff member will keep accurate records of drug 
dispensation routinely during the study.  
For VBR, subjects will be asked to return used bottles and any unused IMP at study visits for 
accountability and compliance assessment. Returned VBR will be counted by study site personnel 
preferably in the presence of the subject. Subjects who forget to return VBR at a given visit will 
be asked to return them at the next study visit. Dose administration of VBR will be recorded in the 
subject diary. 
As AB-729 will be administered in the clinic by qualified study personnel, the study site will be 
responsible for performing IMP accountability following administration of each injection of 
AB-729. 


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6.1.3.1 
Return or Disposal of IMP  
Procedures for the return of VBR or provisions for onsite destruction (where approved 
prospectively by Assembly) are described in the Pharmacy Manual. 
 
Non-Investigational Medicinal Products(s) (NIMPs) 
6.2.1 
Nucleos(t)ide/Reverse Transcriptase Inhibitor (NrtI) 
The non-investigational medicinal product (NIMP) to be used in this study is NrtI. Acceptable 
NrtIs for administration in this study are TAF, TDF, or ETV. The NrtI will not be provided by the 
Sponsor unless required by the country or study site. 
6.2.1.1 
Formulation  
Details of the NrtI formulations are specified in the respective package inserts. 
6.2.1.2 
Packaging and Labeling  
Details of the NrtI packaging and labeling are specified in the respective package inserts. 
6.2.1.3 
Dosage and Administration  
Details for the NrtI dosage and administration are specified in the respective package inserts. The 
NrtI should be taken with VBR at approximately the same time each day. 
6.2.1.4 
Storage and Handling  
Details for the NrtI storage and handling are specified in the respective package inserts. 
6.2.2 
Accountability for NIMPs  
Oversight of background medication (NrtI) according to product label will be provided by the 
Investigator. Dose administration of NIMPs will be recorded in the subject diary. 
 
Concomitant Medications  
A concomitant medication is defined as any prescription or over-the-counter preparation, including 
vitamins, medications, vaccinations, herbal preparations and supplements that is taken by a subject 
during the conduct of the clinical trial.  
All concomitant medications taken from the date the informed consent is signed through end of 
study or “lost to follow-up” must be recorded in the subject’s source documentation. This 
information should include the name of the medication, the dosage, the start and stop dates, and 
the indication for which the concomitant medication was administered. 


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6.3.1 
Prohibited Concomitant Therapy  
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters [ie, P-glycoprotein] or metabolizing enzymes [ie, cytochrome P450s]) may result 
in PK interactions that increase or decrease the exposure of VBR or the concomitant medication. 
Examples of representative medications which are prohibited from 28 days prior to Day 1 through 
2 weeks after the last dose of VBR or “lost to follow-up” are listed in Table 8. Investigational 
agents are also prohibited. Provisions regarding concomitant medications described in the 
respective NrtI package inserts must also be followed during the study through the end of the 
follow-up period. 
Medications with narrow therapeutic indices should be avoided or used with caution 
(representative medications are shown in Table 8). Narrow therapeutic drugs that are substrates 
for CYP2C9 are prohibited. 
Should subjects need treatment with any prohibited concomitant medication, the Medical Monitor 
must be consulted prior to initiation of the new medication. In instances where a prohibited 
concomitant medication is initiated prior to discussion with the Medical Monitor, the Investigator 
must notify the Sponsor as soon as he/she is aware. 
Note that systemic (oral, injectable, or implanted) hormonal contraceptives are not considered as 
an acceptable means of contraception for female subjects of child-bearing potential (Appendix 2) 
up to 28 days after the last dose of VBR (Groups 1 and 2 in Figure 6). For AB-729, the use of 
hormonal contraceptives is acceptable for female subjects of child-bearing potential as long as they 
use a second non-hormonal form of contraception during the study and up to 6 months after the 
last dose of AB-729 (Group 3 in Figure 6). 
Table 8. 
Prohibited Concomitant Therapies  
Drug Class 
Prohibited Medications 
Use with Caution 
Antiarrhythmics 
 
Quinidine 
Anticonvulsants 
Phenytoin, carbamazepine, 
phenobarbital, oxcarbazepine 
Digoxin 
Antidepressants 
 
Amitriptyline, doxepin, fluoxetine, 
venlafaxine 
Antimycobacterials 
Rifamycins 
 
Cardiac Medications 
Warfarin, digoxin 
Irbesartan, losartan 
Hypoglycemics 
Troglitazone 
Glimepiride, glipizide, glyburide, 
nateglinide, rosiglitazone, tolbutamide, 
chlorpropamide, nateglinide 
Herbal/Natural 
Supplements 
St. John’s Wort, echinacea, milk 
thistle, grapefruit/grapefruit juice 
 


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Drug Class 
Prohibited Medications 
Use with Caution 
Nonsteroidal 
anti-inflammatory drugs 
(NSAIDs) 
 
Celecoxib, diclofenac, ibuprofen, 
lornoxicam, meloxicam, naproxen, 
piroxicam, suprofen 
Others 
Barbiturates, modafinil 
 
 
 
Randomization, Blinding, and Treatment Codes  
6.4.1 
Randomization  
All subjects will be assigned a unique Subject identification (ID) at Screening and will be 
randomized upon successful completion of the Screening assessments. Upon confirmation of 
subject eligibility on Day 1, an Interactive Response Technology (IRT) system will assign eligible 
subjects to a study treatment, as shown in Table 7. Additional information on the use of the IRT 
system is provided in the IRT User Manual. 
6.4.2 
Blinding  
This is an open-label study. 


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7 DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL  
 
Discontinuation of Study Treatment  
With the exception of treatment cessation based on Treatment Stopping Criteria (see Section 
4.1.1), if an individual subject is not satisfactorily tolerating their assigned treatment due to any 
AEs in the judgment of the Investigator, then, upon consultation with the Sponsor, the Investigator 
may discontinue treatment with VBR and/or AB-729 depending on the treatment group 
assignment. Discontinuation from treatment does not mean discontinuation from the study. 
Subjects who prematurely discontinue their assigned treatment regimen should immediately 
undergo the assessments listed for the Premature Termination visit (Section 8.5) and then continue 
scheduled follow-up assessments (Table 11).  
• If both or either IMP is discontinued, the subject may remain on NrtI as clinically indicated 
at the discretion of the Investigator.  
• For subjects in Group 1, if the NrtI is discontinued, then VBR must also be discontinued; 
treatment with AB-729 may be continued following discussion with the Medical Monitor. 
In this event, subjects will not be required to undergo a premature termination visit, and 
will continue with their scheduled visits, as planned.  
 
Criteria for Discontinuation of Study Treatment  
With the exception of treatment cessation based on Treatment Stopping Criteria (see Section 
4.1.1), study drug treatment may be discontinued in the following instances:  
• Intercurrent illness that would, in the judgement of the Investigator, affect assessments of 
clinical status to a significant degree 
• Unacceptable toxicity as defined in Section 9.10 (Toxicity Management), or toxicity that, 
in the judgment of the Investigator, compromises the ability to continue study-specific 
procedures or is considered to not be in the subject’s best interest 
• Lack of efficacy (virologic failure) 
• Subject noncompliance 
• Pregnancy during the study  
• Discontinuation of the study at the request of the Sponsor, a regulatory agency or an 
Institutional Review Board or Independent Ethics Committee (IRB/IEC) 


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Subject Discontinuation/Withdrawal from the Study  
A subject 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 or Sponsor for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. At the time of discontinuing from the 
study, if possible, a Premature Termination visit should be conducted (Section 8.5). 
7.3.1 
Subject Lost to Follow-Up  
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and is unable to be contacted by the study site. The following actions must be taken if a subject 
fails to return to the clinic for a required study visit: 
• The site must attempt to contact the subject, reschedule the missed visit as soon as possible, 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record. 
Should the subject continue to be unreachable, they will be considered lost to follow-up. 


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8 STUDY PROCEDURES AND ASSESSMENTS  
 
Schedule of Assessments  
All procedures for Cohort 1 of this study are outlined in Table 9.  


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Table 9. 
Schedule of Assessments (Cohort 1) – On-Treatment for All Subjects  
Period or Visit 
Screen 
On Treatment 
PT a UV b 
Study Day or Week  
D-45 to  
D-1 
D 1 
Wk  
2 
Wk  
4 
Wk  
8 
Wk  
12 
Wk  
16 
Wk  
20 
Wk  
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48 
NA 
NA 
Visit Windows (days)  
NA 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
NA 
NA 
Informed Consent(s)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical history & 
HBV history  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical exam  
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Symptom-directed physical exam 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
12-lead ECG c 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Review of concomitant 
medications & AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver staging  
X d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fibroscan® (if available)  
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
FibroTest®, APRI 
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Chemistry, hematology, 
coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CrCl  
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
AFP, HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV genotype  
X f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA (COBAS® TaqMan®) 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
HBV RNA (COBAS®)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV TNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Qualitative HBeAg  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
HBeAb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Quantitative HBsAg g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAb g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
HBcrAg 
X 
X 
 
 
 
  
 
 
 
 
 
  
 
 
X  
X  
 


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Period or Visit 
Screen 
On Treatment 
PT a UV b 
Study Day or Week  
D-45 to  
D-1 
D 1 
Wk  
2 
Wk  
4 
Wk  
8 
Wk  
12 
Wk  
16 
Wk  
20 
Wk  
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48 
NA 
NA 
Visit Windows (days)  
NA 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
NA 
NA 
HBsAg isoforms and immune 
complexes 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sample for HBV resistance 
monitoring  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Virology back-up sample h  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune biomarkers/cytokines 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
PBMCs i 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
RNAi biomarker sample 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCV Ab, HDV Ab, HIV Ab, HAV 
Ab, HEV Ab  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm subject eligibility  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense VBR  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
 
 
VBR administration (Groups 1, 
2)  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
NrtI administration (All 
subjects) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AB-729 administration (Group 1, 
3)  
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
VBR accountability  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review subject dosing diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review injection site reaction diary 
(Groups 1 and 3)  
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Sparse PK of VBR (Groups 1, 2)  
 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
Sparse PK of NrtI (All subjects) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sparse PK of AB-729 (Group 1, 
3) j   
 
X j 
 
 
X 
 
X 
 
X 
 
X 
 
X j 
 
 
 
 
Optional intensive PK substudy 
of AB-729 
 
X k  
 
 
 
 
 
 
 
 
 
 
X k 
 
 
 
 
Optional pharmacogenomic 
sample 
 
 
 
 
 
 
X l 
 
 
 
 
 
 
 
 
 
 


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Period or Visit 
Screen 
On Treatment 
PT a UV b 
Study Day or Week  
D-45 to  
D-1 
D 1 
Wk  
2 
Wk  
4 
Wk  
8 
Wk  
12 
Wk  
16 
Wk  
20 
Wk  
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48 
NA 
NA 
Visit Windows (days)  
NA 
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
NA 
NA 
Assessment of Treatment Stopping 
Criteria (see Section 4.1.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X m 
 
 
Abbreviations: Ab=antibody; AE=adverse event; AFP=alpha fetoprotein; APRI=aspartate aminotransferase to platelet ratio index; CrCl=creatinine clearance; D=day; 
DNA=deoxyribonucleic acid; ECG=electrocardiogram; HbA1c=glycated hemoglobin; HBcrAg=hepatitis B core-related antigen; HBeAb=anti-hepatitis B e antigen antibody; 
HBeAg=hepatitis B e antigen; HBsAb=anti-hepatitis B surface antigen antibody; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; 
HDV=hepatitis D virus; HEV=hepatitis E virus; HIV=human immunodeficiency virus; IRT= Interactive Response Technology; NA=not applicable; NrtI=nucleos(t)ide/reverse 
transcriptase inhibitor; PK=pharmacokinetic(s); PT=Premature Termination visit; RNA=ribonucleic acid; TNA=total nucleic acids; UV=Unscheduled visit; Wk(s)=week(s); 
VBR=vebicorvir.  
a 
Subjects who prematurely discontinue their assigned treatment regimen before the Week 48 visit should immediately undergo the assessments listed for the Premature 
Termination visit and then continue with Weeks 52 to 96 follow-up assessments (see Table 11). 
b 
Any subject with ALT elevation as defined in Section 9.10.4 should return to the clinic for an Unscheduled visit. 
c 
Any clinically significant ECG result will be confirmed.  
d 
At Screening, liver staging will be done EITHER via FibroScan ® (if available)/ other Sponsor-approved hepatic imaging method OR via liver biopsy.  
e 
A serum pregnancy test is required at Screening for female subjects of child-bearing potential. On Day 1, both urine and serum will be performed (subjects may begin 
treatment based on urine results; any subjects negative by urine subsequently found to be positive on serum should immediately discontinue treatment). All post-Day 1 
pregnancy tests may be conducted by urine dipstick. If positive on dipstick, reflex to serum. 
f 
HBV genotype samples will be collected and stored for analysis by sequence methodology. 
g 
Quantitative HBsAg assay will be performed at Screening and all study visits. If quantitative HBsAg is <LLOQ, then reflex to qualitative HBsAg. HBsAb is performed 
at Screening, Day 1, and Week 48. Additionally, if HBsAg is <LLOQ then reflex testing of HBsAb will also be performed. 
h 
The virology back-up sample will be used for retesting the specified HBV parameters. 
i 
PBMC collection at selected sites only; not to be collected at subsequent timepoints if not collected at Day 1. 
j 
A sparse PK sample will be collected for AB-729 at 2 hours (±1 hour) postdose at Weeks 8, 16, 24, and 32 visits. At Day 1 and Week 40, a sparse PK sample will be 
collected at 2 hours (±1 hour) postdose from subjects who do not participate in the intensive PK substudy. 
k 
Optional intensive PK substudy of AB-729. Samples will be collected predose, and at 0.5 (±3 min), 1 (±6 min), 2 (±10 min), 4 (±10 min), and 6 (±10 min)- hours 
postdose (see Section 8.9.1.2). 
l 
Pharmacogenomic sample will be obtained only from subjects who provide an additional informed consent. The sample can be collected at a later visit if not collected at 
Week 16. 
m 
Subjects will either stop their treatment altogether or continue with NrtI administration based on assessment of Treatment Stopping Criteria (Section 4.1.1) utilizing 
laboratory results from the Week 48 Visit. Subjects will remain on assigned oral agents (ie, VBR+NrtI for groups 1 and 2, and NrtI for Group 3) beyond the Week 48 
visit until all laboratory results are available to adjudicate the Treatment Stopping Criteria. 
 
 


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Table 10. 
Schedule of Assessments (Cohort 1) – Off-treatment Follow-Up for Subjects Meeting Treatment Stopping Criteria   
Study Day or Week  
Wk  
50 
Wk  
52 
Wk  
54 
Wk  
56 
Wk  
60 
Wk  
64 
Wk  
68 
Wk  
72 
Wk  
76 
Wk 
80 
Wk  
84 
Wk  
88 
Wk  
92 
Wk  
96 
Visit Windows (days)  
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Weight 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical exam  
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Symptom-directed physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG a 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Review of concomitant medications 
& AEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fibroscan® (if available)  
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
FibroTest®, APRI 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Chemistry, hematology, 
coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CrCl  
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pregnancy test b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV DNA (COBAS® TaqMan®) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV RNA (COBAS®)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV TNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Qualitative HBeAg  
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
HBeAb 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Quantitative HBsAg c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBcrAg 
 
 
 
 
X 
  
 
X 
 
 
X 
  
 
X 
HBsAg isoforms  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune complexes 
 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
Sample for HBV resistance 
monitoring  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Virology back-up sample d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune biomarkers/cytokines 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
PBMCs e 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
RNAi biomarker sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sparse PK of VBR (off-treatment; 
Groups 1, 2)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Day or Week  
Wk  
50 
Wk  
52 
Wk  
54 
Wk  
56 
Wk  
60 
Wk  
64 
Wk  
68 
Wk  
72 
Wk  
76 
Wk 
80 
Wk  
84 
Wk  
88 
Wk  
92 
Wk  
96 
Visit Windows (days)  
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
VBR Accountability (Groups 1, 2) f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: Ab=antibody; AE=adverse event; APRI=aspartate aminotransferase to platelet ratio index; CrCl=creatinine clearance; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; HBcrAg=hepatitis B core-related antigen; HBeAb=anti-hepatitis B e antigen antibody; HBeAg=hepatitis B e antigen; HBsAg=hepatitis B surface 
antigen; NrtI=nucleos(t)ide/reverse transcriptase inhibitor; PK=pharmacokinetic(s); RNA=ribonucleic acid; TNA=total nucleic acids; UV=Unscheduled visit; Wk(s)=week(s); 
VBR=vebicorvir.  
a 
Any clinically significant ECG result will be confirmed. 
b 
Pregnancy tests may be conducted by urine dipstick. If positive on dipstick, reflex to serum. 
c 
If quantitative HBsAg is <LLOQ, then reflex to qualitative HBsAg. HBsAb is performed at Screening, Day 1, and Week 48. Additionally, if HBsAg is <LLOQ then 
reflex testing of HBsAb will also be performed. 
d 
The virology back-up sample will be used for retesting the specified HBV parameters. 
e 
PBMC collection at selected sites only; not to be collected at subsequent timepoints if not collected at Day 1. 
f 
Subjects will either stop their treatment altogether or continue with NrtI administration based on assessment of Treatment Stopping Criteria (Section 4.1.1) utilizing 
laboratory results from the Week 48 Visit. Subjects will remain on assigned oral agents (ie, VBR+NrtI for groups 1 and 2, and NrtI for Group 3) beyond the Week 48 
visit until all laboratory results are available to adjudicate the Treatment Stopping Criteria. 
Table 11. 
Schedule of Assessments (Cohort 1) – Follow-up for Rest of the Subjects  
Study Day or Week  
Wk  
52 
Wk  
56 
Wk  
60 
Wk  
64 
Wk  
68 
Wk  
72 
Wk  
76 
Wk  
80 
Wk  
84 
Wk 
88 
Wk  
92 
Wk  
96 
Visit Windows (days)  
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Weight 
 
 
 
 
 
X 
 
 
 
 
 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical exam  
 
 
 
 
 
X 
 
 
 
 
 
X 
Symptom-directed physical exam 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
12-lead ECG a 
 
 
X 
 
 
 
 
 
 
 
 
X 
Review of concomitant medications & 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fibroscan® (if available)  
 
 
 
 
 
X 
 
 
 
 
 
X 
FibroTest®, APRI 
 
 
 
 
 
X 
 
 
 
 
 
X 
Chemistry, hematology, coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CrCl  
 
 
 
 
 
X 
 
 
 
 
 
X 
Pregnancy test b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV DNA (COBAS® TaqMan®) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 


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Study Day or Week  
Wk  
52 
Wk  
56 
Wk  
60 
Wk  
64 
Wk  
68 
Wk  
72 
Wk  
76 
Wk  
80 
Wk  
84 
Wk 
88 
Wk  
92 
Wk  
96 
Visit Windows (days)  
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
HBV RNA (COBAS®)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV TNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Qualitative HBeAg  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
HBeAb 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Quantitative HBsAg c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBcrAg 
 
 
X 
 
 
X 
 
 
X 
 
 
 X 
HBsAg isoforms  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune complexes 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
Sample for HBV resistance monitoring  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Virology back-up sample d  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune biomarkers/cytokines 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
PBMCs e 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
RNAi biomarker sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NrtI administration (see Sections 4.1.1, 
4.1.2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review subject dosing diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sparse PK of VBR (Groups 1, 2)  
X 
 
 
 
 
 
 
 
 
 
 
 
VBR accountability (Groups 1, 2) f 
X 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: Ab=antibody; AE=adverse event; APRI=aspartate aminotransferase to platelet ratio index; CrCl=creatinine clearance; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; HBcrAg=hepatitis B core-related antigen; HBeAb=anti-hepatitis B e antigen antibody; HBeAg=hepatitis B e antigen; HBsAg=hepatitis B surface 
antigen; NrtI=nucleos(t)ide/reverse transcriptase inhibitor; PK=pharmacokinetic(s); RNA=ribonucleic acid; TNA=total nucleic acids; UV=Unscheduled visit; Wk(s)=week(s); 
VBR=vebicorvir.  
a 
Any clinically significant ECG result will be confirmed. 
b 
Pregnancy tests may be conducted by urine dipstick. If positive on dipstick, reflex to serum. 
c 
If quantitative HBsAg is <LLOQ, then reflex to qualitative HBsAg. HBsAb is performed at Screening, Day 1, and Week 48. Additionally, if HBsAg is <LLOQ then 
reflex testing of HBsAb will also be performed. 
d 
The virology back-up sample will be used for retesting the specified HBV parameters. 
e 
PBMC collection at selected sites only; not to be collected at subsequent timepoints if not collected at Day 1. 
f 
Subjects will either stop their treatment altogether or continue with NrtI administration based on assessment of Treatment Stopping Criteria (Section 4.1.1) utilizing 
laboratory results from the Week 48 Visit. Subjects will remain on assigned oral agents (ie, VBR+NrtI for groups 1 and 2, and NrtI for Group 3) beyond the Week 48 
visit until all laboratory results are available to adjudicate the Treatment Stopping Criteria. 


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Study Visit Assessments   
To reduce the risk of potential exposure to COVID-19, study visits may be conducted by home 
health personnel in the home of the subject and study drug may be shipped by courier directly 
from the study site to the subject or provided via other alternative mechanisms of provision. 
Subjects must provide prior consent (verbal or written) for home visits and direct shipment of 
study drug to their home. Telemedicine visits may be allowed if the clinical site or subject is 
directly affected by local COVID restrictions. Blood sampling for telemedicine visits may be 
drawn by home health personnel or via subject visit to a local laboratory. 
 
Subject Enrollment and Treatment Assignment  
Following provision of informed consent and completion of all Screening and Day 1 assessments, 
if a subject meets all protocol eligibility requirements the Investigator or designee will randomize 
the subject using the IRT system described in Section 6.4.1 and Table 7. Protocol waivers will not 
be granted for any reason. 
8.3.1 
Screening Visits 
The following Screening assessments must be completed within 45 days of the scheduled Day 1 
visit: 
• Obtain written informed consent prior to the initiation of any Screening procedures 
• Record demographics and medical history, including HBV history 
• Measure height and weight 
• Record vital signs (temperature, heart rate, respiration rate, and blood pressure) 
• Complete physical examination (excluding breast and genitalia, unless indicated) 
• 12-lead ECG 
• Review of concomitant medications  
• Review of AEs occurring after provision of informed consent 
• Liver staging (via FibroScan (if available)/other Sponsor-approved hepatic imaging 
method OR via liver biopsy)  
• FibroTest®, APRI  
• Obtain blood samples for the following: 
o Safety laboratory tests: chemistry, hematology, coagulation, CrCl 


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o Virology: HBV genotype sample, HBV total nucleic acids (TNA), HBV DNA, HBV 
RNA, HBsAg, qualitative HBeAg, HBsAb, HBeAb, HBsAg isoforms and immune 
complexes, HBcrAg, HBV resistance monitoring sample  
o Virology back-up sample (to be used for retesting HBV parameters) 
o Serology: HAV, HCV, hepatitis D virus (HDV), hepatitis E virus (HEV), HIV 
o Other: AFP, glycated hemoglobin (HbA1c), pregnancy test for female subjects of 
child-bearing potential 
• Obtain urine sample for: 
o Urine drug test 
• Confirm subject eligibility 
8.3.2 
Day 1 Visit  
The following procedures must be completed at Day 1, prior to the first dose of study drug: 
• Update medical history, including HBV history 
• Measure weight 
• Vital signs (temperature, heart rate, respiration rate, and blood pressure) 
• Complete physical examination 
• 12-lead ECG 
• Review AEs and concomitant medications 
• Obtain blood samples for the following: 
o Safety laboratory tests: chemistry, hematology, coagulation, CrCl 
o Virology: HBV TNA, HBV DNA, HBV RNA, HBsAg, HBeAg, HBsAb, HBeAb, 
HBsAg isoforms and immune complexes, HBcrAg, HBV resistance monitoring sample  
o Virology back-up sample (to be used for retesting HBV parameters) 
o Other:  
▪ Pregnancy test for female subjects of child-bearing potential 
▪ Sparse PK samples for VBR and NrtI 


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▪ Sparse PK samples for AB-729 at 2 hours (±1 hour) postdose (for subjects who are 
not participating in the AB-729 optional intensive PK substudy only) 
▪ Blood samples for AB-729 intensive PK substudy (optional) will be collected at the 
timepoints listed in Section 8.8.5 
▪ Cytokines/Immune biomarkers 
▪ PBMCs (at selected sites only) 
▪ RNAi biomarker 
• Obtain urine samples for the following: 
o Pregnancy test for female subjects of child-bearing potential 
o Urinalysis 
• Confirm subject eligibility 
• Complete randomization (IRT) 
• IMP (VBR and AB-729) and NIMP (NrtI) administration during clinic visit 
• Dispense VBR bottles  
• Provide dosing diary to the subject and record first dose administration 
• Provide injection site reaction diary for subjects in Groups 1 and 3 
8.3.3 
Week 2 Through Week 48 Visits (±3 Days) 
The following assessments will be performed at Study Weeks 2, 4, 8, 12, 16, and every 4 weeks 
thereafter through Week 48 (inclusive) unless otherwise indicated: 
• Measure body weight (Weeks 24 and 48 only) 
• Record vital signs (temperature, heart rate, respiration rate and blood pressure)  
• Complete physical examination (excluding breast and genitalia, unless indicated; Weeks 
24 and 48 only); all other visits, symptom-directed physical examination  
• 12-lead ECG (Weeks 12, 24, 36, and 48 only) 
• FibroScan (if available; Weeks 24 and 48 only) 
• Review AEs and concomitant medications 


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• Obtain blood samples for the following: 
o Safety laboratory tests:  
▪ chemistry, hematology, coagulation   
▪ CrCl (Weeks 24 and 48 only) 
o Virology:  
▪ HBV TNA, HBV RNA, HBsAg, HBsAb (only if HBsAg <LLOQ), HBsAg 
isoforms and immune complexes, HBV resistance monitoring sample 
▪ HBV DNA (at Weeks 12, 24, 36, and 48 only) 
▪ HBeAg, HBeAb, HBsAb, HBcrAg (at Week 48 only) 
▪ Virology back-up sample (to be used for retesting HBV parameters) 
o Other: 
▪ FibroTest, APRI (both at Weeks 24 and 48 only) 
▪ Sparse PK samples for VBR and NrtI  
▪ Sparse PK samples for AB-729 at 2 hours (±1 hour) postdose (at Weeks 8, 16, 24, 
and 32 only) and also at Week 40 from subjects who are not participating in the 
optional intensive PK substudy 
▪ Blood samples for AB-729 intensive PK substudy (optional) will be collected after 
the last dose (at Week 40 only) at the timepoints listed in Section 8.8.5  
▪ Cytokines/Immune biomarkers (at Weeks 2, 4, 8, 12, 20, 28, 36, and 44 only) 
▪ PBMCs (at selected sites at Weeks 2, 4, 8, 12, 20, 28, 36, and 44 only; not to be 
collected at subsequent timepoints if not collected at Day 1) 
▪ RNAi biomarker 
▪ Pharmacogenomics sample (optional, at Week 16 only); collected only in subjects 
who provide additional informed consent and can be collected at a later visit if not 
collected at Week 16 
• Obtain urine samples for the following: 
o Pregnancy test for female subjects of child-bearing potential 
o Urinalysis 


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• Review subject injection site reaction diary (Groups 1 and 3) at Weeks 2, 12, 20, 28, 36, 
and 44 
• Subject dosing diary  
• Assess VBR accountability (Groups 1 and 2) 
• Dispense VBR bottles (excluding Week 2); final dispensation at Week 44 
• Assessment of Treatment Stopping Criteria (see Section 4.1.1 for details) 
• VBR and NrtI administration once daily at home; Subjects will continue to receive VBR 
and NrtI beyond the Week 48 visit, until all laboratory results are available to adjudicate 
individual subject Treatment Stopping Criteria (see Section 4.1.1). 
• AB-729 administration in clinic at Weeks 8, 16, 24, 32, and 40; last administration of 
AB-729 at Week 40  
8.3.4 
Week 50 Through Week 96 Off-Treatment Follow-Up Visits for Subjects Meeting 
Treatment Stopping Criteria (±5 Days)  
The following follow-up assessments will be performed from Study Weeks 50 through 96 for 
subjects meeting Treatment Stopping Criteria (see Table 10). Note: If a subject is determined to 
meet the NrtI-restart criteria at any time during the follow-up, he/she should follow the schedule 
of visits specified in Section 8.3.5 and Table 11:  
• NrtI and VBR will continue to be administered at home until laboratory results from the 
Week 48 visits are available to determine if an individual subject meets Treatment Stopping 
Criteria (see Section 4.1.1). Once a subject meets the Treatment Stopping Criteria and is 
notified by the site, subject will discontinue treatment with NrtI and VBR.  
• Measure body weight (Weeks 72 and 96 only) 
• Record vital signs (temperature, heart rate, respiration rate, and blood pressure)  
• Complete physical examination (excluding breast and genitalia, unless indicated; Week 72 
and 96 only); all other visits, symptom-directed physical examination  
• 12-lead ECG (Weeks 60 and 96 only) 
• Review AEs and concomitant medications 
• FibroScan (if available; Weeks 72 and 96 only) 
• Obtain blood samples for the following: 
o Safety laboratory tests:  


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▪ chemistry, hematology, coagulation 
▪ CrCl (Weeks 72 and 96 only) 
o Virology:  
o HBV DNA, HBV TNA, HBV RNA 
o HBsAg, HBsAb (only if HBsAg <LLOQ), HBsAg isoforms, HBV resistance 
monitoring sample 
o Immune complexes (Weeks 52, 56, 60, 64, 72, 84, and 96 only)  
o HBeAg, HBeAb, HBcrAg (Weeks 60, 72, 84, and 96 only) 
o Virology back-up sample (to be used for retesting HBV parameters) 
o Other: 
▪ FibroTest, APRI (both at Week 72 and 96 only) 
▪ A single off-treatment blood sample for sparse PK of VBR (Groups 1 and 2; Week 
50 only) 
▪ Cytokines/Immune biomarkers (Weeks 56, 64, 72, 84, and 96 only) 
▪ PBMCs (at selected sites at Weeks 56, 64, 72, 84, and 96; not to be collected at 
subsequent timepoints if not collected at Day 1) 
▪ RNAi biomarker 
• Obtain urine samples for the following: 
o Pregnancy test for female subjects of child-bearing potential 
o Urinalysis 
• VBR accountability (Groups 1 and 2; Week 50 only) 
8.3.5 
Week 52 Through Week 96 Follow-Up Visits for Rest of the Subjects (±5 Days)  
The following follow-up assessments will be performed every 4 weeks from Study Weeks 52 
through 96, for subjects who do NOT meet the Treatment Stopping Criteria, or subjects who meet 
the NrtI-restart criteria after having met Treatment Stopping Criteria, or subjects who prematurely 
discontinue treatment with VBR/AB-729 at any time (see Table 11): 


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• NrtI and VBR will continue to be administered at home until laboratory results from the 
Week 48 visits are available to adjudicate the individual subject Treatment Stopping 
Criteria (see Section 4.1.1). Once a subject is determined to not meet the Treatment 
Stopping Criteria, he/she will be notified by the site, and the subject will discontinue 
treatment with VBR.  
• NrtI administration once daily at home through Week 96 
• Measure body weight (Weeks 72 and 96 only) 
• Record vital signs (temperature, heart rate, respiration rate, and blood pressure)  
• Complete physical examination (excluding breast and genitalia, unless indicated; Week 72 
and 96 only); all other visits, symptom-directed physical examination  
• 12-lead ECG (Weeks 60 and 96 only) 
• Review AEs and concomitant medications 
• FibroScan (if available; Weeks 72 and 96 only) 
• Obtain blood samples for the following: 
o Safety laboratory tests:  
▪ chemistry, hematology, coagulation 
▪ CrCl (Weeks 72 and 96 only) 
o Virology:  
o HBV TNA, HBV RNA 
o HBV DNA (Weeks 60, 72, 84, and 96 only)  
o HBsAg, HBsAb (only if HBsAg <LLOQ), HBsAg isoforms, HBV resistance 
monitoring sample 
o Immune complexes (Weeks 52, 56, 60, 64, 72, 84, and 96 only)  
o HBeAg, HBeAb, HBcrAg (Weeks 60, 72, 84, and 96 only) 
o Virology back-up sample (to be used for retesting HBV parameters) 
o Other: 
▪ FibroTest, APRI (both at Week 72 and 96 only) 


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▪ A single off-treatment blood sample for sparse PK of VBR (Groups 1 and 2; Week 
52 only) 
▪ Cytokines/Immune biomarkers (Weeks 56, 64, 72, 84, and 96 only) 
▪ PBMCs (at selected sites at Weeks 56, 64, 72, 84, and 96; not to be collected at 
subsequent timepoints if not collected at Day 1) 
▪ RNAi biomarker 
• Obtain urine samples for the following: 
o Pregnancy test for female subjects of child-bearing potential 
o Urinalysis 
• Subject dosing diary  
• VBR accountability (Groups 1 and 2; Week 52 only) 
 
Unscheduled Visit  
An unscheduled visit may be performed at any time at the discretion of Investigator in order to 
further evaluate a subject. The specific assessments to be performed at these visits would be 
determined by the Investigator according to nature of the subject specific follow-up required, 
however at a minimum the assessments would include the following: 
• Record vital signs (temperature, heart rate, respiration rate, and blood pressure)  
• Symptom-directed physical examination 
• Review AEs and concomitant medications 
• Obtain blood samples for the following, as applicable: 
o Safety laboratory tests: chemistry, hematology, coagulation, CrCl 
o Virology: HBV TNA, HBV DNA, HBV RNA, HBsAg, HBsAg isoforms and immune 
complexes, HBV resistance monitoring sample 
o Virology back-up sample (to be used for retesting HBV parameters) 
o Other:  
▪ Sparse PK sample for VBR and NrtI 
▪ Cytokines/immune biomarkers 


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▪ PBMCs (at selected sites, if feasible) 
▪ RNAi biomarker 
• Obtain urine samples, as applicable for: 
o Pregnancy test for female subjects of child-bearing potential 
o Urinalysis 
• Assess VBR accountability and review subject dosing diary, as applicable 
Assessments performed should be documented in the subject’s source documentation. Clinical 
laboratory assessments should be conducted through the central laboratory. The minimum 
Unscheduled Visit assessments to be completed when managing ALT elevations are noted in 
Section 9.10.4. 
 
Premature Termination Visit 
Should a subject prematurely discontinue their assigned treatment regimen (Section 7.1) or 
discontinue from the study (Section 7.2), a Premature Termination visit should be scheduled. 
While the Investigator may include additional assessments and evaluations determined by the 
status of the individual subject, at the minimum, the following assessments should be performed 
as soon as feasibly possible: 
• Record vital signs (temperature, heart rate, respiration rate, and blood pressure)  
• Complete physical examination (excluding breast and genitalia, unless indicated) 
• 12-lead ECG  
• Review AEs and concomitant medications 
• FibroScan (if available) 
• Obtain blood samples for the following: 
o Safety laboratory tests: chemistry, hematology, coagulation, CrCl 
o Virology: HBV TNA, HBV DNA, HBV RNA, HBeAg, HBeAb, HBsAg, HBsAb (only 
if HBsAg <LLOQ), HBcrAg, HBsAg isoforms and immune complexes, HBV 
resistance monitoring sample 
o Virology back-up sample (to be used for retesting HBV parameters) 
o Other: 
▪ FibroTest, APRI  


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▪ Sparse PK sample for VBR and NrtI 
▪ Cytokines/Immune biomarkers 
▪ PBMCs (at selected sites only) 
▪ RNAi biomarker 
• Obtain urine samples for the following: 
o Pregnancy test for female subjects of child-bearing potential 
o Urinalysis 
• Subject injection site reaction diary for subjects in Groups 1 and 3  
• Subject dosing diary  
• Assess VBR accountability  
 
Assessment of Efficacy  
8.6.1 
Quantification of HBV Total Nucleic Acids (TNA) 
HBV TNA will be quantified by an in-house assay at Assembly. For this assay, HBV nucleic acids 
are extracted from plasma using commercially available purification kits following the 
manufacturer’s instructions. HBV nucleic acids are then quantified by RT-qPCR with dual 
pan-genotypic primer probes that amplify sequences in the HBc and HBx genes. Additional details 
concerning the methodology, collection and processing of the samples are described in the Study 
Laboratory Manual. HBV TNA will be measured at the timepoints indicated in Section 8 and the 
Schedule of Assessments (Table 9, Table 10, Table 11). 
8.6.2 
Quantification of HBV DNA 
HBV DNA will be quantified using a commercially available HBV test with LLOQ of 10 IU/mL, 
at a central reference laboratory. Additional details concerning the collection and processing of the 
samples are described in the Study Laboratory Manual. HBV DNA will be measured at the 
timepoints indicated in Section 8 and the Schedule of Assessments (Table 9, Table 10, Table 11). 
Additional higher sensitivity assays for HBV DNA may also be implemented dependent upon 
virologic response to treatment. The Sponsor also reserves the right to use alternate HBV virology 
assays with comparable LLOQ if the (originally) specified assays become unavailable. 
8.6.3 
Quantification of HBV RNA  
HBV RNA will be quantified using the commercially available COBAS assay (Roche Diagnostics, 
US) at a central reference laboratory. Additional details concerning the methodology, collection 
and processing of the samples are described in the Study Laboratory Manual. HBV RNA will be 


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measured at the timepoints indicated in Section 8 and the Schedule of Assessments (Table 9, Table 
10, Table 11). Additional higher sensitivity assays for HBV RNA may also be implemented 
dependent upon virologic response to treatment. 
8.6.4 
Quantification of HBV Antigens and Antibodies  
To ensure standardization of the analytical methodologies utilized in this study, HBV antigens (ie, 
HBeAg, HBcrAg, HBsAg) and HBV antibodies (ie, HBeAb, HBsAb) will be measured by 
quantitative and/or qualitative assays at a central reference laboratory. In cases where a 
quantitative assay is negative or <LLOQ, reflex qualitative testing will be done. Details regarding 
the specific methodologies, collection and processing of samples are described in the Study 
Laboratory manual. These parameters will be measured at the timepoints indicated in Section 8 
and the Schedule of Assessments (Table 9, Table 10, Table 11). 
 
Resistance Monitoring  
To monitor for HBV resistance, serum samples will be collected at Screening and on Day 1 and at 
each visit thereafter (Section 8 and the Schedule of Assessments [(Table 9, Table 10, Table 11]). 
The core protein gene and polymerase coding region and the region containing the AB-729 target 
site will be sequenced for all subjects on Day 1 and will be attempted for all viremic subjects at 
Week 48 and Week 72. Samples from those subjects with evidence of virologic failure, such as 
confirmed virologic breakthrough (2 consecutive visits with a ≥1 log10 IU/mL increase in on-
treatment HBV DNA from on-treatment nadir or 2 consecutive visits with HBV DNA ≥LLOQ 
after having been <LLOQ) will also be sequenced.  
 
Assessment of Safety  
8.8.1 
Physical Examination  
A complete or symptom-directed physical examination will be performed at timepoints specified 
in (Table 9, Table 10, Table 11). Height and weight will also be measured and recorded.  
Complete physical examinations will be performed by the Investigator or qualified subinvestigator 
at the time points indicated in the Study Procedures section (Section 8; Table 9, Table 10, Table 
11). The complete physical examination will consist of the following body systems: head, eyes, 
ears, nose, and throat; cardiovascular; respiratory; gastrointestinal; dermatologic; musculoskeletal; 
nervous; extremities; and lymph nodes. Additional body systems may be evaluated at the 
Investigator’s discretion. Examination of the breast and genitalia are not required unless clinically 
indicated. 
Additional symptom-directed physical examinations will be performed at the time points indicated 
in the Study Procedures section (Section 8; Table 9, Table 10, Table 11). Additional symptom-
directed or complete physical examinations may be performed at the Investigator’s discretion 
throughout the course of the study. If the subject reports feeling unwell or has ongoing AEs, the 
Investigator or qualified subinvestigator will examine the appropriate body system(s). 


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8.8.2 
Vital Signs  
Vital sign assessments will include temperature, heart rate, respiration rate, and blood pressure at 
timepoints specified in the Schedule of Assessments (Table 9, Table 10, Table 11). 
8.8.3 
Electrocardiograms  
A standard 12-lead ECG will be obtained as specified in the Schedule of Assessments (Table 9, 
Table 10, Table 11). Prior to the conduct of 12-lead ECGs, subjects should rest in a supine position 
for 10 minutes. Electrocardiograms should be conducted in accordance with local practice and 
equipment. The ECG assessment will include interpretation of the tracings (eg, rhythm, presence 
of arrhythmia or conduction defects, morphology, any evidence of myocardial infarction, or ST 
segment, T-wave, and Uwave abnormalities). The Investigator or a physician subinvestigator is 
responsible for reviewing and overreading the ECG interpretation, for assessing whether the ECG 
machine interpretation findings are accurate, appropriate, normal or abnormal, and for providing 
corrected interpretations as appropriate. In addition, any abnormal ECGs will be assessed for 
clinical significance. 
Additional ECGs may be obtained if clinically indicated and will be obtained if abnormal and 
clinically significant or thought to be an error (eg, lead placement error, movement artifact, etc.). 
Any additional relevant data obtained by the Investigator during the course of this study will be 
recorded in the subject’s source documentation. The Investigator or a physician subinvestigator 
will review all ECGs, evaluate the results, and sign/date the tracing or report. For any ECG 
abnormality that the Investigator considers clinically significant, the Investigator will:  
• Repeat the ECG;  
• Obtain follow-up ECG(s) if any significant abnormalities are detected after study drug 
administration to document resolution and as clinically indicated; 
• Record as an AE any ECG abnormality that: (1) is confirmed and the Investigator considers 
clinically significant; (2) requires a subject to be discontinued from the study; or (3) the 
abnormality requires a subject to receive treatment (Section 8). 
8.8.4 
Clinical Safety Laboratory Assessments  
Clinical laboratory tests will be performed at the designated central laboratories at the timepoints 
indicated in Section 8 and the Schedule of Assessments (Table 9, Table 10, Table 11). Should any 
laboratory parameter require urgent testing to support immediate medical care of a subject, 
samples should be collected for both local and central laboratory assessment. The local result may 
be used to manage the emergent medical situation, however only the results from the central 
laboratory will be reported in the study database for analysis purposes. 
The specific components of the clinical laboratory tests are listed below in Table 12. 


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Table 12. 
Clinical Laboratory Tests  
Panel  
Tests  
Chemistry  
Glucose, sodium, potassium, chloride, bicarbonate, calcium, blood urea nitrogen, 
creatinine, creatine kinase, uric acid, total and direct bilirubin, ALT, AST, GGT, 
alkaline phosphatase, LDH, triglycerides, total cholesterol, phosphorous (inorganic), 
total protein, albumin, amylase, lipase 
Hematology  
Hemoglobin, hematocrit, red blood cell count, RBC indices (MCV), reticulocyte count, 
white blood cell count including, lymphocytes (total and differential), monocytes, 
neutrophils, eosinophils, basophils, platelet counts 
ALT Elevation 
Management 
(Section 9.10.4) 
ALT, AST, total bilirubin, serum albumin, creatine kinase, INR, HBV DNA, 
quantitative HBV serologies (HBeAg [reflex qualitative HBeAg if quantitative HBeAg 
is negative] and HBsAg [reflex qualitative HBsAg if quantitative HBsAg is negative]), 
HAV immunoglobulin M (IgM), HCV RNA, HDV RNA, HEV IgM, ANA, smooth 
muscle antibodies and anti-LKM1 antibodies, EBV DNA, CMV DNA, HSV DNA, and 
total IgG. 
Coagulation  
Prothrombin time/INR and aPTT 
Urinalysis  
pH, specific gravity, protein, glucose, ketones, and occult blood 
FibroTest  
alpha-2-macroglobulin, haptoglobin, apolipoprotein A1, GGT, total Bilirubin, ALT 
APRI 
AST, platelet count 
Other  
AFP, HbA1c, creatinine clearance calculated by Cockcroft-Gault (Cockcroft 1976) 
Pregnancy Tests 
For females of child-bearing potential only; a serum pregnancy test must be performed 
at Screening, and both serum and urine are required at Day 1; a urine pregnancy test 
must be performed at all subsequent visits, if positive, confirm with a serum pregnancy 
test 
Urine Drug Test  
Amphetamine/methamphetamine, barbiturates, benzodiazepines, cocaine metabolite, 
ethanol, opiates, phencyclidine, and propoxyphene 
Serology a 
HAV, HCV, HDV, HEV, and HIV 
Virology  
HBV DNA, HBV RNA, HBsAg b, HBeAg, HBcrAg, HBsAb and HBeAb, HBV 
resistance monitoring 
Abbreviations: AFP=alpha fetoprotein; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; 
AST=aspartate aminotransferase; DNA=deoxynucleic acid;; GGT=gamma-glutamyl transferase; HAV=hepatitis A virus; 
HbA1c=glycated hemoglobin; HBcrAg=hepatitis B core-related antigen; HBeAb=anti-hepatitis B e antigen antibody; 
HBeAg=hepatitis B e antigen; HBsAb=anti-hepatitis B surface antigen antibody; HBsAg= hepatitis B surface antigen; 
HBV=hepatitis B virus; HCV=hepatitis C virus; HDV=hepatitis D virus; HEV=hepatitis E virus; INR=international normalized 
ratio; MCV=mean corpuscular volume; RBC=red blood cell; RNA=ribonucleic acid. 
a 
If antibody positive, reflex to DNA or RNA (as applicable) 
b 
Quantitative HBsAg assay will be performed at Screening and all study visits. If quantitative HBsAg is <LLOQ, then 
reflex to qualitative HBsAg. HBsAb is performed at Screening, Day 1, and Week 48. Additionally, if HBsAg is 
<LLOQ then reflex testing of HBsAb will also be performed. 


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8.8.5 
Injection Site Reaction Diary 
Subjects enrolled in Groups 1 and 3 will be provided an injection site reaction diary to capture 
information regarding the nature of any changes at the site of the AB-729 subcutaneous injection(s) 
occurring while as an outpatient, including the resolution of these events. These subjects will be 
instructed to contact the clinical site with any new AEs they observe at the injection site(s) to 
determine if an unscheduled clinic visit is needed for formal assessment of the AEs.  
 
Assessment of Pharmacokinetics  
The details of PK blood sampling procedures and sample management will be provided in the 
Study Laboratory Manual. 
8.9.1.1 
Vebicorvir Pharmacokinetic Assessment  
Single PK blood samples will be collected for all subjects receiving VBR at each on-treatment 
visit and at a single timepoint off treatment at Week 52 for sparse PK analysis of VBR (Table 9, 
Table 10, Table 11). Note the Day 1 PK sample collection should be done prior to the first dose of 
study drug.  
8.9.1.2 
AB-729 Pharmacokinetic Assessment  
An optional intensive PK substudy of AB-729 will be performed after the first 60 mg subcutaneous 
dose on Day 1 and after the last dose at Week 40. The plasma PK parameters to be estimated are 
listed in Section 10.4.6. Blood samples will be collected at the following timepoints: predose, and 
at 0.5 (±3 min), 1 (±6 min), 2 (±10 min), 4 (±10 min), and 6 (±10 min)-hours postdose. 
Single PK blood samples will be collected from all subjects receiving AB-729 at Weeks 8, 16, 24, 
and 32 at 2 hours (±1 hour) postdose for sparse PK analysis of AB-729 (Table 9). 
A sparse PK sample will also be collected at Day 1 and Week 40 at 2 hours (±1 hour) postdose 
from those subjects who do not participate in the optional intensive PK substudy. 
8.9.1.3 
NrtI Pharmacokinetic Assessment  
Single PK blood samples will be collected for all subjects receiving NrtI at each on-treatment visit 
for sparse PK analysis of NrtI (Table 9). Note the Day 1 PK sample collection should be done prior 
to the first dose of study drug. 
 
Exploratory Biomarkers 
HBsAg isoforms, immune complexes, immune biomarkers, cytokines and characterization of 
PBMC function and immune cell phenotypes may be conducted using validated assays. Additional 
details concerning the methodology, collection and processing of the samples are described in the 
Study Laboratory Manual.  


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An RNAi biomarker to indicate RNAi activity may be assessed using a validated Rapid 
Amplification of complementary DNA ends (RACE) assay. Additional details concerning the 
methodology, collection and processing of the samples are described in the Study Laboratory 
Manual.  
These exploratory assessments may be evaluated at the timepoints indicated in Section 8 and the 
Schedule of Assessments (Table 9, Table 10, Table 11). 
 
Use of Residual Samples for Optional Future Research  
In addition to the study-specific Informed Consent Form (ICF) to be signed by each subject, a 
separate consent form, or a separate specific signature within the main ICF, will be required to 
document a subject’s agreement to allow the use of unused or residual biomarker and/or virologic 
samples collected as part of the protocol assessments for optional future research. 
The specimens collected for optional future research will be used to increase knowledge and 
understanding of the biology of HBV and related diseases and to study the association of 
biomarkers with disease pathogenesis, progression, and/or treatment outcomes, including efficacy, 
AEs, and the process of drug absorption and disposition. 
These specimens may be used also to develop biomarker or diagnostic assays for HBV and 
establish the performance characteristics of these assays. The collection and analysis of optional 
future research specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for patients in 
the future. Residual samples will not be used for genetic testing. 
Samples will be securely stored by the Sponsor or at a Sponsor-approved third-party storage 
management facility. Samples will be stored in a coded fashion, and no researcher will have access 
to the key. The key will be securely held by the Investigator at the clinical site such that there will 
be no direct ability for a researcher to connect a sample to a specific individual. Additional research 
samples will be retained for the maximum time allowed by applicable law. 
Further details of sample collection and processing will be provided to the site in the Study 
Laboratory Manual. 


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9 ADVERSE EVENTS AND TOXICITY MANAGEMENT  
 
Definition of Adverse Event  
An AE is any untoward medical occurrence in a study subject administered a study drug regardless 
of the causal relationship with treatment. 
An AE, therefore, can be any unfavorable and unintended sign, symptom, or disease temporally 
associated with participation in an investigational study, whether or not considered study drug 
related. In addition to new events, any increase in the severity or frequency of a preexisting 
condition that occurs after the subject signs the ICF for participation is considered an AE. This 
includes any side effect, injury, toxicity, or sensitivity reaction. AEs may also include 
complications associated with protocol mandated procedures.  
An AE does not include the following: 
• Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an AE and must be reported. 
• Preexisting diseases, conditions, or clinically significant laboratory abnormalities present 
or detected before the screening visit that do not worsen during the study 
• Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions) 
• Overdose without clinical sequelae  
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not 
an AE. It is considered to be preexisting and should be documented on the medical history 
electronic Case Report Form (eCRF). 
 
Documenting Adverse Events  
Adverse events will be monitored and recorded from the written informed consent obtained 
through end of study (completion of follow-up period or “lost to follow-up”). Investigators will 
ask the subject at each visit if they have experienced any untoward effects since the last study visit. 
All AEs will be entered in the eCRFs; refer to the eCRF Completion Guidelines for additional 
information.  
 
Assessment of Intensity 
The severity of each AE and laboratory abnormality is to be assessed by the Investigator according 
to the modified Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
AEs (Appendix 1), which grades the severity of clinical AEs and laboratory abnormalities in a 
4-category system. 


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For AEs not included in Appendix 1, the following guidelines will be used to describe severity: 
• Mild (Grade 1): Mild symptoms causing no or minimal interference with usual social and 
functional activities with intervention not indicated 
• Moderate (Grade 2): Moderate symptoms causing greater than minimal interference with 
usual social & functional activities with intervention indicated 
• Severe (Grade 3): Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated (Of note, the term 
“severe” does not necessarily equate to “serious”) 
• Life-Threatening (Grade 4): Potentially life-threatening symptoms causing inability to 
perform basic self-care functions with intervention indicated to prevent permanent 
impairment, persistent disability, or death 
 
Assessment of Causality 
All AEs must have their relationship to study intervention assessed by the clinician who examines 
and evaluates the subject based on temporal relationship and his/her clinical judgment. Each AE 
must be recorded in the source documentation, whether serious or not serious. For the purposes of 
this study each event is to be assessed with regard to the following causality categorizations, in the 
Investigator’s considered judgment: 
• Not related: An AE with sufficient evidence to accept that there was no causal relationship 
to administration of study drug (eg, no temporal relationship because the study drug was 
administered after the onset of the event, an investigation showed that study drug was not 
administered, another cause was proven). 
• Related: An AE occurred in a plausible time relationship to administration of study drug 
and that could not be explained by a concurrent disease or other drugs or events. The 
response to withdrawal of the drug (dechallenge) was clinically reasonable. 
 
Adverse Event Follow-up 
All AEs should be followed up to resolution unless the event is considered by the Investigator to 
be unlikely to resolve due to the subject’s underlying disease, or the subject is lost to follow-up. 
 
Serious Adverse Events 
9.6.1 
Definition of Serious Adverse Event 
An SAE is any event that meets any of the following criteria: 
• Death 
• Life-threatening 


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• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject.  
• Other: Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent 1 of the outcomes listed in this definition. Examples of such events are: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
9.6.2 
Definition of Terms 
• Life threatening: An AE is life-threatening if the subject was at immediate risk of death 
from the event as it occurred; ie, it does not include a reaction that if it had occurred in a 
more serious form might have caused death. For example, drug-induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life threatening even 
though drug induced hepatitis can be fatal. 
• Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization 
for elective surgery or routine clinical procedures that are not the result of AEs (eg, elective 
surgery for a preexisting condition that has not worsened) need not be considered AEs or 
SAEs. If anything untoward is reported during the procedure, that occurrence must be 
reported as an AE, either “serious” or “non-serious” according to the usual criteria. 
• In general, hospitalization signifies that the subject 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. When 
in doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious. 
• Disability/incapacitating: An AE is incapacitating or disabling if the experience results in 
a substantial and/or permanent disruption of the subject's ability to carry out normal life 
functions. 


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9.6.3 
Reporting Serious Adverse Events 
All SAEs must be reported by the investigational staff within 24 hours of learning about the event 
using the SAE Report form to the Sponsor or its designee (eg, CRO Pharmacovigilance group). 
Refer to the Study Reference Manual for contact information for reporting SAEs. 
The initial report should be promptly followed by detailed, written reports, which will include 
copies of relevant hospital case reports, autopsy reports, and other documents when requested and 
applicable. 
For a follow-up report to the authorities, the monitor may be required to collect further information 
for a final evaluation of the case. Reporting to the respective country Health Authorities will be 
the responsibility of the Sponsor and the CRO. 
The CRO will be responsible for informing all central Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) of SAEs as required. It will be the responsibility of 
the individual Investigators to inform any local IRBs/IECs of SAEs as required. Correspondence 
with the IRB(s)/IEC(s) relating to the reporting of SAEs will be retained in the study file. 
 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs or 
SAEs 
Laboratory abnormalities are usually not recorded as AEs or SAEs. Clinical laboratory 
abnormalities that require medical or surgical intervention or lead to study drug interruption or 
discontinuation must be recorded as an AE or SAE, if applicable. The modified DAIDS Table for 
Grading the Severity of Adult and Pediatric AEs (Appendix 1) will be used to assess the severity 
of clinical laboratory abnormalities. In addition, clinical laboratory or other abnormal assessments 
(eg, ECG and vital signs) that are associated with signs and/or symptoms must be recorded as an 
AE or SAE if they meet the definition of an AE or SAE described in Sections 9.1 and 9.6. If the 
clinical laboratory abnormality or abnormal assessment is part of a syndrome or diagnosis, record 
the syndrome or diagnosis (eg, anemia), not the clinical laboratory result (ie, decreased 
hemoglobin).  
 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
which is above the maximum recommended dose as per protocol or in the product labelling (as it 
applies to the daily dose of the subject in question). The Medical Monitor may be contacted for 
questions concerning potential cases of overdose. An overdose is not in and of itself considered to 
be an AE unless it results in untoward medical effects. Any AE associated with an overdose or 
incorrect administration of study drug should be entered in the subject’s source documentation and 
Adverse Event eCRF. If the associated AE fulfills the criteria of an SAE, then the event should be 
reported to the Sponsor or CRO within 24 hours after the site learns of the event. 


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Pregnancy 
9.9.1 
Female Subjects Who Become Pregnant 
The Investigator will collect pregnancy information on any female subject who becomes pregnant 
while participating in this study. The initial information will be recorded on the Pregnancy 
Reporting form and submitted to the Sponsor or its designee within 24 hours of learning of a 
subject’s pregnancy. Refer to the Study Reference Manual for contact information for reporting a 
pregnancy. 
The subject will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the subject and the neonate and the information will be forwarded 
to the Sponsor or its designee. 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. 
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. A 
spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as such. 
Any female subject who becomes pregnant while participating in the study will discontinue the 
study drug immediately. 
9.9.2 
Male Subjects With Partners Who Become Pregnant 
The Investigator will attempt to collect pregnancy information on any male subject’s female 
partner who becomes pregnant while the male subject is participating in this study.  
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the Investigator will record pregnancy information on the Pregnancy Reporting form and submit 
it to the Sponsor or its designee 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. Refer to the Study Reference Manual for contact information for reporting a pregnancy. 
 
Toxicity Management  
Administration of study drug may be interrupted or discontinued due to a clinical event or 
laboratory abnormality. The Medical Monitor should be consulted prior to dose interruption or 
discontinuation of study drug unless the Investigator believes that immediate action is warranted 
to ensure the continued safety of subject. 


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Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat testing 
within 3 days of receipt of results and before study drug interruption or discontinuation, unless 
such a delay is not consistent with good medical practice. 
Any questions regarding toxicity management should be directed to the Medical Monitor. 
9.10.1 
Grades 1 and 2 Clinical Event or Laboratory Abnormality  
• Continue study drug at the discretion of the Investigator. 
9.10.2 
Grade 3 Clinical Event or Laboratory Abnormality  
• For Grade 3 clinical event or clinically significant laboratory abnormality, the study drug 
may be continued if considered to be unrelated to investigational medicinal product. 
• For a Grade 3 clinical event or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to the study drug, the study drug should be 
withheld until the toxicity returns to ≤Grade 2. 
• If a laboratory abnormality recurs to ≥Grade 3 following rechallenge with the study drug 
and is considered related to the study drug, then the study drug should be permanently 
discontinued and the subject managed according to local practice. Recurrence of laboratory 
abnormalities considered unrelated to the study drug may not require permanent 
discontinuation. 
9.10.3 
Grade 4 Clinical Event or Laboratory Abnormality  
• For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to the study drug, the study drug 
should be permanently discontinued and the subject managed according to local practice. 
The subject should be followed as clinically indicated until the laboratory abnormality 
returns to Baseline or is otherwise explained, whichever occurs first. A clinically 
significant Grade 4 laboratory abnormality that is not confirmed by repeat testing should 
be managed according to the algorithm for the new toxicity grade. 
• The study drug may be continued without dose interruption for a clinically nonsignificant 
Grade 4 laboratory abnormality (eg, Grade 4 creatine kinase after strenuous exercise, or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical 
event considered unrelated to the study drug. 
9.10.4 
Management of Alanine Aminotransferase (ALT) Elevations 
All subjects participating in the study will be closely monitored for ALT elevations and/or signs 
of potential decline in hepatic function (see Figure 7). Subjects experiencing ALT elevations ≥2× 
Baseline (Day 1) or on-treatment nadir and >2× ULN during study treatment or during post-
treatment follow-up should be closely monitored with regular Unscheduled Visits every 1 to 2 


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weeks at the discretion of the Investigator. At these visits, the following laboratory tests will be 
performed: ALT, AST, total bilirubin (if total bilirubin is elevated, reflex to direct bilirubin), serum 
albumin, INR and creatine kinase. The Investigator will determine if other Unscheduled Visit 
assessments should be performed. Additionally, the following guidance is provided for 
management of subjects with ALT elevations: 
• ALT Elevation Without Declining Hepatic Function 
o All subjects with an ALT elevation on treatment, defined as ALT >2× Baseline or on treatment 
nadir and ≥10× ULN, should have the ALT findings confirmed within 3 days of receipt of the 
original results. All subjects should return for an Unscheduled Visit. 
o If the ALT elevation is confirmed, then an additional Unscheduled Visit will be performed to 
further evaluate the subject. At this visit, the following laboratory tests will be performed: 
ALT, AST, total bilirubin (if total bilirubin is elevated, reflex to direct bilirubin), serum 
albumin, INR, creatine kinase, HBV DNA, quantitative HBV serologies (HBeAg [reflex 
qualitative HBeAg if quantitative HBeAg is negative] and HBsAg [reflex qualitative HBsAg 
if quantitative HBsAg is negative]), HAV immunoglobulin M (IgM), HCV RNA, HDV RNA, 
HEV IgM, ANA, smooth muscle antibodies and anti-LKM1 antibodies, EBV DNA, CMV 
DNA, HSV DNA, and total IgG. The Investigator will determine if other Unscheduled Visit 
assessments should be performed.   
▪ 
If an intercurrent illness is determined to be causal, subjects with an ALT elevation 
without declining hepatic function and without contraindications may continue 
treatment and the intercurrent illness should be treated as deemed medically 
appropriate by the Investigator. 
▪ Subjects with an ALT elevation without declining hepatic function and without 
contraindications may continue treatment with study drug under close observation. 
▪ If ALT is rising at the confirmatory visit, subjects should return for an Unscheduled 
Visit every 2 to 5 days until the ALT elevation has stabilized. At these visits, the 
following laboratory tests will be performed: ALT, AST, total bilirubin (if total 
bilirubin is elevated, reflex to direct bilirubin), serum albumin, INR, creatine 
kinase, HBV DNA, quantitative HBV serologies (HBeAg [reflex qualitative 
HBeAg if quantitative HBeAg is negative] and HBsAg [reflex qualitative HBsAg 
if quantitative HBsAg is negative]). The Investigator will determine if other 
assessments specified in Section 8.4 should be performed. Subjects whose ALT has 
stabilized should continue to be monitored weekly (or more frequently, as deemed 
necessary by the Investigator) until ALT values return to normal or Baseline levels. 
▪ Subjects with an ALT elevation without declining hepatic function and without 
contraindications should discontinue study drug if the ALT remains persistently 
elevated for >4 weeks  
• ALT Elevation With Declining Hepatic Function 


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o Subjects with confirmed ALT elevation with biochemical evidence of declining hepatic 
function should be discontinued from study treatment. This is defined as:  
▪ ALT elevation ≥2× Baseline or nadir and >2× ULN AND 
– Direct bilirubin increase to ≥2× Baseline and ≥2× ULN OR  
– Albumin decline ≥0.5 g/dL OR INR >1.5× Baseline OR  
– Symptoms of liver inflammation (eg, fatigue, weakness, lack of appetite, 
nausea, vomiting, jaundice, or discolored feces) 
o Subjects with evidence of declining hepatic function should return for an Unscheduled Visit 
every 2 to 5 days until the relevant laboratory values stabilize. Subjects whose hepatic function 
has stabilized should continue to be monitored weekly (or more frequently as deemed 
necessary by the Investigator) until the relevant laboratory values return to normal or Baseline.  
All subjects with ALT elevation without or with declining hepatic function should continue to be 
followed on their regular study visit schedule, with the addition of unscheduled visits as described 
above. If the posttreatment ALT elevation has not substantially resolved by the last study follow-up 
visit, subjects should continue to return to clinic as deemed medically appropriate by the 
Investigator, in consultation with the Sponsor until the ALT elevation is documented to be either 
resolved or resolving (defined as consistent ALT declines of 10% or more or normalization of 
ALT) on at least 2 successive visits. 
Following cessation of study drug treatment under this protocol, all subjects will be closely 
followed for ALT elevations and/or signs of potential decline in hepatic function. This applies to 
all subjects whether they prematurely discontinue study drug or complete the study treatment per 
protocol. Any subject with a post-treatment ALT elevation without evidence of declining hepatic 
function or a post-treatment ALT elevation with evidence of declining hepatic function as defined 
above, will be evaluated as noted above. 
If 5 or more subjects meet these flare management criteria, the relevant regulatory agencies will 
be notified, and subsequent steps will be determined after consultation with these agencies. 


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Figure 7. 
Schematic for Safety Management of ALT Elevation 
ALT elevation 
   x BL or nadir 
AND
>2 x ULN
ALT Elevation 
> 2 x BL or nadir 
AND 
     x ULN
Subject returns for 
Unscheduled Visit 
within 3 days of 
receiving the 
original results
If ALT Elevation is 
confirmed, subject 
returns for Initial 
ALT Elevation 
Monitoring Visit
If ALT is rising at 
previous visits, 
subject returns every 
2-5 days until ALT is 
stabilized
ALT Increase
ALT Elevation
Confirmation of ALT 
Elevation
Initial ALT Elevation 
Monitoring
Subsequent ALT Elevation 
Monitoring Visits
Closely monitor with regular 
Unscheduled Visits every 1 
to 2 Wks at the discretion of 
the Investigator
Use ALT Elevation lab kit 
• Vital Signs
• Symptom-directed PE
• Con med & AE review
• Complete lab analyses 
(safety, virology & PK) 
Use ALT Elevation lab kit 
The following parameters will 
be measured:
• ALT, AST, T-Bil, Alb, INR, CK
Use Unscheduled lab kit 
• ALT, AST, T-Bil, Alb, INR, CK
• HBV DNA
• Quant-HBeAg
• 
If <LLOQ reflex Qual-HBeAg
• Quant-HBsAg
• 
If <LLOQ reflex Qual-HBeAg
• HAV IgM, HCV RNA, HDV RNA & HEV IgM, 
ANA, smooth muscle Abs, anti-LKM1 Abs, 
EBV DNA, CMV DNA, HSV DNA, total IgG
Use ALT Elevation lab kit 
The following parameters will 
be measured:
• ALT, AST, T-Bil, Alb, INR, CK
• HBV DNA
• Quant-HBeAg
• 
If <LLOQ reflex Qual-HBeAg
• Quant-HBsAg
• 
If <LLOQ reflex Qual-HBeAg
 
 


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10 STATISTICAL CONSIDERATIONS  
 
General Considerations 
This section provides the key details of the statistical analyses to be performed using data captured 
according to this protocol. A complete Statistical Analysis Plan (SAP) describing all planned 
analyses will be finalized prior to database lock.  
 
Determination of Sample Size 
Cohort 1 will enroll virologically suppressed subjects on NrtI therapy with HBeAg negative 
cHBV. Approximately 60 subjects will be randomized to receive 1 of the following 3 treatments, 
VBR+AB-729+NrtI, VBR+NrtI, or AB-729+NrtI in a 2:1:1 ratio.  
Up to 2 additional cohorts, with approximately 60 subjects per cohort, may be added in future 
protocol amendments, for a maximum sample size of approximately 180 subjects. 
This is a proof-of-concept study. The sample size is similar to that previously utilized for this type 
of study and is not based upon statistical considerations. 
 
Analysis Populations 
The following populations will be considered for analysis of various endpoints: 
• Randomized Analysis Set: It includes all randomized subjects who satisfied the inclusion 
and exclusion criteria described in this protocol. 
• Full Analysis Set: It includes all randomized subjects, classified according to the treatment 
group into which they were randomized regardless of the actual treatment received, who 
took at least 1 dose of study drug. It is the main analysis population for the efficacy 
analysis. 
• Safety Analysis Set: It includes all subjects, classified according to the actual treatment 
received regardless of random assignment, who took at least 1 dose of study drug. This is 
the main analysis population for all safety analyses. 
• Pharmacokinetic-Evaluable Set: It consists of all subjects, classified according to the actual 
treatment received regardless of random assignment, who receive at least 1 dose of study 
drug. At least 1 pharmacokinetic blood sample following a dose of study treatment is 
required for inclusion in this analysis. This is the main analysis population for all 
pharmacokinetic analyses. 
Based on the actual deviations, the criteria for exclusion of subjects from the different data sets 
will be specified and updated, if necessary, prior to database lock. 


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Planned Analyses  
All safety, PK, and antiviral activity endpoints will be summarized using descriptive statistics by 
treatment groups. Continuous endpoints will be described using the mean, standard deviation, 
median, minimum, and maximum. Categorical endpoints will be described using the number and 
percent of subjects who meet the endpoint criterion. 
Analyses by treatment group will be presented as follows: 
• Efficacy analyses: according to the treatment to which subjects were randomized 
• Safety and pharmacokinetic analyses: according to the treatment received 
Due to sample size limitations, no formal statistical inference is planned. 
10.4.1 
Disposition of the Study Subjects 
The disposition of subjects will be described with summaries by treatment group of the number of 
subjects in each analysis set described above, the number of subjects who completed the study, 
and the number of subjects for whom study drug was permanently discontinued (including the 
reasons for discontinuation). Randomized Analysis Set will be used to produce this analysis. 
10.4.2 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using standard descriptive methods 
by treatment group and overall. Demographic summaries will include age, sex, race, ethnicity, 
body weight, and body mass index. Baseline disease characteristics data will include, but not 
limited to, years positive for HBV, HBV genotype, HBV DNA, HBV RNA, HBeAg, HBsAg, 
HBcrAg, and ALT levels at Baseline.  
10.4.3 
Extent of Exposure  
Extent of exposure to study drug will be examined by assessing the total duration of study drug 
exposure and the level of adherence to the study drug by treatment group for the Safety Analysis 
Set. 
10.4.4 
Analysis of Efficacy Endpoint(s) 
The efficacy endpoints are described in Section 3.2.2. The efficacy analysis will be based on the 
Full Analysis Set.  
In addition to the descriptive statistics at each time point, treatment comparisons may be 
performed. The continuous variables, such as mean change from Baseline, will be evaluated using 
a regression model with Baseline values and stratification as covariates. The binary variables, such 
as the proportion of subjects who meet the endpoint criterion, will evaluated using a 
Cochran-Mantel-Haenszel test adjusting for the stratification factor.   


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10.4.5 
Analysis of Safety Endpoints  
All safety endpoints will be summarized using data from the Safety Analysis Set. Safety analyses 
will involve examination of the incidence, severity and type of TEAEs reported, changes from 
Baseline in laboratory test results and in vital signs to specified time points throughout the study, 
and concomitant medications use. 
10.4.5.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
A TEAE will be defined as any AE that begins on or after the date of first dose of study drug 
through end of study (completion of follow-up period or “lost to follow-up”).  
Summaries (number and percentage of subjects) of TEAEs by system organ class and preferred 
term will be provided by treatment group. Summaries will include all TEAEs, TEAEs considered 
related to study treatment by investigators, TEAEs by Grade, and SAEs. All AEs, emergent or 
nonemergent, will be listed by subject. Any TEAEs leading to premature discontinuation from the 
study intervention and serious TEAEs will be presented as a separate table or a listing. 
10.4.5.2 
Clinical Laboratory Evaluation  
Laboratory values will be graded according to DAIDS criteria (Appendix 1). Laboratory 
parameters will be summarized by treatment group at each visit. Incidence of graded laboratory 
abnormalities will be summarized by treatment group. Listings will be provided for clinical 
laboratory values for each subject grouped by laboratory panel. 
10.4.5.3 
Other Safety Evaluations 
Individual data for physical examination findings, prior and concomitant medications and medical 
history will be provided. Vital signs measurements and 12-lead ECGs will be listed by subject and 
summarized by incidence of events/abnormalities or descriptive statistics as appropriate. 
10.4.6 
Analysis of Pharmacokinetic Endpoints  
Population PK analysis may be performed outside the scope of this study. 
Pharmacokinetic analysis of AB-729 for an optional intensive PK substudy will be conducted 
using the Pharmacokinetic-Evaluable Set defined in Section 10.3. Plasma PK parameters of 
AB-729-AS and the AB-729-AS(N-1)3’ and AB-729-AS(N-2)3’ metabolites for each subject will 
be estimated over the sampling interval using noncompartmental analysis and summarized by 
treatment group using descriptive statistics. Plasma PK parameters to be estimated, as data allow, 
are listed below in Table 13. Additional parameters may be analyzed, as appropriate. A minimum 
of 10 subjects from Group 1 and 5 subjects from Group 3 (Figure 6) will need to provide blood 
samples from Cohort 1 for PK analysis. 


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Table 13. 
Pharmacokinetic Parameters and Definitions  
Parameter  
Definition  
Cmax 
maximum observed plasma concentration 
Tmax 
time of maximum observed plasma concentration 
AUC0-t 
area under the concentration time curve from the time of dosing to the last measurable 
concentration 
AUCTAU 
area under the concentration time curve from the time of dosing to the end of the dosing 
interval 
CTAU 
plasma concentration at the end of the dosing interval 
Ctrough 
predose plasma concentration 
AI 
accumulation index for AUCTAU calculated as final dose/first dose 
 
Interim Analysis  
No formal interim analyses are planned. As an open-label study, the data will be reviewed 
periodically.  
 
Handling of Missing Data  
Statistical considerations and methodology for handling missing data will be detailed in the SAP. 
 
Multiplicity Adjustment  
No formal inference is planned in this study; hence, no multiplicity adjustment is required. 
 


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11 RESPONSIBILITIES  
 
Investigator Responsibilities 
11.1.1 
Good Clinical Practice 
This study will be conducted in compliance with IRB/IEC and International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines; Title 21 Part 56 of the US Code 
of Federal Regulations (CFR) relating to IRBs/IECs and GCP as described in the US FDA CFR 
(21 CFR § 50, 56, 312; China GCP; applicable ICH guidelines regarding clinical safety data 
management (E2A, E2B(R3)); European Community directives 2001/20, 2001/83, 2003/94 and 
2005/28 as enacted into local law, and with ICH guidelines regarding scientific integrity (E4, E8, 
E9, and E10). In addition, this study will adhere to all local regulatory requirements, and 
requirements for data protection. 
11.1.2 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Before initiating a trial/study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IRB/IEC for the study protocol/amendment(s), written ICF, 
any consent form updates, subject recruitment procedures (eg, advertisements), and any written 
information to be provided to subjects and a statement from the IRB/IEC that they comply with 
GCP requirements. The IRB/IEC approval must identify the protocol version as well as the 
documents reviewed. 
11.1.3 
Informed Consent 
The Investigator will explain the benefits and risks of participation in the study to each subject or 
the subject’s legally acceptable representative and obtain written informed consent. Written 
informed consent must be obtained prior to the subject entering the study and before initiation of 
any study-related procedure (including administration of investigational product). 
The Sponsor or its designee will provide a sample ICF. The final, version dated, ICF must be 
agreed to by the Sponsor or its designees and the IRB/IEC and will contain all elements in the 
sample form, in language readily understood by the subject. Each subject’s original consent form 
must be personally signed and dated by the subject or by the subject’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. The original, 
signed ICF will be retained by the Investigator. The Investigator will supply all enrolled subjects 
with a copy of their signed ICF. 
The ICF may need to be revised during the study should important new information become 
available that may be relevant to the safety of the subject. In this instance approval should always 
be given by the IRB/IEC and existing subjects informed of the changes and reconsented. This is 
documented in the same way as previously described. 
The Investigator should encourage subjects to inform their primary physician about their 
participation in the clinical study. 


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11.1.4 
Confidentiality 
All information generated in this study is considered confidential and must not be disclosed to any 
person or entity not directly involved with the study unless prior written consent is gained from 
the Sponsor. However, authorized regulatory officials, IRB/IEC personnel, and the Sponsor and 
the Sponsor’s authorized representatives are allowed full access to the records. 
Identification of subjects and eCRFs shall be by Subject Number only. If required, the subject's 
full name may be made known to an authorized regulatory agency or other authorized official. 
11.1.5 
Study Files and Retention of Records 
Records must be retained in accordance with the current ICH guidelines on GCP. All essential 
study documents including records of subjects, source documents, eCRFs, and investigational 
product inventory must be kept on file. 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region, or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational products. However, essential documents may be retained for a 
longer period if required by the applicable regulatory requirements or by agreement with the 
Sponsor. The Sponsor is responsible for informing the Investigator when these documents need no 
longer be retained. 
The Investigator will not dispose of any records relevant to this study without written permission 
from the Sponsor and will give the Sponsor the opportunity to collect such records. The 
Investigator shall take responsibility for maintaining adequate and accurate hard copy source 
documents of all observations and data generated during this study. Such documentation is subject 
to inspection by the Sponsor, its representatives, and regulatory authorities. 
If an Investigator moves, withdraws from an investigation, or retires, responsibility for maintaining 
the records may be transferred to another person who will accept responsibility. Notice of transfer 
must be made to and agreed by the Sponsor. 
11.1.6 
Audits and Inspections 
The Sponsor or their designee, the CRO, may conduct audits at the investigative sites including, 
but not limited to, drug supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents. All medical records (progress notes) must be 
available for audit. The Investigator agrees to participate with audits conducted at a convenient 
time in a reasonable manner. 
Government regulatory authorities may also inspect the site during or after the study. The 
Investigator or designee should contact the Sponsor and/or the CRO, immediately if this occurs. 
The site must cooperate fully with regulatory authorities or other audits conducted at a convenient 
time in a reasonable manner. 


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The purpose of an audit is to assess whether ethical, regulatory, and quality requirements are 
fulfilled. 
11.1.7 
Protocol Compliance 
It is the responsibility of the Investigator to ensure that the study is conducted at their respective 
site in accordance with this protocol. Protocol compliance assessments will be conducted during 
routine site monitoring visits. 
 
Sponsor Responsibilities 
11.2.1 
Protocol Amendments and Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by the Sponsor. A protocol change intended to eliminate an apparent immediate hazard 
to subjects may be implemented immediately, provided the IRB/IEC is notified within 5 days. 
Any permanent, significant change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC and the Investigator must await approval 
before implementing the changes. The Sponsor will submit protocol amendments to the 
appropriate regulatory authorities for approval. 
If, in the judgment of the IRB/IEC, the Investigator, and/or the Sponsor, the amendment to the 
protocol substantially changes the study design and/or increases the potential risk to the subject 
and/or has an impact on the subject's involvement as a study subject, the currently approved written 
ICF will require similar modification. In such cases, subjects will be required for to sign the 
amended informed consent prior to continued participation in the study. 
11.2.2 
Data Management 
A set of data management documents will be created under the responsibility of the Sponsor, or 
designated CRO, to describe the processes being used to ensure data quality. 
The data management plan, and other associated documentations, will specify data capture 
methods, who is authorized to enter data, decisions about ownership of data, source data storage, 
which data will be transferred (including timing of transfers), and the origin/destination of data. 
11.2.3 
Study Report and Publications 
The Sponsor or its designee is responsible for preparing and providing the appropriate regulatory 
authorities with the Clinical Study Report (CSR) according to the applicable regulatory 
requirements. CSR will be developed in accordance with the ICH E3 Guideline on the ‘Structure 
and Content of Clinical Study Reports’. Local country requirements will be considered during 
CSR preparation. 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all proposed manuscripts or abstracts to the Sponsor before 


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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 publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a coordinating 
Investigator will be designated by mutual agreement.  
Assembly Biosciences follows the guidelines and recommendations of the International 
Committee of Medical Journal Editors (ICMJE) and the International Society for Medical 
Publication Professionals (ISMPP) when preparing publications associated with clinical studies 
(Battisti 2015, ICMJE 2019). 
 
 


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From https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.27532 
Papatheodoridis GV, Chan HL, Hansen BE, et al (2015) Risk of hepatocellular carcinoma in chronic 
hepatitis B: assessment and modification with current antiviral therapy. J Hepatol 62(4):956-967. 
Pungpapong S and Kim WR (2013) In the eye of the B-holder: natural history of chronic hepatitis B. 
Hepatology 58(1):6-8. 
Schweitzer A, Horn J, Mikolajczyk RT, et al (2015) Estimations of worldwide prevalence of chronic 
hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet 
386(10003):1546-1555. 
Sorrell MF, Belongia EA, Costa J, et al (2009) National Institutes of Health Consensus Development 
Conference Statement: management of hepatitis B. Ann Intern Med 150(2):104-110. 
Terrault (2018) Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 
hepatitis B guidance. Hepatology 67(4):1560-1599. 
Wang J, Shen T, Huang X, et al (2016) Serum hepatitis B virus RNA is encapsidated pregenome RNA that 
may be associated with persistence of viral infection and rebound. J Hepatol 65(4):700-710. 
WHO 
(2019) 
Hepatitis 
B: 
fact 
sheet. 
Retrieved 
July 
2019. 
 
From 
http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed March 13, 2020. 
Yim HJ and Lok AS (2006) Natural history of chronic hepatitis B virus infection: what we knew in 1981 
and what we know in 2005. Hepatology 43(2 Suppl 1):S173-181. 
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APPENDICES  
APPENDIX 1. TOXICITY GRADING SCALE FOR ADVERSE EVENTS AND 
LABORATORY ABNORMALITIES 
Adapted from the U.S. National Institutes of Health (Division of AIDS) Table for Grading 
Severity of Adult Adverse Experiences (Corrected Version 2.1, July 2017) 
[https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf]  
MAJOR CLINICAL CONDITIONS 
Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
CARDIOVASCULAR 
Arrhythmia  
(by ECG or physical 
examination) 
Specify type, if 
applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention 
indicated 
Non-life-threatening 
symptoms AND 
Non-urgent 
intervention 
indicated 
Life-threatening 
arrhythmia OR 
Urgent intervention 
indicated 
Blood Pressure 
Abnormalities 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a 
visit) 
≥ 18 years of age 
140 to < 160 mmHg 
systolic  
OR 90 to 
< 100 mmHg 
diastolic 
≥ 160 to 
< 180 mmHg 
systolic  
OR ≥ 100 to 
< 110 mmHg 
diastolic 
≥ 180 mmHg 
systolic  
OR  
≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously 
diagnosed with 
hypertension (e.g., 
malignant 
hypertension) OR 
Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected 
with oral fluid 
replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use 
of vasopressors or 
mechanical 
assistance to 
maintain blood 
pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms 
with ischemia 
(stable angina) OR 
New testing 
consistent with 
ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
No symptoms AND 
Laboratory or 
cardiac imaging 
abnormalities 
Symptoms with 
mild to moderate 
activity or exertion 
Symptoms at rest or 
with minimal 
activity or exertion 
(e.g., hypoxemia) 
OR Intervention 
indicated (e.g., 
oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive 
medications, 
ventricular assist 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
device, heart 
transplant) 
Hemorrhage  
(with significant 
acute blood loss) 
NA 
Symptoms AND No 
transfusion 
indicated 
Symptoms AND 
Transfusion of 
≤ 2 units packed 
RBCs indicated 
Life-threatening 
hypotension OR 
Transfusion of 
> 2 units 
packed RBCs (for 
children, packed 
RBCs > 10 cc/kg) 
indicated 
Prolonged PR 
Interval or AV 
Block 
Report only one 
> 16 years of age 
PR interval 0.21 to 
< 0.25 seconds 
PR interval 
≥ 0.25 seconds OR 
Type I 2nd degree 
AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause 
≥ 3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval 2 
0.45 to 0.47 seconds 
> 0.47 to 
0.50 seconds 
> 0.50 seconds OR 
≥ 0.06 seconds 
above baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated 
serious ventricular 
dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
 
NA 
Symptoms AND No 
intervention 
indicated 
Symptoms AND 
Intervention 
indicated 
Life-threatening 
embolic event (e.g., 
pulmonary 
embolism, 
thrombus) 
DERMATOLOGIC  
Alopecia  
(scalp only) 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Bruising  
Localized to one 
area 
Localized to more 
than one area 
Generalized  
NA 
Cellulitis  
NA 
Non-parenteral 
treatment indicated 
(e.g., oral 
antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, 
antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue 
necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
Marked or 
generalized causing 
greater than 
minimal 
NA 
NA 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
usual social & 
functional activities 
interference with 
usual social & 
functional activities 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus 3 
(without skin 
lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional activities 
Itching causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 
Rash 
Specify type, if 
applicable 
Localized rash  
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial 
ulcerations of 
mucous membrane 
limited to one site 
Extensive or 
generalized bullous 
lesions OR 
Ulceration of 
mucous membrane 
involving two or 
more distinct 
mucosal sites OR 
Stevens-Johnson 
syndrome OR Toxic 
epidermal 
necrolysis 
ENDOCRINE AND METABOLIC 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled 
despite treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar 
nonketotic coma, 
end organ failure) 
Gynecomastia 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring 
intervention or 
causing inability to 
perform usual social 
& functional 
activities 
NA 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
Hyperthyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
Minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy5 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes  NA 
GASTROINTESTINAL  
Anorexia  
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss 
Loss of appetite 
associated with 
significant weight 
loss 
Life-threatening 
consequences OR 
Aggressive 
intervention 
indicated (e.g., tube 
feeding, total 
parenteral nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
therapeutic 
paracentesis) 
Bloating or 
Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical 
intervention 
indicated 
Radiologic, 
endoscopic, or 
operative 
intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation  
NA  
Persistent 
Constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
≥ 1 year of age 
Transient or 
Intermittent 
episodes of 
unformed stools OR 
Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to 6 
stools over baseline 
per 24-hour period 
Increase of ≥ 7 
stools per 24-hour 
period OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Dysphagia or 
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention 
indicated 
Life-threatening 
reduction in oral 
intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or 
Stomatitis 
Report only one and 
specify location 
Mucosal erythema 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) 
OR Tissue necrosis 
OR Diffuse 
spontaneous 
mucosal bleeding 
Nausea 
Transient 
(< 24 hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 
48 hours 
Persistent nausea 
resulting in minimal 
oral intake for 
> 48 hours OR 
Rehydration 
Life-threatening 
consequences (e.g., 
hypotensive shock) 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
indicated (e.g., IV 
fluids) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention 
indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting  
Transient or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
MUSCULOSKELETAL 
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic 
self-care functions 
Arthritis 
Stiffness or joint 
swelling causing no 
or minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint 
stiffness or swelling 
causing inability to 
perform basic self-
care functions 
Myalgia 
(generalized) 
Muscle pain causing 
no or Minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle 
pain causing 
inability to perform 
basic self-care 
functions 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic 
findings OR 
Operative 
intervention 
indicated 
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care 
functions 
Osteopenia6 
≥ 30 years of age 
BMD t-score 
-2.5 to -1 
NA 
NA 
NA 
< 30 years of age 
BMD z-score  
-2 to -1 
NA 
NA 
NA 
Osteoporosis6 
≥ 30 years of age 
NA 
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing 
life-threatening 
consequences 
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing 
life-threatening 
consequences 
NEUROLOGIC 
Acute CNS 
Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., 
stroke with 
neurological deficit) 
Altered Mental 
Status 
(for Dementia, see 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance below) 
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, 
lethargy, or 
somnolence causing 
inability to perform 
usual social & 
functional activities 
Delirium OR 
Obtundation OR 
Coma 
Ataxia 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with ataxia detected 
on examination 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic 
self-care functions 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention deficit 
disorder) Specify 
type, if applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on 
parttime basis 
indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a 
fulltime basis 
indicated 
Disability causing 
inability to perform 
basic self-care 
functions OR 
Institutionalization 
indicated 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
Headache 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated OR 
Headache with 
significant 
impairment of 
alertness or other 
neurologic function 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy)  
Specify type, if 
applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater than 
minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional 
activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Alteration (includes 
paresthesia and 
painful neuropathy) 
Specify type, if 
applicable 
Minimal paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration 
or paresthesia 
causing greater than 
minimal 
interference with 
usual social & 
functional activities 
Sensory alteration 
or paresthesia 
causing inability to 
perform usual social 
& functional 
activities 
Disabling sensory 
alteration or 
paresthesia causing 
inability to perform 
basic self-care 
functions 
Seizures New Onset 
Seizure ≥ 18 years 
of age 
NA 
NA 
1 to 3 seizures 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Pre-existing Seizure 
NA 
Increased frequency 
from previous level 
of control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Syncope 
Near syncope 
without loss of 
Loss of 
consciousness with 
Loss of 
consciousness AND 
Hospitalization or 
NA 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
consciousness (e.g., 
pre-syncope) 
no intervention 
indicated 
intervention 
required 
PREGNANCY, PUERPERIUM, AND PERINATAL 
Stillbirth (report 
using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal death 
occurring at 
≥ 20 weeks 
gestation 
NA 
Preterm Birth 
(report using 
mother’s participant 
ID) 
Live birth at 34 to 
< 37 weeks 
gestational age 
Live birth at 28 to 
<  34 weeks 
gestational age 
Live birth at 24 to 
< 28 weeks 
gestational age 
Live birth at 
< 24 weeks 
gestational age 
Spontaneous 
Abortion or 
Miscarriage7 (report 
using mother’s 
participant ID) 
Report only one 
Chemical pregnancy 
Uncomplicated 
spontaneous 
abortion or 
miscarriage 
Complicated 
spontaneous 
abortion or 
miscarriage 
NA 
PSYCHIATRIC 
Insomnia  
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing more than 
minimal 
interference with 
usual social & 
functional activities 
Severe difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing inability to 
perform usual social 
& functional 
activities requiring 
intervention or 
hospitalization 
NA 
Psychiatric 
Disorders 
(includes anxiety, 
depression, mania, 
and psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
Intervention 
indicated OR 
Behavior causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
Hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to 
self or others OR 
Acute psychosis OR 
Behavior causing 
inability to perform 
basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to 
kill oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial 
or complete plans 
but no attempt to do 
so OR 
Hospitalization 
indicated 
Suicide attempted 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
RESPIRATORY  
Acute 
Bronchospasm 
Forced expiratory 
volume in 1 second 
or peak flow 
reduced to ≥ 70 to 
< 80% OR Mild 
symptoms with 
intervention not 
indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to 
< 70% OR 
Symptoms with 
intervention 
indicated OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to 
< 50% OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow < 25% 
OR Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or 
Respiratory Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal 
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on 
exertion causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Nasal flaring 
OR Intercostal 
retractions OR 
Pulse oximetry 90 
to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure 
with ventilator 
support indicated 
(e.g., CPAP, 
BPAP, intubation) 
SENSORY 
Hearing Loss 
≥ 12 years of age 
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention 
indicated 
Profound bilateral 
hearing loss 
(>80 dB at 2 kHz 
and above) OR 
Non-serviceable 
hearing (i.e., 
>50 dB audiogram 
and <50% speech 
discrimination) 
Tinnitus 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis 
with symptoms OR 
Medical 
Posterior or 
panuveitis OR 
Operative 
Disabling visual 
loss in affected 
eye(s) 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
intervention 
indicated 
Intervention 
indicated 
Vertigo 
Vertigo causing no 
or minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic 
self-care functions 
Visual Changes 
(assessed from 
baseline) 
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing greater than 
minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional 
activities 
Disabling visual 
loss in affected 
eye(s) 
SYSTEMIC 
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with no 
intervention 
indicated 
 
Generalized 
urticaria OR 
Angioedema with 
intervention 
indicated OR 
Symptoms of mild 
bronchospasm 
Acute anaphylaxis 
OR Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome8 
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion) 
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
 
Incapacitating 
symptoms of fatigue 
or malaise causing 
inability to perform 
basic self-care 
functions 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life -threatening 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6 to < 39.3°C 
or ≥ 101.5 to < 
102.7°F 
≥ 39.3 to < 40.0°C 
or ≥ 102.7 to < 
104.0°F 
≥ 40.0°C or ≥ 
104.0°F 
Pain9 (not 
associated with 
study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal 
interference with 
usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Pain causing 
inability to perform 
usual social & 
functional activities 
Disabling pain 
causing inability to 
perform basic 
self-care functions 
OR Hospitalization 
indicated 
Serum Sickness10 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention 
indicated (e.g., 
steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight  
> 5 to 19 years of 
age 
WHO BMI z-score 
< -1 to -2 
WHO BMI z-score 
< -2 to -3 
WHO BMI z-score 
< -3 
WHO BMI z-score 
< -3 with 
life-threatening 
consequences 
Unintentional 
Weight Loss 
(excludes 
postpartum weight 
loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from 
baseline OR 
Aggressive 
intervention 
indicated (e.g., tube 
feeding, total 
parenteral nutrition) 
URINARY 
Urinary Tract 
Obstruction 
NA 
Signs or symptoms 
of urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction 
Signs or symptoms 
of urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing 
life-threatening 
consequences 
2 
As per Bazett’s formula. 
3 
For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section. 
4 
Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5 
Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen. 
6 
BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). 
Assessment of osteoporosis at the primary health-care level. Technical Report. World Health Organization 
Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the University of 
Sheffield. 
7 
Definition: A pregnancy loss occurring at <20 weeks gestational age. 
8 
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath.  
9 
For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section. 
10 
Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea.  


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SITE REACTIONS TO INJECTIONS AND INFUSIONS 
 
Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life-threatening 
Injection Site Pain 
or 
Tenderness 
Report only one 
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb 
 
Pain or tenderness 
causing greater than 
minimal limitation 
of use of limb 
 
Pain or tenderness 
causing inability to 
perform usual social 
& functional 
activities 
Pain or tenderness 
causing inability to 
perform basic self-
care function OR 
Hospitalization 
indicated 
Injection Site 
Erythema or 
Redness12  
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 to 
< 100 cm2 surface 
area OR Symptoms 
causing greater than 
minimal 
interference with 
usual social & 
functional activities 
 
 
≥ 10 cm in diameter 
OR ≥ 100 cm2 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially 
life-threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or 
Swelling  
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Injection Site 
Pruritus 
Itching localized to 
the injection site 
that is relieved 
spontaneously or in 
< 48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 hours 
treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional 
activities 
NA 
12 
Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured 
surface area. 
 
 
 


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LABORATORY VALUES* CHEMISTRIES  
 
Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life-threatening 
Acidosis 
NA 
pH ≥ 7.3 to < LLN 
pH < 7.3 without 
life-threatening 
consequences 
pH < 7.3 with 
life-threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to < LLN  
30 to < LLN 
≥ 2.0 to < 3.0  
≥ 20 to < 30 
< 2.0 
 < 20 
NA 
Alkaline 
Phosphatase, High 
1.25 to < 2.5 x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without 
life-threatening 
consequences 
pH > 7.5 with 
life-threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase 
(Pancreatic) or 
Amylase (Total), 
High  
Report only one 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, 
High Report only 
one 
1.25 to < 2.5 x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low 
(mEq/L; mmol/L) 
16.0 to < LLN  
16.0 to < LLN 
11.0 to < 16.0  
11.0 to < 16.0 
8.0 to < 11.0  
8.0 to < 11.0 
< 8.0  
< 8.0 
Bilirubin  
Direct Bilirubin13, 
High  
> 28 days of age 
NA 
NA 
> ULN with other 
signs and symptoms 
of hepatotoxicity 
> ULN with 
life-threatening 
consequences (e.g., 
signs and symptoms 
of liver failure) 
Total Bilirubin, 
High  
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6 to < 11.5  
2.65 to < 2.88 
11.5 to < 12.5  
2.88 to < 3.13 
12.5 to < 13.5  
3.13 to < 3.38 
≥ 13.5 
 ≥ 3.38 
Calcium (Ionized), 
High (mg/dL; 
mmol/L) 
> ULN to < 6.0  
> ULN to < 1.5 
6.0 to < 6.4  
1.5 to < 1.6 
6.4 to < 7.2  
1.6 to < 1.8 
≥ 7.2 
 ≥ 1.8 
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8 to < 8.4  
1.95 to < 2.10 
7.0 to < 7.8  
1.75 to < 1.95 
6.1 to < 7.0  
1.53 to < 1.75 
< 6.1  
< 1.53 
Calcium (Ionized), 
Low (mg/dL; 
mmol/L) 
< LLN to 4.0  
< LLN to 1.0 
3.6 to < 4.0  
0.9 to < 1.0 
3.2 to < 3.6  
0.8 to < 0.9 
< 3.2  
< 0.8 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life-threatening 
Cardiac Troponin I, 
High 
NA 
NA 
NA 
Levels consistent 
with myocardial 
infarction or 
unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, 
High 
3 to < 6 x ULN 
6 to < 10x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
**Report only one 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase to 1.3 
to < 1.5 x 
participant’s 
baseline 
> 1.8 to < 3.5 x 
ULN OR Increase 
to 1.5 to < 2.0 x 
participant’s 
baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x 
participant’s 
baseline 
Creatinine 
Clearance 14 or 
eGFR, Low 
**Report only one 
NA 
< 90 to 60 ml/min 
or ml/min/1.73 m2 
OR 10 to < 30% 
decrease from 
participant’s 
baseline 
< 60 to 30 ml/min 
or ml/min/1.73 m2 
OR 30 to < 50% 
decrease from 
participant’s 
baseline 
< 30 ml/min or 
ml/min/1.73 m2 OR 
≥ 50% decrease 
from participant’s 
baseline or dialysis 
needed 
Glucose (mg/dL; 
mmol/L) Fasting, 
High 
110 to 125  
6.11 to < 6.95 
> 125 to 250  
6.95 to < 13.89 
> 250 to 500  
13.89 to < 27.75 
≥ 500  
≥ 27.75 
Nonfasting, High 
116 to 160  
6.44 to < 8.89 
> 160 to 250  
8.89 to < 13.89 
> 250 to 500  
13.89 to < 27.75 
≥ 500 
 ≥ 27.75 
Glucose, Low 
(mg/dL; mmol/L) 
≥ 1 month of age 
55 to 64  
3.05 to <3.55 
40 to < 55  
2.22 to < 3.05 
30 to < 40  
1.67 to < 2.22 
< 30  
< 1.67 
Lactate, High 
ULN to < 2.0 x 
ULN without 
acidosis 
≥ 2.0 x ULN 
without acidosis 
Increased lactate 
with pH < 7.3 
without 
life-threatening 
consequences 
Increased lactate 
with pH < 7.3 with 
life-threatening 
consequences 
Lipase, High 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, 
Fasting, High  
≥ 18 years of age 
200 to < 240  
5.18 to < 6.19 
240 to < 300  
6.19 to < 7.77 
≥ 300  
≥ 7.77 
NA 
LDL, Fasting, High 
≥ 18 years of age 
130 to < 160  
3.37 to < 4.12 
160 to < 190 
4.12 to < 4.90 
≥ 190  
≥ 4.90 
NA 
Triglycerides, 
Fasting, High 
150 to 300  
1.71 to 3.42 
>300 to 500  
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
 > 11.4 
Magnesium15, Low 
(mEq/L; mmol/L) 
1.2 to < 1.4  
0.60 to < 0.70 
0.9 to < 1.2  
0.45 to < 0.60 
0.6 to < 0.9  
0.30 to < 0.45 
< 0.6  
< 0.30 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life-threatening 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN  
0.65 to < LLN 
1.4 to < 2.0  
0.45 to < 0.65 
1.0 to < 1.4  
0.32 to < 0.45 
< 1.0  
< 0.32 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to < 6.0  
5.6 to < 6.0 
6.0 to < 6.5  
6.0 to < 6.5 
6.5 to < 7.0  
6.5 to < 7.0 
≥ 7.0 
 ≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to < 3.4  
3.0 to < 3.4 
2.5 to < 3.0  
2.5 to < 3.0 
2.0 to < 2.5  
2.0 to < 2.5 
< 2.0  
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to < 150  
146 to < 150 
150 to < 154  
150 to < 154 
154 to < 160  
154 to < 160 
≥ 160  
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to < 135  
130 to < 135 
125 to < 130  
125 to < 130 
121 to < 125  
121 to < 125 
≤ 120  
≤ 120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to < 10.0  
0.45 to < 0.59 
10.0 to < 12.0  
0.59 to < 0.71 
12.0 to < 15.0  
0.71 to < 0.89 
≥ 15.0  
≥ 0.89 
HEMATOLOGY 
Absolute CD4+ 
Count, Low 
(cell/mm3; cells/L) 
> 5 years of age (not 
HIV infected) 
300 to < 400  
300 to < 400 
200 to < 300  
200 to < 300 
100 to < 200  
100 to < 200 
< 100  
< 100 
Absolute 
Lymphocyte Count, 
Low (cell/mm3; 
cells/L) > 5 years of 
age (not HIV 
infected) 
600 to < 650 
0.600 x 109 to  
< 0.650 x 109 
500 to < 600  
0.500 x 109 to  
< 0.600 x 109 
350 to < 500 
0.350 x 109 to  
< 0.500 x 109 
< 350  
< 0.350 x 109 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000  
0.800 x 109 to 1.000 
x 109 
600 to 799  
0.600 x 109 to 0.799 
x 109 
400 to 599  
0.400 x 109 to 0.599 
x 109 
< 400  
< 0.400 x 109 
Fibrinogen, 
Decreased  
(mg/dL; g/L) 
100 to < 200  
1.00 to < 2.00  
OR  
0.75 to < 1.00 x 
LLN 
75 to < 100  
0.75 to < 1.00  
OR  
≥ 0.50 to < 0.75 x 
LLN 
50 to < 75  
0.50 to < 0.75  
OR  
0.25 to < 0.50 x 
LLN 
< 50  
< 0.50  
OR  
< 0.25 x LLN OR 
Associated with 
gross bleeding 
Hemoglobin16, Low 
(g/dL; mmol/L)17 
≥ 13 years of age 
(male only) 
10.0 to 10.9  
6.19 to 6.76 
9.0 to < 10.0  
5.57 to < 6.19 
7.0 to < 9.0  
4.34 to < 5.57 
< 7.0  
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4  
5.88 to 6.48 
8.5 to < 9.5  
5.25 to < 5.88 
6.5 to < 8.5  
4.03 to < 5.25 
< 6.5  
< 4.03 
INR, High (not on 
anticoagulation 
therapy) 
1.1 to < 1.5 x ULN 
1.5 to < 2.0 x ULN 
2.0 to < 3.0 x ULN 
≥ 3.0 x ULN 
Methemoglobin (% 
hemoglobin) 
5.0 to < 10.0% 
10.0 to < 15.0% 
15.0 to < 20.0% 
≥ 20.0% 


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Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life-threatening 
PTT, High (not on 
anticoagulation 
therapy) 
1.1 to < 1.66 x ULN 
1.66 to < 2.33 x 
ULN 
2.33 to < 3.00 x 
ULN 
≥ 3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000 to < 
125,000  
100.000 x 109 to  
< 125.000 x 109 
50,000 to < 100,000 
50.000 x 109 to  
< 100.000 x 109 
25,000 to < 50,000 
25.000 x 109 to  
< 50.000 x 109 
< 25,000  
< 25.000 x 109 
PT, High (not on 
anticoagulation 
therapy 
1.1 to < 1.25 x ULN 
1.25 to < 1.50 x 
ULN 
1.50 to < 3.00 x 
ULN 
≥ 3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 2.499 
x 109 
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109 
1,000 to 1,499 
1.000 x 109 to 1.499 
x 109 
< 1,000  
< 1.000 x 109 
URINALYSIS 
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or ≤ 250 
mg 
2+ or ˃ 250 to  
≤ 500 mg 
> 2+ or > 500 mg  
NA 
Hematuria (not to 
be reported based 
on dipstick findings 
or on blood believed 
to be of menstrual 
origin) 
6 to < 10 RBCs per 
high power field 
≥ 10 RBCs per high 
power field 
Gross, with or 
without clots OR 
With RBC casts OR 
Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+ or higher 
NA 
* 
Reminder: An asymptomatic abnormal laboratory finding without an accompanying AE should not be reported to 
DAIDS in an expedited time frame unless it meets protocol-specific reporting requirements. 
13 
Direct bilirubin >1.5 mg/dL in a participant <28 days of age should be graded as grade 2, if <10% of the total bilirubin. 
** 
Reminder: Choose the method that selects for the higher grade. 
14 
Use the applicable formula (ie, Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in mL/min/1.73m2). Sites 
should choose the method defined in their study and when not specified, use the method most relevant to the study 
population.  
15 
To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 
16 
Male and female sex are defined as sex at birth. For transgender participants ≥13 years of age who have been on 
hormone therapy for more than 6 consecutive months, grade hemoglobin based on the gender with which they identify 
(ie, a transgender female should be graded using the female sex at birth hemoglobin laboratory values). 
17 
The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading hemoglobin results 
obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using 
appropriate conversion factor for the particular laboratory. 
 
 
 


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APPENDIX 
2. 
PREGNANCY 
PRECAUTIONS 
AND 
THE 
DEFINITION 
OF 
CHILD-BEARING POTENTIAL AND CONTRACEPTIVE REQUIREMENTS 
Pregnancy Precautions 
The effect of VBR and AB-729 on pregnancy has not been assessed. In preclinical studies, there 
was no evidence of embryo-fetal toxicity with VBR, while maternal toxicity was observed in initial 
dose range-finding studies with AB-729 in rats and rabbits (further studies are ongoing); refer to 
the respective IBs for details. Pregnancy precautions are required and contraceptive requirements 
for female subjects of child-bearing potential are described below. 
Definition of Female Subjects of Child-bearing Potential  
A female subject is considered of child-bearing potential unless they are in the following 
categories: 
• Premenarchal 
• Premenopausal with 1 of the following: 
o Documented hysterectomy  
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
• Postmenopausal: A postmenopausal state is defined as age >54 years with no menses for 
12 months without an alternative medical cause. 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, Müllerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Documentation to determine child-bearing potential can come from the site personnel’s review of 
the subject’s medical records, medical examination, or medical history interview. 
Contraceptive Requirements 
The drug-drug interaction of VBR and systemic (oral/injectable/implantable) hormonal 
contraceptives has not been assessed and so systemic hormonal contraceptives are not considered 
an effective contraceptive method for female subjects of child-bearing potential for the purposes 
of this study.  
Female subjects of child-bearing potential (defined above) must agree to use dual effective 
contraceptive methods for the duration of the study and follow-up, or for at least 28 days after the 
last dose of VBR (Group 2 in Figure 6) and 6 months after the last dose of AB-729 (Groups 1 and 
3 in Figure 6) if the subject prematurely discontinues from the study.  


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Effective contraceptive methods include male or female condom (may not be used together due to 
increased risk of breakage), vasectomy, tubal sterilization, intra-uterine device (IUD), diaphragm, 
or cervical cap. Female subjects of childbearing potential must have a negative serum pregnancy 
test at Screening and a negative urine pregnancy test prior to receiving the first dose of study drug 
on Day 1. 
All male subjects must agree to use dual effective contraceptive methods with their female partners 
(if their female partner is of child-bearing potential) for the duration of the study and follow-up, 
or for at least 28 days after the last dose of VBR (Group 2 in Figure 6) and for 6 months after the 
last dose of AB-729 (Groups 1 and 3 in Figure 6) if they prematurely discontinue the study. In this 
case, effective contraceptive methods may include systemic (oral/injectable/implantable) 
hormonal contraceptives, vasectomy, tubal sterilization, IUD, diaphragm, or cervical cap. Male 
subjects must avoid sperm donation from the time of the first dose of study drug and throughout 
the study period or for at least 28 days after the last dose of VBR (Group 2 in Figure 6) and for 6 
months after the last dose of AB-729 (Groups 1 and 3 in Figure 6) if they prematurely discontinue 
the study. 
 
 


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APPENDIX 3. PROTOCOL AMENDMENT SUMMARY OF CHANGES  
The changes in Amendment 1 to the Original Protocol for Study ABI-H0731-204 dated 20 Nov 
2020, have been summarized in the table below. Deletions are reflected with strikethrough and 
additions are in bold. A redline version of the protocol amendment with all edits to the original 
protocol has also been provided.  
Section  
(In Original 
Protocol) 
Change Made  
Rationale  
Section 
3.1.2, 
Synopsis  
The following secondary objective in bold has 
been added:   
• 
To evaluate the off-treatment durability 
of response to treatment with VBR and 
ABI-729 
With the addition of 
Treatment Stopping Criteria, 
an additional objective of the 
study becomes evaluation of 
off-treatment durability of 
response to study treatment.  
Section 
3.2.2, 
Synopsis  
The eight secondary endpoint has been 
modified as follows:  
• Proportion of subjects with abnormal 
ALT at Baseline who have normal ALT 
(by central laboratory and American 
Association for the Study of Liver Diseases 
[AASLD] criteria) at each timepoint 
The following additional endpoints in bold 
have been added:  
• Proportion 
of 
subjects 
achieving 
Treatment Stopping Criteria at end of 
treatment (EOT) 
• Proportion of subjects who remain off-
treatment at end of study (EOS) 
The last secondary endpoint has been 
modified as follows:  
• Analysis of VBR, and AB-729 drug 
concentrations. NrtI drug concentrations 
may be analyzed, as needed 
The phrase “abnormal ALT at 
Baseline” has been added to 
clarify the endpoint. 
The additional endpoints 
address the objective added 
above.  
To clarify that NrtI drug 
concentrations may be 
evaluated only as needed. 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
Section 
3.2.3, 
Synopsis 
The following additional endpoint has been 
added:  
• 
Proportion of subjects who continued 
NrtI after Week 48 and subsequently 
met the Treatment Stopping Criteria  
With the addition of 
Treatment Stopping Criteria, 
an additional objective of the 
study becomes evaluation of 
off-treatment durability of 
response to study treatment. 
Figure 6, 
Section 4.1, 
Synopsis  
The following statement has been added to the 
Synopsis to be consistent with Section 4.1:  
Up to 2 additional cohorts may be added in 
future protocol amendments to evaluate 
other populations and/or treatment 
regimens. 
The study design schematic has been updated 
to add the planned assessment of Treatment 
Stopping Criteria on Week 48 and the off 
treatment follow up of subjects who meet the 
Treatment Stopping Criteria on Week 48. 
Sections 4.1.1 and 4.1.2 have been created to 
add the following in-bold text:  
Treatment Stopping Criteria 
At Week 48, all subjects will have an 
assessment of Treatment Stopping Criteria. 
Any subjects who meet the below Treatment 
Stopping Criteria, will discontinue their 
assigned treatment including NrtI, and 
continue 
with 
off-treatment 
follow-up 
through Week 96, unless they meet the NrtI-
restart criteria specified below. Decisions to 
discontinue assigned treatment and undergo 
off-treatment follow-up will be based on 
laboratory results from blood samples 
collected at the Week 48 visit. Subjects will 
remain on their assigned oral agents (ie, 
VBR+NrtI for Groups 1 and 2; NrtI for 
Group 3) until Week 48 laboratory results 
The addition of the Treatment 
Stopping Criteria enables the 
assessment of the functional 
cure after 48 weeks of 
treatment and the evaluation 
of the duration of sustained 
functional cure with 3 
different treatment regimens. 
 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
required for Treatment Stopping Criteria 
assessment are available. 
Treatment Stopping Criteria are:  
• ALT < 2 × ULN, and 
• HBV DNA < LLOQ, and 
• HBsAg < 100 IU/mL 
Subjects who do not meet the Treatment 
Stopping Criteria with Week 48 laboratory 
results will continue treatment with NrtI 
alone and will remain in follow-up through 
Week 96. 
NrtI-Restart Criteria:  
Subjects who meet the Treatment Stopping 
Criteria at the Week 48 assessment but 
subsequently meet ANY of the below NrtI-
Restart Criteria, will restart treatment with 
NrtI and remain in follow-up through Week 
96.  
NrtI-Restart Criteria are:  
• Alanine aminotransferase (ALT) > 
10 × upper limit of normal (ULN), 
confirmed by repeat 
• ALT > Baseline and > ULN, 
confirmed by repeat, and  
o Direct bilirubin > 2.0 × ULN, 
confirmed by repeat, or 
o International Normalized 
Ratio > 1.5, confirmed by 
repeat 
• ALT ≥ 2 – 5 × ULN AND HBV DNA 
> 2000 IU/mL for 12 weeks 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
• ALT elevations ≥ 5 – 10 × ULN AND 
HBV DNA > 2000 IU/mL for 4 
weeks 
• Any clinical decompensation, 
regardless of HBV DNA level 
• 
Investigator discretion 
At Week 48, subjects will discontinue VBR 
and/or AB-729 (as applicable) and undergo 48 
weeks of follow-up while remaining on NrtI. 
Section 4.3  
The following in-bold text has been added:  
All subjects will receive their assigned 
treatment for 48 weeks. Subjects will continue 
to 
receive 
assigned 
oral 
agents 
(ie, 
VBR+NrtI for Groups 1 and 2, and NrtI for 
Group 3) until all laboratory results from 
the Week 48 visit are available to determine 
each individual subject treatment action, 
based on Treatment Stopping Criteria 
(discontinuation 
of 
all 
treatment 
or 
continuation of NrtI; see Section 4.1.1). 
To clarify that subjects 
should continue to receive 
their assigned oral agents till 
the results from their Week 
48 laboratory tests are 
available to enable the 
subsequent treatment action 
for the subject. 
Section 5.4  
The following in-bold text has been added:  
Screen failures are defined as subjects who 
consent to participate in the clinical study but 
are not subsequently randomized to study 
treatment. Minimal information to be retained 
on all screen failures includes demography, 
screen failure details, eligibility criteria, and 
any SAE information. Data regarding HBV 
genotype and HBV viral variants, if generated, 
will 
also 
be 
retained 
to 
further 
our 
understanding of the epidemiology of HBV 
and the natural frequency of polymorphisms 
present in the HBV sequences around the core 
To enable enrollment of 
subjects who are eligible 
upon resolution or 
stabilization of an acute 
exclusionary condition and to 
clarify that the screening 
period may be extended if 
laboratory results are not 
available within the 45-day 
screening period, while 
ensuring the safety 
assessment at Baseline 
remains current. 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
and polymerase regions and the AB-729 target 
site.  
Individuals who do not meet the protocol 
eligibility criteria for participation in this study 
(screen failure) may not be rescreened, 
however, be allowed to rescreen (once). 
Rescreening may occur following resolution 
of 
acute 
exclusionary 
conditions 
or 
stabilization 
of 
conditions 
that 
were 
exclusionary and reversible (eg, unstable 
hypothyroidism, electrolyte abnormalities) 
and with the approval of the study Medical 
Monitor. 
A single retest for a laboratory parameter(s) is 
permitted if there is a specific issue related to 
the collection, shipping, processing or analysis 
of a sample (eg, receipt of a hemolyzed sample 
at the testing laboratory, or samples received 
by the testing laboratory outside of the 
acceptable temperature range, or resolved 
intercurrent illness). If more than 45 days are 
required to obtain a result of a screening 
procedure and/or test, the screening period 
may be extended till results are obtained. 
However, the clinical safety laboratory tests 
may need to be repeated under the 
instruction of the study Medical Monitor if 
the screening period is beyond 45 days.  
Section 
6.1.2.4  
The text in bold has been added: 
AB-729 is administered once every 8 weeks as 
a 60 mg subcutaneous injection at specified 
clinic visits. 
For clarity. 
Section 6.3  
The text has been modified as follows:  
All concomitant medications taken from the 
date the informed consent is signed through 
24 weeks after the last dose end of study drug 
To correct and provide the 
intended follow up of 
concomitant medications, 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
or “lost to follow-up” must be recorded in the 
subject’s source documentation.  
which is through the end of 
the study.  
Section 6.3.1  The text has been modified as follows:  
Paragraph 1:  
Examples of representative medications which 
are prohibited from 28 days prior to Day 1 
through 24 2 weeks after the last dose of study 
drug VBR or “lost to follow-up” are listed in 
Table 8. 
Paragraph 4:  
Note that systemic (oral, injectable, or 
implanted) hormonal contraceptives are not 
considered as an acceptable means of 
contraception for female subjects of child-
bearing potential (Appendix 2) up to 30 28 
days after the last dose of VBR (Groups 1 and 
2 in Figure 6). 
The edits to Paragraph 1 are 
made to correct the duration 
of prohibited concomitant 
medications, which should be 
through 2 weeks after the last 
dose of VBR, since this is 
sufficient time for clearance 
of VBR (as well as ABI-729) 
from the subjects. 
In Paragraph 4, the total 
number of days after last dose 
of VBR for adherence to 
study contraceptive 
guidelines has been changed 
from 30 to 28 days to align 
with the current general 
guidelines from the Sponsor 
with respect to clinical trials 
and is not related to any 
safety concern. 
Sections 7.1  
The following modifications have been made: 
Paragraph 1:   
With the exception of treatment cessation 
based on Treatment Stopping Criteria (see 
Section 4.1.1), Iif an individual subject is not 
satisfactorily 
tolerating 
their 
assigned 
treatment due to any AEs in the judgment of 
the Investigator, then, upon consultation with 
the Sponsor, the Investigator may discontinue 
treatment with VBR and/or AB-729 depending 
on 
the 
treatment 
group 
assignment.  
Discontinuation from treatment does not mean 
discontinuation from the study. Subjects who 
prematurely 
discontinue 
their 
assigned 
To make the distinction 
between general criteria for 
discontinuation of study 
treatment at any time during 
the study and the Treatment 
Stopping Criteria specified to 
enable assessment of 
functional cure at Week 48 of 
treatment. The reference to 
Table 11 has been added to 
clarify that such subjects 
should follow the 
assessments specified in 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
treatment 
regimen 
should 
immediately 
undergo the assessments listed for the 
Premature Termination visit (Section 8.5) and 
then continue scheduled follow-up assessments 
(Table 11). 
Table 11 of Protocol 
Amendment 1. 
Section 7.2 
The following modifications have been made: 
Paragraph 1:   
“With the exception of treatment cessation 
based on Treatment Stopping Criteria (see 
Section 4.1.1), Sstudy drug treatment may be 
discontinued in the following instances”  
Table 9  
The Table title has been modified as follows:  
Schedule of Assessments (Cohort 1) – On-
Treatment for All Subjects 
The follow up visits column from Table 9 has 
been removed from the table.  
In Table 9, the NrtI and VBR administration 
and NrtI and VBR PK assessments have been 
separated into distinct rows, instead of being 
coupled together. The study treatment group 
numbers have been added in parentheses next 
to these assessments to clarify which subjects 
undergo the assessments based on their 
assigned treatment. 
A row for assessment of Treatment Stopping 
Criteria on Week 48 has been added, with the 
following corresponding footnote m:  
m Subjects will either stop their treatment 
altogether or continue with NrtI 
administration based on assessment of 
Treatment Stopping Criteria (Section 4.1.1) 
utilizing laboratory results from the Week 
48 Visit. Subjects will remain on assigned 
oral agents (ie, VBR+NrtI for groups 1 and 
The edits have been made to 
add clarity to the assessments 
planned for the follow-up 
period and to accommodate 
the Treatment Stopping 
Criteria evaluation at Week 
48. 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
2, and NrtI for Group 3) beyond the Week 
48 visit until all laboratory results are 
available to adjudicate the Treatment 
Stopping Criteria. 
The follow up visits have been specified in 
new tables, ie, Table 10 and Table 11. Table 
10 lists the follow up visits and assessments 
only for subjects who meet the Treatment 
Stopping Criteria at Week 48 assessment. 
Table 11 lists the follow up visits and 
assessments for the rest of the subjects in the 
study. All footnotes specific to the follow-up 
period in Table 9 have been deleted and 
applied as appropriate to Tables 10 and 11. 
Consequently, the footnote labels in Table 9 
have been reordered and re-alphabetized.  
Section 8.3.3 
The following edits are made:  
• Review subject injection site reaction 
diary (Groups 1 and 3) at Weeks 2, 
12, 20, 28, 36, and 44 
• Assess VBR accountability (Groups 1 
and 2) 
• Assessment of Treatment Stopping 
Criteria (see Section 4.1.1 for details) 
• VBR and NrtI administration once 
daily at home; last administration of 
Subjects will continue to receive 
VBR at and NrtI beyond the Week 
48 visit, until all laboratory results 
are available to adjudicate 
individual subject Treatment 
Stopping Criteria (see Section 4.1.1) 
For clarity and alignment 
with Table 9 
Section 8.3.4 
The following edits are made:  
To align with the addition of 
assessment of Treatment 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
Section Title:  
Week 52 50 Through Week 96 Off-treatment 
Follow-up Visits for Subjects Meeting 
Treatment Stopping Criteria (± 5 Days) 
Paragraph 1:  
At Week 48, subjects will discontinue VBR 
and/or AB-729 (as applicable) and be observed 
for 48 weeks of follow-up. During the follow-
up period, subjects will remain on NrtI. The 
following follow-up assessments will be 
performed every 4 weeks from Study Weeks 
52 50 through 96 up period, unless otherwise 
stated for subjects meeting Treatment 
Stopping Criteria (see Table 10). Note: If a 
subject is determined to meet the NrtI-
restart criteria at any time during the 
follow-up, he/she should follow the schedule 
of visits specified in Section 8.3.5 and Table 
11.  
The following edits have been made to the list 
of assessments:   
• NrtI and VBR will continue to be 
administered at home until laboratory 
results from the Week 48 visits are 
available to determine if an individual 
subject meets Treatment Stopping 
Criteria (see Section 4.1.1). Once a 
subject meets the Treatment Stopping 
Criteria and is notified by the site, 
subject will discontinue treatment with 
NrtI and VBR 
• Measure body weight (Weeks 72 and 96 
only) 
Stopping Criteria at Week 48 
to the study design.  


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
• Complete 
physical 
examination 
(excluding breast and genitalia, unless 
indicated; Weeks 72 and 96 only); all 
other visits, symptom-directed physical 
examination  
• Review 
AEs 
and 
concomitant 
medications; concomitant medications up 
to Week 72 only 
• HBV DNA, HBV TNA, HBV RNA 
• HBV DNA (Weeks, 60, 72, 84, and 96 
only)  
▪ FibroTest, APRI (both at Week 
72 and 96 only) 
▪ A single off-treatment blood 
sample for sparse PK of VBR 
(Groups 1 and 2; Week 52 50 
only) 
• VBR accountability (Groups 1 and 2; 
Week 50 only) 
Section 8.3.5 
The section has been added to list assessments 
during the follow-up period for the rest of the 
subjects in the study.  
The following text has been added:  
Week 52 Through Week 96 Follow-Up Visits 
for Rest of the Subjects (±5 Days) 
The following follow-up assessments will be 
performed every 4 weeks from Study Weeks 
52 through 96, for subjects who do NOT 
meet the Treatment Stopping Criteria, or 
subjects who meet the NrtI-restart criteria 
after having met Treatment Stopping 
To align with the addition of 
assessment of Treatment 
Stopping Criteria at Week 48 
to the study design. 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
Criteria, or subjects who prematurely 
discontinue treatment with VBR/AB-729 at 
any time (see Table 11): 
• NrtI and VBR will continue to be 
administered 
at 
home 
until 
laboratory results from the Week 48 
visits are available to adjudicate the 
individual 
subject 
Treatment 
Stopping Criteria (see Section 4.1.1). 
Once a subject is determined to not 
meet 
the 
Treatment 
Stopping 
Criteria, he/she will be notified by the 
site, and the subject will discontinue 
treatment with VBR.  
• NrtI administration once daily at home 
through Week 96 
• Measure body weight (Weeks 72 and 
96 only) 
• Record vital signs (temperature, 
heart rate, respiration rate, and 
blood pressure)  
• Complete 
physical 
examination 
(excluding breast and genitalia, 
unless indicated; Week 72 and 96 
only); all other visits, symptom-
directed physical examination  
• 12-lead ECG (Weeks 60 and 96 only) 
• Review 
AEs 
and 
concomitant 
medications 
• FibroScan (if available; Weeks 72 
and 96 only) 
• Obtain 
blood 
samples 
for 
the 
following: 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
o Safety laboratory tests:  
▪ chemistry, 
hematology, 
coagulation 
▪ CrCl (Weeks 72 and 96 only) 
o Virology:  
o HBV TNA, HBV RNA 
o HBV DNA (Weeks 60, 72, 84, 
and 96 only)  
o HBsAg, 
HBsAb 
(only 
if 
HBsAg 
<LLOQ), 
HBsAg 
isoforms, 
HBV 
resistance 
monitoring sample 
o Immune complexes (Weeks 
52, 56, 60, 64, 72, 84, and 96 
only)  
o HBeAg, 
HBeAb, 
HBcrAg 
(Weeks 60, 72, 84, and 96 
only) 
o Virology back-up sample (to 
be used for retesting HBV 
parameters) 
o Other: 
▪ FibroTest, APRI (both at 
Week 72 and 96 only) 
▪ A single off-treatment blood 
sample for sparse PK of VBR 
(Groups 1 and 2; Week 52 
only) 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
▪ Cytokines/Immune 
biomarkers (Weeks 56, 64, 72, 
84, and 96 only) 
▪ PBMCs (at selected sites at 
Weeks 56, 64, 72, 84, and 96; 
not 
to 
be 
collected 
at 
subsequent timepoints if not 
collected at Day 1) 
▪ RNAi biomarker 
• Obtain 
urine 
samples 
for 
the 
following: 
o Pregnancy 
test 
for 
female 
subjects 
of 
child-bearing 
potential 
o Urinalysis 
• NrtI administration at home  
• Subject dosing diary  
• VBR accountability (Groups 1 and 
2; Week 52 only) 
Section 8.4  
“As applicable” has been added to collection 
of blood samples for various tests and urine 
samples for pregnancy or urinalysis, and for 
the assessment of VBR accountability and 
review of subject dosing diary. 
To allow for flexibility to the 
assessments that need to be 
carried out during an 
unscheduled visit, based on 
the judgement of the 
Investigator. 
Section 8.6.2 
The following edits have been made:  
HBV DNA will be quantified using the a 
commercially available COBAS TaqMan 
HBV test with LLOQ of 10 IU/mL, Version 
2.0 (Roche Diagnostics, US) at a central 
reference laboratory.  
The central lab has a new 
commercially available HBV 
DNA assay (Cobas 6800) 
with LLOQ 10 IU/mL, 
replacing the COBAS 
TaqMan assay. The 
additional added text 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
The Sponsor also reserves the right to use 
alternate HBV virology assays with 
comparable LLOQ if the (originally) 
specified assays become unavailable. 
provides flexibility in case 
the assays changes during the 
course of the study 
Section 8.6.4  Added the following sentence:  
In cases where a quantitative assay is 
negative or <LLOQ, reflex qualitative 
testing will be done 
To provide more complete 
guidance. 
Section 8.7  
The text in bold has been added:  
Samples from those subjects with evidence of 
virologic failure, such as confirmed virologic 
breakthrough (2 consecutive visits with a 
≥1 log10 IU/mL increase in on-treatment HBV 
DNA from on-treatment nadir or 2 
consecutive visits with HBV DNA ≥LLOQ 
after having been <LLOQ) will also be 
sequenced. 
To provide more complete 
guidance. 
Table 10  
The list of laboratory tests under ALT 
elevation management has been updated as 
follows:  
ALT, AST, total bilirubin, serum albumin, 
creatine kinase, INR, HBV DNA, 
quantitative HBV serologies (HBeAg [reflex 
qualitative HBeAg if quantitative HBeAg is 
negative] and HBsAg [reflex qualitative 
HBsAg if quantitative HBsAg is negative]), 
HAV immunoglobulin M (IgM), HCV 
RNA, HDV RNA, HEV IgM, ANA, smooth 
muscle antibodies and anti-LKM1 
antibodies, EBV DNA, CMV DNA, HSV 
DNA, and total IgG. 
The footnote ‘a’ has been deleted 
Perform fractionated bilirubin, if total 
bilirubin >ULN 
The list of laboratory tests 
has been updated for 
completion, despite 
duplication of some tests 
specified in other rows of 
Table 10. 
Fractionated bilirubin should 
be performed regardless of 
total bilirubin levels. 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
Sections 
8.9.1.1, 
8.9.1.3 
The following text in bold has been added:  
Note the Day 1 PK sample collection should 
be done prior to the first dose of study 
drug. 
To clarify that the Day 1 PK 
sample collection for VBR 
and NrtI PK assessment 
should be done prior to the 
first dose of study drug. 
Section 
9.10.4  
The following changes have been made:  
Paragraph 2:  
o All subjects with an ALT elevation on 
treatment, defined as ALT >2× Baseline or 
on treatment nadir and ≥10× ULN, should 
have the ALT findings confirmed within 3 
days of receipt of the original results. All 
subjects should return for an Unscheduled 
Visit. At this visit subjects will undergo a 
symptom-directed physical examination, 
vital 
signs, 
review 
of 
concomitant 
medications and AEs, and the following 
laboratory tests: ALT, AST, total bilirubin 
(if total bilirubin is elevated, reflex to direct 
bilirubin), serum albumin, creatine kinase 
and INR. The Investigator will determine if 
other assessments specified in Section  
should be performed. 
Paragraph 3:  
o If the ALT elevation is confirmed, then an 
additional Unscheduled Visit will be 
performed to further evaluate the subject. 
At this visit, the following laboratory tests 
will be performed: ALT, AST, total 
bilirubin (if total bilirubin is elevated, 
reflex to direct bilirubin), serum albumin, 
INR, 
creatine 
kinase, 
HBV 
DNA, 
quantitative HBV serologies (HBeAg 
[reflex qualitative HBeAg if quantitative 
HBeAg is negative] and HBsAg [reflex 
qualitative HBsAg if quantitative HBsAg is 
The edits clarify the sequence 
of assessments and laboratory 
tests to be followed in the 
event of ALT elevation in 
subjects.  
The tests for ANA, smooth 
muscle antibodies and anti-
LKM1 antibodies, EBV 
DNA, CMV DNA, HSV 
DNA, and total IgG, have 
been added to exclude other 
etiologies for ALT elevation. 
Albumin decline INR >1.5 is 
more conservative than >2 
and is supported by scientific 
literature.  
The reference to the US FDA 
has been deleted since Study 
204 is not being conducted in 
the USA. 
The figure has been added for 
clarity.  


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
negative]), 
HAV 
immunoglobulin 
M 
(IgM), HCV RNA, HDV RNA, and HEV 
IgM, ANA, smooth muscle antibodies 
and anti-LKM1 antibodies, EBV DNA, 
CMV DNA, HSV DNA, and total IgG. 
The Investigator will determine if other 
Unscheduled Visit assessments specified 
in Section should be performed.   
The albumin-decline criteria have been 
modified as follows for subjects with declining 
hepatic function: 
• Albumin decline ≥0.5 g/dL OR INR > 2 
1.5× Baseline (Day 1) OR 
If 5 or more subjects meet these flare 
management criteria, the US FDA and other 
relevant regulatory agencies will be notified, 
and subsequent steps will be determined after 
consultation with these agencies. 
Figure 7 has been added as a schematic for the 
safety management plan for ALT elevations.  
Appendix 2  
The following changes have been made:  
Female subjects of child-bearing potential 
(defined above) must agree to use dual 
effective contraceptive methods for the 
duration of the study and follow-up, or for at 
least 30 28 days after the last dose of VBR 
(Group 2 in Figure 6) and 6 months after the 
last dose of AB-729 (Groups 1 and 3 in Figure 
6 if the subject prematurely discontinues from 
the study.  
Effective contraceptive methods include male 
or female condom (may not be used together 
due to increased risk of breakage), vasectomy, 
tubal sterilization, intra-uterine device (IUD), 
diaphragm, or cervical cap. Female subjects of 
To clarify that: 
a. The total number of days 
after last dose of VBR for 
adherence to study 
contraceptive guidelines 
has been changed from 30 
to 28 days to align with 
the current general 
guidelines from the 
Sponsor with respect to 
clinical trials and is not 
related to any safety 
concern 


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Section  
(In Original 
Protocol) 
Change Made  
Rationale  
childbearing potential must have a negative 
serum pregnancy test at Screening and a 
negative urine pregnancy test prior to receiving 
the first dose of study drug on Day 1. 
All male subjects must agree to use a condom 
and an additional dual effective contraceptive 
methods with their female partners (if their 
female partner is of child-bearing potential) for 
the duration of the study and follow-up, or for 
at least 30 28 days after the last dose of VBR 
(Group 2 in Figure 6) and for 6 months after 
the last dose of AB-729 (Groups 1 and 3 in 
Figure 6) if they prematurely discontinue the 
study. In this case, effective contraceptive 
methods 
may 
include 
systemic 
(oral/injectable/implantable) 
hormonal 
contraceptives (for Group 3 only), vasectomy, 
tubal sterilization, IUD, diaphragm, or cervical 
cap. Male subjects must avoid sperm donation 
from the time of the first dose of study drug and 
throughout the study period or for at least 30 
28 days after the last dose of VBR (Group 2 in 
Figure 6) and for 6 months after the last dose 
of AB-729 (Groups 1 and 3 in Figure 6) if they 
prematurely discontinue the study. 
 
 
 
b. Only female subjects of 
childbearing potential 
(rather than all female 
subjects) are required to 
have a negative serum 
pregnancy test at 
Screening and a negative 
urine pregnancy test prior 
to receiving the first dose 
of study drug on Day 1. 
This change aligns with 
the instruction provided 
in Section 5.2 and the 
Schedule of Assessment 
c. Male subjects do not 
necessarily have to use a 
condom with their female 
partners, rather the use of 
any dual effective 
contraceptive methods is 
acceptable 
Female partners of male 
subjects of the study who are 
of child-bearing potential 
may use hormonal 
contraceptives as an effective 
contraceptive method, 
regardless of the treatment 
assigned to their male 
partners 
 
 
 


 
Study Title: A Randomized Phase 2a, Multicenter, Open-Label, Multiple-Cohort Study 
Evaluating Regimens Containing Vebicorvir in Subjects with Chronic Hepatitis B Virus 
Infection 
NCT Number: NCT04820686 
Date of Document: 22 May 2023 


ABI-H0731-204 
Statistical Analysis Plan – Final Analysis 
Version 2.0 
Assembly Biosciences 
Proprietary and Confidential 
Page 1 of 41 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Sponsor:  
Assembly Biosciences, Inc  
331 Oyster Point Blvd 
South San Francisco, CA 94080  
(833) 509-4583 
 
 
Protocol Number: 
ABI-H0731-204 
 
 
Protocol Title: 
A Randomized Phase 2a, Multicenter, Open-Label, 
Multiple-Cohort Study Evaluating Regimens 
Containing Vebicorvir in Subjects with Chronic 
Hepatitis B Virus Infection 
 
 
Product: 
Vebicorvir (VBR; formerly ABI-H0731) 
AB-729 
 
 
Protocol Version (Date): 
Amendment 1 (27 October 2021)  
Indication: 
Chronic Hepatitis B Virus Infection  
Analysis Type: 
Final Analysis for Synoptic CSR 
 
Analysis Plan Version (Date): 
Version 2.0 (22 May 2023) 
Analysis Plan Author: 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


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STATISTICAL ANALYSIS PLAN APPROVAL FORM 
Protocol Title: 
A Randomized Phase 2a, Multicenter, Open-Label, Multiple-
Cohort Study Evaluating Regimens Containing Vebicorvir in 
Subjects with Chronic Hepatitis B Virus Infection  
Protocol Number: 
ABI-H0731-204 
SAP Version (Date): 
Version 2.0 (22 May 2023) 
The SAP was subject to critical review and has been approved . 
Name and Title 
Approval Signature/Date 
 
 
Assembly Biosciences 
 
 
Signature applied in Veeva eTMF. See e-signature 
page. 
 
 
 
 
 
 
Assembly Biosciences 
 
Signature applied in Veeva eTMF. See e-signature 
page. 
 
 
 
 
 
 
 
 
Assembly Biosciences 
 
Signature applied in Veeva eTMF. See e-signature 
page. 
 
 
 


 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 3 
LIST OF ABBREVIATIONS ........................................................................................................................................ 6 
1. 
INTRODUCTION ................................................................................................................................................ 8 
1.1. 
Study Objectives ...................................................................................................................................... 8 
1.2. 
Study Design ............................................................................................................................................ 9 
Treatment Stopping Criteria ................................................................................................................... 10 
NrtI-Restart Criteria ............................................................................................................................... 11 
1.3. 
Sample Size and Power .......................................................................................................................... 11 
1.4. 
Methods of Assigning Subjects to Treatment ........................................................................................ 12 
1.4.1. 
Randomization ..................................................................................................................... 12 
1.4.2. 
Blinding ................................................................................................................................ 12 
2. 
TYPE OF PLANNED ANALYSIS .................................................................................................................... 13 
2.1. 
Interim Analyses .................................................................................................................................... 13 
2.2. 
Final Analysis ........................................................................................................................................ 13 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................ 14 
3.1. 
Analysis Sets .......................................................................................................................................... 14 
3.1.1. 
All Randomized Analysis Set ............................................................................................... 14 
3.1.2. 
Full Analysis Set .................................................................................................................. 14 
3.1.3. 
Safety Analysis Set ............................................................................................................... 14 
3.2. 
Subject Grouping ................................................................................................................................... 14 
3.3. 
Strata and Covariates .............................................................................................................................. 15 
3.4. 
Data Handling Conventions and Transformations ................................................................................. 15 
3.5. 
Missing Data and Outliers ...................................................................................................................... 16 
3.5.1. 
Missing Data ........................................................................................................................ 16 
3.5.2. 
Outliers ................................................................................................................................. 16 
3.6. 
Analytic Definitions ............................................................................................................................... 16 
3.6.1. 
Definition of Study Drug ...................................................................................................... 16 
3.6.2. 
Definition of Baseline .......................................................................................................... 16 
3.6.3. 
Definition of Study Phase and End of Study ........................................................................ 16 
3.6.4. 
Definition of Study Day ....................................................................................................... 17 
3.6.5. 
Analysis Visit Windows ....................................................................................................... 17 
3.6.6. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window ................................................................................................................................ 23 
4. 
SUBJECT DISPOSITION .................................................................................................................................. 24 
4.1. 
Subject Enrollment and Disposition ....................................................................................................... 24 
4.2. 
Extent of Study Drug Exposure and Compliance ................................................................................... 25 
4.2.1. 
Duration of Exposure to Study Drug .................................................................................... 25 
4.2.2. 
Study Drug Compliance ....................................................................................................... 25 
4.2.2.1. 
On-Treatment Compliance ............................................................................. 26 
4.3. 
Protocol Deviations ................................................................................................................................ 26 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 28 
5.1. 
Demographics and Baseline Characteristics .......................................................................................... 28 
5.2. 
Baseline Disease Characteristics ............................................................................................................ 28 
5.3. 
Medical History ...................................................................................................................................... 29 
6. 
EFFICACY ANALYSES ................................................................................................................................... 30 


 
 
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6.1. 
Efficacy Endpoints ................................................................................................................................. 30 
6.1.1. 
Definition of Efficacy Endpoints .......................................................................................... 30 
6.1.2. 
Analysis Methods for Efficacy Endpoints ............................................................................ 30 
7. 
SAFETY ANALYSES ........................................................................................................................................ 31 
7.1. 
Adverse Events and Deaths .................................................................................................................... 31 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 31 
7.1.2. 
Adverse Event Severity ........................................................................................................ 31 
7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 31 
7.1.4. 
Serious Adverse Events ........................................................................................................ 31 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 31 
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events ....................................... 31 
7.1.5.2. 
Incomplete Dates ............................................................................................ 31 
7.1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 32 
7.2. 
Laboratory Evaluations .......................................................................................................................... 33 
7.2.1. 
Graded Laboratory Values ................................................................................................... 33 
7.2.1.1. 
Treatment-Emergent Laboratory Abnormalities ............................................. 33 
7.2.1.2. 
Summaries of Laboratory Abnormalities ........................................................ 33 
7.2.2. 
Ungraded Laboratory Values ............................................................................................... 34 
7.2.3. 
ALT Elevation ...................................................................................................................... 34 
7.2.3.1. 
ALT Elevation without Declining Hepatic Function ...................................... 34 
7.2.3.2. 
ALT Elevation with Declining Hepatic Function ........................................... 34 
7.3. 
Vital Signs .............................................................................................................................................. 35 
7.4. 
Prior and Concomitant Medications ....................................................................................................... 35 
7.4.1. 
Prior Medications ................................................................................................................. 35 
7.4.2. 
Concomitant Medications ..................................................................................................... 36 
7.5. 
Electrocardiogram Results ..................................................................................................................... 37 
7.6. 
Other Safety Measures ........................................................................................................................... 37 
8. 
REFERENCES ................................................................................................................................................... 38 
9. 
SOFTWARE ....................................................................................................................................................... 39 
10. DOCUMENT HISTORY .................................................................................................................................... 40 
11. APPENDICES .................................................................................................................................................... 41 
 
 
 
 


 
 
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LIST OF IN-TEXT TABLES 
 
Table 3-1 
On-Treatment Phase Analysis Visit Windows for Efficacy (HBV TNA, HBV RNA, 
HBsAg), Vital Signs, and Laboratory Assessments ............................................................... 18 
Table 3-2 
On-Treatment Analysis Visit Windows for HBV DNA, HBcrAg, and ECG ......................... 19 
Table 3-3 
Off-Treatment Phase Analysis Visit Windows for HBV DNA, HBV TNA, HBV 
RNA, HBsAg, Vital Signs, Chemistry, Hematology, Coagulation, and Urinalysis for 
Subjects Meeting Treatment Stopping Criteria ...................................................................... 19 
Table 3-4 
Off-Treatment Phase Analysis Visit Windows for HBcrAg and HBeAg for Subjects 
Meeting Treatment Stopping Criteria ..................................................................................... 20 
Table 3-5 
Off-Treatment Phase Analysis Visit Windows for Subjects Meeting Treatment 
Stopping Criteria for ECG ...................................................................................................... 21 
Table 3-6 
Off-Treatment Phase for Subjects Not Meeting Treatment Stopping Criteria and 
NrtI-Restart Phase Analysis Visit Windows for HBV TNA, HBV RNA, HBsAg, 
Vital Signs, Chemistry, Hematology, Coagulation, and Urinalysis........................................ 21 
Table 3-7 
Off-Treatment Phase for Subjects Not Meeting Treatment Stopping Criteria and 
NrtI-Restart Phase Analysis Visit Windows for HBV DNA, HBcrAg, and HBeAg .............. 22 
Table 3-8 
Off-Treatment Phase for Subjects Not Meeting Treatment Stopping Criteria and 
NrtI-Restart Phase Analysis Visit Windows for ECG ............................................................ 23 
 
 
LIST OF IN-TEXT FIGURES 
 
Figure 1-1:  
Study Overview ........................................................................................................................ 9 
 


 
 
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LIST OF ABBREVIATIONS 
AASLD 
american association for the study of liver diseases  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
BLOQ 
below the limit of quantitation 
BMI 
body mass index 
cHBV 
chronic hepatitis B virus infection  
CI 
confidence interval 
CSR 
clinical study report 
DAIDS  
Division of AIDS  
DNA 
deoxyribonucleic acid  
ECG 
electrocardiogram 
eCRF 
case report form 
EDC 
electronic data capture  
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
FAS 
full Analysis Set 
HBcAb 
antibody to the HBV core antigen  
HBcrAg  
hepatitis B core-related antigen 
HBeAb 
HBeAg antibody  
HBeAg  
hepatitis B “e” antigen 
HBsAb 
HBsAg antibody  
HBsAg 
hepatitis B surface antigen  
HBV 
hepatitis B virus  
HLGT 
high-level group term 
HLT 
high-level term 
ID 
identification 
INR 
international normalized ratio  
IPD 
important protocol deviation(s) 
IRT 
interactive response technology 
LLOQ 
lower limit of quantitation  
LLT 
lower-level term 
LOD 
limit of detection 
LOQ 
limit of quantitation 
MedDRA 
medical dictionary for regulatory activities 
NrtI 
Nucleos(t)ide reverse transcriptase inhibitor 


 
 
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PD 
protocol deviation(s) 
PT 
preferred term 
Q1, Q3 
first quartile, third quartile 
QD 
once daily  
RNA  
ribonucleic acid  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
TNA 
total nucleic acid 
ULN 
upper limit of normal 
VBR 
vebicorvir 
WHO 
world health organization 


 
 
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1. 
INTRODUCTION 
Study ABI-H0731-204 is a randomized Phase 2a, multicenter, open-label, multiple-cohort study 
evaluating the safety and antiviral activity of Vebicorvir (VBR) and AB-729 in combination with 
other chronic hepatitis B virus (HBV) infection (cHBV) treatments in subjects with cHBV. The 
target population is male or female subjects, 18 to 50 years of age, inclusive, with no evidence of 
cirrhosis or end-stage liver disease. Cohort 1 is prespecified and will enroll virologically-
suppressed subjects on nucleos(t)ide reverse transcriptase inhibitor (NrtI) therapy with hepatitis 
B virus “e” antigen (HBeAg) negative cHBV. Approximately 60 subjects will be enrolled in 
Cohort 1 of this study. Up to 2 additional cohorts, with approximately 60 subjects per cohort, 
may be added in future protocol amendments, for a maximum sample size of approximately 180 
subjects. 
 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study ABI-H0731-204. This SAP is based on the study protocol Amendment 1, dated 27 
October 2021 and the electronic case report form (eCRF). In February 2023, Assembly and 
Arbutus jointly made the decision to discontinue study ABI-H0731-204, following the 
observation that AB-729 in dual combination with NrtI alone and as a triple combination with 
VBR promoted similar on-treatment declines in HBsAg, as has been observed in other AB-729 
studies. Thus, there appears to be limited additional benefit to subjects continuing in the post-
treatment study period as currently defined in the protocol. The study was prematurely 
terminated after every active subject completed 48-week treatment period. 
The SAP will be finalized before database lock. Only key safety and efficacy endpoints will be 
performed. Any changes made after the finalization of the SAP will be documented in the 
Synoptic CSR. 
1.1. 
Study Objectives 
The primary objective of Cohort 1 is:  
• To evaluate the safety and tolerability of combination treatment with VBR, AB-729, and 
NrtI 
The secondary objectives of Cohort 1 are:  
• To evaluate the effect of adding VBR and AB-729 to NrtI on reduction in and loss of 
HBsAg 
• To evaluate the effect of adding VBR and AB-729 to NrtI in reducing HBV 
deoxyribonucleic acid (DNA) levels  
• To evaluate the effect of adding VBR and AB-729 to NrtI in reducing HBV ribonucleic 
acid (RNA) levels  


 
 
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• To evaluate the effect of adding VBR and AB-729 to NrtI in reducing other HBV 
antigens (ie, hepatitis B core-related antigen [HBcrAg])  
• To evaluate the effect of adding VBR and AB-729 to NrtI on hepatitis B surface antigen 
(HBsAg) seroconversion 
• To evaluate the effect of adding VBR and AB-729 to NrtI on normalization of alanine 
aminotransferase (ALT) 
• To evaluate the off-treatment durability of response to treatment with VBR and AB-729 
• To evaluate the pharmacokinetics (PK) of VBR and AB-729 when coadministered with 
NrtI 
 
The exploratory objectives of Cohort 1 are:  
• To evaluate the emergence of resistance to VBR and AB-729 when coadministered with 
NrtI 
• To evaluate the effect of VBR, AB-729, and NrtI on immunological biomarkers, where 
applicable 
• To evaluate the effect of VBR, AB-729, and NrtI on HBsAg isoforms and immune 
complexes, where applicable 
• To evaluate the effect of AB-729 on an HBV-derived RNA interference biomarker, 
where applicable 
1.2. 
Study Design 
This study will assess the safety, antiviral activity, and PK of VBR and AB-729 administered in 
combination with other cHBV treatments in subjects with cHBV. Cohort 1 is prespecified and 
will enroll virologically-suppressed subjects on NrtI therapy with HBeAg negative cHBV. 
Approximately 60 eligible subjects will be randomized 2:1:1 in 1 of 3 treatment groups as shown 
in  
Figure . Up to 2 additional cohorts may be added in future protocol amendments to evaluate 
other populations and/or treatment regimens. 


 
 
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Figure 1-1.  
Study Design Schematic for Study ABI-H0731-204 
 
Abbreviations: VBR=vebicorvir; NrtI= nucleos(t)ide /reverse transcriptase inhibitor; Wk=week. 
 
Treatment with VBR and NrtI will be administered orally, once daily; treatment with AB-729 
will be administered subcutaneously, once every 8 weeks, for a total of 6 doses. Group 1 will 
receive VBR+AB-729+NrtI, Group 2 will receive VBR+NrtI, and Group 3 will receive AB-
729+NrtI. Treatment assignments will be stratified by HBsAg level (ie, HBsAg ≤1000 IU/mL vs 
>1000 IU/mL) during the Screening visit.  
 
Treatment Stopping Criteria 
At Week 48, all subjects will have an assessment of Treatment Stopping Criteria. Any subjects 
who meet the below Treatment Stopping Criteria, will discontinue their assigned treatment 
including NrtI, and continue with off-treatment follow-up through Week 96, unless they meet the 
NrtI-restart criteria. Decisions to discontinue assigned treatment and undergo off-treatment 
follow-up will be based on laboratory results from blood samples collected at the Week 48 visit. 
Subjects will remain on their assigned oral agents (ie, VBR+NrtI for Groups 1 and 2; NrtI for 
Group 3) until Week 48 laboratory results required for Treatment Stopping Criteria assessment 
are available. 
 
Following the announcement of the study early termination in February 2023, Treatment 
Stopping Criteria were not applicable to the subjects who subsequently reached the Week 48 
visit. In this scenario, subjects were to complete the Premature Termination Visit and undergo 
assessments as outlined in protocol Section 8.5 at the time of the next protocol defined follow up 
visit. At that time, subjects were to discontinue VBR and study defined NrtI, as applicable, and 
were to transition to regular standard of care treatment and follow-up outside of the study. 
 
Treatment Stopping Criteria are:  
• ALT < 2 × upper limit of normal (ULN), and 
• HBV DNA < lower limit of quantitation (LLOQ), and 


 
 
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• HBsAg < 100 IU/mL 
Subjects who do not meet the Treatment Stopping Criteria with Week 48 laboratory results will 
continue treatment with NrtI alone and will remain in follow-up through Week 96. 
NrtI-Restart Criteria  
Subjects who meet the Treatment Stopping Criteria at the Week 48 assessment but subsequently 
meet ANY of the below NrtI-Restart Criteria, will restart treatment with NrtI and remain in 
follow-up through Week 96.  
 
NrtI-Restart Criteria are:  
• ALT > 10 ×ULN, confirmed by repeat 
• ALT > Baseline and > ULN, confirmed by repeat, and  
o Direct bilirubin > 2.0 × ULN, confirmed by repeat, or 
o International Normalized Ratio > 1.5, confirmed by repeat 
• ALT ≥ 2 – 5 × ULN AND HBV DNA > 2000 IU/mL for 12 weeks 
• ALT elevations ≥ 5 – 10 ×ULN AND HBV DNA > 2000 IU/mL for 4 weeks 
• Any clinical decompensation, regardless of HBV DNA level 
• Investigator discretion 
 
The schedule of study procedures is presented in tabular form in Tables 9 through 11 of the study 
protocol. 
1.3. 
Sample Size and Power 
Approximately 60 subjects will be randomized in Cohort 1 as shown in Table 1-2. Up to 2 
additional cohorts may be subsequently enrolled by future protocol amendments, for a maximum 
sample size of approximately 180 subjects. 
 
 
Table 1-2. 
Subject Treatment Assignment for Study ABI-H0731-204 Cohort 1 
Treatment Group  
Study Treatment  
Mode of Delivery  
Number of Subjects per 
Group 
1 
VBR+AB-729+NrtI 
VBR and NrtI: Oral; 
AB-729: Subcutaneous 
30 
2 
VBR+NrtI 
Oral 
15 
3 
AB-729+NrtI 
AB-729: Subcutaneous; 
15 


 
 
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NrtI: Oral 
Total Subjects Planned: 
60 
Abbreviations: NrtI=nucleos(t)ide/reverse transcriptase inhibitor; VBR=vebicorvir. 
 
This is a proof-of-concept study. The sample size is similar to that previously utilized for this 
type of study and is not based upon statistical considerations. 
1.4. 
Methods of Assigning Subjects to Treatment 
1.4.1. 
Randomization 
All subjects will be assigned a unique Subject identification (ID) at Screening and will be 
randomized upon successful completion of the Screening assessments. Upon confirmation of 
subject eligibility on Day 1, an Interactive Response Technology (IRT) system will assign eligible 
subjects to a study treatment. Additional information on the use of the IRT system is provided in 
the IRT User Manual. 
 
In Cohort 1, the IRT system will assign eligible subjects in a 2:1:1 ratio to receive either VBR+AB-
729+NrtI, VBR+ NrtI, or AB-729+NrtI for 48 weeks. Treatment assignments will be stratified by 
HBsAg level (ie, HBsAg ≤1000 IU/mL vs >1000 IU/mL) during the Screening visit. 
 
1.4.2. 
Blinding 
Not applicable as this is an open-label study. 


 
 
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2. 
TYPE OF PLANNED ANALYSIS 
2.1. 
Interim Analyses 
No formal interim analyses are planned. As an open-label study, the data will be reviewed 
periodically.  
 
2.2. 
Final Analysis 
As of 14 February 2023, the study was terminated early. The final analysis to support a Synoptic 
CSR will be performed after all subjects have discontinued or completed the study, outstanding 
data queries have been resolved or adjudicated as unresolvable, and the data have been cleaned 
and finalized.   


 
 
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3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.  
No formal statistical testing is planned. Hence no multiplicity adjustment is required. 
3.1. 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing. For each analysis set, the number and percentage of subjects eligible for 
inclusion will be summarized by treatment group. A listing of reasons for exclusion from 
analysis sets will be provided by subject. 
3.1.1. 
All Randomized Analysis Set 
All Randomized Analysis Set includes all subjects who were randomized in the study, classified 
according to the treatment group into which they were randomized regardless of the actual 
treatment received. 
3.1.2. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized subjects, classified according to the 
treatment group into which they were randomized regardless of the actual treatment received 
who took at least 1 dose of a study drug. This is the primary analysis set for efficacy analyses. 
3.1.3. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects, classified according to the actual treatment 
received regardless of random assignment, who took at least 1 dose of a study drug. This is the 
primary analysis set for safety analyses. 
3.2. 
Subject Grouping 
For analyses based on the All Randomized Analysis Set and FAS, subjects will be grouped 
according to the treatment to which they were randomized. For analyses based on the Safety 
Analysis Set , subjects will be grouped according to the actual treatment received. The actual 
treatment received will differ from the randomized treatment only when their actual treatment 
differs from randomized treatment for the entire treatment duration. 


 
 
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3.3. 
Strata and Covariates 
Subjects will be randomly assigned to treatment groups via an IRT system in a 2:1:1 ratio to receive 
either VBR+AB-729+NrtI, VBR+NrtI, or AB-729+NrtI using a stratified randomization schedule. 
Stratification will be by HBsAg level (ie, HBsAg ≤1000 IU/mL vs >1000 IU/mL) during the 
Screening visit. 
 
If there are discrepancies in stratification factor values between the IRT and the clinical database, 
the values recorded in the clinical database will be used for analyses. Given that the study is 
early terminated, a sensitivity analysis of the efficacy endpoints will not be performed for the 
stratification discrepancy. 
3.4. 
Data Handling Conventions and Transformations 
Subject age collected at Screening visit will be used for analyses and presented in listings. The 
age is derived in the electronic data capture (EDC) system based on year of birth and informed 
consent date. 
Laboratory data that are continuous in nature but are less than the lower limit of quantitation 
(LLOQ), less than the limit of detection (LOD), or above the upper limit of quantitation (LOQ) 
will be imputed for the purposes of calculating descriptive statistics. 
A value that is half of the LLOQ will be used to calculate descriptive statistics if the datum is 
reported in the form of <x or <=x (where x is considered the LLOQ or LOD), or is reported as 
not detected. For example, if the reported datum is “<10”, then a value of 5 will be assigned. If 
the LLOQ is reported in log units, the imputed value will be half of the equivalent non-log 
LLOQ value. 
A value that is 1 significant value unit above the upper LOQ will be used to calculate descriptive 
statistics if the datum is reported in the form of “> x” (where x is considered the LOQ). For 
example, if the result of a continuous laboratory test is >20, a value of 21 will be assigned. If the 
result of a continuous laboratory test is >20.1, a value of 20.2 will be assigned.  
The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of “≥ 
x” (where x is considered the LOQ). 
For selected analyses, virology efficacy data will be transformed to the logarithmic (base 10) 
scale. 
Total bilirubin values entered as < 0.2 mg/dL will be analyzed as 0.1 mg/dL; direct bilirubin 
values entered as < 0.1 mg/dL will be analyzed as 0.05 mg/dL (according to the methods of 
Nehls and Akland, 1973).  
 


 
 
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3.5. 
Missing Data and Outliers 
3.5.1. 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document. 
For missing last dose date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in Section 
7.1.5.2, and for prior and concomitant medications in Section 7.3.2. 
3.5.2. 
Outliers 
Outliers will be identified during the data management review process. No sensitivity analyses 
will be conducted. All data will be included in the data analysis. 
3.6. 
Analytic Definitions 
3.6.1. 
Definition of Study Drug 
In this study, study drug is defined as VBR and AB-729. 
3.6.2. Definition of Baseline  
In general, Baseline will be defined as the last non-missing evaluation prior to the first dose on 
Day 1. Change from Baseline will be defined as the result at desired timepoint minus the result at 
Baseline. 
 
3.6.3. 
Definition of Study Phase and End of Study 
The analyses will include all the data collected in this study based on three phases defined as 
follows. 
• On-Treatment Phase: when a subject is undergoing treatment with AB-729, VBR, or 
both per treatment group (ie, from first dose of either study drug through the last dose of 
VBR +1 day or last dose of AB-729 +56 days, whichever is later) 
• Off-Treatment Phase: after a subject has discontinued AB-729, VBR, or both per 
treatment group, and prior to NrtI restart if applicable (ie, after the last dose of VBR +1 
day or last dose of AB-729 +56 days, whichever is later, until the end of study or before 
the first dose of NrtI if it was restarted) 
• NrtI-Restart Phase: after a subject has restarted NrtI, following the Off-Treatment 
Phase (ie, from the first dose of restarted NrtI through the end of study) 
 


 
 
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End of study is defined as when the last subject completes the last follow-up or is considered 
“lost to follow-up”, whichever is later.  
 
Subjects may prematurely discontinue study drug earlier prior to the Week 48 visit. The end 
dates of the On-Treatment Phase may vary for individual subjects based on their last dose dates 
as defined in Section 3.6.3. 
3.6.4. 
Definition of Study Day 
The first dose date of VBR and of AB-729 will be calculated where applicable. Study Day 1 is 
defined as the first dose date of study drug, which is the minimum of the first dose dates of VBR 
and of AB-729 in a treatment group. If the first dose date is missing, the date of randomization 
will be used. 
The last dose date of VBR and of AB-729 will be calculated where applicable. The last dose date 
of each drug will be the end date on the respective study drug end of treatment eCRF. The last 
dose date of study drug will be defined as the maximum of the last dose dates of VBR and of 
AB-729 in a treatment group. 
For the On-Treatment Phase, study day will be calculated from Study Day 1 and derived as 
follows: 
• For days prior to the first dose: Assessment Date – Study Day 1 
• For postdose study days: Assessment Date – Study Day 1 + 1 
For the Off-Treatment Phase, the Off-Treatment Day 1 will be defined as the day after the last 
dose date of study drug VBR or 56 days after last dose of AB-729, whichever is later. The off-
treatment study day will be calculated from the last dose date and derived as Assessment Date – 
Off-Treatment Day 1 + 1. 
For the NrtI-Restart Phase, the NrtI-Restart Day 1 will be defined as the first dose date of 
restarted NrtI. The NrtI-Restart study day will be calculated from the first dose of NrtI and 
derived as Assessment Date – First Dose Date of NrtI + 1. 
3.6.5. 
Analysis Visit Windows 
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows. For the On-Treatment Phase, data will be 
summarized up to Week 48 visit or premature termination visit. For the Off-Treatment Phase, the 
data will be summarized by treatment action up to the end of study, or up to NrtI restart for 
applicable patients. For the NrtI-Restart Phase, data will be summarized only for applicable 
subjects who restarted NrtI after having discontinued AB-729, VBR, or both. 


 
 
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The analysis windows for the On-Treatment Phase assessments of HBV TNA, HBV RNA, 
HBsAg, Vital signs, Chemistry, Hematology, Coagulation, and Urinalysis are provided in Table 
3-1.  
For the On-Treatment Phase assessments of HBeAg, only the analysis visits of Baseline and 
Week 48 will be presented in the summary tables. Any non-baseline on-treatment visit will be 
categorized under analysis visit Week 48. 
 
Table 3-1 
On-Treatment Phase Analysis Visit Windows for Efficacy (HBV TNA, 
HBV RNA, HBsAg), Vital Signs, and Laboratory Assessments 
Nominal Visit 
On-Treatment Phase 
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Baseline 
1 
(none) 
1 
Week 2 
14 
2 
21 
Week 4 
28 
22 
42 
Week 8 
56 
43 
70 
Week 12 
84 
71 
98 
Week 16 
112 
99 
126 
Week 20 
140 
127 
154 
Week 24 
168 
155 
182 
Week 28 
196 
183 
210 
Week 32 
224 
211 
238 
Week 36 
252 
239 
266 
Week 40 
280 
267 
294 
Week 44 
308 
295 
322 
Week 48 
336 
323 
350 
Week 52 
364 
351 
378 
Week 56 
392 
379 
≥392 
 
The analysis windows for the On-Treatment Phase assessments of HBV DNA, HBcrAg, and 
electrocardiogram (ECG) are provided in Table 3-2. 


 
 
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Table 3-2 
On-Treatment Analysis Visit Windows for HBV DNA, HBcrAg, and 
ECG  
Nominal Visit 
On-Treatment Phase 
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Baseline 
1 
(none) 
1 
Week 12 
84 
2 
126 
Week 24 
168 
127 
210 
Week 36 
252 
211 
294 
Week 48 
336 
295 
≥336 
 
The analysis windows for the Off-Treatment Phase assessments for subjects meeting Treatment 
Stopping Criteria of HBV DNA, HBV TNA, HBV RNA, HBsAg, Vital signs, Chemistry, 
Hematology, Coagulation, and Urinalysis are provided in Table 3-3.  
Table 3-3 
Off-Treatment Phase Analysis Visit Windows for HBV DNA, HBV 
TNA, HBV RNA, HBsAg, Vital Signs, Chemistry, Hematology, 
Coagulation, and Urinalysis for Subjects Meeting Treatment Stopping 
Criteria  
Nominal Visit 
Off-Treatment Phase  
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
 Off-Treatment Day 1 
1 
(none) 
1 
Off-Treatment Week 4 
28 
2 
42 
Off-Treatment Week 8 
56 
43 
70 
Off-Treatment Week 
12 
84 
71 
98 
Off-Treatment Week 
16 
112 
99 
126 
Off-Treatment Week 
20 
140 
127 
154 
Off-Treatment Week 
24 
168 
155 
182 
Off-Treatment Week 
28 
196 
183 
210 
Off-Treatment Week 
32 
224 
211 
238 
Off-Treatment Week 
36 
252 
239 
266 


 
 
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Nominal Visit 
Off-Treatment Phase  
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Off-Treatment Week 
40 
280 
267 
294 
Off-Treatment Week 
44 
308 
295 
322 
Off-Treatment Week 
48 
336 
323 
≥ 336 
 
The analysis windows for the Off-Treatment Phase assessments of HBcrAg and HBeAg for 
subjects meeting Treatment Stopping Criteria are provided in Table 3-4.  
 
Table 3-4 
Off-Treatment Phase Analysis Visit Windows for HBcrAg and HBeAg 
for Subjects Meeting Treatment Stopping Criteria  
Nominal Visit 
Off-Treatment Phase  
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Off-Treatment Day 1 
1 
(none) 
1 
Off-Treatment Week 
12 
84 
2 
126 
Off-Treatment Week 
24 
168 
127 
210 
Off-Treatment Week 
36 
252 
211 
294 
Off-Treatment Week 
48 
336 
295 
≥ 336 
 
The analysis windows for Off-Treatment Phase assessments for subjects meeting Treatment 
Stopping Criteria of ECG are provided in Table 3-5. 
Off-Treatment Phase Analysis Visit Windows for HBcrAg and HBeAg for Subjects Meeting 
Treatment Stopping Criteria 


 
 
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Table 3-5 
Off-Treatment Phase Analysis Visit Windows for Subjects Meeting 
Treatment Stopping Criteria for ECG 
Nominal Visit 
Off-Treatment Phase  
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Off-Treatment Day 1 
1 
(none) 
1 
Off-Treatment Week 
12 
84 
2 
210 
Off-Treatment Week 
48 
336 
211 
≥ 366 
 
The analysis windows for the Off-Treatment Phase assessments for subjects not meeting 
Treatment Stopping Criteria of HBV TNA, HBV RNA, HBsAg, Vital signs, Chemistry, 
Hematology, Coagulation, and Urinalysis are provided in Table 3-6.  
The analysis windows for the NrtI-Restart Phase assessments of the same categories as the 
previous paragraph also follow Table 3-6.  
Table 3-6 
Off-Treatment Phase for Subjects Not Meeting Treatment Stopping 
Criteria and NrtI-Restart Phase Analysis Visit Windows for HBV 
TNA, HBV RNA, HBsAg, Vital Signs, Chemistry, Hematology, 
Coagulation, and Urinalysis  
Nominal Visit 
Off-Treatment/NrtI-Restart Phase  
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Off-Treatment/NrtI-
Restart Day 1 
1 
(none) 
1 
Off-Treatment/NrtI-
Restart Week 4 
28 
2 
42 
Off-Treatment/NrtI-
Restart Week 8 
56 
43 
70 
Off-Treatment/NrtI-
Restart Week 12 
84 
71 
98 
Off-Treatment/NrtI-
Restart Week 16 
112 
99 
126 
Off-Treatment/NrtI-
Restart Week 20 
140 
127 
154 
Off-Treatment/NrtI-
Restart Week 24 
168 
155 
182 
Off-Treatment/NrtI-
Restart Week 28 
196 
183 
210 


 
 
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Nominal Visit 
Off-Treatment/NrtI-Restart Phase  
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Off-Treatment/NrtI-
Restart Week 32 
224 
211 
238 
Off-Treatment/NrtI-
Restart Week 36 
252 
239 
266 
Off-Treatment/NrtI-
Restart Week 40 
280 
267 
294 
Off-Treatment/NrtI-
Restart Week 44 
308 
295 
322 
Off-Treatment/NrtI-
Restart Week 48 
336 
323 
≥ 336 
 
The analysis windows for the Off-Treatment Phase assessments for subjects not meeting 
Treatment Stopping Criteria of HBV DNA, HBcrAg, and HBeAg are provided in Table 3-7.  
The analysis windows for the NrtI-Restart Phase assessments of the same categories as the 
previous paragraph also follow Table 3-7.  
Table 3-7 
Off-Treatment Phase for Subjects Not Meeting Treatment Stopping 
Criteria and NrtI-Restart Phase Analysis Visit Windows for HBV 
DNA, HBcrAg, and HBeAg 
Nominal Visit 
Off-Treatment/NrtI-Restart Phase  
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Off-Treatment/NrtI-
Restart Day 1 
1 
(none) 
1 
Off-Treatment/NrtI-
Restart Week 12 
84 
2 
126 
Off-Treatment/NrtI-
Restart Week 24 
168 
127 
210 
Off-Treatment/NrtI-
Restart Week 36 
252 
211 
294 
Off-Treatment/NrtI-
Restart Week 48 
336 
295 
≥ 336 
The analysis windows for the Off-Treatment Phase assessments for subjects not meeting 
Treatment Stopping Criteria of ECG are provided in Table 3-8.  
The analysis windows for the NrtI-Restart Phase assessments of the same categories as the 
previous paragraph also follow Table 3-8.  


 
 
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Table 3-8 
Off-Treatment Phase for Subjects Not Meeting Treatment Stopping 
Criteria and NrtI-Restart Phase Analysis Visit Windows for ECG 
Nominal Visit 
Off-Treatment/NrtI-Restart Phase  
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Off-Treatment/NrtI-
Restart Day 1 
1 
(none) 
1 
Off-Treatment/NrtI-
Restart Week 12 
84 
2 
210 
Off-Treatment/NrtI-
Restart Week 48 
336 
211 
≥ 366 
 
3.6.6. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window 
Depending on the statistical analysis method, single values may be required for each analysis 
window. If a single value is needed, but multiple valid, nonmissing measurements exist in an 
analysis window, records will be chosen based on the following rules: 
• For baseline, the last nonmissing value on or prior to the first dose date of study drug will be 
selected, unless specified differently. If there are multiple records with the same time or no 
time recorded on the same day, the record with the lowest accession number will be used. 
• For postbaseline values: 
o The record closest to the nominal day for that visit will be selected. 
o If there are 2 records that are equidistant from the nominal day, the later record will be 
selected. 
o If there is more than 1 record on the selected day with the same time, the retest record 
will be selected. If there is no clear indication for which record is the retest record, then 
the record with the lowest accession number will be used. 


 
 
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4. 
SUBJECT DISPOSITION 
4.1. 
Subject Enrollment and Disposition 
A summary of subject enrollment will be provided by treatment group for each country, 
Investigator within a country, and overall. The summary will present the number and percentage 
of subjects randomized. For each column, the denominator for the percentage calculation will be 
the total number of subjects analyzed for that column. 
A similar enrollment table will be provided by randomization stratum. The denominator for the 
percentage of subjects in the stratum will be the total number of randomized subjects. If there are 
discrepancies in the value used for stratification assignment between the IRT and the clinical 
database, the value collected in the clinical database will be used for the summary. A listing of 
subjects with discrepancies in the value used for stratification assignment between the IRT and 
the clinical database at the time of data finalization will be provided. The randomization 
schedule used for the study will be provided as an appendix to the CSR. 
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects in each of the categories listed below: 
• All Randomized Analysis Set 
• Full Analysis Set 
• Safety Analysis Set 
The number and percentage of the subjects in the following categories will be summarized using 
the Safety Analysis Set: 
• Completed study drug VBR 
• Did not complete study drug VBR with reasons for premature study drug discontinuation 
• Completed study drug AB-729 
• Did not complete study drug AB-729 with reasons for premature study drug discontinuation  
• Completed study  
• Did not complete the study with reasons for study discontinuation 
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the Safety Analysis Set 
corresponding to that column. 


 
 
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The following by-subject listings will be provided by subject ID number in ascending order: 
• Reasons for premature study drug or study discontinuation 
• Dispensed bottle number and lot number for VBR, lot number for AB-729 
The proportion of subjects meeting treatment stopping criteria will be summarized. A by-subject 
listing detailing each subject’s treatment stopping decision and the HBV DNA, HBsAg, and 
ALT results from their last on-treatment (i.e. week 48) study visit will be included.  
4.2. 
Extent of Study Drug Exposure and Compliance 
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of compliance relative to the study drug regimen specified in the 
protocol. 
4.2.1. 
Duration of Exposure to Study Drug 
Total duration of exposure to each study drug will be defined as the last dose date minus the first 
dose date plus 1 for VBR and plus 56 days for AB-729, regardless of any temporary 
interruptions in study drug administration, and will be expressed in weeks using up to 1 decimal 
place (eg, 4.5 weeks). Duration (weeks) = Duration (days) /7. The last dose date of individual 
study drug is defined in Section 3.6.3. If the last study drug dose date is missing, the latest date 
among the study drug end date, clinical visit date, laboratory sample collection date, and vital 
signs assessment date that occurred during the on-treatment period will be used for subjects 
included in the final analyses or the last available date in the database snapshot for subjects who 
were still on treatment at the time of an interim analysis.  
The total duration of exposure to study drug will be summarized using descriptive statistics. 
Summaries will be provided by treatment group and study drug for the Safety Analysis Set. The 
expected total duration of on-treatment therapy for all subjects is 48 weeks. The distribution of 
subjects by the total number of weeks on therapy (ie. ≤4 weeks, >4-8 weeks, >8-12 weeks, >12-
16 weeks, >16-20 weeks, >20-24 weeks, >24-36 weeks, and >36-48 weeks, ≥48 weeks) will be 
presented. The cumulative distribution of subjects will also be presented using the following 
cutoffs: at least 1 dose, ≥2 weeks, ≥4 weeks, ≥8 weeks, ≥12 weeks, ≥24 weeks, ≥36 weeks, and 
≥48 weeks. For AB-729, the distribution of subjects by number of injections will be summarized. 
 
4.2.2. 
Study Drug Compliance  
Compliance will be calculated for study drugs VBR and AB-729. 
The total number of tablets (VBR) and injections (AB-729) administered will be summarized using 
descriptive statistics.  
The presumed total number of tablets (VBR) administered to a subject will be determined by the 
data collected on the drug accountability CRF using the following formula: 


 
 
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Total Number of Tablets Administered  
= (∑No. of Tablets Dispensed) −(∑No. of Tablets Returned) 
The presumed total volume of injections (AB-729) administered to a subject will be determined 
by summing the volume administered during each visit containing an injection, as reported on 
each relevant week’s study drug administration CRF. 
4.2.2.1. 
On-Treatment Compliance 
The level of on-treatment compliance to the study drug will be determined by the total amount of 
study drug administered relative to the total amount of study drug expected to be administered 
during a subject’s actual on-treatment period. 
The level of on-treatment compliance for each study drug will be expressed as a percentage 
using the following formula: 
On-Treatment Compliance 
(%) = (
Total Amount of Study Drug Administered
Total Amount of Study Drug Expected to be Administered on Treatment)  x 100 
Per protocol, each subject receiving VBR is expected to take three 100 mg tablets of VBR daily 
during the on-treatment phase. In a 48-week period, a total of 1008 tablets would be expected. 
Each subject receiving AB-729 is expected to receive a 60 mg (0.33 mL) injection once every 8 
weeks during the on-treatment phase. In a 48-week period, a total of 360 mg (2 mL) over 6 
injections would be expected. 
For subjects who prematurely discontinue, the denominator will be the total amount of study 
drug expected to be administered by the date of premature discontinuation.  
Descriptive statistics for the level of on-treatment compliance with the number and percentage of 
subjects belonging to compliance categories (e.g., < =80%, > 80-90%, and ≥ 90%) will be 
provided by treatment group for the Safety Analysis Set.  
A by-subject listing of study drug administration and drug accountability will be provided by 
subject ID number in ascending order and visit in chronological order. 
4.3. 
Protocol Deviations  
Subjects who did not meet the eligibility criteria for study entry but enrolled in the study will be 
summarized. The number and percentage of subjects who did not meet at least 1 eligibility 
criterion will be provided for specific criteria by treatment group based on the All Randomized 
Analysis Set. A by-subject listing will be provided for those subjects who did not meet at least 1 
eligibility (inclusion or exclusion) criterion. The listing will present the eligibility criterion (or 
criteria if more than 1 deviation) that subjects did not meet and related comments, if collected. 


 
 
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Protocol deviations (PDs) occurring after subjects entered the study are documented during 
routine monitoring. The number and percentage of subjects with important PDs (IPDs) by 
deviation category will be summarized by treatment group for All Randomized Analysis Set. A 
table will be provided to summarize any COVID-19 related PDs with the deviation reason by 
treatment groups. A by-subject listing will be provided for those subjects with any protocol 
deviations. 
A table will be provided to summarize any COVID-19 related PDs with the deviation reason by 
treatment groups. Any visits that were not performed will be summarized by reason (ie, adverse 
event, COVID-19 restrictions, and Other). A listing of subjects who had study disruption due to 
COVID-19 will be provided with a description. 


 
 
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5. 
BASELINE CHARACTERISTICS 
5.1. 
Demographics and Baseline Characteristics 
Subject demographic variables (ie, age, age group [<40/ ≥ 40 years], sex, race, and ethnicity), 
baseline characteristics (body weight [in kg], height [in m], body mass index [BMI; in kg/m2]) 
will be summarized by treatment group and overall using descriptive statistics for continuous 
variables and using number and percentage of subjects for categorical variables. The summary of 
demographic data will be provided for the Safety Analysis Set. 
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order. 
5.2. 
Baseline Disease Characteristics 
Baseline disease characteristics will be summarized by treatment group and overall. Summary 
descriptive statistics will be used for continuous variables and the number and percentage of 
subjects will be used for categorical variables. The following factors will be included, but not 
limited to: 
• Years positive for HBV 
• HBV Genotype 
• Baseline NrtI type 
• Years on current HBV treatment 
• Baseline HBV DNA (log10 IU/mL) 
• Baseline HBV RNA (log10 U/mL) 
• Baseline HBV total nucleic acid (TNA) (log10 IU/mL) 
• Baseline HBeAg (log10 IU/mL) 
• Baseline HBcrAg (log10 kU/mL) 
• HBcrAg groups (< LLOQ, < 500, < 100, < 10) 
• Baseline HBsAg (log10 IU/mL) 
• HBsAg groups (< LLOQ, ≤ 1000, > 1000 IU/mL) 
• Baseline HBeAg antibody (HBeAb)  


 
 
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• Baseline HBsAg antibody (HBsAb)  
• Baseline ALT (U/L)  
• Baseline ALT groups (>ULN [Covance], >ULN [American Association for the Study of 
Liver Diseases (AASLD)]  
• Liver biopsy staging   
• Fibroscan result 
• Metavir Fibrosis Stage 
 
A by-subject listing of baseline disease characteristics will be provided by subject ID number in 
ascending order. 
5.3. 
Medical History 
Medical history collected at Screening will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version (v) 23.1.  
Medical history will be summarized by preferred term (PT), treatment group and overall. 
Subjects who report 2 or more medical history items that are coded to the same PT will be 
counted only once by the unique coded term in the summary. The summary will be provided for 
the Safety Analysis Set.  
HBV specific medical history will be summarized by mode of HBV infection, treatment group 
and overall. The summary will be provided for the Safety Analysis Set.  
A by-subject listing of medical history will be provided by subject ID number in ascending 
order. 


 
 
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6. 
EFFICACY ANALYSES 
The primary analysis set for efficacy analyses will be the FAS, defined in Section 3.1.2. All the 
efficacy analyses will be performed for each cohort separately. The following sections describe 
the primary and secondary analyses for the efficacy endpoints. 
6.1. 
Efficacy Endpoints 
6.1.1. 
Definition of Efficacy Endpoints 
The efficacy endpoints of Cohort 1 are:  
• Mean change in log10 HBsAg from Baseline at each timepoint 
• Mean change in log10 HBV RNA from Baseline at each timepoint 
• Mean change in log10 HBcrAg from Baseline at each timepoint 
• Mean change in TNA quantitative from Baseline at each timepoint 
• ALT results and change from Baseline 
6.1.2. 
Analysis Methods for Efficacy Endpoints 
The observed and mean change in log10 HBV RNA, HBV TNA, HBsAg, HBcrAg, and ALT 
from Baseline will be summarized using descriptive statistics (sample size, mean, SD, median, 
Q1, Q3, minimum, and maximum) by phase, treatment group, and treatment action at each visit.  
For the On-Treatment Phase, analysis will be performed to compare the mean changes of log10 
HBV RNA, log10 HBV TNA, log10 HBsAg, log10 HBcrAg, and ALT from Baseline to each 
timepoint between VBR+AB-729+NrtI and VBR+NrtI, and between VBR+AB-729+NrtI and 
AB-729+NrtI. The primary comparison for mean change endpoints will be made using an 
analysis of covariance (ANCOVA) model, including baseline value, the stratification factors, and 
treatment group as covariates. The estimated least square means of treatment effects and 
estimated difference in treatment effects between treatment groups at Week 48 will be presented 
along with the 95% CIs and p-values. The analysis will be based on observed data.  
  


 
 
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7. 
SAFETY ANALYSES 
7.1. 
Adverse Events and Deaths 
7.1.1. 
Adverse Event Dictionary 
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version (v) 23.1. System organ class (SOC), high-level group 
term (HLGT), high-level term (HLT), preferred term (PT), and lower-level term (LLT) will be 
provided in the AE dataset. 
 
7.1.2. 
Adverse Event Severity 
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to the toxicity 
criteria specified in the protocol. The severity grade of events for which the investigator did not 
record severity will be categorized as “missing” for tabular summaries and data listings. The 
missing category will be listed last in summary presentation. 
7.1.3. 
Relationship of Adverse Events to Study Drug 
Related AEs are those for which the Investigator selected “Related” on the AE eCRF to the 
question of “Relationship to Study Treatment” based on the his/her clinical assessment. Events 
for which the Investigator fails to record a relationship to an applicable study drug will be 
considered related to study drug for summary purposes. However, by-subject data listings will 
show the relationship as missing. 
7.1.4. 
Serious Adverse Events 
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met protocol-
specified definitions of a SAE.  
7.1.5. 
Treatment-Emergent Adverse Events  
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as any AEs with an onset date/time 
equal to or after the study drug start date/time through end of study . 
7.1.5.2. 
Incomplete Dates 
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dose date of 
any study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met: 


 
 
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• The AE onset date is in the same as or after the month and year (or year) of the first dose date 
of any study drug, and 
• The AE onset date is in the same as or before the month and year (or year) of the end of 
study 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dose date of any study drug, will be considered to be treatment emergent. 
In addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dose date of any study drug 
will be considered treatment emergent. 
7.1.6. 
Summaries of Adverse Events and Deaths 
Treatment-emergent AEs will be summarized based on the Safety Analysis Set. Tables will be 
created per study phase (i.e. On-Treatment Phase, Off-Treatment Phase, and NrtI-Restart Phase). 
A brief, high-level summary of the number and percentage of subjects who experienced at least 1 
TEAE in the categories described below will be provided by treatment group. The brief summary 
will also include treatment-related TEAEs, treatment-related TE SAEs, and TEAEs leading to 
premature study discontinuation. All deaths observed in the study will also be included in this 
summary. In addition, a table for each category showing the number and percentage of subjects 
will be provided by PT and treatment group in descending order of total frequency: 
• TEAEs  
• TEAEs by severity grade  
• TEAEs related to AB-729 
• TEAEs related to VBR 
• TE SAEs 
• TE SAEs related to AB-729 
• TE SAEs related to VBR 
• TEAEs leading to premature study drug AB-729 discontinuation 
• TEAEs leading to premature study drug VBR discontinuation 
• TEAEs leading to study discontinuation 
• TEAEs leading to death (ie, outcome of death)  


 
 
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• COVID-19 specific TEAEs 
• COVID-19 specific TE SAEs 
Multiple events will be counted only once per subject in each summary. For summary by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual subject during the study.  
A data listing containing all AEs will be provided.  
7.2. Laboratory Evaluations 
7.2.1. 
Graded Laboratory Values 
The criteria specified in the study protocol will be used to grade laboratory results as normal (no 
grade), mild (Grade 1), moderate (Grade 2), severe (Grade 3) or potentially life threatening 
(Grade 4). See Appendix 1 of the protocol for detailed DAIDS grading criteria on the relevant 
laboratory tests. For laboratory tests with criteria for both increased and decreased levels, 
analyses for each direction (ie, increased, decreased) will be presented separately. 
7.2.1.1. 
Treatment-Emergent Laboratory Abnormalities 
Treatment-emergent laboratory abnormalities are defined as values that increase at least 1 
toxicity grade from Baseline at any postbaseline time point. If the relevant baseline laboratory 
value is missing, any abnormality of at least Grade 1 observed within the time frame specified 
above will be considered treatment emergent. 
7.2.1.2. 
Summaries of Laboratory Abnormalities 
A summary (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test and treatment group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given laboratory test. 
Treatment-emergent lab abnormalities will be summarized based on the Safety Analysis Set. 
Tables will be created per study phase (i.e. On-Treatment Phase, Off-Treatment Phase, and NrtI-
Restart Phase). 
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values in each phase.  
The maximum post-baseline grade in each phase will be tabulated for each laboratory test, and 
percentages will be based on the number of subjects with a post-baseline evaluation of the 
specific laboratory test. The laboratory abnormalities during the follow-up period will also be 
summarized. 


 
 
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A by-subject listing of graded laboratory abnormalities will be provided by subject ID number 
and visit in chronological order. This listing will include all test results that were collected 
throughout the study for the lab test of interest, with all applicable severity grades displayed. 
7.2.2. 
Ungraded Laboratory Values 
Treatment-emergent abnormal direct bilirubin will be summarized by cohort and treatment 
group. A treatment-emergent abnormal direct bilirubin record is defined as a record with value > 
baseline and >=ULN in the phase. The highest direct bilirubin measurement will be counted for 
each subject. A by-subject listing of visits  
Treatment-emergent abnormal direct bilirubin will be summarized based on the Safety Analysis 
Set. Tables will be created per study phase (i.e. On-Treatment Phase, Off-Treatment Phase, and 
NrtI-Restart Phase). 
7.2.3. 
ALT Elevation 
7.2.3.1. 
ALT Elevation without Declining Hepatic Function 
All subjects with an ALT elevation on treatment, defined as ALT >2 × Baseline or on-treatment 
nadir and ≥10 × ULN, should have the ALT findings confirmed within 3 days of receipt of the 
original results. 
7.2.3.2. 
ALT Elevation with Declining Hepatic Function  
Subjects with confirmed ALT elevation with evidence of declining hepatic function should be 
discontinued prematurely from study treatment. This is defined as:  
• ALT elevation ≥2 × Baseline (Day 1) or nadir and >2 × ULN AND 
• Direct bilirubin increase to ≥2 × Baseline (Day 1) and ≥2 × ULN OR  
• Albumin decline ≥0.5 g/dL from Baseline OR international normalized ratio (INR) >2 × 
Baseline (Day 1) OR  
• Symptoms of liver inflammation (eg, fatigue, weakness, lack of appetite, nausea, vomiting, 
jaundice or discolored feces) 
The number of subjects meeting the above criteria will be summarized by treatment group. 
Clinical signs or symptoms of liver inflammation will not be included in the summary. For 
individual laboratory tests, subjects will be counted once based on the most severe postbaseline 
values. For the composite criteria, subjects will be counted once when the criteria are met at the 
same visit. The denominator is the number of subjects in the Safety Analysis Set who have 
nonmissing postbaseline values. A listing of subjects who met at least 1 of the above criteria will 
be provided. 


 
 
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7.3. 
Vital Signs 
Vital signs will be summarized for the on-treatment phase. 
Descriptive statistics will be provided by treatment group for vital signs (systolic and diastolic 
blood pressure [mmHg], pulse [beats/min], respiration [breaths/min], and body temperature [oC]) 
as follows: 
• Baseline value 
• Values at each postbaseline time visit 
• Change from Baseline at each postbaseline visit 
A Baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of study drug. Change from Baseline to a postbaseline visit will be calculated for 
any postbaseline visit including follow-up visits. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.6.5.  
A by-subject listing of vital signs will be provided by subject ID number and visit in 
chronological order.  
7.4. 
Prior and Concomitant Medications 
Medications collected at screening and during the study will be coded using World Health 
Organization (WHO) Drug dictionary (WHODrug Global 1 Sep 2020). 
7.4.1. 
Prior Medications 
Prior medications are defined as any medications taken before a subject took the first study drug. 
Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug class 
Level 2 and preferred name using the number and percentage of subjects for each treatment 
group and overall. A subject reporting the same medication more than once will be counted only 
once within each ATC drug class. The summary will be ordered alphabetically by ATC medical 
class and then by preferred term in order of descending overall frequency within each ATC 
medical class. For drugs with the same frequency, sorting will be done alphabetically. 
A medication will be considered as a prior medication if it meets one the following criteria: 
• A medication with a start date prior to the first dose date of study drug will be included in 
the prior medication summary regardless of when the stop date is.  


 
 
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• If a partial start date is entered, the medication will be considered prior unless the month 
and year (if day is missing) or year (if day and month are missing) of the start date are 
after the first dose date.  
• A medication with a completely missing start date will be included in the prior 
medication summary, unless otherwise specified. 
Summaries will be based on the Safety Analysis Set. 
7.4.2. 
Concomitant Medications 
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by ATC drug class Level 2 and preferred name 
using the number and percentage of subjects for each treatment group. A subject reporting the 
same medication more than once within each ATC drug class will be counted only once when 
calculating the number and percentage of subjects who received that medication. Medications 
may appear under multiple ATC drug classes. The summary will be ordered alphabetically by 
ATC medical class and then by preferred term in descending overall frequency within each ATC 
medical class. For drugs with the same frequency, sorting will be done alphabetically. 
A medication will be considered as a concomitant medication if it meets one the following 
criteria: 
• A medication with a start date prior to or on the first dose date of study drug, and 
continued to be taken after the first dose date.  
• A medication started after the first dose date  
• If a partial start date is entered, any medication with the month and year (if day is 
missing) or year (if day and month are missing) before the study drug stop date and the 
stop date after the first dose date of study drug. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are 
missing) after the date of first study drug  
• A medications started and stopped on the same day as the first dose  
• Medications with completely missing start and stop dates, unless otherwise specified. 
A medications with a stop date prior to the date of first dose date of study drug will be excluded 
from the summary.  
Summaries of prior and concomitant medications and HBV concomitant medications will be 
based on the Safety Analysis Set.  
All the prior and concomitant medications will be provided in a by-subject listing sorted by 
subject ID number and administration date in chronological order. 


 
 
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7.5. 
Electrocardiogram Results 
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline 
values will be presented by treatment group using the following categories:  
• normal 
• abnormal (not clinically significant)  
• abnormal (clinically significant)  
• missing/not done 
The number and percentage of subjects in each cross-classification group of the shift table will 
be presented. Subjects with a missing value at baseline or postbaseline will not be included in the 
denominator for percentage calculation.  
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order. 
7.6. 
Other Safety Measures 
Since the study is terminated early, no additional safety measures specified in the protocol will 
be performed. 


 
 
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8. 
REFERENCES 
Nehls G, Akland G. Procedures for Handling Aerometric Data. Journal of the Air Pollution 
Control Association 1973;23 (3):180-4. 
 


 
 
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9. 
SOFTWARE 
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA. 
  


 
 
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10. 
DOCUMENT HISTORY 
Version 
Date 
(DD MMM YYYY) 
Summary of Changes 
1.0 
17 MAY 2023 
Original 
2.0 
22 MAY 2023 
Updated section 4.2.2. for Study Drug Compliance 


 
 
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11. 
APPENDICES 
None 


Signature Page for VV-TMF-60087 v2.0
Signature Page for VV-TMF-60087 v2.0
Reason for signing: Approved
Name: 
Role: A
Date of signature: 23-May-2023 04:57:00 GMT+0000
Reason for signing: Approved
Name: 
Role: A
Date of signature: 23-May-2023 14:52:44 GMT+0000
Reason for signing: Approved
Name: 
Role: A
Date of signature: 23-May-2023 15:24:14 GMT+0000