Clinical trial NCT04398134
Conditions: Chronic Hepatitis B
Keywords: HBV hepatitis B
Sponsor: Assembly Biosciences
Start date: 2020-08-28; Completion date: 2021-12-28
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 2a study will assess the safety, antiviral activity, and pharmacokinetics (PK) of ABI-H2158 administered once daily for up to 72 weeks in combination with entecavir (ETV) in participants with chronic hepatitis B virus (HBV) infection.

Detailed description:

Arms: arm 1: ABI-2158 300 mg tablet once daily for 72 weeks plus ETV 0.5 mg tablet once daily for 96 weeks arm 2: Placebo matching ABI-2158 300 mg tablet once daily for 72 weeks plus ETV 0.5 mg tablet once daily for 96 weeks
Interventions: intervention 1: ABI-H2158 intervention 2: Placebo intervention 3: Entecavir (ETV)
Intervention descriptions: intervention 1: 3 X 100 mg tablets for oral administration intervention 2: Sugar pill manufactured to mimic the ABI-H2158 tablets intervention 3: 0.5 mg tablet for oral administration

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL TITLE: 
A Phase 2a, Multicenter, Single-Blind, Placebo-Controlled, 
Multiple Cohort Study Evaluating ABI-H2158-Containing 
Regimens in Chronic Hepatitis B Infection 
 
STUDY NUMBER: 
ABI-H2158-201 
 
DRUG: 
ABI-H2158 
 
REFERENCE NUMBERS: 
 
 
SPONSOR: 
Assembly Biosciences 
331 Oyster Point Boulevard, 4th Floor 
South San Francisco, California 94080, USA 
(833) 509-4583 
 
PROTOCOL: 
Amendment 2, 14 December 2020 
Amendment 1, 12 February 2020 
ORIGINAL: 
20 December 2019 
 
CONFIDENTIALITY STATEMENT 
The information contained in this protocol 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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INVESTIGATOR STATEMENT 
Protocol Title: 
A Phase 2a, Multicenter, Single-Blind, Placebo-Controlled, Multiple 
Cohort Study Evaluating ABI-H2158-Containing Regimens in 
Chronic Hepatitis B Infection 
Protocol Number: 
ABI-H2158-201 
Protocol: 
Amendment 2, 14 December 2020 
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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Protocol Amendment Summary of Changes Table 


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Protocol ABI-H2158-201 Amendment 2 
 
 
 
 


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1 SYNOPSIS 
 
 
 
Protocol 
Number: 
ABI-H2158-201 
Title:  
A Phase 2a, Multicenter, Single-Blind, Placebo-Controlled, Multiple Cohort Study 
Evaluating ABI-H2158-Containing Regimens in Chronic Hepatitis B Infection 
Phase: 
2a 
Number of 
Subjects: 
Approximately 80 
Study Duration:  
Up to 45 days for Screening, 72 weeks of treatment, and 24 weeks of follow-up 
Rationale:  
Chronic hepatitis B infection (CHB) is a major cause of liver-related morbidity and 
mortality worldwide. ABI-H2158 is a direct acting antiviral agent targeting the hepatitis B 
virus (HBV) core protein. It is anticipated that ABI-H2158 administered in combination 
with entecavir (ETV), a standard of care (SOC) nucleos(t)ide analogue (NrtI), will be safe, 
reduce viral nucleic acid (ie, HBV DNA and HBV pre-genomic [pg] RNA) to a greater 
extent than ETV alone, which will lead to subsequent reductions in viral antigens (ie, 
HBeAg, HBcrAg, and HBsAg) in subjects with CHB. This study will explore the safety of 
the ABI-H2158+ETV combination and its antiviral activity as measured by effects on 
serum HBV DNA, HBV pgRNA, and HBV antigens. 
Target 
Population: 
Male or female subjects with CHB, 18 to 65 years of age, inclusive, with no evidence of 
cirrhosis or end-stage liver disease. Cohort 1 will enroll treatment-naïve subjects with 
HBeAg positive CHB. Cohort 2 will enroll treatment-naïve subjects with HBeAg negative 
CHB. 
Test Product: 
Active treatment: ABI-H2158 300 mg administered orally, once daily, in addition to ETV 
Reference 
Product: 
Placebo (PBO) treatment: ABI-H2158 matching PBO administered orally, once daily, in 
addition to ETV 
Study Design: 
This is a Phase 2a, multicenter, randomized, single-blind (ie, investigational site and 
subjects are blinded), PBO-controlled study, evaluating the safety, antiviral activity, and 
pharmacokinetics (PK) of ABI-H2158 administered in combination with ETV in subjects 
with CHB. Multiple parallel cohorts will be enrolled in the study. In Cohort 1 
approximately 40 treatment-naïve subjects with HBeAg- positive CHB will be randomized 
3:1 to receive investigational agent (300 mg ABI-H2158 [n=30] or matching PBO [n=10]) 
in combination with ETV for 72 weeks. In Cohort 2 approximately 40 treatment-naïve 
subjects with HBeAg negative CHB will be randomized 3:1 to receive investigational agent 
(300 mg ABI-H2158 [n=30] or matching PBO [n=10]) in combination with ETV for 72 
weeks. Treatment assignments for Cohort 1 will be stratified by the HBV DNA level 
measured at the Screening visit (ie, ≥8.0 log10 IU/mL versus <8.0 log10 IU/mL) and for 
Cohort 2, subjects will be stratified by the HBV DNA level measured at the Screening visit 
(ie, ≥6.0 log10 IU/mL versus <6.0 log10 IU/mL). Safety, antiviral activity, and PK will be 
assessed during treatment and the 24-week follow-up period. During the follow-up period 
all subjects will remain on ETV. 


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Objectives:  
Primary Objectives: 
• 
To evaluate the safety and tolerability of ABI-H2158 when administered in 
combination with ETV in subjects with CHB 
• 
To evaluate the effect of ABI-H2158 in reducing HBV DNA in subjects with CHB 
Secondary Objectives: 
• 
To evaluate the PK of ABI-H2158 and ETV in subjects with CHB 
• 
To evaluate the effect of ABI-H2158 in reducing HBV pgRNA levels in subjects 
with CHB 
• 
To evaluate the effect of ABI-H2158 in reducing HBV antigens (ie, HBeAg, 
HBcrAg and HBsAg) in subjects with CHB 
• 
To evaluate the effect of ABI-H2158 on normalization of alanine aminotransferase 
(ALT) in subjects with abnormal ALT 
• 
To evaluate the emergence of resistance to ABI-H2158 when administered in 
combination with ETV 
Exploratory Objectives: 
• 
To assess the relationship between new and known viral biomarkers and virologic 
and/or clinical outcomes 
• 
For subjects who provide an optional pharmacogenomic sample, to evaluate the 
potential contribution of host genomics to clinical or virologic outcomes and/or 
drug disposition 
Primary 
Endpoint:  
Primary Endpoints: 
• 
The proportion of subjects with adverse events (AEs), premature treatment 
discontinuation, and abnormal laboratory results 
• 
The change in mean log10 HBV DNA from Baseline to Week 24 for 
ABI-H2158+ETV and PBO+ETV 
Secondary 
Endpoints: 
Secondary Endpoints: 
• 
Analysis of ABI-H2158 and ETV drug concentrations: 
o Trough levels and trough to peak ratios of ABI-H2158 on 
ABI-H2158+ETV 
o Trough levels and trough to peak ratios of ETV on ABI-H2158+ETV and 
PBO+ETV 
• 
The change in mean log10 HBV DNA for ABI-H2158+ETV and PBO+ETV at each 
timepoint 
• 
The change in mean log10 HBV pgRNA from Baseline to Week 24 and at each 
timepoint for ABI-H2158+ETV and PBO+ETV 
• 
The proportion of subjects with a reduction in HBV DNA below the assay lower 
limit of quantitation (LLOQ) for ABI-H2158+ETV and PBO+ETV at each 
timepoint 
• 
The proportion of subjects with a reduction in HBV pgRNA below the assay 
LLOQ for ABI-H2158+ETV and PBO+ETV at each timepoint 
• 
The change in serum viral antigens (ie, HBeAg, HBcrAg and HBsAg) on 
ABI-H2158+ETV and PBO+ETV at each timepoint 
• 
The proportion of subjects with abnormal ALT at Baseline who have normal ALT 
at Week 24 and at each timepoint on ABI-H2158+ETV and PBO+ETV 


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• 
The incidence of HBV variants with reduced susceptibility to ABI-H2158 
Exploratory 
Endpoints: 
Exploratory Endpoints: 
• 
The proportion of subjects with loss (defined as below LLOQ) or decline in 
HBsAg, HBcrAg, HBeAg or new biomarkers on ABI-H2158+ETV and 
PBO+ETV at each timepoint 
• 
The proportion of subjects with HBsAg seroconversion (loss of HBsAg and 
appearance of HBsAb) or HBeAg seroconversion (loss of HBeAg and appearance 
of HBeAb) on ABI-H2158+ETV and PBO+ETV at each timepoint for applicable 
cohort 
• 
The proportion of subjects whose HBV DNA is below the assay LLOQ and “target 
not detected” on ABI-H2158+ETV and PBO+ETV at each timepoint 
• 
Pharmacogenomic correlations may be performed with clinical or virologic 
outcomes for subjects who provide an additional informed consent. Known gene 
variants and PK and/or safety of ABI-H2158 and its metabolites may be evaluated.  
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 on statistical considerations. 
All safety, antiviral activity and PK endpoints will be summarized using descriptive 
statistics by dose groups within cohorts. Continuous endpoints will be described using the 
mean, standard deviation, median, minimum, 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. Assessment of 
antiviral activity will be compared by dose groups within cohorts using an appropriate 95% 
confidence intervals where appropriate. 
Key 
Eligibility: 
Inclusion Criteria 
 
Subjects must meet all the following inclusion criteria in order to be eligible for the 
study: 
1. Willing and able to provide informed consent 
2. Male or female between the ages 18 and 65 years (inclusive) 
3. Female subjects must be non-pregnant and have a negative serum pregnancy test 
at Screening and a negative urine pregnancy test predose on Day 1 
4. Chronic hepatitis B infection, defined as HBV infection for ≥6 months 
documented, for example, by at least two measurements of HBsAg positivity 
and/or detectable HBV DNA ≥6 months apart (inclusive of Screening). For 
subjects without clear documentation of CHB, anti-hepatitis B core antigen 
immunoglobulin M (IgM) antibody to the HBV core antigen (HBcAb) must be 
negative at Screening to exclude acute HBV infection 
5. Body mass index (BMI) 18 to 36 kg/m2 and a minimum body weight of 45 kg 
(inclusive) 
6. HBV DNA ≥2 × 105 IU/mL for subjects who are treatment naïve HBeAg positive 
7. HBV DNA > 2 x 103 IU/mL for subjects who are treatment naïve HBeAg negative 


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8. HBsAg >1000 IU/mL at Screening for subjects who are treatment naïve HBeAg 
positive 
9. Lack of cirrhosis or advanced liver disease as documented by the following: 
o Liver biopsy results of METAVIR F0-F2 (absence of bridging 
fibrosis or cirrhosis) within 1 year of Screening 
OR 
o Fasting FibroScan ≤8 kPa within 3 months of Screening (including 
Screening visit) or other Sponsor-approved hepatic imaging study 
(hepatic magnetic resonance elastography [MRE]) within 6 months of 
Screening indicating lack of cirrhosis or advanced liver disease (F0-
F2 or equivalent) 
Subjects with a fasting FibroScan >8 kPa and ≤10 kPa are excluded from 
study participation unless a liver biopsy within the 1 year before Day 1 
confirms the absence of bridging fibrosis and cirrhosis. Subjects with a 
FibroScan >10 kPa are excluded from study participation 
If results from both liver biopsy and FibroScan are available, then the result 
reporting the most advanced liver disease will be used to determine eligibility 
for the study 
10. Agreement to comply with protocol-specified contraceptive requirements (Refer 
to Appendix 3) 
11. Agreement to abstain from alcohol abuse [defined as alcohol consumption 
exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of 
alcohol)] and the use of illicit substances from screening until end of the study 
12. In good general health, except for CHB  
13. Have the ability to take oral medication and, in the opinion of the Investigator, be 
willing to adhere to study treatment. 
14. Candidate for treatment with ETV and have no contraindications as described in 
the approved product labelling 
 
Exclusion Criteria 
 
Subjects who meet any of the following exclusion criteria will not be eligible for the study: 
1. Prior treatment for CHB; specifically 
a. lamivudine, telbivudine or adefovir (any duration) 
b. NrtI treatment for >4 weeks 
c. HBV core inhibitors (any duration) 
d. Previous treatment with an investigational agent for HBV infection 
2. Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), 
hepatitis E virus (HEV), or hepatitis D virus (HDV) 


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3. Females who are lactating, or wish to become pregnant during the course of the 
study 
4. History or evidence of advanced liver disease 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 
5. History of persistent alcohol abuse (alcohol consumption exceeding 2 standard 
drinks per day on average [1 standard drink = 10 grams of alcohol]) or illicit drug 
abuse within 3 years before Screening 
6. Clinically significant cardiac or pulmonary disease, chronic or recurrent renal or 
urinary tract disease, liver disease other than CHB, endocrine disorder, 
autoimmune disorder, diabetes mellitus requiring treatment with insulin or 
hypoglycemic agents, 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 
7. History of hepatocellular carcinoma (HCC) 
8. A 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  
9. Poorly controlled or unstable hypertension; or sustained systolic blood pressure 
(BP) ≥160 mmHg or <90 mmHg, or diastolic BP >95 mmHg or <50 mmHg at 
Screening  
10. History or presence of electrocardiogram (ECG) abnormalities deemed clinically 
significant including: 
a. Personal or family history of prolonged QT syndrome or family history of 
sudden death  
b. QTcF >450 msec (males) or >470 msec (females) or <300 msec at Screening 
or Day 1 visit  
c. ECG with QRS and/or T-wave judged to be unfavorable for a consistently 
accurate QT measurement as judged by the Investigator at Screening  
d. Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, 
Wolff-Parkinson-White Syndrome, or cardiac pacemaker at Screening or 
Day 1 visit 
11. History of hypersensitivity or idiosyncratic reaction to any components or 
excipients of the investigational drug or PBO formulation 
12. History of any significant food or drug-related allergic reactions such as, 
anaphylaxis, Stevens-Johnson syndrome, or urticaria 
13. The following exclusionary laboratory results at Screening: 
a. Platelet count <100,000/mm3 


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b. Albumin < lower limit of normal (LLN) 
c. Total bilirubin >1.2 × upper limit of normal (ULN) unless known Gilbert’s 
syndrome; subjects with Gilbert’s syndrome are eligible for study participation 
if the direct bilirubin is within the normal range 
d. Direct bilirubin >1.2 × ULN 
e. ALT >5 × ULN 
f. Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is > ULN 
but <100 ng/mL, the subject is eligible if a hepatic imaging study prior to 
initiation of study drug reveals no lesions indicative of possible HCC 
g. International Normalized Ratio (INR) >1.5 × ULN 
h. Glomerular filtration rate (GFR) <60 mL/min/1.73 m2 by Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation (Levey 2009) 
i. 
Serum hemoglobin A1c (HbA1c) >6.5% 
j. 
Any other laboratory abnormality deemed clinically significant by the Sponsor 
or the Investigator 
 
14. Subjects receiving prohibited concomitant medications, grapefruit (whole fruit and 
juice), herbal or over-the-counter medications (Section 6.4.1) within 7 days or 5 
half-lives (if known), whichever is longer, prior to administration of the first dose 
of study drug and for the duration of the study period 
15. Participation in another clinical trial 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 
16. Donated or lost >500 mL of blood within 2 months prior to Screening, or plasma 
donation within 7 days prior to Screening 


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TABLE OF CONTENTS 
1 
SYNOPSIS ....................................................................................................................... 9 
2 
INTRODUCTION ......................................................................................................... 20 
2.1 
Background ............................................................................................................... 20 
2.2 
ABI-H2158 ................................................................................................................. 21 
2.2.1 
General Information ........................................................................................... 21 
2.2.2 
Preclinical Pharmacology and Toxicology.......................................................... 21 
2.2.3 
Clinical Studies with ABI-H2158 ........................................................................ 23 
2.3 
Study Rationale ......................................................................................................... 30 
3 
STUDY OBJECTIVES AND ENDPOINTS ................................................................. 32 
3.1 
Study Objectives ........................................................................................................ 32 
3.1.1 
Primary Objective ............................................................................................... 32 
3.1.2 
Secondary Objectives .......................................................................................... 32 
3.1.3 
Exploratory Objectives ....................................................................................... 32 
3.2 
Study Endpoints ........................................................................................................ 32 
3.2.1 
Primary Endpoint................................................................................................ 32 
3.2.2 
Secondary Endpoints ........................................................................................... 33 
3.2.3 
Exploratory Endpoints ........................................................................................ 33 
4 
STUDY PLAN ................................................................................................................ 34 
4.1 
Study Design .............................................................................................................. 34 
4.2 
Dose Justification ...................................................................................................... 35 
4.3 
Study Treatment ....................................................................................................... 36 
4.4 
Duration of Treatment .............................................................................................. 36 
5 
POPULATION............................................................................................................... 37 
5.1 
Number of Subjects ................................................................................................... 37 
5.2 
Inclusion Criteria ...................................................................................................... 37 
5.3 
Exclusion Criteria ..................................................................................................... 38 
5.4 
Lifestyle Consideration ............................................................................................. 41 
5.5 
Strategies for Retention and Safety .......................................................................... 41 
6 
INVESTIGATIONAL MEDICAL PRODUCTS .......................................................... 42 
6.1 
Randomization, Blinding and Treatment Codes ...................................................... 42 
6.1.1 
Randomization..................................................................................................... 42 
6.1.2 
Blinding ................................................................................................................ 42 
6.2 
Description and Handling of ABI-H2158 and Matching Placebo ........................... 43 
6.2.1 
Formulation ......................................................................................................... 43 
6.2.2 
Packaging and Labeling ...................................................................................... 43 
6.2.3 
Storage and Handling .......................................................................................... 43 
6.3 
Description and Handling of Entecavir .................................................................... 43 
6.4 
Prior and Concomitant Medications ........................................................................ 43 
6.4.1 
Prohibited Concomitant Therapy ....................................................................... 44 
6.5 
Drug Accountability .................................................................................................. 44 
6.6 
Study Drug Compliance ............................................................................................ 45 
6.7 
Return or Disposal of Study Drug ............................................................................ 45 
7 
STUDY ASSESSMENTS AND PROCEDURES .......................................................... 46 
7.1 
Subject Enrollment and Treatment Assignment...................................................... 46 
7.1.1 
Screen Failures .................................................................................................... 46 
7.2 
Screening Assessments (Day -45 to Day -1) .............................................................. 46 


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7.3 
Day 1 .......................................................................................................................... 47 
7.4 
Study Weeks 2 Through 72 ....................................................................................... 48 
7.5 
Follow-up Assessments .............................................................................................. 49 
7.6 
Unscheduled Visit ...................................................................................................... 49 
7.7 
Premature Termination Visit ................................................................................... 50 
7.8 
Study Assessments ..................................................................................................... 51 
7.8.1 
Demographics, Medical and HBV History ......................................................... 51 
7.8.2 
Liver Staging ....................................................................................................... 51 
7.8.3 
Physical Examination .......................................................................................... 51 
7.8.4 
Electrocardiograms ............................................................................................. 51 
7.8.5 
Vital Signs ............................................................................................................ 52 
7.8.6 
Clinical Laboratory Tests ................................................................................... 52 
7.8.7 
HBV Virology ...................................................................................................... 53 
7.8.8 
Pharmacokinetic Assessments............................................................................. 54 
7.9 
Discontinuation ......................................................................................................... 54 
7.9.1 
Discontinuation From Treatment ....................................................................... 54 
7.9.2 
Discontinuation From Study ............................................................................... 55 
7.9.3 
Subjects Lost to Follow-up .................................................................................. 55 
7.10 
End of Study Definition............................................................................................. 56 
7.11 
Resistance Monitoring .............................................................................................. 56 
7.12 
Use of Subject Samples for Exploratory Objectives Research ................................ 56 
8 
ADVERSE EVENTS ..................................................................................................... 57 
8.1 
Documenting Adverse Events ................................................................................... 57 
8.2 
Assessment of Intensity ............................................................................................. 57 
8.3 
Assessment of Causality ............................................................................................ 58 
8.4 
Expectedness.............................................................................................................. 58 
8.5 
Abnormal Laboratory Test Values ........................................................................... 58 
8.6 
Adverse Event Follow-up .......................................................................................... 58 
8.7 
Pregnancy .................................................................................................................. 58 
8.7.1 
Female subjects who become pregnant............................................................... 58 
8.7.2 
Male subjects with partners who become pregnant ........................................... 59 
9 
SERIOUS ADVERSE EVENTS .................................................................................... 60 
9.1 
Definition of Serious Adverse Event ......................................................................... 60 
9.2 
Reporting Serious Adverse Events ........................................................................... 61 
9.3 
Overdose .................................................................................................................... 61 
9.4 
Management of ALT Elevations ............................................................................... 61 
10 STATISTICAL CONSIDERATIONS .......................................................................... 65 
10.1 
General Considerations............................................................................................. 65 
10.2 
Sample Size Determination ....................................................................................... 65 
10.3 
Analysis Populations ................................................................................................. 65 
10.4 
Planned Analysis and Reports .................................................................................. 66 
10.4.1 
Analysis of Primary Endpoint(s) ........................................................................ 66 
10.4.2 
Analysis of Secondary and Exploratory Endpoints ........................................... 66 
10.4.3 
Analysis of Pharmacokinetic Endpoints ............................................................. 66 
10.4.4 
Analysis of Safety Endpoints ............................................................................... 66 
10.5 
Interim Analysis ........................................................................................................ 67 
10.6 
Data Review Committee (DRC) ................................................................................ 67 
11 RESPONSIBILITIES .................................................................................................... 68 


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11.1 
Investigator Responsibilities ..................................................................................... 68 
11.1.1 
Good Clinical Practice ......................................................................................... 68 
11.1.2 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)......... 68 
11.1.3 
Informed Consent ................................................................................................ 68 
11.1.4 
Confidentiality ..................................................................................................... 69 
11.1.5 
Study Files and Retention of Records ................................................................. 69 
11.1.6 
Audits and Inspections ........................................................................................ 69 
11.1.7 
Protocol Compliance ........................................................................................... 70 
11.2 
Sponsor Responsibilities ........................................................................................... 70 
11.2.1 
Protocol Amendments and Modifications .......................................................... 70 
11.2.2 
Data Management ............................................................................................... 70 
11.2.3 
Study Report and Publications ........................................................................... 70 
12 REFERENCES .............................................................................................................. 72 
13 APPENDICES ................................................................................................................ 74 
14 APPENDIX 1: SCHEDULE OF ASSESSMENTS TABLE ......................................... 75 
15 APPENDIX 2: TOXICITY GRADING SCALE FOR ADVERSE EVENTS AND 
LABORATORY ABNORMALITIES........................................................................... 79 
16 APPENDIX 3: PREGNANCY PRECAUTIONS AND THE DEFINITION OF 
CHILDBEARING POTENTIAL AND CONTRACEPTIVE REQUIREMENTS ... 102 
17 APPENDIX 4: CYTOCHROME P450 3A4 INHIBITORS AND CYP3A4, 2C8, AND 
2C19 SUBSTRATES, PROTON PUMP INHIBITORS, H-2 RECEPTOR 
BLOCKERS, AND ANTACIDS ................................................................................. 104 
LIST OF TABLES 
Table 1:  
Summary of ABI-H2158 Pharmacokinetic Parameters Following Single Oral Doses
 ................................................................................................................................... 25 
Table 2:  
Summary of ABI-H2158 Pharmacokinetic Parameters Following Single and 
Multiple 300 mg Once-daily Oral Doses of ABI-H2158 .......................................... 26 
Table 3:  
Treatment-emergent Adverse Events in Subjects with Chronic Hepatitis B Infection 
(Cohorts 1 and 2, Part 3; preliminary) .................................................................... 26 
Table 4:  
Treatment-emergent Laboratory Abnormalities by Grade in Subjects with CHB 
(Cohorts 1 and 2, Part 3; preliminary) .................................................................... 28 
Table 5:  
Clinical Laboratory Tests ......................................................................................... 52 
Table 6:  
Pharmacokinetic Sample Collection ........................................................................ 54 
 
LIST OF FIGURES 
Figure 1:  
Study Overview ......................................................................................................... 35 
Figure 2: 
Management of ALT Elevation ................................................................................ 64 
 


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AE 
adverse event 
AFP 
alpha fetoprotein 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma-concentration curve 
AUC0-24 
area under the plasma-concentration curve from time 0 to 24 hours postdose 
AUC0-inf 
area under the plasma-concentration curve from time 0 extrapolated to infinity 
BMI 
body mass index 
cccDNA 
covalently closed circular DNA 
CFR 
Code of Federal Regulations 
CHB 
chronic hepatitis B infection 
CI 
core inhibitor 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
C24hr 
trough plasma concentration 
Cmax 
maximum plasma concentration 
Cp 
[HBV] core protein 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DAIDS 
Division of AIDS 
DDI 
drug-drug interaction 
DRC 
Data Review Committee 
EC50 
50% effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ETV 
entecavir 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HAV 
hepatitis A virus 
HbA1c 
hemoglobin A1c 
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 
HCC 
hepatocellular carcinoma 


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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HEV 
hepatitis E virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
intrauterine device 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse effect level 
NrtI 
nucleos(t)ide reverse transcriptase inhibitor of the HBV polymerase; also called 
nucleos(t)ide analogues or nucleos(t)ides 
OC 
oral contraceptive 
pgRNA 
[HBV] pre-genomic RNA 
PHH 
primary human hepatocytes 
PK 
pharmacokinetic(s) 
PBO 
placebo 
QD 
once daily 
RBC 
red blood cell 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
standard of care 
Sponsor 
Assembly Biosciences 
SVR 
sustained virologic response 
t1/2 
terminal elimination half-life 
TEAE 
treatment emergent adverse event 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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2 INTRODUCTION 
2.1 
Background 
Worldwide >240 million people are chronically infected with the hepatitis B virus (HBV), and chronic 
hepatitis B infection (CHB) 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 CHB (Colvin 2010, El-Serag 2012, EASL 2017, 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, WHO 
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 over 4 million acute HBV 
infections worldwide each year (WHO 2015). 
The clinical stages of HBV represent different risks for ongoing liver injury depending on the degree of 
HBV replication and individuals’ concurrent immune responses to HBV infection (Yim 2006, Hoofnagle 
2007, Lok 2009, Sorrell 2009, EASL 2012, Pungpapong 2013, Gish 2015). The standard virologic and 
serologic markers for HBV infection include HBV deoxyribonucleic acid (DNA), antibody to HBsAg 
(HBsAb), hepatitis B “e” antigen (HBeAg), antibody to HBeAg (HBeAb), and in almost all patients, 
antibody to the HBV core antigen (HBcAb). More recently, HBV pre-genomic RNA (pgRNA) and HBV 
core-related antigen (HBcrAg) have also been used as markers of infection. Historically, treatment goals 
include prevention of HBV-related liver injury through suppression of HBV DNA to low levels, 
achievement of HBeAg loss and seroconversion, and loss of HBsAg and seroconversion. A transition to 
an HBsAg negative, minimally replicative state is rare but usually durable and, if it precedes the 
development of cirrhosis and HCC, is associated with improved long-term clinical outcomes (EASL 
2012). As such, HBsAg seroconversion is considered a “functional cure” and a potential endpoint for 
HBV therapy. However, as HBsAg is derived from both covalently closed circular DNA (cccDNA) as 
well as integrated HBV DNA, sustained undetectable HBV DNA without HBsAg loss after stopping 
treatment may be considered as an intermediate goal (Cornberg 2019). 
Currently, there are 2 clinically accepted treatment options for CHB, interferon alfa (IFNα) and 
nucleos(t)ide (NrtI) reverse transcriptase inhibitors 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 2012). However, there is a proportion of individuals who do 
not achieve complete viral suppression on current NrtI therapy to levels below quantitation on 
commercial assays, and there is evidence that those who are below quantitation still have infectious HBV 
(Agarwal 2018, Burdette 2019). Importantly, the level of HBV replication as measured by HBV DNA 
in those treated with and without virologic response has been predictive of progression of liver disease 
and risk of hepatocellular carcinoma (Papatheodoridis 2015, EASL 2017). Further, despite suppression 
of HBV DNA for extended periods of time, the template for ongoing viral replication, cccDNA, is not 
eliminated in most patients. As a result, off-treatment sustained virologic responses (SVRs) with 
currently approved agents are rare, necessitating long-term chronic suppressive treatment approaches. 
There is a need for improved, novel HBV therapies that further reduce HBV replication and produce a 
substantially higher rate of therapeutic responses that will be durable post-treatment, which are predicted 
to afford improved long-term patient outcomes, ie, reduction of HBV-associated hepatic inflammation 
leading to reduced morbidity and mortality from end-stage liver disease and HCC. 


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ABI-H2158 is a novel, second-generation HBV core inhibitor (CI) discovered by Assembly Biosciences, 
which is being developed as a potential therapeutic agent for the treatment of CHB. ABI-H2158 inhibits 
HBV replication by interfering with essential functions of the HBV core protein (Cp), and therefore 
inhibits HBV replication by different mechanisms than NrtIs or IFNα. Thus, inhibition of HBV Cp 
functions by ABI-H2158, when used in combination with currently approved HBV antivirals, or other 
investigational HBV therapies may offer the potential to improve therapy for chronic HBV infection and 
potentially provide patients with enhanced rates of SVR following a finite treatment period. 
2.2 
ABI-H2158 
2.2.1 General Information 
General information concerning ABI-H2158 is described in the Investigator’s Brochure (IB). 
2.2.2 Preclinical Pharmacology and Toxicology 
Refer to the ABI-H2158 IB for a complete summary of the nonclinical and toxicology studies performed 
to date. In addition to those described in the IB, chronic toxicity studies have also been completed in rat 
and monkey for 6 and 9 months, respectively, of once-daily (QD) dosing. A detailed review of the 
findings from these two studies are provided in Sections 2.2.2.1 and 2.2.2.2 below. 
2.2.2.1 Rat 6-Month Oral Toxicity Study with 21-Day Recovery 
The objectives of this Good Laboratory Practice (GLP) study were to evaluate the toxicity and 
toxicokinetic profile of ABI-H2158 and its desmethyl metabolite, AB017213, following once daily oral 
gavage administration of ABI-H2158 to male and female Sprague-Dawley rats for 6 months, and to 
assess reversibility of any observed effects over a 21-day dose-free recovery period. Dose levels of 
ABI-H2158 were: 0 mg/kg/day (Group 1; vehicle control), 25 mg/kg/day (Group 2; Low), 75 mg/kg/day 
(Group 3; Mid) and 225 mg/kg/day (Group 4; High). The dosing volume was 7.5 mL/kg. Main study 
groups of animals contained 15/sex/group, and recovery groups (Low, Mid and High dose levels) 
contained 5/sex/group. Toxicokinetic groups consisted of 3/sex/group in the vehicle control and 
9/sex/group in the drug treatment groups.  
There were no ABI-H2158-related effects on clinical observations, body weight, food consumption, 
ophthalmology, coagulation, or urine parameters. Occasional, sporadic decreases of small magnitude in 
body weight gain were observed that were considered ABI-H2158-related and non-adverse. 
ABI-H2158-related increases in serum glucose and serum alanine aminotransferase (ALT) levels were 
noted in both males and females on Days 44 and 46, respectively. The statistically significant increases 
in glucose were dose-dependent, present in both sexes and ranged from 11%-25% in the males and 
10%-25% in the females. Statistically significantly elevated ALT levels were noted in both males (37%) 
and females (24%) dosed with 225 mg/kg. These changes were not considered adverse due to small 
magnitudes of change and lack of persistence over time. 
ABI-H2158-related microscopic findings were observed in the liver. Centrilobular hepatocyte 
vacuolation was frequent in males, and uncommon in females. In males it was minimal to moderate, and 
occurred in all groups administered ABI-H2158, but in females it was minimal and was observed at 
≥75 mg/kg. In males, incidence and severity were greater at ≥75 mg/kg as compared to 25 mg/kg. At 


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recovery termination, centrilobular hepatocyte vacuolation was still present, but was limited to males at 
≥75 mg/kg and was less severe (few mild and no moderate instances), indicating reversibility.  
ABI-H2158-related organ weight changes were observed for the kidneys and adrenals. Statistically 
significant increased absolute and relative kidney weights were observed for females administered 
225 mg/kg ABI-H2158. Increased kidney weights correlated microscopically with vacuolation of 
medullary tubules (minimal to moderate). At completion of the recovery period vacuoles were not 
evident in the kidneys, indicating recovery. Statistically significant increased absolute and relative 
adrenal gland weights were observed for females administered 225 mg/kg ABI-H2158; however, there 
was not a microscopic correlate. These findings in kidneys, adrenals and livers were not considered 
adverse.  
Oral administration of ABI-H2158 (25, 75 or 225 mg/kg/day) to male and female Sprague-Dawley rats 
for 182 days was well tolerated with no observed adverse effects. Therefore, the no-observed-adverse 
effect level (NOAEL) for male and female rats was considered to be 225 mg/kg/day, the highest dose 
administered in this study. The corresponding Day 182 maximum plasma concentration (Cmax) and area 
under the plasma concentration time curve (AUC) from time 0 to 24-hour postdose (AUC0-24) exposures 
ranged from 95.4 (males) and 214 (females) µg/mL and 1,500 (males) and 2,800 (females) hr*µg/mL, 
respectively, which exceed the exposures obtained at the NOAEL dose in the 14-day rat study. 
2.2.2.2 Cynomolgus Monkey 9-Month Oral Toxicity Study with 28-Day Recovery 
The objectives of this GLP study were to evaluate the toxicity and toxicokinetic profile of ABI-H2158 
and its desmethyl metabolite, AB017213, in male and female Cynomolgus monkeys after once daily oral 
gavage administration of ABI-H2158 for 9 months, and to assess reversibility of any effects over a 
28-day dose-free period. Study animals (6/sex/group in Groups 1 and 4, and 4/sex/group in Groups 2 
and 3) were assigned to four groups and treated with 0 mg/kg/day (Group 1; vehicle control), 
20/15 mg/kg/day (Group 2), 60/30 mg/kg/day (Group 3) and 120 mg/kg/day (Group 4) of ABI-H2158. 
The dosing volume was 4 mL/kg. Two animals/sex/group from Groups 1 and 4 were used for assessment 
of reversibility. The initial dose levels administered to Groups 2 and 3 (20 and 60 mg/kg/day, 
respectively) were decreased to 15 and 30 mg/kg/day, respectively, on Day 21/19 (males/females) in 
order to increase the separation in exposure between these groups and the high dose group 
(120 mg/kg/day).  
There was no ABI-H2158-related mortality or moribundity during this study. One Group 4 male was 
found dead on Day 192; the cause of death was pulmonary edema and inflammation in the lungs which 
was suggestive of aspiration pneumonia, likely related to the dosing procedure.  
There were no ABI-H2158-related effects on food consumption, ophthalmology, electrocardiography, 
hematology, coagulation, urinalysis, or organ weights. There were no ABI-H2158-related macroscopic 
or microscopic findings. 
Non-adverse ABI-H2158-related clinical abnormalities were limited to an increased incidence of 
non-severe hair loss for the Group 3 and 4 males when compared to the controls. Non-adverse 
ABI-H2158-related effects on body weight were limited to slightly lower mean body weights for the 
Group 3 and 4 females vs. controls at completion of dosing. At the initiation of the dosing period, mean 
body weights for the Group 3 and 4 females were 2 and 0.4%, respectively, lower than that of the 
controls, while at the end of the dosing period, they were both 10% lower than that of the controls. 


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Non-adverse ABI-H2158-related effects on serum chemistry parameters were limited to slightly lower 
serum lactate dehydrogenase (LDH) levels for the Group 2-4 males and females throughout the dosing 
period. Mean LDH values were comparable to control group values by the end of the recovery period. 
The LDH changes were not considered adverse due to the low magnitude, lack of microscopic correlates 
and reversibility. 
Once daily oral (gavage) administration of ABI-H2158 to male and female Cynomolgus monkeys at 
dose levels of 0, 20/15, 60/30 or 120 mg/kg/day for 273 consecutive days was well tolerated. 
Non-adverse, ABI-H2158-related findings were limited to increased incidence of non-severe hair loss 
for the 60/30 and 120 mg/kg/day males, slightly lower body weights for the 60/30 and 120 mg/kg/day 
females vs controls, and lower serum lactate dehydrogenase levels for all ABI-H2158-treated male and 
female groups. Following daily oral doses for 9-months, the NOAEL for ABI-H2158 was considered to 
be 120 mg/kg/day for male and female Cynomolgus monkeys, a dose level yielding Day 273 mean 
plasma Cmax of 14.4-19.8 µg/mL (average 17.1 µg/mL) and AUC0-24 of 182-223 hr*µg/mL (average of 
203 hr*µg/mL). These exposures are approximately twice the average exposures at the NOAEL dose in 
the 14-day monkey study (Cmax of 9.6 µg/mL and AUC0-24 of 86.6 hr*µg/mL), and approximately 
20%-25% of the exposure levels that caused acute liver toxicity and morbidity at the 100 mg dose in the 
14-day monkey study (Cmax and AUC0-24 of 62.6 µg/mL and 1,035 hr*µg/mL). 
2.2.3 Clinical Studies with ABI-H2158 
Clinical experience with ABI-H2158 consists of 3 ongoing early-phase clinical studies: (1) a Phase 1a/1b 
dose-ranging study in healthy subjects and treatment-naïve subjects with CHB, ABI-H2158-101; (2) a 
relative bioavailability study in healthy subjects, ABI-H2158-102; (3) a drug-drug interaction (DDI) 
study in healthy subjects, ABI-H2158-103. Summary information on these studies is provided below 
with more complete and updated information described in the current version of the ABI-H2158 IB. 
2.2.3.1 ABI-H2158-101 
ABI-H2158-101 is an ongoing Phase 1a/b, randomized, single- and multiple-dose, dose escalation, 
partially -blinded, PBO-controlled study in healthy subjects and subjects with CHB. This study is the 
first-in-human and first-in-patient study of ABI-H2158 and is being conducted in 3 parts. Part 1 was 
designed to assess the dose-related safety, tolerability, and pharmacokinetic (PK) profile of ABI-H2158 
and its metabolite following single ascending doses (SADs) in healthy subjects, and to assess the effect 
of food on ABI-H2158. Part 2 was designed to assess multiple-ascending dosing (MAD) in healthy 
subjects. Part 3 is designed to assess the antiviral activity of ABI-H2158 as monotherapy in subjects with 
CHB. 
Part 1 and Part 2 of the study have been completed. In Part 1, there were 5 dose cohorts with 8 subjects 
each evaluating single oral doses of 5 mg to 500 mg of ABI-H2158. In each cohort, 6 subjects were 
randomized to receive ABI-H2158 and 2 were randomized to PBO. In Part 2, there was a single dose 
cohort which evaluated multiple doses of ABI-H2158 of 300 mg administered for 10 days. In this cohort, 
6 subjects were randomized to receive ABI-H2158 and 2 subjects were randomized to PBO. A summary 
of the safety and PK data from Parts 1 and 2 is summarized below; refer to the ABI--H2158 IB for more 
details. Part 3 is currently ongoing. Each cohort includes 9 subjects: 7 subjects randomized to receive 
ABI-H2158 and 2 randomized to PBO. At this time, treatment has been completed in two cohorts, 
100 mg once daily (QD; Cohort 1) and 300 mg QD (Cohort 2) administered for 14 days. Cohort 3 


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evaluating 500 mg QD is currently ongoing. Available safety, and antiviral activity data are summarized 
below.   
2.2.3.1.1 Parts 1 and 2: Safety in Healthy Subjects 
The final, unblinded safety data are available for Parts 1 and 2 in which 48 healthy subjects were enrolled, 
36 of whom received ABI-2158 and 12 of whom received PBO. Across the groups, study drugs were 
generally well tolerated. No subjects discontinued treatment due to adverse events (AEs). Overall, 11% 
(4 of 36 subjects) who received ABI-H2158 and 17% (2 of 12 subjects) who received PBO experienced 
treatment-emergent AEs. All the AEs were Grade 1. The AE reported by more than 2 subjects who 
received ABI-H2158 was headache (3 subjects [8%] who received ABI-H2158 and 1 subject [8%] who 
received PBO). There have been no serious adverse events (SAEs) or deaths. Most laboratory 
abnormalities were Grade 1. No subjects experienced graded elevations in ALT. There have been no 
Grade 3 or 4 laboratory abnormalities. 
2.2.3.1.2 Part 1: Single Dose Pharmacokinetics in Healthy Subjects 
ABI-H2158 was rapidly absorbed with median time to maximum plasma concentration (Tmax) ranging 
between 1 and 4 hours. The extent of exposure as measured by the AUC, as well as the trough plasma 
concentration (C24hr) increased proportionally with the dose. The Cmax, however, was slightly less 
than dose proportional. Summary PK parameters following single oral dose administration are 
summarized in Table 1. In general, the overall systemic exposure to ABI-H2158 was well-characterized 
with sampling time capturing more than 95% of the AUC at all dose levels except for the lowest dose, 
which was greater than 85%. The PK of ABI-H2158 appears to be linear with similar terminal 
elimination half-life (t1/2), CL/F, and Vz/F (data not shown) across dose levels, suggesting there are no 
saturable processes involved within this exposure range. 
Five of the 6 subjects that received ABI-H2158 100 mg in the fasted cohort returned to receive 
ABI-H2158 100 mg in the fed state. ABI-H2158 was administered 30 minutes after the start of a high-fat 
breakfast in Period 2. No evidence of a significant food effect was seen on the PK profile of ABI-H2158 
(Table 1). 


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Table 1:  
Summary of ABI-H2158 Pharmacokinetic Parameters Following Single Oral 
Doses 
Parameters 
5 mg 
fasting 
25 mg 
fasting 
100 mg 
fasting 
100 mg 
fed 
300 mg 
fasting 
500 mg 
fasting 
AUC0-24 
(hr*µg/mL) 
1.25 (32.7%) 
5.80 (21.2%) 
22.3 (31.8%) 
25.2 (11.7%) 
41.6 (35.5%) 
85.9 (43.8%) 
AUC0-inf (hr* 
µg/mL) 
1.51 (40.6%) 
8.00 (30.3%) 
31.8 (35.9%) 
37.5 (20.9%) 
65.0 (36.1%) 
133 (57.7%) 
Cmax (µg/mL) 
0.169 (29.6%) 0.544 (33.0%) 
1.93 (31.7%) 
2.01 (10.5%) 
3.632 (29.4%) 
6.48 (37.1%) 
Tmax (hr) 
1 (0.5, 2) 
1.5 (1, 3) 
1 (1, 2) 
2 (1, 4) 
2.5 (1, 4) 
4 (2, 5) 
C24hr (µg/mL) 
0.0209 (47.7%) 0.114 (38.2%) 
0.464 (45.1%) 
0.542 (29.7%) 
0.938 (37.9%) 
2.09 (70.8%) 
t1/2 (hr) 
9.8 (2.9) 
12.9 (2.9) 
14.4 (2.3) 
16.1 (4.5) 
20.7 (7.3) 
16.0 (4.3) 
AUC0-24: Area under the plasma-concentration curve from time 0 to 24 hours postdose; C24hr: trough plasma concentration;  
Cmax: maximum plasma concentration; t1/2: terminal elimination half-life; Tmax: time to Cmax 
Geometric mean (Geometric CV%) are presented for AUCs, Cmax, and C24hr; Median (min, max) are presented for Tmax;  
Mean (SD) are presented for t1/2. 
2.2.3.1.3 Part 2: Multiple Dose Pharmacokinetics in Healthy Subjects 
The PK of ABI-H2158 on Day 1 was consistent with the PK observed in the SAD part of the study, at 
the same dose level. Accumulation ratios between 1.5 and 2 suggest an effective accumulation half-life 
ranging from 16 to 24 hours, in line with the observed t1/2 in the SAD part of the study, suggesting that 
the PK of ABI-H2158 is not time dependent. The summary noncompartmental PK parameters obtained 
for ABI-H2158 in plasma are presented in Table 2. 


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Table 2:  
Summary of ABI-H2158 Pharmacokinetic Parameters Following Single and 
Multiple 300 mg Once-daily Oral Doses of ABI-H2158 
Parameters 
ABI-H2158 
Day 1 
Day 10 
AR 
AUC0-24hr (hr*µg/mL) 
33.3 (83.4%) 
55.1 (102%) 
1.7 (0.6) 
Cmax (µg /mL) 
2.84 (88.8%) 
4.21 (92.0%) 
1.5 (0.4) 
Tmax (hr) 
2.5 (1, 4) 
2 (2, 4) 
- 
C24hr (µg/mL) 
0.757 (90.5%) 
1.38 (126%) 
2.0 (0.9) 
t1/2 (hr) 
14.3 (2.5) 
18.4 (6.2) 
- 
AR: accumulation ratio Day 10/Day 1; AUC0-24: Area under the plasma-concentration curve from time 0 to 24 hours postdose;  
AUC0-inf: Area under the plasma-concentration curve from time 0 extrapolated to infinity; C24hr: trough plasma concentration;  
Cmax: maximum plasma concentration; t1/2: terminal elimination half-life; Tmax: time to Cmax 
Geometric mean and CV% are presented for AUCs, Cmax, and C24hr; Median (min, max) are presented for Tmax;  
Mean (SD) are presented for t1/2. 
a Half-life was not determined since the terminal elimination phase was not sampled. 
2.2.3.1.4 Part 3: Safety and Antiviral Activity in Subjects with CHB 
Preliminary, unblinded safety data are available for Cohorts 1 and 2 in Part 3. In each cohort, 7 subjects 
were randomized to receive ABI-H2158 (100 mg in Cohort 1 and 300 mg in Cohort 2) and 2 were 
randomized to PBO. Across these cohorts the study drug has been generally well tolerated. No subjects 
have discontinued treatment due to AEs. Overall, 36% (5 of 14 subjects) who received ABI-H2158 and 
50% (2 of 4 subjects) who received PBO have experienced treatment-emergent AEs (Table 3). All AEs 
have been Grade 1, except for one Grade 2 AE. The only AEs reported by more than 1 subject who 
received ABI-H2158 was headache (2 subjects). There have been no Grade 3 or 4 AEs, no SAEs, and 
no deaths. 
Table 3:  
Treatment-emergent Adverse Events in Subjects with Chronic Hepatitis B 
Infection (Cohorts 1 and 2, Part 3; preliminary) 
System Order Class 
   Preferred Term 
Placebo 
(N=4) 
n (%) 
ABI-H2158 
100 mg 
(N=7) 
n (%) 
ABI-H2158 
300 mg 
(N=7) 
n (%) 
Any adverse event 
2 (50.0) 
3 (42.9) 
2 (28.6) 
Metabolism and Nutrition Disorder 
   Grade 2 Hypertriglyceridaemia  
0 
0 
1 (14.3) 
1 (14.3) 
Nervous System Disorders  
   Grade 1 Headache 
   Grade 1 Dizziness 
1 (25.0) 
1 (25.0) 
0 
2 (28.6) 
1 (14.3) 
1 (14.3) 
1 (14.3) 
1 (14.3) 
0 
Gastrointestinal Disorders 
   Grade 1 Abdominal Pain Upper 
0 
1 (14.3) 
1 (14.3) 
0 


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System Order Class 
   Preferred Term 
Placebo 
(N=4) 
n (%) 
ABI-H2158 
100 mg 
(N=7) 
n (%) 
ABI-H2158 
300 mg 
(N=7) 
n (%) 
Skin and Subcutaneous Tissue Disorders 
   Grade 1 Rash  
0  
1 (14.3) 
1 (14.3) 
0 
General Disorders  
   Grade 1 Fatigue 
0 
1 (14.3) 
1 (14.3) 
0 
Investigations 
   Grade 1 ALT Increase 
1 (25.0) 
1 (25.0) 
0 
0 
ALT: alanine aminotransferase. 
Twelve subjects (86%) who received ABI-H2158 and 3 subjects (75%) who received PBO have 
experienced graded laboratory abnormalities, most of which have been Grade 1 or 2 (Table 4). Four 
subjects (29%) who received ABI-H2158 and 1 subject (25%) who received PBO have experienced 
Grade 1 elevations in ALT; the ALT elevation observed by the subject who received PBO was reported 
as a Grade 1 AE considered possibly related to study drug by the Investigator. There was 1 Grade 3 
elevated cholesterol experienced by a subject who received ABI-H2158, which was not reported as an 
AE. There have been no Grade 4 laboratory abnormalities. 


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Table 4:  
Treatment-emergent Laboratory Abnormalities by Grade in Subjects with CHB 
(Cohorts 1 and 2, Part 3; preliminary) 
Laboratory 
Abnormality 
Grade 
Placebo 
(N=4) 
n (%) 
ABI-H2158 
100 mg 
(N=7) 
n (%) 
ABI-H2158 
300 mg 
(N=7) 
n (%) 
Any 
All 
3 (75) 
7 (100) 
5 (71) 
Elevated AST 
1 
1 (25) 
2 (28.6) 
1 (14.3) 
Elevated ALT 
1 
1 (25) 
2 (28.6) 
2 (28.6) 
Amylase 
1 
0 
2 (28.6) 
0 
Cholesterol 
1 
2 
3 
1 (25) 
0 
0 
0 
0 
1 (14.3) 
1 (14.3) 
2 (28.6) 
0 
Creatinine 
1 
1 (25) 
0 
0 
Calcium 
1 
0 
1 (14.3) 
0 
Uric acid 
1 
1 (25) 
1 (14.3) 
0 
Glucose 
1 
0 
1 (14.3) 
0 
Triglycerides 
1 
2 
0 
0 
1 (14.3) 
1 (14.3) 
1 (14.3) 
0 
ALT: alanine aminotransferase; AST: aspartate aminotransferase. 
Treatment-emergent laboratory abnormality is defined as worsened toxicity grade (DAIDS, July 2017, version 2.1) compared with 
Baseline. 
 
Preliminary antiviral data are available for Cohorts 1 and 2. The ABI-H2158 100 mg QD dose 
demonstrated potent antiviral activity as reflected by mean 2.3 log10 and 2.1 log10 reductions in HBV 
DNA and HBV pgRNA, respectively, over the 14-day dosing interval. In Cohort 2 evaluating 
ABI-H2158 300 mg QD, the mean reductions in HBV DNA and HBV pgRNA were 2.5 log10 IU/mL 
and 2.12 log10 IU/mL over the 14-day dosing interval. At this time, a third dose group evaluating 
ABI-H2158 500 mg QD is currently ongoing. 
2.2.3.2 ABI-H2158-102 
ABI-H2158-102 is an ongoing Phase 1, randomized, open-label, 3-way crossover study, designed to 
evaluate the relative bioavailability of a new 100 mg ABI-H2158 tablet (Test) formulation relative to a 
prior 25 mg ABI-H2158 tablet (Reference) formulation, and to determine the effect of food on the PK 
of the ABI-H2158 100 mg film-coated tablets in healthy subjects. One cohort of 15 healthy subjects was 
randomly assigned in 3 groups of 5 subjects each to receive single doses of the Test and Reference tablet 
formulations under fasting conditions and Test tablet formulation under fed conditions during 
3 sequential dosing periods. Each dose period was separated by a minimum 7-day washout period 
(inclusive). The Test formulation is intended for use in the current ABI-H2158-201 study in subjects 
with CHB. 
Preliminary safety data are available, and the study drug has been generally well tolerated by the 
15 subjects enrolled in the study. No subjects have discontinued treatment due to AEs. Overall, 27% 


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(4 of 15 subjects) enrolled have experienced treatment-emergent AEs, most of which were Grade 1 or 
Grade 2 and no AE was reported by more than 1 subject. One subject experienced elevated ALT and 
aspartate aminotransferase (AST) which were reported as Grade 1 AEs considered unlikely related to 
study drug by the Investigator. One subject experienced Grade 3 laboratory abnormalities of elevated 
triglycerides and elevated low-density lipoprotein which were reported as Grade 3 AEs and were 
considered unlikely related to study drug by the Investigator. No Grade 4 AEs or SAEs have been 
reported and no deaths have occurred. No other clinically significant laboratory abnormalities have been 
reported as AEs. 
Interim PK estimates of AUC and Cmax of ABI-H2158 were analyzed using analysis of variance with 
sequence, period, and treatment as fixed effects and subject within sequence as the random effect on 
naturally logarithmic-transformed values. Geometric least squares mean ratios of the 300 mg reference 
group (12 x 25 mg tablets) relative to the 300 mg test group (3 x 100 mg tablet) for Cmax and AUC from 
time 0 extrapolated to infinity (AUC0-inf) are 94.9 (100,600 and 106,000 ng/mL, respectively) and 80.4 
(4720 and 5870 ng*hr/mL, respectively). Exposures after administration of the 300 mg test (3 x 100 mg 
tablets) in the fed state after a high-fat meal increased approximately 40% as measured by AUC0-inf 
(143,000 ng*hr/mL) and approximately 30% for Cmax (6160 ng/mL). 
2.2.3.3 ABI-H2158-103 
ABI-H2158-103 is an ongoing Phase 1, single-center, open-label, fixed-sequence, drug-drug interaction 
study, split into 5 cohorts each planned to enroll 16 healthy subjects. The primary objective is to evaluate 
the effect of multiple-dose itraconazole (Cohort 1), rifampin (Cohort 2), and esomeprazole (Cohort 3) 
on the single-dose PK of ABI-H2158, and the effect of multiple-dose ABI-H2158 on the single-dose PK 
of midazolam (Cohort 4) and the multiple-dose PK of an oral contraceptive (OC) consisting of ethinyl 
estradiol and levonorgestrel (Cohort 5). Cohorts may be run consecutively or concurrently, with each 
subject only allowed to participate in one of the following cohorts: 
• Cohort 1: Single oral doses of ABI-H2158 on Days 1 and 9; QD oral doses of itraconazole on 
Days 6 through 13 
• Cohort 2: Single oral doses of ABI-H2158 on Days 1 and 12; QD oral doses of rifampin on Days 6 
through 16 
• Cohort 3: Single oral doses of ABI-H2158 on Days 1 and 11; QD oral doses of esomeprazole on 
Days 6 through 11 
• Cohort 4: Single oral doses of midazolam on Days 1 and 11; QD oral doses of ABI-H2158 on 
Days 2 through 11 
• Cohort 5/Cycle 1: QD oral doses of active OC (ethinyl estradiol/levonorgestrel) on Days 1 through 
21 and PBO OC on Days 22 through 28 
• Cohort 5/Cycle 2: QD oral doses of active OC (ethinyl estradiol/levonorgestrel) on Days 1 through 
21, PBO OC on Days 22 through 26, and QD oral doses of ABI-H2158 on Days 11 through 24  
In each cohort, serial PK blood samples will be collected before dosing and at specified timepoints after 
dosing as indicated in the PK sampling time schedules for each cohort. 


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Preliminary safety data are available, and the study drug has been generally well tolerated by the 
77 subjects that have received study drug to date. No subjects have discontinued treatment due to AEs. 
Overall, 32% (25 of 77 subjects) enrolled have experienced treatment-emergent AEs, all of which were 
Grade 1 or 2. To date, the most frequently reported AEs were headache (6 subjects) and nausea 
(5 subjects). No Grade 3 or 4 AEs or SAEs have been reported and no deaths have occurred. No clinically 
significant laboratory abnormalities have been reported. 
Coadministration of itraconazole (CYP3A inhibitor probe) and ABI-H2158 resulted in markedly 
increased ABI-H2158 exposure. Coadministration of rifampin (CYP3A, CYP2C19, CYP2C9, CYP2B6, 
CYP2C8 inducer and OATP inhibitor probe) and ABI-H2158 resulted in markedly decreased ABI-
H2158 exposure. Coadministration of 300 mg ABI-H2158 with the proton pump inhibitor/stomach pH 
modifier (neutralizes stomach acidity), esomeprazole (40 mg), resulted in markedly decreased ABI-
H2158 exposure. 
Coadministration of 300 mg ABI-H2158 with midazolam (2 mg) (CYP3A substrate probe) resulted in 
mildly decreased midazolam exposure.  
Coadministration of 300 mg ABI-H2158 with OC ethinyl estradiol 30 mcg/levonorgestrel 150 mcg 
(CYP3A4 substrate probe) resulted in minimally reduced ethinyl estradiol and levonorgestrel exposure. 
2.3 
Study Rationale 
Current approved therapies are generally safe, well tolerated and effective at suppressing viral replication 
in most patients but do not eliminate viral replication and SVR is rare. Novel therapeutic modalities are 
required to improve chronic suppressive regimens and support finite duration therapy. The HBV Cp is 
involved in multiple steps in the HBV life cycle, including both viral replication and the establishment 
of new cccDNA (Levrero 2009, Belloni 2013). Inhibition of HBV Cp represents a novel therapeutic 
strategy for the treatment of CHB (Yang 2019). Interim analyses of Phase 2a studies, demonstrated 
subjects treated with the first-generation CI ABI-H0731 with a NrtI compared to those treated with NrtI 
alone achieved faster and deeper declines in HBV DNA and in HBV pgRNA, a surrogate marker of 
cccDNA. In these studies, the observed declines in HBV pgRNA correlated with reductions in HBeAg, 
HBcrAg, and HBsAg (Sulkowski 2019). 
ABI-H2158 is a second-generation CI being developed by Assembly Biosciences. In vitro, ABI-H2158 
has demonstrated potent antiviral activity as measured by inhibition of HBV DNA with a 50% effective 
concentration (EC50) of 22 nM in HepAD38 cells and 41 nM in primary human hepatocytes (PHH). In 
the PHH infected cells, the EC50s for inhibition of HBV pgRNA, HBeAg, and HBsAg production were 
216 nM, 204 nM, and 160 nM, respectively. ABI-H2158 is currently being evaluated as monotherapy in 
a Phase 1b clinical study (ABI-H2158-101) in treatment-naïve subjects with HBeAg positive CHB 
(Section 2.2.3.1). In the initial dose group tested (100 mg ABI-H2158 QD), the mean declines in HBV 
DNA and HBV pgRNA from Baseline to Day 15 were 2.3 log10 IU/mL (range 1.7, -3.0) and 2.1 log10 
IU/mL (range 1.5, -2.7), respectively. At the 300 mg QD dose level, the mean declines in HBV DNA 
and HBV pgRNA from Baseline to Day 15 were 2.5 log10 IU/mL (range 0.8, -3.3) and 2.12 log10 IU/mL 
(range 1.4, 2.6). At this time, a third dose group evaluating ABI-H2158 500 mg QD is currently ongoing. 
Based on these data, the addition of ABI-H2158 to NrtI therapy may improve treatment responses 
compared with NrtI alone. It is anticipated that the addition of ABI-H2158 to entecavir (ETV) will be 
well tolerated and increase the rate and extent of decline in HBV DNA and HBV pgRNA. Furthermore, 


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ABI-H2158 may prevent the establishment of cccDNA more completely than ETV alone, resulting in a 
corresponding decline in HBV antigens reflective of cccDNA transcription (eg, HBeAg and HBcrAg). 
This study will explore the safety of the ABI-H2158+ETV combination in subjects with CHB and 
evaluate the antiviral activity as measured by the effects on HBV nucleic acids and HBV antigens. 


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3 STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 Primary Objective 
• To evaluate the safety and tolerability of ABI-H2158 when administered in combination with 
ETV in subjects with CHB 
• To evaluate the effect of ABI-H2158 in reducing HBV DNA in subjects with CHB 
3.1.2 Secondary Objectives 
• To evaluate the PK of ABI-H2158 and ETV in subjects with CHB 
• To evaluate the effect of ABI-H2158 in reducing HBV pgRNA levels in subjects with CHB 
• To evaluate the effect of ABI-H2158 in reducing HBV antigens (ie, HBeAg, HBcrAg, and 
HBsAg) in subjects with CHB 
• To evaluate the effect of ABI-H2158 on normalization of ALT in subjects with abnormal ALT 
• To evaluate the emergence of resistance to ABI-H2158 when administered in combination with 
ETV 
3.1.3 Exploratory Objectives 
• To assess the relationship between new and known viral biomarkers and virologic and/or clinical 
outcomes 
• For subjects who provide an optional pharmacogenomic sample, to evaluate the potential 
contribution of host genomics to clinical or virologic outcomes and/or drug disposition 
3.2 
Study Endpoints 
3.2.1 Primary Endpoint 
The primary endpoints are: 
• The proportion of subjects with AEs, premature treatment discontinuation, and abnormal 
laboratory results 
• The change in mean log10 HBV DNA from Baseline to Week 24 for ABI-H2158+ETV and 
PBO+ETV 


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3.2.2 Secondary Endpoints 
The secondary endpoints are: 
• Analysis of ABI-H2158 and ETV drug concentrations: 
o Trough levels and trough to peak ratios of ABI-H2158 on ABI-H2158+ETV 
o Trough levels and trough to peak ratios of ETV on ABI-H2158+ETV and PBO+ETV 
• The change in mean log10 HBV DNA for ABI-H2158+ETV and PBO+ETV at each timepoint 
• The change in mean log10 HBV pgRNA from Baseline to Week 24 and at each timepoint for 
ABI-H2158+ETV and PBO+ETV 
• The proportion of subjects with a reduction in HBV DNA below the assay lower limit of 
quantitation (LLOQ) for ABI-H2158+ETV and PBO+ETV at each timepoint 
• The proportion of subjects with a reduction in HBV pgRNA below the assay LLOQ for 
ABI-H2158+ETV and PBO+ETV at each timepoint 
• The change in serum viral antigens (ie, HBeAg, HBcrAg, and HBsAg) on ABI-H2158+ETV and 
PBO+ETV at each timepoint 
• The proportion of subjects with abnormal ALT at Baseline who have normal ALT at Week 24 
and at each timepoint on ABI-H2158+ETV and PBO+ETV 
• The incidence of HBV variants with reduced susceptibility to ABI-H2158 
3.2.3 Exploratory Endpoints 
Exploratory endpoints will include: 
• The proportion subjects with loss (defined as below LLOQ) or decline in HBsAg, HBcrAg, 
HBeAg or new biomarkers on ABI-2158+ETV and PBO+ETV at each timepoint 
• The proportion of subjects with HBsAg seroconversion (loss of HBsAg and appearance of 
HBsAb) or HBeAg seroconversion (loss of HBeAg and appearance of HBeAb) on 
ABI-H2158+ETV and PBO+ETV at each timepoint for applicable cohort 
• The proportion of subjects whose HBV DNA is below the assay LLOQ and “target not detected” 
on ABI-H2158+ETV and PBO+ETV at each timepoint 
• Pharmacogenomic correlations may be performed with clinical or virologic outcomes for 
subjects who provide an additional informed consent. Known gene variants and PK and/or safety 
of ABI-H2158 and its metabolites may be evaluated 


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4 STUDY PLAN 
4.1 
Study Design 
This Phase 2a, multicenter, randomized, single-blind (ie, investigational site and subjects are blinded), 
PBO-controlled study will assess the safety, antiviral activity, and PK of ABI-H2158 administered QD 
in combination with ETV in subjects with CHB. It is planned that multiple parallel cohorts will be 
enrolled in the study. 
The first treatment cohort will evaluate ABI-H2158 300 mg in combination with ETV (n=30) compared 
to ETV alone (n=10) in treatment-naïve subjects with HBeAg positive CHB. The second treatment 
cohort will evaluate ABI-H2158 300 mg in combination with ETV (n=30) compared to ETV alone (n=10) 
in treatment-naïve subjects with HBeAg negative CHB.  Additional cohorts may be added by future 
protocol amendment(s) based, in part, upon emergent safety, antiviral activity, and PK data from the 
ABI-H2158 regimens evaluated in the ongoing Phase 1b study ABI-H2158-101 (Section 2.2.3.1). 
In Cohort 1, subjects will be randomized in a 3:1 ratio to receive 300 mg ABI-H2158+ETV (n=30) or 
matching PBO+ETV (n=10) for 72 weeks (Figure 1). Treatment assignments will be stratified by the 
HBV DNA level measured at the Screening visit (ie, ≥8.0 log10 IU/mL versus <8.0 log10 IU/mL). After 
completing treatment at Week 72, or following premature treatment discontinuation, all subjects will 
enter a 24-week follow-up period. During the follow-up period all subjects will remain on ETV and 
undergo the follow-up assessments described in Section 7.5. After completing the 24-week follow-up 
period, all subjects will resume management by their treating physician in accordance with local standard 
of care. 
In Cohort 2, subjects will be randomized in a 3:1 ratio to receive 300 mg ABI-H2158+ETV (n=30) or 
matching PBO+ETV (n=10) for 72 weeks (Figure 1). Treatment assignments will be stratified by the 
HBV DNA level measured at the Screening visit (ie, ≥6.0 log10 IU/mL versus <6.0 log10 IU/mL). After 
completing treatment at Week 72, or following premature treatment discontinuation, all subjects will 
enter a 24-week follow-up period. During the follow-up period all subjects will remain on ETV and 
undergo the follow-up assessments described in Section 7.5. After completing the 24-week follow-up 
period, all subjects will resume management by their treating physician in accordance with local standard 
of care. 
Additional cohort may be added to this study by future protocol amendment(s) in order to evaluate other 
doses of ABI-H2158, other ABI-H2158-containing regimens, and/or other subgroups of patients with 
CHB. 


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Figure 1:  
Study Overview 
  BL          Wk2          Wk4          Wk8          Wk12          Wk16          Wk20          Wk24                    Wk48                                   Wk72                                              Wk96
On Treatment
24 Week Follow-up
Monthly Clinic Visits Wks 24-72
Cohort 1 (n=40)
Treatment-naïve HBeAg-positive: ABI-H2158 300 mg + ETV (n=30) vs PBO + ETV (n=10)  
Treatment-naïve HBeAg-negative: ABI-H2158 300 mg + ETV (n=30) vs PBO + ETV (n=10)  
ETV
ETV
Cohort 2 (n=40)
ETV is continued during 
the Follow-Up Period
 
 
PBO: placebo; ETV: entecavir; HBeAg: hepatitis B “e” antigen; NrtI: nucleos(t)ide reverse transcriptase inhibitor of the hepatitis B virus 
polymerase. 
The schedule of study procedures is described in Section 7 and presented in tabular form in Appendix 1. 
In addition to the routine medical oversight of the study, safety will also be closely monitored by an 
internal Data Review Committee (DRC). The team membership, roles and responsibilities and the 
frequency of analyses will be specified within the DRC Charter. 
An assessment of PK data will be performed after all subjects in each cohort have completed their Week 
4 study visit (or discontinued study without completing Week 4) in order to confirm the absence of 
important drug interactions between ABI-H2158 and ETV at steady state. A detailed review of the 
planned PK analyses in this study is provided in Section 7.8.8. 
4.2 
Dose Justification 
In the ongoing Phase 1a/b clinical study ABI-H2158-101 (Section 2.2.3.1), single ABI-H2158 doses of 
5 mg, 25 mg, 100 mg, and 300 mg QD were administered to healthy subjects (6 active, 2 PBO per dose 
level). Following completion of the SAD assessment, ABI-H2158 was subsequently administered as 300 
mg QD to healthy subjects for 10 days (6 active, 2 PBO). Finally, in treatment-naïve subjects with 
HBeAg positive CHB, ABI-H2158 100 mg and 300 mg (7 active, 2 PBO per dose level) was 
administered once daily for 14 days. No safety signals have been observed in a cumulative data analysis. 
All dose levels were well tolerated and no subject prematurely discontinued treatment due to AEs. There 
were no Grade 3 or 4 AEs or SAEs. Treatment-emergent AEs did not increase in frequency or severity 
with either dose or duration. All treatment-emergent laboratory abnormalities were Grade 1 or Grade 2. 
Preliminary data indicates that there is a dose-dependent decrease in HBV DNA at doses of 100 mg and 
300 mg daily in subjects with CHB (Section 2.3).  The results of the following doses of ABI-H2158 (500 
mg QD and 300 mg BID) for 14 days is described in the current version of the ABI-H2158 IB. 
Interim analysis indicates exposures in the 100 mg and 300 mg CHB patient cohorts are similar to 
exposures in healthy volunteers. Mean Day 14 Cmax values in the 100 mg and 300 mg CHB cohorts are 
3390 and 8400 ng/mL, respectively, and mean Day 14 AUC0-24 are 46,100 and 112,000 ng*hr/mL, 
respectively. 


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It is anticipated that the 300 mg QD regimen will be safe and provide sufficient ABI-H2158 exposure to 
evaluate the antiviral effect in CHB subjects in this study, and within the dose range that has been well 
tolerated in healthy volunteers and subjects with CHB to date. 
4.3 
Study Treatment 
This study is designed to evaluate the safety, PK, and antiviral activity of various ABI-H2158-containing 
regimens in subjects with CHB. These regimens will be evaluated in multiple treatment cohorts. Cohort 1 
will enroll treatment-naïve subjects with HBeAg positive CHB and Cohort 2 will enroll treatment-naïve 
subjects with HBeAg negative CHB. 
The study treatment (ABI-H2158 or PBO) will be administered in combination with a standard-of-care 
known effective therapy (ETV). All subjects will receive ABI-H2158 or matching PBO as three 100 mg 
tablets QD. ETV will be administered as a single 0.5 mg tablet QD. ABI-H2158, matching PBO, and 
ETV will be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next 
meal) at approximately the same time each day. Further information is provided in the ETV package 
insert. On study visit days, ABI-H2158 or PBO will be administered in the clinic; subjects will self-
administer assigned treatment on all other days. On study visit days which include PK collection (Section 
7), subjects will administer ABI-H2158 or PBO and ETV in the clinic except for Week 16 and Week 20. 
Study personnel will document the time of study drug administration in the subject’s medical record. 
Subjects will be required to record the dates and times of each dose of study drug (ie, ABI-H2158 or 
PBO and ETV) they self-administer in the dosing diary provided to them at the Day 1 visit.  
4.4 
Duration of Treatment 
All subjects will receive their randomized treatment assignment in a blinded manner for up to 72 weeks. 
After completing treatment at Week 72, or following premature treatment discontinuation, all subjects 
will enter a 24-week follow-up period. During the follow-up period all subjects will remain on ETV and 
undergo the follow-up assessments described in Section 7.5. After completing the 24-week follow-up 
period, all subjects will resume management by their treating physician in accordance with local standard 
of care. 


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5 POPULATION 
5.1 
Number of Subjects 
A total of approximately 80 subjects (40 subjects per Cohorts 1 and 2) are planned.  
5.2 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria in order to be eligible for the study: 
1. Willing and able to provide informed consent 
2. Male or female between the ages 18 and 65 years (inclusive) 
3. Female subjects must be non-pregnant and have a negative serum pregnancy test at Screening and 
a negative urine pregnancy test predose on Day 1  
4. Chronic HBV infection, defined as HBV infection for ≥6 months documented, for example, by at 
least two measurements of HBsAg positivity and/or detectable HBV DNA ≥6 months apart 
(inclusive of Screening). For subjects without clear documentation of CHB, anti-hepatitis B core 
antigen immunoglobulin M (IgM) antibody to the HBV core antigen (HBcAb) must be negative at 
Screening to exclude acute HBV infection 
5. Body mass index (BMI) 18 to 36 kg/m2 and a minimum body weight of 45 kg (inclusive) 
6. HBV DNA ≥2 × 105 IU/mL for subjects who are treatment naïve HBeAg positive  
7. HBV DNA >2 x 103 IU/mL for subjects who are treatment naïve HBeAg negative  
8. HBsAg >1000 IU/mL at Screening for subjects who are treatment naïve HBeAg positive 
9. Lack of cirrhosis or advanced liver disease as documented by the following: 
o Liver biopsy results of METAVIR F0-F2 (absence of bridging fibrosis or cirrhosis) within 
1 year of Screening 
OR 
o Fasting FibroScan ≤8 kPa within 3 months of Screening (including Screening visit) or other 
Sponsor-approved hepatic imaging study (hepatic magnetic resonance elastography [MRE]) 
within 6 months of Screening indicating lack of cirrhosis or advanced liver disease (F0-F2 
or equivalent) 
Subjects with a fasting FibroScan >8 kPa and ≤10 kPa are excluded from study participation 
unless a liver biopsy within the 1 year before Day 1 confirms the absence of bridging fibrosis 
and cirrhosis. Subjects with a FibroScan >10 kPa are excluded from study participation 
If results from both liver biopsy and FibroScan are available, then the result reporting the most 
advanced liver disease will be used to determine eligibility for the study 


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10. Agreement to comply with protocol-specified contraceptive requirements (Refer to Appendix 3) 
11. Agreement to abstain from alcohol abuse [defined as alcohol consumption exceeding 2 standard 
drinks per day on average (1 standard drink = 10 grams of alcohol)] and the use of illicit substances 
from screening until end of the study 
12. In good general health, except for CHB 
13. Have the ability to take oral medication and, in the opinion of the Investigator, be willing to adhere 
to study treatment 
14. Candidate for treatment with ETV and have no contraindications as described in the approved 
product labelling 
5.3 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible for the study: 
1. Prior treatment for CHB; specifically 
a. lamivudine, telbivudine or adefovir (any duration) 
b. NrtI treatment for >4 weeks 
c. HBV core inhibitors (any duration) 
d. Previous treatment with an investigational agent for HBV infection 
2. Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis E virus 
(HEV), or hepatitis D virus (HDV) 
3. Females who are lactating, or wish to become pregnant during the course of the study 
4. History or evidence of advanced liver disease 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 
5. History of persistent alcohol abuse (alcohol consumption exceeding 2 standard drinks per day on 
average [1 standard drink = 10 grams of alcohol]) or illicit drug abuse within 3 years of Screening 
6. Clinically significant cardiac or pulmonary disease, chronic or recurrent renal or urinary tract 
disease, liver disease other than CHB, endocrine disorder, autoimmune disorder, diabetes mellitus 
requiring treatment with insulin or hypoglycemic agents, 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 
7. History of HCC 


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8. 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 
9. Poorly controlled or unstable hypertension; or sustained systolic blood pressure (BP) ≥160 mmHg 
or <90 mmHg, or diastolic BP >95 mmHg or <50 mmHg at Screening 
10. History or presence of electrocardiogram (ECG) abnormalities deemed clinically significant 
including: 
a. Personal or family history of prolonged QT syndrome or family history of sudden death 
b. QTcF >450 msec (males) or >470 msec (females) or <300 msec at Screening or Day 1 visit 
c. ECG with QRS and/or T-wave judged to be unfavorable for a consistently accurate QT 
measurement as judged by the Investigator at Screening 
d. Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, 
Wolff-Parkinson-White Syndrome, or cardiac pacemaker at Screening or Day 1 visit 
11. History of hypersensitivity or idiosyncratic reaction to any components or excipients of the 
investigational drug or PBO formulation 
12. History of any significant food or drug-related reactions such as anaphylaxis, Stevens-Johnson 
syndrome, or urticaria 
13. The following exclusionary laboratory results at Screening: 
a. Platelet count <100,000/mm3 
b. Albumin < lower limit of normal (LLN) 
c. Total bilirubin >1.2 × upper limit of normal (ULN) unless known Gilbert’s syndrome; subjects 
with Gilbert’s syndrome are eligible for study participation if the direct bilirubin is within the 
normal range 
d. Direct bilirubin >1.2 × ULN 
e. ALT >5 × ULN 
f. Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is > ULN but <100 ng/mL, 
the subject is eligible if a hepatic imaging study prior to initiation of study drug reveals no 
lesions indicative of possible HCC 
g. International normalized ratio (INR) >1.5 × ULN 
h. Glomerular filtration rate (GFR) <60 mL/min/1.73 m2 by Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation (Levey 2009) 
i. Serum hemoglobin A1c (HbA1c) >6.5% 


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j. Any other laboratory abnormality deemed clinically significant by the Sponsor or the 
Investigator 
14. Subjects receiving prohibited concomitant medications, grapefruit (whole fruit and juice), herbal or 
over-the-counter medications (Section 6.4.1) within 7 days or 5 half-lives (if known), whichever is 
longer, prior to administration of the first dose of study drug and for the duration of the study 
period 
15. Participation in another clinical trial 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 
16. Donated or lost >500 mL of blood within 2 months prior to Screening, or plasma donation within 
7 days prior to Screening 
 
 


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5.4 
Lifestyle Consideration 
During this study, subjects are asked to: 
• Abstain from abuse of alcohol (defined as alcohol consumption exceeding 2 standard drinks per day 
on average [1 standard drink = 10 grams of alcohol]) and from any use of illicit substances for the 
duration of the study 
• Abstain from the use of herbal or other supplements 
• Abstain from use of prohibited concomitant medication, grapefruit (whole fruit and juice), and over-
the-counter concomitant medications (Section 6.4.1)  
• Use dual effective birth control methods as outlined in Appendix 3. 
5.5 
Strategies for Retention and Safety 
To reduce immediate risk to study subjects and minimize potential exposure to COVID-19, study visits 
may be conducted by a home health care provider in the home or agreed location 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 health care 
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-19 restrictions. Blood and urine sampling for 
telemedicine visits may be drawn by a home health care provider.  
 
 


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6 INVESTIGATIONAL MEDICAL PRODUCTS 
6.1 
Randomization, Blinding and Treatment Codes 
6.1.1 Randomization 
Within each treatment cohort, randomization of eligible subjects to their respective treatment 
assignments will be performed centrally using an Interactive Response Technology (IRT) system. 
Following successful completion of Screening assessments and confirmation of subject eligibility, site 
personnel will enter the subject specific information in the IRT system and following acceptable 
completion of the procedure will receive a subject number and treatment assignment. For both Cohorts1 
and 2, the IRT system will assign eligible subjects in a 3:1 ratio to receive 300 mg ABI-H2158+ETV 
(n=30) or matching PBO+ETV (n=10). Individual subject treatment assignments will be stratified 
according to the HBV DNA level measured at the Screening visit (ie, HBeAg positive ≥8.0 log10 IU/mL 
versus <8.0 log10 IU/mL, and HBeAg negative ≥6.0 log10 IU/mL versus <6.0 log10 IU/mL). Additional 
information on the use of the IRT is provided in the IRT user manual. 
6.1.2 Blinding 
Study subjects, Investigators and other site personnel administering the study drug, performing the 
clinical assessments and handling data on the study subjects, will be blinded to individual subject 
treatments assignments (ie, ABI-H2158+ETV therapy or PBO+ETV therapy) throughout the duration 
of the study. Since decreases in HBV pgRNA may unblind site personnel, HBV pgRNA results will not 
be provided to sites until study completion. 
A limited internal Sponsor team will be unblinded to individual subjects’ treatment assignments 
throughout the study to ensure timely analysis of any emergent safety/tolerability issues, and completion 
of the prespecified safety data reviews that will be performed by the Data Review Committee (DRC) 
(see Section 10.6). The unblinded individuals will be identified in the DRC Charter along with their 
specific roles and responsibilities. All other Sponsor personnel will remain blinded until completion of 
the study. The contract research organization’s (CRO’s) Medical Monitor may be unblinded to individual 
subjects’ treatment assignments where required for assessment of emergent safety/tolerability issues. 
6.1.2.1 Unblinding in Emergency Situations 
Requests can be made to unblind an individual study subject for emergencies or urgent situations. Prior 
to unblinding, and if the situation permits, the Investigator should first contact the Sponsor and/or 
authorized Medical Monitor to discuss the case. However, the final decision whether to unblind a subject 
will be the Investigator’s decision, and the Investigator need not wait for the unblinding permission to 
be granted by the Sponsor/CRO Medical Monitor in emergency situations where identification of the 
individual treatment assignment is required for the immediate medical management of the subject. 
Access to the unblinded treatment assignment should be limited to the minimum number of people 
required for emergent management of the subject. The actual treatment assignment must not be disclosed 
to the subject and/or other study personnel, including site monitors, office staff; nor should there be any 
written or verbal disclosure of the code in the subject’s study documents. 
The request for unblinding should include the protocol number, site number, subject identifier (eg, 
subject number), treating Investigator’s contact info, a detailed reason for the unblinding, and date the 


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information is needed. All key correspondence between the requestor and Sponsor or CRO Medical 
Monitor should be saved in the Trial Master File (TMF). 
The IRT system will be used as the unblinding tool. In the event that an individual subject’s treatment 
assignment is unblinded, the date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable. Any treatment assignments that are unblinded must 
be immediately reported to the CRO Medical Monitor and the Sponsor. Code-break IRT access is given 
to the Investigator/designated person at the site and to the designated Medical Monitor(s) for the study. 
6.2 
Description and Handling of ABI-H2158 and Matching Placebo 
6.2.1 Formulation 
The ABI-H2158 drug product is a tablet formulation containing ABI-H2158 free base and standard 
pharmaceutical excipients including hypromellose, sodium lauryl sulfate, croscarmellose sodium, 
microcrystalline cellulose, lactose monohydrate, magnesium stearate, and Opadry film coating. 
ABI-H2158 100 mg tablets are manufactured according to Good Manufacturing Practice (GMP). 
Matching PBO tablets containing microcrystalline cellulose, lactose monohydrate, croscarmellose 
sodium, magnesium stearate, and Opadry film coating, are also manufactured according to GMP. 
6.2.2 Packaging and Labeling 
ABI-H2158 tablets and matching PBO tablets are packaged in high density polyethylene bottles fitted 
with child-resistant screw caps, induction sealed and shipped to sites under ambient conditions. 
Study drug will be labelled in accordance with US FDA requirements and EU GMP Annex 13, 
Investigational Medicinal Products. Additional local labelling requirements in countries of study conduct 
will be incorporated in the study drug label(s). 
6.2.3 Storage and Handling 
Bottled drug product at the study sites should be stored at controlled room temperature (15°C to 30°C 
[59°F to 89°F]) in a secure, locked location at the sites, accessible only to designated study personnel. 
6.3 
Description and Handling of Entecavir 
All subjects participating in this study will initiate and continue oral administration of 0.5 mg ETV 
tablets, QD, for the duration of the study. ETV tablets will either be provided by Assembly Biosciences 
or sourced locally by the site. Provision of ETV for the purposes of the study will be discussed and 
agreed with each investigational site prior to study conduct. Details describing the packaging, labelling, 
storage, and handling of ETV are described in the package insert. 
6.4 
Prior and 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 administered to a study 
subject during the conduct of the clinical trial. For randomized subjects, concomitant medications are 
discouraged, unless they are prescribed by the Investigator for treatment of an emergent medical event 


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occurring during the course of the study. No concomitant procedures will be performed during the study 
unless approved by the Investigator. 
All concomitant medications taken from the date that the Informed Consent Form (ICF) is signed, 
through end of study (completion of follow-up period) must be recorded in the subject’s source 
documentation. This information should include the name of the medication or treatment, the dose and 
regimen, the start and stop dates, and the indication for which the concomitant medication was 
administered. 
6.4.1 Prohibited Concomitant Therapy 
As the potential for DDIs between ABI-H2158 and other compounds has not yet been fully evaluated, 
consumption of grapefruit (whole fruit and juice) is prohibited. Medications with narrow therapeutic 
indices should be avoided. In particular, medications metabolized by cytochrome P450 (CYP) 
isoenzymes 3A4, 2C8, and 2C19 should be avoided (see Appendix 4). Proton pump inhibitors, H-2 
receptor blockers, antacids, or herbal medications intended to change stomach pH should not be taken 
with ABI-H2158. In addition, inducers and inhibitors of CYP3A4 should be avoided. 
Provisions regarding concomitant medications described in the ETV product labeling must also be 
followed during the study. 
The designated Medical Monitor may be consulted for any questions regarding acceptable or prohibited 
concomitant medication use during the study. As previously described, concomitant medications, over-
the-counter medications, and supplements must be recorded in the subject’s source documentation. 
6.5 
Drug Accountability 
Regulatory requirements stipulate accounting of all investigational drug 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 study drug was administered. The Investigator is responsible for 
the accountability of all study drug at their site. This includes all used and unused study drug containers 
and unused study drug (ie, ABI-H2158, matching PBO, and ETV). 
The study site is to use a study drug accountability record to document study drug disposition. All items 
on this form are to be fully completed. The Sponsor or the CRO will confirm if the method of recording 
study drug accountability by the site and the location of study drug records at the site is appropriate. 
Each time designated site personnel dispense study drug for a subject, he or she is to record the date 
dispensed, the quantity of study drug 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 study drug. The site monitor 
will review the study drug accountability records during monitoring visits. The site pharmacist or 
designated staff member will keep accurate records of drug dispensation routinely during the study. 
Study drug dispensation is planned for Day 1 and at designated scheduled visits thereafter during the 
treatment period. ETV dispensation is also planned for designated scheduled visits during the follow-up 
period (Section 7; Appendix 1). 


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6.6 
Study Drug Compliance 
To monitor study drug compliance and to facilitate drug accountability at the study site, subjects will be 
required to record each dose of ABI-H2158 or PBO and ETV they take in a dosing diary provided to 
them at the Day 1 visit. Subjects will also be asked to return used bottles and any unused study drug at 
study visits for accountability and compliance assessment. Returned ABI-H2158 or PBO and ETV will 
be counted and reconciled against the diary entries by study site personnel preferably in the presence of 
the subject. Subjects who forget to return study drugs at a given visit will be asked to return them at the 
next study visit. 
6.7 
Return or Disposal of Study Drug 
Procedures for the return of study drug or provisions for onsite destruction (where approved 
prospectively by the Sponsor) are described separately in the Pharmacy Manual. 


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7 STUDY ASSESSMENTS AND PROCEDURES 
The schedule of assessments to be conducted in the study is provided in tabular form in Appendix 1. 
7.1 
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 then randomize the 
subject using the IRT system described in Section 6.1.1. Protocol waivers will not be granted. 
7.1.1 Screen Failures 
Screen failures are defined as subjects who sign consent, are assigned a subject number, and are screened 
but subsequently never randomized to study treatment. Minimal information to be retained on all screen 
failures includes demography, screen failure details, eligibility criteria, and any SAE information. 
Individuals who do not meet the protocol eligibility criteria for participation in this study (screen failure) 
may not be rescreened, however, a single retest for a laboratory parameter(s) is permitted if there is 
considered to be 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). 
Subjects who previously screen failed due to Inclusion Criteria 7 (HBeAg ≥500 IU/mL at Screening) 
under Protocol Amendment 1 may be rescreened for the study. The subject will be assigned a new subject 
number and will be required to be re-consented.  
7.2 
Screening Assessments (Day -45 to Day -1) 
It is recommended, though not mandated, that invasive procedures, such as a liver biopsy (if required) 
are not conducted until it has been determined that the subject is broadly eligible for study participation. 
The following Screening assessments must be completed within 45 days of the scheduled Day 1 visit.  
Subjects who meet all study eligibility requirements but are not able to complete the Day 1 visit within 
the prespecified 45-day window, may be rescreened for the study. 
• Obtain written informed consent 
• Record demographics and medical history, including HBV history 
• Liver staging (as required per inclusion criteria; ie, fasting FibroScan or liver biopsy) 
• Measure height and body weight 
• 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 


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• Review of AEs occurring after provision of informed consent 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety Labs: Chemistry, hematology, coagulation, serum AFP, urinalysis, urine drug test, 
follicle-stimulating hormone (FSH) (all females regardless of fertility status), serum 
pregnancy test 
o Virology/Immunology:  HBV DNA, HBsAg, HBeAg, HBsAb, HBeAb, sample for HBV 
sequencing and HBV nucleic acids, HIV Ab, HCV Ab, HDV Ab, hepatitis A virus (HAV) 
(IgM), HEV (IgM), HBcAb (for subjects without clear documentation of CHB) 
7.3 
Day 1 
The following assessments must be completed at Day 1 prior to dosing: 
• Update medical history, including HBV history 
• Measure body weight 
• Vital signs (temperature, heart rate, respiration rate and blood pressure) 
• Complete physical examination (excluding breast and genitalia, unless indicated) 
• 12-lead ECG 
• Review concomitant medications 
• Confirm subject eligibility 
• Complete randomization (IRT) 
• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety Labs: Chemistry, hematology, coagulation, urinalysis, urine drug test, serum and 
urine pregnancy test 
o Virology/Immunology: HBV genotype, HBV DNA, HBV pgRNA, HBsAg, HBeAg, 
HBcrAg, HBsAb, HBeAb, sample for HBV sequencing and HBV nucleic acids 
o Pharmacogenomic Sample: Optional and only collected in subjects who provide additional 
informed consent 
o PK Samples: Predose samples for ABI-H2158 or PBO and ETV. Postdose samples for ABI-
H2158 and ETV between 2 to and 4 hours following study drug administration. See Section 
7.8.8 for additional information. 


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• Study drug dispensation  
• Study drug administration (ABI-H2158 or PBO and ETV) during clinic visit. Provide dosing 
diary to the subject and record first dose administration 
7.4 
Study Weeks 2 Through 72 
The following assessments are performed at Study Weeks 2, 4, 8, 12, 16, 20, 24 and then every 4 weeks 
thereafter through Week 72 (inclusive) unless otherwise indicated. A visit window of ±3 days is applied 
to each visit through Week 24 and ±5 days from Weeks 28 through 72: 
• Measure body weight (Weeks 24, 48, and 72 only) 
• Vital signs (temperature, heart rate, respiration rate and blood pressure) 
• Complete physical examination (excluding breast and genitalia, unless indicated; Weeks 24, 48 
and 72 only) 
• Symptom-directed physical examination (Not at Weeks 24, 48 or 72) 
• 12-lead ECG (Weeks 12, 24, 36, 48, 60 and 72 only) 
• Review concomitant medications 
• Review AEs 
• Review dosing diary 
• Assess drug accountability (not at Week 2) 
• Study drug dispensation (not at Week 2; through Week 68 only for ABI-H2158 or PBO; and 
through Week 72 for ETV) 
• Study drug administration (ABI-H2158 or PBO and ETV) during clinic visit (Weeks 2, 4, 8, 12, 
24, 28, 48 and 72 only) 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety Labs: Chemistry, hematology, coagulation (not at Week 2), urinalysis (not at week 2), 
and urine pregnancy test (if positive on dipstick, serum pregnancy test should be performed). 
o Virology/Immunology: HBV DNA, HBV pgRNA, HBsAg (not at Week 2), HBeAg (not at 
Week 2), HBcrAg (not at Week 2), HBsAb and HBeAb (Weeks 12, 24, 36, 48, 60, and 72 
only), sample for HBV sequencing and HBV nucleic acids 
o PK Samples: Predose samples for ABI-H2158 or PBO and ETV on Weeks 4, 48, and 72 only.  
Samples for ABI-H2158 or PBO and ETV 30 min to 2 hours postdose on Weeks 2, 8, 12, 24, 
and 28. Samples for ABI-H2158 or PBO and ETV 4 to 6 hours postdose on Weeks 16 and 
20 only). See Section 7.8.8, Table 6 for additional information. 


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7.5 
Follow-up Assessments 
All subjects who complete treatment per protocol or prematurely discontinue treatment will enter a 24-
week follow-up period during which they will have the following assessments performed at 4, 8, 12, and 
24 weeks (±5 days) after the last dose of ABI-H2158 or PBO unless otherwise stated: 
• Measure body weight (24 Weeks post only) 
• Vital signs (temperature, heart rate, respiration rate and blood pressure) 
• Complete physical examination (24 Weeks post only) 
• Symptom-directed physical examination (not at 24 Weeks post) 
• 12-lead ECG (24 Weeks post only) 
• Review concomitant medications 
• Review AEs 
• Assess drug accountability (for ETV) 
• Study drug dispensation (for ETV, 4 Weeks post and 12 Weeks post only) 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety Labs: Chemistry, hematology, coagulation, urinalysis (4 Weeks post, 12 Weeks post, 
and 24 Weeks post only), and urine pregnancy test (if positive on dipstick, serum pregnancy 
test should be performed [4 Weeks post only]).   
o Virology/Immunology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, HBsAb and 
HBeAb (24 Weeks post only) sample for HBV sequencing and HBV nucleic acids 
o PK Sample: Sample for ETV can be collected at the same time with other labs (4 Weeks post 
only)   
7.6 
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: 
• Vital signs (temperature, heart rate, respiration rate and blood pressure) 
• Symptom-directed physical examination 
• Review concomitant medications 


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• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety Labs: Chemistry, hematology, coagulation, urinalysis, urine drug test, and urine 
pregnancy test (if positive on dipstick, serum pregnancy test should be performed). 
o Virology/Immunology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, sample for 
HBV sequencing and HBV nucleic acids 
o PK Samples: Samples for ABI-H2158 or PBO and ETV can be collected at the same time 
with other labs.  See Section 7.8.8 for additional information on PK sampling. 
Assessments performed should be documented in the subject’s source documentation. Clinical 
laboratory assessments should be conducted through the central laboratory. 
7.7 
Premature Termination Visit 
Should a subject prematurely discontinue treatment (Section 7.9.1) or discontinue from the study 
(Section 7.9.2), 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: 
• Vital signs (temperature, heart rate, respiration rate and blood pressure) 
• Complete physical examination (excluding breast and genitalia unless indicated) 
• 12-lead ECG 
• Review concomitant medications 
• Review AEs 
• Review dosing diary and assess drug accountability (if applicable) 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety Labs: Chemistry, hematology, coagulation, urinalysis, urine drug test, and urine 
pregnancy test (if positive on dipstick, serum pregnancy test should be performed). 
o Virology/Immunology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, HBsAb and 
HBeAb, sample for HBV sequencing and HBV nucleic acids  
o PK Samples: Samples can be collected at the same time with other labs. See Section 7.8.8 
for additional information. 


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7.8 
Study Assessments  
This section describes evaluations and procedures to be performed and items to be recorded or available 
on source documents.  Data from some required evaluations may not be required to be recorded on case 
report forms (e.g. laboratory results). For further details, refer to Appendix 1.  
7.8.1 Demographics, Medical and HBV History   
Demographic characteristics including age, race, and ethnicity will be recorded. The Investigator or 
designee will collect a complete medical, surgical, and HBV history at Screening. Any changes to 
medical, surgical, and HBV history since Screening will also be recorded for the duration of the study.  
Height (cm) and body weight (kg) without shoes will be measured and BMI will be calculated using the 
height obtained at Screening. The subject’s BMI will be calculated using metric units and rounded to the 
nearest whole number according to the following formula: BMI = weight (kg)/(height [m])2.  
7.8.2 Liver Staging 
Liver staging is to be performed to determine lack of cirrhosis or advanced liver disease as required by 
inclusion criteria (see Section 5.2).  The methods for noninvasive, simple, and painless procedures are 
(1) Fibroscan (if available) or (2) Magnetic Resonance elastography (MRE). The Medical Monitor may 
be contacted for questions concerning liver staging. 
7.8.3 Physical Examination 
Complete physical examinations will be performed by the Investigator or qualified Sub-Investigator at 
the protocol designated timepoints. 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 protocol designated 
timepoints. Additional symptom-directed of complete physical examinations made 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 Sub-Investigator will examine the appropriate body 
system(s).  
7.8.4 Electrocardiograms 
A standard 12-lead ECG will be obtained as specified in the Schedule of Assessments (Appendix 1).  
Prior to the conduct of the12-lead ECG, subjects should rest in a supine position for 10 mins. ECGs 
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 Sub-Investigator is responsible for reviewing and overreading the ECG 
interpretation, for assessing whether the ECG machine interpretation findings are accurate, appropriate, 


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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 Sub-Investigator 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). 
7.8.5 Vital Signs 
Vital signs will include temperature, heart rate, respiration rate, and blood pressure at timepoints 
specified in the Schedule of Assessments in Appendix 1.  
7.8.6 Clinical Laboratory Tests 
Clinical laboratory tests will be performed at the designated Central laboratories at the timepoints 
indicated in the Schedule of Assessments table in Appendix 1. 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 5. 
Table 5:  
Clinical Laboratory Tests 
Panel 
Tests 
Clinical Chemistry 
Blood glucose levels, serum or plasma electrolytes (sodium, potassium, chloride, bicarbonate), 
calcium, creatine kinase, blood urea nitrogen, creatinine, uric acid, total and direct bilirubin a, 
ALT, AST, GGT, alkaline phosphatase, LDH, amylase, triglycerides, total cholesterol, 
inorganic phosphate or total phosphate, total protein, albumin, lipase, and total serum or 
plasma globulins 
In case of ALT 
Elevation 
ALT, AST, total bilirubin, serum albumin, creatine kinase, and INR 
Hematology 
Complete blood counts: hemoglobin, hematocrit, RBC indices (MCV, MCHC), reticulocyte 
counts, leukocyte counts (total and differential), and platelet counts 


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Panel 
Tests 
Coagulation 
Prothrombin time/INR and aPTT 
Urinalysis 
pH, specific gravity, protein, glucose, ketones, and occult blood 
Other 
AFP, HbA1c, and FSH (ALL Females regardless of fertility status) 
Pregnancy tests 
For females only; a serum pregnancy test must be performed at Screening.   
On Day 1, urine and serum pregnancy test should be performed predose.  Subject may begin 
treatment based on urine results.  Any subject 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.  A positive result disqualifies the subject for study treatment. 
Urine drug Screening 
Amphetamine/methamphetamine, barbiturates, benzodiazepines, cocaine metabolite, ethanol, 
opiates, phencyclidine, and propoxyphene.  
Antibodies 
HCV, HDV, HAV IgM, HEV IgM, and HIV 
AFP: alpha fetoprotein; ALT: alanine aminotransferase; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; 
FSH: follicle-stimulating hormone; GGT: gamma-glutamyl transpeptidase; HAV: hepatitis A virus; HbA1c: hemoglobin A1c; HCV: 
hepatitis C virus; HDV: hepatitis D virus; HEV: hepatitis E virus; HIV: human immunodeficiency virus; IgM: immunoglobulin M; INR: 
International Normalized Ratio; LDH: lactate dehydrogenase; MCHC: mean corpuscular hemoglobin concentration; MCV: mean 
corpuscular volume; RBC: red blood cell; ULN: upper limit of normal. 
a Perform fractionated bilirubin if total bilirubin >ULN. 
7.8.7 HBV Virology 
To provide an assessment of the antiviral efficacy of ABI-H2158 in subjects with CHB, this study will 
evaluate treatment effects on the following parameters: 
• HBV genotyping 
• HBV DNA 
• HBV pgRNA 
• HBsAg 
• HBeAg 
• HBcrAg 
• HBsAb 
• HBeAb 
• HBcAb 
• HBV sequence analysis for assessment of resistance 
To ensure standardization of the virologic methodologies utilized in this study, HBV DNA-related, HBV 
antigen-related and HBV antibody-related virologic assessments will be conducted at a central reference 
laboratory. Subject serum samples for resistance-related sequencing and HBV pgRNA testing will be 
shipped frozen to the Sponsor or a designated third-party laboratory for testing. The HBV virology tests 
will be performed at the timepoints indicated in the Schedule of Assessments table in Appendix 1. HBV 
pgRNA results could unblind individual subject’s treatment assignments and therefore will not be 


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reported to investigative sites or other blinded personnel until completion of the study, the database has 
been locked and the study has been unblinded. 
Additional details concerning the collection and processing of HBV virology samples are described in 
the Laboratory Manual. 
7.8.8 Pharmacokinetic Assessments 
During the study, predose plasma samples will be collected from all subjects to explore the PK profile 
of ABI-H2158 and ETV following combination treatment in subjects with CHB. Additionally, postdose 
samples will be collected. The timing of PK sample collection is outlined in Table 6. Additional details 
regarding the collection, processing, storage, and shipment of PK samples are described in the 
Laboratory Manual. 
Table 6:  
Pharmacokinetic Sample Collection 
Time Period 
Time Relative to Study Drug 
Administration a, 
Study Visit 
Treatment 
Predose 
Day 1, Weeks 4, 48, and 72 
30 min to 2 hours postdose 
Weeks 2, 8, 12, 24, and 28 
2 to 4 hours postdose 
Day 1 
4 to 6 hours postdose 
Weeks 16 and 20 
Follow-up 
Collect at same time with other central 
labs 
At Unscheduled and Premature 
Termination Visits and the Week 4 Post 
Treatment Follow-up visit 
a  
Sample collection times are targeted times. Samples collected outside of these targeted times will not be considered protocol 
deviations. The actual sample collection date/time should be accurately recorded on source documentation. If the subject 
administers study drug at home, a pharmacokinetic sample should be collected during the visit with documentation of date and time 
of the dose in the subject’s source documents. 
7.9 
Discontinuation 
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 7.7). If the subject withdraws consent for 
disclosure of future information, the Sponsor may retain and continue to use any data collected before 
such a withdrawal of consent. If a subject withdraws from the study, he/she may request destruction of 
any samples taken and not tested, and the Investigator must document this in the site study records. 
7.9.1 Discontinuation From Treatment 
If an individual subject is not satisfactorily tolerating study drug treatment due to AEs in the judgment 
of the Investigator, then – in consultation with the Sponsor - the subject may discontinue treatment with 
ABI-H2158 or PBO. ETV may be continued at the discretion of the Investigator. A subject also has the 


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right to discontinue treatment with AHI-H2158 or PBO due to his/her wish. Discontinuation from 
treatment does not mean discontinuation from the study. Subjects who prematurely discontinue treatment 
should immediately undergo the assessments listed for the Premature Termination visit (Section 7.7) and 
then continue scheduled follow-up assessments. 
If a subject is determined to have developed substitutions in HBV Cp gene sequences associated with 
viral resistance or blunted treatment response (Section 7.11), then they will discontinue treatment with 
ABI-H2158 or PBO. ETV may be continued at the discretion of the Investigator. Subjects who 
prematurely discontinue treatment should immediately undergo the assessments listed for the Premature 
Termination visit (Section 7.7) and then continue scheduled follow-up assessments. 
In this study, subjects will be closely monitored for any evidence of worsening hepatic function. 
Procedures to be followed for these subjects are described in Section 9.4. Study treatment will be 
discontinued in subjects with confirmed evidence of declining hepatic function during treatment, a 
Premature Termination visit (Section 7.7) will be completed and subjects will subsequently undergo the 
follow-up assessments described in Section 7.5. 
Any subjects negative by urine pregnancy test at Baseline (Day 1) who are subsequently found to be 
positive on serum pregnancy test should immediately discontinue treatment with ABI-H2158 or PBO. 
ETV may be continued if indicated based on Investigator judgment in accordance with local practice 
and the approved ETV package insert. These subjects may be replaced at the discretion of the Sponsor. 
7.9.2 Discontinuation From Study 
Discontinuation from study (ie, withdrawal of consent) means that the subject does not wish to receive 
further protocol-required treatments or undergo protocol-required procedures, and the subject does not 
wish to, or is unable to continue further study participation. Subjects who discontinue from the study 
during follow-up should undergo the assessments listed for the Premature Termination visit (Section 7.7). 
Subject data up to withdrawal of consent will be included in the analysis of the study, and where 
permitted, publicly available data can be included after withdrawal of consent. 
7.9.3 Subjects 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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7.10 End of Study Definition 
The study will be completed when the last subject completes the 24 Weeks Post Follow-up period, or is 
considered “lost to follow-up,” (Section 7.9.3) whichever is later. 
7.11 Resistance Monitoring 
To assess potential HBV Cp gene sequences associated with viral resistance or blunted treatment 
response, serum samples from subjects at each visit will be collected (Section 7). Samples from those 
subjects with evidence of nonresponse to treatment, such as viral breakthrough (ie, ≥1 log10 increase in 
on-treatment HBV DNA from on-treatment nadir) or if there is no apparent and consistent decline in 
HBV nucleic acids throughout the study, will be selected for HBV Cp gene sequencing, with sequence 
comparisons to baseline sequences, as well as comparisons to Cp gene sequences from subjects who 
received PBO and HBV database sequences. 
7.12 Use of Subject Samples for Exploratory Objectives Research 
With the subject’s approval and as approved by local IRBs/IECs and Country Regulatory Agencies, 
biological samples collected to assess the relationship between new and known viral biomarkers and 
virologic and/ or clinical outcomes, will be stored by the Sponsor or their designee. Apart from the 
analysis described in exploratory objectives (Sections 3.1.3 and 3.2.3), these samples could be used to 
research CHB, its complications, and other conditions for which individuals with CHB are at increased 
risk, and to improve treatment. The Sponsor will also have a code-link that will allow linking the 
biological specimens with the phenotypic data from each subject, maintaining the blinding of the identity 
of the subject. 
 
 


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8 ADVERSE EVENTS 
An AE is any untoward medical occurrence in a study subject administered an investigational product(s) 
regardless of the causal relationship with treatment. 
An AE, therefore, can be any unfavorable and unintended sign (including laboratory finding), symptom, 
or disease temporally associated with participation in an investigational study, whether or not considered 
drug-related. In addition to new events, any increase in the severity or frequency of a pre-existing 
condition that occurs after the subject signs the ICF for participation is considered an adverse event. This 
includes any side effect, injury, toxicity, or sensitivity reaction. 
8.1 
Documenting Adverse Events 
Adverse events will be monitored throughout the entire study. 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 electronic case report forms (eCRFs) provided: a description of the event, severity, time of 
occurrence, duration, any action (eg, treatment and follow-up tests), and the outcome should be provided 
along with the Investigator’s assessment of the relationship to the study treatment. 
Adverse events will be recorded from the time written informed consent is signed through end of study 
(completion of follow-up period). 
8.2 
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 2), which grades the severity of clinical AEs and laboratory abnormalities in a 4-category 
system. 
For AEs not included in Appendix 2, the following guidelines will be used to describe severity: 
• Mild (Grade 1): Mild symptoms causing no or minimal interference with usual social & 
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 
Note that an AE or laboratory abnormality that is life-threatening as it exists constitutes an SAE. 


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8.3 
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. 
8.4 
Expectedness 
An AE is considered “unexpected” if it is not listed in the IB or is not listed at the specificity or severity 
that has been observed. The CRO and Sponsor Medical Monitors will be responsible for determining 
whether an AE is expected or unexpected. 
8.5 
Abnormal Laboratory Test Values 
In the event of abnormal laboratory test values, the tests should be repeated immediately. If the 
Investigator considers the abnormality to be clinically significant, it should be reported as an AE and 
followed up until it returns to the normal range and/or an adequate explanation of the abnormality is 
found. 
8.6 
Adverse Event Follow-up 
After the initial AE or SAE report, the Investigator will follow-up proactively on each subject and 
provide further information to the CRO/Sponsor on the subject’s condition. During the study, all AEs or 
SAEs 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. 
8.7 
Pregnancy 
8.7.1 Female subjects who become pregnant 
Any female subject who becomes pregnant while participating in the study including the 24-week 
follow-up period will discontinue the study drug(s) immediately.  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 for 6 to 8 weeks after birth. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 


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The Investigator must inform the Sponsor of the pregnancy.  The initial information will be recorded on 
the Pregnancy Reporting form and submitted to the CRO Pharmacovigilance group within 24 hours of 
learning of a subject’s pregnancy.  
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 post-study pregnancy related SAE considered reasonably related to the study drug(s) by the 
Investigator will be reported to the Sponsor. While the Investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through spontaneous reporting. 
8.7.2 Male subjects with partners who become pregnant 
If a female partner of a male subject participating in this study becomes pregnant, the Investigator will 
ask the pregnant female partner to consent to be followed through to the end of her pregnancy and the 
neonate for 6 to 8 weeks after birth. This applies only to male subjects who receive the study drug. 
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 
CRO Pharmacovigilance group within 24 hours of learning of the partner’s pregnancy. The female 
partner will 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 after birth. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for the procedure. 


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9 SERIOUS ADVERSE EVENTS 
9.1 
Definition of Serious Adverse Event 
An SAE is any event that meets any of the following criteria: 
• Death 
• Life-threatening 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject who received ABI-H2158 
• 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 one 
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 
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 pre-existing 
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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9.2 
Reporting Serious Adverse Events 
All SAEs must be reported within 24 hours of learning about the event using the SAE Report form to 
the CRO Pharmacovigilance group. 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. This additional information will be requested, if necessary, by the 
responsible monitor within 5 days of receipt of the alert report. This is to ensure that the initial reporting 
of SAEs is made to the Health Authorities within the required time period. 
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. 
9.3 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. 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. 
9.4 
Management of 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 2). 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 1-2 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 
(Section 7.6).  
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 


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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 IgM, HCV RNA, HDV RNA, and HEV IgM. The 
Investigator will determine if other Unscheduled Visit assessments should be performed.  
▪ If an intercurrent cause 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 to qualitative HBeAg if 
quantitative HBeAg is negative] and HBsAg [reflex to qualitative HBsAg if 
quantitative HBsAg is negative]). The Investigator will determine if other 
Unscheduled Visit assessments should be performed. Subjects whose ALT has 
stabilized should continue to be monitored weekly (or more frequently, as deemed 
necessary by the treating physician) until ALT values return to normal or Baseline 
levels. 
• ALT Elevation with Declining Hepatic Function  
o Subjects with confirmed ALT elevation with evidence of declining hepatic function should 
be discontinued 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 OR INR >2 × Baseline (Day 1) 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 (Day 1).  
All subjects with ALT elevation with or without 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 post-treatment 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. The Unscheduled Visit module in the case report form should be utilized 
as needed to gather additional clinical and laboratory data until the ALT elevation is documented to be 


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either resolved or resolving (defined as consistent ALT declines of 10% or more or normalization of 
ALT) on at least 2 successive visits. 
If 2 or more subjects meet these ALT elevation management criteria, the US FDA and other relevant 
regulatory agencies will be notified, and subsequent steps will be determined after consultation with 
these agencies. 
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.  
 
 


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Figure 2: 
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
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 
10.1 General Considerations 
Information regarding the safety, antiviral activity and PK analyses is provided below. A SAP containing 
the detailed planned statistical methods will be finalized prior to locking of the study database for the 
analyses, and it will form the basis for the programming of the displays and analyses of the final study 
data. The plan will define populations to be used for each analysis endpoint, outline all data handling 
conventions including missing data methods, and specify statistical methodology to be used for analysis 
of safety and antiviral activity. 
Sample size permitting, subgroup analyses will be conducted to assess virologic endpoints in subjects 
infected with different HBV genotypes and for subject subgroups with different baseline characteristics 
which could potentially influence the antiviral activity, safety, or PK observations in this study, eg, 
pre-treatment ALT level, HBsAg level, HBeAg level, ethnicity, gender, etc. These and other subgroup 
analyses will be further defined in the SAP. 
10.2 Sample Size Determination 
Forty treatment-naïve subjects with HBeAg positive CHB will be enrolled in Cohort 1 and 40 treatment-
naïve subjects with HBeAg negative CHB will be enrolled in Cohort 2. Subjects will be randomized to 
receive either placebo or 300 mg ABI-H2158 in a 1:3 ratio. That is, in Cohort 1 and in Cohort 2, 
10 subjects will be randomized to treatment with placebo, and 30 subjects will be randomized to 
treatment with ABI-H2158. This sample size is not based on statistical considerations but is adequate 
for a proof-of-concept study. 
10.3 Analysis Populations 
The following populations will be considered for analysis of various endpoints: 
• Randomized Analysis Set: It includes all randomized subjects, classified according to the 
treatment group into which they were randomized regardless of the actual treatment received. 
• 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. 


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10.4 Planned Analysis and Reports 
10.4.1 Analysis of Primary Endpoint(s) 
The primary endpoint is the change in mean log10 HBV DNA from Baseline to Week 24 for 
ABI-H2158+ETV compared to PBO+ETV. The primary comparison will be made using an analysis of 
covariance (ANCOVA) model, including baseline value, the stratification factors and treatment group.  
The estimated least square means of treatment effects and estimated difference in treatment effects 
between treatment groups will be presented along with the 95% confidence intervals and p-values. 
10.4.2 Analysis of Secondary and Exploratory Endpoints 
Secondary and exploratory endpoints will be analyzed descriptively. All secondary and exploratory 
endpoints will be summarized (Section 3.2.2 and Section 3.2.3). 
For continuous variables, such as observed and change from Baseline HBV DNA values at each 
timepoint, descriptive statistics will be used, and will include the number, mean, standard deviation, 
median, minimum, maximum, and, where appropriate, a 95% confidence interval. Missing data methods 
and imputation rules will be defined in the SAP. Additional sensitivity analysis may also be performed 
and will be described in the study SAP. 
For categorical variables, such as subjects with a reduction in HBV DNA below LLOQ, descriptive 
statistics will include number and percent who meet the endpoint criterion. 
10.4.3 Analysis of Pharmacokinetic Endpoints 
The following will be analyzed descriptively after all subjects in each cohort have completed their Week 
4 study visit (interim) and end of study (final): 
Trough levels and trough to peak ratios of ABI-H2158 on ABI-H2158+ETV therapy 
Trough levels and trough to peak ratios of ETV on ABI-H2158+ETV therapy as compared with 
PBO+ETV therapy 
After all subjects have completed Week 4 (or discontinued before completing Week 4), PK data will be 
reviewed by an unblinded pharmacology reviewer to ensure ETV steady state PK levels are not being 
affected by combination treatment with ABI-H2158. Similarly, the potential impact of ETV on the steady 
state PK levels of ABI-H2158 will be assessed. All PK timepoints will be included in the final analysis. 
10.4.4 Analysis of Safety Endpoints 
The safety parameters to be assessed are described in Section 7.8 Displays for safety results will utilize 
descriptive statistics. No formal hypothesis testing of safety data is planned.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Incidence of each body system and preferred term will be tabulated for each treatment group. Treatment-
emergent adverse events (TEAE) are defined as those reported on or after the first dose of study 
drug through 28 days from the last dose of study drug. Summaries will include all TEAEs, TEAEs 


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considered related to study treatment by investigators, Graded TEAEs, and SAEs. All AEs, emergent or 
non-emergent, will be listed by subject. Any TEAEs leading to premature discontinuation from the study 
intervention and serious TEAEs will be presented by listing. 
Clinical laboratory results will be summarized descriptively by treatment group including values, 
changes from Baseline, and incidence of laboratory abnormalities. Laboratory results will be listed for 
each subject. 
Vital sign data and ECG findings reported at each visit will be displayed by treatment, using descriptive 
statistics for observed and change from Baseline values. 
10.5 Interim Analysis 
This study will be conducted in a single-blind manner. A DRC as described in Section 10.6 will be 
assembled with an unblinded Sponsor team to perform regular review of safety and antiviral activity 
data. The DRC will also review the interim PK analysis described in Section 10.4.3. Details concerning 
these analyses will be documented in the SAP and the DRC charter. 
10.6 Data Review Committee (DRC) 
To assess the safety and/or efficacy of ABI-H2158 for planning and development of this compound, an 
Assembly internal unblinded team independent of the blinded study team will be assembled as a DRC. 
This committee will consist of at least one representative from Clinical Research, Biostatistics, and may 
include other personnel as necessary. The Medical Monitor and clinical research staff directly interacting 
with the study center will not be unblinded to the subject treatment assignment. The Assembly internal 
unblinded team will be granted access to unblinded clinical data at the individual subject or group 
summary level including treatment assignments to closely monitor study progress and drug safety.  
The membership, conduct, and meeting schedule of the DRC Charter as specified in Assembly SOPs. 
 


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11 RESPONSIBILITIES 
11.1 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; 
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 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 and by the person who conducted the informed consent discussion. In the case where the 
subject is unable to read, an impartial witness must be present during the entire informed consent 
discussion.  After the subject has orally consented to participation in the trial, the witness’ signature on 
the form will attest that the information in the consent form was accurately explained and understood. 
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 identification codes and not by their name (e.g. subject 
number). The Investigator should keep a subject enrollment log showing codes, names, and addresses.  
The Investigator must maintain documents not for submission to the Sponsor or designees (eg, subject’s 
written consent forms) in strict confidence.  
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 
The Investigator must maintain adequate and accurate records 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 


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cooperate fully with regulatory authorities or other audits conducted at a convenient time in a reasonable 
manner. 
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. 
11.2 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 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 documents will specify data capture methods, who is 
authorized to enter the data, decisions about ownership of data, source data storage, which data will be 
transferred (including timing of transfers), and the origin/destination of the data. 
11.2.3 Study Report and Publications 
The Sponsor or its designee is responsible for preparing and providing the appropriate regulatory 
authorities with Clinical Study Reports (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 submission. 


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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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12 REFERENCES 
Agarwal K, Brunetto M, Seto WK, et al (2018) 96weeks treatment of tenofovir alafenamide vs. tenofovir 
disoproxil fumarate for hepatitis B virus infection. J Hepatol 68(4):672-681. 
Battisti WP, Wager E, Baltzer L, et al (2015) Good Publication Practice for Communicating Company-
Sponsored Medical Research: GPP3. Ann Intern Med 163(6):461-464. 
Belloni L, Li L, Palumbo G, et al (2013) HAPs hepatitis B virus (HBV) capsid inhibitors block core protein 
interaction with the viral minichromosome and host cell genes adn affect cccDNA transcription and stability: 
138. Hepatology 58:277A. 
Burdette D, Cathcart A, Shauf A, et al (2019) PS-150-Evidence for the presence of infectious virus in the serum 
from chronic hepatitis B patients suppressed on nucleos (t)ide therapy with detectable but not quantifiable HBV 
DNA. Journal of Hepatology 70(1):e95. 
Colvin H, Mitchell AE (2010). Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of 
Hepatitis B and C. Washington, D.C., The National Academies Press. 
Cornberg M, Lok AS, Terrault NA, et al (2019) Guidance for design and endpoints of clinical trials in chronic 
hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference. Hepatology. 
EASL (2012) Clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 
57(1):167-185. 
EASL (2017) Clinical Practice Guidelines on the management of hepatitis B virus infection. Journal of 
Hepatology 67(2):370-398. 
El-Serag HB (2012) Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 
142(6):1264-1273 e1261. 
Gish RG, Given BD, Lai CL, et al (2015) Chronic hepatitis B: Virology, natural history, current management 
and a glimpse at future opportunities. Antiviral Res 121:47-58. 
Hoofnagle JH, Doo E, Liang TJ, et al (2007) Management of hepatitis B: summary of a clinical research 
workshop. Hepatology 45(4):1056-1075. 
ICMJE (2019) Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals.  International committee of medical journal editors.  from http://www.icmje.org/icmje-
recommendations.pdf. 
Lampertico P and Liaw YF (2012) New perspectives in the therapy of chronic hepatitis B. Gut 61 Suppl 1:i18-
24. 
Levey AS, Stevens LA, Schmid CH, et al (2009) A new equation to estimate glomerular filtration rate. Ann 
Intern Med 150(9):604-612. 
Levrero M, Pollicino T, Petersen J, et al (2009) Control of cccDNA function in hepatitis B virus infection. J 
Hepatol 51(3):581-592. 
Lok AS and McMahon BJ (2009) Chronic hepatitis B: update 2009. Hepatology 50(3):661-662. 


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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. 
Sulkowski M, Agarwal K, Fung SK, et al (2019) Continued therapy with ABI-H0731+NrtI results in sequential 
reduction/loss of HBV DNA, HBV RNA, HBeAg, HBcrAg and HBsAg in HBeAg positive patients The liver 
Meeting 2019, Boston, MA, AASLD from https://www.aasld.org/sites/default/files/2019-10/2019-TLM-
LateBreakingAbstracts-v2.pdf 
WHO (2015) Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection.   
Retrieved 14 Dec 2020 from https://www.who.int/hepatitis/publications/hepatitis-b-guidelines/en/. 
WHO (2019) Hepatitis B Fact Sheet.   Retrieved October 10, 2019 from 
http://www.who.int/mediacentre/factsheets/fs204/en/. 
Yang L, Liu F, Tong X, et al (2019) Treatment of Chronic Hepatitis B Virus Infection Using Small Molecule 
Modulators of Nucleocapsid Assembly: Recent Advances and Perspectives. ACS Infect Dis 5(5):713-724. 
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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13 APPENDICES 








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b 
Liver staging is to be performed to determine lack of cirrhosis or advanced liver disease as required by inclusion criteria. 
c 
Examination of the breasts and genitalia are not required unless indicated. 
d 
During the study, any clinically significant ECG result should be confirmed, and if confirmed, should be recorded as an AE. 
e 
Study drug dispensation from Week 72 onwards and drug accountability from 4 weeks post treatment onwards only applies to ETV therapy; ETV will be continued throughout the 24-week follow-
up period. 
 
f  
If quantitative HBsAg or HBeAg are negative at any visit subsequent to Screening, reflex to qualitative. 
g 
HBcAb is performed if the subject has no clear documentation of CHB per Inclusion Criteria #4.  
h 
A serum pregnancy test is required at Screening. On Day 1, urine and serum pregnancy test should be performed predose.  Subjects may begin treatment based on urine results; any subjects 
negative by urine subsequently found to be positive on serum should immediately discontinue treatment and may be replaced. All post-Day 1 pregnancy tests may be conducted by urine dipstick. If 
positive on dipstick, reflex to serum. 
i  
If the subject inadvertently administers study drug prior to collection, a PK sample should still be drawn. Refer to Section 7.8.8. 
j  
Subjects who discontinue treatment before Week 72 should immediately undergo the assessments listed for the Premature Termination visit and then continue the scheduled follow-up assessments. 
k  
Any subjects with ALT elevation (defined as ALT ≥2 × Baseline and ≥10 × ULN) should return to the clinic for an Unscheduled Visit (see Section 9.4): 
 
 


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15 APPENDIX 2: TOXICITY GRADING SCALE FOR ADVERSE EVENTS AND LABORATORY ABNORMALITIES 
Adapted from the US National Institutes of Health (Division of AIDS) Table for Grading Severity of Adult Adverse Experiences (Corrected Version 2.1 
July 2017).  
MAJOR CLINICAL CONDITIONS 
Cardiovascular 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life- 
Threatening 
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) 
 
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 
subject not previously diagnosed with 
hypertension (eg, 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 (eg, hypoxemia) 
OR Intervention indicated (eg, 
oxygen) 
Life-threatening consequences OR 
Urgent intervention indicated (eg, 
vasoactive medications, ventricular 
assist 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 indicated 


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Cardiovascular 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life- 
Threatening 
Prolonged PR Interval or AV Block  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 Interval1 
0.45 to 0.47 seconds 
> 0.47 to 0.50 seconds 
> 0.50 seconds OR 
 0.06 seconds above baseline 
Life-threatening consequences (eg, 
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 (eg, 
pulmonary embolism, thrombus) 
1 As per Bazett’s formula. 












































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16 APPENDIX 3: PREGNANCY PRECAUTIONS AND THE DEFINITION OF 
CHILDBEARING POTENTIAL AND CONTRACEPTIVE REQUIREMENTS 
Pregnancy Precautions 
Embryofetal development studies with ABI-H2158 have not been conducted in animals, and so 
the effects of ABI-H2158 on pregnancy are unknown. Contraceptive requirements for female 
subjects of childbearing potential are required as described below. 
Definition of Female Subjects of Childbearing Potential  
A female subject is considered of childbearing potential following menarche and until becoming 
postmenopausal unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study drug, additional evaluation should be considered. 
Female subjects in the following categories are not considered of childbearing potential:  
• Premenarchal 
• Premenopausal with one of the following: 
o Documented hysterectomy  
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
• Postmenopausal: A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
o A high FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with more than 1 FSH 
measurement is required. 
o Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
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. 


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Documentation to determine childbearing potential can come from the site personnel’s review of the 
subject’s medical records, medical examination, or medical history interview. 
Contraceptive Requirements 
The DDI study with ABI-H2158 and OC that contains levonorgestrel and ethinyl estradiol concluded 
that oral contraceptives may be used as one of the dual effective birth control methods. Female subjects 
of childbearing potential (defined above) must agree to use dual effective birth control methods for the 
duration of the study and follow-up. Effective birth control methods include male or female condom 
(may not be used together due to increased risk of breakage), vasectomy, tubal sterilization, intrauterine 
device (IUD), diaphragm, oral contraceptives or cervical cap. Female subjects must have a negative 
serum pregnancy test at Screening and a negative urine pregnancy test prior to receiving the first dose 
of study drug at Day 1. 
All male subjects must agree to use dual effective birth control methods with their female partners if 
they are of childbearing potential for the duration of the study and follow-up. In this case, effective birth 
control methods include systemic (oral/injectable) hormonal birth control, male or female condom (may 
not be used together due to increased risk of breakage), vasectomy, tubal sterilization, IUD, diaphragm, 
or cervical cap. 


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17 APPENDIX 4: CYTOCHROME P450 3A4 INHIBITORS AND CYP3A4, 2C8, 
AND 2C19 SUBSTRATES, PROTON PUMP INHIBITORS, H-2 RECEPTOR 
BLOCKERS, AND ANTACIDS 
The following drugs are known inhibitors of CYP3A4 and stomach pH modifying agents and should 
be avoided when taking ABI-H2158: 
CYP3A4 Inhibitors 
HIV antivirals 
indinavir; nelfinavir; ritonavir, saquinavir 
Other 
clarithromycin; itraconazole; ketoconazole; nefazodone; saquinavir; idelalisib, 
ribociclib, telithromycin; aprepitant; erythromycin; fluconazole; grapefruit (whole fruit 
and juice); netupitant/palonosetrone, verapamil; diltiazem; voriconazole cimetidine; 
amiodarone; NOT azithromycin; chloramphenicol; boceprevir; ciprofloxacin; 
delaviridine; diethyl-dithiocarbamate; fluvoxamine; gestodene; imatinib; mibefradil; 
mifepristone; norfloxacin; norfluoxetine; starfruit; telaprevir; voriconazole 
Stomach pH Modifying Agents 
Proton pump inhibitors 
esomeprazole; lansoprazole; omeprazole; pantoprazole 
H-2 receptor blockers 
cimetidine, famotidine, nizatidine, ranitidine 
Other 
Aluminum hydroxide, magnesium carbonate, magnesium hydroxide, sodium 
bicarbonate, calcium carbonate 
The following drugs are known substrates of CYP3A4, 2C19, and 2C8 and should be avoided when taking ABI-
H2158: 
CYP3A4 Substrates 
Macrolide antibiotics 
clarithromycin; erythromycin; NOT azithromycin; telithromycin 
Anti-arrhythmics 
quinidine→3-OH 
Benzodiazepines 
alprazolam; diazepam→3OH; midazolam; triazolam 
Immune modulators 
cyclosporine; tacrolimus (FK506) 
HIV antivirals 
indinavir; nelfinavir; ritonavir; saquinavir 
Prokinetic 
cisapride 
Antihistamines 
astemizole; chlorpheniramine; terfenadine 
Calcium channel blockers 
amlodipine; diltiazem; felodipine; lercanidipine; nifedipine; nisoldipine; nitrendipine; 
verapamil 
HMG CoA reductase 
inhibitors 
atorvastatin; cerivastatin; lovastatin; NOT pravastatin; NOT rosuvastatin; simvastatin 
Steroid 6beta-OH 
estradiol; hydrocortisone; progesterone; testosterone 
Miscellaneous 
alfentanil; aprepitant; aripiprazole; boceprevir; buspirone; carbamazepine; cafergot; 
caffeine→TMU; cilostazol; cocaine; codeine-N-demethylation; dapsone; 
dexamethasone; dextromethorphan; docetaxel; domperidone; eplerenone; fentanyl; 
finasteride; gleevec; haloperidol; irinotecan; LAAM; lidocaine; methadone; 
nateglinide; nevirapine; ondansetron; pimozide; propranolol; quetiapine; quinine; 
risperidone; romidepsin; salmeterol; sildenafil; sirolimus; sorafenib; sunitinib; 
tamoxifen; taxol; telaprevir; terfenadine; torisel; trazodone; vemurafenib; vincristine; 
zaleplon; ziprasidone; zolpidem 


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CYP2C19 Substrates 
Proton pump inhibitors 
esomeprazole; lansoprazole; omeprazole; pantoprazole 
Anti-epileptics 
diazepam→Nor; phenytoin(O); S-mephenytoin; phenobarbitone; amitriptyline; 
carisoprodol; citalopram; chloramphenicol; clomipramine; clopidogrel; 
cyclophosphamide; hexobarbital; imipramine N-DeME; indomethacin; labetalol; 
R-mephobarbital; moclobemide; nelfinavir; nilutamide; primidone; progesterone; 
proguanil; propranolol; teniposide; R-warfarin→8-OH; voriconazole 
CYP2C8 Substrates 
 
Amodiaquine, cerivastatin, paclitaxel, repaglinide, selexipag, sorafenib, torsemide 
 
The following drugs are known inducers of CYP3A4 and should be avoided when taking ABI-H2158: 
CYP3A4 Inducers 
 
Barbiturates, brigatinib, carbamazepine, efavirenz, enzalutamide, glucocorticoids, 
modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, 
rifampin, st. john’s wort, troglitazone 
Source: The Flockhart Table. http://medicine.iupui.edu/clinpharm/ddis/main-table# (Accessed 16 Dec 2019). 
 
 


ABI-H2158-201 
Statistical Analysis Plan 
Version 1.0 
Assembly Biosciences 
Proprietary and Confidential 
Page 1 of 34 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Sponsor:  
Assembly Biosciences, Inc  
331 Oyster Point Blvd 
South San Francisco, CA 94030  
 
 
Protocol Number: 
ABI-H2158-201  
 
 
Protocol Title: 
A Phase 2a, Multicenter, Single-Blind, Placebo-
Controlled, Multiple Cohort Study Evaluating ABI-
H2158-Containing Regimens in Chronic Hepatitis B 
Infection 
 
Product: 
ABI-H2158 
 
 
Protocol Version (Date): 
Amendment 2 (14 December 2020) 
Amendment 2/ GBR-2 (17 December 2020) 
Amendment 2/KOR-1 (05 February 2021) 
 
Indication: 
Chronic Hepatitis B Virus Infection  
Analysis Type: 
Final Analysis For Synoptic CSR 
 
Analysis Plan Version (Date): 
Version 1.0 (25 January 2022) 
 
Analysis Plan Author: 
 
 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


ABI-H2158-201 
Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN APPROVAL FORM 
Protocol Title: 
A Phase 2a, Multicenter, Single-Blind, Placebo-Controlled, 
Multiple Cohort Study Evaluating ABI-H2158-Containing 
Regimens in Chronic Hepatitis B Infection 
Protocol Number: 
ABI-H2158-201 
SAP Version (Date): 
Version 1.0 (25 January 2022) 
The SAP was subject to critical review and has been approved by the participating members. 
Name and Title 
Approval Signature/Date 
 
Vice President, Biometrics 
Assembly Biosciences 
 
 
See e-signature page 
 
 
Vice President, Clinical 
Development 
Assembly Biosciences 
 
 
See e-signature page 
 
 
Chief Medical Officer 
Assembly Biosciences 
 
 
See e-signature page 
 
 
 


 
 
ABI-H2158-201  
Statistical Analysis Plan 
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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 
1.3. 
Sample Size and Power .......................................................................................................................... 10 
1.4. 
Methods of Assigning Subjects to Treatment ........................................................................................ 10 
1.4.1. 
Randomization ..................................................................................................................... 10 
1.4.2. 
Blinding ................................................................................................................................ 11 
2. 
TYPE OF PLANNED ANALYSIS .................................................................................................................... 12 
2.1. 
DRC Interim Analyses ........................................................................................................................... 12 
2.2. 
Final Analysis ........................................................................................................................................ 12 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................ 13 
3.1. 
Analysis Sets .......................................................................................................................................... 13 
3.1.1. 
All Randomized Analysis Set ............................................................................................... 13 
3.1.2. 
Full Analysis Set .................................................................................................................. 13 
3.1.3. 
Safety Analysis Set ............................................................................................................... 13 
3.2. 
Subject Grouping ................................................................................................................................... 13 
3.3. 
Strata and Covariates .............................................................................................................................. 14 
3.4. 
Data Handling Conventions and Transformations ................................................................................. 14 
3.5. 
Missing Data and Outliers ...................................................................................................................... 15 
3.5.1. 
Missing Data ........................................................................................................................ 15 
3.5.2. 
Outliers ................................................................................................................................. 15 
3.6. 
Analysis Visit Windows ......................................................................................................................... 15 
3.6.1. 
Definition of Study Day ....................................................................................................... 15 
3.6.2. 
Analysis Visit Windows ....................................................................................................... 16 
3.6.3. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window ................................................................................................................................ 18 
4. 
SUBJECT DISPOSITION .................................................................................................................................. 19 
4.1. 
Subject Enrollment and Disposition ....................................................................................................... 19 
4.2. 
Extent of Study Drug Exposure ............................................................................................................. 20 
4.2.1. 
Duration of Exposure to Study Drug .................................................................................... 20 
4.2.2. 
Study Drug Compliance ....................................................................................................... 20 
4.2.2.1. 
On-Treatment Compliance ............................................................................. 20 
4.3. 
Protocol Deviations ................................................................................................................................ 21 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 22 
5.1. 
Demographics and Baseline Characteristics .......................................................................................... 22 
5.2. 
Baseline Disease Characteristics ............................................................................................................ 22 
5.3. 
Medical History ...................................................................................................................................... 23 
6. 
EFFICACY ANALYSES ................................................................................................................................... 24 
6.1. 
Primary Efficacy Endpoint ..................................................................................................................... 24 
6.1.1. 
Definition of the Primary Efficacy Endpoint ....................................................................... 24 
6.1.2. 
Primary Analysis of the Primary Efficacy Endpoint ............................................................ 24 
6.2. 
Changes From Protocol-Specified Efficacy Analyses............................................................................ 24 


 
 
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7. 
SAFETY ANALYSES ........................................................................................................................................ 25 
7.1. 
Adverse Events and Deaths .................................................................................................................... 25 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 25 
7.1.2. 
Adverse Event Severity ........................................................................................................ 25 
7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 25 
7.1.4. 
Serious Adverse Events ........................................................................................................ 25 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 25 
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events ....................................... 25 
7.1.5.2. 
Incomplete Dates ............................................................................................ 25 
7.1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 26 
7.2. 
Laboratory Evaluations .......................................................................................................................... 27 
7.2.1. 
Graded Laboratory Values ................................................................................................... 27 
7.2.1.1. 
Treatment-Emergent Laboratory Abnormalities ............................................. 27 
7.2.1.2. 
Summaries of Laboratory Abnormalities ........................................................ 27 
7.2.2. 
ALT Elevation ...................................................................................................................... 28 
7.2.2.1. 
ALT Elevation without Declining Hepatic Function ...................................... 28 
7.2.2.2. 
ALT Elevation with Declining Hepatic Function ........................................... 28 
7.3. 
Vital Signs .............................................................................................................................................. 28 
7.4. 
Prior and Concomitant Medications ....................................................................................................... 29 
7.4.1. 
Prior Medications ................................................................................................................. 29 
7.4.2. 
Concomitant Medications ..................................................................................................... 30 
7.5. 
Electrocardiogram Results ..................................................................................................................... 30 
8. 
REFERENCES ................................................................................................................................................... 32 
9. 
SOFTWARE ....................................................................................................................................................... 33 
10. SAP REVISION .................................................................................................................................................. 34 
 
 
 
 


 
 
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LIST OF IN-TEXT TABLES 
 
Table 3-1. 
On-Treatment Analysis Visit Windows for Study Assessments ............................................ 16 
Table 3-2. 
On-Treatment Analysis Visit Windows for ECG ................................................................... 17 
Table 3-3. 
Off-Treatment Analysis Visit Windows for Study Assessments ............................................ 17 
Table 3-4. 
Off-Treatment Analysis Visit Windows for ECG .................................................................. 17 
 
 
LIST OF IN-TEXT FIGURES 
 
Figure 1-1.  
Study Overview ...................................................................................................................... 10 
 


 
 
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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  
DILI 
drug induced liver injury 
DNA 
deoxyribonucleic acid  
DRC 
data review committee 
ECG 
electrocardiogram 
eCRF 
case report form 
EDC 
electronic data capture  
ET 
early termination 
ETV 
entecavir 
FAS 
full analysis set 
Hb 
hemoglobin 
HBcrAb 
antibody to the HBV core-related 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 
IPD 
important protocol deviation(s) 
IRT 
interactive response technology 
LLOQ 
lower limit of quantitation  
LLT 
lower-level term 
LOQ 
limit of quantitation 
MedDRA 
medical dictionary for regulatory activities 
PBO 
placebo  


 
 
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PD 
protocol deviation(s) 
pgRNA  
pregenomic RNA  
PT 
preferred term 
PK 
pharmacokinetics 
 
Q1, Q3 
first quartile, third quartile 
QD 
once daily  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
ULN 
upper limit of normal 
 


 
 
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1. 
INTRODUCTION 
Study ABI-H2158-201 is a Phase 2a, multicenter, randomized, single-blind, placebo (PBO)-
controlled, multiple cohort study evaluating ABI-H2158-containing regimens in chronic hepatitis 
B virus (HBV) infection (cHBV). The target population is male or female subjects with cHBV, 
18 to 65 years of age, inclusive, with no evidence of cirrhosis or end-stage liver disease. Cohort 1 
will enroll treatment-naïve subjects with hepatitis B virus “e” antigen (HBeAg) positive cHBV. 
Cohort 2 will enroll treatment-naïve subjects with HBeAg negative cHBV. 
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-H2158-201. This SAP is based on the Study Protocol Amendment 2, dated 14 
December 2020; UK country-specific protocol amendment, dated 17 December 2020; Korea-
country specific protocol amendment, dated 05 February 2021; ABI-H2158-201 Protocol 
Clarification Letter for Amendment 2; dated 14 Dec 2020, 07 September 2021; and the 
electronic case report form (eCRF). On 01 September 2021, Assembly made the decision to 
discontinue the development of ABI-H2158 following the observation of elevated alanine 
aminotransferase (ALT) levels consistent with drug-induced liver injury (DILI) in study ABI-
H2158-201. Therefore, only key safety and efficacy endpoints will be performed. The SAP will 
be finalized before final database lock. Any changes made after the finalization of the SAP will 
be documented in the Synoptic CSR. 
1.1. 
Study Objectives 
The primary objectives of this study are as follows: 
• To evaluate the safety and tolerability of ABI-H2158 when administered in combination with 
entecavir (ETV) in subjects with cHBV 
• To evaluate the effect of ABI-H2158 in reducing HBV DNA in subjects with cHBV 
The secondary objectives of this study are as follows: 
• To evaluate the pharmacokinetics (PK) of ABI-H2158 and ETV in subjects with cHBV 
• To evaluate the effect of ABI-H2158 in reducing HBV pregenomic RNA (pgRNA) levels in 
subjects with cHBV 
• To evaluate the effect of ABI-H2158 in reducing HBV antigens (ie, HBeAg, hepatitis B core-
related antigen [HBcrAg] and hepatitis B surface antigen [HBsAg]) in subjects with cHBV 
• To evaluate the effect of ABI-H2158 on normalization of ALT in subjects with abnormal 
ALT 
• To evaluate the emergence of resistance to ABI-H2158 when administered in combination 
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The exploratory objectives of this study are as follows: 
• To assess the relationship between new and known viral biomarkers and virologic and/or 
clinical outcomes 
• For subjects who provide an optional pharmacogenomic sample, to evaluate the potential 
contribution of host genomics to clinical or virologic outcomes and/or drug disposition 
1.2. 
Study Design 
This study will assess the safety, antiviral activity, and pharmacokinetics (PK) of ABI-H2158 
administered once daily (QD) in combination with ETV in subjects with cHBV. Multiple parallel 
cohorts will be enrolled in the study.  
In Cohort 1, approximately 40 treatment-naïve subjects with HBeAg positive cHBV will be 
randomized in a 3:1 ratio to receive 300 mg ABI-H2158+ETV (n=30) or matching PBO+ETV 
(n=10) for 72 weeks (Figure 1-1). In Cohort 2, approximately 40 treatment-naïve subjects with 
HBeAg negative cHBV will be randomized in a 3:1 ratio to receive 300 mg ABI-H2158+ETV 
(n=30) or matching PBO+ETV (n=10) for 72 weeks (Figure 1-1). Treatment assignments for 
Cohort 1 will be stratified by the HBV DNA level measured at the Screening visit (ie, ≥8.0 log10 
IU/mL versus <8.0 log10 IU/mL) and for Cohort 2 will be stratified by the HBV DNA level 
measured at the Screening visit (ie, ≥6.0 log10 IU/mL versus <6.0 log10 IU/mL).  
After completing treatment at Week 72, or following premature treatment discontinuation, all 
subjects will enter a 24 week follow-up period. During the follow-up period all subjects will 
remain on ETV and undergo the follow-up assessments. After completing the 24-week follow-up 
period, all subjects will resume management by their treating physician in accordance with local 
standard of care. 
The schedule of assessments is presented in Protocol Appendix 1.  
An assessment of PK data will also be performed after all subjects have completed study Week 4 
(or discontinued study without completing Week 4) in order to confirm the absence of important 
drug interactions between ABI-H2158 and ETV at steady state.  
Following the early termination of Study ABI-H2158-201, in accordance with the ABI-H2158-
201 Protocol Clarification Letter for Amendment 2 dated 14 Dec 2020, 07 September 2021, 
subjects were instructed to complete the follow-up assessments through 12 weeks after the last 
dose of study medication. 
Throughout the 12-week follow-up period, all subjects should continue treatment with ETV. 


 
 
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Figure 1-1.  
Study Overview 
 
Abbreviations: PBO: placebo; ETV: entecavir; HBeAg: hepatitis B “e” antigen. 
 
1.3. 
Sample Size and Power 
It is planned that approximately 80 subjects (40 subjects per Cohort 1 and Cohort 2) will be 
enrolled in this study. Subjects will be randomized to receive either 300 mg ABI-H2158 or PBO 
or in a 3:1 ratio. That is, 30 subjects randomized to treatment with ABI-H2158 per Cohort 1 and 
Cohort 2 and 10 subjects will be randomized to treatment with PBO per Cohort 1 and 2. This 
sample size is not based on statistical considerations but is considered adequate for a 
proof-of-concept study. 
1.4. 
Methods of Assigning Subjects to Treatment 
1.4.1. 
Randomization 
Within each treatment cohort, randomization of eligible subjects to their respective treatment 
assignments will be performed centrally using an Interactive Response Technology (IRT) 
system. Following successful completion of Screening assessments and confirmation of subject 
eligibility, site personnel will enter the subject specific information in the IRT system and 
following acceptable completion of the procedure will receive a subject identification number 
and treatment assignment. Additional information on the use of the IRT is provided in the IRT 
User Manual. 
In Cohort 1, the IRT system will assign treatment-naïve subjects with HBeAg positive cHBV 
subjects in a 3:1 ratio to receive either 300 mg ABI-H2158+ETV (n=30) versus matching 
PBO+ETV (n=10). Individual subject treatment assignments will be stratified according to the 
HBV DNA level measured at the Screening visit (ie, ≥8.0 log10 IU/mL versus <8.0 log10 IU/mL).  
In Cohort 2, the IRT system will assign treatment-naïve subjects with HBeAg negative cHBV 
subjects in a 3:1 ratio to receive either 300 mg ABI-H2158+ETV (n=30) versus matching 


 
 
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PBO+ETV (n=10). Individual subject treatment assignments will be stratified according to the 
HBV DNA level measured at the Screening visit (ie, ≥6.0 log10 IU/mL versus <6.0 log10 IU/mL). 
 
1.4.2. 
Blinding 
This is a single-blind study. Subjects, Investigators and other site personnel administering study 
drug, performing the clinical assessments, and handling data on the study subjects, will be 
blinded to individual subject treatments assignments (ie, ABI-H2158+ETV or PBO+ETV) 
throughout the duration of the study. The CRO and Sponsor study team responsible for study 
execution will also remain blinded to mitigate any potential operational bias. A DRC, comprising 
a limited number of internal Sponsor members who are independent of the study team, will be 
unblinded to individual subjects’ treatment assignments for the prespecified safety data reviews 
(see Section 2.1). 
 


 
 
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2. 
TYPE OF PLANNED ANALYSIS 
2.1. 
DRC Interim Analyses 
An internal DRC will perform regular unblinded reviews of safety data to ensure timely analysis 
of any emergent safety/tolerability issues, and completion of the prespecified safety data reviews. 
As this is an exploratory Phase 2a study, the DRC will also assess the unblinded HBV virology 
parameter (HBeAg, HBsAg, HBcrAg, HBV DNA and HBV pgRNA) results at prespecified 
timepoints before the final analysis to make strategic decisions relating to drug development. The 
aggregated virology data may be released for external communication. 
The initial DRC review will be conducted after approximately 25% of planned enrolled subjects 
in Cohort 1 have completed at least 4 weeks of treatment. Additional meetings will be scheduled 
approximately every month. In addition to regular review of safety and virology data, the DRC 
will also review the interim PK analysis when all randomized subjects in each cohort or 
approximately 2-5 subjects from South Korean sites, have completed Week 4 assessments or 
discontinued before completing Week 4. 
The DRC will comprise Sponsor’s representatives from Clinical Research and Biometrics. Other 
functional area members may be included as necessary. The DRC’s role and responsibilities and 
the scope of the analysis will provided in a charter, which will define the DRC membership, 
meeting logistics, and meeting frequency. The DRC members will not be directly involved in the 
study conduct and will not have interactions with the study sites. The unblinded study results 
they may review and the meeting minutes, along with any decisions or recommendations made, 
will be archived in a secure location. All other Sponsor personnel will remain blinded until 
completion of the study.  
The study remains blinded following the study termination. The DRC meetings are held to 
review and monitor the safety data after study drug discontinuation before the study unblinding.  
 
2.2. 
Final Analysis 
As of 01 September 2021, the study is early terminated. The final analysis to support a ‘Synoptic 
Clinical Study Report’ will be performed after all subjects have discontinued or completed the 
12-week follow-up visits, 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.  
Given that the study is early terminated, no formal statistical testing will be performed. 
By-subject listings will be presented for all subjects in the All Randomized Analysis Set and 
sorted by subject identification (ID) number, visit date, and time (if applicable) in chronological 
order within the subject. The treatment group to which subjects were randomized will be used in 
the listings. 
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 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 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 


 
 
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treatment received will differ from the randomized treatment only when their actual treatment 
differs from randomized treatment for the entire treatment duration. 
3.3. 
Strata and Covariates 
Subjects will be randomly assigned to treatment groups via IRT in a 3:1 ratio to receive either 
300 mg ABI-H2158+ETV (n=30) versus matching PBO+ETV (n=10) using a stratified 
randomization schedule. Stratification will be based on the HBV DNA level measured at the 
Screening visit as follows: 
• For Cohort 1, HBV DNA level measured at the Screening visit, ≥8.0 log10 IU/mL versus <8.0 
log10 IU/mL.  
• For Cohort 2, HBV DNA level measured at the Screening visit, ≥6.0 log10 IU/mL versus <6.0 
log10 IU/mL.  
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.   
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 the year of birth and 
informed consent date. 
In general, laboratory data that are continuous in nature but are less than the lower limit of 
quantitation (LLOQ) or above the upper limit of quantitation (LOQ) will be imputed to the value 
of the lower or upper limit minus or plus 1 significant digit, respectively (eg, if the result of a 
continuous laboratory test is <20, a value of 19 will be assigned). 
• A value that is 1 unit less than the LLOQ 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 
values are reported as <50 and <5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as <1 or <0.1, 
etc. For values reported as <1 or <0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics. 
• A value that is 1 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). Values with 
decimal points will follow the same logic as above. 
• The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤x” or “≥x” (where x is considered the LOQ). 
For selected analyses, virology efficacy data will be transformed to the logarithmic (base 10) 
scale (log10 IU/mL). 


 
 
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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).  
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 efficacy data is described in Section 6. The handling of missing or 
incomplete dates for AE onset is described in Section 7.1.5.2. 
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. 
Analysis Visit Windows 
3.6.1. 
Definition of Study Day 
In this study, study drug is defined as ABI-H2158 (or matching PBO) and ETV.  
The first dose date of ABI-H2158/PBO and of ETV will be calculated. Study Day 1 is defined as 
the first dose date of study drug, which is the minimum of the first dose dates of ABI-H2158 
/PBO and ETV in a treatment group. If the first dose date is missing, the date of randomization 
will be used. 
The last dose date of ABI-H2158/PBO and of ETV will be calculated. The last dose date for each 
drug will be the end date on the respective “Subject Disposition: End of the Treatment” eCRF. 
The last dose date of study drug will be defined as the maximum of the last dose dates of ABI-
H2158/PBO and ETV in a treatment group. 
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 follow-up period, the follow-up Study Day 1 is defined as the day after the last dose date 
of ABI-H2158/PBO and the follow-up study day will be calculated from the last dose date and 
derived as Assessment Date − Last Dose Date of ABI-H2158/PBO. 






 
 
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3.6.3. 
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 baseline value will be the average of the measurements 
for continuous data, or the measurement with the lowest severity for categorical data (eg, 
normal will be selected over abnormal for safety ECG findings). 
• For postbaseline values: 
o The record closest to the nominal day for that visit will be selected with the exception of 
virology parameters in which the latest record will be selected. For the virology 
parameters, the later record 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.   


 
 
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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 randomized, and the number of subjects in each of the categories 
listed: 
• 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 ABI-H2158/PBO  
• Did not complete ABI-H2158/PBO and reasons for study drug discontinuation  
• Completed ETV  
• Did not complete ETV and reasons for study drug discontinuation  
• Completed study  
• Did not complete the study and 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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4.2. 
Extent of Study Drug Exposure  
Extent of exposure to ABI-H2158/PBO and to ETV will be examined by assessing the total 
duration of exposure to each drug.  
4.2.1. 
Duration of Exposure to Study Drug 
Total duration of exposure to a drug will be defined as last dose date minus first dose date plus 1, 
regardless of any temporary interruptions in drug administration, and will be expressed in weeks 
using up to 1 decimal place (eg, 4.5 weeks). Duration (weeks) = Duration (days) /7.  If the last 
dose date is missing, the latest date among the 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 ABI-H2158/PBO and to ETV will be summarized using 
descriptive statistics. Summaries will be provided by treatment group for the Safety Analysis Set. 
The expected total duration of on-treatment therapy for all subjects is 72 weeks. The distribution of 
subjects by the total number of weeks on therapy (ie, <12 weeks, 12 -<24 weeks, 24 -<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, ≥48 weeks, and  ≥72 weeks. 
4.2.2. 
Study Drug Compliance  
The total number of tablets administered and average daily dose will be summarized using 
descriptive statistics.  
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula: 
Total Number of Tablets Administered  
= (∑No. of Tablets Dispensed) −(∑No. of Tablets Returned) 
4.2.2.1. 
On-Treatment Compliance 
The level of on-treatment compliance to ABI-H2158/PBO and to ETV 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 will be expressed as a percentage using the following 
formula: 
On-Treatment Compliance (%) = (
Total Amount of Study Drug Administered
Study Drug Expected to be Administered on Treatment)  x 100 


 
 
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Descriptive statistics for the level of on-treatment compliance with the number and percentage of 
subjects belonging to compliance categories (e.g., < 80%, ≥ 80 to < 90%, ≥ 90%) will be 
provided by treatment group for the Safety Analysis Set.  
The by-subject listings 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. 
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 
by-subject listing will be provided for those subjects with any PDs. 
A table will be provided to summarize any COVID-19 related PDs with the deviation reason by 
treatment group. A table will also be provided to summarize visits that were not performed along 
with the reason they were not performed. A by-subject listing of subjects who missed visits along 
with reasons for missed visit will be provided. 


 
 
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5. 
BASELINE CHARACTERISTICS 
5.1. 
Demographics and Baseline Characteristics 
Subject demographic variables (ie, age, age group [<50/ ≥50 years], sex, race, and ethnicity), 
baseline characteristics (body weight, height, 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 HBV DNA (log10 IU/mL) 
• Baseline HBV DNA groups: ≥8.0 log10 IU/mL and <8.0 log10 IU/mL for Cohort 1, and 
≥6.0 log10 IU/mL, <6.0 log10 IU/mL for Cohort 2 
• Baseline HBV pgRNA (log10 U/mL) 
• Baseline HBeAg (log10 IU/mL) 
• HBeAg group (< LLOQ) 
• Baseline HBcrAg (log10 kU/mL) 
• HBcrAg group (< LLOQ) 
• Baseline HBsAg (log10 IU/mL) 
• HBsAg group (< LLOQ) 
• Baseline HBeAg antibody (HBeAb)  


 
 
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• Baseline HBsAg antibody (HBsAb)  
• Baseline antibody to the HBV core-related antigen (HBcrAb) 
• Baseline ALT (U/L)  
• ALT group (>ULN [Covance], >ULN [AASLD])  
• 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) v23.0. 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. The 
efficacy analyses will be performed for the 2 cohorts separately. Nominal p-values will be 
presented for any treatment comparisons. No multiplicity adjustment will be made.  
6.1. 
Primary Efficacy Endpoint 
6.1.1. 
Definition of the Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in mean log10 HBV DNA from Baseline to Week 24 
for ABI-H2158+ETV compared to PBO+ETV.  
6.1.2. 
Primary Analysis of the Primary Efficacy Endpoint 
The primary comparison will be made using an analysis of covariance (ANCOVA) model, 
including baseline value, stratification factors, and treatment group. The estimated least square 
means of treatment effects and estimated difference in treatment effects between treatment 
groups at Week 24 will be presented along with the 95% CIs and p-values. The primary analysis 
will be based on observed data. 
Summary statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
provided for the observed and change from Baseline by treatment group and study visit.  
Analysis will be based on observed data only. No imputation will be done for missing data. 
 
6.2. 
Changes From Protocol-Specified Efficacy Analyses  
Since the study is terminated early, the analyses for the key secondary and other secondary 
endpoints specified in the protocol are not performed. 
 


 
 
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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) v23.0. 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 misses to record a relationship to ABI-H2158/PBO or to ETV will be 
considered related to the corresponding 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 on or 
after first dose date of study drug and no later than 28 days after permanent discontinuation of 
ABI-H2158/PBO. 
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 
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 
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• The AE onset is in the same or after the month and year (or year) of the first dose date of 
study drug, and 
• The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 28 days after the date of the last dose of ABI-H2158/PBO 
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 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 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. 
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. 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  
• TE SAEs 
• TEAEs leading to ABI-H2158/PBO discontinuation 
• TEAEs leading to ETV discontinuation 
• TEAEs leading to study discontinuation 
• TEAEs related to ABI-H2158/PBO 
• TEAEs related to ETV 
• TE SAEs related to ABI-H2158/PBO 
• TE SAEs related to ETV 
• COVID-19 specific TEAEs 
• COVID-19 specific TE SAEs 


 
 
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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 brief, high-level summary of the number and percentage of subjects who experienced at least 1 
off-treatment AE in the same categories as the TEAEs except for the AEs leading to ABI-
H2158/PBO discontinuation will be provided by treatment group. 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. The off-treatment AEs are counted starting from 29 
days after the last dose of ABI-H2158/PBO. 
A data listing containing all AEs will be provided. 
7.2. 
Laboratory Evaluations 
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods based on the Safety Analysis Set. The laboratory values that 
are below LLOQ or above the upper limit of quantitation will be listed as such, and the closest 
imputed value will be used for the purpose of calculating summary statistics as specified in 
Section 3.4.  
7.2.1. 
Graded Laboratory Values 
The criteria specified in the study protocol will be used to grade laboratory results as normal 
(Grade 0), mild (Grade 1), moderate (Grade 2), severe (Grade 3) or potentially life threatening 
(Grade 4). See Protocol Appendix 2 for detailed DAIDS grading criteria on the relevant 
laboratory tests. Grade 0 includes all values that do not meet the criteria for an abnormality of at 
least Grade 1. 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, up to and including the date of last 
dose of ABI-H2158/PBO plus 28 days or subjects who permanently discontinued ABI-
H2158/PBO. 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 graded 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: 
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 28 days after last dose date of ABI-H2158/PBO. 


 
 
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The maximum postbaseline grade observed up to 28 days after last dose date will be tabulated 
for each laboratory test, and percentages will be based on the number of subjects with a 
postbaseline evaluation of the specific laboratory test.  
Graded lab abnormalities will be also be summarized for the off-treatment period. Lab 
abnormalities are included starting from 29 days after the last dose of ABI-H2158/PBO. 
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. 
ALT Elevation 
7.2.2.1. 
ALT Elevation without Declining Hepatic Function 
A confirmed ALT elevation on treatment is defined as ALT >2 × Baseline or on-treatment nadir 
and ≥10 × ULN(Covance) at 2 consecutive visits. 
7.2.2.2. 
ALT Elevation with Declining Hepatic Function  
A confirmed ALT elevation with evidence of declining hepatic function is defined as meeting the 
following criteria at 2 consecutive visits:  
• ALT elevation ≥2 × Baseline (Day 1) or nadir and >2 × ULN(Covance) AND 
• Direct bilirubin increase to ≥2 × Baseline (Day 1) and ≥2 × ULN(Covance) OR  
• Albumin decline ≥0.5 g/dL OR INR >2 × Baseline (Day 1) OR  
• Symptoms of liver inflammation (eg, fatigue, weakness, lack of appetite, nausea, vomiting, 
jaundice or discolored feces) 
The number and subjects meeting the above laboratory 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. 
7.3. 
Vital Signs 
Descriptive statistics will be provided by treatment group for vital signs including heart 
rate, respiration rate, blood pressure, and body temperature as follows: 
• Baseline value 
• Values at each postbaseline time visit 


 
 
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• 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. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.6.3.   
A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], respiration rate 
[breaths/min], heart rate [bpm] and body temperature) 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 WHODrug-Global-
B3 v202003 of the World Health Organization (WHO) Drug dictionary. 
7.4.1. 
Prior Medications 
Prior medications are defined as any medications taken before a subject took the first dose of 
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.  
• 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 of study drug.  
• 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.   


 
 
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7.4.2. 
Concomitant Medications 
Concomitant medications are defined as medications taken while a subject was taking 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 but prior to or on the last dose date of study 
drug.  
• 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 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 first dose date of study drug 
• A medication started and stopped on the same day as the first dose date or the last dose 
date of study drug  
• 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 or a start date 
after the last dose date of study drug will be excluded from the summary.  
Summaries will be based on the Safety Analysis Set.  
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order. 
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 


 
 
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• 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. 


 
 
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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. 
SAP REVISION 
Revision Date 
(DD MMM YYYY) 
Section 
Summary of Revision 
Reason for Revision 
 
 
 
 
 
 
 
 
 


Signature Page for 
Signature Page for 
Reason for signing: Approved
Name: 
Role: A
Date of signature: 25-Jan-2022 19:22:38 GMT+0000
Reason for signing: Approved
Name: 
Role: A
Date of signature: 25-Jan-2022 20:36:07 GMT+0000
Reason for signing: Approved
Name: 
Role: A
Date of signature: 25-Jan-2022 21:51:58 GMT+0000