Clinical trial NCT04891770
Conditions: Chronic Hepatitis B
Sponsor: Gilead Sciences
Start date: 2021-08-14; Completion date: 2024-07-19
Enrollment: 103 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the safety and tolerability of study treatment(s) (selgantolimod-containing combination therapies) and to evaluate the efficacy of study treatment(s) as measured by the proportion of participants who achieve functional cure, defined as hepatitis B surface antigen (HBsAg) loss and hepatitis B virus (HBV)deoxyribonucleic acid (DNA) \< lower limit of quantitation (LLOQ) at Follow-up (FU) Week 24 in participants with chronic hepatitis B (CHB).

Detailed description:

Arms: arm 1: Nucleos(t)ide(s) (NUC)-suppressed participants with chronic hepatitis B (CHB) will receive tenofovir alafenamide (TAF) 25 mg orally once daily (QD) for 36 weeks and VIR-2218 200 mg subcutaneously (SC) once every 4 weeks (Q4W) for 24 weeks. From Week 12 onwards, participants will receive selgantolimod (SLGN) 3 mg orally once a week (QW) for 24 weeks and nivolumab 0.3 mg/kg intravenously (IV) Q4W for up to 24 weeks (only up to protocol amendment 2, nivolumab was no longer administered post implementation of protocol amendment 2). Participants who are on TAF treatment will continue TAF treatment over the duration of study follow-up. Participants will be followed up for 48 weeks post treatment. arm 2: Viremic participants with CHB will receive VIR-2218, 200 mg SC Q4W for 24 weeks. From Week 12 onwards, participants will receive SLGN 3 mg orally QW for 24 weeks and nivolumab 0.3 mg/kg IV Q4W for up to 24 weeks (only up to protocol amendment 2, nivolumab was no longer administered post implementation of protocol amendment 2). Participants who meet the criteria to initiate NUC treatment will receive TAF 25, mg orally, QD during the study. Participants will be followed up for 48 weeks post treatment. arm 3: Viremic participants with CHB will receive SLGN 3 mg orally QW for 24 weeks and nivolumab 0.3 mg/kg IV Q4W for up to 24 weeks. .

Viremic participants who meet the criteria to initiate NUC treatment will receive TAF 25 mg orally QD during the study. Participants will be followed up for 48 weeks post treatment.

All treatments were administered up to protocol amendment 2 and after the implementation of protocol amendment 2, the treatments were discontinued for Cohort 2 Group B based on Sponsor decision.
Interventions: intervention 1: Tenofovir Alafenamide intervention 2: VIR-2218 intervention 3: Nivolumab intervention 4: Selgantolimod
Intervention descriptions: intervention 1: Administered as film-coated oral tablets intervention 2: Administered as a sub-cutaneous (SC) injection intervention 3: Administered intravenously intervention 4: Administered as film-coated oral tablets

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2a, Open-Label Study to Evaluate the Safety and Efficacy 
of Selgantolimod (SLGN)-Containing Combination Therapies for 
the Treatment of Chronic Hepatitis B (CHB) 
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
ANZCTR Trial ID:
EudraCT Number:
ClinicalTrials.gov 
Identifier:
This is a non-IND study
Not Available 
2021-000672-11
NCT04891770
Indication:
Chronic Hepatitis B
Protocol ID:
GS-US-465-4439
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List. 
Protocol Version/Date:
Original:
04 March 2021
Amendment 1:
20 April 2022 
Amendment 2:
12 April 2023
This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, and that are consistent with 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
regulatory requirements.
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or under 
control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable institutional review board or 
independent ethics committee. The information is only to be used by you in connection with authorized 
clinical studies of the investigational drug described in the protocol. You will not disclose any of the 
information to others without written authorization from Gilead Sciences, Inc., except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered.
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................6
LIST OF IN-TEXT FIGURES........................................................................................................................................6
PROTOCOL SYNOPSIS................................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................................23
1.
INTRODUCTION................................................................................................................................................28
1.1.
Background..............................................................................................................................................28
1.2.
General Information About Study Drugs ................................................................................................29
1.2.1.
General Information About Selgantolimod...........................................................................29
1.2.2.
General Information About Nivolumab ................................................................................31
1.2.3.
General Information About Tenofovir Alafenamide (TAF) .................................................31
1.2.4.
General Information About VIR-2218 ..................................................................................32
1.3.
Rationale for the Current Study...............................................................................................................32
1.3.1.
Rationale for Modifications to Study Design........................................................................32
1.3.2.
Rationale for This Study as Originally Designed..................................................................33
1.4.
Rationale for Dose Selection of Study Drugs..........................................................................................33
1.4.1.
Rationale for Dose Selection of Selgantolimod ....................................................................33
1.4.2.
Rationale for Dose Selection of Nivolumab..........................................................................34
1.4.3.
Rationale for Dose Selection of TAF ....................................................................................34
1.4.4.
Rationale for Dose Selection of VIR-2218 ...........................................................................35
1.5.
Benefit/Risk Assessment for the Study ...................................................................................................36
1.6.
Compliance..............................................................................................................................................40
2.
OBJECTIVES.......................................................................................................................................................41
3.
STUDY DESIGN.................................................................................................................................................42
3.1.
Endpoints.................................................................................................................................................42
3.2.
Study Design ...........................................................................................................................................42
3.2.1.
Changes to Study Design.......................................................................................................42
3.3.
Study Treatments.....................................................................................................................................43
3.4.
Duration of Treatment .............................................................................................................................44
3.5.
Follow-up Period.....................................................................................................................................45
3.6.
Treatment Discontinuation Criteria.........................................................................................................45
3.7.
End of Study............................................................................................................................................45
3.8.
Poststudy Care.........................................................................................................................................45
3.9.
Source Data .............................................................................................................................................45
3.9.1.
Biomarker Samples to Address the Study Objectives...........................................................45
3.9.4.
Pharmacokinetic Assessments...............................................................................................47
4.
PARTICIPANT POPULATION..........................................................................................................................49
4.1.
Number of Participants and Participant Selection...................................................................................49
4.1.1.
Participant Replacement........................................................................................................49
4.2.
Inclusion Criteria.....................................................................................................................................49
4.3.
Exclusion Criteria....................................................................................................................................50
5.
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................................53
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5.1.
Randomization and Treatment Assignment ............................................................................................53
5.1.1.
Randomization/Enrollment....................................................................................................53
5.1.2.
Blinding .................................................................................................................................53
5.2.
Description and Handling of SLGN, TAF, and VIR-2218, and Nivolumab...........................................53
5.2.1.
Formulation ...........................................................................................................................53
5.2.2.
Packaging and Labeling ........................................................................................................54
5.2.3.
Storage and Handling ............................................................................................................55
5.3.
Dosage and Administration of SLGN, TAF, VIR-2218, and Nivolumab...............................................56
5.3.1.
Selgantolimod........................................................................................................................56
5.3.2.
Nivolumab .............................................................................................................................56
5.3.3.
Tenofovir Alafenamide .........................................................................................................56
5.3.4.
VIR-2218...............................................................................................................................56
5.4.
Prior and Concomitant Medications........................................................................................................56
5.5.
Accountability for Investigational Medicinal Product: SLGN, TAF, VIR-2218, and 
Nivolumab ...............................................................................................................................................60
5.5.1.
Investigational Medicinal Product Return or Disposal .........................................................61
6.
STUDY PROCEDURES......................................................................................................................................62
6.1.
Study Procedure Details ..........................................................................................................................62
6.1.1.
Medical History.....................................................................................................................62
6.1.2.
Complete Physical Examination............................................................................................62
6.1.3.
Vital Signs .............................................................................................................................62
6.1.4.
12-Lead Electrocardiograms .................................................................................................62
6.1.5.
Clinical Laboratory Tests/Assessments for Safety Evaluations............................................63
6.1.6.
Creatinine Clearance .............................................................................................................64
6.1.7.
Ophthalmologic Examination................................................................................................64
6.1.8.
HBV Sequence Analysis .......................................................................................................64
6.1.9.
Digital Droplet Polymerase Chain Reaction .........................................................................64
6.1.10.
Sparse PK Sampling..............................................................................................................64
6.1.12.
Biomarker Samples ...............................................................................................................65
6.1.15.
Management of Participants Impacted by the COVID-19 Pandemic ...................................66
6.2.
Participant Enrollment and Treatment Assignment ................................................................................66
6.3.
Pretreatment Assessments .......................................................................................................................66
6.3.1.
Prescreening Visit..................................................................................................................66
6.3.2.
Screening Visit ......................................................................................................................66
6.3.3.
Baseline/Day 1 Assessments .................................................................................................68
6.4.
Randomization.........................................................................................................................................69
6.5.
Treatment Schedule.................................................................................................................................70
6.6.
Post-Day 1 Treatment Assessments ........................................................................................................70
6.7.
Follow-up Assessments...........................................................................................................................72
6.8.
Immunologic Testing...............................................................................................................................73
6.8.1.
Biomarker Sample Collection During Treatment Period ......................................................74
6.8.2.
Biomarker Sample Collection During Follow-up .................................................................74
6.9.
Assessments for Early Discontinuation of Study Treatment...................................................................74
6.9.1.
Criteria for Discontinuation of Study Treatment...................................................................74
6.9.2.
Criteria for Individual Dose Modification.............................................................................76
6.9.3.
Study and/or Cohort Discontinuation Criteria.......................................................................76
6.9.4.
Premature Study Discontinuation..........................................................................................76
6.10.
End of Study............................................................................................................................................77
6.11.
Poststudy Care.........................................................................................................................................77
6.12.
Sample Storage........................................................................................................................................77
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT................................................................................78
7.1.
Definitions of Adverse Events and Serious Adverse Events...................................................................78
7.1.1.
Adverse Events......................................................................................................................78
7.1.2.
Serious Adverse Events.........................................................................................................78
7.1.3.
Study Drugs and Gilead Concomitant Therapy Special Situations Reports .........................79
7.2.
Assessment of Adverse Events and Serious Adverse Events..................................................................80
7.2.1.
Assessment of Causality for Study Drugs and Procedures ...................................................80
7.2.2.
Assessment of Severity..........................................................................................................80
7.3.
Investigator Reporting Requirements and Instructions ...........................................................................81
7.3.1.
Requirements for Collection Prior to Study Drug Initiation .................................................81
7.3.2.
Adverse Events......................................................................................................................81
7.3.3.
Serious Adverse Events.........................................................................................................81
7.3.4.
Study Drug Special Situations Reports .................................................................................81
7.3.5.
Concomitant Therapy Reports...............................................................................................81
7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports.......................................82
7.4.1.
Serious Adverse Event Reporting Process ............................................................................82
7.4.2.
Special Situations Reporting Process ....................................................................................83
7.5.
Gilead Reporting Requirements ..............................................................................................................85
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events...........................................................................................................................85
7.7.
Toxicity Management..............................................................................................................................86
7.7.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event ..................................................86
7.7.2.
Grade 3 Laboratory Abnormality or Clinical Event..............................................................86
7.7.3.
Grade 4 Laboratory Abnormality or Clinical Event..............................................................87
7.7.4.
Toxicity Management of Immune-Related Adverse Events Observed 
With Nivolumab....................................................................................................................87
7.7.5.
ALT Elevation or Flare Management on Treatment and Treatment-Free 
Follow-up ..............................................................................................................................88
8.
STATISTICAL CONSIDERATIONS.................................................................................................................91
8.1.
Analysis Objectives and Endpoints.........................................................................................................91
8.1.1.
Analysis Objectives...............................................................................................................91
8.1.2.
Primary Endpoint...................................................................................................................92
8.1.3.
Secondary Endpoint...............................................................................................................92
8.2.
Planned Analyses.....................................................................................................................................92
8.2.1.
Primary Analysis ...................................................................................................................92
8.2.2.
Final Analysis........................................................................................................................92
8.3.
Analysis Conventions..............................................................................................................................92
8.3.1.
Analysis Sets .........................................................................................................................92
8.4.
Demographic and Baseline Characteristics Analysis..............................................................................93
8.5.
Efficacy Analysis.....................................................................................................................................94
8.5.1.
Primary Analysis ...................................................................................................................94
8.5.2.
Secondary Analyses...............................................................................................................94
8.5.3.
Analysis of Other Endpoints of Interest ................................................................................94
8.6.
Safety Analysis........................................................................................................................................94
8.6.1.
Extent of Exposure ................................................................................................................95
8.6.2.
Adverse Events......................................................................................................................95
8.6.3.
Laboratory Evaluations .........................................................................................................96
8.6.4.
Other Safety Evaluations.......................................................................................................96
8.7.
Pharmacokinetic Analysis .......................................................................................................................96
8.9.
Sample Size .............................................................................................................................................97
9.
RESPONSIBILITIES...........................................................................................................................................98
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9.1.
Investigator Responsibilities ...................................................................................................................98
9.1.1.
Good Clinical Practice...........................................................................................................98
9.1.2.
Financial Disclosure ..............................................................................................................98
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval................................................................................................................................98
9.1.4.
Informed Consent ..................................................................................................................98
9.1.5.
Confidentiality.......................................................................................................................99
9.1.6.
Study Files and Retention of Records ...................................................................................99
9.1.7.
Case Report Forms ..............................................................................................................101
9.1.8.
Investigator Inspections.......................................................................................................101
9.1.9.
Protocol Compliance ...........................................................................................................101
9.2.
Sponsor Responsibilities .......................................................................................................................101
9.2.1.
Protocol Modifications ........................................................................................................101
9.2.2.
Study Reports and Publications...........................................................................................102
9.3.
Joint Investigator/Sponsor Responsibilities ..........................................................................................102
9.3.1.
Payment Reporting ..............................................................................................................102
9.3.2.
Access to Information for Monitoring.................................................................................102
9.3.3.
Access to Information for Auditing or Inspections .............................................................102
9.3.4.
Premature Study Termination..............................................................................................102
10.
REFERENCES...................................................................................................................................................103
11.
APPENDICES....................................................................................................................................................108
11.1.
Investigator Signature Page...................................................................................................................109
11.2.
Pandemic Risk Assessment and Mitigation Plan ..................................................................................110
11.3.
Study Procedures Tables .......................................................................................................................113
11.4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and Contraceptive 
Requirements.........................................................................................................................................124
11.5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............................128
11.6.
Management of Clinical and Laboratory Adverse Events ....................................................................152
11.7.
Amendment History ..............................................................................................................................152
11.7.1.
Amendment 2 (12 April 2023) ............................................................................................152


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LIST OF IN-TEXT TABLES
Table 1.
Dose Modification and Monitoring .........................................................................................12
Table 2.
Starting Commercial NUC Treatment Criteria........................................................................13
Table 3.
Estimated Median VIR-2218 Liver Tissue Exposure in Humans Based on PK-PD 
Model.......................................................................................................................................36
Table 4.
List of Agents Disallowed Due to Potential Interaction With SLGN .....................................58
Table 5.
Disallowed Concomitant Medications While on TAF ............................................................60
Table 6.
Dose Modification and Monitoring .........................................................................................89
Table 7.
Starting Commercial NUC Treatment Criteria........................................................................90
LIST OF IN-TEXT FIGURES
Figure 1.
GS-US-465-4439: Study Design Schema*..............................................................................43


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2a, Open-Label Study to Evaluate the Safety and Efficacy 
of Selgantolimod (SLGN)-Containing Combination Therapies for 
the Treatment of Chronic Hepatitis B (CHB)
IND Number:
ANZCTR Trial ID:
Clinical Trials.gov 
Identifier:
This is a non-IND study
Not Available
NCT04891770
EudraCT Number:
2021-000672-11
Study Centers 
Planned:
Approximately 30 centers globally 
Objectives:
The primary objectives of this study are as follows:
•
To evaluate the safety and tolerability of study treatment(s)
•
To evaluate the efficacy of study treatment(s) as measured by 
the proportion of participants who achieve functional cure, 
defined as negative qualitative hepatitis B surface antigen 
(HBsAg loss) and hepatitis B virus (HBV) DNA < lower limit 
of quantitation (LLOQ) at Follow-up (FU) Week 24
The secondary objectives of this study are as follows: 
•
To evaluate the proportion of participants with HBsAg loss with 
and without anti-HBsAg seroconversion during the study 
•
To evaluate in participants with CHB who are hepatitis B e 
antigen (HBeAg) positive at baseline the proportion of 
participants who achieve HBeAg loss with and without 
anti-HBeAg seroconversion during the study
•
To evaluate the proportion of participants who remain off 
nucleos(t)ide(s) (NUC) treatment during FU
•
To evaluate the proportion of participants experiencing HBV 
virologic breakthrough (defined as confirmed HBV DNA 
≥ LLOQ after 2 consecutive HBV DNA < LLOQ in participants 
who are complying with NUC therapy OR confirmed HBV 
DNA ≥ 1 log10 IU/mL increase from nadir on treatment) during 
study treatment(s)
 
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Study Design:
This is a Phase 2, open-label study to evaluate the safety and 
efficacy of SLGN-containing combination therapies in CHB 
participants. The study will consist of 2 cohorts (Cohorts 1, and 2).
Approximately 40 NUC-suppressed and 60 viremic CHB-infected 
participants, may be enrolled and assigned into a cohort below. 
Each cohort will enroll a minimum of 20% HBeAg-positive 
participants, and up to 20% of participants can have HBsAg 
≤ 100 IU/mL.
NUC-suppressed Cohort
Cohort 1 (n = 40):
•
Tenofovir alafenamide (TAF) 25-mg tablet administered orally 
once daily for 36 weeks
•
VIR-2218 200 mg administered as subcutaneous (SC) injection 
once every 4 weeks for 24 weeks (total 6 doses)
At Week 12, add-on and initiate the below treatment:
•
SLGN 3 mg (2  1.5-mg tablets) administered orally while 
fasting once a week on the same day for 24 weeks (total 
24 doses)
•
Nivolumab 0.3 mg/kg administered intravenously (IV) once 
every 4 weeks for up to 24 weeks (up to 6 doses)
Viremic Cohort (Cohort 2)
Cohort 2 (n = 60):
Participants will be randomized 2:1 into Cohort 2 Groups A and B 
and stratified by HBsAg > or ≤ 3 log10 IU/mL.
Group A (n = 40):
•
VIR-2218 200 mg administered as SC injection once every 
4 weeks for 24 weeks (total 6 doses)
At Week 12, add-on and initiate the below treatment:
•
SLGN 3 mg (2  1.5-mg tablets) administered orally while 
fasting once a week on the same day for 24 weeks (total 
24 doses)
•
Nivolumab 0.3 mg/kg administered IV once every 4 weeks for 
up to 24 weeks (up to 6 doses)
Group B (n = 20):
•
SLGN 3 mg (2  1.5-mg tablets) administered orally while 
fasting once a week on the same day for up to 24 weeks (up to 
24 doses)
•
Nivolumab 0.3 mg/kg administered IV once every 4 weeks for 
up to 24 weeks (up to 6 doses)


Selgantolimod 
Protocol GS-US-465-4439 
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CONFIDENTIAL 
Final 
Amendment2 
NOTE: Nivolumab dosing was stopped in this study. This was a 
sponsor decision based on a benefit risk assessment of the use of 
nivolumab in HBV cure. 
As the study had completed emollment and all pa1ticipants were in 
treatment when the decision was made to stop nivolumab 
administration, the following amendments to the protocol were 
implemented: 
• 
Stop fmt her nivolumab administration for all study paiticipants 
across all coho1ts 
• 
Continue treatment with VIR-2218 and SLGN through Week 36 
for Coho1ts 1 and 2 (Group A) 
• 
Discontinue all study treatment for Coho1t 2 Group B 
pa1ticipants with next follow up visit being EOT for those still 
in treatment period 
• 
Stop all sample collections related to nivolumab 
• 
NUC therapy cessation is no longer required for our NUC 
treated patients (Coho1t 1) 
Follow-up Period: 
At the end of treatment, all paiticipants will enter a FU period 
• 
All paiticipants not on T AF treatment at end of treatment (EOT) 
will enter a treatment-free follow-up (TFFU) period 
• 
Paiticipants who ai·e on T AF treatment will continue T AF 
treatment over the duration of the follow up period 
Paiticipants who initiated TFFU prior to the approval of this 
amendment and stopped NUC treatment may continue offNUCs 
after discussion between participant and investigator on the benefits 
and risks of continuing off NUCs in TFFU. Those who decide to 
restait NUCs would initiate commercial NUC treatment. 
Pharmacokinetic assessments 
Sparse Pharmacokinetic Collection 
Spai·se (timed) plasma/semm PK samples will be obtained at 
specific in-clinic treatment visits at any time between 1 to 5 hours 
postdose relative to SLGN and/or VIR-2218 administration unless 
othe1wise indicated. 
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Alanine Aminotransferase (ALT) Elevation or Flare 
Management 
On-Treatment ALT Management 
Final 
Amendment2 
Paiiicipants with on-treatment sennn ALT elevation > 2 x nadir or 
> 2 x baseline value and ~ 5 x ULN, with or without associated 
symptoms should be managed according to the guidance below. 
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All elevated serum ALT should be confirmed as soon as possible 
and ideally within 3 days of receipt of results. During the visit, a 
clinical assessment of the participant should be performed. The 
assessment should include a physical examination, evaluation of the 
participant’s mental status, and the following laboratory tests: 
•
Laboratory parameters: serum ALT and aspartate 
aminotransferase (AST), total bilirubin, gamma-glutamyl 
transferase (GGT), international normalized ratio (INR), serum 
albumin, and alcohol screening.
•
If the ALT elevation is confirmed, the central clinical laboratory 
will conduct reflex testing for plasma HBV DNA, serology for 
HBV (HBsAg, HBsAb, HBeAg, and HBeAb), hepatitis D virus 
(HDV), hepatitis A virus (HAV) immunoglobulin M (IgM), 
hepatitis C virus (HCV), and hepatitis E virus (HEV).
•
Liver biopsy may be collected for participants meeting Hy’s law 
(ALT > 3  ULN and Total Bilirubin > 2  ULN; AST 
> 3  ULN and Total Bilirubin > 2  ULN) with suspected 
drug-induced-liver-injury (DILI)
Based on the results of the confirmatory tests, the following study 
treatment modifications are recommended (Table 1):
Table 1.
Dose Modification and Monitoring
Liver Toxicity Parameters
Action
Confirmed, ALT ≥ 10 × ULN 
without evidence of hepatic 
toxicity as defined below
Cohort 1: Hold VIR-2218 and SLGN treatment. 
Participant should be monitored weekly or more 
frequently if clinically indicated until ALT < 5 × 
ULN. Restarting study treatment (VIR-2218, 
SLGN) may be considered when ALT < 5  ULN 
in discussion with the medical monitor. Study 
treatment should be restarted in line with the 
original assigned administration schedule.
Cohort 2: Initiate TAF 25 mg once daily and 
hold SLGN, and/or VIR-2218 dose. Participant 
should be monitored weekly or more frequently if 
clinically indicated until ALT < 5 × ULN. 
Restarting study treatment (VIR-2218, and 
SLGN) may be considered when ALT < 5  ULN 
in discussion with the medical monitor. Study 
treatment should be restarted in line with the 
original assigned administration schedule.
Persistent ALT > 2 × baseline and 
≥ 5 × ULN without evidence of 
hepatic toxicity, as defined below
Continue study treatment(s), ALT should be 
evaluated every 2 weeks or more frequently as 
clinically needed, until ALT < 5 × ULN


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Confirmed ALT > 2 × nadir, with 
evidence of hepatic toxicity, 
defined as any one of the 
following confirmed laboratory 
abnormalities:
•
Total bilirubin > 2 × ULN
•
Elevated INR > 0.5 above 
baseline AND > ULN 
•
Abnormal serum albumin 
> 1 g/dL decrease from 
baseline 
Cohort 1: Permanently discontinue study 
treatment(s) except TAF 25 mg once daily. 
Participant should be monitored weekly until 
ALT < 5 × ULN, and total bilirubin, INR, and 
albumin values return to normal or baseline 
levels.
Cohort 2: Initiate commercially approved NUC 
treatment once daily and permanently discontinue 
study treatment(s). Participant should be 
monitored weekly until ALT < 5 × ULN, and 
total bilirubin, albumin, and/or INR values return 
to normal or baseline levels 
ALT = alanine aminotransferase; INR = international normalized ratio; 
NUC = nucleos(t)ide(s); SLGN = selgantolimod; TAF = tenofovir alafenamide; 
ULN = upper limit of normal
Treatment-Free Follow-up ALT Management
All eligible participants will enter a TFFU period after completion 
of study treatment, in which they will undergo close safety 
monitoring. The proportion of participants who achieve HBsAg loss 
or are able to remain off NUC therapy during TFFU period will be 
assessed. Table 2 provides guidance for initiating commercially 
approved NUC treatment, in participants who experience rebound 
of HBV DNA and ALT levels. Any deviation from Table 2 should 
be discussed in advance with the medical monitor. 
If unscheduled visits are required for ALT monitoring, a clinical 
assessment of the participant should be performed. The assessment 
should include a physical examination, evaluation of the 
participant’s mental status and the following laboratory tests: 
•
Laboratory parameters: serum ALT and AST, total and direct 
bilirubin, GGT, INR, serum albumin, plasma HBV DNA, 
quantitative HBsAg, peripheral blood mononuclear cells 
(PBMC) for immune profiling, and alcohol screen.
•
At the initial confirmatory visit, collect serology for HDV, HAV 
IgM, HCV, and HEV.
Participants with HBV DNA < LLOQ and ALT elevation/flare 
meeting any of the below table criteria, should be evaluated for 
alternative liver disease etiologies by the investigator and in 
discussion with the medical monitor. Liver biopsy may be collected 
at the investigator’s discretion.
Participants with HBV DNA > LLOQ and ALT elevation/flare 
should be managed according to the following table: 
Table 2.
Starting Commercial NUC Treatment 
Criteria
Liver Toxicity Parameters
Action
I 


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Confirmed ALT ≥ 10 × ULN with no 
evidence of hepatic toxicity, as 
defined below.
Initiate NUC treatment and monitor 
weekly until ALT < 5 × ULN, and 
every 2 weeks until ALT < 2  ULN, 
or more frequently if clinically 
indicated.
ALT ≥ 5  ULN without evidence of 
hepatic toxicity, as defined below
ALT should be evaluated every 
2 weeks or more frequently as 
clinically needed, until 
ALT < 2 × ULN. 
Confirmed ALT > ULN with 
evidence of hepatic toxicity, defined 
as any one of the following confirmed 
laboratory abnormalities: 
•
Total bilirubin > 2  nadir AND 
> 2.5 mg/dL in the absence of 
Gilbert’s disease
•
Elevated INR > 0.5 above nadir 
AND > ULN 
•
Abnormal serum albumin 
> 1 g/dL decrease from baseline
Initiate NUC treatment and monitor 
weekly or more frequently if 
clinically indicated until return to 
baseline levels or within normal 
reference range. Liver biopsy may be 
considered if appropriate for 
participant management.
Confirmed, HBV DNA 
> 20,000 IU/mL (HBeAg positive) or 
> 2,000 IU/mL (HBeAg negative) 
and
persistent ALT > ULN without 
evidence of hepatic toxicity, as 
defined above, for > 8 weeks
Initiating NUC treatment may be 
considered in discussion with medical 
monitor. 
ALT = alanine aminotransferase; DNA = deoxyribonucleic acid; HBV = hepatitis B virus; 
INR = international normalized ratio; NUC = nucleos(t)ide(s); ULN = upper limit of 
normal
Individual Treatment Modification Criteria
Study treatment(s) that are considered related by the investigator to 
any of the following event(s) will be held in a participant until 
resolution of the event:
•
Any study drug–related adverse event (AE) ≥ Grade 3
•
A confirmed, clinically significant laboratory test abnormality 
(other than ALT) ≥ Grade 3 considered study drug(s) related by 
the investigator.
Study treatment(s) may be reinitiated following resolution of the 
above event(s) after discussion with the medical monitor. Study 
treatment(s) should be restarted in line with their preassigned 
schedules.
Individual Treatment Discontinuation Criteria


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Study treatment(s) that are considered related by the investigator to 
any of the below events will be permanently discontinued:
•
Any on treatment uveitis confirmed by ophthalmologic 
evaluation
•
Any confirmed recurrence of study drug–related Grade 3 or 4 
(excluding laboratory abnormalities) AE following dose 
interruption mandates permanent discontinuation of study 
drug(s)
•
Any study drug–related ≥ Grade 3 AE not able to be medically 
managed (eg, nausea with antiemetics)
•
Any study drug–related Grade 4 AE (excluding laboratory 
abnormalities)
•
Unacceptable toxicity or toxicity that, in the judgment of the 
investigator, compromises the ability to continue study specific 
procedures or is considered not to be in the participant’s best 
interest
•
Any confirmed study drug–related laboratory abnormality 
≥ Grade 3 following rechallenge
•
A clinically significant Grade 4 laboratory abnormality
•
Virological breakthrough as defined in Section 2
Additional criteria for permanent discontinuation of study 
treatment(s):
•
Intercurrent illness that would, in the judgment of the 
investigator, affect assessments of clinical status to a significant 
degree
•
Hepatic disease progression or lack of efficacy defined as 
participants in Cohorts 1 or 2 (Group A), who do not achieve 
HBsAg decline ≥ 0.2 log10 IU/mL at Week 12
•
Participant requests to discontinue for any reason
•
Participant noncompliance
•
Pregnancy during the study
•
At the discretion of the investigator, Gilead, a regulatory agency 
or an institutional review board (IRB) or independent ethics 
committee (IEC)
Number of 
Participants 
Planned:
Approximately 100 participants


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Target Population:
Adult, noncirrhotic, participants with CHB infection who are 
viremic or virally suppressed on a commercially approved HBV 
NUC treatment.
Duration of 
Treatment:
TAF 25-mg tablet will be administered orally once daily for up to 
84 weeks, as applicable, in Cohort 1
VIR-2218 200 mg SC will be administered once every 4 weeks for 
24 weeks (6 doses) 
Nivolumab 0.3 mg/kg IV was administered once every 4 weeks for 
up to 24 weeks (up to 6 doses)
SLGN 3 mg (2  1.5-mg tablets) will be administered orally while 
fasting once a week on the same day for up to 24 weeks (up to 24 
doses) 
NOTE: Nivolumab dosing was stopped in this study. This was a 
sponor decision based on a benefit risk assessment on the use of 
nivolumab in HBV cure. SLGN was discontinued for Cohort 2 
Group B.
Diagnosis and Main 
Eligibility Criteria:
Male and nonpregnant female participants, ages 18 to 65 years, 
inclusive, with chronic HBV infection without the presence of 
cirrhosis, and who are viremic or virally suppressed on NUC 
treatment for at least 6 months may be eligible for the study.
Refer to Section 4 of the protocol for detailed Inclusion and 
Exclusion criteria.
Study Procedures/
Frequency:
This study includes prescreening (optional), screening, treatment, 
and follow-up assessments.
After consent is obtained, screening assessments will be completed 
within 45 days prior to the Baseline/Day 1 treatment. All 
participants will complete the study treatments described below. 
Cohort 1:
•
Screening Visit
•
Treatment Period Visits: Baseline/Day 1, Weeks 4, 8, 12, 13, 
14, 16, 20, 24, 28, 32, and 36 
•
FU Visits: Weeks 1, 4, 8, 12, 16 (for women of childbearing 
potential), 24 (Primary), 36, and 48
Cohort 2:
•
Screening Visit 
•
Group A:
Treatment Period Visits: Baseline/Day 1, Weeks 4, 8, 12, 
13, 14, 16, 20, 24, 28, 32, and 36


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FU Visits: Weeks 1, 4, 8, 12, 16 (for women of childbearing 
potential), 24 (Primary), 36, and 48
•
Group B: 
Treatment Period Visits: Baseline/Day 1, Weeks 1, 2, 4, 8, 
12, , 14, 16, 20, and 24
FU Visits: Weeks 1, 4, 8, 12, 16 (for women of childbearing 
potential), 24 (Primary), 36, and 48
Screening assessments include: 
•
Obtain informed consent 
•
Review of inclusion/exclusion criteria
•
Obtain medical history (including HBV disease and treatment 
history)
•
Review concomitant medications
•
Complete physical examination
•
Vital signs
•
Body weight and height
•
12-Lead electrocardiogram (ECG) (Participants must rest 
quietly in the supine position for a minimum of 5 minutes prior 
to the recording)
•
Chest x-ray
•
Ophthalmologic examination
•
FibroScan (where available and as necessary for liver disease 
staging)
•
Sample collection for:
Safety laboratory tests (hematology, chemistry, and 
coagulation)
AST to platelet ratio index (APRI), FibroTest, α-fetoprotein 
(computed tomography [CT] scan with contrast for 
participants with α-fetoprotein ≥ 50 ng/mL at screening)
Serology testing to exclude HCV, HDV, and HIV infection
Quantitative plasma HBV DNA
Quantitative HBV serum HBsAg, HBcrAg, HBeAg, and 
HBV RNA 
Qualitative HBV serology HBeAg, HBeAb, and HBsAg, 
HBsAb
Estimated CLcr (using the Cockcroft-Gault method)
Other screening laboratory tests: urinalysis, urine drug 
screen, alcohol screen, autoantibodies, quantification of 


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thyroid-stimulating hormone (TSH) levels, and serum 
β human chorionic gonadotropin (β-hCG) (females of 
childbearing potential only), follicle-stimulating hormone 
(FSH) (for female participants who are < 54 years old who 
are not on hormonal contraception and who have stopped 
menstruating for ≥ 12 months but do not have 
documentation of ovarian hormonal failure)
Serum sample for HBV viral sequencing, genotyping 
sample, and ddPCR
•
Record any serious adverse events (SAEs) and all AEs related to 
protocol mandated procedures occurring after signing of the 
consent form.
Treatment assessments include: 
•
Vital signs 
•
Weight 
•
Review AEs 
•
Review concomitant medications
•
Complete Physical Examination
•
Symptom-directed physical examination
•
12-Lead ECG (Participants must rest quietly in the supine 
position for a minimum of 5 minutes prior to the recording)
•
Symptoms-directed ophthalmologic examination
•
Sample collection for:
Safety laboratory tests (hematology and chemistry; 
coagulation)
APRI and FibroTest
Quantitative plasma HBV DNA 
Quantitative serum HBsAg, HBcrAg, HBeAg, and HBV 
RNA 
Qualitative HBV serology HBeAg, HBeAb, and HBsAg, 
HBsAb
Collection of PBMC, whole blood, serum, and plasma 
samples for biomarker analysis
Sparse PK samples
Urine pregnancy test (females of childbearing potential 
only) 
Urinalysis
Estimated CLcr (using Cockcroft-Gault method)


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• 
• 
Final 
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-
Sernm sample for HBV viral sequencing, genotyping 
sample, and ddPCR 
• 
Perfo1m study drng accountability, dispensation, and 
administration (TAF, as needed, nivolumab IV, SLGN, and 
VIR-2218 SC) 
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Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
CONFIDENTIAL 
Final 
Amendment2 
Selgantolimod will be supplied as tablets in strengths of 1.5 mg. 
SLGN 3 mg (2 x 1.5-mg tablets) will be administered while fasting, 
once a week, on the same day. Participants must be fasting for at 
least 8 hours overnight (no food or drinks, except water) and 
continue through the morning, with no food or drinks, including 
water, 1 hour before to 2 hours after dosing. After 2 hours postdose, 
water is allowed and after 4 hours postdose, participants are allowed 
food and drinks. Participants should take their other prescribed 
medications, including NUC treatment, no earlier than 2 hours after 
SLGN dosing or, if medications require dosing with food, no earlier 
than 4 hours after SLGN dosing. 
VIR-2218, 200 mg/mL, solution for injection will be supplied as 
0.5 mL single dose vials. VIR-2218 200 mg (2 x 0.5 mL solution) 
will be administered SC. 
Nivolumab (Opdivo®) 40 mg/4 mL solution for injection was 
supplied as single dose vials. Nivolumab 0.3 mg/kg was 
administered as IV infusion over 45-60 minutes. 
TAF 25-mg tablet orally once daily with food. 
None 
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Criteria for 
Evaluation:
Safety:
Safety will be evaluated by assessment of clinical laboratory tests 
and AEs collected through FU Week 48. The primary safety 
analysis will be evaluated through 30 days posttreatment of 
SLGN ± nivolumab ± VIR-2218.
Posttreatment is defined as the following:
•
For VIR-2218 and nivolumab, posttreatment will start 4 weeks 
after last dose. 
•
For SLGN, posttreatment will start 1 week after last dose.
Posttreatment for each cohort will be based on the last study drug(s) 
end of the treatment window duration that is the longest.
The safety analysis will also be conducted through FU Week 24 as a 
secondary safety analysis.
Efficacy:
Primary efficacy endpoint:
•
The proportion of participants who achieve functional cure, 
defined as HBsAg loss and HBV DNA < LLOQ at FU Week 24
Secondary efficacy endpoints:
•
The proportion of participants with HBsAg loss with and 
without anti-HBsAg seroconversion during the study
•
The proportion of participants with HBeAg loss with and 
without anti-HBeAg seroconversion during the study in 
participants with CHB who are HBeAg positive at baseline
•
The proportion of participants who remain off NUC treatment 
during FU
•
The proportion of participants experiencing HBV virologic 
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Phannacokinetics: 
Statistical Methods: 
Final 
Amendment2 
Sparse PK blood samples will be collected at specific in-clinic 
treatment visits for all paiiicipants at the time points specified in the 
protocol. 
concentrations of SLGN and VIR-2218, and sernm concentrntions 
of nivolumab may be analyzed (as applicable, from existing 
samples). 
The primaiy analysis will be conducted after all participants within 
each coho1i have completed FU Week 24 or eai·ly tenninated from 
the study prior to FU Week 24. 
The primaiy efficacy endpoint is the proportion of participants who 
achieve functional cme, defined as HBsAg loss and HBV 
DNA < LLOQ at FU Week 24. 
The primaiy efficacy analysis will summai·ize the prima1y efficacy 
endpoint for each treatment coho1i . A point-estimate with 2-sided 
95% exact CI will be constrncted for the propo1iions using the 
binomial distribution (Clopper-Peai·son method). 
The secondaiy efficacy endpoints will be summai·ized by treatment 
coho1i. 
Continuous secondaiy endpoints will be summarized using 
conventional descriptive statistics (n, mean, SD, median, first 
quaitile [Ql], third quaitile [Q3], minimum, and maximum) by 
treatment coho1i. 
Categorical secondaiy endpoints will be summarized by number 
and percentage of paiiicipants who meet the endpoint by treatment 
cohort. 
Safety will be evaluated by treatment coho1i. It will be sUilllnai·ized 
by the number and percentage of participants with AEs or 
laborato1y abno1malities for categorical values or by the 
conventional descriptive statistics (n, mean, SD, median, Ql, Q3, 
minimum, and maximum) for continuous data. 
Sample Size 
pa1ticipants in each treatment coho1t was decided based on clinical 
expenence. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice, 
including archiving of essential documents. 
CONFIDENTIAL 
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
z
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the log concentration of drug versus time curve of the drug
Ab
antibody
ABW
actual body weight
ADR
adverse drug reaction
AE
adverse event
ALT
alanine aminotransferase
AMA
antimitochondrial antibodies
ANA
antinuclear antibodies
APRI
AST to Platelet Ratio Index
AST
aspartate aminotransferase 
AUC
area under the concentration versus time curve
AUC0-24
partial area under the concentration versus time curve from time “0” to time “24”
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCinf
area under the concentration versus time curve extrapolated to infinite time, calculated 
as AUClast + (Clast/z)
β-hCG
β human chorionic gonadotropin
cccDNA
covalently closed circular DNA
CD
cluster of differentiation
CFR
Code of Federal Regulations
CHB
chronic hepatitis B
CI
confidence interval
CK
creatine kinase
Clast
last observed quantifiable concentration of the drug
CLcr
creatinine clearance
CL/F
apparent oral clearance
Cmax
maximum observed concentration of drug
COPD
chronic obstructive pulmonary disease 
COVID-19
coronavirus disease 19
CRF
case report form
CRO
contract (or clinical) research organization
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DDI
drug-drug interaction
ddPCR
digital droplet polymerase chain reaction


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DILI
drug-induced-liver injury
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation 
EDC
electronic data capture
ELIspot
enzyme-linked immunospot assay
EOT
end of treatment
ESC+
Enhanced Stabilization Chemistry Plus
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
FU
follow-up
GalNAc
N-acetyl-galactosamine ligand
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
Gilead
Gilead Sciences, Inc.
GSI
Gilead Sciences, Inc.
HAV
hepatitis A virus
HBV
hepatitis B virus
HBcrAg
hepatitis B core-related antigen
HBeAb
hepatitis B e antibody
HBeAg
hepatitis B e antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDPE
high-density polyethylene
HDV
hepatitis D virus
HEV
hepatitis E virus
HIV, HIV-1
human immunodeficiency virus, type 1
HLA
human leukocyte antigen
HLGT
high-level group term
HLT
high-level term
IB
investigator’s brochure


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ICF
informed consent form
ICH
International Conference on Harmonization (of Technical Requirements for 
Registration of Pharmaceuticals for Human Use)
IEC
independent ethics committee
IFN
interferon
Ig
immunoglobulin 
IgM
immunoglobulin M
IL
interleukin
IND
investigational new drug (application)
INR
international normalized ratio
irAE
immune-related AE
IRB
institutional review board
IRR
infusion-related reaction
ISR
injection site reaction
IV
intravenous
LDH
lactic acid dehydrogenase
LDL
low-density lipoprotein
LLOQ
lower limit of quantitation
LLT
lower-level term
mAb
monoclonal antibody
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NK
natural killer cells
NOAEL
no-observed-adverse-effect-level
NRTI
nucleoside reverse transcriptase inhibitor
NSAID
nonsteroidal anti-inflammatory drug
NUC
nucleos(t)ide(s)
OAV
oral antiviral
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamic(s)
PD-1
programmed cell death protein 1
PEG
polyethylene glycol
PG
pharmacogenomic
PgRNA
pregenomic RNA
PHH
primary human hepatocytes
PI
principal investigator
PK
pharmacokinetic(s)
PS
PT
Patient Safety
preferred term


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QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave, representing the time for both ventricular depolarization and repolarization to 
occur
QTcF
QT interval corrected for heart rate using the Fridericia formulation
Q1
first quartile
Q3
third quartile
RBC
red blood cell
RNA
ribonucleic acid
RT
reverse transcriptase
SADR
serious adverse drug reaction
SAE
serious adverse event 
SC
subcutaneous(ly)
Scr
serum creatinine
SD
standard deviation
SDV
source data verification
siRNA
short interfering RNA
SLGN
selgantolimod
SMA
smooth muscle antibodies
SMQ
Standardised MedDRA Query
SNP
single-nucleotide polymorphism
SOC
system organ class
SOP
standard operating procedure
SSR
special situation report
SUSAR
suspected unexpected serious adverse reaction
TAF
tenofovir alafenamide (Vemlidy®)
TDF
tenofovir disoproxil fumarate
TEAE
treatment-emergent adverse event
TE
treatment emergent 
TFFU
treatment-free follow-up
TFV
tenofovir
Tlast
time (observed time point) of Clast
TLR
toll-like receptor
Tmax
the time (observed time point) of Cmax
TNF
tumor necrosis factor
TPO
thyroid peroxidase
TSH
thyroid-stimulating hormone
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (λz)
ULN
upper limit of normal
US, USA
United States, United States of America
WBC
white blood cell


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WHV
woodchuck hepatitis virus
WHsAg
woodchuck hepatitis virus surface antigen


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1.
INTRODUCTION
1.1.
Background
Chronic hepatitis B (CHB) is a major public health care issue worldwide and one of the principal 
causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The hepatitis B 
virus (HBV) is easily transmissible through perinatal, percutaneous, and sexual exposure 
{World Health Organization (WHO) 2015b}. Following acute HBV infection, 5% to 10% of 
adults and up to 90% of children fail to produce an immune response adequate to clear the 
infection; these individuals become chronic carriers of the virus {Zuckerman 1996}. Individuals 
who develop CHB are at substantial risk of cirrhosis, hepatic decompensation, and HCC, which 
will afflict 15% to 40% of patients with CHB in the absence of effective treatment 
{Ratnam 2006, World Health Organization (WHO) 2015a}. Liver cancer is the third leading 
cause of cancer deaths globally, with the highest burden of disease found in regions where HBV 
is endemic {Global Burden of Disease Cancer Collaboration 2015}. Recent reports estimated 
that 250 to 350 million individuals were living with HBV (ie, are hepatitis B surface antigen 
[HBsAg]-positive) in 2010, representing a worldwide prevalence of 3.6%, with considerable 
geographic variability {Schweitzer 2015, World Health Organization (WHO) 2015c}. In 2015, 
an estimated 654,000 deaths were due to HBV infection and associated complications, placing it 
among the top 20 causes of mortality worldwide {G. B. D. Mortality Causes of Death 
Collaborators 2016}. 
The loss of HBsAg, accompanied by seroconversion to anti-HBsAg, is the accepted endpoint for 
anti-HBV therapy endorsed by the American Association for the Study of Liver Diseases, the 
European Association for the Study of the Liver, and the Asian Pacific Association for the Study 
of the Liver allowing for cessation of therapy {European Association for the Study of the Liver 
(EASL) 2012, European Association for the Study of the Liver (EASL) 2017, Lok 2009}, 
{Sarin 2015, Terrault 2016}. Clearance of HBsAg has been associated with improvements in 
liver histology, including the reversal of cirrhosis, a decreased risk of HCC, and prolonged 
survival, and is considered evidence of a functional cure {Benias 2011, Fattovich 1998, 
Kim 2013}. Nucleos(t)ide (NUC) analogs are the standard-of-care for CHB treatment, providing 
durable suppression of viral replication that results in long-term clinical benefits with a reduced 
risk of liver complications {Dienstag 2003, Liaw 2011, Lok 2013}. However, treatment with 
NUCs rarely results in clearance of HBsAg {Kwon 2011}. Thus, new treatment options that 
enhance rates of HBsAg clearance are needed; such treatments will allow patients to discontinue 
life-long oral antiviral (OAV) therapy and provide a finite-duration treatment option for a 
functional cure. A finite therapy is expected to be applicable to a broader population of those 
chronically infected with HBV, including immunotolerant patients who are currently untreated.
The host immune response to HBV infection plays a pivotal role in whether acute infection is 
resolved or becomes chronic. Individuals who are able to clear HBV infection spontaneously 
following an acute infection display a vigorous, polyclonal, HBV-specific cluster of 
differentiation (CD)8+ and CD4+ T-cell response {Rehermann 2005}. In contrast, CHB is 
associated with a limited and dysfunctional CD8+ T-cell response, as well as impaired natural 


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killer (NK) cell antiviral function {Peppa 2010, Rehermann 2005}. Suppression of HBV DNA 
with NUC analogs has been associated with overall improvements in the ability of the immune 
system to respond to HBV antigens {Evans 2008, Mizukoshi 2004, Sherman 2013}. The 
suppression of HBV DNA also results in the reduction of regulatory T cells, an increase in 
HBV-specific CD8+ T cells and reduction in exhaustion markers (such as programmed cell death 
protein 1 [PD-1]) on CD8+ T cells {Evans 2008, Sherman 2013}. These improvements, 
however, are modest and do not result in durable immune control with loss of HBsAg in the 
majority of treated participants. However, further control of HBV viral antigens with HBV DNA 
suppression and the enhancement of virus-specific immune responses, may theoretically enhance 
rates of durable control of HBV.
1.2.
General Information About Study Drugs
1.2.1.
General Information About Selgantolimod
Selgantolimod (SLGN, also GS-9688) is a Toll-like receptor 8 (TLR8) agonist that induces the 
cellular immune mediator interleukin (IL)-12 and the antiviral cytokines tumor necrosis factor 
(TNF)-α and interferon (IFN)- γ in vitro in peripheral blood mononuclear cells (PBMCs). 
Cytokine induction by SLGN is comparable in PBMCs from patients with CHB and from 
healthy donors. Selgantolimod induces little to no IFN-α (a cytokine induced by TLR7 agonists) 
in human PBMCs in vitro, indicating that SLGN is a potent and selective TLR8 agonist in 
primary human immune cells. Selgantolimod activates monocytes and professional antigen-
presenting cells (pAPCs) in vitro in PBMCs from healthy donors. It also activates NK cells and 
total CD8+ T cells in vitro in PBMCs isolated from both healthy donors and patients with CHB. 
Additionally, SLGN increases IFN-γ production and reduces expression of the inhibitory 
receptor PD-1 by HBV-specific CD8+ T cells. Cytokines induced by SLGN in healthy human 
donor PBMCs in vitro reduce the levels of HBV DNA, HBV RNA, HBsAg, and hepatitis B e 
antigen (HBeAg) in HBV-infected primary human hepatocytes (PHH). Prophylactic treatment 
with cytokines induced by SLGN prevents establishment of HBV covalently-closed circular 
DNA (cccDNA) in PHH in vitro.
In cynomolgus monkeys, dose-dependent induction of serum IL-12p40, IL-1RA, and other 
cytokines was observed following oral administration of SLGN at doses ≥ 0.3 mg/kg. These 
pharmacodynamic (PD) markers are consistent with TLR8 activation. In woodchucks chronically 
infected with the woodchuck hepatitis virus (WHV), once-weekly oral administration of 3 mg/kg 
SLGN for 8 weeks resulted in > 2 log10 IU/mL reduction of serum woodchuck hepatitis virus 
surface antigen (WHsAg) and WHV DNA in 4 of 6 woodchucks. This antiviral response was 
sustained in 3 of 6 woodchucks until the end of study. Moreover, these 3 animals developed 
detectable anti-WHsAg and had > 95% reduction in intrahepatic WHV cccDNA at the end of 
study.
Selgantolimod shows low systemic concentrations across multiple species (rat, dog, and 
cynomolgus monkey), indicating low potential for immune activation in the periphery. Mouse 
and cynomolgus monkey toxicology studies of ≥ 13 weeks (≥ 14 doses) demonstrated that SLGN 
was well tolerated and nonadverse at doses up to 10 mg/kg/week in the mouse and 
30 mg/kg/week in the monkey. At the highest observed exposure in a clinical study 
(GS-US-389-2022) with a clinical dose of 3 mg, the exposure margins at the no observed adverse 


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effect level (NOAEL) based on the AUC are approximately 192-fold and 37-fold for mouse and 
cynomolgus monkey, respectively.
A first-in-human (FIH) pharmacokinetic (PK) and food-effect study (GS-US-389-2021) was 
completed in healthy participants. For the 48 participants who received a single dose of 0.5, 1.5, 
3, or 5 mg of SLGN, the dose was generally safe and resulted in dose-dependent increases in 
serum IL-12p40 and IL-1RA. For the 12 participants who received a single dose of 1.5 mg in 
both the fed and fasted states, SLGN plasma concentrations were similar between the 2 states, 
whereas serum IL-12p40 and IL-1RA were strongly reduced when SLGN was dosed with food. 
Based on these data, subsequent clinical evaluations are conducted under fasted conditions. 
A drug-drug interaction (DDI) study (GS-US-389-5545) to evaluate the PK and 
pharmacodynamics (PD) of SLGN upon coadministration with a representative proton pump 
inhibitor (omeprazole) or histamine 2 receptor antagonist (famotidine) was completed in healthy 
participants. Statistical comparisons of SLGN AUC between SLGN administered alone versus in 
combination with either omeprazole or famotidine were within the predefined no-effect DDI 
boundary of 70% to 143%, indicating a lack of significant effect on SLGN PK. There was no 
clinically significant impact of omeprazole or famotidine on relevant PD markers of SLGN. 
These data demonstrate that SLGN may be administered without regard to acid-reducing agents 
such as omeprazole or famotidine thereby not warranting any dosing adjustments.
Limited dosing of SLGN has been evaluated in participants with CHB (Studies 
GS-US-389-2022, GS-US-389-2024, and GS-US-389-2025) and was shown to be generally safe 
and well tolerated. In the GS-US-389-2022 study, doses of 1.5 mg and 3 mg resulted in 
dose-dependent induction of IL-12p40 and IL-1RA, with no evidence of tachyphylaxis with up 
to 4 doses of SLGN. Pharmacokinetic data show similar exposures in participants with CHB 
compared with healthy participants in the FIH study, with no accumulation over time. At the 
interim Week 48 analysis for Study GS-US-389-2024, 1 participant (HBeAg negative in the 
SLGN 1.5-mg dose group) met the primary endpoint of ≥ 1 log10 IU/mL decline from baseline in 
HBsAg at Week 24. Based on the interim safety data from Studies GS-US-389-2024 and 
GS-US-389-2025, nausea, vomiting, and iridocyclitis were added as adverse drug reactions 
(ADRs) for SLGN at the current stage of development.
For further information on SLGN, refer to the investigator’s brochure (IB) for SLGN.
1.2.1.1.
Ongoing Studies
There is an ongoing Phase 1b study assessing safety, tolerability, and efficacy of once-weekly 
administration of SLGN 3 mg in special populations with CHB (GS-US-389-5458). This study is 
evaluating SLGN in 3 populations with CHB: (1) immune tolerant HBV with HBV DNA 
≥ 1  107 IU/mL, (2) patients with inactive HBV (HBV DNA ≤ 2000 IU/mL) at screening, and 
(3) HBV/hepatitis D virus (HDV) coinfected participants on suppressive NUC therapy. Based on 
the interim safety data at Week 24, no new safety issues for SLGN have been observed.


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1.2.2.
General Information About Nivolumab 
Nivolumab (Opdivo®, BMS), an anti-PD-1 immunoglobulin (Ig)G4 monoclonal antibody (mAb), 
is approved for the treatment of metastatic melanoma and is under development for other 
malignancies including lung cancer and HCC. The clinical dose of nivolumab is 3 mg/kg 
intravenously (IV) every 2 weeks, though initial dose ranging studies in melanoma demonstrated 
equivalent receptor occupancy of peripheral lymphocyte PD-1 at doses as low as 0.1 mg/kg 
{Topalian 2012}. In those studies, clinical effect for melanoma was observed at all doses tested. 
The lowest doses of 0.1 mg/kg and 0.3 mg/kg were not associated with Grade 3 or 4 serious 
adverse events (SAEs) or Grade 3 or 4 adverse events (AEs) of special interest (including 
autoimmune AEs) and had lower rates of treatment-related Grade 3 or 4 AEs compared with 
higher dose groups. 
Nivolumab has also been studied in a single dose study in hepatitis C virus (HCV) (N = 45) with 
dose ranges of 0.03 mg/kg to 10 mg/kg {Gardiner 2013}. The majority of AEs were Grade 1 or 2 
with a single Grade 4 alanine aminotransferase (ALT) elevation in the highest dose evaluated. 
All immune-related AEs (irAE) were mild to moderate and resolved without intervention. 
Reductions in HCV RNA were modest and seen in 5/45 (11%) of treated participants at doses as 
low as 0.1 mg/kg, although the highest dose of 10 mg/kg induced a > 4 log10 IU/mL reduction in 
HCV RNA in 3 participants (n = 20 total at this dose).
Nivolumab has also been evaluated for HCC (related to HCV, HBV or neither), where a 
subpopulation of 66 HBV-infected participants with HCC were dosed with nivolumab at doses 
of 0.1 mg/kg to 3.0 mg/kg IV every 2 weeks. No participants with HBV in either the dose 
escalation phase or in the expansion phase discontinued treatment due to study drug toxicity. 
Among the HBV-infected participants with HCC who received nivolumab at 3.0 mg/kg IV every 
2 weeks (n = 51), no participants experienced Grade 3 or 4 ALT/aspartate aminotransferase 
(AST) increases and 6% (n = 3) experienced a Grade 3 or 4 treatment-related AE 
{El-Khoueiry 2017}.
For further information on nivolumab, refer to the current approved product label for nivolumab.
1.2.2.1.
Ongoing Studies 
There are no other ongoing Gilead-sponsored studies with nivolumab. 
1.2.3.
General Information About Tenofovir Alafenamide (TAF)
Vemlidy® (TAF, GS-7340) is a novel oral prodrug of tenofovir (TFV), a NUC analog that 
inhibits HIV-1 reverse transcription. Tenofovir is metabolized intracellularly to the active 
metabolite, tenofovir diphosphate, a competitive inhibitor of HIV-1 reverse transcriptase (RT) 
and HBV RT that terminates the elongation of the viral DNA chain. 
For further information on TAF, please refer to the approved product label for TAF.


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1.2.4.
General Information About VIR-2218
VIR-2218 is a short interfering RNA (siRNA) that targets a region of the HBV genome that is 
common to all HBV viral transcripts. The siRNA is chemically modified using Enhanced 
Stabilization Chemistry Plus (ESC+) consisting of 2’-fluoro (2’F), 2’-O-methoxy (2’OMe) 
ribose sugar modifications, phosphorothioate backbone modifications, glycol nucleic acid 
modification, and conjugation to a triantennary N-acetyl-galactosamine ligand (GalNAc) at the 
3’ end of the sense strand, to facilitate delivery to hepatocytes through the asialoglycoprotein 
receptor. The drug product, VIR-2218, is the drug substance of VIR-2218 formulated in water 
for subcutaneous (SC) injection. VIR-2218 is pharmacologically active against HBV genotypes 
A through J; see the current IB for additional information on VIR-2218. The use of siRNA offers 
a novel strategy for the treatment of chronic HBV infection. The siRNAs are 19-21 base-pair 
RNA duplexes that exploit the endogenous RNA-interference pathway to enable 
sequence-specific RNA cleavage and degradation. One siRNA can have multiple antiviral 
effects, including degradation of the pregenomic RNA (pgRNA), thus inhibiting viral replication, 
and degradation of all viral messenger RNA transcripts, thereby preventing expression of viral 
proteins. This may result in the return of a functional immune response directed against HBV, 
especially if combined with other therapies, in particular, immune modulatory agents.
By contrast, nucleoside reverse transcriptase inhibitors (NRTIs) act at a distinct part of the viral 
life cycle and have a different mechanism of action than VIR-2218. NRTIs inhibit the action of 
HBV RNA polymerase, blocking the reverse transcription of the viral pgRNA to viral DNA and 
preventing the production of infectious virions. NRTIs, however, do not directly impact the 
production of viral proteins such as HBsAg. Reduction of HBsAg-containing noninfectious 
subviral particles by VIR-2218 is considered an important differentiator from current treatments.
For further information, refer to the IB for VIR-2218.
1.3.
Rationale for the Current Study
1.3.1.
Rationale for Modifications to Study Design
Nivolumab was chosen in the initial study design, as an immunomodulator, in order to reverse 
HBV mediated T-cell exhaustion to induce an HBV-specific immune response to subsequently 
achieve an HBV functional cure. 
Nivolumab dosing was stopped for all participants in this study. This was a sponsor decision 
based on a benefit risk assessment of the use of nivolumab in HBV cure. For Cohort 2 Group B, 
where participants were originally designed to be treated with SLGN and nivolumab, Gilead 
made the decision to stop all treatment in this cohort on account of low likelihood of efficacy 
with SLGN alone, based on results from previous studies {Gane 2023, Janssen 2021}. Study 
participants in Cohorts 1 and 2 (Group A) will continue all other treatments (SLGN and 
VIR-2218) up to Week 36.


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1.3.2.
Rationale for This Study as Originally Designed 
Given the low rate of HBsAg loss with currently available therapies and the treatment burden 
associated with life-long treatment to maintain viral suppression, there is a need to identify new 
therapies that may provide durable HBsAg loss with a finite treatment duration. The host 
immune response to HBV infection plays a pivotal role in whether acute infection is resolved or 
becomes chronic. Individuals who are able to clear HBV infection spontaneously following an 
acute infection display a vigorous, polyclonal, HBV-specific CD8+ and CD4+ T-cell response 
{Rehermann 2005}. In contrast, CHB is associated with a limited and dysfunctional CD8+ T-cell 
response, as well as impaired NK-cell antiviral function {Peppa 2010, Rehermann 2005}. The 
primary objective of this Phase 2 study is to evaluate the safety, tolerability, and efficacy of 
novel HBV immunomodulatory containing combination regimens in association with or without 
a HBV targeted siRNA for the treatment of participants with CHB.
This Phase 2 study was originally intended to evaluate the safety and efficacy of combination 
treatment with 2 immunomodulatory agents, a toll-like receptor 8 (TLR8) agonist, SLGN, and a 
PD-1 checkpoint inhibitor, nivolumab, with and/or without siRNA, VIR-2218, in both virally 
suppressed and viremic participants with CHB. The aim of the virally suppressed cohort was to 
evaluate the hypothesis that maximum viral and antigen reduction before immunomodulation 
therapy will improve HBV-specific immune response to combination treatment. In contrast, the 
aim of the viremic cohorts is to evaluate the hypothesis that immune modulation in the presence 
of active liver inflammation caused by HBV infection will improve HBV-specific immune 
response to treatment. Immune active, viremic patients have been well characterized by a 
pro-inflammatory state with the presence of high viral burden and active liver inflammation. The 
effectiveness of immunomodulatory agents targeting functional improvement of exhausted 
HBV-specific CD8+ T cell in immune active patients with and without an siRNA has not yet 
been evaluated. 
Multiple studies have recently demonstrated that NUCs can be safely stopped with a close safety 
monitoring plan in a noncirrhotic patient population {Buti 2019}. Therefore, participants who 
are virally suppressed, HBeAg negative and have HBsAg < 100 IU/mL at end of treatment 
(EOT), will enter a treatment-free follow-up (TFFU) period after completion of study treatment, 
where they will be closely followed with safety visits every 4 weeks in the first 3 months and 
then every 8 weeks for a total of 48 weeks. Criteria for initiation of NUC treatment during 
follow-up (FU) period have been defined to guide investigators and allow for evaluation of 
predictors of response. The aim of the TFFU period will be to evaluate the continued 
off-treatment response to siRNA and/or SLGN plus nivolumab, which have all demonstrated 
prolonged/sustained activity beyond the dosing period {Gane 2020}. 
1.4.
Rationale for Dose Selection of Study Drugs
1.4.1.
Rationale for Dose Selection of Selgantolimod
The safety, PD, and PK of SLGN have been evaluated in healthy volunteers and participants 
with CHB. Selgantolimod has demonstrated dose-dependent induction of IL-12p40 and IL-1RA, 
PD markers of SLGN pharmacological activity, and comparable PK in both populations 


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(GS-US-389-2021 and GS-US-389-2022). Food effect evaluation on SLGN disposition in the 
FIH study (GS-US-389-2021) showed comparable SLGN plasma exposures in the fed and fasted 
state, however, the PD markers markedly reduced in the presence of food which led to dosing of 
SLGN in fasted conditions in subsequent clinical evaluations.
The safety and efficacy of SLGN 1.5 mg and 3 mg weekly for 24 weeks in combination with 
NUC therapy has been evaluated in 2 ongoing Phase 2 studies in virally suppressed and viremic 
participants with CHB (GS-US-389-2024 and GS-US-389-2025, respectively) and in the 
Phase 1b study assessing safety and efficacy of once-weekly administration of SLGN 3 mg 
coadministered with nivolumab (dosed IV every 4 weeks) in virally suppressed participants 
(GS-US-493-5342). Safety data from these studies indicate that SLGN treatment (at doses of 
1.5 mg and/or 3 mg, once weekly) was generally safe and well tolerated.
Based on the collective clinical data available to date, in this study, once-weekly dosing of 
SLGN 3 mg (the higher of the 2 evaluated doses) for 24 weeks in fasted state was proposed for 
administration with nivolumab ± VIR-2218.
For further information, refer to the current IB for SLGN.
1.4.2.
Rationale for Dose Selection of Nivolumab
In a Phase 1 study, GS-US-330-1938, the safety and efficacy of a single IV dose of nivolumab 
0.3 mg/kg was evaluated in virally suppressed participants with CHB. After the single IV 
administration, 3 out of 22 (14%) participants had > 0.5 log10 IU/mL reduction in HBsAg with 
1 participant achieving > 1 log10 IU/mL reduction. This participant achieved HBsAg loss and 
anti-HBs seroconversion 10 weeks after completing the study, as reported by the investigator 
{Gane 2019}. Overall, single IV administration of nivolumab 0.3 mg/kg was safe and well 
tolerated. No deaths, SAEs, Grade 3 or 4 AEs, or laboratory abnormalities, except for the 
1 participant who achieved HBsAg loss and had a Grade 3 ALT flare, were reported. The only 
nivolumab-related AEs as determined by the investigator were fatigue, headache, and cough 
which were reported in only 1 participant each. Additionally, in Study GS-US-493-5342, 
nivolumab 0.3 mg/kg once every 4 weeks (dosed IV for 12 weeks), alone or in combination with 
SLGN in virally suppressed participants with CHB, was shown to be generally safe.
Based on these data, this study will evaluate the safety and efficacy of 0.3 mg/kg nivolumab 
dosed IV once every 4 weeks for 24 weeks in combination with: SLGN and VIR-2218 in virally 
suppressed participants with CHB, and SLGN ± VIR-2218 in viremic participants with CHB.
1.4.3.
Rationale for Dose Selection of TAF
TAF 25 mg administered orally once daily with food is the approved dose for the treatment of 
CHB virus infection in adults (≥ 18 years of age) with compensated liver disease 
{VEMLIDY 2020}.


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1.4.4.
Rationale for Dose Selection of VIR-2218
Available safety, tolerability, antiviral activity, and PK/PD data from Parts A-C of Study 
VIR-2218-1001 were considered when selecting dose levels for VIR-2218 in combination with 
VIR-3434. In Part A of the VIR-2218-1001 study, a single SC dose of VIR-2218 was 
administered to healthy participants over the dose range of 50 to 900 mg. In Parts B and C of the 
study, 2 doses of VIR-2218 given 4 weeks apart, ranging from 20 to 200 mg were administered 
to participants with chronic HBV infection. VIR-2218 was well tolerated across all dose levels 
evaluated, with no significant safety signals observed. 
In healthy adult participants, VIR-2218 was absorbed after SC injection with median Tmax of 4 to 
7 hours in plasma. Consistent with rapid GalNAc-mediated liver uptake {Nair 2017}, VIR-2218 
was not measurable in plasma beyond 48 hours for any participant. PK data following a single 
SC dose suggest that VIR-2218 AUC0-12 and Cmax exposures increase with dose and were slightly 
greater than dose-proportional across the dose range evaluated. Available PK data from HBV 
participants were similar to that observed in healthy participants. No accumulation of VIR-2218 
in plasma was evident following a second dose of VIR-2218 administered 4 weeks apart in 
participants with chronic HBV infection. 
Despite rapid elimination of VIR-2218 from plasma, prolonged presence is anticipated in the 
liver, based on tissue PK of VIR-2218 in nonclinical species and data from other 
GalNAc-conjugated siRNA molecules {Janas 2018}. Since no direct measurement of liver PK 
was available from human participants in the study, liver PK data from nonclinical studies were 
initially used to predict human liver PK based on allometric scaling. Using a model describing 
the onset, peak, and durability of PD response for a chemically similar ESC-GalNAc-siRNA 
{Attarwala 2017} and available rat tissue PK data for VIR-2218, the human liver half-life of 
VIR-2218 was previously estimated to be approximately 40 days. An updated analysis was 
conducted using measured HBsAg following VIR-2218 treatment in participants with chronic 
HBV infection (from Study VIR-2218-1001 Parts B and C). A sequential PK-PD modeling 
approach was applied to estimate PK parameters of VIR-2218 in plasma, then an effect 
compartment representing the site of drug action in liver was used to link the plasma PK and 
HBsAg reduction observed over time in an indirect response PK-PD model. The PK-PD model 
described the observed VIR-2218 plasma PK and HBsAg data well and predicted a half-life of 
approximately 80 days in the liver.
The liver half-life of VIR-2218 of 80 days was used to estimate VIR-2218 liver tissue exposure 
in humans (Table 3). The median liver exposures for the proposed VIR-2218 doses (6 doses of 
200 mg given every 4 weeks) are estimated to not exceed the projected liver exposure of the 
highest dose at which the safety and tolerability of VIR-2218 has been demonstrated (ie, 900 mg 
single dose).


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Table 3.
Estimated Median VIR-2218 Liver Tissue Exposure in Humans Based 
on PK-PD Model
Simulated Dosing Regimen
Cmax (μg/g)
AUC (h*μg/g)
900 mg single dose
61.1
34,300 (135,000) a
200 mg Q4W  6
52.9
34,100 b
PD = pharmacodynamics; PK = pharmacokinetics; Q4W = once every 4 weeks
a
For single dose regimens, partial AUClast up to Day 29 is presented; AUCinf is also presented in parenthesis.
b
For multiple dose regimens, AUC refers to AUClast during the 28-day dosing interval following 2 or 6 doses of VIR-2218.
Taken together, the observed safety and tolerability of VIR-2218, in conjunction with 
estimations of VIR-2218 liver exposure, support the VIR-2218 regimen selected for this study 
1.5.
Benefit/Risk Assessment for the Study
Chronic hepatitis B remains a global health concern with significant morbidity worldwide. The 
loss of HBsAg with seroconversion is the gold standard endpoint for anti- HBV therapy and 
allows for cessation of treatment {European Association for the Study of the Liver (EASL) 2012, 
Liaw 2012, Lok 2009}. Loss of serum HBsAg is associated with improvement in both the rates 
of liver cirrhosis and the development of HCC in patients with CHB, and in increased survival 
rate {Idilman 2012, Kim 2013, Moucari 2009, Simonetti 2010}. While HBsAg loss is the 
ultimate goal of treatment, it occurs at a very low rate and over several years: less than 1% of 
patients treated with NUC analogs achieve clearance of HBsAg. Thus, new treatment options 
that enhance rates of HBsAg loss with seroconversion are needed.
Selgantolimod 
Selgantolimod treatment alone have been evaluated in multiple Phase 1 and Phase 2 studies in 
both healthy volunteers and participants with CHB. The longest durations of treatment were 
evaluated in 2 Phase 2 studies, GS-US-389-2024 (NUC-suppressed participants with CHB) and 
GS-US-389-2025 (treatment-naive participants with CHB), that administered placebo, SLGN 
1.5 mg, or 3 mg once weekly with a NUC for 24 weeks to 93 participants with CHB. 
Selgantolimod up to 3 mg once weekly was safe and well tolerated in 102 participants with CHB 
(48 participants in Study GS-US-389-2024 and 54 participants in Study GS-US-389-2025). 
Based on pooled safety review of the SLGN studies, 3 potential ADRs related to SLGN of 
nausea, vomiting, and iridocyclitis were identified. Majority of these ADRs reported have been 
mild or moderate in severity. To mitigate the impact of ADR of nausea and vomiting for SLGN, 
the use of antiemetic (eg, ondansetron) is allowed in the study. A Grade 2 iridocyclitis (in the 
SLGN 1.5-mg dose group) was the only SAE reported that was considered related to SLGN by 
the investigator and led to early study drug discontinuation. This occurred in a participant who 
tested positive for the human leukocyte antigen (HLA)-B27 haplotype, a genetic risk factor 
associated with various immune disorders including anterior uveitis. No Grade 3 or 4 AEs 
considered related to SLGN treatment have been reported in the studies, except for 1 Grade 3 AE 
of rhinorrhea considered possibly related by the investigator that was reported in Study 
GS-US-389-2025. Additional safety results can be found in the IB for SLGN. 


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Nivolumab
In oncology, nivolumab treatment alone has been well characterized and the risks of irAEs are 
listed in the approved product label for nivolumab {OPDIVO 2022}. 
The risk of irAEs has been observed upon administration of nivolumab and other anti PD-1 
mAbs in the oncology setting {Friedman 2016}. These events are a class effect of all immune 
checkpoint inhibitors including nivolumab.
The use of nivolumab in HBV cure was based on the hypothesis that lower doses of the product 
with less frequent dosing would result in a reduced risk of irAEs. In Gilead studies, including 
Study GS-US-465-4439, nivolumab has been dosed at approximately 1/10th of the clinically 
approved oncology dose and is administered as only 1 infusion every 4 weeks for up to 6 doses. 
In prior Gilead studies involving patients with HBV, the use of nivolumab alone, or in 
combination with SLGN for up to 3 doses every 4 weeks, was well tolerated {Gane 2019}. 
However, irAEs have been observed at low doses of other anti-PD1 mAbs in non-oncology 
indications {Gubser 2022}. Therefore, the sponsor decision was to stop further dosing of 
nivolumab based on a benefit-risk assessment of the use of nivolumab in HBV cure.
VIR-2218
VIR-2218 is an siRNA that targets a specific sequence in the HBV virus. The safety and 
tolerability of VIR-2218 has been evaluated in an ongoing Phase 1/2 study, VIR-2218-1001 that 
evaluated single doses of VIR-2218 up to 900 mg administered SC in healthy participants 
(Part A) and a regimen of 2 doses administered 4 weeks apart at doses up to 200 mg in 
participants with CHB (Part B/C). In Part A, 59.5% of VIR-2218 participants (22 of 37) and 50% 
of placebo participants (6 of 12) had at least 1 AE, each of which was Grade 1 or 2 in severity 
with the exception of a single Grade 3 AE of respiratory tract infection (considered not related to 
study drug). The most common AEs in VIR-2218 participants were headache (24.3%; 9 of 37 
participants), and upper respiratory tract infection, contact dermatitis, injection site bruising, and 
injection site pain (8.1% each; 3 of 37 participants). Three VIR-2218 participants (8.1%) had 
AEs considered related to study drug by the investigator, including headache, injection site pain, 
and abdominal pain, each of which was Grade 1 in severity. Seven VIR-2218 participants 
(18.9%) had injection site reactions (ISRs). All ISRs were Grade 1 in severity and resolved 
within 12 days of onset. 
In Part B/C, 54.2% of VIR-2218 participants (13 of 24) and 25% of placebo participants (2 of 8) 
had at least 1 AE, each of which was Grade 1 or 2 in severity with the exception of 1 Grade 3 
nonserious AE of hypophosphatemia (considered not related to study drug), a known ADR of 
tenofovir disoproxil fumarate (TDF) with which the participant was receiving treatment. The 
most common AEs in VIR-2218 participants were headache (25.0%; 6 of 24 participants), and 
dizziness, fatigue, and myalgia (8.3% each; 2 of 24 participants). Five participants (20.8%) had 
AEs considered related to study drug by the investigator, including headache, injection site pain, 
and pyrexia, each of which was Grade 1 or 2 in severity. Two VIR-2218 participants (8.3%) each 
had 1 ISR. All ISRs were Grade 1 in severity and resolved within 3 days of onset. Injection site 
reactions were reported in the 50-mg and 100-mg dose cohorts. One treatment-emergent (TE) 


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SAE was reported in Study VIR-2218-1001 in a participant administered 100 mg VIR-2218. The 
SAE of headache was Grade 2 in severity and considered related to study drug by the 
investigator, but the Gilead determined that the constellation of concurrent symptoms (fever, 
headache, nausea, vomiting, and dehydration) was more consistent with a viral syndrome than a 
drug reaction and assessed the event as not related to study drug. Two participants had a non-TE 
SAE considered not related to study drug by the investigator; 1 participant had depression and 
1 participant committed suicide (outcome of death). The death (suicide) occurred approximately 
9 months after last study drug administration.
Selgantolimod + Nivolumab 
In the Phase 1b study, GS-US-493-5342, the combination of SLGN 3 mg oral once weekly plus 
nivolumab 0.3 mg/kg IV every 4 weeks for 12 weeks was evaluated in 14 participants with CHB. 
The combination treatment for 12 weeks was generally safe and well tolerated. The most 
common (> 1 participant) AEs considered related to study drugs by the investigator were nausea 
(n = 6), vomiting (n = 5), headache (n = 2), diarrhea (n = 2), and fatigue (n = 2). To mitigate the 
risk of nausea and vomiting, the use of antiemetics (eg, ondansetron) was allowed during the 
study. No Grade 3 or 4 AEs or SAEs were reported, and no Grade 3 laboratory abnormalities 
were observed. A single Grade 4 laboratory abnormality of elevated lipase was reported 
in 1 asymptomatic participant at posttreatment Week 4 that resolved to below upper limit of 
normal (ULN) 12 weeks later.
Selgantolimod + Nivolumab + VIR-2218
The risk of SLGN plus nivolumab with VIR-2218 is unknown. In nonclinical studies, the 
primary finding for both SLGN and nivolumab was inflammatory cell infiltrates of various 
organs and tissues; an anticipated pharmacological effect of each of the single agents. With 
SLGN at ≥ 3 mg/kg/week in the mouse, nonadverse findings included mononuclear cell 
infiltrates in multiple tissues. Effects became adverse at 30 mg/kg in the kidney, esophagus, 
thymus, spleen, mesenteric lymph node, mandibular salivary gland, Harderian gland, and/or 
lacrimal gland. These findings were partially reversed and/or not observed following the 4-week 
recovery period. In the monkey, SLGN-related nonadverse microscopic findings of inflammatory 
cellular infiltrates were observed in the liver and stomach; All effects exhibited reversibility at 
the end of the recovery phase. The NOAEL in mice and monkeys for SLGN was 10 mg/kg and 
30 mg/kg orally once weekly for 26 weeks and 13 weeks, respectively, and for nivolumab was 
50 mg/kg IV twice weekly for 13 weeks. These doses were associated with exposures (AUC) 
that were 192, 37 and 21 higher, respectively, than the human exposure after a single oral 
3 mg dose of SLGN (selgantolimod IB) and 3 mg/kg dose every 2 weeks IV of nivolumab (Food 
and Drug Administration [FDA] Pharmacology Review 4 Dec 2014). For VIR-2218, the liver 
(rats), kidney (rats), and injection site (rats and monkeys) were identified as potential target 
tissues in the pivotal 6-month (rat), and 9-month (monkey) repeat-dose toxicity studies, typical 
findings of the siRNA class. In rats, nonadverse microscopic liver findings included 
hepatocellular hypertrophy, vacuolation, increased mitoses, single cell necrosis, and basophilic 
granules in Kupffer cells. Basophilic granules were also observed in renal tubular epithelial cells. 
These changes were accompanied by minimal increases in bilirubin (female rats at high dose in 


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4-week study) or minimal to mild increases in ALT and AST (male rats at mid-dose in 6-month 
study). The microscopic changes were partially reversible and the clinical pathology changes 
were fully reversible at the end of the 13-week recovery period. In rats and monkeys, nonadverse 
microscopic findings at the injection sites and draining lymph nodes were noted at all dose levels 
in both sexes and were only partially reversible at the end of the recovery period. The NOAELs 
were 150 mg/kg (rats) and 300 mg/kg (monkeys); the highest doses tested. At the proposed 
clinical dose of 200 mg in this study, the estimated AUClast in humans is approximately 48-fold 
lower compared to the NOAEL in the 6-month rat study, and 187-fold lower compared to the 
NOAEL in the 9-month monkey study.
Based on the large exposure margins in the toxicology studies for the single agents, the risk for 
an exaggerated inflammatory response from the combination of these agents at the proposed 
doses in this Phase 2 clinical study is considered low. The potential for unpredicted off-target 
effects with the combination is considered negligible since nivolumab as an mAb is specific for 
its intended target and off-target activity has not been observed with SLGN even at very high 
exposure margins. While the liver and kidney were identified as target organs for VIR-2218, 
effects were observed at high exposure margins and exaggerated toxicity with SLGN at clinically 
relevant doses is low. Combination toxicity study of the 3 agents were not conducted since the 
potential risks of combining the 3 agents are predictable with low probability of occurrence at 
the proposed doses in this study. Therefore, the nonclinical studies of the single agents are 
considered sufficient for supporting this Phase 2 proof-of-concept study of the combination of 
3 mg SLGN orally once weekly and 0.3 mg/kg nivolumab IV once every 4 weeks and VIR-2218 
every 4 weeks.
Overall Benefit/Risk
Based on emerging safety data from the study, the sponsor decision was to 1) stop further dosing 
of nivolumab across all cohorts based on a benefit-risk assessment of the use of nivolumab in 
HBV cure, and to 2) stop all treatment in Cohort 2 Group B on account of low likelihood of 
efficacy of continuing with SLGN alone {Gane 2023, Janssen 2021}. Cohort 1 and Cohort 2 
(Group A) will continue receiving all study treatment without nivolumab administration.
Gilead has determined that all participants will complete the protocol-specified follow-up period 
through posttreatment Week 48, including those who have completed treatment or have stopped 
study treatment, and that the benefit-risk profile of this study is considered to remain positive 
following amendments to the protocol described above.
All participants enrolled in Cohort 1 were switched from their prescribed antiviral to TAF 
(25 mg) in order to ensure consistency of treatment. Additional risk mitigation strategies that 
have been incorporated into the protocol from the beginning of the study include a requirement 
for participants enrolled in this study to have adequate hematologic function at study entry and 
sufficient hepatic reserve (F0-F2). The protocol will follow participants closely with frequent 
virtual or in-clinic visits to routinely monitor AEs, laboratory abnormalities, ophthalmologic 
examinations, and vital sign changes. The study also allows for more frequent monitoring visits 
based on investigator’s discretion for safety monitoring. In addition, specific parameters that 
would lead to dose modification, interruption, or discontinuation are included in Section 6.9.1 


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and toxicity management of irAEs are included in Section 7.7.4. Based on historical enrollment 
rates (internal data), participants with CHB in this study will be enrolled in a staggered fashion 
over the course of at least 8 to 12 months. Enrollment in Cohorts 1 and 2 will be enrolled in 
parallel. In summary, potential risks of the novel HBV treatment regimens evaluated in this study 
have been minimized by dose selection, study design, and inclusion criteria.
An infectious disease pandemic may pose additional risks to study drug availability, study visit 
schedule, and adherence to protocol-specified safety monitoring or laboratory assessments. 
Refer to Appendix 11.2 further details on the pandemic risk assessment and mitigation plan.
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are as follows:
•
To evaluate the safety and tolerability of study treatment(s)
•
To evaluate the efficacy of study treatm’ent(s) as measured by the proportion of participants 
who achieve functional cure, defined as HBsAg loss and HBV DNA < lower limit of 
quantitation (LLOQ) at FU Week 24
The secondary objectives of this study are as follows: 
•
To evaluate the proportion of participants with HBsAg loss with and without anti-HBsAg 
seroconversion during the study
•
To evaluate in participants with CHB who are HBeAg positive at baseline, the proportion of 
participants who achieve HBeAg loss with and without anti-HBeAg seroconversion during 
the study
•
To evaluate the proportion of participants who remain off NUC treatment during FU
•
To evaluate the proportion of participants experiencing HBV virologic breakthrough (defined 
as confirmed HBV DNA ≥ LLOQ after 2 consecutive HBV DNA < LLOQ in participants 
who are complying with NUC therapy OR confirmed HBV DNA ≥ 1 log10 IU/mL increase 
from nadir on treatment) during study treatment(s)
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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is as follows:
•
The proportion of participants who achieve functional cure, defined as HBsAg loss and HBV 
DNA < LLOQ at FU Week 24
The secondary endpoints of this study are as follows:
•
The proportion of participants with HBsAg loss with and without anti-HBsAg 
seroconversion during the study
•
The proportion of participants with HBeAg loss with and without anti-HBeAg 
seroconversion during the study in participants with CHB who are HBeAg positive at 
baseline
•
The proportion of participants who remain off NUC treatment during FU
•
The proportion of participants experiencing HBV virologic breakthrough during study 
treatment(s) as defined in Section 2
3.2.
Study Design
This is an open-label study to evaluate the safety and efficacy of SLGN-containing combination 
therapies in participants with CHB. 
Approximately 40 NUC-suppressed and 60 viremic CHB-infected participants, may be enrolled 
and assigned into a cohort below (Section 3.3). Each cohort will enroll a minimum of 20% of 
HBeAg-positive participants, and up to 20% of participants can have HBsAg ≤ 100 IU/mL.
3.2.1.
Changes to Study Design
Nivolumab dosing was stopped by Gilead based on emerging safety data from this study, other 
studies, and pertinent patient and prescriber insights {Cohen C. 2020}. As the study had 
completed enrollment and all participants were in treatment when the decision was made to stop 
nivolumab administration, the following measures were implemented:
•
Stop further nivolumab administration for all study participants across all cohorts.
•
Continue treatment with VIR-2218 and SLGN through Week 36 for Cohorts 1 and 2 
(Group A).


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•
Discontinue all study treatment for Cohort 2 Group B participants with next follow-up visit 
being EOT for those still in treatment period.
•
Stop all sample collections related to nivolumab. 
•
NUC therapy cessation is no longer required for our NUC treated patients (Cohort 1).
Figure 1.
GS-US-465-4439: Study Design Schema* 
IV = intravenous; NUC = nucleos(t)ide(s); PO = oral; Q4W = every 4 weeks; QD = once daily; QW = every week; 
SLGN = selgantolimod; SC = subcutaneous; TAF = tenofovir alafenamide 
a
Viremic participants who meet criteria to initiate NUC treatment will receive TAF 25 mg once daily for up to 36 weeks 
during the study. 
b
SLGN dosed while fasting once a week, on the same day, for 24 weeks.
c
Participants will continue to receive TAF per Section 3.5.
*
NOTE: Nivolumab dosing was stopped in this study and all treatments in Cohort 2 Group B were discontinued. This was a 
sponor decision based on a benefit risk assessment on the use of nivolumab in HBV cure. Rationale is provided in Section 1.3.1.
3.3.
Study Treatments
NUC-suppressed Cohort
Cohort 1 (n = 40):
•
TAF 25-mg tablet administered orally once daily for 36 weeks
•
VIR-2218 200 mg administered via SC injection once every 4 weeks for 24 weeks (total 
6 doses)
At Week 12, add-on and initiate the below treatment:
•
SLGN 3 mg (2  1.5-mg tablets) administered orally while fasting once a week on the same 
day for 24 weeks (total 24 doses)
•
Nivolumab 0.3 mg/kg administered IV once every 4 weeks for up to 24 weeks (up to 6 doses)
2:1 ratio
COHORT 1
(n = 40)
COHORT 2
Group A (n = 40) 
and 
Group B (n = 20)
TAF 25 mg PO administered QD for up to 36 weeks plus
VIR-2218 200 mg SC Q4W for 24 weeks
At Week 12, add-on the below treatment:
SLGN 3 mg PO administered QW for 24 weeks plus
nivolumab 0.3 mg/kg IV Q4W for up to 24 weeks
Group B: SLGNb 3 mg PO administered QW for up to 24 
weeks plus
nivolumab 0.3 mg/kg IV administered Q4W for up to 24 weeks
FOLLOW-UP 
FOR 
48 WEEKSc
Group A: VIR-2218 200 mg SC administered Q4W for 24 
weeks
At Week 12, add-on the below treatment:
SLGNb 3 mg PO administered QW for 24 weeks plus
nivolumab 0.3 mg/kg IV administered Q4W for up to 24 weeks 
NUC-SUPPRESSED
COHORT
(40 
PARTICIPANTS)
VIREMIC 
COHORTS
a
 (60 
PARTICIPANTS)
;--~-~i-----' 
.--------'-----
H 
\ I 
t 
i 
' 


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Viremic Cohort 
Cohort 2 (n = 60)
Participants will be randomized 2:1 into Cohort 2 (Groups A and B) and stratified by 
HBsAg > or ≤ 3 log10 IU/mL. 
Group A (n = 40): 
•
VIR-2218 200 mg administered via SC injection once every 4 weeks for 24 weeks (total 
6 doses)
At Week 12, add-on and initiate the below treatment:
•
SLGN 3 mg (2  1.5-mg tablets) administered orally while fasting once a week on the same 
day for 24 weeks (total 24 doses)
•
Nivolumab 0.3 mg/kg administered IV once every 4 weeks for up to 24 weeks (up to 6 doses)
Group B (n = 20): 
•
SLGN 3 mg (2  1.5-mg tablets) administered orally while fasting once a week on the same 
day for up to 24 weeks (up to 24 doses)
•
Nivolumab 0.3 mg/kg administered IV once every 4 weeks for up to 24 weeks (up to 6 doses)
3.4.
Duration of Treatment
The duration of study treatment are as follows: 
•
TAF 25-mg tablet will be administered orally once daily up to 84 weeks (inclusive of 
48 Week FU), as applicable, in Cohort 1.
•
VIR-2218 200 mg SC will be administered once every 4 weeks for 24 weeks (6 doses).
•
Nivolumab 0.3 mg/kg IV will be administered once every 4 weeks for up to 24 weeks (up to 
6 doses).
•
SLGN 3 mg (2  1.5-mg tablets) will be administered orally while fasting once a week on the 
same day for up to 24 weeks (up to 24 doses).
After completing study treatments all participants will undergo 48 weeks of FU.
NOTE: Nivolumab dosing was stopped in this study and all treatments in Cohort 2 Group B were 
discontinued. Rationale is provided in Section 1.3.1.


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3.5. 
Follow-up Period 
At the end of treatment, all participants will enter the FU period. 
• 
All pa1ticipants not on T AF treatment at EOT will enter a TFFU period. 
Final 
Amendment2 
• 
Paiticipants who are on T AF ti·eatment will continue T AF ti·eatment over the duration of 
study follow-up. 
• 
Paiticipants who initiated TFFU prior to the approval of this amendment and stopped NUC 
ti·eatment may continue off NUCs after discussion between paiticipant and investigator on 
the benefits and risks of continuing offNUCs in TFFU. Those who decide to restait NUCs 
would initiate commercial NUC treatment. 
3.6. 
Treatment Discontinuation Criteria 
Refer to Section 6.9 for detailed individual and ti·eatinent discontinuation criteria. 
3.7. 
End of Study 
The end of this study will be last paiticipant's last observation. 
3.8. 
Poststudy Care 
Once a paiticipant has completed study paiticipation, the long-tenn care of the paiticipant will be 
the responsibility of their primaiy ti·eating physicians. 
3.9. 
Source Data 
The source data for this study will be obtained from electronic data capture (EDC), centi·al 
laborato1y , local laborato1y, specialty laborato1y (for PK and/or PD data). 
3.9.1. 
Biomarker Samples to Address the Study Objectives 
T e spec1 1c ana yses may mc u e, ut w1 not e nmte to, t e 10mar ers 
and assays listed below. Because biomai·ker science is a rapidly evolving ai·ea of investigation, 
and AEs ai·e difficult to predict, it is not possible to specify prospectively all tests that will be 
done on the specimens provided. The testing outlined below is based upon the current state of 
scientific knowledge. It may be modified during or after the end of the study to remove tests no 
longer indicated and/or to add new tests based upon the growing state of the art knowledge. 
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• 
Evaluation of HBV-specific T-cells response to hepatitis B antigen peptides by 
enzyme-linked immunospot assay (ELispot) 
• 
Evaluation of T-cell, NK-cell, and B-cell subsets by flow cytometiy 
• 
Evaluation of peripheral gene expression 
• 
Evaluation of peripheral T-cell and B-cell receptor repe1ioire 
• 
Evaluation of sernm and plasma cytokine levels 
• 
Evaluation of TLR8 single-nucleotide polymorphism (SNP) 
• 
Evaluation of HLA genotypes 
• 
Evaluation of whole blood ti·anscriptome profiling 
Final 
Amendment2 
Samples collected for biomarker assessments will be desn-oyed no later than 15 years after the 
end of the study or per countiy requirements. 
-
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3.9.4. 
3.9.4.1. 
Pharmacokinetic Assessments 
Sparse Phaimacokinetic Collection 
Final 
Amendment2 
Spai·se (timed) blood PK samples will be obtained at specific in-clinic treatment visits at any 
time between 1 to 5 hours postdose relative to SLGN and/or VIR-2218 administration unless 
othe1wise indicated. 
See Section 6.1.10 for sparse PK sampling collection visit details. 
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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection
Cohorts 1 and 2 will enroll approximately 100 male and nonpregnant female participants, 
ages 18 to 65 years, inclusive, with CHB infection without the presence of cirrhosis, and who are 
viremic or virally suppressed on NUC treatment for at least 6 months. 
4.1.1.
Participant Replacement
Participants who discontinue before the end of study will not be replaced.
4.2.
Inclusion Criteria
Participants must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Must have the ability to understand and sign a written informed consent form (ICF), which 
must be obtained prior to initiation of study procedures
2) Adult male and nonpregnant, nonlactating female participants, 18 to 65 years (19-65 years of 
age in Republic of Korea) of age inclusive based on the date of the screening visit
3) Documented evidence of chronic HBV infection (eg, HBsAg positive for more than 
6 months) with detectable HBsAg levels (> 1.5 log10 IU/mL) at screening
4) Screening electrocardiogram (ECG) without clinically significant abnormalities and with 
QTcF interval (QT corrected using Fridericia’s formula) ≤ 450 msec for males and 
≤ 470 msec for females.
5) Females of childbearing potential (as defined in Appendix 11.4) must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test at baseline prior to 
enrollment
6) Male and female participants of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol-specified method(s) of contraception as described in 
Appendix 11.4. Must be willing and able to comply with all study requirements.
Participants in Cohort 1 should meet the following additional criteria to be eligible to participate 
in this study:
7) Have been on a commercially available HBV NUC treatment(s) (ie, TAF, TDF, entecavir, 
adefovir, lamivudine, telbivudine, either as single agents or in combination) with no change 
in regimen for 3 months prior to screening and willing to initiate TAF 25 mg.


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8) Have a historical HBV DNA < LLOQ, measured at least once at local laboratory, 6 or more 
months prior to screening.
9) HBV DNA < LLOQ by central laboratory at screening 
Participants in Cohort 2 should meet the following additional criterion at screening to be eligible 
to participate in this study:
10) HBV DNA > 2000 IU/mL (HBeAg negative) and HBV DNA > 20,000 IU/mL (HBeAg 
positive) 
4.3.
Exclusion Criteria
Participants who meet any of the following exclusion criteria are not eligible to be enrolled in 
this study:
1) Extensive bridging fibrosis or cirrhosis as defined clinically by any 1 of the following:
a) Metavir ≥ 3 or Ishak fibrosis score ≥ 4 by a liver biopsy within 1 year of screening, or, in 
the absence of an appropriate liver biopsy, either:
b) Screening FibroTest score of > 0.48 and AST to platelet ratio index (APRI) > 1 by central 
laboratory, or
c) Historical (within ≤ 6 months of screening) or current FibroScan with a result > 9 kPa 
If liver biopsy is available, the liver biopsy result supersedes (b) and/or (c, if available)
If an appropriate liver biopsy is not available, fibrosis will be evaluated by (b) and/or (c, if 
available). In the event of discordance between (b) and (c), the FibroScan results will take 
precedence.
2) Participants meeting any of the following laboratory parameters at screening:
a) Hemoglobin < 12 g/dL (for males) or < 11 g/dL (for females)
b) White blood cell (WBC) count < 2500 cells/mm3
c) Neutrophil count < 1500 cell/mm3 (or < 1000 cell/mm3 if considered a physiological 
variant in a participant of African descent)
d) ALT ≥ 2  ULN (Cohort 1 only), ALT > 5  ULN (Cohort 2)
e) International normalized ratio (INR) > ULN unless the participant is stable on an 
anticoagulant regimen affecting INR
f)
Albumin < 3.5 g/dL


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g) Direct bilirubin > 1.5  ULN
h) Platelet Count < 100,000/μL
i)
Positive autoantibodies, defined as any one or more of the following:
i)
Antinuclear antibodies (ANA) > 1:80
ii) Smooth muscle antibodies (anti-SMA) > 1:80
iii) Antimitochondrial antibodies (AMA) > 1:40
iv) Anti-thyroid peroxidase (anti-TPO) > 35 IU/mL
j)
Estimated creatinine clearance (CLcr) < 60 mL/min (using the Cockcroft-Gault method) 
based on serum creatinine and actual body weight as measured at the screening 
evaluation, ie,
Male:
(140 − Age [years])  (Weight [kg]) = CLcr (mL/min)
72  (Serum Creatinine [mg/dL])
Female: 
(140 − Age [years])  (Weight [kg])  0.85 = CLcr (mL/min)
72  (Serum Creatinine [mg/dL])
3) Participants in Cohort 2: Received OAV treatment for HBV within 6 months of screening. 
Participants who meet criteria for initiation of NUC treatment as judged by the principal 
investigator (PI) during screening should be excluded from Cohort 2.
4) Coinfection with HIV, HCV, or HDV. Participants who are HCV antibody (Ab) or HDV Ab 
positive, but have a documented negative HCV RNA or HDV RNA, respectively, are 
eligible.
5) Current or prior history of HCC (eg, as evidenced by prior imaging) or screening 
α-fetoprotein ≥ 50 ng/mL without imaging to rule out HCC
6) Current or prior history of clinical hepatic decompensation (eg, ascites, encephalopathy, or 
variceal hemorrhage).
7) Malignancy within 5 years prior to screening, with the exception of specific cancers that are 
cured by surgical resection (eg, basal cell skin cancer). Participants under evaluation for 
possible malignancy are not eligible
8) Significant cardiovascular, ophthalmological, pulmonary, or neurological disease in the 
opinion of the investigator


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9) Diagnosis of any autoimmune disease (eg, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, ulcerative colitis, pneumonitis, autoimmune hepatitis, 
sarcoidosis, psoriasis of greater than mild severity, autoimmune uveitis, autoimmune 
nephritis, thyroiditis), poorly controlled diabetes mellitus, significant psychiatric illness, 
severe chronic obstructive pulmonary disease (COPD), hemoglobinopathy, retinal disease, or 
are immunosuppressed
10) Chronic liver disease of a non-HBV etiology (eg, Wilson’s disease, hemochromatosis, 
alpha-1-antitrypsin deficiency, cholangitis), except for nonalcoholic fatty liver disease
11) Received solid organ or bone marrow transplant
12) Received prolonged therapy with immunomodulators (eg, corticosteroids) or biologics 
(eg, mAb, IFN, nivolumab) within 6 months of screening
13) Have received inactivated vaccinations (eg, injectable influenza or pneumococcal) within 
4 weeks prior to randomization or received live vaccinations within 4 weeks prior to 
screening
14) Use of another investigational agent within 90 days of screening, unless allowed by the 
sponsor
15) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
participant compliance
16) Known hypersensitivity to study drug or formulation excipients
17) Women who are breastfeeding, pregnant, or who wish to become pregnant during the course 
of the study
18) Female participants unwilling to refrain from egg donation and in vitro fertilization during 
and until at least 5 months after last study drug dose.
19) Male participants unwilling to refrain from sperm donation during and until at least 5 months 
after the last study drug dose
20) Use of any prohibited concomitant medications as described in Section 5.4
21) Believed by the study investigator to be inappropriate for study participation for any reason 
not otherwise listed.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Treatment Assignment
5.1.1.
Randomization/Enrollment
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
study enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or study-wide at any time.
Screening and enrollment may be placed on hold based on investigator’s discretion, or in 
accordance with local regulation due to COVID-19 impact.
Cohort 1 and 2 will enroll in parallel. 
Cohort 2 (Group A and B): In the viremic cohorts, participants will be randomized 2:1 into 
Cohort 2 Groups A and B and stratified by HBsAg > or ≤ 3 log10 IU/mL. 
5.1.2.
Blinding
Blinding of treatment response is critical to the integrity of this clinical study and therefore, 
quantitative HBsAg will be blinded to the investigative sites for the duration of the study. The 
sponsor or designee may unblind investigators to individual participant results as needed for 
safety reasons.
5.2.
Description and Handling of SLGN, TAF, and VIR-2218, and Nivolumab
5.2.1.
Formulation
5.2.1.1.
Selgantolimod
Selgantolimod tablets, 1.5 mg, have been formulated with microcrystalline cellulose, mannitol, 
croscarmellose sodium, and magnesium stearate. Tablets are round, plain-faced, film-coated, and 
white. The white tablet film-coating contains polyvinyl alcohol, titanium dioxide, polyethylene 
glycol (PEG) 3350, and talc.
5.2.1.2.
Nivolumab
Commercially available product of nivolumab injection will be used for this study. Further 
information regarding formulation is available in the current approved product label for 
nivolumab.
NOTE: Nivolumab dosing was stopped by Gilead based on a sponsor benefit risk assessment. 
Rationale is provided in Section 1.3.1.


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5.2.1.3.
Tenofovir Alafenamide
Each film-coated tablet contains tenofovir alafenamide fumarate equivalent to 25 mg of TAF and 
have been formulated with croscarmellose sodium, lactose monohydrate, magnesium stearate, 
and microcrystalline cellulose. The tablets are yellow, round, film-coated, and debossed with 
“GSI” on one side of the tablet and “25” on the other side of the tablet.
5.2.1.4.
VIR-2218
VIR-2218 is a clear, colorless to pale yellow solution, which will be supplied by Gilead as a 
sterile solution for SC injection at a free acid concentration of 200 mg/mL. 
5.2.2.
Packaging and Labeling
5.2.2.1.
Selgantolimod
Selgantolimod, 1.5 mg, tablets are packaged in clear polyvinyl chloride 
(PVC)/polychlorotrifluoroethylene (PCTFE) film blister strips and sealed with aluminum foil 
lidding material. Each blister strip contains 4 round tablets sealed with an aluminum push 
through lidding material. Selgantolimod blister strips in the quantity needed for a 4-week supply 
of SLGN (ie, 2 strips/8 tablets) are placed into a paperboard child-resistant wallet system in 
accordance with the dosage strategy.
Study drug(s) to be distributed to centers in participating countries shall be labeled to meet 
applicable requirements of the United States (US) FDA, European Union (EU) Guideline to 
Good Manufacturing Practice -Annex 13 (Investigational Medicinal Products), and/or other local 
regulations.
5.2.2.2.
Nivolumab
Commercially available product of nivolumab injection will be used for the study. Study drug(s) 
to be distributed to centers in participating countries shall be labeled to meet applicable 
requirements of the US FDA, EU Guideline to Good Manufacturing Practice -Annex 13 
(Investigational Medicinal Products), and/or other local regulations (See Section 1.3.1).
5.2.2.3.
Tenofovir Alafenamide
TAF tablets are packaged in white, high-density polyethylene (HDPE) bottles and enclosed with 
a polypropylene continuous-thread, child-resistant cap, lined with an induction activated 
aluminum foil liner. Each bottle contains 30 tablets, silica gel desiccant, and polyester coil. Study 
drug(s) to be distributed to centers in participating countries shall be labeled to meet applicable 
requirements of the US FDA, EU Guideline to Good Manufacturing Practice -Annex 13 
(Investigational Medicinal Products), and/or other local regulations.


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5.2.2.4.
VIR-2218 
VIR-2218 Solution for Injection, 200 mg/mL, are packaged in 2R vials. Each vial is filled with 
0.5 mL solution. Study drug(s) to be distributed to centers in participating countries shall be 
labeled to meet applicable requirements of the US FDA, EU Guideline to Good Manufacturing 
Practice -Annex 13 (Investigational Medicinal Products), and/or other local regulations. 
5.2.3.
Storage and Handling
5.2.3.1.
Selgantolimod
The SLGN tablets are packaged in blister strips/wallet system should be stored below 30 °C. 
Storage conditions are specified on the label.
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Measures that minimize drug contact with the body should always be considered 
during handling, preparation, and disposal procedures. Appropriate precautions should be 
followed to avoid direct eye contact or exposure when handling. Any unused study drug should 
be disposed of in accordance with local requirements.
5.2.3.2.
Nivolumab
Nivolumab vials must be stored in a secure area at 2-8 °C. Commercial product of nivolumab 
injection will be used for the study. Further information regarding storage and handling are 
available in the current approved product label for nivolumab (See Section 1.3.1).
5.2.3.3.
Tenofovir Alafenamide
TAF bottles should be stored at 25 C (77 F); excursions permitted from 15 C to 30 C (59 °F 
to 86 °F). Storage conditions are specified on the label. All drug products should be stored in a 
securely locked area, accessible only to authorized site personnel. To ensure the stability of the 
study drug and to ensure proper product identification, the drug product should not be stored in a 
container other than the container in which they are supplied. Measures that minimize drug 
contact with the body should always be considered during handling, preparation, and disposal 
procedures. Appropriate precautions should be followed to avoid direct eye contact or exposure 
when handling. Any unused study drug should be disposed of in accordance with local 
requirements.
5.2.3.4.
VIR-2218 
VIR-2218 solution for injection should be stored upright, at 2C to 8C. Storage conditions are 
specified on the label. Measures that minimize drug contact with the body should always be 
considered during handling, preparation, and disposal procedures. Appropriate precautions 
should be followed to avoid direct eye contact or exposure when handling. Any unused study 
drug should be disposed of in accordance with local requirements.


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5.3.
Dosage and Administration of SLGN, TAF, VIR-2218, and Nivolumab
5.3.1.
Selgantolimod
Selgantolimod will be supplied as tablets in strengths of 1.5 mg. SLGN 3 mg (2  1.5-mg tablets) 
will be administered while fasting once a week, on the same day. Participants must be fasting for 
at least 8 hours overnight (no food or drinks, except water) and continue through the morning, 
with no food or drinks, including water, 1 hour before to 2 hours after dosing. After 2 hours 
postdose, water is allowed; and after 4 hours postdose, participants are allowed food and drinks. 
Participants should take their other prescribed medications, including NUC treatment, no earlier 
than 2 hours after SLGN dosing or, if medications require dosing with food, no earlier than 
4 hours after SLGN dosing.
5.3.2.
Nivolumab
Nivolumab 40 mg/4 mL solution for injection will be supplied as single dose vials. Nivolumab 
0.3 mg/kg will be administered as IV infusion over 45-60 minutes. This slower rate of infusion 
was shown in a PK study of nivolumab to lower the risk of infusion-related reactions (IRRs) 
compared with a rapid rate of infusion over 30 minutes {OPDIVO 2022} (See Section 1.3.1).
5.3.3.
Tenofovir Alafenamide 
TAF 25-mg tablet orally once daily with food.
5.3.4.
VIR-2218 
VIR-2218, 200 mg/mL, solution for injection will be supplied as 0.5 mL single dose vials. 
VIR-2218 200 mg (2  0.5 mL solution) will be administered SC. 
5.4.
Prior and Concomitant Medications
Concomitant/previous medications including over-the-counter medications, vitamins, and 
supplements that have been taken up to 30 days prior to screening, and the ones taken up to 
4 weeks after discontinuation of study treatment need to be recorded in the source documents 
and electronic case report forms (eCRFs). 
For participants requiring treatment with a concomitant medication (including treatment of an 
AE) after starting study drug(s), the participant’s continued participation in the study should be 
re-evaluated by the investigator, in consultation with the medical monitor (or designee) on an 
ongoing, case-by-case basis. The investigator is authorized to administer acetaminophen or 
ibuprofen for the treatment of minor ailments occurring on study without prior consultation with 
the medical monitor. Acetaminophen is the preferred agent, followed by ibuprofen. The medical 
monitor should be consulted before administering acetaminophen at doses ≥ 2 g/day and 
ibuprofen as a single dose of > 200 mg or > 400 mg/day. Where an alternative to acetaminophen 
is needed, ibuprofen may be administered with milk or a light snack to minimize the chance of 
gastrointestinal side effects. Coadministration of an antiemetic (eg, ondansetron) at the discretion 
of the investigators is allowed in this study. Antiemetics will be administered following local 
guidelines and regulations.


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There are no substantial safety data regarding the concomitant administration of the COVID‑19 
vaccines and SLGN, TAF, VIR-2218, and nivolumab. Participants are allowed to receive the 
COVID‑19 vaccine, and study visits should continue as planned if vaccination occurs while the 
participant is on the study. Investigators should follow local guidelines for concomitant 
administration of the COVID-19 vaccines with the study drugs.
The following medications, not including protocol-specified study treatment(s), are prohibited in 
all cohorts for the entirety of the screening period through the end of study treatment due to 
interaction with study treatment(s) or the underlying HBV infection: 
•
Systemic chemotherapeutic agents, systemic corticosteroids (prednisone equivalent of 
> 10 mg/day for > 2 weeks, except short-term use of prednisone as a steroid burst [< 1 week 
of use] and treatment of irAEs in this study), immunosuppressants (eg, azathioprine), mAbs 
(eg, infliximab), or immunomodulating agents 
•
Investigational agents or devices for any indication (unless approved by Gilead) 
•
Hematologic-stimulating agents (eg, erythropoiesis-stimulating agents, granulocyte colony 
stimulating factor, thrombopoietin mimetics)
Additional Concomitant Medication Restrictions:
For Cohorts 1 and 2 (Group A)
During treatment with SLGN, use of the medications listed below and in Table 3 are prohibited 
for a minimum of 21 days prior to the first dose of SLGN through the last dose of SLGN plus 
7 days.
For Cohort 2 (Group B)
During treatment with SLGN, use of the medications listed below and in Table 4 are prohibited 
during the screening period and for a minimum of 21 days prior to the baseline/Day 1 visit 
through the last dose of SLGN plus 7 days.
Data from the DDI study indicates that cytochrome P450 (CYP)3A plays a major role in SLGN 
metabolism and therefore the administration of potent CYP3A inhibitors/inducers is not 
permitted in this study. Additionally, participants will be required to refrain from consumption of 
grapefruit juice, grapefruits, Seville oranges and Seville orange juice 72 hours prior to the first 
dose of SLGN and through the last dose of study treatment(s) plus 7 days.
The following list of medications and nutritional products are prohibited (as indicated above) due 
to potential interaction with SLGN. This is not an exhaustive list of agents. Any medications not 
in Table 4 should be reviewed with Gilead prior to dosing during the specified period.


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Table 4.
List of Agents Disallowed Due to Potential Interaction With SLGN
Drug Class
Agents Disallowed 
Antibiotics
Clarithromycin, rifabutin, rifampin, rifapentine, telithromycin, 
troleandomycin
Anticonvulsants
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin
Antimycobacterials
Rifapentine, rifabutin, rifampin
Antidepressants
Nefazodone
Antifungals
Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole
Antiviral
VIEKIRA PAK (ombitasvir/paritaprevir/ritonavir & dasabuvir), telaprevir, 
danoprevir, boceprevir
Cardiac Medications
Mibefradil
Diuretics
Conivaptan
GI Motility Agentsa
Cisapride, metoclopramide, domperidone, mosapride citrate, pruclopride, 
itopride hydrochloride, levosulpride
Hematologic-stimulating agents 
Erythropoiesis-stimulating agents; granulocyte colony stimulating factor 
(GCSF); and thrombopoietin (TPO) mimetics
Herbal/Natural Supplements
St. John’s Wort, Echinacea, Milk thistle (ie, silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
Other
Apalutamide, avasimive, enzalutamide, idelalisib, lumacaftor, nitotane 
GI = gastrointestinal; SLGN = selgantolimod
a
GI motility agents are prohibited starting 2 days prior to SLGN dosing and for the 24 hours postdose.
There are no DDIs or contraindications mentioned in the product information for nivolumab 
{OPDIVO 2022}.
Additionally, given the safety profile of multiple doses of VIR-2218 has not been well 
characterized and the use of VIR-2218 in combination with IFN has not previously been 
assessed, the administration of any potentially hepatotoxic medications during the study should 
be considered only if no therapeutic alternative can be identified and after a careful consideration 
of the potential risks and benefits for the participant. Medications that are potentially hepatotoxic 
or associated with drug-induced liver injury (DILI) include, but are not limited to, the following 
{Bjornsson 2016}:
•
Aspirin > 3 g/day or ibuprofen ≥ 1.2 g/day
•
Tricyclic antidepressants
•
Valproate
•
Phenytoin
•
Amiodarone


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•
Anabolic steroids
•
Allopurinol
•
Amoxicillin-clavulanate
•
Minocycline
•
Nitrofurantoin
•
Sulfamethoxazole/trimethoprim
•
Erythromycin
•
Rifampin
•
Azole antifungals
•
Herbal or natural remedies
During treatment with TAF, use of the following medications listed below and in Table 5 are 
prohibited for a minimum of 21 days prior to the baseline/Day 1 visit through the end of study:
•
Investigational agents or devices for any indication
•
Agents that reduce renal function or compete for active tubular secretion with TFV 
(eg, cidofovir, acyclovir, valacyclovir, ganciclovir, famciclovir, valganciclovir, high dose or 
multiple nonsteroidal anti-inflammatory drugs [NSAIDs], probenecid)
•
Nephrotoxic agents (eg, aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, 
cisplatin, pentamidine, cyclosporine, tacrolimus)
•
Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [≤ 1 week of use] and treatment of irAEs in this study), 
immunosuppressant, or immunomodulating agents
Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters such as, P-glycoprotein) with study drug(s) may result in PK interactions. Any 
medications not on the list above should be reviewed with Gilead prior to randomization and 
during the study treatment.


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Table 5.
Disallowed Concomitant Medications While on TAF
Medication Class
Prohibited Medications
Anticonvulsants
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: 
may lower concentration of TAF and/or TFV
Antimycobacterials
Rifapentine, rifabutin, rifampin
Herbal/Natural Supplements
St. John’s Wort, echinacea, milk thistle (ie, silymarin), 
Chinese herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
TAF = Tenofovir alafenamide; TFV = tenofovir
5.5.
Accountability for Investigational Medicinal Product: SLGN, TAF, 
VIR-2218, and Nivolumab
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgment of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to participants must be returned to the site.
Each study site must keep accountability records that capture:
•
The date received and quantity of study drug 
•
The date, participant number, and the study drug kit number dispensed
•
The date, quantity of used and unused study drug returned, along with the initials of the 
person recording the information


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5.5.1.
Investigational Medicinal Product Return or Disposal
Gilead recommends that used and unused study drug supplies be destroyed at the site. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead, the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for electronic trial master file. If study drug is destroyed at the site, the investigator must 
maintain accurate records for all study drugs destroyed. Records must show the identification 
and quantity of each unit destroyed, the method of destruction, and the person who disposed of 
the study drug. Upon study completion, copies of the study drug accountability records must be 
filed at the site. Another copy will be returned to Gilead. 
If the site does not have an appropriate SOP for drug destruction, used and unused study drug 
supplies are to be sent to the designated disposal facility for destruction. The study monitor will 
provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each participant enrolled in the study are presented in 
tabular form in Appendix 11.3 and described in the text that follows. 
The investigator must document any deviation from the protocol procedures and notify Gilead or 
the contract (or clinical) research organization (CRO).
6.1.
Study Procedure Details 
6.1.1.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing; history of prior and current use of nicotine or 
nicotine-containing products, alcohol, and illegal drugs; and history of current and prior (within 
previous 30 days) medication; and all prior medication administered to treat HBV infection
6.1.2.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: head, neck, and thyroid; eyes, ears, nose, throat, mouth, and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological.
6.1.3.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and oral, ear or forehead temperature. 
Blood pressure will be measured using the following standardized process:
•
Participant should sit for ≥ 5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level
•
Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery
•
Measure and record the blood pressure to the nearest 2 mm Hg mark on the manometer or to 
the nearest whole number on an automatic device
6.1.4.
12-Lead Electrocardiograms
Participants will be required to rest in a supine position for 5 minutes prior to making a 
recording. The investigator (or qualified designee) should review the ECG traces recorded in real 
time for clinically significant abnormalities. On-treatment ECGs should be compared with the 
participant’s Day 1 as part of routine safety monitoring.


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QTc interval will be reported using Fridericia’s correction: QTcF = QT/RR1/3.
6.1.5.
Clinical Laboratory Tests/Assessments for Safety Evaluations
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Appendix 11.3.
•
Hematology: hematocrit, hemoglobin, platelet count, red blood cell (RBC) count, WBC 
count with differential (absolute and percentage), including lymphocytes, monocytes, 
neutrophils, eosinophils, basophils, and mean corpuscular volume (MCV)
•
Chemistry: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, 
total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), 
triglycerides, total protein, albumin, lactic acid dehydrogenase (LDH), creatine kinase (CK), 
bicarbonate, blood urea nitrogen, calcium, chloride, creatinine (see below), glucose, 
phosphorus, magnesium, potassium, sodium, uric acid, and lipase (reflex amylase testing is 
performed in participants with total lipase > 1.5 × ULN)
•
Coagulation panel: prothrombin time, activated partial thromboplastin time, and INR
•
Qualitative HBV serology (HBeAg and hepatitis B e antibody [HBeAb]; and HBsAg [reflex 
HBsAb if HBsAg is negative])
•
Quantitative HBV serology (HBsAg, HBcrAg, HBeAg [if applicable], and HBV RNA)
•
Serum sample for HBV viral sequencing, genotyping sample, and ddPCR
•
Quantitative plasma HBV DNA
•
Thyroid-stimulating hormone (TSH) levels
•
Pregnancy test: serum or urine β human chorionic gonadotropin (β-hCG) pregnancy test (if 
positive, requires immediate confirmation with serum β-hCG)
Follicle-stimulating hormone (FSH) testing (FSH test is required for female participants 
who are < 54 years old who are not on hormonal contraception and who have stopped 
menstruating for ≥ 12 months but do not have documentation of ovarian hormonal 
failure)
•
Urinalysis: appearance, blood, color, glucose, leukocyte esterase, pH, protein, urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
•
Urine drug (amphetamines, cocaine, methadone, opiates) and alcohol screen
•
Autoantibodies: ANA, anti-SMA, AMA, and anti-TPO


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6.1.6.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft 1976} using 
actual body weight (ABW).
Male: 
CLcr (mL/min) = [140 - age (years)]  ABW(kg)
72  Scr
Female:
 CLcr (mL/min) = [140 - age (years)]  ABW(kg)  0.85
72  Scr
Scr = serum creatinine (mg/dL)
ABW = actual body weight
6.1.7.
Ophthalmologic Examination
Ophthalmologic examinations will be performed as applicable for Cohorts 1 and 2 during 
screening, at Week 12, 24, 36, and early discontinuation (ED) to assess ophthalmologic findings, 
including slit lamp and fundoscopic examination (both eyes). An examination of the full retinal 
field should be conducted noting changes or abnormalities.
Additional symptoms-directed ophthalmologic examinations may be conducted at investigator’s 
discretion during the study for all participants in Cohorts 1 and 2.
See Section 6.6 and Schedule of Assessments in Appendix 11.3 for more details on time points 
for examination in specific cohorts. 
6.1.8.
HBV Sequence Analysis 
Sequence analysis of the HBV full genome may be performed (if applicable) to assess if the 
presence of mutations at baseline and/or enrichment at posttreatment time points are associated 
with treatment response. As it may not be known at the time of the visit whether a participant is 
viremic or if it will be their last study visit, a separate virology sample for potential sequence 
analyses will be collected at each study visit.
6.1.9.
Digital Droplet Polymerase Chain Reaction
If participant has HBV DNA ≤ LLOQ, ddPCR will be conducted. 
6.1.10.
Sparse PK Sampling
Sparse (timed) blood PK samples will be obtained at specific in-clinic treatment visits at any 
time between 1 to 5 hours postdose relative to SLGN and/or VIR-2218 administration unless 
otherwise indicated.


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Plasma concentrations of SLGN and VIR-2218 may be analyzed. Serum concentrations of 
nivolumab may be analyzed (as applicable, from existing samples).
•
Sparse PK collection visits for VIR-2218 in Cohort 1 and Cohort 2 Group A:
Baseline/Day 1 (predose and postdose), Weeks 12 and 20
•
Sparse PK collection visits for SLGN in Cohort 1 and Cohort 2 Group A: 
Weeks 12, 20, and 32 
•
Sparse PK collection visits for SLGN in Cohort 2 Group B:
Baseline/Day 1, Weeks 12 and 20 
6.1.12.
Biomarker Samples
Whole blood, serum, and plasma samples will be collected as detailed in Appendix 11.3 for 
biomarker analysis. Additional whole blood samples will be collected for PBMC isolation and 
gene expression (PaxGene RNA).
Reference Section 3.9 for additional information on Biomarker Samples.
CCI


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6.1.15.
Management of Participants Impacted by the COVID-19 Pandemic
Local regulation and guidance should be followed in the management of participants impacted 
by the COVID-19 pandemic. Study-specific guidance provided by Gilead regarding crisis 
management communications should also be referenced.
6.2.
Participant Enrollment and Treatment Assignment
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
study enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or study-wide at any time.
Screening and enrollment may be placed on hold based on investigator’s discretion, or in 
accordance with local regulation due to COVID-19 impact.
6.3.
Pretreatment Assessments
6.3.1.
Prescreening Visit
At the investigator’s discretion, participants may be asked to consent to HBeAg testing prior to 
screening procedures in order to ensure the required minimum of 20% HBeAg-positive 
participants for each cohort. Once a participant’s HBeAg status has been confirmed, the 
participant may then be able to complete the screening procedures.
6.3.2.
Screening Visit
Participants will be screened within 45 days prior to baseline Day 1 visit. 
With Gilead’s approval, candidates who fail to meet eligibility criteria by screening evaluations 
may be re-screened if there is a reasonable expectation that the candidate will be eligible after 
repeat screening. Gilead must approve all re-screening requests.
CCI
CCI


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Retests of screening laboratory parameters are permitted once only if there is reason to believe 
the retest value will be within accepted parameters, if the initial value was either due to a sample 
processing error, inconsistent with a recent local laboratory result, or due to an extenuating 
circumstance (eg, intercurrent infection).
The following will be performed and documented at screening:
•
Written informed consent
•
Review of inclusion/exclusion criteria
•
Obtain medical history (including HBV disease, treatment history, and historical HBV 
genotype [if available] for cohort 1 only)
•
Review concomitant medications
•
Complete physical examination
•
Vital signs
•
Body weight and height
•
12-Lead ECG (participants must rest quietly in the supine position for a minimum of 
5 minutes prior to the recording)
•
Chest x-ray
•
Ophthalmologic examination
•
FibroScan (where available and as necessary for liver disease staging)
•
Sample collection for:
Safety laboratory tests (hematology, chemistry, and coagulation)
APRI, FibroTest, α-fetoprotein (computed tomography [CT] scan with contrast for 
participants with α-fetoprotein ≥ 50 ng/mL at screening)
Serology testing to exclude HCV, HDV, and HIV infection
Quantitative plasma HBV DNA
Serum sample for HBV viral sequencing (resistance surveillance) and ddPCR
Quantitative HBV serum HBsAg, HBcrAg, HBeAg (if not performed during 
prescreening), and HBV RNA 


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Qualitative HBV serology HBeAg, HBeAb (if not performed during prescreening), and 
HBsAg, HBsAb
Estimated CLcr (using the Cockcroft-Gault method)
Other screening laboratory tests: urinalysis, urine drug screen, alcohol screen, 
autoantibodies, quantification of TSH levels and serum β-hCG (females of childbearing 
potential only), FSH (test is required for female participants who are < 54 years old who 
are not on hormonal contraception and who have stopped menstruating for ≥ 12 months 
but do not have documentation of ovarian hormonal failure)
•
Record any SAEs and all AEs related to protocol-mandated procedures occurring after 
signing of the ICF.
Participants meeting all of the inclusion criteria and none of the exclusion criteria will return to 
the clinic within 45 days after screening for randomization into the study.
From the time of obtaining informed consent through the first administration of study drug, 
record all SAEs, as well as any AEs related to protocol-mandated procedures on the AE eCRF. 
All other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history, are to be considered medical history. See Section 7, 
Adverse Events and Toxicity Management, for additional details.
6.3.3.
Baseline/Day 1 Assessments
All baseline tests and procedures must be completed prior to the receipt of the first dose of study 
drug(s). Participants screened within 45 days before baseline will be eligible to participate in the 
study.
Initiation of treatment with study drug(s) should take place on the day of the baseline visit 
(Day 1). 
Cohorts 1 and 2
•
Vital signs 
•
Weight 
•
Review AEs 
•
Review concomitant medications
•
Complete physical examination 
•
12-Lead ECG (Participants must rest quietly in the supine position for a minimum of 
5 minutes prior to the recording)


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• 
Symptoms-directed ophthalmologic examination 
• 
Sample collection for: 
-
Safety laborato1y tests (hematology and chemistiy; coagulation) 
-
APRI and FibroTest 
-
Quantitative plasma HBV DNA 
-
Quantitative HBV sennn HBsAg, HBcrAg, HBeAg, and HBV RNA 
-
Qualitative HBV serology HBeAg, HBeAb, HBsAg, and HBsAb 
-
Sernm sample for HBV viral sequencing and genotyping sample (baseline) 
-
Sparse PK ( sparse PK for SLGN not required for Coho1is 1 and 2 [ Group A]) 
-
Urine pregnancy test (females of childbearing potential only) 
-
Urinalysis 
-
Estimated CLcr (using Cockcroft-Gault method) 
• 
I 
Final 
Amendment2 
• 
Perfo1m study diug dispensation, and adininisti·ation (TAF, as needed, VIR-2218 SC, and 
SLGN) 
• 
Biomarker Samples: collection of PBMC, whole blood, sennn, and plasma samples for 
biomarker analysis 
6.4. 
Randomization 
Viremic Cohort 2 (Group A and B) Only 
Paiiicipants will be randomized 2:1 into Coho1i 2 Group A and Band su-atified by HBsAg > or 
:S 3 log10 ID/mL. 
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6.5.
Treatment Schedule
Cohort 1:
•
Baseline/Day 1, Week 4, and Week 8 - SC VIR-2218 
•
Week 12, 16, and 20 - SC VIR-2218; add-on IV nivolumab 
•
Week 24, 28, and 32 - IV nivolumab
•
Oral TAF dose daily for 36 weeks 
•
Oral SLGN dose weekly for 24 weeks, starting Week 12 through Week 35
Cohort 2:
Group A:
•
Baseline/Day 1, Weeks 4 and 8 - SC VIR-2218
•
Weeks 12, 16, and 20 - SC VIR-2218; add-on IV nivolumab 
•
Weeks 24, 28, and 32 - IV nivolumab 
•
Oral SLGN dose weekly for 24 weeks, starting Week 12 through Week 35
Group B:
•
Baseline/Day 1, Weeks 4, 8, 12, 16, and 20 - IV nivolumab 
•
Oral SLGN dose weekly for 24 weeks, starting Day 1 through Week 23 
6.6.
Post-Day 1 Treatment Assessments
The post-Day 1 treatment assessments have a visit window of ± 2 days (except for 
Weeks 13 and 14 in Cohort 1 and Weeks 1, 2, 13, 14 in Cohort 2), and EOT will have a window 
of −5 days. Posttreatment assessments include the following, performed in a fasted state at all 
visits from baseline/Day 1 through EOT or in event of ED, unless specifically noted:
All participants will complete the following post-Day 1 study visits:
Cohort 1: Weeks 4, 8, 12, 13*, 14, 16, 20, 24, 28, 32, and 36 (EOT)
Cohort 2 Group A: Weeks 4, 8, 12, 13*, 14, 16, 20, 24, 28, 32, and 36 (EOT)
Cohort 2 Group B: Weeks 1*, 2, 4, 8, 12, 14, 16, 20, and 24 (EOT)


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Vital signs 
• 
Symptom-directed physical examination (at Weeks 4, 8, 14 to 32, if applicable) 
• 
Complete physical examination ( at Weeks 12 and EOT) 
• 
Weight (at Week 12, and EOT) 
• 
Review AEs and concomitant medications (at Weeks 1 *, 2, 4, 8, 12, 13*, and 14 to EOT) 
• 
12-lead ECG (Paiiicipants must rest quietly in the supine position for a minimum of 
5 minutes prior to the recording) (at Weeks 12 and EOT) 
• 
Sample collection for: 
• 
-
Safety laborato1y tests (hematology and chemistiy; coagulation) (at Weeks 4, 8, 12, 14 to 
EOT) 
-
APRI and FibroTest (at Weeks 12, and EOT) 
-
Quantitative plasma HBV DNA (at Weeks 4, 8, 12, 14 to EOT) 
-
Quantitative HBV sennn HBsAg, HBcrAg, HBeAg, and HBV RNA (at Weeks 4, 8, 12, 
14 to EOT) 
-
Qualitative HBV serology HBeAg, HBeAb, HBsAg, and HBsAb (at Weeks 4, 8, 12, 14 
to EOT) 
-
Spai·se PK samples (Coho1is 1 and 2 [Group A] at Day 1, Weeks 12, 20, and 32; Cohort 2 
[Group B] at Weeks 12 and 20) 
-
Sernm sample for HBV viral sequencing and genotyping sample (at Weeks 4, 8, 12, 14 to 
EOT) 
-
Urinalysis (4, 8, 12, 16 to EOT) 
-
Urine pregnancy test (females of childbeai·ing potential only; at Weeks 4, 8, 12, 16, 20, 
and EOT; and at Weeks 24, 28, and 32, if applicable) 
-
Estimated CLcr (using Cockcroft-Gault method) (at Weeks 12 and EOT) 
-
Quantification ofTSH levels at EOT (Coho1i 1 and 2 [Group A], Weeks 24 and 36; 
Coho1i 2 [Group B], Weeks 12 and 24) 
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• 
Ophthalmologic Examination (- 4 to + 10 days of visit) 
-
Coho1i 1 and 2 [Group A]: Week 24 and 36 
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Coho1i 2 [Group B]: Week 12 and 24 and EOT for participants who stop dosing before 
Week 24. 
-
Symptom-directed ophthalmologic examination (at Weeks 4, 8, 14 to 32, if applicable) 
• 
Study treatment 
-
Study drng accountability and review dosing diaiy 
-
Study diug dispensation 
-
Study diug administration (Oral TAF, as needed, SC VIR-2218, and oral SLGN) 
* Treatment Assessments on Week 1 and Week 13 (Phone CallNirtual Visit) 
The following evaluations ai·e to be completed at phone call or virtual visit: 
• 
Review of AEs and concomitant medications 
• 
Review of dosing diaiy and treatment compliance 
6.7. 
Follow-up Assessments 
The FU assessments have the following visit windows: Coho1i 1: Week 1 (+ 3 days), Weeks 4 to 
16 (± 5 days), and Weeks 24 to 48 (± 14 days); Coho1i 2: Weeks 1 (± 2 days), and Weeks 4 to 16 
(± 5 days), and Weeks 24 to 48 (± 14 days). FU assessments include the following: 
• 
All paiticipants will complete following FU visits: Weeks 1 *, 4, 8*, 12, 16* (for women of 
childbeai·ing potential), 24 (Primaiy), 36, and 48 
• 
Vital signs (at Weeks 4 to 48) 
• 
Symptom-directed physical examination (at Weeks 4 to 48) 
• 
Symptom-directed ophthalmologic examination (at Weeks 4 to 48) 
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•
Weight (At Week 48 only)
•
12-lead ECG (At Week 48 only)
•
Review AEs and concomitant medications (At Week 1*, 8*, 16*, at Weeks 4 to 48)
•
Sample collection for:
Safety laboratory tests (hematology and chemistry; coagulation) (at Weeks 4 to 48)
APRI and FibroTest (at Weeks 12 and 48)
Quantitative plasma HBV DNA (at Weeks 4 to 48)
Quantitative HBV serum HBsAg, HBcrAg, HBeAg, and HBV RNA (at Weeks 4 to 48) 
Qualitative HBV serology HBeAg, HBeAb, HBsAg, and HBsAb (at Weeks 4 to 48)
•
Urine pregnancy test (females of childbearing potential only, every 4 weeks through 
Week 48; Week 8 and Week 16 collection will be a virtual/telephonic visit)
•
Serum sample for HBV viral sequencing and genotyping sample (baseline) (at Weeks 4 to 
48)
•
Estimated CLcr (using Cockcroft-Gault method) (at Week 48 only)
*FU Visit Week 1, Week 8, and Week 16 (Phone Call/Virtual Visit)
The following evaluations are to be completed at the FU Week 1 phone call or virtual visit:
•
Review of AEs and concomitant medications
•
Review of laboratory results from EOT visit to determine entry into TFFU
Participants who discontinue the study treatment(s) prematurely will be followed for the 
reminder of the study according to the defined study visits and procedures.
6.8.
Immunologic Testing
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6.8.1.
Biomarker Sample Collection During Treatment Period
Cohort 1
Baseline/Day 1 (predose), Week 12 (pre-SLGN dose, 4 and 24-72 hours postdose), Week 14 
(predose), Week 32 (pre-SLGN dose, 4 and 24-72 hours postdose).
Cohort 2
Group A:
Baseline/Day 1 (predose), Week 12 (pre-SLGN dose, 4 and 24-72 hours postdose), Week 14 
(predose), Week 32 (pre-SLGN dose, 4 and 24-72 hours postdose)
Group B:
Baseline/Day 1 (pre-SLGN dose, 4, and 24-72 hours postdose), Week 2 (predose), Week 20 
(pre-SLGN dose, 4, and 24-72 hours postdose) 
6.8.2.
Biomarker Sample Collection During Follow-up 
Biomarker samples will be collected at FU Week 24 for Cohorts 1 and 2.
6.9.
Assessments for Early Discontinuation of Study Treatment
6.9.1.
Criteria for Discontinuation of Study Treatment 
Study treatment(s) that are considered related by the investigator to any of the below event(s) 
will be held in a participant until resolution of the event:
•
Any study drug–related AE ≥ Grade 3
•
A confirmed, clinically significant laboratory test abnormality (other than ALT) ≥ Grade 3 
considered study drug(s) related by the investigator
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Study treatment(s) may be reinitiated following resolution of the above event(s) after discussion 
with the medical monitor. Study treatment(s) should be restarted in line with their preassigned 
schedules.
Study treatment(s) that are considered related by the investigator to any of the below events will 
be permanently discontinued:
•
Any on-treatment uveitis, confirmed by ophthalmologic evaluation
•
Any confirmed recurrence of study drug–related Grade 3 or 4 (excluding laboratory 
abnormalities) AE following dose interruption mandates permanent discontinuation of study 
drug(s)
•
Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered not to be in the participant’s 
best interest
•
Any study drug–related Grade 4 AE (excluding laboratory abnormalities)
•
Any study drug–related ≥ Grade 3 AE not able to be medically managed (eg, nausea with 
antiemetics)
•
Any confirmed study drug–related laboratory abnormality ≥ Grade 3 following rechallenge
•
A clinically significant Grade 4 laboratory abnormality
•
Virological breakthrough: as defined in Section 2
Additional criteria for permanent discontinuation of study treatment(s):
•
Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree
•
Hepatic disease progression or lack of efficacy defined as participants in Cohorts 1 and 2 
(Group A) who do not achieve HBsAg decline ≥ 0.2 log10 IU/mL at Week 12
•
Participant requests to discontinue for any reason
•
Participant noncompliance
•
Pregnancy during the study 
•
At the discretion of the investigator, Gilead, a regulatory agency or an institutional review 
board (IRB), or independent ethics committee (IEC).


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If a participant discontinues study dosing (eg, as a result of an AE), every attempt should be 
made to keep the participant in the study and continue to perform the required study-related FU 
and procedures.
6.9.2.
Criteria for Individual Dose Modification 
Dose modification and discontinuation criteria for participants with ALT elevations or flare by 
treatment and cohort are provided in Section 7.7 Toxicity Management
6.9.3.
Study and/or Cohort Discontinuation Criteria
Study treatment(s) that is considered related by the investigator(s) to the graded toxicities in a 
cohort will be held in all participants if ≥ 3 participants experience a Grade 3 AE or 
≥ 2 participants experience a Grade 4 or SAE (excluding ALT), in the same system organ class 
(SOC). Decisions to reinitiate continuation of dosing will be made by the medical monitor upon 
review of all safety data generated by participants dosed to date.
Study and/or cohort may be discontinued at the request of Gilead, a regulatory agency, or an IRB 
or IEC.
6.9.4.
Premature Study Discontinuation
A primary goal of this study is to assess the safety of a combination of products in participants 
with CHB. Therefore, every effort should be made to retain participants on study to assess safety 
outcomes. Participants who stop study treatments must therefore be maintained on study and 
continue study evaluations. 
If this is not possible or acceptable to the participant or investigator, the participant may be 
withdrawn from the study and an early study discontinuation visit should be performed. The 
early study discontinuation visit should be performed within 14 days from determination by 
participant or investigator of study discontinuation.
Other reasons for study discontinuation:
•
Request by participant to withdraw from study
•
Request by study investigator or participant’s primary physician/provider
The following assessments will be performed at the study discontinuation visit:
•
Perform complete physical examination
•
Ophthalmologic examination and chest x-ray, as needed
•
Collect vital signs and body weight


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12-lead ECG (Paiiicipant must rest quietly in the supine position for a minimum of 5 minutes 
prior to the recording) 
• 
Review AEs and concomitant medications 
• 
Obtain blood samples for laborato1y assessments as follows: 
-
Safety laborato1y tests (hematology and chemistiy and coagulation) 
-
Urinalysis 
-
Qualitative and quantitative HBV serology (HBsAg, HBcrAg, HBeAg, and HBV RNA) 
-
Quantitative plasma HBV DNA 
-
Sernm sample for HBV viral sequencing 
-
Sernm pregnancy test (females of childbeai·ing potential only) 
-
Estimated CLcr (using Cockcroft-Gault method) 
-
APRI and FibroTest 
-TSH 
6.10. 
End of Study 
The end of this study will be last paiiicipant's last observation. 
6.11. 
Poststudy Care 
Once a paiiicipant has completed their study paiiicipation, the long-tenn care of the paiiicipant 
will return to the responsibility of their primaiy ti·eating physicians. 
6.12. 
Sample Storage 
The stored biological samples may be used by Gilead or its research pa1iner for future testing to 
provide additional data. to answer questions that relate to the main study. At the end of this study, 
these sam les ma be retained in stora e b Gilead for a eriod u to 15 ears. 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events and Serious Adverse Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study participant administered a study 
drug, which does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated 
with the use of a study drug, whether or not the AE is considered related to the study drug. 
Adverse events may also include pretreatment or posttreatment complications that occur as a 
result of protocol-specified procedures or special situations (Section 7.1.3). 
An AE does not include the following:
•
Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an AE and must be reported.
•
Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen.
•
Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions).
•
Overdose without clinical sequelae (Section 7.1.3).
•
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed and not related to a protocol-associated procedure is not an AE but 
rather considered to be preexisting and should be documented as medical history.
Preexisting events that increase in severity or change in nature after study drug initiation or 
during or as a consequence of participation in the clinical study will also be considered AEs.
7.1.2.
Serious Adverse Events
An SAE is defined as an event that, at any dose, results in the following:
•
Death
•
A life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the participant was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death if it were more severe.)
•
In-patient hospitalization or prolongation of existing hospitalization


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•
Persistent or significant disability/incapacity
•
A congenital anomaly/birth defect
•
A medically important event or reaction: Such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is reportable under 
expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. 
7.1.3.
Study Drugs and Gilead Concomitant Therapy Special Situations Reports
Special situation reports (SSRs) include all reports of medication error, abuse, misuse, overdose, 
occupational exposure, drug interactions, exposure via breastfeeding, unexpected benefit, 
transmission of infectious agents via the product, counterfeit of falsified medicine, and 
pregnancy regardless of an associated AE. 
Medication error is any unintentional error in the prescribing, dispensing, preparation for 
administration or administration of a study drug while the medication is in the control of a health 
care professional, patient, or consumer. Medication errors may be classified as a medication error 
without an AE, which includes situations of missed dose, medication error with an AE, 
intercepted medication error, or potential medication error.
Abuse is defined as persistent or sporadic intentional excessive use of a study drug by a 
participant.
Misuse is defined as any intentional and inappropriate use of a study drug that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a study 
drug given per administration or cumulatively which is above the maximum recommended dose 
as per protocol or in the product labeling (as it applies to the daily dose of the participant in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the participant has taken the excess dose(s). Overdose cannot be established 
when the participant cannot account for the discrepancy, except in cases in which the 
investigator has reason to suspect that the participant has taken the additional dose(s).
Occupational exposure is defined as exposure to a study drug as a result of one’s professional or 
nonprofessional occupation.
Drug interaction is defined as any drug/drug, drug/food, or drug/device interaction.


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Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial. 
Transmission of infectious agents is defined as any suspected transmission of an infected agent 
through a Gilead study drug.
Counterfeit or falsified medicine: Any study drug with a false representation of (a) its identity, 
(b) its source, or (c) its history.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug using clinical judgment and the following considerations:
•
No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, concomitant medication).
•
Yes: There is reasonable possibility that the AE may have been caused by the study drug.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:
•
No: Evidence exists that the AE has an etiology other than the study procedure.
•
Yes: The AE occurred as a result of protocol procedures (eg, venipuncture).
7.2.2.
Assessment of Severity 
The severity of AEs will be graded using the Gilead Sciences Inc. (GSI) Toxicity Grading Scale, 
Version 01 April 2015, with the exception of IRRs. For each episode, the highest grade attained 
should be reported as defined in the Toxicity Grading Scale (Appendix 11.5).
Grading of IRRs will be done according to the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0 found on the National Cancer Institute (NCI) website:
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf


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7.3.
Investigator Reporting Requirements and Instructions 
7.3.1.
Requirements for Collection Prior to Study Drug Initiation
After informed consent, but prior to initiation of study medication, the following types of events 
must be reported on the applicable eCRFs: all SAEs and AEs related to protocol-mandated 
procedures.
7.3.2.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until the end of the study including the posttreatment FU visit and report them on the eCRFs as 
instructed.
All AEs should be followed until resolution or until the AE is stable, if possible. Gilead may 
request that certain AEs be followed beyond the protocol-defined FU period.
7.3.3.
Serious Adverse Events
All SAEs, including deaths regardless of cause or relationship, that occur after the participant 
first consents to participate in the study (ie, signing the ICF) and throughout the duration of the 
study, including the posttreatment FU visit, must be reported on the applicable eCRFs and to 
Patient Safety (PS, formerly Global Patient Safety) as instructed below in this section. This also 
includes any SAEs resulting from protocol-associated procedures performed after the ICF is 
signed.
Investigators are not obligated to actively seek SAEs after the protocol-defined FU period; 
however, if the investigator learns of any SAEs that occur after the protocol-defined FU period 
has concluded and the event is deemed relevant to the use of study drug, the investigator should 
promptly document and report the event to Gilead PS.
Instructions for reporting SAEs are described in Section 7.4.1.
7.3.4.
Study Drug Special Situations Reports
All study drug SSRs that occur from study drug initiation and throughout the duration of the 
study, including the posttreatment FU visit, must be reported to Gilead PS (Section 7.4.2). 
Adverse events and SAEs resulting from SSRs must be reported in accordance to the AE and 
SAE reporting guidance (Section 7.3).
7.3.5.
Concomitant Therapy Reports
7.3.5.1.
Gilead Concomitant Therapy Special Situations Report
Special situation reports involving a Gilead concomitant therapy (not considered study drug), 
that occurs after the participant first consents to participate in the study (ie, signing the ICF) and 


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throughout the duration of the study, including the posttreatment FU visit, must be reported to 
Gilead PS utilizing the paper SSR (Section 7.4.2.2).
7.3.5.2.
Non-Gilead Concomitant Therapy Report
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the SSR form; however, for special situations that result in AEs due to a non-Gilead concomitant 
medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
All clinical sequelae in relation to these SSRs will be reported as AEs or SAEs at the same time 
using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available.
7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports
7.4.1.
Serious Adverse Event Reporting Process
•
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be transmitted by email or fax when requested and applicable. 
Transmission of such documents should occur without personal participant identification, 
maintaining the traceability of a document to the participant identifiers.
•
Additional information may be requested to ensure the timely completion of accurate safety 
reports.
•
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the participant’s eCRF and the SAE narrative section of the Safety 
Report Form eCRF.
7.4.1.1.
Electronic Serious Adverse Event Reporting Process 
•
Site personnel will record all SAE data on the applicable eCRFs and from there transmit the 
SAE information to Gilead PS within 24 hours of the investigator’s knowledge of the event 
from ICF signature throughout the duration of the study, including the protocol-required 
posttreatment FU period. Detailed instructions can be found in the eCRF completion 
guidelines.


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•
If for any reason it is not possible to record and transmit the SAE information electronically, 
record the SAE on the paper SAE reporting form and transmit within 24 hours to:
Gilead PS
Email: Safety_fc@gilead.com 
or
Fax: 1-650-522-5477
•
As soon as it is possible to do so, any SAE reported via paper must be transcribed on the 
applicable eCRFs according to instructions and within the timelines outlined in the eCRF 
completion guidelines.
•
If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. If the database is not locked, any SAE reported via paper must be 
transcribed as soon as possible on the applicable eCRFs and transmitted to PS.
•
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by email or fax when requested and applicable. 
Transmission of such documents should occur without personal participant identification, 
maintaining the traceability of a document to the participant identifiers.
•
Additional information may be requested to ensure the timely completion of accurate safety 
reports.
•
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the participant’s eCRF and the SAE narrative section of the Safety 
Report Form eCRF.
7.4.2.
Special Situations Reporting Process 
7.4.2.1.
Paper Special Situations Reporting Process for Study Drug
•
All SSRs will be recorded on the SSR form and transmitted by emailing or faxing the report 
form within 24 hours of the investigator’s knowledge of the event to the attention of Gilead 
PS from study drug initiation throughout the duration of the study, including the 
protocol-required posttreatment FU period.
Gilead PS
Email: Safety_fc@gilead.com 
or
Fax: 1-650-522-5477


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7.4.2.2.
Reporting Process for Gilead Concomitant Medications
•
Special situations that involve Gilead concomitant medications that are not considered study 
drug must be reported within 24 hours of the investigator’s knowledge of the event to Gilead 
PS utilizing the paper SSR form to:
Gilead PS
Email: Safety_fc@gilead.com 
or
Fax: 1-650-522-5477
•
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
•
Special situations involving non-Gilead concomitant medications do not need to be reported 
on the SSR form; however, special situations that result in AEs due to a non-Gilead 
concomitant medication, must be reported as an AE.
7.4.2.3.
Pregnancy Reporting Process
•
The investigator should report pregnancies in female study participants and/or female 
partners of male participants who are identified after initiation of study drug and throughout 
the study, including the posttreatment FU period, to Gilead PS using the pregnancy report 
form within 24 hours of becoming aware of the pregnancy. Contact details for transmitting 
the pregnancy report form are as follows:
Gilead PS
Email: Safety_fc@gilead.com 
or
Fax: 1-650-522-5477
•
The pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate 
a pregnancy without medical reasons.
•
All other premature terminations of pregnancy (eg, a spontaneous abortion, an induced 
therapeutic abortion due to complications or other medical reasons) must be reported within 
24 hours as an SAE, as described in Section 7.4.1. The underlying medical reason for this 
procedure should be recorded as the AE term.
•
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Section 7.4.1. Furthermore, any SAE occurring as an adverse pregnancy outcome after 
study completion must be reported to the Gilead PS.
•
The participant should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome of the pregnancy/partner pregnancy should be reported to Gilead PS 
using the pregnancy outcome report form. If the end of the pregnancy/partner pregnancy 


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occurs after the study has been completed, the outcome should be reported directly to Gilead 
PS. Gilead PS contact information is as follows: email: Safety_FC@gilead.com and 
fax: +1 (650) 522-5477.
•
Refer to Appendix 11.4 for Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements.
7.5.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA CFR, 
the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and other country-specific 
legislation or regulations, Gilead may be required to expedite to worldwide regulatory agencies 
reports of SAEs, which may be in the form of line listings, serious adverse drug reactions 
(SADRs), or suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable. 
All investigators will receive either a safety letter or quarterly SUSAR line listing (applicable for 
United Kingdom and European Economic Area sites) notifying them of relevant SUSAR reports 
associated with any study drug. The investigator should notify the IRB or IEC of SUSAR reports 
as soon as is practical, where this is required by local regulatory agencies, and in accordance 
with the local institutional policy. 
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, urinalysis) that require 
medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, ECG, x-rays, vital signs) that are associated with 
signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE 
or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin).
Severity should be recorded and graded according to the GSI Grading Scale (see reference table 
in Appendix 11.5: Toxicity Grading Scale, Version 01 April 2015). For AEs associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of 
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7.7.
Toxicity Management 
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 11.6.
•
Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before study drug discontinuation, 
unless such a delay is not consistent with good medical practice
•
Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities (Appendix 11.5)
•
When restarting study drug following resolution of the AE, the study drug should be restarted 
at full dose or modified dose that is dependent upon discussion with the medical monitor
•
Any recurrence of the study drug–related Grade 3 or 4 clinical or clinically significant 
laboratory AE following dose interruption mandates permanent discontinuation of study drug
•
Administration of study drug(s) may be discontinued due to a clinical or laboratory event. 
The medical monitor should be consulted prior to dose discontinuation of study drug(s) 
unless the investigator believes that immediate action is warranted to ensure the continued 
safety of the participant
•
Any questions regarding toxicity management should be directed to the medical monitor.
7.7.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator.
7.7.2.
Grade 3 Laboratory Abnormality or Clinical Event
•
For Grade 3 laboratory abnormality or clinical event, study drug may be continued if the 
event is considered to be unrelated to study drug
•
For any study drug–related, Grade 3 AE, study drug should be held
•
For any study drug–related ≥ Grade 3 AE not able to be medically managed (eg, nausea with 
antiemetics), study drug should be permanently discontinued
•
For a confirmed laboratory abnormality, study drug–related Grade 3, study drug would be 
held until toxicity returns to ≤ Grade 2. If a laboratory abnormality recurs to ≥ Grade 3 
following rechallenge, study drug should be permanently discontinued, and the participant 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to study drug may not require permanent discontinuation.


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For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing within 3 calendar days that is considered to be related to study drug, study drug 
should be withheld until the toxicity returns to  Grade 2
7.7.3.
Grade 4 Laboratory Abnormality or Clinical Event
•
For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing within 3 calendar days, the study drug should be permanently 
discontinued, and the participant managed according to local practice. The participant should 
be followed as clinically indicated until the laboratory abnormality returns to Day 1 of 
treatment or is otherwise explained, whichever occurs first. A clinically significant Grade 4 
laboratory abnormality that is not confirmed by repeat testing should be managed according 
to the algorithm for the new toxicity grade.
•
A Grade 4 laboratory abnormality or clinical event that is not considered clinically 
significant by the investigator may also be tested for confirmation and study drug continued 
at the discretion of the investigator.
•
The study drug may be continued without dose interruption for a clinically nonsignificant 
Grade 4 laboratory abnormality (eg, Grade 4 CK after strenuous exercise or triglyceride 
elevation that is nonfasting or that can be medically managed).
7.7.4.
Toxicity Management of Immune-Related Adverse Events Observed With 
Nivolumab
Adverse events related to the use of immunomodulatory therapies such as nivolumab are 
immunologic in etiology. They may occur at any time from shortly after first dose to many 
months after the last dose and can affect multiple organs simultaneously. Most irAEs observed 
with anti-PD-1/programmed cell death ligand 1 (PD-L1) mAbs are reversible with early 
detection and treatment discontinuation or treatment with immunomodulating agents such as 
corticosteroids. Investigators should exercise clinical judgment regarding best clinical 
management, based on the symptoms and condition of the individual participant. 
General instructions:
•
Monitor all participants closely for signs and symptoms of irAEs, including signs related to 
gastrointestinal, endocrine, hepatic, ophthalmologic, or cardiac irAEs.
•
Early evaluations with radiographic imaging, relevant laboratory testing, procedures and 
speciality consultation should be considered.
•
Initiate high dose steroid (prednisone 1-2 mg/kg) when indicated for appropriate Grade 3-4 
irAEs.
•
The investigator must notify the Gilead medical monitor in a timely manner upon 
identification of any potential irAE regardless of grade or seriousness.


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•
Report all irAEs that meet serious criteria in accordance with Sections 7.3.3 and 7.4.
According to the approved product label for nivolumab, patients should be monitored 
continuously (at least up to 5 months after the last dose) as an ADR with nivolumab may occur at 
any time during or after discontinuation of therapy. 
For more detailed management guidance, refer to the current approved product label for 
nivolumab {OPDIVO 2022}.
7.7.5.
ALT Elevation or Flare Management on Treatment and Treatment-Free 
Follow-up
On-Treatment ALT Management
Participants with on-treatment serum ALT elevation > 2 × nadir or > 2 × baseline value and 
≥ 5 × ULN, with or without associated symptoms should be managed according to the guidance 
below. 
All elevated serum ALT should be confirmed as soon as possible and ideally within 3 days of 
receipt of results. During the visit, a clinical assessment of the participant should be performed. 
The assessment should include a physical examination, evaluation of the participant’s mental 
status, and the following laboratory tests: 
•
Laboratory parameters: serum ALT and AST, total bilirubin, GGT, INR, and serum albumin, 
alcohol screening
•
If the ALT elevation is confirmed, the central clinical laboratory will conduct reflex testing 
for plasma HBV DNA, serology for HBV (HBsAg, HBsAb, HBeAg and HBeAb), HDV, 
hepatitis A virus (HAV) IgM, HCV, and HEV
•
Liver biopsy may be collected for participants meeting Hy’s law (ALT > 3  ULN and Total 
Bilirubin > 2  ULN; AST > 3  ULN and Total Bilirubin > 2  ULN) with suspected DILI
Additional confirmatory tests such as HDV RNA, HDV IgM, and HEV RNA may be performed 
locally as per local regulations after further discussion with the Gilead’s Medical Monitor.
Based on the results of the confirmatory tests, the following study treatment modifications are 
recommended (Table 6). 


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Table 6.
Dose Modification and Monitoring
Liver Toxicity Parameters 
Action
Confirmed, ALT ≥ 10 × ULN without evidence of 
hepatic toxicity as defined below
Cohort 1: Hold VIR-2218 and SLGN treatment. 
Participant should be monitored weekly or more 
frequently if clinically indicated until ALT < 5 × ULN. 
Restarting VIR-2218 and/or SLGN treatment may be 
considered when ALT < 5  ULN in discussion with 
the medical monitor. Study treatment should be 
restarted in line with the original assigned 
administration schedule. 
Cohort 2: Initiate TAF 25 mg once daily and hold 
VIR-2218 and SLGN dose. Participant should be 
monitored weekly or more frequently if clinically 
indicated until ALT < 5 × ULN. Restarting VIR-2218 
and/or SLGN treatment may be considered when 
ALT < 5  ULN in discussion with the medical 
monitor. Study treatment should be restarted in line 
with the original assigned administration schedule.
Persistent ALT > 2 × baseline and ≥ 5 × ULN without 
evidence of hepatic toxicity, as defined below
Continue study treatment(s), ALT should be evaluated 
every 2 weeks or more frequently as clinically needed, 
until ALT < 5 × ULN
Confirmed ALT > 2 × nadir, with evidence of hepatic 
toxicity, defined as any one of the following confirmed 
laboratory abnormalities:
•
Total bilirubin > 2 × ULN
•
Elevated INR > 0.5 above baseline AND > ULN 
•
Abnormal serum albumin > 1 g/dL decrease from 
baseline 
Cohort 1: Permanently discontinue study treatment(s) 
except TAF 25 mg once daily. Participant should be 
monitored weekly until ALT < 5 × ULN, and total 
bilirubin, INR, and albumin values return to normal or 
baseline levels. 
Cohort 2: Initiate commercially approved NUC 
treatment once daily and permanently discontinue 
study treatment(s). Participant should be monitored 
weekly until ALT < 5 × ULN, and total bilirubin, 
albumin, and/or INR values return to normal or 
baseline levels 
ALT = alanine aminotransferase; INR = international normalized ratio; NUC = nucleos(t)ide(s); SLGN = selgantolimod; 
TAF = tenofovir alafenamide; ULN = upper limit of normal
Treatment-Free Follow-up ALT Management 
All participants not on NUC treatment will enter TFFU period after completion of study 
treatment, in which they will undergo close safety monitoring. The proportion of participants 
who achieve HBsAg loss or are able to remain off NUC therapy during TFFU period will be 
assessed. Table 7 provides guidance for initiating commercially approved NUC treatment, in 
participants who experience rebound of HBV DNA and ALT levels. Any deviation from the 
table should be discussed in advance with medical monitor. 
If unscheduled visits are required for ALT monitoring, a clinical assessment of the participant 
should be performed. The assessment should include a physical examination, evaluation of the 
participant’s mental status and the following laboratory tests: 


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•
Laboratory parameters: serum ALT and AST, total and direct bilirubin, GGT, INR, serum 
albumin, plasma HBV DNA, quantitative HBsAg, PBMC for immune profiling, and alcohol 
screen.
•
At the initial confirmatory visit, collect serology for HDV, HAV IgM, HCV, and HEV.
Participants with HBV DNA ≤ LLOQ and ALT elevation/flare meeting any of the below table 
criteria should be evaluated for alternative liver disease etiologies by the investigator and in 
discussion with the medical monitor. Liver biopsy may be collected at the investigator’s 
discretion.
Participants with HBV DNA > LLOQ and ALT elevation/flare should be managed according to 
the table below: 
Table 7.
Starting Commercial NUC Treatment Criteria
Liver Toxicity Parameters
Action
Confirmed ALT ≥ 10 × ULN with no evidence of 
hepatic toxicity, as defined below.
Initiate NUC treatment and monitor weekly until ALT 
< 5 × ULN, and every 2 weeks until ALT < 2  ULN, 
or more frequently if clinically indicated.
ALT ≥ 5  ULN without evidence of hepatic toxicity, 
as defined below
ALT should be evaluated every 2 weeks or more 
frequently as clinically needed, until ALT < 2 × ULN. 
Confirmed ALT > ULN with evidence of hepatic 
toxicity, defined as any one of the following confirmed 
laboratory abnormalities: 
•
Total bilirubin > 2  nadir AND > 2.5 mg/dL in 
the absence of Gilbert’s disease
•
Elevated INR > 0.5 above nadir AND > ULN 
•
Abnormal serum albumin > 1 g/dL decrease from 
baseline
Initiate NUC treatment and monitor weekly or more 
frequently if clinically indicated until return to baseline 
levels or within normal reference range. Liver biopsy 
may be considered if appropriate for participant 
management.
Confirmed, HBV DNA > 20,000 IU/mL (HBeAg 
positive) or > 2,000 IU/mL (HBeAg negative) and
persistent ALT > ULN without evidence of hepatic 
toxicity, as defined above, for > 8 weeks
Initiating NUC treatment may be considered in 
discussion with the medical monitor. 
ALT = alanine aminotransferase; DNA = deoxyribonucleic acid; HBeAg = hepatitis B e antigen; HBV = hepatitis B virus; 
NUC = nucleos(t)ide(s); ULN = upper limit of normal


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are as follows:
•
To evaluate the safety and tolerability of study treatment(s)
•
To evaluate the efficacy of study treatment(s) as measured by the proportion of participants 
who achieve functional cure, defined as HBsAg loss and HBV DNA < LLOQ at FU Week 24
The secondary objectives of this study are as follows: 
•
To evaluate the proportion of participants with HBsAg loss with and without anti-HBsAg 
seroconversion during the study
•
To evaluate in participants with CHB who are HBeAg positive at baseline, the proportion of 
participants who achieve HBeAg loss with and without anti-HBeAg seroconversion during 
the study
•
To evaluate the proportion of participants who remain off NUC treatment during FU
•
To evaluate the proportion of participants experiencing HBV virologic breakthrough during 
study treatment(s)
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8.1.2.
Primary Endpoint
The primary efficacy endpoint is the proportion of participants who achieve functional cure, 
defined as HBsAg loss and HBV DNA < LLOQ at FU Week 24.
8.1.3.
Secondary Endpoint
Secondary efficacy endpoints of this study are as follows:
•
The proportion of participants with HBsAg loss with and without anti-HBsAg 
seroconversion during the study
•
The proportion of participants with HBeAg loss with and without anti-HBeAg 
seroconversion during the study in participants with CHB who are HBeAg positive at 
baseline
•
The proportion of participants who remain off NUC treatment during FU
•
The proportion of participants experiencing HBV virologic breakthrough during study 
treatment(s)
8.2.
Planned Analyses
8.2.1.
Primary Analysis
The primary analysis will be conducted after all participants within each cohort have completed 
FU Week 24 or early terminated from the study prior to FU Week 24.
8.2.2.
Final Analysis
The final analysis will be performed at the end of the study, after all participants have completed 
the study or early terminated from the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized. 
8.3.
Analysis Conventions
8.3.1.
Analysis Sets
8.3.1.1.
Efficacy
The primary analysis set for efficacy analysis is the Full Analysis Set (FAS), defined as all 
participants who are enrolled and have received at least 1 dose of study drug. Participants will be 
analyzed according to the treatment(s) to which they were assigned.
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Safety 
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The prirmuy analysis set for safety analyses is the Safety Analysis Set, defined as all paiiicipants 
who have received at least 1 dose of study drng. Paiticipants will be analyzed according to the 
treatment( s) they actually received. 
8.3.1.3. 
Phaimacokinetics 
The PK Analysis Set will include all enrolled paiiicipants who took at least 1 dose of study chug 
and have at least 1 nonmissing concentration value repo1ied by the PK laborato1y. 
8.3.1.4. 
Biomai·kers 
The Biomai·ker Analysis Set will include all enrolled paiiicipants who took at least 1 dose of the 
study chug and have at least 1 nonmissing biomai·ker value for each respective biomarker. 
8.3.1.5. 
Data Handling Conventions 
For the primaiy efficacy endpoint and the categorical seconda1y efficacy endpoints, missing data 
will be handled using a missing= failure approach. For continuous secondaiy endpoints, a 
missing = excluded approach will be employed. 
For selected analyses, HBsAg and HBV DNA data (IU/mL) will be transfonned to the 
logarithmic (base 10) scale (log10 IU/mL). 
For summaiy statistics, PK concentration values below the limit of quantitation will be treated as 
zero at predose and one-half of the LLOQ for postdose time points. 
8.4. 
Demographic and Baseline Characteristics Analysis 
Demographic and baseline measurements will be summarized by coho1i using standai·d 
descriptive methods. 
Demographic sUllllllai·ies will include sex, race/ethnicity, randomization stratification group (if 
applicable), and age. 
Baseline data will include a summaiy of body weight, height, body mass index, HBsAg 
(log10 IU/mL), HBV DNA (log10 IU/mL), HBeAg/HBeAb status, HBV genotype, ALT, and 
additional endpoints as necessaiy. 
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8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary analysis will be performed separately for each cohort when the last participant in 
each cohort reaches FU Week 24.
The proportion of participants who achieve functional cure at FU Week 24 will be analyzed for 
each treatment cohort. A point estimate with a 2-sided 95% exact CI will be constructed for the 
proportion using the binomial distribution (Clopper-Pearson method).
8.5.2.
Secondary Analyses
The secondary efficacy endpoints will be summarized by treatment cohort.
Continuous secondary endpoints will be summarized using conventional descriptive statistics 
(n, mean, SD, median, first quartile [Q1], third quartile [Q3], minimum, and maximum) by 
treatment cohort.
Categorical secondary endpoints will be summarized by number and percentage of participants 
who meet the endpoint by treatment cohort.
8.5.3.
Analysis of Other Endpoints of Interest
Continuous endpoints will be summarized using conventional descriptive statistics (n, mean, SD, 
median, Q1, Q3, minimum, and maximum) by treatment cohort.
Categorical endpoints will be summarized by number and percentage of participants who meet 
the endpoint by treatment cohort.
8.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests and AEs. The primary safety 
analysis will be evaluated through 30 days posttreatment. 
Posttreatment is defined as the following:
•
For VIR-2218 and nivolumab, posttreatment will start 4 weeks after last dose. 
•
For SLGN, posttreatment will start 1 week after last dose.
Posttreatment for each cohort will be based on the last study drug(s) end of the treatment window 
duration that is the longest.
The safety analysis will also be conducted through FU Week 24 as a secondary safety analysis.
All safety data collected during the study will be included in data listings.


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8.6.1.
Extent of Exposure
A participant’s extent of exposure to study drug data will be generated from the study drug 
administration data. Exposure data will be summarized by treatment cohort. 
8.6.2.
Adverse Events
Clinical and laboratory AEs will be coded using the MedDRA. System organ class, high-level 
group term (HLGT), high-level term (HLT), preferred term (PT), and lower-level term (LLT) 
will be attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
AE (TEAE) will be defined as:
•
Any AE that begins on or after the date of first dose of any study drug and no later than 
30 days posttreatment of SLGN + nivolumab ± VIR-2218 
•
Any AE leading to premature discontinuation of any study drug
Summaries (number and percentage of participants) of TEAEs (by SOC and PT) will be 
provided by treatment group:
•
All TEAEs
•
TEAEs of Grade 3 or higher
•
All TE treatment-related AEs
•
TE treatment-related AEs of Grade 3 or higher
•
All TE SAEs
•
All TE treatment-related SAEs
•
All TEAEs leading to premature discontinuation of any study drug
•
All TEAEs leading to temporary interruption of any study drug
•
AEs of special interest (eg, uveitis)
Summaries (number and percentage of participants) of all on-treatment and posttreatment 
potential irAEs (by SOC and PT), as defined by relevant MedDRA Standardised MedDRA 
Queries (SMQs), will be provided by treatment group. 
All AEs collected during the study will be presented in the data listings.


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8.6.3.
Laboratory Evaluations
Selected laboratory data (using units) will be summarized using only observed data. Data and 
change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme in Appendix 11.5.
Incidence of TE laboratory abnormalities, defined as values that increase at least one toxicity 
grade from baseline at any time postbaseline up to 30 days posttreatment of 
SLGN + nivolumab ± VIR-2218, will be summarized by treatment group. If baseline data are 
missing, then any graded abnormality (ie, at least a Grade 1) will be considered TE. 
This analysis will also be provided through FU Week 24.
All laboratory abnormalities will be included in the listings of laboratory data.
8.6.4.
Other Safety Evaluations
Individual data for ECG and vital signs measurements will be listed by participant and 
summarized for each treatment group by visit by incidence of events/abnormalities or descriptive 
statistical summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate.
8.7.
Pharmacokinetic Analysis 
Plasma concentrations of SLGN and VIR-2218 may be analyzed. Serum concentrations of 
nivolumab may be analyzed (as applicable, from existing samples).
Concentration data from all sparse and intensive blood PK samples may be pooled with data 
from other studies and may be used for estimation of population PK parameters.
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with International Council 
for Harmonisation (of Technical Requirements for Pharmaceuticals for Human Use) (ICH) 
E6(R2) addendum to its guideline for GCP and applicable laws and regulations.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide prompt and accurate documentation of their 
financial interest or arrangements with Gilead or proprietary interests in the study drug during 
the course of a clinical study. This documentation must be provided prior to the investigator’s 
(and any subinvestigator’s) participation in the study. The investigator and subinvestigator agree 
to notify Gilead of any change in reportable interests during the study and for 1 year following 
completion of the study. Study completion is defined as the date when the last participant 
completes the protocol-defined activities.
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
The investigator (or Gilead as appropriate according to local regulations) will submit this 
protocol, ICF, and any accompanying material to be provided to the participant (such as 
advertisements, participant information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study participant activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the participant after initial IRB/IEC approval, with the exception of those necessary 
to reduce immediate risk to study participants.
9.1.4.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study before undertaking any study-related procedures. The investigator 
must use the most current IRB- or IEC-approved ICF for documenting written informed consent. 
Each ICF (or assent as applicable) will be appropriately signed and dated by the participant or 
the participant’s legally authorized representative, the person conducting the consent discussion, 
and an impartial witness (if required by IRB or IEC or local requirements). 


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Confidentiality 
Final 
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The investigator must ensure that paiiicipants' anonymity will be strictly maintained and that 
their identities ai·e protected from unauthorized paiiies. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of bi1ih) will be recorded on any fo1m 
or biological sample submitted to Gilead or the laborato1y. Laborato1y specimens must be 
labeled in such a way as to protect paiiicipant identity while allowing the results to be recorded 
to the proper pa1iicipant. Refer to specific laborato1y instructions. 
NOTE: The investigator must keep a screening log with details for all participants screened and 
emolled in the study, in accordance with the site procedures and regulations. Paiiicipant data will 
be processed in accordance with all applicable regulations. 
The investigator agrees that all info1mation received from Gilead, including but not limited to the 
IB, this protocol, case repo1i fonns (CRFs)/eCRFs, study diug info1mation, and any other study 
info1mation, remain the sole and exclusive prope1iy of Gilead during the conduct of the study 
and thereafter. This info1mation is not to be disclosed to any third pa1iy (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior written 
consent from Gilead. The investigator fmi her agrees to take all reasonable precautions to prevent 
the disclosure by any employee or agent of the study site to any third paiiy or othe1wise into the 
public domain. 
9.1.6. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator's study file and 
(2) paiiicipant clinical source documents. 
The investigator's study file will contain the protocol/amendments, CRFs/eCRFs, governmental 
approval with conespondence, the ICF(s), dmg records, staff cmTiculum vitae and authorization 
fo1ms, and other appropriate documents and con espondence. 
The required source data should include sequential notes containing at least the following 
info1mation for each paiiicipant: 
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Participant identification
•
Documentation that participant meets eligibility criteria, ie, medical history, physical 
examination, and confirmation of diagnosis (to support inclusion and exclusion criteria)
•
Documentation of the reason(s) a consented participant is not enrolled
•
Participation in study (including study number)
•
Study discussed and date of informed consent
•
Dates of all visits
•
Documentation that protocol-specific procedures were performed
•
Results of efficacy parameters, as required by the protocol
•
Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return
•
Record of all AEs and other safety parameters (start and end date; causality and severity) and 
documentation that adequate medical care has been provided for any AE
•
Concomitant medication (start and end date; dose if relevant; dose changes)
•
Date of study completion and reason for ED, if it occurs
All clinical study documents must be retained by the investigator for at least 2 years or according 
to local laws, whichever is longer, after the last approval of a marketing application in an ICH 
region (ie, US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, for 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Gilead. The investigator 
must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
participant, appropriate copies should be made for storage away from the site.


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9.1.7.
Case Report Forms
An eCRF casebook will be completed by an authorized study personnel member whose training 
for this function is completed in the EDC system unless otherwise directed. The eCRF casebook 
will only capture the data required per the protocol schedule of events and procedures unless 
collected by a nonelectronic data capture vendor system (eg, central laboratory). The 
Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility are available. Data entry should be performed in accordance with the CRF 
Completion Guidelines provided by Gilead. Subsequent to data entry, a study monitor may 
perform source data verification (SDV). System-generated or manual queries will be issued in 
the EDC system as data discrepancies are identified by the study monitor or Gilead personnel 
who routinely review the data for completeness, correctness, and consistency. The site 
investigator, site coordinator, or other designee is responsible for responding to the queries in a 
timely manner, within the system, either by confirming the data as correct or updating the 
original entry, and providing the reason for the update (eg, data entry error). Original entries as 
well as any changes to data fields will be stored in the audit trail of the system. Regular oversight 
by the principal investigator of the data entered into the EDC system is expected to occur on an 
ongoing basis throughout the study to ensure quality and completeness. At a minimum, before 
any interim, final, or other time points (as instructed by Gilead), the investigator will apply 
his/her electronic signature to confirm that the forms have been reviewed and that the entries 
accurately reflect the information in the source documents. At the conclusion of the study, Gilead 
will provide the site investigator with a read-only archive copy of the data entered. This archive 
must be stored in accordance with the records retention requirements outlined in Section 9.1.6.
9.1.8.
Investigator Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, to IRBs/IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study participants, 
may be made only by Gilead. The investigator must submit all protocol modifications to 
IRB/IEC and regulatory authorities in accordance with local requirements and receive 
documented IRB/IEC and regulatory authority approvals before modifications may be 
implemented.


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9.2.2.
Study Reports and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies) when 
applicable and in accordance with local regulatory requirements. Gilead will ensure that the 
report meets the standards set out in the ICH Guideline for Structure and Content of Clinical 
Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain cases. For 
studies with sites in countries following the EU Regulation No. 536/2014, a CSR will be 
submitted within 1 year (6 months for pediatric studies, in accordance with Regulation [EC] 
No. 1901/2006) after the global end of study (as defined in Section 3.7).
Investigators in this study may communicate, orally present, or publish study data in scientific 
journals or other scholarly media in accordance with the Gilead clinical trial agreement.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol (eg, attendance at investigator meetings). If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to federal and state agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any participant records 
needed to verify the entries in the CRF/eCRF. The investigator agrees to cooperate with the 
monitor to ensure that any problems detected through any type of monitoring (central, on-site) 
are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the medical monitor immediately. The investigator agrees to provide 
to representatives of a regulatory agency or Gilead access to records, facilities, and personnel for 
the effective conduct of any inspection or audit.
9.3.4.
Premature Study Termination
Both Gilead and the investigator reserve the right to terminate the study at any time. Should this 
be necessary, both parties will arrange discontinuation procedures and notify the participants, 
appropriate regulatory authority, and IRB/IEC. In terminating the study, Gilead and the 
investigator will ensure that adequate consideration is given to the protection of the participants’ 
interests.


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10.
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Benias P, Min A. Goals of Antiviral Therapy for Hepatitis B: HBeAg Seroconversion, HBsAg 
Seroconversion, Histologic Improvement, and Possible Impact on Risk of 
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Buti M, Berg T, Chan H, Suri V, Wang H, Gaggar A, et al. Evaluation of HBV Outcomes After 
Treatment Discontinuation From 4 Phase 3 Studies [Poster THU-205]. EASL: 
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Cohen C., Block J., Ibrahim Y. The Voice of the Patient: Living with Chronic Hepatitis B. 
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European Association for the Study of the Liver (EASL). EASL 2017 Clinical Practice 
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Evans A, Riva A, Cooksley H, Phillips S, Puranik S, Nathwani A, et al. Programmed death 1 
expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B 
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G. B. D. Mortality Causes of Death Collaborators. Global, Regional, and National Life 
Expectancy, All-Cause Mortality, and Cause-Specific Mortality for 249 Causes of 
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Gane E, Dubar PR, Brooks AE, Zhao Y, Tan SK, Lau AH, et al. Efficacy and Safety of 24 
Weeks Treatment with Oral TLR8 Agonist Selgantolimod (GS-9688, SLGN) in 
Virally Suppressed Adult Patients with Chronic Hepatitis B: A Phase 2 Study 
[Abstract 71]. The Digital International Liver Congress (ILC); 2020 27-29 
August. 
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blockade with nivolumab with and without therapeutic vaccination for virally 
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Gane EJ, Dunbar PR, Brooks AE, Zhang F, Chen D, Wallin JJ, et al. Safety and efficacy of the 
oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under 
viral suppression. J Hepatol 2023;78:513-23.
Gardiner D, Lalezari J, Lawitz E, DiMicco M, Ghalib R, Reddy KR, et al. A randomized, 
double-blind, placebo-controlled assessment of BMS-936558, a fully human 
monoclonal antibody to programmed death-1 (PD-1), in patients with chronic 
hepatitis C virus infection. PLoS ONE 2013;8 (5):e63818.
Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, 
Moradi-Lakeh M, et al. The Global Burden of Cancer 2013. JAMA oncology 
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Gubser C, Chiu C, Lewin SR, Rasmussen TA. Immune checkpoint blockade in HIV. 
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Idilman R, Cinar K, Seven G, Bozkus Y, Elhan A, Bozdayi M, et al. Hepatitis B surface antigen 
seroconversion is associated with favourable long-term clinical outcomes during 
lamivudine treatment in HBeAg-negative chronic hepatitis B patients. J Viral 
Hepat 2012;19 (3):220-6.
Janas MM, Harbison CE, Perry VK, Carito B, Sutherland JE, Vaishnaw AK, et al. The 
Nonclinical Safety Profile of GalNAc-conjugated RNAi Therapeutics in Subacute 
Studies. Toxicol Pathol 2018;46 (7):735-45.
Janssen H, Lim Y, Kim H, Tseng CH, Coffin C, Elkashab M, et al. Safety and Efficacy of Oral 
TLR8 Agonist Selgantolimod in Viremic Adult Patients With Chronic Hepatitis B 
[Poster 2429]. International Liver Congress 2021 23–26 June. 
Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, et al. HBsAg seroclearance after nucleoside 
analogue therapy in patients with chronic hepatitis B: clinical outcomes and 
durability. Gut 2013;63:1325-32.
Kwon H, Lok AS. Hepatitis B therapy. Nature reviews. Gastroenterology & hepatology 2011;8 
(5):275-84.
Liaw Y-F, Kao J-H, Piratvisuth T, Chan HLY, Chien R-N, Liu C-J, et al. Asian-Pacific 
consensus statement on the management of chronic hepatitis B: a 2012 update. 
Hepatol International 2012;6:531-61.
Liaw YF. Impact of hepatitis B therapy on the long-term outcome of liver disease. Liver Int 
2011;31 Suppl 1:117-21.
Lok AS. Evolution of nucleoside/tide analogues for hepatitis B: is the ideal drug here yet? J 
Hepatol 2009;51 (2):416-8.
Lok AS. Hepatitis: Long-term therapy of chronic hepatitis B reverses cirrhosis. Nature reviews. 
Gastroenterology & hepatology 2013;10 (4):199-200.
Mizukoshi E, Sidney J, Livingston B, Ghany M, Hoofnagle JH, Sette A, et al. Cellular immune 
responses to the hepatitis B virus polymerase. J Immunol 2004;173 (9):5863-71.
Moucari R, Korevaar A, Lada O, Martinot-Peignoux M, Boyer N, Mackiewicz V, et al. High 
rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients 
responding to interferon: a long-term follow-up study. J Hepatol 2009;50 
(6):1084-92.
Nair JK, Attarwala H, Sehgal A, Wang Q, Aluri K, Zhang X, et al. Impact of enhanced metabolic 
stability on pharmacokinetics and pharmacodynamics of GalNAc-siRNA 
conjugates. Nucleic Acids Res 2017;45 (19):10969-77.
OPDIVO, Bristol-Myers Squibb. OPDIVO (nivolumab) injection, for intravenous use. U.S. 
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Peppa D, Micco L, Javaid A, Kennedy PT, Schurich A, Dunn C, et al. Blockade of 
immunosuppressive cytokines restores NK cell antiviral function in chronic 
hepatitis B virus infection. PLoS pathogens 2010;6 (12):e1001227.
Ratnam I, Chiu C, Kandala NB, Easterbrook PJ. Incidence and risk factors for immune 
reconstitution inflammatory syndrome in an ethnically diverse HIV type 
1-infected cohort. Clin Infect Dis 2006;42 (3):418-27.
Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. 
Nature reviews 2005;5 (3):215-29.
Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice 
guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2015.
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence 
of chronic hepatitis B virus infection: a systematic review of data published 
between 1965 and 2013. Lancet 2015;386:1546-55.
Sherman AC, Trehanpati N, Daucher M, Davey RT, Masur H, Sarin SK, et al. Augmentation of 
hepatitis B virus-specific cellular immunity with programmed death 
receptor-1/programmed death receptor-L1 blockade in hepatitis B virus and 
HIV/hepatitis B virus coinfected patients treated with adefovir. AIDS Res Hum 
Retroviruses 2013;29 (4):665-72.
Simonetti J, Bulkow L, McMahon BJ, Homan C, Snowball M, Negus S, et al. Clearance of 
hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort 
chronically infected with hepatitis B virus. Hepatology 2010;51 (5):1531-7.
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines 
for treatment of chronic hepatitis B. Hepatology 2016;63 (1):261-83.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 
2012;366 (26):2443-54.
VEMLIDY, Gilead Sciences Inc. VEMLIDY® (tenofovir alafenamide) tablets, for oral use. U.S. 
Prescribing Information. Foster City, CA. Revised August. 2020:
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World Health Organization (WHO). Hepatitis C Fact sheet N° 164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/. Updated July 2015. 
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11.
APPENDICES


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11.1.
Investigator Signature Page
GILEAD SCIENCES, INC.
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
STUDY ACKNOWLEDGMENT
A Phase 2a, Open-Label Study to Evaluate the Safety and Efficacy of Selgantolimod 
(SLGN)-Containing Combination Therapies for the Treatment of Chronic Hepatitis B (CHB)
GS-US-465-4439, Amendment 2 12 April 2023
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval.
[See appended electronic signature]
Medical Monitor
Signature
[See appended electronic signature]
Date
INVESTIGATOR STATEMENT
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein 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 access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study.
Principal Investigator Name (Printed)
Signature
Date
Site Number
PPD


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11.2.
Pandemic Risk Assessment and Mitigation Plan
During an ongoing pandemic, potential risks associated with participants being unable to attend 
study visits have been identified for this study. 
These risks can be summarized as follows:
1) Study drug supplies to participants and sites:
a) Participants may be unable to return to the site for a number of visits to get the study 
drug, or the site may be unable to accept any participant visits. Without study drugs, the 
participant would not be able to stay on the study drug as planned per protocol.
Mitigation plan: Study drug supplies may be provided to the participant from the site without a 
clinic visit, once it is confirmed that the participant may safely continue on study drug as 
determined by the principal investigator (PI). A virtual study visit, via phone or video 
conferencing, must be performed prior to remote study drug resupply. At the earliest opportunity, 
the site will schedule in-person participant visits and return to the protocol’s regular schedule of 
assessments. A qualified courier may be utilized to ship the study drug from sites to study 
participants if permitted by local ethic committee (EC)/institutional review boards 
(IRB)/Regulatory Authority as applicable and with sponsor's approval.
b) Shipments of study drug could be delayed because of transportation issues. Without study 
drug participant would not be able to stay on the study drug as planned per protocol.
Mitigation plan: The sites' study drug inventory should be closely monitored. Site staff should 
notify the sponsor or delegate if they foresee shortage in study drug inventory or if there is any 
interruption in local shipping service. The sponsor will continue to monitor inventory at the 
study drug depot and study sites. Manual shipments will be triggered as necessary.
2) Participant safety monitoring and FU:
c) Participants may be unable or unwilling to come to the study site for their scheduled 
study visits as required per protocol.
Mitigation plan: For participants who may be unable or unwilling to visit the study site for their 
scheduled study visits as required per protocol, the PI or qualified delegate will conduct a virtual 
study visit, via phone or video conferencing, to assess the participant within target visit window 
date whenever possible. During the virtual study visit, the following information at minimum 
will be reviewed: 
i)
Confirm if participant has experienced any adverse events (AEs)/serious adverse 
events (SAEs)/special situations (including pregnancy) and FU on any unresolved 
AE/SAEs.
ii) Review current list of concomitant medications and document any new concomitant 
medications.


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iii) If applicable, confirm participants study drug supply is sufficient to last until the next 
planned visit date. If study drug resupply is needed it will be provided as described 
above in (1).
iv) If applicable, remind participant to maintain current dosing and to keep all dispensed 
study drug kits for return at the next on-site visit.
d) Participants may be unable or unwilling to travel to the site for planned assessments (eg, 
safety blood draws); hence samples may not be sent for central lab analyses.
Mitigation plan: Local labs may be utilized as appropriate to monitor participant safety until the 
participant can return to the site for their regular FU per protocol. Any laboratory assessments 
conducted at a local lab due to the pandemic will be documented accordingly. Pregnancy testing 
may be performed using a home urine pregnancy test if local lab pregnancy testing is not 
feasible.
e) Participants may be unable or unwilling to attend the study visit to sign an updated 
informed consent form (ICF) version.
Mitigation plan: The site staff will follow their approved consent process and remain in 
compliance with local EC/IRB and national laws and regulations. Remote consent will be 
allowed if has been approved by the local EC/IRB. The consent process will be documented and 
confirmed by normal consent procedure at the earliest opportunity.
3) Protocol and monitoring compliance:
f)
Protocol deviations may occur, in case scheduled visits cannot occur as planned per 
protocol.
Mitigation plan: If it is not possible to complete a required procedure, an unscheduled visit 
should be conducted as soon as possible when conditions allow. The situation should be recorded 
and explained as a protocol deviation. Any missed participant visits or deviation to the protocol 
due to the pandemic must be reported in the eCRF and described in the clinical study report. Any 
virtual study visits that are conducted in lieu of clinic visits due to the pandemic will be 
documented as a protocol deviation related to the pandemic.
g) Monitors may be unable to carry out source data review (SDR) or (SDV), or study drug 
accountability or assess protocol and Good Clinical Practice (GCP) compliance. This 
may lead to delays in SDV, an increase in protocol deviations, or under reporting of AEs.
Mitigation plan: The study monitor is to remain in close communication with the site to ensure 
data entry and query resolution. In compliance with Gilead policy, a remote SDV should not be 
arranged). The study monitor is to reference the Study Monitoring Plan for guidance on how to 
conduct a remote monitoring visit. The study staff is to save and document all relevant 
communication in the study files. The status of sites that cannot accept monitoring visits and/or 
participants on site, must be tracked centrally and updated on a regular basis.


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4) Missing data and data integrity:
h) There may be an increased amount of missing data due to participants missing 
visits/assessments. This could have an impact on the analysis and the interpretation of 
clinical study data. 
Mitigation plan: Implications of a pandemic on methodological aspects for the study will be 
thoroughly assessed and documented, and relevant actions will be taken as appropriate (ie, 
modification of the statistical analysis plan) and in compliance with Regulatory Authorities’ 
guidance. Overall, the clinical study report will describe the impact of the pandemic on the 
interpretability of study data.
Risks will be assessed continuously, and temporary measures will be implemented to mitigate 
these risks as part of a mitigation plan, as described above. These measures will be 
communicated to the relevant stakeholders as appropriate and are intended to provide alternate 
methods that will ensure the evaluation and assessment of the safety of participants who are 
enrolled in this study. 
Since these potential risks are considered mitigated with the implementation of these measures, 
the expected benefit-risk assessment of selgantolimod (SLGN), VIR-2218, and TAF in study 
participants remains unchanged.


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11.3.
Study Procedures Tables
Appendix Table 1.
Study Procedures Table for NUC-Suppressed Cohort 1
Treatment Cycles
Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeksb
Screening 
(45 days)
Baseline 
Day 1
4
8
12
13c
14
16
20
24
28
32
36/EOT
EDd
1c
4
8c
12
16c
24
36
48
Written Informed 
Consente
X
Review of 
Inclusion/Exclusion 
Criteria
X
Medical History
X
AEs & Concomitant 
Medicationsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical 
Examination
X
X
X
X
X
Symptom-directed 
physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Body weight 
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGg
X
X
X
X
X
X
Chest x-ray
X
Xh
Ophthalmologic 
examinationi
X
X
X
Xh
Symptom-directed 
ophthalmologic 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory 
tests (hematology & 
chemistry; 
coagulation)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
APRI
X
X
X
X
X
X
X
FibroTest 
X
X
X
X
X
X
X


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Treatment Cycles
Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeksb
Screening 
(45 days)
Baseline 
Day 1
4
8
12
13c
14
16
20
24
28
32
36/EOT
EDd
1c
4
8c
12
16c
24
36
48
FibroScanj
X
α-fetoprotein (HCC 
imaging [eg, CT 
scan] is required for 
participants with 
α-fetoprotein 
≥ 50 ng/mL at 
screening)
X
Serology testing to 
exclude HCV, HDV, 
and HIV infectionk
X
Quantitative plasma 
HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum sample for 
HBV viral 
sequencing 
(resistance 
surveillance) and 
ddPCR
X
Serum sample for 
HBV viral 
sequencing 
(resistance 
surveillance) and 
genotyping sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quantitative HBV 
Serum HBsAg, 
HBcrAg, HBeAg, 
and HBV RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Qualitative HBV 
serology HBeAg, 
HBeAb, and HBsAg, 
HBsAb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 115
12 April 2023
Treatment Cycles
Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeksb
Screening 
(45 days)
Baseline 
Day 1
4
8
12
13c
14
16
20
24
28
32
36/EOT
EDd
1c
4
8c
12
16c
24
36
48
Biomarker Samples: 
Collection of PBMC, 
whole blood, serum, 
and plasma samples 
for biomarker 
analysisl, m
X
Xl
X
Xm
X
Sparse PK for 
VIR-2218n
X
X
X
Sparse PK for SLGNn
X
X
X
Estimated creatinine 
clearance (using the 
Cockcroft-Gault 
method)
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug and 
Alcohol Screen
X
Autoantibodies 
X
TSH
X
X
X
X
FSHo
X
Serum Pregnancy 
Testp
X
X
Urine Pregnancy 
Testp
X
X
X
X
X
X
X
X
X
X
X
Xp
X
Xp
X
X
X
Enrollment
X
Dispense and 
Administer TAF as 
appropriate
Tenofovir alafenamide (TAF) 25-mg tablet administered orally daily for up to 84 weeks
Dispense & 
Administer VIR-2218 
SC as appropriate
X
X
X
X
X
X
Dispense & 
Administer SLGNq as 
appropriate
X
X
X
X
X
X
X
X


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 116
12 April 2023
Treatment Cycles
Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeksb
Screening 
(45 days)
Baseline 
Day 1
4
8
12
13c
14
16
20
24
28
32
36/EOT
EDd
1c
4
8c
12
16c
24
36
48
Study Drug 
Accountability
X
X
X
X
X
X
X
X
X
X
AE = adverse event; APRI = AST to Platelet Ratio Index; CT = computed tomography; ddPCR = digital droplet polymerase chain reaction; ECG = electrocardiogram; ED = early discontinuation; 
EOT = end of treatment; FSH = follicle-stimulating hormone; FU = follow-up; HBcrAg = hepatitis B core-related antigen; HBeAb = hepatitis B e antibody; HBeAg = hepatitis B e antigen; 
HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HDV = hepatitis D virus; 
IV = intravenous; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetic; SAE = serious adverse event; SC = subcutaneous; SLGN = selgantolimod; TAF = tenofovir alafenamide; 
TSH = thyroid-stimulating hormone
a
All study visits except for Weeks 13 and 14.
b
FU Week 1 will have a visit window of + 3 days, FU Weeks 4 through FU Week 16 will have a visit window of ± 5 days, and FU Weeks 24 through FU Week 48 will have a visit window of ± 14 
days.
c
Week 13, FU Week 1, FU Week 8, and FU Week 16 will be conducted as a virtual/telephonic visit to review AEs, concomitant medications, and overall health of the participant by investigator.
d
The ED visit should be performed within 14 days from notification of study discontinuation. If ED is done in FU period, all of these procedures should be performed.
f
Record any SAEs and all AEs related to protocol-mandated procedures occurring after signing of the informed consent form. After drug administration, report all AEs and SAEs.
g
Participants must rest quietly in the supine position for a minimum of 5 minutes prior to the recording.
h
At ED visit, these procedures are optional and to be done as needed.
i
Ophthalmologic examination at screening should be performed during the screening window, ie, within 45 days of randomization. Ophthalmologic examinations post-Day 1 should occur within −4 
to +10 days of visit.
j
FibroScan testing where applicable for liver disease staging.
k
In the event of a positive result for serology and/or antigen testing for HIV, HDV, or HCV, reflex tests will be performed as necessary.
l
Collect pre-SLGN dose administration on Week 12, 4 hours and 24-72 hours postdose.
m
Collect pre-SLGN dose administration on Week 32, 4 hours, and 24-72 hours postdose. 
n
The sparse PK collection for VIR-2218 at baseline/Day 1 should occur predose and postdose. Postdose sparse PK collection should occur any time between 1 and 5 hours postdose relative to 
VIR-2218, and/or SLGN administration. 
o
FSH test is required for female participants who are < 54 years old who are not on hormonal contraception and who have stopped menstruating for ≥ 12 months but do not have documentation of 
ovarian hormonal failure.
p
For female participants of childbearing potential, the serum pregnancy test will be performed at screening. Urine pregnancy test will be performed at all other visits as indicated. Positive urine 
pregnancy test will be confirmed with serum pregnancy test. Pregnancy testing should include prevention counseling. FU Week 8 and Week 16 urine pregnancy test will be a virtual/telephonic 
visit for females participants of childbearing potential.
q
SLGN tablets will be administered while fasting once a week, on the same day.
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Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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s
Intensive PK sample to be drawn at any one visit at Week 20, 24, 28 or 32 relative to SLGN dosing in clinic on the morning of the intensive PK visit. Collection will occur at predose, 0.25, 0.5, 1, 
1.5, 2, 3, 4, 5, 8, 10, 12 and 24 hours postdose (8, 10, 12 hour collections are optional).
t
Intensive PK sample to be drawn on Baseline/Day 1 and at Week 20 relative to VIR-2218 dosing in clinic on the morning of the intensive PK visit. Collection will occur at predose, 0.25, 0.5, 1, 
1.5, 2, 3, 4, 5, 8, 10, 12 and 24 hours postdose (8, 10, 12 hour collections are optional).
CCI


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 118
12 April 2023
Appendix Table 2.
Study Procedures Table for Viremic Cohort 2 
Screenin
g
(45 days)
BL 
Day 1
Treatment Cycles
Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeks b
Cohort 2 
Group B 
only
Cohort 2 
Group A only
1
c
2d
4
8
12
13
c
14
16
20
24
28
32
24
(Cohort 2 
Group B)
/ 36 
(Cohort 2 
Group A)
ED
e
1b,c
4
8c
12
1
6
24
36
48
Written Informed 
consentf
X
Review of 
Inclusion/
Exclusion 
Criteria
X
Medical History
X
AEs & 
Concomitant 
Medicationsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete 
Physical 
Examination
X
X
X
X
X
Symptom-
directed physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
(Cohort 
2 
Group B
)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Body weight
X
X
X
(Cohort 
2 
Group B
)
X
(Cohort 
2 
Group B
)
X
X
X
X
X
X
X
X
X
12-lead ECGh
X
X
X
X
X
X
Chest x-ray
X
Xi


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 119
12 April 2023
Screenin
g
(45 days)
BL 
Day 1
Treatment Cycles
Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeks b
Cohort 2 
Group B 
only
Cohort 2 
Group A only
1
c
2d
4
8
12
13
c
14
16
20
24
28
32
24
(Cohort 2 
Group B)
/ 36 
(Cohort 2 
Group A)
ED
e
1b,c
4
8c
12
1
6
24
36
48
Ophthalmologic 
examinationj
X
X
(Cohort 
2 
Group B
)
X
X
Xi
Symptom-
directed 
ophthalmologic 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory 
tests (hematology 
& chemistry; 
coagulation)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
APRI
X
X
X
X
X
X
X
FibroTest 
X
X
X
X
X
X
X
FibroScank
X
α-fetoprotein 
(HCC imaging 
[eg, CT scan] is 
required for 
participants with 
α-fetoprotein ≥ 50 
ng/mL at 
screening)
X
Serology testing 
to exclude HCV, 
HDV, and HIV 
infectionl
X
Quantitative 
plasma HBV 
DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 120
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Screenin
g
(45 days)
BL 
Day 1
Treatment Cycles
Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeks b
Cohort 2 
Group B 
only
Cohort 2 
Group A only
1
c
2d
4
8
12
13
c
14
16
20
24
28
32
24
(Cohort 2 
Group B)
/ 36 
(Cohort 2 
Group A)
ED
e
1b,c
4
8c
12
1
6
24
36
48
Serum sample for 
HBV viral 
sequencing 
(resistance 
surveillance) and 
ddPCR
X
Serum sample for 
HBV viral 
sequencing 
(resistance 
surveillance) and 
genotyping 
sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quantitative 
HBV Serum 
HBsAg, HBcrAg, 
HBeAg, and 
HBV RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Qualitative HBV 
serology HBeAg, 
HBeAb, and 
HBsAg, HBsAb 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biomarker 
Samples: 
Collection of 
PBMC, whole 
blood, serum and 
plasma samples 
for biomarker 
analysism,n
X 
m,n
Xn
Xm
X
m
Xn
X
m
X
Sparse PK for 
VIR-2218o
X
X
X
Sparse PK for 
SLGNp
Xp
X
X
Xp


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 121
12 April 2023
Screenin
g
(45 days)
BL 
Day 1
Treatment Cycles
Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeks b
Cohort 2 
Group B 
only
Cohort 2 
Group A only
1
c
2d
4
8
12
13
c
14
16
20
24
28
32
24
(Cohort 2 
Group B)
/ 36 
(Cohort 2 
Group A)
ED
e
1b,c
4
8c
12
1
6
24
36
48
Estimated 
creatinine 
clearance (using 
the Cockcroft-
Gault method)
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug and 
Alcohol Screen
X
Autoantibodies 
X
TSH
X
X 
(Cohort 
2 
Group B
)
X
X
X
FSHq
X
Serum Pregnancy 
Testr
X
X
Urine Pregnancy 
Testr
X
X
X
X
X
X
X
X
X
X
X
X
r
X
Xr
X
X
X
Enrollment
X
Dispense & 
Administer VIR-
2218 SC as 
appropriate 
(Group A only)
X
X
X
X
X
X
Dispense & 
Administer 
SLGNs as 
appropriate
(Group A only)
X
X
X
X
X
X
X
X


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 122
12 April 2023
Screenin
g
(45 days)
BL 
Day 1
Treatment Cycles
Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeks b
Cohort 2 
Group B 
only
Cohort 2 
Group A only
1
c
2d
4
8
12
13
c
14
16
20
24
28
32
24
(Cohort 2 
Group B)
/ 36 
(Cohort 2 
Group A)
ED
e
1b,c
4
8c
12
1
6
24
36
48
Dispense & 
Administer 
SLGNs as 
appropriate
(Group B only)
X
X
X
X
X
X
X
X
X
X
Study Drug 
Accountability
X
X
X
X
X
X
X
X
X
X
X
AE = adverse event; APRI = AST to Platelet Ratio Index; BL = baseline; CT = computed tomography; ddPCR = digital droplet polymerase chain reaction; 
ECG = electrocardiogram; ED = early discontinuation; EOT = end of treatment; FSH = follicle-stimulating hormone; FU = follow-up; HBcrAg = hepatitis B core-related antigen; 
HBeAb = hepatitis B e antibody; HBeAg = hepatitis B e antigen; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HDV = hepatitis D virus; IV = intravenous; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetic; SAE 
= serious adverse event; SC = subcutaneous; SLGN = selgantolimod; TAF = tenofovir alafenamide; TSH = thyroid-stimulating hormone
a
All study visits (± 2 days), except for Weeks 1, 2, 13, and 14.
b
FU Week 1 will have a visit window of ± 2 days, FU Weeks 4 through FU Week 16 will have a visit window of ± 5 days, and FU Weeks 24 through FU Week 48 will have a 
visit window of ± 14 days. 
c
Week 1 (Cohort 2 Group B only), Week 13 (Cohort 2 Group A only), and FU Week 1, Week 8, and Week 16 will be conducted as a virtual/telephonic visit to review AEs, 
concomitant medications, and overall health of the participant by investigator. 
d
Week 2 visit is only applicable for Cohort 2 Group B. 
e
The ED visit should be performed within 14 days from notification of study discontinuation.
g
Record any SAEs and all AEs related to protocol mandated procedures occurring after signing of the consent form. After drug administration, report all AEs and SAEs.
CCI
CCI
CCI
CCI


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Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 123
12 April 2023
h
Participants must rest quietly in the supine position for a minimum of 5 minutes prior to the recording.
i
At ED visit, these procedures are optional and to be done as needed.
j
Ophthalmologic examination at screening should be performed during the screening window, ie, within 45 days of randomization. Ophthalmologic examinations post-Day 1 
should occur within −4 to +10 days of visit.
k
FibroScan testing where applicable for liver disease staging.
l
In the event of a positive result for serology and/or antigen testing for HIV, HDV, or HCV, reflex tests will be performed as necessary.
m
Cohort 2 Group A biomarker collection. Collect pre-SLGN dose administration at Baseline/Day 1, Week 12, 4 hours and 24-72 hours postdose. Collect at Week 14, predose. 
Collect pre-SLGN dose administration at Week 32, 4 hours and 24-72 hours postdose.
n
Cohort 2 Group B biomarker collection. Collect pre-SLGN dose administration on Baseline/Day 1, 4 hours and 24-72 hours postdose. Collect at Week 2, pre-dose. Collect 
pre-SLGN dose administration at Week 20, 4 hours and 24-72 hours postdose. 
o
The sparse PK collection for VIR-2218 at baseline/Day 1 should occur predose and postdose. Postdose sparse PK collection for VIR-2218 should occur any time between 1 
and 5 hours postdose relative to VIR-2218 administration.
p
Sparse PK collection for SLGN should occur any time between 1 and 5 hours postdose relative to SLGN administration. The collection at Baseline/Day 1 is only applicable to 
Cohort 2 Group B. The collection at Week 32 is only applicable to Cohort 2 Group A. 
q
FSH test is required for female participants who are < 54 years old who are not on hormonal contraception and who have stopped menstruating for ≥ 12 months but do not 
have documentation of ovarian hormonal failure.
r
For female participants of childbearing potential, the serum pregnancy test will be performed at screening. Urine test will be performed at all other visits as indicated. Positive 
urine test will be confirmed with serum test. Pregnancy testing should include prevention counseling. FU Week 8 and Week 16 urine pregnancy test will be a 
virtual/telephonic visit for female participants of childbearing potential.
s
SLGN tablets will be administered while fasting once a week on the same day.
u
For Group A, intensive PK sample to be drawn at any one visit at Week 20, 24, 28 or 32 relative to SLGN dosing in clinic on the morning of the intensive PK visit. For 
Group B, sample will be collected Week 12 or later relative to SLGN dosing in clinic on the morning of the intensive PK visit.
v
Group A and B: Collection will occur at Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12 and 24 hours postdose (8, 10 and 12 hour collections are optional).
w
For Group A only, intensive PK sample to be drawn on Baseline/Day 1 and at Week 20 relative to VIR-2218 dosing in clinic on the morning of the intensive PK visit. 
CCI


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Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 124
12 April 2023
11.4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
1)
Definitions
a.
Definition of Childbearing Potential
For the purposes of this study, a female born participant is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming postmenopausal unless the 
participant is permanently sterile or has medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women < 54 years of age with amenorrhea of ≥ 12 months may also be considered 
postmenopausal if their follicle-stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy. 
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female participant of any age.
b.
Definition of Male Fertility
For the purposes of this study, a male born participant is considered fertile after the initiation of 
puberty unless the participant is permanently sterile by bilateral orchidectomy or medical 
documentation.
2)
Contraception Requirements for Female Participants
a.
Study Drug Effects on Pregnancy and Hormonal Contraception
Tenofovir alafenamide (TAF)
Data from clinical pharmacokinetic interaction studies of TAF have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Nonclinical toxicity studies in 
animals (rats and rabbits) of TAF have demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of TAF in pregnant women. 
Please refer to the latest version of the IB for additional information.
Nivolumab
There are no data on the use of nivolumab in pregnant women. Studies in animals have shown 
embryofetal toxicity. Nivolumab is not recommended during pregnancy. Women of childbearing 
potential should use effective contraception for at least 5 months following the last dose of 
nivolumab. It is unknown whether nivolumab is secreted in human milk. Because many 
medicinal products, including antibodies, can be secreted in human milk, a risk to the 
newborns/infants cannot be excluded. Please refer to the latest version of nivolumab product 
information for additional information.


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Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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Selgantolimod
There is no clinical data available on SLGN treatment in pregnant women. Nonclinical studies in 
rabbits showed no adverse effect on fertility but did show a possible risk of 
teratogenicity/fetotoxicity during embryo-fetal development. Therefore, the use of highly 
effective contraception will be required for participation in this study. Nonclinical studies 
showed no genotoxicity.
Nonclinical studies demonstrate low induction potential with once weekly dosing of SLGN. 
Based on this data, no reduction in the exposure of hormonal contraception is expected.
Please refer to the latest version of the IB for additional information.
VIR-2218
There are no available data on the use of VIR-2218 in pregnant women to evaluate a 
drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. 
No adverse effects on pregnancy or embryo-fetal development related to VIR-2218 were 
observed in rats and in rabbits. No studies have been conducted in animals on the effect of 
VIR-2218 on fertility and pre/postnatal development. Nonclinical studies showed no 
genotoxicity. 
Women of childbearing potential are required to have a negative pregnancy test, cannot be breast 
feeding, must use highly effective contraception during the study, should continue using 
contraception for a least 1 month following the last dose of VIR-2218, and meet any other 
contraception requirements specified in the protocol. Male participants with female partners of 
childbearing potential must agree to meet the contraception requirements specified in the 
protocol.
Please refer to the latest version of the VIR-2218 IB for additional information.
There is no metabolic enzyme (or transporter) induction effect that is expected from either 
nivolumab or VIR-2218. Therefore, because SLGN is not an inducer, none of the drugs used in 
this trial either alone or in combination are expected to yield a reduction of exposure of hormonal 
contraception.
Because many medicinal products can be secreted in human milk, a risk to newborns/infants 
cannot be excluded.
b.
Contraception Requirements for Female Participants of Childbearing 
Potential 
The inclusion of female participants of childbearing potential requires the use of highly effective 
contraceptive measures with a failure rate of < 1% per year. They must have a negative serum 
pregnancy test at screening and a negative pregnancy test at the screening visit prior to 
randomization. Pregnancy tests will be performed at monthly intervals thereafter until the end of 
contraception requirement. 


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 126
12 April 2023
Duration of required contraception for female participants in this clinical trial should start from 
screening visit until 30 days after the last dose of TAF, SLGN, or VIR-2218 or for 5 months after 
the last dose of nivolumab whichever contraception ending date is latest. If a participant requires 
a commercially approved nucleos(t)ide analog treatment, the investigator will provide 
contraception requirements according to the local label for the specific marketed product and 
again taking into consideration whichever contraception ending date is latest. 
Female participants must agree to one of the following contraceptive methods: 
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the participant’s preferred and usual 
lifestyle. 
Or 
Consistent and correct use of 1 of the following methods of birth control listed below: 
•
Hormonal or nonhormonal intrauterine device (IUD)
•
Subdermal contraceptive implant
•
 Bilateral tubal occlusion (upon medical assessment of surgical success) 
•
Vasectomy in the male partner (upon medical assessment of surgical success) 
Or 
Female participants who wish to use a hormonally-based method must use it in conjunction with 
a barrier method, preferably a male condom. Hormonal methods are restricted to those associated 
with the inhibition of ovulation. Hormonally-based contraceptives and barrier methods permitted 
for use in this protocol are as follows: 
•
Hormonal methods (each method must be used with a barrier method, preferably male 
condom) 
Oral contraceptives (either combined or progesterone only) 
Injectable progesterone 
Transdermal contraceptive patch 
Contraceptive vaginal ring 
•
Barrier methods (each method must be used with a hormonal method) 
Male condom (with or without spermicide) 


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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Female condom (with or without spermicide) 
Diaphragm with spermicide 
Cervical cap with spermicide 
Sponge with spermicide
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved. 
Female participants must also refrain from egg donation and in vitro fertilization during 
treatment and until the end of contraception requirement.
3)
Contraception Requirements for Male Participants
It is theoretically possible that a relevant systemic concentration of study drug may be achieved 
in a female partner from exposure of the male participant’s seminal fluid and poses a potential 
risk to an embryo/fetus. Therefore, male participants with female partners of childbearing 
potential must use condoms during treatment until 30 days after the last dose of TAF, SLGN, or 
VIR-2218 or for 5 months after last dose of nivolumab whichever contraception ending date is 
latest. If a participant requires a commercially approved nucleos(t)ide analog treatment, the 
investigator will provide contraception requirements according to the local label for the specific 
marketed product and again taking into consideration whichever contraception ending date is 
latest. If the female partner of childbearing potential is not pregnant, additional contraception 
recommendations should also be considered. 
Male participants must also refrain from sperm donation during treatment and until the end of 
contraception requirement.
4)
Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together.
5) 
Procedures to be Followed in the Event of Pregnancy
Female participants will be instructed to notify the investigator if they become pregnant or 
suspect they are pregnant at any time from start of the study to the end of the study. Nivolumab, 
SLGN and VIR-2218 must be discontinued immediately. Interruption of other drugs should be 
considered upon discussion with the medical monitor.
Male participants whose partner has become pregnant or suspects she is pregnant from start of 
study to the end of the contraception requirement must also report the information to the 
investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are 
outlined in Section 7.4.2.3.


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Protocol GS-US-465-4439
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Amendment 2
CONFIDENTIAL
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11.5.
GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities
Antiviral Toxicity Grading Scale Version 01 April 2015 will be used to grade all adverse events 
(AEs), with the exception of infusion-related reactions (IRRs).
For grading of IRRs, the Common Terminology Criteria for Adverse Events (CTCAE) Version 
5.0 found on the NCI website will be used:
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf


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Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 129
12 April 2023
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric  57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to  8.5 g/dL 
75 to  85 g/L
6.5 to  7.5 g/dL 
65 to  75 g/L
 6.5 g/dL
 65 g/L
HIV NEGATIVE
Adult and Pediatric  57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease 
from Baseline
2.5 to  3.5 g/dL
25 to  35 g/L
9.0 to  10.0 g/dL
90 to  100 g/L
OR
Any decrease 
from Baseline
3.5 to  4.5 g/dL
35 to  45 g/L
7.0 to  9.0 g/dL
70 to  90 g/L
OR
Any decrease from Baseline
 4.5 g/dL
 45 g/L
 7.0 g/dL
 70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to  8.5 g/dL
70 to  85 g/L
6.0 to  7.0 g/dL
60 to < 70 g/L
 6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to  9.5 g/dL
80 to  95 g/L
7.0 to  8.0 g/dL
70 to  80 g/L
 7.0 g/dL
 70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 
 12.0 g/dL
100 to  120 g/L
9.0 to  10.0 g/dL
90 to  100 g/L
 9.0 g/dL
 90 g/L
1000 to 1300/mm3
750 to  
1000/mm3
500 to  750/mm3
 500/mm3
Absolute Neutrophil Count (ANC)
Adult and Pediatric, 
≥ 7 Months# 
1.00 to 1.30 GI/L
0.75 to  1.00 
GI/L
0.50 to  0.75 GI/L
 0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric > 13 Years
300 to 400/mm3
300 to 400/μL
200 to  300/mm3
200 to  300/μL
100 to  200/mm3
100 to  200/μL
 100/mm3
 100/μL


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Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 130
12 April 2023
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric  13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to  600/mm3
0.50 to  0.60 GI/L
350 to  500/mm3
0.35 to  0.50 GI/L
 350/mm3
 0.35 GI/L
Platelets 
100,000 to 
< 125,000/mm3
100 to  125 GI/L
50,000 to 
 100,000/mm3
50 to  100 GI/L
25,000 to  50,000/mm3
25 to  50 GI/L
 25,000/mm3
 25 GI/L
2000/mm3 to 
2500/mm3
1,500 to 
 2,000/mm3
1000 to  1,500/mm3
 1000/mm3
WBCs 
2.00 GI/L to 
2.50 GI/L
1.50 to  2.00 GI/L
1.00 to  1.50 GI/L
 1.00 GI/L
100 to 200 mg/dL
75 to  100 mg/dL
50 to  75 mg/dL
 50 mg/dL
Hypofibrinogenemia
1.00 to 2.00 g/L
0.75 to  1.00 g/L
0.50 to  0.75 g/L
 0.50 g/L
 ULN to 
600 mg/dL
 600 mg/dL
—
—
Hyperfibrinogenemia
 ULN to 6.0 g/L
 6.0 g/L
—
—
20 to 40 μg/mL
 40 to 50 μg/mL
 50 to 60 μg/mL
 60 μg/mL
Fibrin Split Product 
20 to 40 mg/L
 40 to 50 mg/L
 50 to 60 mg/L
 60 mg/L
Prothrombin Time
 1.00 to 1.25  
ULN
 1.25 to 1.50  
ULN 
 1.50 to 3.00  ULN 
 3.00  ULN 
International Normalized Ratio of prothrombin time 
(INR)
1.1 to 1.5  ULN
>1.5 to 2.0  ULN
>2.0 to 3.0  ULN
> 3.0  ULN
Activated Partial
Thromboplastin Time
 1.00 to 1.66  
ULN
 1.66 to 2.33  
ULN
 2.33 to 3.00  ULN
 3.00  ULN
Methemoglobin 
5.0 to 10.0%
 10.0 to 15.0%
 15.0 to 20.0%
 20.0% 


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 131
12 April 2023
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
130 to <LLN 
mEq/L
125 to  130 mEq/L
121 to  125 mEq/L
 121 mEq/L
Hyponatremia 
130 to <LLN 
mmol/L
125 to  130 mmol/L
121 to  125 mmol/L
 121 mmol/L
>ULN to 150 
mEq/L
 150 to 154 mEq/L
 154 to 159 mEq/L
 159 mEq/L
Hypernatremia 
>ULN to 150 
mmol/L
 150 to 154 mmol/L
 154 to 159 mmol/L
 159 mmol/L
3.0 to <LLN 
mEq/L
2.5 to  3.0 mEq/L
2.0 to  2.5 mEq/L
 2.0 mEq/L
Hypokalemia 
Adult and Pediatric
 1 Year
3.0 to <LLN 
mmol/L
2.5 to  3.0 mmol/L
2.0 to  2.5 mmol/L
 2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 
mmol/L
2.5 to  3.0 mEq/L
2.5 to <3.0 mmol/L
2.0 to  2.5 mEq/L
2.0 to <2.5 mmol/L
 2.0 mEq/L
<2.0 mmol/L
Hyperkalemia 
Adult and Pediatric
 1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 
mmol/L
 6.0 to 6.5 mEq/L
 6.0 to 6.5 mmol/L
 6.5 to 7.0 mEq/L
 6.5 to 7.0 mmol/L
 7.0 mEq/L
 7.0 mmol/L
Infant <1 Year
>ULN to 6.0 
mEq/L
>ULN to 6.0 
mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
 6.5 to 7.0 mEq/L
 6.5 to 7.0 mmol/L
 7.0 mEq/L
 7.0 mmol/L
Hypoglycemia
Adult and Pediatric
 1 Month
55 to 64 mg/dL
3.03 to 
3.58 mmol/L
40 to  55 mg/dL
2.20 to  3.03 mmol/L
30 to  40 mg/dL
1.64 to  2.20 mmol/L
 30 mg/dL
 1.64 mmol/L


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 132
12 April 2023
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Infant,  1 Month
50 to 54 mg/dL
2.8 to 
3.0 mmol/L
40 to  50 mg/dL
2.2 to  2.8 mmol/L
30 to  40 mg/dL
1.7 to  2.2 mmol/L
 30 mg/dL
 1.7 mmol/L
116 to 
160 mg/dL
 160 to 250 mg/dL
 250 to 500 mg/dL
 500 mg/dL
Hyperglycemia, Nonfasting 
6.42 to 
8.91 mmol/L
 8.91 to 13.90 mmol/L
 13.90 to 
27.79 mmol/L
 27.79 
mmol/L
Hyperglycemia, Fasting
110 to 
125 mg/dL
6.08 to 6.96 
mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 
mmol/L
>500 mg/dL
>27.79 
mmol/L
Hypocalcemia 
(corrected for albumin if appropriate*)
Adult and Pediatric
2 Years
7.8 
<LLN mg/dL
1.94 to <LLN 
mmol/L
7.0 to  7.8 mg/dL
1.74 to  1.94 mmol/L
6.1 to  7.0 mg/dL
1.51 to  1.74 mmol/L
 6.1 mg/dL
 1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 
mmol/L
7.0 to <7.8 mg/dL
1.74 to <1.94 mmol/L
6.1 to <7.0 mg/dL
1.51 to < 1.74 mmol/L
< 6.1 mg/dL
< 1.51 
mmol/L
Infant,  7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88 
mmol/L
6.0 to  6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to  6.0 mg/dL
1.36 to < 1.49 mmol/L 
 5.5 mg/dL
< 1.36 
mmol/L
>ULN to 
11.5 mg/dL
 11.5 to 12.5 mg/dL
 12.5 to 13.5 mg/dL
 13.5 mg/dL
Hypercalcemia (corrected for albumin if 
appropriate*) Adult and Pediatric  7 Days
>ULN to 2.88 
mmol/L
 2.88 to 3.13 mmol/L
 3.13 to 3.38 mmol/L
 3.38 mmol/L


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 133
12 April 2023
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Infant,  7 Days
11.5 to 
12.4 mg/dL
2.86 to 3.10 
mmol/L
 12.4 to 12.9 mg/dL
> 3.10 to 3.23 mmol/L
 12.9 to 13.5 mg/dL
> 3.23 to 3.38 mmol/L
 13.5 mg/dL
> 3.38 
mmol/L
3.0 mg/dL to  
LLN
2.5 to < 3.0 mg/dL
2.0 to  2.5 mg/dL
 2.0 mg/dL
Hypocalcemia (ionized)
0.74 mmol/L to 
 LLN
0.62 to  0.74 mmol/L
0.49 to  0.62 mmol/L
 0.49 mmol/L
 ULN to 
6.0 mg/dL
 6.0 to 6.5 mg/dL
 6.5 to 7.0 mg/dL
 7.0 mg/dL
Hypercalcemia (ionized)
 ULN to 1.50 
mmol/L
 1.50 to 1.63 mmol/L
 1.63 to 1.75 mmol/L
 1.75 mmol/L
1.40 to 
<LLN mg/dL
1.2 to <LLN 
mEq/L
1.04 to  1.40 mg/dL
0.9 to  1.2 mEq/L
0.67 to  1.04 mg/dL
0.6 to  0.9 mEq/L
 0.67 mg/dL
 0.6 mEq/L
Hypomagnesemia
0.58 to <LLN 
mmol/L
0.43 to  0.58 mmol/L
0.28 to  0.43 mmol/L
 0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
 14 Years
2.0 to < 
LLN mg/dL
0.63 to  LLN 
mmol/L
1.5 to  2.0 mg/dL
0.47 to  0.63 mmol/L
1.0 to  1.5 mg/dL
0.31 to  0.47 mmol/L
 1.0 mg/dL
 0.31 mmol/L


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Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 134
12 April 2023
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Pediatric 1 Year–14 Years 
3.0 to 
<LLN mg/dL
0.96 to <LLN 
mmol/L
2.5 to  3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to  2.5 mg/dL
0.47 to < 0.80 mmol/L
 1.5 mg/dL
< 0.47 
mmol/L
Pediatric  1 Year
3.5 to 
<LLN mg/dL
1.12 to <LLN 
mmol/L
2.5 to  3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to  2.5 mg/dL
0.47 to < 0.80 mmol/L
 1.5 mg/dL
< 0.47 
mmol/L
Hyperbilirubinemia 
Adult and Pediatric > 14 Days
 1.0 to 1.5  
ULN 
 1.5 to 2.5  ULN
 2.5 to 5.0  ULN 
 5.0  ULN 
Infant,  14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
 25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
 30.0 mg/dL
> 513 μmol/L
Infant,  14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
 25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50  
ULN 
 2.50 to 5.00  ULN 
 5.00 to 10.00  ULN 
 10.00  
ULN
>ULN to 
10.0 mg/dL 
 10.0 to 12.0 mg/dL 
 12.0 to 15.0 mg/dL 
 15.0 mg/dL
Hyperuricemia
>ULN to 597 
μmol/L
 597 to 716 μmol/L
 716 to 895 μmol/L
 895 μmol/L
1.5 mg/dL to  
LLN
87 μmol/L to  
LLN
1.0 to  1.5 mg/dL
57 to  87 μmol/L
0.5 to  1.0 mg/dL
27 to  57 μmol/L
 0.5 mg/dL
 27 μmol/L
Hypouricemia
Adult and Pediatric
≥ 1 year
Infant < 1 Year
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to  1.0 mg/dL
27 to  57 μmol/L
 0.5 mg/dL
 27 μmol/L


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Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 135
12 April 2023
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine** 
 1.50 to 
2.00 mg/dL
 133 to 177 
μmol/L
 2.00 to 3.00 mg/dL
 177 to 265 μmol/L
 3.00 to 6.00 mg/dL 
 265 to 530 μmol/L
 6.00 mg/dL
 530 μmol/L
16.0 mEq/L to 
 LLN 
11.0 to  16.0 mEq/L
8.0 to  11.0 mEq/L
 8.0 mEq/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mmol/L to 
 LLN
11.0 to  16.0 mmol/L
8.0 to  11.0 mmol/L
 8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/L to <LLN
8.0 to  11.0 mEq/L
 8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to  11.0 mmol/L
 8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
 750 to 1200 mg/dL
 8.47–13.55 mmol/L
 1200 mg/dL
 13.55 
mmol/L
130 to 
160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
LDL (Fasting)
Adult
3.35 to 4.15 
mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
110 to 
130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
LDL (Fasting)
Pediatric >2 to <18 years
2.84 to 3.37 
mmol/L
>3.37 to 4.92 mmol/L
>4.92 mmol/L
200 to 
239 mg/dL
 239 to 300 mg/dL
 300 mg/dL
NA
Hypercholesterolemia
(Fasting)
5.16 to 6.19 
mmol/L
 6.19 to 7.77 mmol/L
 7.77 mmol/L


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Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 136
12 April 2023
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Pediatric  18 Years
170 to 
199 mg/dL
4.39 to 5.15 
mmol/L
 199 to 300 mg/dL
 5.15 to 7.77 mmol/L
 300 mg/dL
 7.77 mmol/L
NA
Creatine Kinase
3.0 to  6.0  
ULN
6.0 to  10.0  ULN
10.0 to  20.0  ULN
 20.0  ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL.
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for male participants > 70 years. Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0. 
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50  ULN
 2.50 to 5.00  ULN
 5.00 to 10.00  ULN
 10.00  ULN
ALT (SGPT) 
1.25 to 2.50  ULN
 2.50 to 5.00  ULN
 5.00 to 10.00  ULN
 10.00  ULN
GGT
1.25 to 2.50  ULN
 2.50 to 5.00  ULN
 5.00 to 10.00  ULN
 10.00  ULN
Alkaline Phosphatase 
1.25 to 2.50  ULN
 2.50 to 5.00  ULN
 5.00 to 10.00  ULN
 10.00  ULN
Total Amylase
 1.0 to 1.5  ULN
 1.5 to 2.0  ULN
 2.0 to 5.0  ULN
 5.0  ULN
Pancreatic Amylase
 1.0 to 1.5  ULN
 1.5 to 2.0  ULN
 2.0 to 5.0  ULN
 5.0  ULN
Lipase 
 1.0 to 1.5  ULN
 1.5 to 3.0  ULN
 3.0 to 5.0  ULN
 5.0  ULN
-
2.0 to  LLN g/dL
20 to  LLN g/L
 2.0 g/dL
 20 g/L
NA
Albumin
Pediatrics <16 years 
≥ 16 years
3.0 g/dL to  LLN
30 g/L to  LLN
2.0 to  3.0 g/dL
20 to  30 g/L
 2.0 g/dL
 20 g/L
NA


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 137
12 April 2023
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
Females
> ULN - 10 RBC/HPF
 10-75 RBC/HPF
> 75 RBC/HPF
NA
Males
6-10 RBC/HPF
 10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
 10 Years
200 to 999 mg/24 h
> 999 to 1999 mg/24 h
> 1999 to 3500 mg/24 h
 3500 mg/24 h
Pediatric  3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
> 499 to 799 mg/m2/24 h
> 799 to 1000 mg/m2/24 h
 1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 
•
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratory tests, toxicity grades will only be assigned to 
Dipstick Hematuria.
•
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.
•
If the severity of a clinical AE could fall under either one of two grades (eg, the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 138
12 April 2023
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND 
Non-urgent medical 
intervention indicated
Symptomatic, 
non-life-threatening AND 
Non-urgent medical 
intervention indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant 
acute blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of  2 units 
packed RBCs (for children 
 10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of  2 units 
packed RBCs indicated (for 
children  10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
 159–179 mmHg systolic 
OR 
 99–109 mmHg diastolic
 179 mmHg systolic 
OR 
 109 mmHg diastolic
Life-threatening 
consequences (eg, malignant 
hypertension) OR 
Hospitalization (other than 
ER visit) indicated
Pediatric  17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥ 95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening 
consequences (eg, malignant 
hypertension) OR 
Hospitalization indicated 
(other than ER visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with 
non-life-threatening 
physiologic consequences 
OR Effusion with 
nonurgent intervention 
indicated
Life-threatening 
consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
 0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
 3.0 sec
Complete AV block 
Pediatric  16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval  0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc 
interval  0.50 sec OR 
Increase in interval 
 0.06 sec above baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric  16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc 
interval  0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(eg, anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated 
(eg, anticoagulation, lysis 
filter, invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode 
(associated with a procedure 
of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening 
symptomatic CHF
Life-threatening CHF


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RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 
25% to 49% 
Cyanosis OR FEV1 or peak 
flow  25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal 
interference with usual social & 
functional activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities 
Respiratory failure with 
ventilatory support indicated
Pediatric  14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities OR Pulse 
oximetry  90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis 
OR Medical intervention 
indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional 
activities
Disabling visual loss in affected 
eye(s)


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SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or 
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash with vesicles 
or limited number of bullae 
OR Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson 
syndrome OR Ulceration 
of mucous membrane 
involving two or more 
distinct mucosal sites OR 
Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening 
consequences OR Aggressive 
intervention indicated 
(eg, tube feeding or total 
parenteral nutrition)
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening 
consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening 
consequences (eg, sepsis or 
perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
 1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of  3 stools 
over baseline/24 hour
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24-hours. 
Bloody diarrhea OR Increase 
of  7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening 
consequences 
(eg, hypotensive shock)
Pediatric  1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention 
indicated
Life-threatening reduction in 
oral intake


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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal 
bleeding OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient ( 24-hours) or 
intermittent nausea with no 
or minimal interference 
with oral intake
Persistent nausea resulting in 
decreased oral intake for 
24-48-hours
Persistent nausea resulting in 
minimal oral intake for 
 48-hours OR Aggressive 
rehydration indicated 
(eg, IV fluids)
Life-threatening 
consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences (eg, sepsis, 
circulatory failure, 
hemorrhage)
Proctitis (functional- 
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
OR Medical intervention 
indicated 
Symptoms causing inability 
to perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening 
consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening 
consequences 
(eg, hypotensive shock)


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in 
Personality-Behavior or in 
Mood (eg, agitation, 
anxiety, depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater 
than minimal interference 
with usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others 
(eg, suicidal/homicidal 
ideation or attempt, acute 
psychosis) OR Causing 
inability to perform basic 
self-care functions
Altered Mental Status 
For Dementia, see 
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference 
with usual social & 
functional activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic 
self-care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater 
than minimal interference 
with usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay – 
Pediatric  16 Years
Mild developmental delay, 
either motor or cognitive, 
as determined by 
comparison with a 
developmental screening 
tool appropriate for the 
setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities
Symptoms causing inability 
to perform usual social & 
functional activities
Symptoms causing inability 
to perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or 
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic 
self-care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle 
weakness causing no or 
minimal interference with 
usual social & functional 
activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia 
causing no or minimal 
interference with usual 
social & functional 
activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference 
with usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability 
to perform usual social & 
functional activities
Disabling sensory alteration 
or paresthesia causing 
inability to perform basic self-
care functions


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive 
(eg, status epilepticus), or 
difficult to control 
(eg, refractory epilepsy)
Seizure: (preexisting) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of 
preexisting seizures 
(nonrepetitive) without 
change in seizure character 
OR infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality 
(eg, severity or focality) 
Seizures of any kind that are 
prolonged, repetitive 
(eg, status epilepticus), or 
difficult to control 
(eg, refractory epilepsy)
Seizure 
– Pediatric  18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with 
< 24-hours post-ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
5-20 minutes with 
< 24-hours post-ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic 
self-care functions


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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic 
self-care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional 
activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score  –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric  21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(noninjection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional 
activities
Disabling muscle pain 
causing inability to perform 
basic self-care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain 
with radiographic findings 
OR Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic 
self-care functions


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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR laryngeal 
edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability 
to perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability 
to perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
 40.5C 
 104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other than 
ER visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight 
from baseline
10% to 19% loss in body 
weight from baseline
 20% loss in body weight 
from baseline OR Aggressive 
intervention indicated 
(eg, tube feeding or total 
parenteral nutrition)


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INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain 
(pain without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no 
or minimal limitation of use 
of limb
Pain/tenderness limiting use 
of limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional 
activities
Pain/tenderness causing 
inability to perform basic 
self-care function OR 
Hospitalization (other than ER 
visit) indicated for management 
of pain/tenderness
Injection Site Reaction 
(Localized),  15 Years
Erythema OR Induration
of 5  5 cm to 9  9 cm 
(or 2581  cm2)
Erythema OR Induration OR 
Edema  9 cm any diameter 
(or  81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis and 
deeper tissue)
Pediatric  15 Years
Erythema OR Induration 
OR Edema present but 
 2.5 cm diameter
Erythema OR Induration OR 
Edema > 2.5 cm diameter but 
< 50% surface area of the 
extremity segment (eg, upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
 50% surface area of the 
extremity segment 
(eg, upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis and 
deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to 
injection site AND 
Relieved spontaneously or 
with  48 h treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring  48 h treatment 
Generalized itching causing 
inability to perform usual 
social & functional 
activities
NA


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Amendment 2
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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite 
treatment modification
Life-threatening 
consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability 
to perform usual social & 
functional activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences (eg, thyroid 
storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability 
to perform usual social & 
functional activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences (eg, myxedema 
coma)
Lipoatrophy (eg, fat loss 
from the face, 
extremities, buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual 
Bleeding (IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with 
life-threatening 
hypotension OR Operative 
intervention indicated
Urinary Tract 
obstruction (eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing 
life-threatening 
consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic 
antimicrobial treatment 
indicated AND Symptoms 
causing no or minimal 
interference with usual social & 
functional activities
Systemic antimicrobial 
treatment indicated OR 
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities
Systemic antimicrobial 
treatment indicated AND 
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Operative intervention (other 
than simple incision and 
drainage) indicated
Life-threatening 
consequences 
(eg, septic shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


Selgantolimod 
Protocol GS-US-465-4439 
Gilead Sciences, Inc. 
Final 
Amendment2 
11.6. 
Management of Clinical and Laboratory Adverse Events 
Grade 1 
Grade 2 
Grade3 
JVlay continue 
dosing at the 
discretion of the 
investigator 
R epeat lab to 
conf'n'm toxicity 
grade 
If confirmed and considered related to 
investigational medicinal products: 
1. 'Withhold investigational medicinal 
products until :::: Grade 2 
2. Resta1·t all investigational medicinal 
products at full dose 
Grade4 
Repeat lab to 
confirm toxicity 
grade 
If conf'n'med and considered 
um·elated to investigational 
medicinal products, dosing 
may continue at the 
disc1·etion of the investigator 
If confirmed and 
considered related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at 
pe1iodic intervals at 
least weekly until a 
return to baseline or 
is otherwise 
explained 
If Grade 3 or Grade 4 recurrence that is 
confirmed and considered related to 
investigational medicinal products, 
discontinue all investigational medicinal 
products dosing permanently 
If Grade 3 or Grade 4 recurrence that is 
considered unrelated to investigational 
medicinal products, continue all 
investigational medicinal products at the 
same dose at the discretion of the investigator 
If the adverse event is considered related to nivolumab, the investigator must follow the toxicity 
management guidance outlined in the local label for nivolumab. 
11.7. 
Amendment History 
A high-level summaiy of this amendment is provided in tabular fonn in the subsection below, 
with changes listed in order of impo1iance. Minor changes such as the conection of typographic 
enors, grammar, or fonnatting are not detailed. 
Sepai·ate summaiy of change documents for earlier amendments ai·e available upon request. 
A sepai·ate tracked change (red-lined) document compai·ing the Protocol Amendment 1 to this 
amendment will be made available upon the publication of this protocol. 
11.7.1. 
Amendment 2 (12 April 2023) 
Rationale fo1· Key Changes Included in Amendment 2 
References to nivolumab were modified throughout the protocol due to Gilead's 
decision to discontinue nivolumab dosing across study cohorts. 
An ongoing study (GS-US-389-5458) assessing the safety, tolerability and 
efficacy of once-weekly administration of SLGN 3 mg in special populations with 
chronic hepatitis B virus (CHB) was added. 
CONFIDENTIAL 
Page 152 
Affected Sections 
Throughout the protocol, as 
required 
Section 1.2.1.1 
12 April 2023 


Selgantolimod
Protocol GS-US-465-4439
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 153
12 April 2023
Rationale for Key Changes Included in Amendment 2
Affected Sections
Figure 1 was updated in order to reflect the current changes to study design.
Section 3.2
A new section to describe the rationale for modifications to the study design was 
added following the decision to discontinue nivolumab dosing.
Sections 1.3.1
Benefit/Risk Assessment for nivolumab and Overall Benefit/Risk was updated 
following discontinuation of nivolumab in this study.
Section 1.5
Number of viremic chronic hepatitis B (CHB)-infected participants was reduced 
from 80 to 60 participants to reflect a prior sponsor decision that cohort 3 would 
not be enrolled.
Synopsis, Section 3.2, and 
throughout the protocol, as 
required
A new subsection for changes to the study design was added.
Section 3.2.1
All incidences of ‘Participants who remain on nucleos(t)ide (NUC) treatment into 
follow-up (FU) period are not required to attend FU Weeks 2 and 8 visits’ have 
been removed as all participants in Cohort 1 will remain on NUCs throughout the 
FU period.
Synopsis and Section 6.7
FU period was updated to outline the procedures following the change to study 
design.
Synopsis and Section 3.5
An individual treatment modification criterion (Any on treatment uveitis, 
confirmed by ophthalmologic evaluation) was moved to individual treatment 
discontinuation criteria after confirmation that no rechallenge is required 
following the resolution of the AE.
Synopsis and Section 6.9.1
A new section for toxicity management of irAEs observed with nivolumab was 
added.
Section 11.5
AE of special interest (eg, uveitis) was added to the safety analysis.
Section 8.6.2
FU Week 8 virtual/telephonic visit pregnancy test was changed across all cohorts.
Section 11.3 and throughout 
the protocol, as required.
The visit windows for FU Weeks 24 through FU Week 48 (for Cohorts 1 and 2) 
were extended to ± 14 days.
Sections 11.3 and 6.7
FU Week 2 was removed in order to simplify the FU period for participants.
Section 11.3 and throughout 
the protocol, as required
References to Cohort 3 were removed throughout the protocol due to the decision 
to discontinue this cohort.
Throughout the protocol, as 
required
Incidences of Global Patient Safety have been changed to Patient Safety (PS).
Section 7 and throughout 
the protocol, as required
Minor changes included to correct typographical errors.
Throughout the protocol, as 
required


Prot-GS-US-465-4439-amd-2
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Development
eSigned
13-Apr-2023
16:49:46
CCI

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2a, Open-Label Study to Evaluate the Safety and 
Efficacy of Selgantolimod (SLGN)-Containing Combination 
Therapies for the Treatment of Chronic Hepatitis B (CHB)
Name of Test Drug:
Selgantolimod
Study Number:
GS-US-465-4439
Protocol Version (Date):
Amendment 2: 12 April 2023
Analysis Type:
Primary and Final Analysis 
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
18 April 2024
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
GILEAU 


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Statistical Analysis Plan – Primary and Final Analysis
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...............................................................................................................................1
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS.................................................................................................................7
1.
INTRODUCTION..................................................................................................................................................8
1.1.
Study Objectives and Endpoints................................................................................................................8
1.2.
Study Design .............................................................................................................................................9
1.2.1.
Changes to Study Design.......................................................................................................10
1.3.
Sample Size and Power ...........................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS......................................................................................................................12
2.1.
Primary Analysis .....................................................................................................................................12
2.2.
Final Analysis..........................................................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................13
3.1.
Analysis Sets ...........................................................................................................................................13
3.1.1.
All Enrolled Analysis Set ......................................................................................................13
3.1.2.
All Randomized Analysis Set................................................................................................13
3.1.3.
Full Analysis Set....................................................................................................................13
3.1.4.
Safety Analysis Set................................................................................................................14
3.1.5.
Follow-Up (FU) Analysis Set................................................................................................14
3.1.6.
SLGN Pharmacokinetic Analysis Set....................................................................................14
3.1.7.
SLGN Pharmacokinetic (PK) Substudy Analysis Set...........................................................14
3.2.
Participant Grouping ...............................................................................................................................14
3.3.
Strata and Covariates...............................................................................................................................14
3.4.
Examination of Participant Subgroups....................................................................................................15
3.5.
Multiple Comparisons .............................................................................................................................15
3.6.
Missing Data and Outliers.......................................................................................................................15
3.6.1.
Missing Data..........................................................................................................................15
3.6.2.
Outliers ..................................................................................................................................15
3.7.
Data Handling Conventions and Transformations ..................................................................................15
3.8.
Analysis Visit Windows..........................................................................................................................17
3.8.1.
Definition of Study Day ........................................................................................................17
3.8.2.
Analysis Visit Windows........................................................................................................17
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................23
4.
PARTICIPANT DISPOSITION ..........................................................................................................................25
4.1.
Participant Enrollment and Disposition...................................................................................................25
4.2.
Extent of Study Drug Exposure and Adherence......................................................................................27
4.2.1.
Duration of Exposure to Study Drug.....................................................................................27
4.2.2.
Adherence to Study Drug ......................................................................................................28
4.3.
Protocol Deviations .................................................................................................................................31
4.4.
Assessment of COVID-19 Impact...........................................................................................................31
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19.....................................................31
4.4.2.
Protocol Deviations Due to COVID-19 ................................................................................31


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4.4.3.
Missed and Virtual Visits due to COVID-19 ........................................................................31
4.4.4.
Adverse Events Due to COVID-19 .......................................................................................32
4.4.5.
Overall Assessment of COVID-19 Pandemic Impact...........................................................32
5.
BASELINE CHARACTERISTICS .....................................................................................................................33
5.1.
Demographics and Baseline Characteristics ...........................................................................................33
5.2.
Other Baseline Characteristics ................................................................................................................33
5.3.
Medical History.......................................................................................................................................34
6.
EFFICACY ANALYSES.....................................................................................................................................35
6.1.
Primary Efficacy Endpoint......................................................................................................................35
6.1.1.
Definitions of Primary Efficacy Endpoint.............................................................................35
6.1.2.
Statistical Hypothesis for Primary Efficacy Endpoint...........................................................35
6.1.3.
Analysis of Primary Efficacy Endpoint.................................................................................35
6.1.4.
Subgroup Analysis of Primary Efficacy Endpoint ................................................................36
6.2.
Secondary Efficacy Endpoints ................................................................................................................36
6.2.1.
Definitions of Secondary Efficacy Endpoints .......................................................................36
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints...........................................................37
6.4.
Other Efficacy Analysis ..........................................................................................................................38
7.
SAFETY ANALYSES.........................................................................................................................................39
7.1.
Adverse Events and Deaths.....................................................................................................................39
7.1.1.
Adverse Event Dictionary .....................................................................................................39
7.1.2.
Adverse Event Severity .........................................................................................................39
7.1.3.
Relationship of Adverse Events to Study Drug.....................................................................39
7.1.4.
Relationship of Adverse Events to Study Procedures ...........................................................39
7.1.5.
Serious Adverse Events.........................................................................................................39
7.1.6.
Treatment-Emergent (TE) Adverse Events (AEs), Non-TEAEs, and AEs 
Through FU Week 24............................................................................................................40
7.1.7.
Summaries of Adverse Events and Deaths............................................................................41
7.1.8.
Additional Analysis of Adverse Events – Potential irAEs....................................................43
7.1.9.
Additional Analysis of Adverse Events – Potential Uveitis..................................................43
7.2.
Laboratory Evaluations ...........................................................................................................................43
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................44
7.2.2.
Graded Laboratory Values ....................................................................................................44
7.2.3.
Liver-related Laboratory Evaluations....................................................................................45
7.3.
Body Weight, Height, and Vital Signs ....................................................................................................46
7.4.
Prior HBV and Concomitant Medications ..............................................................................................47
7.4.1.
Prior HBV Medications.........................................................................................................47
7.4.2.
Concomitant Medications......................................................................................................47
7.5.
Electrocardiogram Results.......................................................................................................................48
7.6.
Other Safety Measures ............................................................................................................................48
8.
PHARMACOKINETIC (PK) ANALYSES.........................................................................................................49
8.1.
PK Sample Collection .............................................................................................................................49
8.2.
PK Analyses Related to Intensive PK Sampling.....................................................................................49
8.2.1.
Estimation of PK Parameters.................................................................................................49
8.2.2.
PK Parameters .......................................................................................................................50
8.3.
PK Analyses Related to Sparse PK Sampling.........................................................................................51
8.4.
Changes From Protocol-Specified PK Analyses.....................................................................................52
9.
REFERENCES.....................................................................................................................................................53
10.
SOFTWARE.........................................................................................................................................................54
CCI


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11.
SAP REVISION...................................................................................................................................................55
12.
APPENDICES......................................................................................................................................................56
12.1.
Data Collection........................................................................................................................................67
12.2.
Determination of COVID-19 Related Information from CRF Comment ...............................................67
LIST OF IN-TEXT TABLES
Table 3-1.
Cohort 1 and Cohort 2 Group A: Analysis Visit Windows for On-treatment Vital 
Signs, Hematology, Chemistry, Coagulation, Quantitative Plasma HBV DNA, 
Quantitative HBV (serum HBsAg, HBcrAg, HBeAg, and HBV RNA), Qualitative 
HBV Serology (HBeAg, hepatitis B e antibody (HBeAb), HBsAg, and hepatitis B 
surface antibody (HBsAb))......................................................................................................19
Table 3-2.
Cohort 1 and Cohort 2 Group A: Analysis Visit Windows for On-treatment 
Urinalysis.................................................................................................................................19
Table 3-3.
Cohort 1 and Cohort 2 Group A: Analysis Visit Windows for On-treatment Body 
Weight .....................................................................................................................................20
Table 3-4.
Cohort 1 and Cohort 2 Group A: Analysis Visit Windows for On-treatment APRI, 
FibroTest, ECG, and Estimated Creatinine Clearance (using the Cockcroft-Gault 
method)....................................................................................................................................20
Table 3-5.
Cohort 1 and Cohort 2 Group A: Analysis Visit Windows for On-treatment 
Ophthalmologic Examination..................................................................................................20
Table 3-6.
Cohort 2 Group B: Analysis Visit Windows for On-treatment Hematology, 
Chemistry, Coagulation, Quantitative Plasma HBV DNA, Quantitative HBV (serum 
HBsAg, HBcrAg, HBeAg, and HBV RNA), Qualitative HBV Serology (HBeAg, 
HBeAb, HBsAg, and HBsAb).................................................................................................21
Table 3-7.
Cohort 2 Group B: Analysis Visit Windows for On-treatment Vital Signs ............................21
Table 3-8.
Cohort 2 Group B: Analysis Visit Windows for On-treatment Urinalysis, and Body 
Weight .....................................................................................................................................22
Table 3-9.
Cohort 2 Group B: Analysis Visit Windows for On-treatment APRI, FibroTest, 
ECG, Estimated Creatinine Clearance (using the Cockcroft-Gault method), and 
Ophthalmologic Examination..................................................................................................22
Table 3-10.
Cohort 1, Cohort 2 Groups A and B: Analysis Visit Windows for Posttreatment 
Hematology, Chemistry, Coagulation, Quantitative Plasma HBV DNA, HBV 
genotyping, Quantitative HBV Serology (HBsAg, HBcrAg, HBeAg, and HBV 
RNA), Qualitative HBV Serology (HBeAg, HBeAb, HBsAg, and HBsAb) and Vital 
Signs ........................................................................................................................................22
Table 3-11.
Cohort 1, Cohort 2 Groups A and B: Analysis Visit Windows for Posttreatment 
APRI and FibroTest.................................................................................................................23
Table 3-12.
Cohort 1, Cohort 2 Groups A and B: Analysis Visit Windows for Posttreatment 
Body Weight, ECG, Estimated Creatinine Clearance (using the Cockcroft-Gault 
method)....................................................................................................................................23
Table 8-1.
Study Treatments and Associated Analyte..............................................................................50
Table 8-2.
PK Parameters for Each Analyte.............................................................................................50
LIST OF IN-TEXT FIGURES
Figure 1-1.
Study Design Schema*............................................................................................................10


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CK
creatine kinase
COVID-19
coronavirus disease 19
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
ddPCR
digital droplet polymerase chain reaction
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
FAS
Full Analysis Set
HBV
hepatitis B virus
HBcrAg
hepatitis B core-related antigen
HBeAb
hepatitis B e antibody
HBeAg
hepatitis B e antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HLGT
high-level group term
HLT
high-level term
IRT
interactive response technology
LTT
lower-level term
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
NUC
nucleos(t)ide(s)
PT
preferred term
Q1, Q3
first quartile, third quartile
PK
pharmacokinetic(s)
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
siRNA
short interfering RNA
SOC
system organ class


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SLGN
selgantolimod
SMQ
Standardized MedDRA Query
TAF
tenofovir alafenamide (Vemlidy®)
TEAE
treatment-emergent adverse event
TE
treatment emergent
TFFU
treatment-free follow-up
TFLs
tables, figures, and listings
ULN
upper limit of normal
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
phase of the log concentration of drug versus time curve of the drug
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCinf
area under the concentration versus time curve extrapolated to infinite time, calculated as 
AUClast + (Clast/z)
AUC0
partial area under the concentration versus time curve from time “0” to time “24”
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf , where “Dose” is the dose of the drug
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 
2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax


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1.
INTRODUCTION
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 GS-US-465-4439. This SAP is based on the study protocol amendment 2 dated 
12 April 2023 and the electronic case report form (eCRF). The SAP will be finalized before the 
Primary Analysis at Follow-up (FU) Week 24 when all participants complete Follow-Up (FU) 
Week 24 or early terminated from the study prior to FU Week 24, and will be used for both 
Primary Analysis and Final Analysis. Any changes made after the finalization of the SAP will be 
documented in the CSR.
1.1.
Study Objectives and Endpoints 
Primary Objective(s)
Primary Endpoint(s)
•
To evaluate the safety and tolerability of study 
treatment(s) 
•
To evaluate the efficacy of study treatment(s) 
as measured by the proportion of participants 
who achieve functional cure, defined as 
hepatitis B surface antigen (HBsAg) loss and 
HBV DNA < LLOQ at FU Week 24 
•
The proportion of participants who achieve 
functional cure, defined as HBsAg loss and 
HBV DNA < LLOQ at FU Week 24
Secondary Objective(s)
Secondary Endpoint(s)
•
To evaluate the proportion of participants 
with HBsAg loss with and without 
anti-HBsAg seroconversion during the study 
•
To evaluate in participants with CHB who are 
hepatitis B e antigen (HBeAg) positive at 
baseline, the proportion of participants who 
achieve HBeAg loss with and without 
anti-HBeAg seroconversion during the study
•
To evaluate the proportion of participants who 
remain off nucleos(t)ide(s) (NUC) treatment 
during FU 
•
To evaluate the proportion of participants 
experiencing HBV virologic breakthrough 
during study treatment(s)
•
The proportion of participants with HBsAg 
loss with and without anti-HBsAg 
seroconversion during the study
•
The proportion of participants with HBeAg 
loss with and without anti-HBeAg 
seroconversion during the study in 
participants with CHB who are HBeAg 
positive at baseline
•
The proportion of participants who remain off 
NUC treatment during FU
•
The proportion of participants experiencing 
HBV virologic breakthrough during study 
treatment(s) as defined in protocol Section 2. 
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1.2.
Study Design
Approximately 40 NUC-suppressed and 60 viremic CHB-infected participants may be enrolled 
and assigned into a cohort below. Each cohort will enroll a minimum of 20% of HBeAg-positive 
participants, and up to 20% of participants can have HBsAg ≤ 100 IU/mL. 
NUC-suppressed Cohort
Cohort 1 (n = 40):
•
TAF 25-mg tablet administered orally once daily for 36 weeks
•
VIR-2218 200 mg administered via SC injection once every 4 weeks for 24 weeks (total 
6 doses)
At Week 12, add-on and initiate the below treatment:
•
SLGN 3 mg (2 × 1.5-mg tablets) administered orally while fasting once a week on the same 
day for 24 weeks (total 24 doses) 
•
Nivolumab 0.3 mg/kg administered IV once every 4 weeks for up to 24 weeks (up to 6 doses)
Viremic Cohort 
Cohort 2 (n = 60) 
Participants will be randomized 2:1 into Cohort 2 (Groups A and B) and stratified by 
HBsAg > or ≤ 3 log10 IU/mL. 
Group A (n = 40): 
•
VIR-2218 200 mg administered via SC injection once every 4 weeks for 24 weeks (total 
6 doses) 
At Week 12, add-on and initiate the below treatment: 
•
SLGN 3 mg (2 × 1.5-mg tablets) administered orally while fasting once a week on the same 
day for 24 weeks (total 24 doses) 
•
Nivolumab 0.3 mg/kg administered IV once every 4 weeks for up to 24 weeks (up to 6 doses) 
Group B (n = 20): 
•
SLGN 3 mg (2 × 1.5-mg tablets) administered orally while fasting once a week on the same 
day for up to 24 weeks (up to 24 doses) 
•
Nivolumab 0.3 mg/kg administered IV once every 4 weeks for up to 24 weeks (up to 6 doses) 


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After completing study treatments all participants will enter the FU period. 
Figure 1-1 provides the study design schema. 
Figure 1-1.
Study Design Schema*
IV = intravenous; NUC = nucleos(t)ide(s); PO = oral; Q4W = every 4 weeks; QD = once daily; QW = every week; 
SLGN = selgantolimod; SC = subcutaneous; TAF = tenofovir alafenamide 
a
Viremic participants who meet criteria to initiate NUC treatment will receive TAF 25 mg once daily for up to 36 weeks 
during the study. 
b
SLGN dosed while fasting once a week, on the same day, for 24 weeks. 
c
Participants will continue to receive TAF per Protocol Section 3.5. 
* 
NOTE: Nivolumab dosing was stopped in this study and all treatments in Cohort 2 Group B were discontinued. This was a 
sponsor decision based on a benefit risk assessment on the use of nivolumab in HBV cure. Rationale is provided in Protocol 
Section 1.3.1.
Additional details regarding study assessments can be found in Appendix 1.
1.2.1.
Changes to Study Design 
Nivolumab dosing was stopped by Gilead as part of benefit-risk assessment based on emerging 
safety data from this study, other studies evaluating anti-PD-1/PD-L1 mAbs, and pertinent 
patient and prescriber insights {Cohen C. 2020}. As the study had completed enrollment and all 
participants were undergoing study treatment when the decision was made to stop nivolumab 
administration, the following measures were implemented: 
•
Stopped further nivolumab administration for all study participants across all cohorts 
•
Continued treatment with VIR-2218 and SLGN through Week 36 for Cohort 1 and Cohort 2 
Group A
•
Discontinued all study treatment for Cohort 2 Group B participants 
•
Stopped all sample collections related to nivolumab
•
NUC treatment cessation was no longer required for NUC treated participants (Cohort 1) 
\ -UC-SUPPR.ESSED 
COHORT! 
TAF 25 mg PO administered QD for up to 36 weeks plus 
COHORT 
____. 
(n = 40) 
1-. 
VIR-2218 200 mg SC Q4W for 24 weeks 
(40 
.-\t Week 12, add-on tbe below treatment: 
PARTICIPA_'\1S) 
SLGN 3 mg PO administered Q\V for 24 weeks plus 
I'-,,. 
nivolumab 0.3 mg/kg IV Q4\V for up to 24 weeks 
Group A: VIR-22 18 200 mg SC administered Q4W for 24 
weeks 
I___. 
At '\Yeek 12, r.dd-011 the below tre,n meru : 
YIR.Ei\fiC 
COHORT? 
SLGNb 3 mg PO administered QW for 24 weeks plus 
FOLLO\"V-UP 
COHORTS' 
I--+ 
Group A (n = 40) 
nivolumab 0.3 mg/kg IV administered Q4W for up to 24 weeks 
FOR 
(60 
and 
2: 1 ratio 
48WEEKS' 
PARTICIPAJ.'\TS) 
Group B (n = 20) 
Group B: SI.GNb 3 mg PO administered QW for up to 24 
i-. 
weeks plus 
nivolumab 0.3 mg/kg IV administered Q4W for up to 24 weeks 


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1.3.
Sample Size and Power
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Primary Analysis
The Primary Analysis will be conducted after all participants have completed FU Week 24 or 
early terminated from the study prior to FU Week 24.
2.2.
Final Analysis
The final analysis will be performed after all participants have completed the study, outstanding 
data queries have been resolved or adjudicated as unresolvable, and the data have been cleaned 
and finalized. 


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, standard deviation (SD) or standard error (SE), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-participant listings will be presented for all participants in the All Enrolled Analysis Set and 
sorted by cohort, treatment group if applicable, and participant ID number in ascending order, 
visit date, and time (if applicable), unless otherwise specified. Data collected on log forms, such 
as AEs, will be presented in chronological order within the participant. The cohort, and treatment 
group if applicable, to which participants were enrolled and/or randomized will be used in the 
listings. Age, sex at birth, race, and ethnicity will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the participants 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 participants eligible for inclusion as well as 
the number and percentage of participants who were excluded and the reasons for their 
exclusion, will be summarized by cohort, and treatment group if applicable.
A listing of reasons for exclusion from analysis sets will be provided by participant.
3.1.1.
All Enrolled Analysis Set 
The All Enrolled Analysis Set includes all participants in Cohort 1 who received a study 
participant identification number in the study after screening, or all participants in Cohort 2 who 
were randomized in the study. 
3.1.2.
All Randomized Analysis Set
The All Randomized Analysis Set includes all participants in Cohort 2 who were randomized in 
the study. 
3.1.3.
Full Analysis Set
The Full Analysis Set (FAS) includes all enrolled participants in Cohort 1, or all randomized 
participants in Cohort 2 who received at least 1 dose of study drug. This is the primary analysis 
set for efficacy analyses. 


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3.1.4.
Safety Analysis Set
The Safety Analysis Set includes all participants who received at least 1 dose of study drug. This 
is the primary analysis set for safety analyses.
3.1.5.
Follow-Up (FU) Analysis Set 
The FU Analysis Set includes all participants who have at least 1 follow-up visit, after 
completing or premature discontinued from the study drugs. 
3.1.6.
SLGN Pharmacokinetic Analysis Set
The SLGN Pharmacokinetic (PK) Analysis Set will include all enrolled participants who took at 
least 1 dose of SLGN and have at least 1 nonmissing SLGN concentration value reported by the 
PK laboratory. This is the primary analysis set for PK analyses associated with SLGN.
3.1.7.
SLGN Pharmacokinetic (PK) Substudy Analysis Set
The SLGN PK Substudy Analysis Set will include all enrolled participants who took at least 
1 dose of SLGN, participated in the PK substudy, and have at least 1 nonmissing postdose SLGN 
concentration. This is the primary analysis set for detailed PK analysis of intensive PK sampling 
associated with SLGN. 
3.2.
Participant Grouping
For analyses based on the FAS, participants will be grouped according to the treatment group to 
which they were enrolled for Cohort 1 or to which they were randomized for Cohort 2. For 
analyses based on the Safety Analysis Set, participants will be grouped according to the actual 
treatment received. The actual treatment received will differ from the enrolled/randomized 
treatment group only when their actual treatment differs from enrolled/randomized treatment for 
the entire treatment duration.
For the PK Analysis Set, participants will be grouped according to the actual treatment they 
received.
3.3.
Strata and Covariates
Cohort 2 participants will be randomized to treatment groups via the interactive voice or web 
response system (IXRS) in a 2:1 ratio using a stratified randomization schedule. Stratification 
will be based on the following variable:
•
HBsAg > 3 log10 IU/mL or HBsAg ≤ 3 log10 IU/mL 
If there are discrepancies in stratification factor values between the IXRS and the clinical 
database, the values recorded in the clinical database will be used for analyses. However, in the 
case that stratification factor data is missing in clinical database, values recorded in the IXRS 
will be used. Additionally, stratification discrepancies will be reviewed and assessed. Based on 
the assessment of stratification discrepancies, a sensitivity analysis of the primary endpoint may 
be performed.


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Demographics, baseline characteristics, participants disposition and enrollment, and efficacy 
endpoints will be evaluated by baseline HBsAg status (HBsAg > or ≤ 3 log10 IU/mL).
3.4.
Examination of Participant Subgroups
There are no prespecified participant subgroupings for efficacy and safety analyses.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.6.
Missing Data and Outliers
3.6.1.
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 dosing date of study drug, imputation rules are described in Section 4.2. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.6.4, and for 
prior HBV and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers of non-PK data will be identified during the data management and data analysis process, 
but no sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:
•
If only month and year of birth is collected, then “15” will be imputed as the day of birth
•
If only year of birth is collected, then “01 July” will be imputed as the day and month of birth
•
If year of birth is missing, then date of birth will not be imputed.
In general, age collected at Day 1 (in years) will be used for analyses and presented in listings. If 
age at Day 1 is not available for a participant, then age derived based on date of birth and the 
Day 1 visit date will be used instead. If an enrolled participant was not dosed with any study 
drug, the enrollment date for Cohort 1 or randomization date for Cohort 2 will be used instead of 
the Day 1 visit date. For screen failures, the date the first informed consent was signed will be 
used for the age derivation. Age required for longitudinal and temporal calculations and analyses 
(e.g., estimates of creatinine clearance, age at date of AE) will be based on age, and derived from 
date of birth and the date of the measurement or event, unless otherwise specified.


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Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:
•
A value that is 1 unit less than the lower LOQ at the same precision level of the originally 
reported value will be used to calculate descriptive statistics if the datum is reported in the 
form of “ x” (where x is considered the lower 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 upper LOQ). Values 
with decimal points will follow the same logic as above.
•
The lower or upper 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 lower or upper LOQ, 
respectively).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (eg, log10 transformation may be used for 
quantitative HBsAg, HBV DNA, HBeAg if applicable, HBV RNA, and HBcrAg) or 
nonparametric analysis methods may be used, as appropriate.
Sparse PK concentration values that are below the limit of quantitation (BLQ) will be presented 
as “BLQ” in the data listing.
Natural logarithm transformation will be used for analyzing non-BLQ concentrations and PK 
parameters in intensive PK samples. Concentration values that are BLQ will be presented as 
“BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 at predose and 
postdose time points for summary purposes. The number of samples will be summarized to 
reflect the actual number of samples assessed at that time point.
At predose, if all concentration values are BLQ, then the mean, and order statistics (minimum, 
Q1, median, Q3, and maximum) will be displayed as 0 and the rest of the summary statistics 
(ie, SD and CV) will be missing. If any values are non-BLQ, then the number of samples, order 
statistics, and all summary statistics will be displayed. 
At any given postdose time point, if more than one-third of the participants have a concentration 
value of BLQ, then only the number of samples and order statistics will be displayed; otherwise, 
order statistics and summary statistics will be displayed.


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The following conventions will be used for the presentation of order statistics for postdose time 
points: 
•
If at least 1 participant has a concentration value of BLQ for the time point, the minimum 
value will be displayed as “BLQ.”
•
If more than 25% of the participants have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”
•
If more than 50% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”
•
If more than 75% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”
•
If all participants have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
Concentration related PK parameters (eg, Clast, Cmax, and Ctau) that are BLQ will be excluded 
before log transformation or statistical model fitting and displayed as described above.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of any study drug and derived as follows:
•
For postdose study days: Assessment Date – First Dosing Date + 1
•
For days prior to the first dose: Assessment Date – First Dosing Date
Therefore, Study Day 1 is the day of first dose of any study drug administration. 
The last dose date of the study drug will be the stop date on the study drug administration eCRF 
for the record where the “study drug was permanently withdrawn” flag is “Yes”. 
3.8.2.
Analysis Visit Windows
Participant visits might not occur on protocol-specified days. Therefore, for the purpose of 
analysis, observations will be assigned to analysis windows as specified in Table 3-1 to 
Table 3-12.
Data collected up to the last on-treatment date + 3 days will be considered as on-treatment data, 
whereas data collected afterwards will be considered as follow-up data. 


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For each drug, the last on-treatment date is defined as follows: 
•
Last on-treatment date for VIR-2218 = (last injection date of VIR-2218 + 28 days) – 1
•
Last on-treatment date for nivolumab = (last injection date of nivolumab + 28 days) – 1
•
Last on-treatment date for selgantolimod = (last dose date of selgantolimod + 7 days) – 1 
For Cohort 1 and Cohort 2 Group A, the composite last on-treatment date is the latest date of the 
last on-treatment date of VIR-2218, nivolumab, or SLGN. 
For Cohort 2 Group B, the composite last on-treatment date is the latest date of the last 
on-treatment date of nivolumab or SLGN. 
Participants are allowed to continue taking TAF after the discontinuation of study treatments, 
hence TAF will not be considered for constructing the analysis windows. 
The follow-up day (FU Day) in Posttreatment tables is defined as:
•
FU Day = Assessment date – composite last on-treatment date. 
A baseline value is defined as the last available value collected on or prior to 
the date of first dose of any study drug. An unscheduled visit prior to the first dosing of study 
drug will be included in the calculation of the baseline value, if applicable. 
The analysis windows for on-treatment assessments are provided in Table 3-1 to Table 3-9. 
Table 3-10 to Table 3-12 provide analysis windows for posttreatment assessments.


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Table 3-1.
Cohort 1 and Cohort 2 Group A: Analysis Visit Windows for 
On-treatment Vital Signs, Hematology, Chemistry, Coagulation, 
Quantitative Plasma HBV DNA, Quantitative HBV (serum HBsAg, 
HBcrAg, HBeAg, and HBV RNA), Qualitative HBV Serology 
(HBeAg, hepatitis B e antibody (HBeAb), HBsAg, and hepatitis B 
surface antibody (HBsAb)) 
Visit Window Study Day
Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
43
Week 8
57
44
71
Week 12
85
72
92
Week 14
99
93
106
Week 16
113
107
127
Week 20
141
128
155
Week 24
169
156
183
Week 28
197
184
211
Week 32
225
212
239
Week 36
253
240
≥ 253
Table 3-2.
Cohort 1 and Cohort 2 Group A: Analysis Visit Windows for 
On-treatment Urinalysis 
Visit Window Study Day
Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
43
Week 8
57
44
71
Week 12
85
72
99
Week 16
113
100
127
Week 20
141
128
155
Week 24
169
156
183
Week 28
197
184
211
Week 32
225
212
239
Week 36
253
240
≥ 253


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Table 3-3.
Cohort 1 and Cohort 2 Group A: Analysis Visit Windows for 
On-treatment Body Weight
Visit Window Study Day
Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
85
2
99
Week 16
113
100
127
Week 20
141
128
155
Week 24
169
156
183
Week 28
197
184
211
Week 32
225
212
239
Week 36
253
240
≥ 253
Table 3-4.
Cohort 1 and Cohort 2 Group A: Analysis Visit Windows for 
On-treatment APRI, FibroTest, ECG, and Estimated Creatinine 
Clearance (using the Cockcroft-Gault method)
Visit Window Study Day
Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
85
2
169
Week 36
253
170
≥ 253
Table 3-5.
Cohort 1 and Cohort 2 Group A: Analysis Visit Windows for 
On-treatment Ophthalmologic Examination
Visit Window Study Day
Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 24
169
2
211
Week 36
253
212
≥ 253


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Table 3-6.
Cohort 2 Group B: Analysis Visit Windows for On-treatment 
Hematology, Chemistry, Coagulation, Quantitative Plasma HBV 
DNA, Quantitative HBV (serum HBsAg, HBcrAg, HBeAg, and HBV 
RNA), Qualitative HBV Serology (HBeAg, HBeAb, HBsAg, and 
HBsAb)
Visit Window Study Day
Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
43
Week 8
57
44
71
Week 12
85
72
92
Week 14
99
93
106
Week 16
113
107
127
Week 20
141
128
155
Week 24
169
156
≥ 169
Table 3-7.
Cohort 2 Group B: Analysis Visit Windows for On-treatment Vital 
Signs
Visit Window Study Day
Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 2
15
2
22
Week 4
29
23
43
Week 8
57
44
71
Week 12
85
72
92
Week 14
99
93
106
Week 16
113
107
127
Week 20
141
128
155
Week 24
169
156
≥ 169


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Table 3-8.
Cohort 2 Group B: Analysis Visit Windows for On-treatment 
Urinalysis, and Body Weight
Visit Window Study Day
Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
43
Week 8
57
44
71
Week 12
85
72
99
Week 16
113
100
127
Week 20
141
128
155
Week 24
169
156
≥ 169
Table 3-9.
Cohort 2 Group B: Analysis Visit Windows for On-treatment APRI, 
FibroTest, ECG, Estimated Creatinine Clearance (using the 
Cockcroft-Gault method), and Ophthalmologic Examination
Visit Window Study Day
Visit
Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
85
2
127
Week 24
169
128
≥ 169
Table 3-10.
Cohort 1, Cohort 2 Groups A and B: Analysis Visit Windows for 
Posttreatment Hematology, Chemistry, Coagulation, Quantitative 
Plasma HBV DNA, HBV genotyping, Quantitative HBV Serology 
(HBsAg, HBcrAg, HBeAg, and HBV RNA), Qualitative HBV Serology 
(HBeAg, HBeAb, HBsAg, and HBsAb) and Vital Signs
Visit Window FU Day
Visit
FU Day
Lower Limit
Upper Limit
FU Week 2*
15
4
22
FU Week 4
29
23
43
FU Week 8
57
44
71
FU Week 12
85
72
127
FU Week 24
169
128
211
FU Week 36
253
212
295
FU Week 48
337
296
≥ 337
* FU Week 2 was defined in protocol amendment 1, but was removed from protocol amendment 2. Since a substantial amount of 
participants have already completed FU Week 2 per protocol amendment 1, this visit will be kept in analysis. 


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Table 3-11.
Cohort 1, Cohort 2 Groups A and B: Analysis Visit Windows for 
Posttreatment APRI and FibroTest 
Visit Window FU Day
Visit
FU Day
Lower Limit
Upper Limit
FU Week 12
85
4
211
FU Week 48
337
212
≥ 337
Table 3-12.
Cohort 1, Cohort 2 Groups A and B: Analysis Visit Windows for 
Posttreatment Body Weight, ECG, Estimated Creatinine Clearance 
(using the Cockcroft-Gault method) 
Visit Window FU Day
Visit
FU Day
Lower Limit
Upper Limit
FU Week 48
337
4
≥ 337
3.8.3.
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. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing, continuous measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:
•
For baseline, the last nonmissing value on or prior to the first dosing date of study drug will 
be selected, unless specified differently. If multiple measurements occur on the same day, the 
last nonmissing value prior to the time of first dosing of study drug will be considered as the 
baseline value. 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 these measurements. 
•
For postbaseline values (except for alanine aminotransferase [ALT]): 
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken except for 
qHBsAg (IU/mL), HBV DNA (IU/mL), and quantitative HBeAg (IU/mL), for which the 
geometric mean will be taken. 


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•
For postbaseline ALT values: 
The record with the largest value within the same analysis window will be selected. 
If there is more than 1 record with the largest value, the latest record will be selected.
If there are multiple largest records with the same time or no time recorded on the same 
day, any one of these measurements can be selected as the analysis value. 
If multiple valid, nonmissing, categorical measurements exist in an analysis window, and a 
single value is needed, records will be chosen based on the following rules:
•
For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected for safety data (eg, normal will 
be selected over abnormal for safety electrocardiogram [ECG] findings), and the most 
conservative value will be selected for efficacy data (eg, negative will be selected over 
positive for HBeAg and HBsAg, whereas positive will be selected over negative for HBeAb 
and HBsAb).
•
For postbaseline values: 
The most conservative value (eg, abnormal will be selected over normal for safety ECG) 
within the analysis window will be selected, except for HBV serology (HBsAg, HBsAb, 
HBeAg, and HBeAb), for which the most favorable value (ie, negative will be selected 
over positive for HBsAg and HBeAg, whereas positive will be selected over negative for 
HBsAb and HBeAb) will be selected.
In the event that more than 1 value within an analysis window are equal, the value 
collected closest to the nominal day will be selected. 
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected. 
If there is more than 1 record on the selected day, the latest record will be selected; if 
these measurements were recorded at the same time or no time recorded, any one of these 
measurements can be selected as the analysis value.


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4.
PARTICIPANT DISPOSITION
4.1.
Participant Enrollment and Disposition
Key study dates (ie, first participant screened, first participant enrolled, last participant enrolled, 
last participant last visit for the primary endpoint, and last participant last visit for the clinical 
study report) will be provided.
A summary of participant enrollment will be provided by cohort for each country or region, 
investigator within a country or region, and study overall. Within Cohort 2, the summary will be 
presented by treatment group (Group A or Group B) and stratification group (HBsAg > 3 or 
HBsAg ≤ 3 log10 IU/mL). The summary will present the number and percentage of participants 
enrolled/randomized. For each column, the denominator for the percentage calculation will be 
the total number of participants analyzed for that column. For Cohort 2, if there are discrepancies 
in the value used for stratification assignment between the IXRS and the clinical database, the 
value collected in the clinical database will be used for the summary. A listing of participants 
with discrepancies in the value used for stratification assignment between the IXRS and the 
clinical database at the time of data finalization will be provided.
The randomization schedule used for Cohort 2 will be provided as an appendix to the CSR.
A summary of participant disposition will be provided by cohort and study overall. Within 
Cohort 2, the summary will be presented by treatment group (Group A or Group B) and 
stratification group (HBsAg > 3 or HBsAg ≤ 3 log10 IU/mL). This summary will present the 
number of participants screened, the number of participants who met all eligibility criteria but 
were not enrolled/randomized with reasons participants not enrolled/randomized, and the number 
of participants in each of the categories listed below:
•
All Enrolled Analysis Set 
•
All Randomized Analysis Set 
•
Full Analysis Set
•
Safety Analysis Set 
•
FU Analysis Set
•
SLGN PK Analysis Set
•
SLGN PK Substudy Analysis Set
•
SLGN completion status
Completed SLGN
Prematurely discontinued SLGN


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•
Reasons for premature discontinuation of SLGN
•
Nivolumab completion status
Nivolumab not initiated
Completed nivolumab
Prematurely discontinued nivolumab
•
Reasons for premature discontinuation of nivolumab
•
VIR-2218 completion status
Completed VIR-2218 
Prematurely discontinued VIR-2218
•
Reasons for premature discontinuation of VIR-2218
•
TAF completion status (for Cohort 1 during treatment phase only)
Completed TAF 
Prematurely discontinued TAF 
•
Reasons for premature discontinuation of TAF
•
FU Completion Status
Continuing FU (for FU Week 24 Analysis)
Completed FU 
Prematurely discontinued FU 
•
Study completion status 
Continuing study (for FU Week 24 Analysis)
Completed study 
Premature discontinued study
•
Reasons for premature discontinuation of study 


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For the status of study drugs, FU completion, and study completion and reasons for premature 
discontinuation, the number and percentage of participants in each category will be provided. 
The denominator for the percentage calculation will be the total number of participants in the 
Safety Analysis Set corresponding to that column. In addition, a flowchart will be provided to 
depict the disposition.
The following by-participant listings will be provided by cohort (and by treatment group for 
Cohort 2), and participant identification (ID) number in ascending order to support the above 
summary tables:
•
Reasons for premature study drug or study discontinuation 
•
Lot number and kit ID
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence relative to the study drug regimen specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to a study drug during treatment period will be defined as follows: 
•
Duration of exposure to TAF = last dosing date of TAF for the treatment period − first dosing 
date of TAF for the treatment period + 1 day 
•
Duration of exposure to SLGN = last dosing date of SLGN − first dosing date of 
SLGN + 7 days 
•
Duration of exposure to VIR-2218 = last injection date of VIR-2218 − first injection date of 
VIR-2218 + 28 days 
•
Duration of exposure to nivolumab = last injection date of nivolumab − first injection date of 
nivolumab + 28 days 
The calculations for duration of exposure to study drugs are made regardless of any temporary 
interruptions in study drug administration and will be expressed in weeks using up to 1 decimal 
place (e.g., 4.5 weeks). If the last study drug dosing date is missing, the latest date among the 
study drug end date, clinical visit date, laboratory sample collection date, and vital signs 
assessment date that occurred during the on-treatment period will be used for participants 
included in the Final Analyses or the last available date in the database snapshot for FU Week 24 
Analysis. If month and year of the last dose are known, and the last study drug dosing date 
imputed above is different from the month collected, the last date of that month will be used. If 
only year of the last dose is known, and the last study drug dosing date imputed above is after the 
year collected, the last date of that year will be used; if the last study drug dosing date imputed 
above is before the year collected, the first date of that year will be used.


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The total duration of exposure to each of the study drugs will be summarized using descriptive 
statistics and using the number (ie, cumulative duration of exposure by weeks) and percentage of 
participants exposed through the following time periods: 1 day, 4 weeks, 8 weeks, 12 weeks, 
16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, and 36 weeks, where applicable. Summaries 
will be drug specific and be provided by cohort (and by treatment group for Cohort 2) for the 
Safety Analysis Set. 
For nivolumab, number of doses administered (ie, 6 doses, 5 doses, 4 doses, 3 doses, 2 doses, 
and 1 dose) will be summarized by cohort (and by treatment group for Cohort 2) for the 
Safety Analysis Set.
No formal statistical testing is planned.
4.2.2.
Adherence to Study Drug
4.2.2.1.
On-Treatment Adherence for TAF (Cohort 1 Only)
The level of on-treatment adherence to TAF 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 
participant’s actual on-treatment period (ie, by Week 36) based on the study drug regimen. 
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Adherence (%) =
Total number of tablets taken
Total number of tablets prescribed × 100
=
∑No. of tablets taken at each dispensing period [1]
∑No. of tablets prescribed at each dispensing period [2] × 100
[1]
Number of tablets taken during a distinct dispensing period for TAF is calculated as the minimum of (a) the daily number of 
tablets prescribed for the study drug multiplied by the duration of treatment at the dispensing period of the same 
dispensing date, and (b) the number of tablets taken for the study drug (number of tablets dispensed minus the number of 
tablets returned). Total number of tablets taken is determined by summing the number of tablets taken from all evaluable 
dispensing periods.
[2]
Number of tablets prescribed at a distinct dispensing period for TAF is calculated as the daily number of tablets prescribed 
for the study drug multiplied by the duration of treatment at the dispensing period of the same dispensing date. Total 
number of tablets prescribed is determined by summing the number of tablets prescribed from all evaluable dispensing 
periods. 
The duration of treatment (in days) at a dispensing period for TAF is calculated as the 
minimum of (a) the last returned date of the same dispensing period for the study drug, (b) date 
of premature discontinuation of the study drug, and (c) next dispensing date of the study drug, 
minus dispensing date of the study drug. 
The next dispensing date is the following dispensing date of the study drug regardless of the 
bottle return date. 
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For a record where the number of tablets returned was missing (with “Yes” answered for “Was 
bottle returned?” question), then this record will be excluded from both denominator and 
numerator calculation. If the number of tablets dispensed was missing or any study drug bottle 
was not returned or the bottle return status was unknown for the same dispensing date, then all 
records for the same dispensing date for that study drug will be excluded from both denominator 
and numerator calculation. 
Adherence up to end of treatment will be calculated for each participant in Cohort 1. 
The number and percentage of participants who return at least 1 bottle and have calculable 
adherence during the study, descriptive statistics (sample size, mean, SD, median, Q1, Q3, 
minimum, and maximum) for adherence up to end of treatment visit (ie, Week 36) along with the 
number and percentage of participants belonging to adherence categories (eg, < 80%, ≥ 80% to 
< 90%, ≥ 90% to < 95%, ≥ 95%) will be summarized for Cohort 1 participants based on the 
Safety Analysis Set. 
4.2.2.2.
On-Treatment Adherence for SLGN
The level of on-treatment adherence to the study drug regimen 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 participant’s actual on-treatment period based on the study drug regimen.
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Adherence (%)
=
Total Amount of SLGN Administered [1]
Total Amount of SLGN Expected to be Administered on Treatment [2] ×
100
[1]
The total amount of SLGN administered to a participant will be determined by ∑No. of tablets dispensed ―
∑No. of tablets returned based on the study drug accountability CRF. 
[2]
The total amount of SLGN expected to be Administered on treatment is determined as follows: 
a
For participants who completed SLGN, the amount of SLGN expected to be administered will be the 6×8 tablets; 
b
For participants who did not complete SLGN, the total amount of SLGN expected to be administered is the sum of number 
of tablets expected to be taken at each dispensing period, which is calculated as the number of on-treatment weeks on or 
before the last dosing date for SLGN multiplied by the number of tablets expected to be taken at each dispensing period 
(ie, 8 tablets). If there are more than 6 dispensing visits for a participant, 6 visits will be used for calculation. 
Descriptive statistics for the level of on-treatment adherence with the number and percentage of 
participants belonging to adherence categories (< 95%, ≥ 95%) will be provided by cohort (and 
by treatment group for Cohort 2) for the Safety Analysis Set. 
4.2.2.3.
On-treatment Adherence for VIR-2218 (Cohort 1 and Cohort 2 Group A only) 
The level of on-treatment adherence to VIR-2218 will be determined by the total amount of 
VIR-2218 administered relative to the total amount of VIR-2218 expected to be administered 
during a participant’s actual on-treatment period based on the study drug regimen.
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The level of on-treatment adherence will be expressed as a percentage using the following 
formula: 
Adherence (%)
=
Total Amount of VIR ― 2218 Administered [1]
Total Amount of VIR ― 2218 Expected to be Administered on Treatment [2]
× 100
[1]
The total amount of VIR-2218 administered to a participant will be determined by ∑No. of vials dispensed ―
(∑No. of vials returned) based on the drug accountability CRF 
[2]
The total amount of VIR-2218 expected to be administered on treatment is determined as follows: 
a
For participants who completed VIR-2218, the amount of VIR-2218 expected to be administered will be the 6 × 2 vials; 
b
For participants who did not complete VIR-2218, the number of VIR-2218 expected to be administered is determined by the 
last on-treatment visit. For example, if the last on-treatment visit is Week 12, the number of VIR-2218 expected to be 
administered for this participant will be 4 × 2 vials. 
Descriptive statistics for the level of on-treatment adherence with the number and percentage of 
participants belonging to adherence categories (< 100%, 100%) will be provided by cohort for 
the Safety Analysis Set. 
4.2.2.4.
On-Treatment Adherence for Nivolumab 
The level of on-treatment adherence to nivolumab 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 participant’s actual on-treatment period based on the study drug regimen.
The level of on-treatment adherence will be expressed as a percentage using the following 
formula: 
Adherence (%)
=
Total No. of Nivolumab Administered [1]
Total No. of Nivolumab Expected to be Administered on Treatment [2] ×
100
[1]
The total number of nivolumab administered to a participant will be determined by the number of doses administered based 
on the study drug administration CRF. 
[2]
The total number of nivolumab expected to be administered on treatment is determined as follows: 
a
For participants who completed nivolumab, the number of nivolumab expected to be administered will be set to 6; 
b
For participants who did not complete nivolumab, the number of nivolumab expected to be administered is determined by 
the last administration visit (for example, for a participant in Cohort 1 and Cohort 2 Group A, if the last administration visit 
is Week 16, the number of nivolumab expected to be administered will be 2; for a participant in Cohort 2 Group B, if the last 
administration visit is Week 16, the number of nivolumab expected to be administered will be 5). 
For participants who never initiate nivolumab, adherence will not be calculated. 
Descriptive statistics for the level of on-treatment adherence with the number and percentage of 
participants belonging to adherence categories (< 50%, 50% to < 75%, 75% to < 100%, 100%) 
will be provided by cohort (and by treatment group for Cohort 2) for the Safety Analysis Set. 
(--------
) 
( 
) 
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4.3.
Protocol Deviations 
Participants who did not meet the eligibility criteria for study entry but enrolled in the study, will 
be summarized regardless of whether they were exempted by the sponsor or not. The summary 
will present the number and percentage of participants who did not meet at least 1 eligibility 
criterion and the number of participants who did not meet specific criteria by treatment group 
based on the All Enrolled/Randomized Analysis Set. A by-participant listing will be provided for 
those participants 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 participants 
did not meet and related comments, if collected.
Protocol deviations occurring after participants entered the study are documented during routine 
monitoring. The number and percentage of participants with important protocol deviations 
(e.g., at least 1, with 1, 2, 3 or more important protocol deviations), and the total number of 
important protocol deviations by deviation category (e.g., eligibility criteria, informed consent) 
will be summarized by cohort (and by treatment group for Cohort 2) for the 
Enrolled/Randomized Analysis Set. A by-participant listing will be provided for those 
participants with important protocol deviation.
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (COVID-19) pandemic which has an 
impact on the study conduct. Some participants were unable to attend onsite visits due to shelter 
in place guidelines, site closures, or other reasons. This section describes how special situations 
due to COVID-19 will be handled in the analysis. Please refer to Appendix 3 for data collection 
and determination of COVID-19 Data.
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19
A by-participant listing of reasons for premature study drug or study discontinuation due to 
COVID-19 will be provided if applicable.
4.4.2.
Protocol Deviations Due to COVID-19
A by-participant listing will be provided for participants with important protocol deviations 
related to COVID-19 if applicable. A separate listing will be provided for participants with 
non-important protocol deviations related to COVID-19 if applicable.
4.4.3.
Missed and Virtual Visits due to COVID-19
A by-participant listing of participants with missed or virtual visits due to COVID-19 will be 
provided by participant ID number in ascending order.
Missed or virtual visits due to COVID-19 will be collected on the visit date CRF page. 


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4.4.4.
Adverse Events Due to COVID-19
AEs of COVID-19 will be included in analyses of AEs if applicable, which will be determined 
through MedDRA COVID-19 SMQ narrow search. A by-participant listing of AEs of 
COVID-19 will be provided if applicable.
4.4.5.
Overall Assessment of COVID-19 Pandemic Impact
For participants affected by COVID-19 infection and/or pandemic while participating in the 
study, a listing of the following individual COVID-19 related outcome categories will be 
provided:
•
Death due to COVID-19
•
Adverse event of COVID-19, as determined by COVID-19 SMQ narrow search
•
Specific adverse event directly associated with the pathogen causing COVID-19, as 
determined by MST
•
Hospitalization (using data from AE eCRF) due to adverse event of COVID-19 as defined 
above
•
Study drug discontinuation due to COVID-19
•
Study discontinuation due to COVID-19
•
Missed visits due to COVID-19
•
Missed key assessments due to COVID-19 (Key assessments are the assessments 
contributing to primary endpoint, ie, FU Week 24 assessments related to qualitative HBsAg 
and quantitative HBV DNA)
In addition, composite broad COVID-19 impact indicator will be derived based on the following 
individual categories defined above: death, adverse event, hospitalization, study drug 
discontinuation, study discontinuation, missed visits, and missed key assessments. Composite 
specific COVID-19 impact indicator will be derived based on death and specific adverse event.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic variables (ie, age, sex, race, and ethnicity) and baseline characteristics 
(body weight [in kg], height [in cm], body mass index [BMI; in kg/m2]) will be displayed by 
cohort and study overall using descriptive statistics for continuous variables and using number 
and percentage of participants for categorical variables. Within Cohort 2, the summary will be 
presented by treatment group (Group A or Group B) and HBsAg category (HBsAg > 3 and 
≤ 3 log10 IU/mL). The summary of demographic data will be provided for the Safety Analysis 
Set. 
A by-participant demographic listing, including the informed consent date, and stratification 
group (for Cohort 2 only), will be provided by cohort (and by treatment group for Cohort 2), and 
participant ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include: 
•
HBsAg (log10 IU/mL) as a continuous variable
•
HBsAg (log10 IU/mL) as categories (< 2, 2 to < 3, 3 to < 4, ≥ 4)
•
HBV DNA (log10 IU/mL) as a continuous variable
•
HBV DNA (log10 IU/mL) as categories (< LLOQ, LLOQ to < 3.3, 3.3 to < 4.3, ≥ 4.3)
•
HBeAg/HBeAb status (negative, positive)
•
HBV genotype 
•
ALT (U/L) as a continuous variable 
•
ALT level as categories based on central laboratory normal range (≤ upper limit of normal 
[ULN], > ULN to 5 × ULN, > 5 × ULN to 10 × ULN, > 10 × ULN) 
•
FibroTest Score as a continuous variable 
•
Fibrosis Stage by FibroTest Score as categories (0.00 to 0.48, 0.49 to 0.74, 0.75 to 1.00) 
•
APRI (≤ 1, > 1) 
•
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•
Previous interferon experience to treat HBV (yes, no) 
•
Duration of being HBV positive (in years) as a continuous variable
•
Mode of HBV infection 
•
Estimated glomerular filtration rate using the Cockcroft-Gault equation (eGFRCG) (mL/min), 
which will be calculated as follows: 
eGFRCG (mL/min) = [(140 – age [years]) × weight (kg) × (0.85 if female)] / (serum 
creatinine [mg/dL] × 72), where weight is actual body weight in kilograms 
These baseline characteristics will be summarized by cohort and study overall using descriptive 
statistics for continuous variables and using number and percentage of participants for 
categorical variables. Within Cohort 2, the summary will be presented by treatment group 
(Group A or Group B) and HBsAg category (HBsAg > 3 and ≤ 3 log10 IU/mL). The summary of 
these baseline characteristics will be provided for the Safety Analysis Set. No formal statistical 
testing is planned.
A by-participant listing of other baseline characteristics, including HBsAg category for Cohort 2, 
will be provided by cohort (and by treatment group for Cohort 2), and participant ID number in 
ascending order.
5.3.
Medical History
General medical history data will be collected at screening and listed only. 


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definitions of Primary Efficacy Endpoint
The primary efficacy endpoint of this study is defined as the proportion of participants who 
achieve functional cure, defined as HBsAg loss and HBV DNA < LLOQ at FU Week 24. 
6.1.2.
Statistical Hypothesis for Primary Efficacy Endpoint
No statistical hypothesis testing will be performed. 
6.1.3.
Analysis of Primary Efficacy Endpoint
The primary efficacy analysis will be performed for the FAS after the last participant has 
completed FU Week 24 assessments or prematurely discontinued study drug. 
Analysis for Cohort 1: 
The point estimates and the 2-sided 95% exact confidence interval (CI) of the primary efficacy 
endpoint will be provided. The CIs of the proportion point estimates will be constructed based on 
the Clopper-Pearson method {Clopper 1934}. 
Analysis for Cohort 2: 
To compare Group A and Group B for HBsAg categories(> 3 and ≤ 3 log10 IU/mL) separately, 
point estimates and the 2-sided 95% exact confidence intervals (CIs) of the primary efficacy 
endpoint will be provided based on the Clopper-Pearson method {Clopper 1934} by HBsAg 
status and overall for each treatment group. 
In addition, point estimates and the 2-sided 95% exact CIs of the proportion difference between 
Group A and Group B will be displayed separately by HBsAg category for each treatment group. 
CIs for the proportion differences will be constructed based on the standardized statistic and 
inverting two 1-sided tests {Chan 1999}. 
To compare Group A and Group B for pooled HBsAg > 3 and ≤ 3 log10 IU/mL participants, the 
proportion differences and the corresponding 95% CIs will be calculated using the 
stratum-adjusted Mantel-Haenszel (MH) method {Koch 1989}, stratified by HBsAg 
category(> 3 and ≤ 3 log10 IU/mL), as follows: 
𝑃1 ― 𝑃2 ± 𝑍(1―𝛼/2) × 𝑆𝐸(𝑃1 ― 𝑃2)


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where 
•
(P1 ― P2) =
∑whdh
∑wh  is the stratum-adjusted MH proportion difference, where dh = P1h ― P1h 
is the proportion difference of group 1 and group 2 in stratum h (h = 1 and 2). 
•
wh =
n1hn2h
n1h + n2h is the weight based on the harmonic mean of sample size for stratum h, where 
n1h and n2h are the sample sizes of groups 1 and 2 in stratum h. 
•
SE(P1 ― P2) =
∑w2h
p1h(1 ― p∗1h)
n1h ― 1
+ p∗2h(1 ― p∗2 )
n2h ― 1
(∑wh2)
, where p∗
1h =
m1h + 0.5
n1h + 1  and p∗
2h =
m2h + 0.5
n2h + 1 , and 
m1h and m2h are the number of participants who achieve the primary efficacy endpoint in 
groups 1 and 2 respectively in stratum h. 
•
Groups 1 and 2 (in the equations above) represent Group A and Group B from Cohort 2 
respectively. 
•
α = 0.05 for this study. 
•
Z(1-α/2) = Z0.975 = 1.96 is the 97.5th percentile of the normal distribution.
If the computed lower confidence bound is less than –1, the lower bound is defined as –1. If the 
computed upper confidence bound is greater than 1, then the upper bound is defined as 1. 
6.1.4.
Subgroup Analysis of Primary Efficacy Endpoint
No subgroup analyses will be performed. 
6.2.
Secondary Efficacy Endpoints 
6.2.1.
Definitions of Secondary Efficacy Endpoints 
•
The proportion of participants with HBsAg loss with and without anti-HBsAg 
seroconversion during the study 
•
The proportion of participants with HBeAg loss with and without anti-HBeAg 
seroconversion during the study in participants with CHB who are HBeAg positive at 
baseline 
•
The proportion of participants who remain off NUC treatment during FU 
•
The proportion of participants experiencing HBV virologic breakthrough (defined as 
confirmed HBV DNA ≥ LLOQ after 2 consecutive HBV DNA < LLOQ in participants who 
are complying with NUC therapy OR confirmed HBV DNA ≥ 1 log10 IU/mL increase from 
nadir on treatment) during study treatment(s) 
J [--] 


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6.2.2.
Analysis Methods for Secondary Efficacy Endpoints 
The secondary efficacy analyses will be performed on FAS. 
•
The proportions of participants with HBsAg loss with and without anti-HBsAg 
seroconversion will be summarized by cohort and visit. 
•
The proportion of participants with HBeAg loss with and without anti-HBeAg 
seroconversion will be summarized by cohort and visit for participants who are HBeAg 
positive at baseline. 
•
The proportion of participants who remain off NUC treatment during FU will be summarized 
by cohort and FU visit.
Data collected on Visit Date CRF will be used to identify participants who entered FU phase. If a 
participant had any follow-up visit with nonmissing visit date, then this participant will be 
considered as entered FU phase. 
For participants who entered the FU phase, if NUC treatment was ended no later than FU 
Week 1 visit, and there is no NUC treatment re-initiation during the FU phase, then this 
participant is considered as remaining off NUC treatment during FU phase. If partial start/stop 
dates are entered, any NUC treatment with the month and year (if day is missing) or year (if day 
and month are missing) of either start or stop date after FU Week 1 will be considered as using 
NUC treatments. Participants with completely missing NUC treatment start and stop dates will 
be considered as using NUC treatments, unless otherwise specified.
A list of NUC treatments can be found in Appendix 3.
•
The proportion of participants experiencing HBV virologic breakthrough during study 
treatment(s) will be summarized by cohort. 
The HBV virologic breakthrough is defined as confirmed HBV DNA ≥ LLOQ after 
2 consecutive HBV DNA < LLOQ in participants who are complying with NUC therapy OR 
confirmed HBV DNA ≥ 1 log10 IU/mL increase from nadir during study treatments.
In addition, a summary table will be provided for HBsAg-related serology results. The 
proportion of participants who have ever had HBsAg loss, confirmed HBsAg loss, on-treatment 
HBsAg loss, posttreatment HBsAg loss (for participants with positive HBsAg at the end of the 
on-treatment period), HBsAg loss with HBsAb seroconversion, HBsAg loss with HBsAb 
seroreversion, and HBsAg loss reversion with or without HBsAb seroconversion will be 
summarized.
For all the above summaries, within Cohort 2, the summary will be presented by treatment group 
(Group A or Group B) and HBsAg category (HBsAg > 3 and ≤ 3 log10 IU/mL).


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HBV serology definitions:
•
HBsAg loss: HBsAg changing from positive at baseline to negative at any postbaseline visit.
•
Confirmed HBsAg loss: HBsAg loss confirmed by any 2 consecutive results.
•
HBsAg loss reversion: Any postbaseline HBsAg positive result following HBsAg loss.
•
HBsAb seroconversion: HBsAb changing from negative or missing at baseline to positive at 
any postbaseline visit.
•
Confirmed HBsAb seroconversion: HBsAb changing from negative or missing at baseline 
to positive at any postbaseline visit confirmed by any 2 consecutive results.
•
HBsAb seroreversion: Any postbaseline HBsAb negative result following HBsAb 
seroconversion.
Both baseline and postbaseline borderline results for HBeAg, HBeAb, HBsAg, and HBsAb will 
be imputed as follows:
•
HBsAb/HBeAb borderline/equivocal  HBsAb/HBeAb negative
•
HBsAg/HBeAg borderline/equivocal  HBsAg/HBeAg positive
Missing data will be treated as a nonevent unless otherwise specified (eg, no HBsAg loss, no 
seroconversion, etc.) 
HBeAg-related terminology is defined similarly.
CCI
CCI


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Adverse events (AEs) will be coded using the current version of the MedDRA. 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 toxicity criteria 
specified by Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
Version 01 April 2015, with the exception of infusion-related reactions (IRRs). For grading of 
IRRs, the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 are used.
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" in the eCRF in response to 
the question for the relatedness to each study treatment, ie, SLGN, TAF, nivolumab, or 
VIR-2218. 
Relatedness will always default to the investigator’s choice, not that of the medical monitor. 
Events for which the investigator did not record relationship to study drug will be considered 
related to study drug for summary purposes. However, by-participant data listings will show the 
relationship as missing. 
7.1.4.
Relationship of Adverse Events to Study Procedures
Study procedure related AEs are those for which the investigator selected “Yes” on the AE case 
report form (CRF) to the question of “Related to Study Procedures.” Relatedness will always 
default to the investigator’s choice, not that of the medical monitor. Events for which the 
investigator did not record relationships to study procedure will be considered related to study 
procedure for summary purposes. However, by-participant data listings will show the 
relationship as missing. 
7.1.5.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with SAEs on the Gilead global safety database before data 
finalization.


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7.1.6.
Treatment-Emergent (TE) Adverse Events (AEs), Non-TEAEs, and AEs 
Through FU Week 24
7.1.6.1.
Definition of TEAEs
TEAEs are defined as 1 or both of the following:
•
Any AEs with an onset date on or after the start date of any study drug and on or before the 
composite last on-treatment date + 30 days after permanent discontinuation of study drug
•
Any AEs leading to premature discontinuation of any study drug 
7.1.6.2.
Definition of Non-TEAEs
Non-TEAEs are defined as defined as any AEs with an onset date after the composite last 
on-treatment date + 30 days after permanent discontinuation of study drug through the end of the 
study. 
7.1.6.3.
Definition of AEs through FU Week 24
AEs through FU Week 24 are defined as any AEs with an onset date on or after the start date of 
any study drug and on or before the composite last on-treatment date + 24 weeks after permanent 
discontinuation of study drug. 
Definitions of the composite last on-treatment date for each cohort can be found in Section 3.8.2.
7.1.6.4.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of any study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. 
The event is considered as TE if both of the following 2 criteria are met:
•
The AE onset is the same as or after the month and year (or year) of the first dosing date of 
any study drug, and
•
The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to the cutoff day in Section 7.1.6.1. 
The event is considered as non-TE if the AE onset date is after the month and year (or year) of 
the date corresponding to the cutoff day in Section 7.1.6.2. 
The event is considered as AEs through FU Week 24 if both of the following 2 criteria are met:
•
The AE onset is the same as or after the month and year (or year) of the first dosing date of 
any study drug, and 
•
The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to the cutoff day in Section 7.1.6.3.


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7.1.7.
Summaries of Adverse Events and Deaths
7.1.7.1.
Summaries of TEAEs 
TEAEs will be summarized based on the Safety Analysis Set. 
The analysis in this section regarding treatment-related TEAEs will be study drug specific 
(ie, SLGN, nivolumab, or VIR-2218) in the summaries.
A brief, high-level summary of the number and percentage of participants who experienced the 
following will be provided for each cohort: any TEAE, any TEAE of Grade 3 or above, any 
TEAE of Grade 2 or above, any treatment-related TEAE, any treatment-related TEAE of Grade 3 
or above, any treatment-related TEAE of Grade 2 or above, any TE SAE, any treatment-related 
TE SAE, any potential immune-related AEs (irAEs), any potential uveitis, any AE leading to 
premature discontinuation of any study drug, any AE leading to temporary interruption of any 
study drug. All deaths (including those that are treatment-emergent and those that are not 
treatment-emergent) observed in the study will also be included in this summary. Within 
Cohort 2, the summary will be presented by treatment group (Group A or Group B). 
Adverse event summaries with the number and percentage of participants who experienced at 
least 1 TEAE will be provided and summarized by SOC and PT for each cohort, and within 
Cohort 2, the summary will be presented by treatment group (Group A or Group B), as follows: 
•
TEAEs
•
TEAEs with Grade 3 or higher 
•
TE treatment-related AEs
•
TE treatment-related AEs with Grade 3 or higher 
•
TE SAEs
•
TE treatment-related SAEs 
•
TEAEs leading to premature discontinuation of any study drug
•
TEAEs leading to temporary interruption of any study drug 
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC, and then by PT in descending order of 
total frequency within each SOC. 
A summary by SOC and PT by severity grade will be provided for TEAEs, TEAEs with Grade 3 
or higher, and TEAEs related to study drug(s), and the most severe grade will be used for those 
TEAEs that occurred more than once in an individual participant during the study. 


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TEAEs, TEAEs with Grade 3 or higher, TEAEs with Grade 2 or higher, TE SAEs, TE 
treatment-related AEs, TE treatment-related AEs with Grade 3 or higher, TE treatment-related 
AEs with Grade 2 or higher, and TE treatment-related SAEs will be summarized by PT only, in 
descending order of total frequency. 
7.1.7.2.
Summaries of Non-TEAEs 
A brief, high-level summary will be provided for non-TEAEs. 
•
Non-TEAEs
•
Non-TEAEs with Grade 3 or higher 
•
Non-TE SAEs
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC, and then by PT in descending order of 
total frequency within each SOC. 
7.1.7.3.
Summaries of AEs Through FU Week 24
A brief, high-level summary will be provided for AEs through FU Week 24. 
In addition, AEs through FU Week 24 for the following summaries will be provided: 
•
AEs through FU Week 24
•
AEs with Grade 3 or higher through FU Week 24 
•
SAEs through FU Week 24 
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC, and then by PT in descending order of 
total frequency within each SOC. 
7.1.7.4.
Listings of AEs and Deaths
Data listings will be provided for the following:
•
All AEs
•
All Non-TEAEs 
•
All AEs with Grade 3 or higher
•
All SAEs
•
All Deaths
•
All AEs leading to premature discontinuation of any study drug
•
All AEs leading to temporary interruption of any study drug


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7.1.8.
Additional Analysis of Adverse Events – Potential irAEs
Potential irAEs will be analyzed based on a broad (all PTs) search from MedDRA SMQs of 
Hypersensitivity and Immune-mediated/Autoimmune Disorders.
The number and percentage of participants who experienced any of the above events will be 
summarized by PT and treatment group for 1) TE potential irAE events, 1) non-TE potential 
irAE events, and 3) potential irAE events through FU Week 24. 
A by-participant listing of identified potential events will be provided. 
7.1.9.
Additional Analysis of Adverse Events – Potential Uveitis
A predefined MedDRA Search Terms (MST) list consisting of ocular PTs reviewed by an 
external ophthalmologist and maintained by Patient Safety through MedDRA upversioning for 
safety monitoring of uveitis in clinical trials will be used for this analysis. 
The number and percentage of participants who experienced potential uveitis will be summarized 
by PT and cohort, and by treatment group within Cohort 2 for 1) TE potential uveitis events, 
2) non-TE potential uveitis events, and 3) potential uveitis events through FU Week 24. 
A by-participant listing of identified potential events will be provided.
The analysis for potential uveitis will be performed for Final Analysis only. 
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. The analysis will be based on values reported in 
conventional units. When values are below the LOQ, they will be listed as such, and the closest 
imputed value will be used for the purpose of calculating summary statistics as specified in 
Section 3.7.
A by-participant listing for laboratory test results will be provided by cohort (and treatment 
group for Cohort 2), participant ID number and visit in chronological order. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities Version 
April 1, 2015 (or CTCAE Version 5.0 severity grade for infusion-related AEs) will be flagged in 
the data listings, as appropriate.
No formal statistical testing is planned.


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7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
for each cohort (and for each treatment group for Cohort 2) for chemistry (including alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, alkaline phosphatase 
[ALP], creatine kinase [CK], fasting total cholesterol, fasting glucose, international normalized 
ratio [INR], lactate dehydrogenase [LDH]), creatinine, and eGFRCG as follows:
•
Baseline values 
•
Values at each postbaseline visit
•
Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date of first dose of any study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
Median (Q1, Q3) of the observed values for ALT will be plotted using a line plot by treatment 
group and visit. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
Version April 1, 2015, will be used to assign toxicity grades to laboratory results for analysis. 
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. 
7.2.2.1.
Treatment-Emergent (TE) Laboratory Abnormalities
TE 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 composite last on-treatment date 
plus 30 days. 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. 
7.2.2.2.
Non-TE Laboratory Abnormalities
Non-TE laboratory abnormalities are defined as values that increase at least 1 toxicity grade from 
the last TE laboratory abnormality after the composite last on-treatment date plus 30 days. If  the 
relevant TE laboratory abnormality for a participant is missing, any abnormality of at least 
Grade 1 observed after the composite last on-treatment date plus 30 days until the end of the 
study will be consider as non-TE.


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7.2.2.3.
Laboratory Abnormalities Through FU Week 24
Laboratory abnormalities through FU Week 24 are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the composite 
last on-treatment date plus 24 weeks. 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 as within FU Week 24.
Definitions of the composite last on-treatment date for each cohort can be found in Section 3.8.2. 
7.2.2.4.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
participants in the study with the given response at baseline and each scheduled postbaseline 
visit.
The following summaries (number and percentage of participants) will be provided by lab test 
and cohort; within cohort 2, the summary will be presented by treatment group (Group A or 
Group B). Participants will be categorized according to the most severe postbaseline abnormality 
grade for a given lab test:
•
Graded laboratory abnormalities
•
Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with nonmissing postbaseline values.
The above summaries will be provided for 1) TE laboratory abnormalities, 2) non-TE laboratory 
abnormalities, and 3) laboratory abnormalities through FU W24. 
By-participant listings of all laboratory abnormalities, and Grade 3 or 4 laboratory abnormalities 
will be provided by cohort, participant ID number and visit in chronological order. The listings 
will include all test results that were collected throughout the study for the lab test of interest, 
with all applicable severity grades or abnormal flags displayed.
7.2.3.
Liver-related Laboratory Evaluations
The following liver-related laboratory abnormalities will be summarized using the number and 
percentage of participants for any postbaseline measurements as follows:
•
Confirmed ALT flare: ALT > 2 × baseline and ≥ 5 × ULN 
•
Confirmed ALT elevation: ≥ 10 × ULN


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•
Confirmed ALT elevation with evidence of hepatic toxicity: ALT > 2 × nadir and one of the 
following confirmed laboratory abnormalities: 
Total bilirubin > 2 × ULN 
Elevated INR > 0.5 above baseline and > ULN 
Abnormal serum ALB > 1 g/dL decrease from baseline 
Central Lab ULNs will be used for all liver-related laboratory evaluations. 
For individual laboratory tests, participants will be counted once based on the most severe 
postbaseline values during the analysis period. For the composite criteria of ALT and total 
bilirubin, INR or ALB, participants will be counted once when the criteria are met at the same 
postbaseline visit date. The denominator is the number of participants in the Safety Analysis Set 
who have nonmissing postbaseline values of all relevant tests at the same postbaseline visit date. 
ALT flare and confirmed ALT elevations will be summarized by cohort; within Cohort 2, the 
summary will be presented by treatment group (Group A or Group B). 
The above summaries will be provided for 1) TE laboratory abnormalities, 2) non-TE laboratory 
abnormalities; 3) laboratory abnormalities through FU Week 24.
Listings of participants who met at least 1 of the above criteria for ALT flares and elevations will 
be provided. For the listings of ALT flares and elevations, AST (U/L), ALB (g/dL), total 
bilirubin (mg/dL), INR, HBsAg (log10 IU/mL) and HBV DNA (log10 IU/mL) will also be 
provided. 
7.3.
Body Weight, Height, and Vital Signs
Descriptive statistics will be provided by cohort (and by treatment group for Cohort 2) for body 
weight, height, BMI, and vital signs as follows:
•
Baseline value
•
Values at each postbaseline visit
•
Change from baseline at each postbaseline visit 
A baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value. Body weight and vital signs measured at 
unscheduled visits will be included for the baseline value selection.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.


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A by-participant listing of vital signs will be provided by participant ID number and visit in 
chronological order. Body weight, height, and BMI will be included in the vital signs listing if 
space permits. If not, they will be provided separately.
7.4.
Prior HBV and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary. 
7.4.1.
Prior HBV Medications
Prior HBV medications are defined as any medications taken before a participant took any of the 
study drugs. 
Prior HBV medications will be summarized by preferred name using the number and percentage 
of participants by cohort (and by treatment group for Cohort 2). A participant reporting the same 
medication more than once will be counted only once when calculating the number and 
percentage of participants who received that medication. The summary will be ordered by 
preferred term in order of descending overall frequency. For drugs with the same frequency, 
sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing 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 
dosing date. Medications 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. No formal statistical testing is planned.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a participant took study drug. 
Use of concomitant medications will be summarized by preferred name using the number and 
percentage of participants for each treatment group. A participant reporting the same medication 
more than once will be counted only once when calculating the number and percentage of 
participants who received that medication. The summary will be ordered by preferred term in 
descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken after the first dosing date or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date, or the last 
dosing date of study drug will also be considered concomitant. Medications with a stop date prior 
to the date of first dosing date of study drug or a start date after the last dosing date of study drug 
will be excluded from the concomitant medication summary. If a partial stop date is entered, any 


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medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. 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) after the study drug stop date will be 
excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary, unless otherwise 
specified. Summaries will be based on the Safety Analysis Set. No formal statistical testing is 
planned.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-participant listing sorted by participant ID number and administration date in chronological 
order.
7.5.
Electrocardiogram Results
Electrocardiogram (ECG) analysis results are intended to identify meaningful abnormalities. If 
potential abnormalities of interest are identified, further analyses may be conducted. 
A shift table of the investigators’ assessment of ECG results at Weeks 12 and 36 for Cohort 1 
and Cohort 2 Group A, or Weeks 12 and 24 for Cohort 2 Group B compared with baseline values 
will be presented by cohort (and by treatment group for Cohort 2) using the following categories: 
normal; abnormal, not clinically significant; abnormal, clinically significant; or missing. The 
number and percentage of participants in each cross-classification group of the shift table will be 
presented. Participants with a missing value at baseline or postbaseline will not be included in 
the denominator for percentage calculation. No formal statistical testing is planned.
A by-participant listing for ECG assessment results will be provided by participant ID number 
and visit in chronological order.
7.6.
Other Safety Measures
For Cohort 1 and Cohort 2 Group A, ophthalmic examinations will be performed at Screening, 
Week 24, and Week 36. For Cohort 2 Group B, ophthalmic examinations will be performed at 
Screening, Week 12, and Week 24. 
A shift table of the overall assessment of ophthalmology results at each visit compared with 
baseline values will be presented for each cohort (and for each treatment group for Cohort 2) 
using the following categories: normal; abnormal, not clinically significant; abnormal, clinically 
significant; or missing/unknown. The number and percentage of participants in each 
cross-classification group of the shift table will be presented. Participants with a missing value at 
baseline or postbaseline will not be included in the denominator for percentage calculation. No 
formal statistical testing is planned. 
By-participant listings for ophthalmology assessment results will be provided by participant 
ID number and visit in chronological order. 


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8. 
PHARMACOKINETIC (PK) ANALYSES 
Only SLGN PK Analysis will be perfo1med for this study. 
8.1. 
PK Sample Collection 
Version 1.0 
For Cohort 1 and Coho1i 2 Group A, sparse (timed) blood PK samples will be obtained at 
Baseline/Day I (predose and postdose), Weeks 12 and 20 at any time between 1 to 5 hours 
postdose relative to SLGN administration unless othe1w ise indicated. 
For Coho1i 2 Group B, sparse (timed) blood PK samples will be obtained at Baseline/Day 1, 
Weeks 12 and 20 at any time between 1 to 5 hours postdose relative to SLGN administration 
unless othe1w ise indicated. 
I 
8.2. 
8.2.1. 
PK Analyses Related to Intensive PK Sampling 
Estimation of PK Parameters 
PK parameters will be estimated using Phoenix WinNonlin® software using standard 
noncompaiimental method. The lineai· up/log down rnle will be used in conjunction with the 
appropriate noncompa1imental model, with input values for dose level, dosing time, plasma 
concentration, and conesponding real-time values, based on drng dosing times whenever 
possible. 
All predose sample times before time-zero will be conve1i ed to 0. 
For ai·ea under the curve (AUC), samples BLQ of the bioanalytical assays occmTing prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of O to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
treated as missing data in WinNonlin. The nominal time point for a key event or dosing interval 
('t) may be used to pe1mit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis. 
Phaimacokinetic pai·ameters such as AUC1au, Az and t112 ai·e dependent on an accurate estimation 
of the te1minal elimination phase of drng. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist. 
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8.2.2.
PK Parameters
PK parameters will be generated for all participants for whom parameters can be derived. The 
analyte presented in Table 8-1 will be evaluated if data are available
Table 8-1.
Study Treatments and Associated Analyte
Treatment Group
Analyte
Cohort 1, Cohort 2 Group A, and Cohort 2 Group B
SLGN
The analyte and parameters presented in Table 8-2 will be used to evaluate the PK objectives of 
the study. The PK parameters to be estimated in this study are listed and defined in the PK 
Abbreviations section.
Table 8-2.
PK Parameters for Each Analyte
Analyte
Parameters
SLGN
AUClast, AUC0-24, AUCinf, %AUCexp, Cmax, Tmax, Clast, 
Tlast, λz, CL/F, and t1/2, as appropriate
Individual participant concentration data and individual participant PK parameters, as 
appropriate, for SLGN will be listed and summarized using descriptive statistics by cohort (and 
by treatment group for Cohort 2). Summary statistics (number of participants, mean, SD, 
coefficient of variation [%CV], median, min, max, Q1, and Q3) will be presented for both 
individual participant concentration data by time point and individual participant PK parameters 
by cohort (and by treatment group for Cohort 2). Moreover, the geometric mean, 95% CI, 
%Geometric CV [%GCV], and the mean and SD of the natural log-transformed values will be 
presented for individual participant PK parameter data. 
Individual concentration data listings and summaries will include all participants with 
concentration data. The sample size for each time point will be based on the number of 
participants with nonmissing concentration data at that time point. The number of participants 
with concentration BLQ, as well as an indicator if more than one-third of the participants are 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
zero at predose and postdose time points. If more than one-third of the values at a postdose time 
point are BLQ then the mean and SD will not be presented at that time point. Concentration 
values will be presented as received from the bioanalytical lab and summary statistics will be 
presented to three significant digits.
Individual PK parameter data listings and summaries will include all participants for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of participants with nonmissing data for that PK parameter. Data and summary statistics will be 
presented to three significant digits.


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The following tables will be provided by cohort (and by treatment group for Cohort 2):
•
Individual participant concentration data and summary statistics
•
Individual participant plasma PK parameters and summary statistics
The following figures may be provided by cohort (and by treatment group for Cohort 2):
•
Individual participant concentration data versus time (on linear and semilogarithmic scales). 
Values of BLQ will be displayed as 0 on the linear scale and missing on the semi-logarithmic 
scale.
•
Mean (± SD) concentration data versus time (on linear and semilogarithmic scales). If more 
than one-third of the values at a postdose time point are BLQ then the mean and SD will not 
be presented at that time point and remaining points connected. If lower error bar (mean-SD) 
is < 0 at a timepoint then it will not be presented at that timepoint.
•
Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales). If 
more than one-half of the values at a timepoint are BLQ then the median and quartile values 
will not be presented at that timepoint, and remaining points connected. If lower error bar 
(Q1) is BLQ at a timepoint then it will be presented as lower LOQ at that timepoint.
The following listings will be provided:
•
PK sampling details by participant, including procedures, differences in scheduled and actual 
draw times, and sample age from the combined intensive and sparse PK samples.
•
Individual data on determination of plasma half-life and corresponding regression correlation 
coefficient
8.3.
PK Analyses Related to Sparse PK Sampling
For PK Analysis Set, sparse (timed) PK data will be summarized by visit and time point, if 
appropriate. Individual participant concentration data will be listed and summarized using 
descriptive statistics by cohort. Summary statistics (n, mean, SD, percent coefficient of variation 
[%CV], median, min, max, Q1, and Q3) will be presented for individual participant 
concentration data by visit and by cohort (and by treatment group for Cohort 2).
Individual concentration data listings and summaries will include all participants with 
concentration data. The sample size for each visit will be based on the number of participants 
with nonmissing concentration data at that time point. The number of participants with 
concentration BLQ will be presented for each time point. For summary statistics, BLQ values 
will be treated as 0 at predose and postdose time points. 


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The following tables will be provided for SLGN by cohort (and by treatment group for 
Cohort 2): 
•
Individual participant concentration data and summary statistics 
The following listing will be provided for SLGN: 
PK sampling details by participant (using concentration data from all sparse and intensive 
plasma PK sampling), including procedures, differences in scheduled and actual draw times, and 
sample age.
8.4.
Changes From Protocol-Specified PK Analyses
For summary statistics, PK concentration values below the limit of quantitation will be treated as 
zero at predose and postdose time points, rather than being treated as zero at predose and 
one-half of the LLOQ for postdose time points. 


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9.
REFERENCES
Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
proportions. Biometrics 1999;55 (4):1202-9.
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Biometrika 1934;26 (4):404-13.
Cohen C., Block J., Ibrahim Y. The Voice of the Patient: Living with Chronic Hepatitis B.  
Hepatitis B Foundation: 2020:55. 
Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data Analysis. Chapter 13 in 
Berry, D.A. (ed.).  Statistical Methodology in the Pharmaceutical Sciences. New 
York: Marcel Dekker, Inc., 1989:pp. 414-21. 


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10.
SOFTWARE
SAS® Software Version 9.X. SAS Institute Inc., Cary, NC, USA.


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES


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Appendix 1.
Schedule of Assessments
Appendix Table 1.
Study Procedures Table for NUC-Suppressed Cohort 1 
Treatment Cycles Week (± 2 days) a
EOT
(−5 days)
Follow-up Weeksb
Screening 
(45 days)
Baseline 
Day 1
4
8
12
13c
14
16
20
24
28
32
36/EOT
EDd
1c
4
8c
12
16c
24
36
48
Written Informed 
Consente
X
Review of 
Inclusion/Exclusion 
Criteria
X
Medical History
X
AEs & Concomitant 
Medicationsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical 
Examination
X
X
X
X
X
Symptom-directed 
physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGg
X
X
X
X
X
X
Chest x-ray
X
Xh
Ophthalmologic 
examinationi
X
X
X
Xh
Symptom-directed 
ophthalmologic 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory 
tests (hematology & 
chemistry; 
coagulation)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
APRI
X
X
X
X
X
X
X


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Treatment Cycles Week (± 2 days) a
EOT
(−5 days)
Follow-up Weeksb
Screening 
(45 days)
Baseline 
Day 1
4
8
12
13c
14
16
20
24
28
32
36/EOT
EDd
1c
4
8c
12
16c
24
36
48
FibroTest
X
X
X
X
X
X
X
FibroScanj
X
α-fetoprotein (HCC 
imaging [eg, CT 
scan] is required for 
participants with
α-fetoprotein
≥ 50 ng/mL at
screening)
X
Serology testing to 
exclude HCV, HDV, 
and HIV infectionk
X
Quantitative plasma 
HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum sample for 
HBV viral 
sequencing 
(resistance 
surveillance) and 
ddPCR
X
Serum sample for 
HBV viral 
sequencing 
(resistance 
surveillance) and 
genotyping sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quantitative HBV 
Serum HBsAg, 
HBcrAg, HBeAg, 
and HBV RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Qualitative HBV 
serology HBeAg, 
HBeAb, and HBsAg, 
HBsAb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Treatment Cycles Week (± 2 days) a
EOT
(−5 days)
Follow-up Weeksb
Screening 
(45 days)
Baseline 
Day 1
4
8
12
13c
14
16
20
24
28
32
36/EOT
EDd
1c
4
8c
12
16c
24
36
48
Biomarker Samples: 
Collection of PBMC, 
whole blood, serum, 
and plasma samples 
for biomarker 
analysisl, m
X
Xl
X
Xm
X
Sparse PK for 
VIR-2218n
X
X
X
Sparse PK for 
SLGNn
X
X
X
Estimated creatinine 
clearance (using the 
Cockcroft-Gault 
method)
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug and 
Alcohol Screen
X
Autoantibodies
X
TSH
X
X
X
X
FSHo
X
Serum Pregnancy 
Testp
X
X
Urine Pregnancy 
Testp
X
X
X
X
X
X
X
X
X
X
X
Xp
X
Xp
X
X
X
Enrollment
X
Dispense and 
Administer TAF as 
appropriate
Tenofovir alafenamide (TAF) 25-mg tablet administered orally daily for up to 84 weeks


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Treatment Cycles Week (± 2 days) a
EOT
(−5 days)
Follow-up Weeksb
Screening 
(45 days)
Baseline 
Day 1
4
8
12
13c
14
16
20
24
28
32
36/EOT
EDd
1c
4
8c
12
16c
24
36
48
Dispense & 
Administer 
VIR-2218 SC as 
appropriate
X
X
X
X
X
X
Dispense & 
Administer SLGNq 
as appropriate
X
X
X
X
X
X
X
X
Study Drug 
Accountability
X
X
X
X
X
X
X
X
X
X
AE = adverse event; APRI = AST to Platelet Ratio Index; CT = computed tomography; ddPCR = digital droplet polymerase chain reaction; ECG = electrocardiogram; ED = early 
discontinuation; EOT = end of treatment; FSH = follicle-stimulating hormone; FU = follow-up; HBcrAg = hepatitis B core-related antigen; HBeAb = hepatitis B e antibody; 
HBeAg = hepatitis B e antigen; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; 
HCV = hepatitis C virus; HDV = hepatitis D virus;
IV = intravenous; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetic; SAE = serious adverse event; SC = subcutaneous; SLGN = selgantolimod; TAF = tenofovir 
alafenamide;
TSH = thyroid-stimulating hormone
a
All study visits except for Weeks 13 and 14.
b
FU Week 1 will have a visit window of + 3 days, FU Weeks 4 through FU Week 16 will have a visit window of ± 5 days, and FU Weeks 24 through FU Week 48 will have a 
visit window of ± 14 days.
c
Week 13, FU Week 1, FU Week 8, and FU Week 16 will be conducted as a virtual/telephonic visit to review AEs, concomitant medications, and overall health of the 
participant by investigator.
d
The ED visit should be performed within 14 days from notification of study discontinuation. If ED is done in FU period, all of these procedures should be performed.
f
Record any SAEs and all AEs related to protocol-mandated procedures occurring after signing of the informed consent form. After drug administration, report all AEs and 
SAEs.
g
Participants must rest quietly in the supine position for a minimum of 5 minutes prior to the recording.
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h
At ED visit, these procedures are optional and to be done as needed.
i
Ophthalmologic examination at screening should be performed during the screening window, ie, within 45 days of randomization. Ophthalmologic examinations post-Day 1 
should occur within −4
j
to +10 days of visit.
k
FibroScan testing where applicable for liver disease staging.
l
In the event of a positive result for serology and/or antigen testing for HIV, HDV, or HCV, reflex tests will be performed as necessary.
m
Collect pre-SLGN dose administration on Week 12, 4 hours and 24-72 hours postdose.
n
Collect pre-SLGN dose administration on Week 32, 4 hours, and 24-72 hours postdose.
o
The sparse PK collection for VIR-2218 at baseline/Day 1 should occur predose and postdose. Postdose sparse PK collection should occur any time between 1 and 5 hours 
postdose relative to VIR-2218, and/or SLGN administration.
p
FSH test is required for female participants who are < 54 years old who are not on hormonal contraception and who have stopped menstruating for ≥ 12 months but do not 
have documentation of
q
ovarian hormonal failure.
s
SLGN tablets will be administered while fasting once a week, on the same day.
u
Intensive PK sample to be drawn at any one visit at Week 20, 24, 28 or 32 relative to SLGN dosing in clinic on the morning of the intensive PK visit. Collection will occur at 
predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12 and 24 hours postdose 
 
v
Intensive PK sample to be drawn on Baseline/Day 1 and at Week 20 relative to VIR-2218 dosing in clinic on the morning of the intensive PK visit. Collection will occur at 
predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12 and 24 hours postdose 
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Appendix Table 2.
Study Procedures Table for NUC-Suppressed Cohort 2 
Treatment Cycles Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeks b
Cohort 2 
Group B
only
Cohort 2
Group A only
Screening
(45 days)
BL
Day 1
1c
2d
4
8
12
13c
14
16
20
24
28
32
24
(Cohort 2
Group B)
/ 36
(Cohort 2
Group A)
EDe
1
b,c
4
8c
12
16
24
36
48
Written Informed 
consentf
X
Review of 
Inclusion/ 
Exclusion Criteria
X
Medical History
X
AEs & 
Concomitant 
Medicationsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical 
Examination
X
X
X
X
X
Symptom- directed 
physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
(Cohort 2
Group B)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Body weight
X
X
X
(Cohort 2
Group B)
X
(Cohort 2
Group B)
X
X
X
X
X
X
X
X
X
12-lead ECGh
X
X
X
X
X
X
Chest x-ray
X
X
i
Ophthalmologic
examinationj
X
X
(Cohort 2
Group B)
X
X
X
i
Symptom-directed 
ophthalmologic 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X


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GS-US-465-4439
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Treatment Cycles Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeks b
Cohort 2 
Group B
only
Cohort 2
Group A only
Screening
(45 days)
BL
Day 1
1c
2d
4
8
12
13c
14
16
20
24
28
32
24
(Cohort 2
Group B)
/ 36
(Cohort 2
Group A)
EDe
1
b,c
4
8c
12
16
24
36
48
Safety laboratory 
tests (hematology 
& chemistry; 
coagulation)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
APRI
X
X
X
X
X
X
X
FibroTest
X
X
X
X
X
X
X
FibroScank
X
α-fetoprotein 
(HCC imaging 
[eg, CT scan] is 
required for 
participants with 
α-fetoprotein 
≥ 50 ng/mL at 
screening)
X
Serology testing to 
exclude HCV, 
HDV, and HIV 
infectionl
X
Quantitative 
plasma HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum sample for 
HBV viral 
sequencing 
(resistance 
surveillance) and 
ddPCR
X
Serum sample for 
HBV viral 
sequencing 
(resistance 
surveillance) and 
genotyping sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Treatment Cycles Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeks b
Cohort 2 
Group B
only
Cohort 2
Group A only
Screening
(45 days)
BL
Day 1
1c
2d
4
8
12
13c
14
16
20
24
28
32
24
(Cohort 2
Group B)
/ 36
(Cohort 2
Group A)
EDe
1
b,c
4
8c
12
16
24
36
48
Quantitative HBV 
Serum HBsAg, 
HBcrAg, HBeAg, 
and HBV RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Qualitative HBV 
serology HBeAg, 
HBeAb, and 
HBsAg, HBsAb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biomarker 
Samples: 
Collection of 
PBMC, whole 
blood, serum and 
plasma samples for 
biomarker 
analysism,n
Xm,n
X
n
X
m
Xm
X
n
Xm
X
Sparse PK for 
VIR-2218o
X
X
X
Sparse PK for 
SLGNp
X
p
X
X
X
p
Estimated 
creatinine 
clearance 
(using the 
Cockcroft-Gault 
method)
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug and 
Alcohol Screen
X
Autoantibodies
X
TSH
X
X
(Cohort 2
Group B)
X
X
X
FSHq
X


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Treatment Cycles Week (± 2 days)a
EOT 
(−5 days)
Follow-up Weeks b
Cohort 2 
Group B
only
Cohort 2
Group A only
Screening
(45 days)
BL
Day 1
1c
2d
4
8
12
13c
14
16
20
24
28
32
24
(Cohort 2
Group B)
/ 36
(Cohort 2
Group A)
EDe
1
b,c
4
8c
12
16
24
36
48
Serum Pregnancy 
Testr
X
X
Urine Pregnancy 
Testr
X
X
X
X
X
X
X
X
X
X
X
X
r
X
Xr
X
X
X
Enrollment
X
Dispense & 
Administer VIR- 
2218 SC as
appropriate 
(Group A only)
X
X
X
X
X
X
Dispense & 
Administer SLGNs 
as appropriate 
(Group A only)
X
X
X
X
X
X
X
X
Dispense & 
Administer SLGNs 
as appropriate 
(Group B only)
X
X
X
X
X
X
X
X
X
X
Study Drug 
Accountability
X
X
X
X
X
X
X
X
X
X
X
AE = adverse event; APRI = AST to Platelet Ratio Index; BL = baseline; CT = computed tomography; ddPCR = digital droplet polymerase chain reaction; 
ECG = electrocardiogram; ED = early discontinuation; EOT = end of treatment; FSH = follicle-stimulating hormone; FU = follow-up; HBcrAg = hepatitis B core-related antigen; 
HBeAb = hepatitis B e antibody; HBeAg = hepatitis B e antigen; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HDV = hepatitis D virus; IV = intravenous; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetic; 
SAE = serious adverse event; SC = subcutaneous; SLGN = selgantolimod; TAF = tenofovir alafenamide; TSH = thyroid-stimulating hormone
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a
All study visits (± 2 days), except for Weeks 1, 2, 13, and 14.
b
FU Week 1 will have a visit window of ± 2 days, FU Weeks 4 through FU Week 16 will have a visit window of ± 5 days, and FU Weeks 24 through FU Week 48 will have a 
visit window of ± 14 days.
c
Week 1 (Cohort 2 Group B only), Week 13 (Cohort 2 Group A only), and FU Week 1, Week 8, and Week 16 will be conducted as a virtual/telephonic visit to review AEs, 
concomitant medications, and overall health of the participant by investigator.
d
Week 2 visit is only applicable for Cohort 2 Group B.
e
The ED visit should be performed within 14 days from notification of study discontinuation.
f
Obtain written informed consent, including Main Informed Consent, 
g
Record any SAEs and all AEs related to protocol mandated procedures occurring after signing of the consent form. After drug administration, report all AEs and SAEs.
h
Participants must rest quietly in the supine position for a minimum of 5 minutes prior to the recording.
i
At ED visit, these procedures are optional and to be done as needed.
j
Ophthalmologic examination at screening should be performed during the screening window, ie, within 45 days of randomization. Ophthalmologic examinations post-Day 1
k
should occur within −4 to +10 days of visit.
l
FibroScan testing where applicable for liver disease staging.
m
In the event of a positive result for serology and/or antigen testing for HIV, HDV, or HCV, reflex tests will be performed as necessary.
n
Cohort 2 Group A biomarker collection. Collect pre-SLGN dose administration at Baseline/Day 1, Week 12, 4 hours and 24-72 hours postdose. Collect at Week 14, predose.
o
Collect pre-SLGN dose administration at Week 32, 4 hours and 24-72 hours postdose.
p
Cohort 2 Group B biomarker collection. Collect pre-SLGN dose administration on Baseline/Day 1, 4 hours and 24-72 hours postdose. Collect at Week 2, pre-dose. Collect 
pre-SLGN dose administration at Week 20, 4 hours and 24-72 hours postdose.
q
The sparse PK collection for VIR-2218 at baseline/Day 1 should occur predose and postdose. Postdose sparse PK collection for VIR-2218 should occur any time between 1 
and 5 hours postdose relative to VIR-2218 administration.
r
Sparse PK collection for SLGN should occur any time between 1 and 5 hours postdose relative to SLGN administration. The collection at Baseline/Day 1 is only applicable to 
Cohort 2 Group B. The collection at Week 32 is only applicable to Cohort 2 Group A.
x
For Group A, intensive PK sample to be drawn at any one visit at Week 20, 24, 28 or 32 relative to SLGN dosing in clinic on the morning of the intensive PK visit. For 
Group B, sample will be collected Week 12 or later relative to SLGN dosing in clinic on the morning of the intensive PK visit.
y
Group A and B: Collection will occur at Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12 and 24 hours postdose 
z
For Group A only, intensive PK sample to be drawn on Baseline/Day 1 and at Week 20 relative to VIR-2218 dosing in clinic on the morning of the intensive PK visit.
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Appendix 2.
Data Collection and Determination of COVID-19 Data
This appendix describes the clinical trial site collection of COVID-19 data and the data 
processing algorithm that will be used to determine COVID-19 related information from CRF 
comment fields.
12.1.
Data Collection
Missed or virtual visits due to COVID-19 will be collected through the visit date CRF page. 
However, some COVID-19 related information will be collected via CRF comment fields (eg. 
comments related to study drug or study discontinuation due to COVID-19, missed key 
assessment due to COVID-19). 
12.2.
Determination of COVID-19 Related Information from CRF Comment
Natural Language Processing (NLP) will be used to search the CRF comment fields to identify 
instances of “COVID-19”, “Virtual”, or synonyms (see Appendix Table 3). The search terms 
will be maintained in a global lookup table and can be modified to tune the NLP model. If 
COVID-19 and Virtual terms are identified through NLP, it will help the determination of study 
drug or study discontinuation due to COVID-19 for certain reasons (eg. participant decision, 
withdrew consent, or investigator discretion), and provide supplemental information to determine 
missed key assessments due to COVID-19.
Appendix Table 3.
Example Search Terms for “COVID-19” and “Virtual” 
Search Terms for “COVID-19”
Search Terms for “Virtual”
COVID19
CORONA
CORONAVIRUS
PANDEMIC
OUTBREAK
CRISIS
LOCKDOWN
QUARANTINE
SHELTER
VIRTUAL
TELEMED
TELEHEALTH
TELEPHONE
REMOTE
TELEMEDICINE
TELECONSULTATION
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SKYPE


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Statistical Analysis Plan – Primary and Final Analysis
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Page 68 of 68
Appendix 3.
List of Nucleos(t)ide (NUC) Therapy 
ENTECAVIR
TELBIVUDINE
TENOFOVIR
TENOFOVIR ALAFENAMIDE
TENOFOVIR ALAFENAMIDE FUMARATE
TENOFOVIR DISOPROXIL FUMARATE
LAMIVUDINE


GS-US-465-4439-SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Global Development
Lead (GDL) eSigned
18-Apr-2024
21:44:05
Biostatistics eSigned
19-Apr-2024
13:44:34
PPD
PPD