Clinical trial NCT04507269
Conditions: Hepatitis B, Chronic
Keywords: Hepatitis B Virus Chronic Hepatitis B HBV Hepatitis
Sponsor: Brii Biosciences Limited
Start date: 2020-08-18; Completion date: 2021-09-30
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is to evaluate the safety, pharmacokinetics characteristics, and antiviral activities of multiple doses of VIR-2218 in adults with chronic HBV infection in mainland China.

Detailed description:

Arms: arm 1: Drug: VIR-2218 VIR-2218 given by subcutaneous injection arm 2: Drug: Placebo Saline given by subcutaneous injection
Interventions: intervention 1: VIR-2218 intervention 2: Placebo
Intervention descriptions: intervention 1: VIR-2218 given by subcutaneous injection intervention 2: Saline given by subcutaneous injection

Protocol documents:
Prot_000.pdf: 
A Phase 2 Randomized, Placebo-Controlled Study in Mainland China to 
Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Activity 
of VIR-2218 
NCT04507269 
Protocol Amendment 2 
23 September 2020 


VIR-2218-1005 
Clinical Study Protocol 
Amendment 2 
 
CONFIDENTIAL 
Page 1 
23 September 2020 
 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 2 Randomized, Placebo-Controlled Study in Mainland 
China to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Antiviral Activity of VIR-2218 
Sponsor: 
Brii Biosciences Ltd. 
Room 301, 3/F, 
Building 7, 
No. 1 Yongtaizhuang North Street, 
Haidian District, Beijing 100192, China 
 
Investigational 
Product: 
VIR-2218 
Clinicaltrials.gov ID: 
NCT04507269 
Indication: 
Chronic Hepatitis B (HBV) Infection 
Protocol ID: 
VIR-2218-1005  
Study Director:  
 
 
Medical Monitor: 
 
 
Protocol 
Version/Date: 
Amendment 2: 23 September 2020 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information that is the property of Brii Biosciences 
Limited. This confidential information is being provided for the purpose of evaluating or 
conducting a clinical study. This confidential information will be protected by you and your 
staff against disclosure to or use by third parties, except as necessary for the evaluation or 
conduct of the study. 
PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2 
23 September 2020 
Amendment 1 
07 April 2020 
Original Protocol 
06 September 2019 
Amendment 2 (23 September 2020) 
The changes and rationale for the changes from the Protocol Amendment 1 dated 07 April 2019 to 
Amendment 2 dated 23 September 2020 are as follows. Wording that has been deleted will be indicated 
with a strikethrough (ex. Word) and new wording will be indicated in Bold type (ex. Word). 
Affected 
Sections: 
Section 5.3 Exclusion Criteria, Item 7 
Original Text: 
Each subject must not meet any of the following exclusion criteria to be eligible 
for enrollment in the study: 
7. Subjects has the following laboratory parameters at screening by central 
laboratory: 
a. creatinine, total bilirubin, international normalized ratio (INR) or prothrombin 
time above the upper limit of normal (ULN) 
Amended Text: 
Each subject must not meet any of the following exclusion criteria to be eligible 
for enrollment in the study: 
7. Subjects has the following laboratory parameters at screening by central 
laboratory: 
a. creatinine or total bilirubin above the upper limit of normal (ULN), OR 
international normalized ratio (INR) above 1.1x ULN 
Rationale: 
Based on the comparison of coagulation data in the same patient population from 
the central laboratory for this study and those from a different central laboratory 
and a certified local clinical laboratory, the central laboratory for this study 
reported higher PT results that were not considered either clinically significant or 
exclusive. INR is a standardized calculation based on the PT result of the specific 
sample versus the PT result of a reference sample. INR has been recognized 
extensively as a standardized marker to evaluate coagulation function in patients 


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with all stages of liver diseases. Changes avoid unnecessary and medically 
inaccurate exclusion of eligible subjects for this study. 
Categorization: Non-substantial 
 
Affected 
Sections: 
Appendix 2 Part One/Two Schedule of Assessments (SoA) for Planned and 
Optional Cohorts in Subjects with Chronic HBV Infection, Footnote h of Vital 
signs 
Original Text: 
On Day 1, vital signs should be measured within 2 hours predose and 4 hours 
post-dose. 
Amended Text: 
On Day 1, vital signs should be measured within 2 hours predose and 4 hours (± 
30 minutes) post-dose. 
Rationale: 
Clarification on the time window for collection of vital signs post-dose on Day 1. 
Categorization: 
Non-substantial 
 
Affected 
Sections: 
Appendix 2 Part One/Two Schedule of Assessments (SoA) for Planned and 
Optional Cohorts in Subjects with Chronic HBV Infection, Footnote j of 
Pregnancy test 
Original Text: 
A blood pregnancy test will be performed at screening and urine pregnancy tests 
will be performed thereafter. 
Amended Text: 
A blood pregnancy test will be performed at screening and urine pregnancy tests 
will be performed thereafter. Urine pregnancy test results from local 
laboratories are acceptable. 
Rationale: 
 Clarification on allowing local laboratory results for urine pregnancy tests. 
Categorization: 
Non-substantial 
 
Affected 
Sections: 
Appendix 3 Part One/Two Pharmacokinetic Assessment Timepoints 
Original Text: 
Converted from the tabular format: PK blood will be collected at 1 hour, 2 hours, 
4 hours, 8 hours, and 24 hours post-dose on Day 1 and Week 4.  


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Amended Text: 
Converted from the tabular format: PK blood will be collected at 1 hour (± 5 
minutes), 2 hours (± 10 minutes), 4 hours (± 30 minutes), 8 hours (± 30 
minutes), and 24 hours (± 2 hours) post-dose on Day 1 and Week 4. 
Rationale: 
 Clarification on the time windows for PK sample collections. 
Categorization: 
Non-substantial 
 
Affected 
Sections: 
Section 8.3.2 Serious Adverse Events 
Original Text: 
Email or fax the SAE form within 24 hours of the investigator’s knowledge of the 
event. Contact information is as follows: 
 
 
       
 
Amended Text: 
Email or fax the SAE form within 24 hours of the investigator’s knowledge of the 
event. Contact information is as follows: 
 
Rationale: 
Changes reflect the correct information of SAE reporting contact. 
Categorization: 
Non-substantial 
 
Affected 
Sections: 
Section 8.5.2 Special Situations Reports 
Original Text: 
All other special situations must be reported to PRA Pharmacovigilance within 24 
hours of the investigator becoming aware of the situation. Contact information is 
as follows: 
 
 
       
 
Amended Text: 
All other special situations must be reported to PRA Pharmacovigilance the 
Sponsor within 24 hours of the investigator becoming aware of the situation. 
Contact information is as follows: 
 
PPD
PPD
PPD
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Rationale: 
Changes reflect the correct information of special situations reporting contact. 
Categorization: 
Non-substantial 
 
 
 




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5. 
SUBJECT POPULATION .........................................................................................33 
5.1. Number of Subjects and Subject Selection .....................................................................33 
5.2. Inclusion Criteria .............................................................................................................33 
5.3. Exclusion Criteria ............................................................................................................34 
6. 
INVESTIGATIONAL MEDICINAL PRODUCTS ....................................................36 
6.1. Randomization, Blinding, and Treatment Codes ............................................................36 
6.1.1. 
Procedures for Breaking of Treatment Codes ...................................................36 
6.2. Description and Handling of VIR-2218 and Placebo ......................................................36 
6.2.1. 
Formulation .......................................................................................................36 
6.2.2. 
Packaging and Labeling ....................................................................................36 
6.2.3. 
Storage and Handling ........................................................................................37 
6.2.4. 
Dosage and Administration of VIR-2218 .........................................................37 
6.3. Investigational Product Accountability ...........................................................................38 
6.4. Concomitant Therapy ......................................................................................................38 
6.4.1. 
Permitted Concomitant Medications .................................................................38 
6.4.2. 
Prohibited Concomitant Medications ................................................................39 
6.5. NrtI Therapy ....................................................................................................................39 
6.6. Contraceptive Requirements ...........................................................................................39 
7. 
STUDY PROCEDURES ............................................................................................41 
7.1. Procedures and Specifications .........................................................................................41 
7.1.1. 
Medical History .................................................................................................41 
7.1.2. 
Assessment of Antiviral Activity and Development of Resistance ..................41 
7.1.3. 
Screening Viral Serology Parameters ...............................................................41 
7.1.4. 
Pharmacokinetic Assessments ..........................................................................41 
7.1.5. 
Exploratory Analyses Samples .........................................................................41 
7.2. Safety Assessments .........................................................................................................42 
7.2.1. 
Physical Examination ........................................................................................42 
7.2.2. 
Alcohol Assessment ..........................................................................................42 
7.2.3. 
Height and Weight ............................................................................................42 
7.2.4. 
Vital Signs .........................................................................................................42 
7.2.5. 
Electrocardiogram .............................................................................................42 
7.2.6. 
Pregnancy Testing .............................................................................................42 
7.2.7. 
Clinical Laboratory Assessments ......................................................................43 


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7.2.8. 
FibroScan ..........................................................................................................45 
8. 
ADVERSE EVENTS MANAGEMENT ....................................................................46 
8.1. Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events .........46 
8.1.1. 
Adverse Events..................................................................................................46 
8.1.2. 
Serious Adverse Events.....................................................................................46 
8.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events ..................................................47 
8.2. Assessment of Adverse Events and Serious Adverse Events ..........................................48 
8.2.1. 
Assessment of Causality for Study Drugs and Procedures ...............................48 
8.2.2. 
Assessment of Severity .....................................................................................48 
8.3. Investigator Requirements and Instructions for Reporting Adverse Events and 
Serious Adverse Events to Sponsor .................................................................................48 
8.3.1. 
Adverse Events..................................................................................................48 
8.3.2. 
Serious Adverse Events.....................................................................................48 
8.4. Sponsor Reporting Requirements ....................................................................................49 
8.5. Special Situations Reports ...............................................................................................49 
8.5.1. 
Definitions of Special Situations .......................................................................49 
8.5.2. 
Instructions for Reporting Special Situations ...................................................50 
9. 
STATISTICAL CONSIDERATIONS ........................................................................52 
9.1. Objectives ........................................................................................................................52 
9.2. Endpoints .........................................................................................................................52 
9.3. Analysis Conventions ......................................................................................................52 
9.3.1. 
Analysis Sets .....................................................................................................52 
9.3.2. 
Data Handling Conventions ..............................................................................52 
9.4. Demographic Data and Baseline Characteristics ............................................................53 
9.5. Safety Analysis ................................................................................................................53 
9.5.1. 
Adverse Events..................................................................................................53 
9.5.2. 
Laboratory Evaluations .....................................................................................53 
9.5.3. 
Other Safety Evaluations...................................................................................53 
9.6. Pharmacokinetic/Pharmacodynamic Analysis ................................................................54 
9.7. Antiviral Activity Analysis ..............................................................................................54 
9.8. Sample Size .....................................................................................................................54 
10. 
RESPONSIBILITIES .................................................................................................55 


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10.1. 
Investigator and Sponsor Responsibilities ..................................................................55 
10.1.1. Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
55 
10.1.2. Informed Consent 
55 
10.1.3. Confidentiality 
55 
10.1.4. Study Files and Retention of Records ...............................................................56 
10.1.5. Electronic Case Report Forms (eCRF) .............................................................56 
10.1.6. Good Clinical Practice 56 
10.1.7. Drug Accountability 
56 
10.1.8. Quality Control and Assurance .........................................................................56 
10.1.9. Protocol Compliance 
57 
10.1.10. Protocol Modifications 57 
10.1.11. Study Report and Publications ..........................................................................57 
10.2. 
Study Monitoring ........................................................................................................57 
10.2.1. Study Discontinuation 58 
11. 
REFERENCES ...........................................................................................................59 
12. 
APPENDICES ............................................................................................................61 
 
Appendix 1. 
Investigator Signature Page .............................................................................62 
Appendix 2.  
Part One/Two Schedule of Study Assessments (SoA) for Planned and 
Optional Cohorts in Subjects with Chronic HBV Infection ............................63 
Appendix 3. 
Part One/Two Pharmacokinetic Assessment Timepoints ................................67 
Appendix 4. 
Cohort Dose Schedule of the Regional Study and the China Study ................68 
 Appendix 5 
Protocol Amendment History ..........................................................................69 
 
LIST OF IN-TEXT TABLES 
 
 
Table 2.  
Part A Dose Escalation Plan ............................................................................24 
Table 3. 
Part B/C Dose Escalation Plan .........................................................................25 
Table 4. 
Study Drug Dose and Administration ..............................................................38 
Table 5. 
Clinical Laboratory Tests .................................................................................44 
 
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LIST OF IN-TEXT FIGURES 
Figure 1. 
SAD Study Design for Part A (VIR-2218-1001 Regional Study) ...................23 
Figure 2. 
MAD Study Design for Part B/C (VIR-2218-1001 Regional Study) ..............23 
Figure 3.  
Study Design for Cohorts.................................................................................29 


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PROTOCOL SYNOPSIS 
Study Title: 
A Phase 2 Randomized, Placebo-Controlled Study in Mainland 
China to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Antiviral Activity of VIR-2218 
Clinical 
Investigative Sites 
Planned: 
Planned to be conducted at multiple clinical investigative sites in 
mainland China. 
Phase 
Phase 2  
Number of Subjects 
Planned: 
Up to 30 subjects 
Target Population: 
Up to 30 adult subjects with HBeAg-negative or HBeAg-positive 
chronic hepatitis B virus (HBV) without cirrhosis on 
nucleos(t)ide reverse transcriptase inhibitor (NrtI) therapy. 
Diagnosis and Main 
Eligibility Criteria 
Adult subjects with chronic HBV infection without cirrhosis on 
NrtI therapy.  
Duration of Study 
Participation: 
Inclusive of screening to post-dose follow-up, the estimated total 
time on study for each subject is up to 20 weeks: screening period 
(4 weeks), dosing period (4 weeks) and post-dose follow-up period 
(12 weeks). 
Additional HBsAg monitoring is required for subjects with a ≥ 1 
1og10 change from baseline (Day 1 predose level) decrease in 
HBsAg achieved by the Week 16 visit. Subjects will be followed 
until the HBsAg level returns to > 90% of the Day 1 predose level 
or Week 48, whichever comes earlier. Additional HBsAg 
monitoring may be discontinued at the Sponsor’s discretion based 
on emerging data. 
Duration of 
Follow-up: 
Post-dose follow-up period: 
All subjects will be followed until Week 16.   
 
Extended follow-up period: 
Extended follow-up visits will occur every 4 weeks starting at Week 
20 and up to Week 48.  


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Objective(s): 
Primary objective: 
 To evaluate the safety and tolerability of multiple doses of VIR-
2218 in subjects with HBeAg-negative and HBeAg-positive 
chronic HBV infection without cirrhosis on NrtI therapy 
Secondary objectives: 
 To characterize the pharmacokinetics (PK) of VIR-2218 in 
subjects with chronic HBV infection without cirrhosis on NrtI 
therapy 
 To assess the antiviral activity of VIR-2218 in subjects with 
chronic HBV infection without cirrhosis on NrtI therapy 
 
 
 
 
  
Study Design: 
This is a phase 2 randomized, double-blind, placebo-controlled study 
of VIR-2218 administrated subcutaneously to adult subjects with 
chronic HBV infection without cirrhosis on NrtI therapy.  The study 
is designed to evaluate the safety, tolerability, PK and antiviral 
activity of VIR-2218.   
This study will be conducted in close collaboration with an ongoing 
phase 1/2 regional study (VIR-2218-1001, ClinicalTrials.gov 
Identifier: NCT03672188) conducted at multiple sites in the Asia-
Pacific region.  The objective of the VIR-2218-1001 regional study 
is to evaluate safety, tolerability, PK and antiviral activity of VIR-
2218 in healthy volunteers (HVs) and patients with chronic HBV 
infection.  The VIR-2218-1001 regional study includes 3 Parts, 
which are a single ascending dose (SAD) study in HV adult subjects 
(Part A), and two multiple ascending dose (MAD) studies in adult 
subjects with HBeAg-negative (Part B) and HBeAg-positive (Part C) 
chronic HBV infection without cirrhosis on NrtI therapy, 
respectively. Safety and efficacy data collected from the VIR-2218-
1001 regional study will be used to guide the conduct of this study.   
A Safety Review Committee (SRC) will perform ongoing reviews of 
safety and tolerability based on data collected through both this study 
and the VIR-2218-1001 regional study.  
This study (VIR-2218-1005) will include two Parts: 
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 Part One: adult subjects with HBeAg-negative chronic HBV 
infection without cirrhosis on NrtI therapy for ≥ 6 months and 
HBV DNA < 90 IU/mL at screening (by central laboratory)  
 Part Two: adult subjects with HBeAg-positive chronic HBV 
infection without cirrhosis on NrtI therapy for ≥ 6 months and 
HBV DNA < 90 IU/mL at screening (by central laboratory)  
The cohort dosing strategy of this study is based on data collected 
from the VIR-2218-1001 regional study. There are two planned 
cohorts (50 mg dose-level and 100 mg dose-level) for each of Part 
One and Part Two of the study. For each of the planned cohorts, 5 
subjects will be randomized 4:1 to VIR-2218 or placebo 
administered 4 weeks apart on Day 1 and Week 4.  
One optional cohort may be added to each study Part One and Part 
Two, wherein 5 subjects will be randomized 4:1 to VIR-2218 or 
placebo, administered on Day 1 and Week 4 at a maximum dose-
level of up to 200 mg.  
The optional cohorts may be initiated after SRC review of a 
minimum of 6 weeks of available safety and antiviral activity data 
from the 200 mg cohorts of the VIR-2218-1001 regional study.   
Study Procedures: 
Screening period: 
Screening will be performed no more than 4 weeks before the Day 1 
visit and will include written informed consent, determination of 
eligibility, collection of demographics and medical history as well as 
physical examination (including vitals), laboratory tests, 12-lead 
Electrocardiogram (ECG) and other assessments per the schedule of 
assessments. Adverse events related to screening activities must be 
collected from the time of consent onwards; any other events 
occurring during the screening period should be reported as medical 
history. All serious adverse events (SAEs) must be collected from the 
time of consent onwards. 
Dosing period: 
The dosing period is outpatient. Eligible subjects will be randomized 
to receive VIR-2218 or placebo within 48 hours before study drug 
administration on Day 1. Subjects will return to the clinical 
investigational site at Week 4 to receive a second dose of the same 
study drug administered on Day 1.   
For subjects enrolled into the optional cohorts, eligible subjects will 
be randomized to receive VIR-2218 or placebo within 48 hours 
before study drug administration on Day 1. Subjects will return to the 


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clinical investigational site at Week 4 to receive a second dose of the 
same study drug administered on Day 1. 
Post-dose follow-up period: 
Subjects will return to the clinical investigative site on an outpatient 
basis for safety, tolerability, PK, and antiviral activity monitoring at 
specified timepoints during this Post dose Follow up period (Week 5 
to Week 16). Additional HBsAg monitoring is required for subjects 
with a ≥ 1 1og10 change from baseline (Day 1 predose level) decrease 
in HBsAg achieved by the Week 16 visit.    
Extended follow-up period: 
Subjects who require additional HBsAg monitoring will return to the 
clinical investigational site for in-person assessments. Extended follow-
up visits will occur every 4 weeks starting at Week 20, and subjects 
will be followed until the HBsAg level returns to > 90% of the Day 1 
predose level or Week 48, whichever comes earlier. Additional HBsAg 
monitoring may be discontinued at the Sponsor’s discretion based on 
emerging data.   
Investigational 
Product, Dose, and 
Mode of 
Administration: 
VIR-2218 is a synthetic, chemically modified small interfering RNA 
(siRNA) targeting HBV RNA with a covalently attached triantennary 
N-acetylgalactosamine (GalNAc) ligand that allows for specific 
uptake by hepatocytes. VIR-2218 will be supplied as a sterile solution 
for subcutaneous injection at a free acid concentration of 200 mg/mL. 
The starting dose level for the planned Cohorts in Parts One and Two 
will be 50 mg and 100 mg; the maximum dose level in the optional 
cohorts will not exceed 200 mg. 
Reference Therapy:
Subjects randomized to placebo will be administered sterile, 
preservative-free normal saline 0.9% solution for subcutaneous 
injection. 
Criteria for 
Evaluation: 
Primary Endpoints 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Clinical assessments including but not limited to laboratory test 
results 
Secondary Endpoints 
 PK parameters of VIR-2218 and possible metabolites (may 
include, but not limited to, maximum plasma concentration, time 
to reach maximum concentration, area under the concentration 
versus time curve [to last measurable timepoint and to infinity], 
percent of area extrapolated, apparent terminal elimination half-
life, clearance, and volume of distribution) 


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 Maximum reduction of serum HBsAg from Day 1 until 12 weeks 
post last dose 
 Number of subjects with serum HBsAg loss at any timepoint 
 Number of subjects with sustained serum HBsAg loss for greater 
than or equal to 6 months post last dose 
 Number of subjects with anti-HBs seroconversion at any timepoint 
 For HBeAg-positive subjects (Part Two only): number of subjects 
with HBeAg loss and/or anti-HBe seroconversion at any timepoint
 
 
 
 
 
 
 
Statistical Methods:
Statistical analyses will be primarily descriptive. All study data will 
be presented by subject data listings. Summary tables will present 
results by cohort for each VIR-2218 dose and placebo, where the 
placebo subjects will be combined across dose cohorts. 
Descriptive statistics will be presented for continuous variables, and 
frequencies and percentages will be presented for categorical and 
ordinal variables. Percentages will be based on the number of 
non-missing values in a dose group. Details will be provided in the 
Statistical Analysis Plan. 
 
This study will be conducted in accordance in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practices (ICH GCP) and applicable state, local, and federal 
regulatory requirements including archiving of essential documents. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
anti-drug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBe 
hepatitis B extracellular antibody 
anti-HBs 
hepatitis B surface antibody 
ALP 
alkaline phosphatase 
ASGPR 
asialoglycoprotein receptor 
AST 
aspartate aminotransferase 
BLQ 
below the limit of quantitation 
BMI 
body mass index 
BUN 
blood urea nitrogen 
cccDNA 
covalently closed circular DNA 
CLcr 
creatinine clearance 
CRF 
case report form 
CTCAE 
common terminology criteria for adverse events 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
ESC+ 
enhanced stabilization chemistry plus 
GalNAc 
N-acetyl-galactosamine 
GCP 
good clinical practice 
GGT 
gamma glutamyl transferase 
GLP 
good laboratory practice 
GNA 
glycol nucleic acid 
 
 
HBcAg 
hepatitis core antigen 
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HBeAg 
hepatitis B e-antigen 
HBsAg 
hepatitis surface antigen 
HBV 
hepatitis B virus 
HBx 
hepatitis B protein X 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HEDs 
human equivalent doses 
HIV 
human immunodeficiency virus 
HLGT 
high-level group term 
HLT 
high-level term  
HV 
healthy volunteer 
ICF 
informed consent form 
ICH 
international conference on harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IWRS 
interactive web response system 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantitation 
LLT 
lower-level term 
MAD 
multiple ascending dose 
MedDRA 
medical dictionary for regulatory activities 
mRNA 
messenger RNA 
NHP 
non-human primate 
NOAELs 
no observed adverse effect levels 
NrtI 
nucleos(t)ide reverse transcriptase inhibitor 
OTC 
over-the-counter 
PEG-IFN 
pegylated interferon-alpha 


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pgRNA 
pregenomic RNA 
PK 
Pharmacokinetics 
Pol/RT 
polymerase, reverse transcriptase 
PT 
preferred term 
Q1 
first quartile  
Q3 
third quartile  
RBC 
red blood cell (count) 
rcDNA 
relaxed-circular DNA 
SAD 
single ascending dose 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
standard deviation 
siRNA 
small interfering RNA 
SoA 
schedule of assessments 
SOC 
system organ class 
SRC 
safety review committee 
SUSAR 
suspected unexpected serious adverse reaction 
TAF 
tenofovir disoproxil fumarate 
TDF 
tenofovir alafenamide 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WBC 
white blood cell (count) 
WHO 
world health organization 
WOCBP 
women of child-bearing potential 
 


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1. 
INTRODUCTION 
1.1. 
Background 
VIR-2218 is a synthetic small interfering RNA (siRNA) therapeutic being developed for the 
treatment of chronic hepatitis B virus (HBV) infection. Chronic HBV infection remains an 
important global public health problem with significant morbidity and mortality (Trepo, 2014). 
According to the World Health Organization (WHO) an estimated 257 million people are living 
with chronic HBV infection worldwide (WHO, 2019; Schweitzer, 2015). Over time, chronic 
HBV infection leads to serious sequelae including cirrhosis, liver failure, hepatocellular 
carcinoma (HCC), and death. Almost 800,000 people are estimated to die annually due to 
sequelae associated with chronic HBV infection (Stanaway, 2016). China has the highest chronic 
HBV burden in the world, with an estimated 90 million people, or almost 7% of China’s 
population, who are chronically infected, resulting in 330,000 deaths each year (WHO, 2015). 
More broadly, HBV prevalence varies geographically, with a range of less than 2% in low to 
greater than 8% in high prevalence countries (Schweitzer, 2015). In high prevalence countries, 
such as those in sub-Saharan Africa and East Asia, transmission occurs predominantly in infants 
and children by perinatal and horizontal routes. In more industrialized countries, new infections 
are highest among young adults and transmission occurs predominantly via injection drug use 
and high-risk sexual behaviors. The risk of developing chronic HBV infection depends on the 
age at the time of infection. While only ~10% of people infected as adults develop chronic HBV 
infection, 90% of infants infected perinatally or during the first 6 months of life, and 20–60% of 
children infected between 6 months and 5 years of age remain chronically infected. Twenty-five 
percent of people who acquire HBV during infancy and childhood will develop primary liver 
cancer or cirrhosis during adulthood. 
HBV is a DNA virus that infects, replicates, and persists in human hepatocytes (Protzer, 2012). 
The small viral genome (3.2 kb), consists of partially double-stranded, relaxed-circular DNA 
(rcDNA) and has 4 open reading frames encoding 7 proteins: HBcAg (HBV core antigen, viral 
capsid protein), HBeAg (hepatitis B e-antigen), HBV Pol/RT (polymerase, reverse transcriptase), 
PreS1/PreS2/HBsAg (large, medium, and small surface envelope glycoproteins), and HBx 
(HBV × antigen, regulator of transcription required for the initiation of infection) (Seeger, 2015; 
Tong, 2016).  
In hepatocytes, rcDNA, the form of HBV nucleic acid that is introduced by the infection virion, 
is converted into a covalently closed circular DNA (cccDNA), which persists in the host cell’s 
nucleus as an episomal chromatinized structure (Allweiss, 2017). cccDNA serves as a 
transcription template for all viral transcripts (Lucifora, 2016). Pregenomic RNA (pgRNA) 
transcripts are reverse transcribed into new rcDNA for new virions, which are secreted without 
causing cytotoxicity. In addition to infectious virions, infected hepatocytes secrete large amounts 
of genome-free subviral particles, that may exceed the number of secreted virions by 10,000-fold 
(Seeger, 2015). Random integration of the virus into the host genome can occur as well, a 
mechanism that contributes to hepatocyte transformation (Levrero, 2016). 
In acute resolving infections, the virus is cleared by effective innate and adaptive immune 
responses that include cytotoxic T cells leading to death of infected hepatocytes, and induction of 


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B cells producing neutralizing antibodies that prevent the spread of the virus (Bertoletti, 2016; 
Maini, 2016; Li, 2016). In contrast, chronic infection is associated with T and B cell dysfunction, 
mediated by multiple regulatory mechanisms including presentation of viral epitopes on 
hepatocytes and secretion of subviral particles (Bertoletti, 2016; Maini, 2016; Burton, 2018). 
Thus, the continued expression and secretion of viral proteins due to cccDNA persistence in 
hepatocytes is considered a key step in the inability of the host to clear the infection. 
Chronic HBV infection is a dynamic process reflecting the interaction between HBV replication 
and host immune responses. The laboratory hallmark of chronic HBV infection is persistence of 
HBsAg in the blood for greater than 6 months, and a lack of detectable anti-HBs. Chronic 
infection is divided into 4 stages based on HBV markers in blood (HBsAg, HBeAg/anti-HBe, 
HBV DNA), and liver disease based on biochemical parameters (alanine aminotransferase 
(ALT)), as well as fibrosis markers (noninvasive or based on liver biopsy) (EASL, 2017). 
Overall, across the various phases of chronic HBV infection, only a minority of patients (less 
than 1% per year) clear the disease as measured by HBsAg seroclearance. 
Currently, there are 2 main treatment options for patients with chronic HBV infection: treatment 
with nucleos(t)ide reverse transcriptase inhibitors (NrtIs) and pegylated interferon-alpha (PEG-
IFN) (Liang, 2015). NrtIs inhibit the production of infectious virions, and often reduce serum 
HBV DNA to undetectable. However, NrtIs do not directly eliminate cccDNA, and therefore, 
transcription and translation of viral proteins continues. Consequently, expression of viral 
epitopes on hepatocytes, secretion of subviral particles, and immune dysfunction remain largely 
unaffected by NrtI therapy. In turn, this necessitates prolonged, often lifelong therapy; 
furthermore, while NrtI therapy reduces the incidence of HCC, it does not eliminate the 
increased risk of HCC that HBV infection confers. In contrast, PEG-IFN can induce long-term 
immunological control, but only in a small percentage of patients (< 10%) (Konerman, 2016). 
The high variability of response, in combination with an unfavorable safety profile make a 
significant number of patients ineligible or unwilling to undergo PEG-IFN treatment.  
The failure of NrtI therapy to eradicate the virus, and the limitations of PEG-IFN therapy 
highlight the clinical need for new HBV therapies that are effective, well tolerated, and do not 
require lifelong administration. To address this unmet need, Vir is developing an investigational 
agent, VIR-2218, for the treatment of chronic HBV infection. In preclinical models, VIR-2218 
inhibits viral replication, translation, and secretion of HBsAg. Therefore, VIR-2218 has the 
potential, alone or in combination with other therapies, to achieve a functional cure of chronic 
HBV infections. 


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1.2. 
VIR-2218 
1.2.1. 
VIR-2218 Description 
VIR-2218 is an siRNA targeting 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 (GNA) 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 (ASGPR). 
The drug product, VIR-2218, is the drug substance VIR-2218 formulated in water for 
subcutaneous (SC) injection.VIR-2218 is pharmacologically active against HBV genotypes 
A through J; see the Investigator’s Brochure for additional information on VIR-2218. 
1.2.2. 
Rationale for VIR-2218 for the Treatment of HBV Infection 
The use of siRNA offers a novel strategy for the treatment of chronic HBV infection. 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 pgRNA, thus inhibiting viral replication, and degradation of 
all viral messenger RNA (mRNA) transcripts, thereby preventing expression of viral proteins. 
This may result in the return of a functional immune response directed against HBV, either alone 
or in combination with other therapies. 
By contrast, 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 DNA 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. 
Subjects randomized to active treatment for this study will receive VIR-2218 added to their 
ongoing NrtI therapy. Such subjects have already been determined by their physician to require 
treatment. Based on the known mechanisms of action there is no risk for pharmacodynamic 
drug-drug interactions or overlapping toxicities between NrtIs and siRNA. 
1.2.3. 
Nonclinical Data 
Refer to the Investigator’s Brochure for VIR-2218 Nonclinical data.  
1.2.4. 
Rationale for Dose Selection 
VIR-2218 doses were determined using a combination of animal toxicology data and available 
clinical data from the ongoing VIR-2218-1001 regional study. 
 
 


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Although dosing in the GLP-toxicology studies was weight based, subjects will receive a fixed 
dose rather than a body weight-based dose because VIR-2218, like other GalNAc-conjugated 
siRNAs, is preferentially taken up by the liver, the therapeutically targeted organ with extended 
tissue half-life, and to a lesser extent distributed to other organs and tissues (Nair, 2014). 
Nonclinical data suggested receptor level changes had minimal impact on efficiency of this 
ASGPR mediated uptake process at pharmacologically relevant dose levels (Willoughby, 2018).  
Therefore, body weight-based dosing is not anticipated to reduce the inter-subject variability in 
the pharmacokinetics (PK) of VIR-2218 in adults, and a fixed dose has the advantage of avoiding 
potential dose calculation errors.  
VIR-2218-1001 regional study 
The ongoing VIR-2218-1001 regional study (ClinicalTrials.gov Identifier: NCT03672188) is a 
randomized, double-blind, placebo-controlled study of VIR-2218 administered subcutaneously to 
healthy adult subjects and adult subjects with chronic HBV infection without cirrhosis who are 
on NrtI therapy. This study is designed to evaluate the safety, tolerability, PK, and antiviral 
activity of VIR-2218. Single ascending dose (SAD) levels are being evaluated in healthy 
volunteers (HVs). Safety data from HVs are then used to support the dose levels evaluated in a 
multiple ascending dose (MAD) study in adult subjects with HBeAg-negative (Part B) and 
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HBeAg-positive (Part C) chronic HBV infection without cirrhosis on NrtI therapy, currently 
being conducted at multiple clinical investigative sites in the Asia-Pacific region. Significant 
ethnic Asian representation is expected in the ongoing healthy volunteer and patient studies. The 
study designs for Part A SAD and Part B/C MAD studies are presented in Figure 1 and Figure 2, 
respectively.  
Figure 1. 
SAD Study Design for Part A (VIR-2218-1001 Regional Study) 
 
a Subject discharge will occur after all assessments are completed on Day 2 
Figure 2. 
MAD Study Design for Part B/C (VIR-2218-1001 Regional Study) 
  
a Additional HBsAg monitoring is required for subjects with HBsAg levels with a > 10% decrease from the Day 1 
predose level at the Week 16 visit. Visits will occur every 4 weeks starting at Week 20 up to Week 48 or until the 
HBsAg level returns to > 90% of the Day 1 predose level. Additional HBsAg monitoring may be discontinued at 
the Sponsor’s discretion based on emerging data. 
 
VIR-2218-1001, Part A: Single Ascending Dose (SAD) Study in Healthy Volunteers 
(Table 2): 
HVs received a single ascending dose of VIR-2218, ranging from 50 to 900 mg. Doses were 
increased stepwise by a factor of 2-fold up to a dose of 400 mg followed by 1.5-fold increases to 
doses of 600 and 900 mg. As of 16 July 2019, data generated in the ongoing VIR-2218-1001 
study demonstrated that single doses of up to 600 mg had an acceptable safety and tolerability 
profile in 41 healthy subjects, 8 of which (20%) are of Asian ethnicity. Based upon review of the 
clinical data from the Safety Review Committee (SRC), the optional dose level of 900 mg will 
be initiated in HVs.  


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Table 2.  
Part A Dose Escalation Plan 
Cohort 
Fixed dose (mg) 
Dose Escalation Factor 
1a 
50 
- 
2a 
100 
2.0-fold 
3a 
200 
2.0-fold 
4a 
400 
2.0-fold 
5a 
600 
1.5-fold 
6a 
900 
1.5-fold 
 
VIR-2218-1001, Part B/C: Multiple Ascending Dose (MAD) Study in HBeAg-negative and 
HBeAg-positive Subjects with Chronic HBV Infection (Table 3): 
For this part of the ongoing VIR-2218-1001 regional study, HBeAg-negative subjects with 
chronic HBV infection are enrolled in Part B, and HBeAg-positive subjects with chronic HBV 
infection are enrolled in Part C. Dose levels were increased stepwise by a factor of 2 up to a 
maximum planned dose level of 200 mg and a cumulative dose of 400 mg in 3 dose-level cohorts 
for HBeAg-negative subjects. To accommodate the anticipated lower prevalence of 
HBeAg-positive patients on NrtI therapy, only 1 dose level cohort (200 mg) was planned for 
HBeAg-positive subjects.  
Data generated in the ongoing VIR-2218-1001 study, as of 16 July 2019, show that multiple 
doses of VIR-2218 up to 100 mg x 2 doses had an acceptable safety and tolerability profile in 13 
subjects with HBV infection, a majority of which (85%) are of Asian ethnicity. Initiation of the 
next higher dose cohort (200 mg) in subjects with HBV infection has been recommended based 
on SRC review on 25 July 2019. Additionally, based on the antiviral activity data collected thus 
far, notable reductions in HBsAg were observed across subjects with HBV infection in both the 
50 mg and 100 mg dose cohorts. Based upon review of the clinical data from the SRC, two 
optional dose levels of 20 mg and 50 mg were initiated in HBeAg-positive subjects. An 
additional optional dose level not to exceed 300 mg may also be initiated based on review of 
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Table 3. 
Part B/C Dose Escalation Plan 
Cohort 
Fixed Dose (mg) 
Dose Escalation Factor 
1b 
50 
- 
2b 
100 
2.0-fold 
3b and 3c 
200 
2.0-fold 
4b  
20 
- 
4c 
50 
- 
Optional: 5b and 5c 
Up to 300 
Up to 1.5-fold 
 
1.3. 
VIR-2218-1005 study 
The cohort dosing strategy of this study is based on data collected from the VIR-2218-1001 
regional study (Appendix 4). There are 2 planned cohorts (50 mg dose-level and 100 mg 
dose-level) for both Part One and Part Two of the study. For each of the planned 50 and 100 
mg dose-level cohorts, 5 subjects will be randomized 4:1 to VIR-2218 or placebo 
administered 4 weeks apart on Day 1 and Week 4.  
One optional cohort may be added to each study part (Part One and Part Two), wherein 5 
subjects will be randomized 4:1 to VIR-2218 or placebo administered 4 weeks apart on Day 
1 and Week 4 at a dose-level of up to 200 mg.  
The optional cohorts may be initiated after SRC review of a minimum of 6 weeks of 
available safety and antiviral activity data from the 200 mg cohorts of the VIR-2218-1001 
regional study.  
1.4. 
Overall Risk/Benefit Assessment 
This study will provide information on the safety, PK, and antiviral activity of VIR-2218, an 
siRNA therapeutic targeting HBV, which has the potential to functionally cure chronic HBV 
infection alone or in combination with other treatment modalities. 
The potential benefits of VIR-2218 over the current standard of care for the treatment of chronic 
HBV infection are: 
 A pan-genotypic therapy for HBV infection that is well-tolerated and administered via 
SC injection for a finite duration of time 
 A reduction in serum HBsAg, which may break immune tolerance against HBV and 
lead to a functional cure 
As VIR-2218 is taken up by the liver, ALT and other liver function tests will be monitored 
during this study. Along with safety reviews performed by the Sponsor during the conduct of the 


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ongoing VIR-2218-1001 regional study, an SRC will perform ongoing reviews of safety and 
tolerability for this study. 
In summary, there is no approved therapy that reduces serum HBsAg in a significant percentage 
of patients. If serum HBsAg can be effectively reduced with a pangenotypic regimen, the 
anticipated safety profile would offer a favorable risk-benefit determinant in patients with 
chronic HBV infection. 


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2. 
OBJECTIVES 
2.1. 
Primary Objective 
To evaluate the safety and tolerability of multiple doses of VIR-2218 in subjects with HBeAg-
negative and HBeAg-positive chronic HBV infection without cirrhosis on NrtI therapy 
2.2. 
Secondary Objectives 
 To characterize the PK of VIR-2218 in subjects with chronic HBV infection without 
cirrhosis on NrtI therapy 
 To assess the antiviral activity of VIR-2218 in subjects with chronic HBV infection 
without cirrhosis on NrtI therapy 
 
 
 
 
 
 
 
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3. 
ENDPOINTS 
3.1. 
Primary Endpoint 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Clinical assessments including but not limited to laboratory test results 
3.2. 
Secondary Endpoints 
 PK parameters of VIR-2218 and possible metabolites (may include, but not limited to, 
maximum plasma concentration, time to reach maximum concentration, area under the 
concentration versus time curve [to last measurable timepoint and to infinity], percent of 
area extrapolated, apparent terminal elimination half-life, clearance, and volume of 
distribution) 
 Maximum reduction of serum HBsAg from Day 1 until 12 weeks post last dose 
 Number of subjects with serum HBsAg loss at any timepoint 
 Number of subjects with sustained serum HBsAg loss for greater than or equal to 6 
months post last dose 
 Number of subjects with anti-HBs seroconversion at any timepoint  
 For HBeAg-positive subjects (Part Two only): number of subjects with HBeAg loss 
and/or anti-HBe seroconversion at any timepoint 
 
 
 
 
 
 
 
 
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4. 
STUDY DESIGN 
4.1. 
Treatment Plan and Regimen 
This is a phase 2 randomized, double-blind, placebo-controlled study of VIR-2218 administered 
SC to adult subjects with chronic HBV infection without cirrhosis on NrtI therapy.  The study is 
designed to evaluate the safety, tolerability, PK and antiviral activity of VIR-2218. This study 
will be conducted in close collaboration with an ongoing phase 1/2 regional study being 
conducted in multiple sites in the Asia-Pacific region (VIR-2218-1001, ClinicalTrials.gov 
Identifier: NCT03672188) described in more detail in Section 1.2.4. 
The study will include two Parts: 
 Part One: adult subjects with HBeAg-negative chronic HBV infection without cirrhosis 
on NrtI therapy for ≥ 6 months and HBV DNA < 90 IU/mL at screening (by central 
laboratory)  
 Part Two: adult subjects with HBeAg-positive chronic HBV infection without cirrhosis 
on NrtI therapy for ≥ 6 months and HBV DNA < 90 IU/mL at screening (by central 
laboratory)  
Each cohort in Part One/Two will be composed of 5 subjects randomized 4:1 to VIR 2218 or 
placebo, respectively. There are two planned cohorts (50 mg dose-level and 100 mg dose-level) 
and 1 optional cohort (≤ 200 mg dose-level) for each of Part One and Part Two of the study. 
Enrollment of the Part One/Two optional cohorts will be according to the same randomization 
scheme and eligibility criteria as the Part One/Two planned cohorts. The optional cohorts may be 
initiated after SRC review of a minimum of 6 weeks of available safety and antiviral activity data 
from the 200 mg cohorts of the VIR-2218-1001 regional study.  
The estimated total duration for each subject is up to 52 weeks, including screening period (4 
weeks), dosing period (4 weeks), post-second dose follow-up period (12 weeks) and extended 
follow-up period (up to 48 weeks) (Figure 3). Additional HBsAg monitoring is required for 
subjects with a ≥ 1 1og10 change from baseline (Day 1 predose level) decrease in HBsAg 
achieved by the Week 16 visit. Extended follow-up visits will occur every 4 weeks starting at 
Week 20, and subjects will be followed until the HBsAg level returns to > 90% of the Day 1 
predose level or Week 48, whichever comes earlier. Additional HBsAg monitoring may be 
discontinued at the Sponsor’s discretion based on emerging data. 
 
Figure 3.  
Study Design for Cohorts 
 
 


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The assessments performed at each visit are described in Appendix 2 for Part One/Two planned 
and optional cohorts. Fasting is not required for any study procedure/assessment.  
Screening period: 
Screening will be performed no more than 4 weeks before the Day 1 visit and will include 
written informed consent, determination of eligibility, collection of demographics and medical 
history as well as physical examination (including vitals), laboratory tests, 12-lead 
Electrocardiogram (ECG) and other assessments per the schedule of assessments.  To exclude 
the presence of cirrhosis, screening will include a mandatory noninvasive assessment of liver 
fibrosis such as a FibroScan evaluation, unless the subject has results from a FibroScan 
evaluation performed within 6 months prior to screening or a liver biopsy performed within 1 
year prior to screening that confirms the absence of Metavir F3 fibrosis or F4 cirrhosis. Adverse 
events related to screening activities must be collected from the time of consent onwards; any 
other events occurring during the screening period should be reported as medical history. All 
SAEs must be collected from the time of consent onwards.  
Dosing period: 
Subjects enrolled will remain outpatient. Subjects will be randomized 4:1 to receive VIR-2218 or 
placebo within 48 hours prior to study drug administration on Day 1. Subject eligibility must be 
confirmed prior to study drug administration on Day 1. Subjects will return to the clinical 
investigative site at Week 4 to receive a second dose of the same study drug administered on 
Day 1. The decision to administer a second dose will be made based on Week 3 laboratory 
values in accordance with dose suspension/stopping criteria in Section 4.6.
 
 
 
Subjects enrolled into the optional cohorts will receive VIR-2218 or placebo on Day 1 and Week 
4 at a maximum dose-level of 200 mg.   
Post-dose follow-up period: 
Subjects will return to the clinical investigative site on an outpatient basis for safety, tolerability, 
PK, and antiviral activity monitoring at specified timepoints during this Post-dose Follow-up 
period (Week 5 to Week 16). Additional HBsAg monitoring is required for subjects with a ≥ 1 
1og10 change from baseline (Day 1 predose level) decrease in HBsAg achieved by the Week 16 
visit.  
Extended follow-up period: 
Subjects who require additional HBsAg monitoring will return to the clinical investigational site 
for in-person assessments. Extended follow-up visits will occur every 4 weeks starting at Week 
20, and subjects will be followed until the HBsAg level returns to > 90% of the Day 1 predose 
level or Week 48, whichever comes earlier. Additional HBsAg monitoring may be discontinued 
at the Sponsor’s discretion based on emerging data.  
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4.2. 
Discontinuations 
Subjects who discontinue prematurely will be followed for safety, and under certain 
circumstances, subjects who discontinue study drug (as described in Section 4.3) may be 
replaced. If a subject discontinues from the study post-dose but before completion of the 
Week 16 visit, an Early Termination (ET) visit should be performed. 
4.3. 
Replacement of Subjects 
Replacement subjects may be enrolled to ensure that the minimum data requirements for 
SRC decisions and study progression are met, as described in Section 4.5. Subjects who do not 
receive the full planned dose, do not receive a second dose, discontinue due to an AE that does 
not meet study progression and dose suspension/stopping rules (Section 4.6), or who withdraw 
from the study, may be replaced with confirmation by the SRC. Subjects who are discontinued 
from treatment for reasons other than experiencing an AE may be replaced following discussion 
between the Sponsor and investigator. 
The replacement subject will be assigned a unique study identification number and will receive 
the same study drug assignment and dose level as the subject who is being replaced and in the 
same blinded fashion. 
4.4. 
Safety Review Committee 
An SRC will perform ongoing reviews of safety, tolerability, and available study data collected 
throughout the study with the primary purpose of protecting the safety of subjects participating in 
this clinical study. The SRC will be governed by an SRC Charter that will be finalized prior to 
screening the first subject. 
The SRC will undertake safety data review prior to initiation of dosing the optional cohorts of 
the study in accordance with the SRC Charter. In addition, ad hoc SRC meetings may take place 
as needed, e.g., for a significant safety event such as a subject or cohort stopping criterion being 
reached (Section 4.6). 
Decisions to suspend dosing or discontinue individual subjects from study drug will be made 
according to predetermined stopping rules (Section 4.6). Additionally, the SRC may recommend 
discontinuation of the study to the Sponsor. The SRC membership composition is described in 
detail in the SRC Charter. 
4.5. 
Study Drug Dosing and Study Progression 
Progression rules are based on the absence of prespecified safety signals. Standard toxicity 
grading according to the current Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5 will be used to grade AEs. The decision to enroll an optional cohort or expand an 
existing cohort will be made by the SRC based on available safety, tolerability, and antiviral 
activity data, if further data are considered necessary to better understand dose response and/or 
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Subjects will receive VIR-2218 or placebo via SC injection according to the schedules provided 
in Appendix 2.  
4.6. 
Stopping Rules 
The following stopping rules are based on potential safety signals. Standard toxicity grading 
according to the CTCAE Version 5.0 will be used to grade AEs. When a cohort is stopped, no 
further study drug will be administered at the dose level and further progression will be 
suspended. An ad hoc SRC meeting will be held, and only following SRC approval, may dosing 
be resumed; if required, additional approval from the concerned regulatory authority and the 
independent ethics committee (IEC)/institutional review board (IRB), in accordance with 
applicable requirements, will be obtained. De-escalation to a lower dose will be allowed at 
Sponsor discretion. 
4.6.1. 
Cohort Stopping Rules  
If any of the criteria described below are met, as determined by the Sponsor medical monitor or 
designee, cohort dosing will be suspended or stopped: 
 If 1 or more subjects experience a Grade 3 study drug-related rash  
 If 2 or more subjects experience the same study drug-related Grade 3 or higher AE  
 If 1 or more subjects experience a study drug-related serious adverse event (SAE)  
 If 1 or more subjects experiences a Grade 4 AE of rash, regardless of assessed causality 
4.6.2. 
Individual Subject Stopping Rules  
Individual subjects who have received 1 dose of study drug will not receive a second dose if any 
the following criteria are met:  
 Serum ALT > 10 × upper limit of normal (ULN) 
 Serum ALT > 5 × ULN, with no change (< 50% of baseline) in HBsAg 
 Serum ALT or AST > 3 × ULN with a concomitant total bilirubin > 2 × ULN  
 Any clinical manifestations of hepatic decompensation including but not limited to 
jaundice, ascites, variceal hemorrhage, hepatic encephalopathy, spontaneous bacterial 
peritonitis, or hepatorenal syndrome 
The investigator should contact the medical monitor in the event that any of the above criteria are 
met, prior to dose discontinuation, unless the investigator believes that immediate action is 
warranted to ensure the continued safety of the subject. 


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5. 
SUBJECT POPULATION 
5.1. 
Number of Subjects and Subject Selection 
A total of up to 30 adult subjects with chronic HBV infection without cirrhosis on NrtI therapy 
are planned to complete this study.  
 Part One Planned/Optional Dose Cohorts: Up to 15 adult subjects with chronic HBV 
infection without cirrhosis who are HBeAg-negative on NrtI therapy 
 Part Two Planned/Optional Dose Cohorts: Up to 15 adult subjects with chronic HBV 
infection without cirrhosis who are HBeAg-positive on NrtI therapy 
5.2. 
Inclusion Criteria 
Each subject must meet all the following inclusion criteria at screening to be eligible for 
enrollment in the study. All laboratory test requirements for inclusion will be performed by 
central laboratory: 
1. Age 18 (or age of legal consent, whichever is older) to 65 years at the time of screening 
2. 12-lead ECG within normal limits; or, with no clinically significant abnormalities at 
screening, as determined by the clinical investigator 
3. Female subjects must have a negative pregnancy test or confirmation of post-menopausal 
status. Post-menopausal status is defined as 12 months with no menses without alternative 
medical cause. Women of child-bearing potential (WOCBP) must have a negative serum 
pregnancy test (using central laboratory) at screening and a negative urine pregnancy test on 
Day 1, cannot be breast feeding, and must be willing to use highly effective methods of 
contraception 14 days before study drug administration through 12 weeks after last study 
drug administration. Refer to Section 6.6 for more information on highly effective methods 
of contraception. 
4. Male subjects with female partners of child-bearing potential must agree to meet 1 of the 
following contraception requirements from the time of study drug administration until the 
last follow-up visit: vasectomy with documentation of azoospermia, or male condom use plus 
partner use of 1 of the contraceptive options listed for contraception for WOCBP. Male 
subjects must also agree not to donate sperm for the 12 weeks following last study drug 
administration. Refer to Section 6.6 for more information on highly effective methods of 
contraception. 
5. Agrees to not donate blood during the duration of the study 
6. Willing to comply with the study requirements and able to provide written informed consent 
7. Weight ≥ 40 kg to ≤ 125 kg  
8. Chronic HBV infection as defined by a positive serum HBsAg for ≥ 6 months 


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9. On NrtI therapy for at least 6 months  
10. HBsAg > 150 IU/mL  
11. HBV DNA < 90 IU/mL  
12. Part One only: HBeAg-negative 
13. Part Two only: HBeAg-positive  
14. Agrees not to increase physical activity from the time of screening through 4 weeks after 
final administration of VIR-2218 
5.3. 
Exclusion Criteria 
Each subject must not meet any of the following exclusion criteria to be eligible for enrollment 
in the study: 
1. Any clinically significant chronic medical condition other than chronic HBV infection that, 
in the opinion of the investigator makes the volunteer unsuitable for participation in the study 
2. Any clinically significant acute condition such as fever (> 38o C) or acute respiratory illness 
within 7 days of first study drug administration 
3. Significant fibrosis or cirrhosis as defined by having either a FibroScan result of > 8.5kPa at 
screening or a liver biopsy within 1 year with Metavir F3 fibrosis or F4 cirrhosis. Refer to 
Section 7.2.8 for more information. 
4. Receipt of a vaccine 14 days prior to Day 1 
5. Previous or current psychiatric condition that precludes compliance with the protocol. 
Specifically excluded are persons with psychoses, ongoing risk for suicide, or history of 
suicide attempt or gesture within the past 5 years 
6. Systolic blood pressure > 140 mmHg and a diastolic blood pressure of > 90 mmHg after 
approximately 10 minutes resting at screening 
7. Subject has the following laboratory parameters at screening by central laboratory: 
a. Creatinine or total bilirubin above the upper limit of normal (ULN), OR 
international normalized ratio (INR) above 1.1x ULN 
b. hemoglobin, ANC, platelets, or albumin below the lower limit of normal (LLN) 
c. White blood cell (WBC), potassium, or sodium above the ULN or below the LLN 
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Study Screening laboratory tests may be repeated once (e.g., for values thought to be 
erroneous) with medical monitor approval. 
8. Received an investigational agent within 90 days before study drug administration or are 
active in the follow-up phase of another clinical study involving interventional treatment. 
Subjects must also agree not to take part in any other study at any time during their 
participation in this study, inclusive of the follow-up period. 
9. Used prescription drugs within 14 days before study drug administration except for a stable 
dose of medication to treat hypertension, inhaler or nebulizer to treat asthma,  hormone 
replacement therapy, antihistamines, and contraceptive therapy (refer to Section 6.4.1 for 
more information). Hypertension must be well controlled on no more than 2 medications or 1 
medication with two active components for > 6 months. Asthma must be well controlled, 
requiring, on average, use of a rescue bronchodilator no more than twice per week. 
10. Use of over-the-counter (OTC) medication or herbal remedy within 14 days before Day 1 
and throughout the study, with the following exceptions of permitted OTC medications: 
Paracetamol (acetaminophen) ≤ 2g/day, aspirin ≤ 3g/day or ibuprofen < 1.2 g/day. 
11. Active infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or 
hepatitis Delta virus as determined by the central laboratory 
12. Consume more than 7 units of alcohol per week (unit: 1 glass of wine [125 mL] = 1 measure 
of spirits [30 mL] = one-half pint of beer [284 mL]). Alcohol is limited to no more than 
1 unit per day for the duration of the study 
13. History or clinical evidence of alcohol or drug abuse, within the 12 months before screening 
or a positive drug screen for amphetamines, cocaine, methadone or opiates at screening 
unless it can be explained by a prescribed medication; the diagnosis and prescription must be 
approved by the investigator. Screening results must be reviewed by the investigator to 
confirm eligibility prior to dosing. 
14. Known hypersensitivity or contraindication to an siRNA or GalNAc 
15. History of intolerance to SC injection 
16. Any conditions which, in the opinion of the investigator, would make the subject unsuitable 
for enrollment or could interfere with the subject’s participation in or completion of the study 
17. Donated more than 500 mL of blood within 90 days before study drug administration 
18. Creatinine clearance (CLcr) < 60 mL/min as calculated by the Cockcroft-Gault formula at 
screening 
19. History of chronic liver disease from any cause other than chronic HBV infection 
20. History of hepatic decompensation, including ascites, hepatic encephalopathy and/or 
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6. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
6.1. 
Randomization, Blinding, and Treatment Codes 
An Interactive Web Response System (IWRS) will be employed to manage subject 
randomization and treatment assignments.  
6.1.1. 
Procedures for Breaking of Treatment Codes 
Blinding of study treatment will be managed by the clinical investigative site’s pharmacy in 
accordance with the Pharmacy Manual. In the event of a medical emergency where breaking the 
blind is required to provide medical care to the subject, the investigator may obtain treatment 
assignment for that subject. IWRS should be used as the primary method of breaking the blind. If 
IWRS cannot be accessed, the investigator should contact the Sponsor medical monitor to break 
the blind. Treatment assignment should remain blinded unless that knowledge is necessary to 
guide subject emergency medical care. The investigator is requested to contact the Sponsor 
medical monitor promptly in case of any treatment unblinding. 
Blinding of study treatment is critical to the integrity of this clinical study and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject. 
The Sponsor or designee may independently unblind cases for expedited reporting of suspected 
unexpected serious adverse reactions (SUSARs) as required by regulators. 
6.2. 
Description and Handling of VIR-2218 and Placebo 
6.2.1. 
Formulation 
VIR-2218 is a clear, colorless to pale yellow solution, which will be supplied by the Sponsor as a 
sterile solution for SC injection at a free acid concentration of 200 mg/mL. Placebo is a sterile, 
preservative-free normal saline 0.9% solution for SC injection, which will be supplied by the 
clinical investigative site or the Sponsor where required. 
6.2.2. 
Packaging and Labeling 
VIR 2218 (solution for SC injection) is packaged in 2-mL glass vials with a fill volume of no 
less than 0.7 mL to allow for complete withdrawal of 0.5 mL of drug product at the pharmacy. 
The container closure system consists of a Type I glass vial, a Teflon-faced 13-mm stopper, and 
a flip-off aluminum seal. 
VIR-2218 and Placebo will be packaged and labeled in a manner consistent with the study 
design and applicable regulations. 


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6.2.3. 
Storage and Handling 
Study drug may be dispensed only by the investigator, by a staff member specifically authorized 
by the investigator, or by pharmacy staff, as appropriate. 
Each clinical investigative site will be responsible for assembly and labeling of injection 
syringe(s) according to procedures detailed in the Pharmacy Manual. The pharmacy staff will 
prepare the study drug using an aseptic technique. The amount (in mg) of study drug to be 
administered will be determined based on the assigned dose level for the cohort for subjects with 
chronic HBV infection. All syringes will be covered to ensure the study blind is maintained since 
the IP solution may have a slight yellow coloring and the placebo (sterile normal saline) is clear. 
Additional details regarding the procedure for preparing study drug, the volume to be loaded into 
each syringe, and how the syringes are to be ‘blinded’ are provided in the Pharmacy Manual. 
No special procedures for the safe handling of VIR-2218 are required. Study drug will be stored 
upright and refrigerated at 2 to 8°C protected from light in the storage area of the clinical 
investigative site pharmacy, in a secure, temperature-controlled, locked environment with 
restricted access. Any deviation from the recommended storage conditions should be reported to 
the Sponsor and use of the study drug halted until authorization for its continued use has been 
provided by the Sponsor or designee. Refer to the Pharmacy Manual for additional storage 
details.  
6.2.4. 
 Dosage and Administration of VIR-2218 
Dose and dose cohorts for this study are described in Sections 1.2.4 and 4.1, respectively. Study 
drug dose and administration are summarized by dose cohort in Table 4. On dosing days, the 
pharmacist or designee will withdraw the required amount of study drug into 1 or more syringes 
containing up to 1.5 mL/ syringe. A qualified clinical investigative site staff member under the 
supervision of the investigator or designee will administer study drug to subjects via SC 
injection. The injection site(s) will be marked and mapped for later observation and should be 
documented. If a local reaction around the injection site occurs, photographs may be obtained. 
Refer to the Pharmacy Manual for detailed study drug preparation and administration 
instructions.  


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Table 4. 
Study Drug Dose and Administration  
Cohort 
Visit Dose 
Level 
(mg) 
Visit Dose 
Volume 
(mL) 
Cumulative 
Dose (mg) 
Injections Per 
Dose 
Administration
Injections 
Total 
Cumulative 
Dose Volume 
(mL) 
Part One 
Low dose 
50 
0.25 
100 
1 
2 
0.50 
High dose 
100 
0.50 
200 
1 
2 
1.0 
Optional  
 200 
 1.0 
 400 
1 
2 
 2.0 
Part Two 
Low dose 
50 
0.25 
100 
1 
2 
0.50 
High dose 
100 
0.50 
200 
1 
2 
1.0 
Optional  
 200 
 1.0 
 400 
1 
2 
 2.0 
6.3. 
Investigational Product Accountability 
The investigator or designee will maintain accurate records of receipt and the condition of the 
study drug supplied for this study, including but not limited to, date of receipt, quantity, and 
temperature. In addition, accurate records will be kept of when and how much study drug is 
dispensed and administered to each subject in the study. Any reasons for departure from the 
protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs.  
Further instructions about drug accountability and disposal are detailed in the Pharmacy Manual. 
6.4. 
Concomitant Therapy 
6.4.1. 
Permitted Concomitant Medications 
The following medications/treatments are permitted: 
 Hormone replacement therapy 
 Oral, injectable, subdermal, intravaginal, or implantable contraceptives, as well as 
intrauterine device, and intrauterine hormone-releasing system are permitted for 
contraception 
 Paracetamol (≤ 2g/day), aspirin (≤ 3g/day), or ibuprofen (< 1.2 g/day) 
 Antihistamines 
 Prescription inhaler or nebulizer to treat asthma (inhaled bronchodilator or inhaled 
steroid). Asthma must be well controlled, defined as historical use of a rescue 
bronchodilator on average no more than twice per week. 


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 A stable dose and regimen of any medication(s) (prescription or OTC) that the subject 
is taking regularly (i.e. medications for chronic conditions such as hypertension, high 
cholesterol, or depression must be unchanged in dose or type for at least 6 months), is 
permitted, except those listed in Section 6.4.2.  
Investigators may initiate new prescription and non-prescription concomitant medications or 
treatments deemed necessary to provide adequate care for AEs or other new onset medical 
conditions, except those listed in Section 6.4.2.  
 
6.4.2. 
Prohibited Concomitant Medications 
The following medications/treatments are prohibited: 
 Any OTC medications or herbal remedy within 14 days before Day 1 and throughout 
the study, except for those specified in Section 6.4.1  
 Any prescription medications within 14 days before study drug administration except 
for those specified in Section 6.4.1 and NrtI therapy 
6.5. 
NrtI Therapy 
Examples of allowed NrtI therapy are listed below, but not limited to: 
 Tenofovir (tenofovir alafenamide (TDF) or tenofovir disoproxil fumarate (TAF) at 
recommended dose for the given tablet) 
 Entecavir 
 Lamivudine 
 Adefovir/adefovir dipivoxil 
6.6. 
Contraceptive Requirements 
WOCBP may be included in this study and include any female subject who has experienced 
menarche and who is not post-menopausal or permanently sterilized (eg, bilateral tubal 
occlusion, hysterectomy, or bilateral salpingectomy). 
WOCBP must be willing to use highly effective methods of contraception 14 days before dose, 
throughout study participation, and for 12 weeks after last dose of study drug administration. 
Highly effective methods of birth control result in a low failure rate (ie, less than 1% per year). 
Birth control methods which are considered highly effective include: 
 Established use of combined (estrogen and progestogen containing) oral, intravaginal, 
or transdermal hormonal methods of contraception associated with inhibition of 
ovulation OR established use of progestogen-only oral, injectable, or implantable 


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hormonal methods of contraception associated with inhibition of ovulation. It is not 
currently known whether VIR-2218 will impact the effectiveness of hormonal 
contraceptive methods; therefore, it is recommended to use an additional form of 
contraception (ie, barrier method) throughout the study and for 12 weeks after last 
study drug administration. 
 Placement of an intrauterine device 
 Placement of an intrauterine hormone-releasing system 
 Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject) 
 True sexual abstinence, when in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. Abstinent 
subjects have to agree to use 1 of the above-mentioned contraceptive methods, if they 
start sexual relationships during the study and for up to 12 weeks after last dose of 
study drug administration, or for as long as the subject is followed on study, 
whichever is longer. 
 Barrier method in combination with hormonal contraceptive, as described above 
Post-menopausal status is defined as 12 months with no menses without an alternative medical 
cause. 
Male subjects with female partners of child-bearing potential must agree to meet 1 of the 
following contraception requirements from the time of study treatment administration until the 
last follow-up visit. 
 Vasectomy with documentation of azoospermia 
 Male condom plus partner use of 1 of the contraceptive options listed above for 
contraception for WOCBP (hormonal contraceptive, intrauterine device) 
Male subjects must also agree not to donate sperm for the 12 weeks following last study drug 
administration.  


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7. 
STUDY PROCEDURES 
7.1. 
Procedures and Specifications 
The Schedule of Assessments (SoA) is provided in Appendix 2 for Part One/Two planned and 
optional cohorts. Unscheduled visits are permitted at the discretion of the investigator as needed 
for safety assessment. 
7.1.1. 
Medical History 
A complete medical history, including details regarding illnesses and allergies, date(s) of onset, 
and whether condition(s) is currently ongoing, medication history, including prior HBV 
treatment history and HBV genotype history (if available), will be collected on all subjects 
during screening and should be updated prior to dosing.  
7.1.2. 
Assessment of Antiviral Activity and Development of Resistance 
During the study, assessments of antiviral activity will include: HBsAg, HBeAg, 
 anti-
HBs, anti-HBe, HBV DNA, 
 and assessment of HBV and NrtI resistance if indicated. 
HBV genome will be sequenced and analyzed for mutations that can confer resistance to 
VIR-2218 and NrtIs in subjects with confirmed HBV breakthrough as defined by 
HBV DNA ≥ 500 IU/mL measured at 2 consecutive study visits. HBV RNA may be sequenced 
to determine if nucleotide changes within the VIR-2218 target site may impact responsiveness. 
Details regarding the processing, shipping, and analysis of the samples are provided in the 
Laboratory Manual. 
7.1.3. 
Screening Viral Serology Parameters 
Screening viral serology parameters include active infection with HIV infection, HCV infection, 
chronic HBV infection and hepatitis Delta virus infection. Chronic HBV infection is defined as 
serum HBsAg for > 6 months. In cases of occult HBV, chronic HBV infection is defined as 
serum HBV DNA positive for > 6 months.  
7.1.4. 
Pharmacokinetic Assessments 
Blood samples will be collected to assess concentrations of VIR-2218 and metabolites, as 
applicable. Timepoints for the collection of samples for VIR-2218 PK analysis of the study are 
provided in Appendix 3.  
Details regarding the processing, shipping, and analysis of the samples are provided in the 
Laboratory Manual. 
 
  
 
 
 
CCI
CCI
CCI


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7.2. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs 
including SAEs, recording of concomitant medications, physical examination findings, alcohol 
assessment, ECG, and laboratory tests. All AEs related to screening activities must be collected 
from the time of consent onwards; any other events occurring during the screening period should 
be reported as medical history. All SAEs must be collected from the time of consent onwards.  
7.2.1. 
Physical Examination 
A full physical examination will include general appearance, head, neck, chest/respiratory, 
heart/cardiovascular, gastrointestinal/liver, extremities, skin, and screening neurological 
assessments. 
A symptom-directed physical examination will be performed according to investigator 
discretion. 
7.2.2. 
Alcohol Assessment 
Alcohol intake during the study will be recorded. 
7.2.3. 
Height and Weight 
Height and body weight will be measured. Body mass index will be calculated from height and 
weight. 
7.2.4. 
Vital Signs 
Vital sign measurements include blood pressure, pulse rate, temperature (oral preferred), and 
respiratory rate. Vital signs should be measured after the subject has rested comfortably for 
approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital 
signs and 12-lead ECGs must be performed before blood sample collections. 
7.2.5. 
Electrocardiogram 
12-lead safety ECGs will be recorded and reviewed on-site by the investigator as outlined in 
Appendix 2.  
7.2.6. 
Pregnancy Testing 
A pregnancy test or confirmation of post-menopausal status must be confirmed for all female 
subjects. Post-menopausal status is defined as 12 months with no menses without alternative 
medical cause. Pregnancy tests will be performed for WOCBP only. Pregnancy testing will be 
performed per the SoA and any time pregnancy is suspected. A WOCBP who is known to be 
pregnant or who does not have a negative pregnancy test at screening is not eligible for study 
participation. A serum pregnancy test will be performed at screening and urine pregnancy tests 
will be performed thereafter. During the study, the results of these pregnancy tests must be 


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known prior to study drug administration. A WOCBP determined to be pregnant while on study 
will be followed until the pregnancy outcome is known, as described in Section 8.5.2.  
7.2.7. 
Clinical Laboratory Assessments 
Clinical laboratory tests that will be performed in this study are presented in Table 5. In the event 
of an unexplained clinically relevant abnormal laboratory test occurring after study drug 
administration, the test should be repeated and followed up at the discretion of the investigator 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality. 


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Table 5. 
Clinical Laboratory Tests 
Hematology 
 
 
Complete blood count with differential
 
Chemistry 
 
 
Albumin
 
Creatinine clearance
 
Blood urea nitrogen (BUN)
 
Gamma glutamyl transferase (GGT)
 
Calcium
 
Glucose
 
Carbon dioxide/bicarbonate
 
Lactate dehydrogenase (LDH)
 
Chloride
 
Potassium
 
Creatine kinase
 
Sodium
 
Creatinine
 
Uric acid
Liver Function Tests 
 
 
Alkaline phosphatase (ALP) 
 
AST
 
ALT
 
Bilirubin (total and direct)
Coagulation Parameters 
 
 
International normalized ratio (INR) time 
 
Prothrombin
Urinalysis 
 
 
Bilirubin
 
Proteins
 
Glucose
 
Red blood cells (RBCs)
 
Ketones
 
Screen for drugs of abuse
 
Leukocytes
 
Specific gravity
 
Microscopy (if clinically indicated)
 
Urobilinogen
 
Nitrite
 
Visual inspection for appearance and color
 
pH 
 
Pregnancy Testing 
 
 
Beta-human chorionic gonadotropin (WOCBP 
 
Urine pregnancy test
Serology 
 
 
Hepatitis B, C, and Delta
 
Human immunodeficiency virus I and II
 
 


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7.2.8. 
FibroScan 
To exclude the presence of cirrhosis, subjects will have a FibroScan evaluation, unless the 
subject has results from a FibroScan evaluation performed within 6 months prior to screening or 
liver biopsy performed within 1 year prior to screening that confirm the absence of Metavir F3 
fibrosis or F4 cirrhosis. If a subject has had both procedures in the specified timeframes, the most 
recent result should be used to determine eligibility. 


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8. 
ADVERSE EVENTS MANAGEMENT 
8.1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events 
8.1.1. 
Adverse Events 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal product, 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 medicinal product, whether or not considered related to the 
medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Pre-existing conditions (recorded as medical history), which change in 
nature or severity should also be considered AEs.  
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 adverse event and must be 
reported. 
 Pre-existing 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 of study drug without clinical sequelae 
 Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not 
an AE. It is considered to be pre-existing and should be documented on the medical 
history Case Report Form (CRF). 
 Unless associated with signs or symptoms, laboratory abnormalities (e.g., low platelets) 
should not be recorded as AEs, as these abnormalities will be captured as laboratory 
abnormalities 
 Procedures should not be recorded as AEs; however, the condition that led to the 
procedure may be an AE 
8.1.2. 
Serious Adverse Events 
An SAE is any event that results in the following: 
 Death 


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 Life-threatening: An AE is life threatening if the subject was at immediate risk of death 
from the event as it occurred; i.e., it does not include a reaction that if it had occurred in a 
more serious form might have caused death. For example, drug induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life threatening 
even though drug induced hepatitis can be fatal. 
 Inpatient hospitalization or prolongation of existing hospitalization: AEs requiring 
hospitalization should be considered SAEs. Hospitalization for elective surgery or routine 
clinical procedures that are not the result of AE (e.g., elective surgery for a pre-existing 
condition that has not worsened) need not be considered AEs or SAEs. If anything 
untoward is reported during the procedure, that occurrence must be reported as an AE, 
either 'serious' or 'non-serious' according to the usual criteria. In general, hospitalization 
signifies that the subject has been detained (usually involving at least an overnight stay) 
at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting. When in doubt as to 
whether 'hospitalization' occurred or was necessary, the AE should be considered serious. 
 Persistent or significant disability/incapacity: an AE is incapacitating or disabling if the 
experience results in a substantial and/or permanent disruption of the subject's ability to 
carry out normal life functions 
 Congenital anomaly/birth defect in the offspring of a subject who received VIR-2218 
Other: Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such events are: 
 Intensive treatment in an emergency room or at home for allergic bronchospasm 
 Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
 Development of drug dependency or drug abuse 
8.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Per Section 8.1.1, laboratory abnormalities without an associated AE (signs or symptoms) and/or 
which do not require medical intervention, are not themselves recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention must be recorded as an AE, as well as an SAE, if 
applicable. In addition, laboratory or other abnormal assessments (e.g., electrocardiogram, 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 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a clinical syndrome, record the syndrome or diagnosis (e.g., anemia), not 
the laboratory result (i.e., decreased hemoglobin). 


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8.2. 
Assessment of Adverse Events and Serious Adverse Events 
The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments. 
8.2.1. 
Assessment of Causality for Study Drugs and Procedures 
Causality (Yes or No) should be determined by the investigator or qualified sub-investigator. An 
answer of Yes, should be entered when, in their opinion, there is either (a) a reasonable 
possibility that the AE is associated with study drug or (b) no reasonable alternative explanation 
can be identified. Otherwise, causality to study drug should be categorized as No. A mere 
possibility of a causal relationship is not grounds for a Yes categorization. 
8.2.2. 
Assessment of Severity 
AE severity should be graded using the CTCAE Version 5.0. 
8.3. 
Investigator Requirements and Instructions for Reporting Adverse Events and 
Serious Adverse Events to Sponsor 
Requirements for collection prior to study drug initiation: 
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported: AEs related to protocol-mandated procedures and all SAEs. 
8.3.1. 
Adverse Events 
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 12 weeks after last administration of study drug.  
All AEs should be followed up until resolution or until the AE is stable, if possible. Sponsor may 
request that certain AEs be followed beyond the protocol-defined follow-up period. 
8.3.2. 
Serious Adverse Events 
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required follow-up period, must be reported as instructed. This also 
includes any SAEs resulting from protocol-mandated procedures performed after informed 
consent is signed. 
Investigators are not obligated to actively seek SAEs after the protocol--defined follow-up 
period. However, if the investigator learns of any SAEs that occur after study participation has 
concluded and the event is deemed relevant to the use of study drug, he/she should promptly 
document and report the event to Sponsor.  


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 For fatal or life-threatening events, copies of hospital case reports, discharge summaries, 
autopsy reports, and other documents should be submitted by email when requested and 
applicable. Transmission of such documents should occur without personal subject 
identification, maintaining the traceability of a document to the subject 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 subject’s electronic case report form (eCRF) and 
the event description section of the SAE form. 
 Email the SAE form within 24 hours of the investigator’s knowledge of the event. 
Contact information is as follows: 
 
8.4. 
 Sponsor Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable US Food and 
Drug Administration Code of Federal Regulations, the EU Clinical Trials Directive 
(2001/20/EC) and relevant updates, and other country-specific legislation or regulations, the 
Sponsor may be required to expedite to worldwide regulatory agencies reports of SAEs, serious 
adverse drug reactions (SADRs), or SUSARs. In accordance with the EU Clinical Trials 
Directive (2001/20/EC), the Sponsor 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 the Sponsor using reference safety 
information specified in the Investigator’s Brochure.  
All investigators will receive a safety letter 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. 
8.5. 
Special Situations Reports 
8.5.1. 
Definitions of Special Situations 
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE. 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer. 
PPD


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Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject. 
Misuse is defined as any intentional and inappropriate use of a medicinal product 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 medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol (as it applies to the daily dose of the subject in question). In cases of a 
discrepancy in drug accountability, overdose will be established only when it is clear that the 
subject has taken the excess dose(s). Overdose cannot be established when the pharmacist cannot 
account for the discrepancy except in cases in which the investigator has reason to suspect that 
the additional dose(s) were administered to the subject. 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
8.5.2. 
Instructions for Reporting Special Situations 
Pregnancy Reporting 
If a female subject becomes pregnant after the first study drug administration through the 
follow-up period (12 weeks after last study drug administration), the investigator must report the 
pregnancy to the Sponsor or designee within 24 hours of being notified of the pregnancy. The 
subject should receive any necessary counseling regarding the risk of continuing the pregnancy 
and the possible effects on the fetus.  
The pregnancy should be followed by the investigator until completion. At the completion of the 
pregnancy, the investigator will document the outcome of the pregnancy. If the outcome of the 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death 
or congenital anomaly, then the investigator should follow the procedures for reporting an SAE 
as outlined in Section 8.3.  
If the partner of a male subject becomes pregnant after study drug administration through the 
follow up period, the subject should report this to the investigator and a Partner Pregnancy 
Information and Consent Form will be provided to allow follow up of the pregnancy as described 
above. 
Reporting Other Special Situations 
All other special situations must be reported to the Sponsor within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study drug 
and/or protocol-required concomitant medications, but do not apply to non-required concomitant 
medications. Contact information is as follows: 
 
PPD


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Special situations involving non-required concomitant medications do not need to be reported; 
however, for special situations that result in AEs due to a non-required concomitant medication, 
the AE should be reported. 
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 special situation reports will be reported as AEs or SAEs 
at the same time. Details of the symptoms and signs, clinical management, and outcome will be 
reported, when available. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Objectives 
The objectives are listed in Section 2. 
9.2. 
Endpoints 
The endpoints are listed in Section 3. 
9.3. 
Analysis Conventions 
Descriptive statistics will be presented for continuous variables, and frequencies and percentages 
will be presented for categorical and ordinal variables. Percentages will be based on the number 
of nonmissing values in a dose group. 
9.3.1. 
Analysis Sets 
Safety 
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes all 
subjects who received at least 1 dose of study drug. 
Pharmacokinetic 
The primary analysis set for PK analyses will be the PK Analysis Set, which includes all subjects 
in the Safety Analysis Set who have at least 1 nonmissing concentration data to provide 
interpretable results for the specific parameters of interest for the analyte under evaluation. 
Antiviral Activity  
The primary analysis set for antiviral activity analyses will be the Antiviral Analysis Set, which 
includes all subjects in the Safety Analysis Set who have at least 1 nonmissing data to provide 
interpretable results for the specific antiviral activity parameters of interest. 
9.3.2. 
Data Handling Conventions 
PK concentration values and PK parameter values below the limit of quantitation (BLQ) will be 
presented as “BLQ” in the data listings. For purposes of graphic presentation, BLQ values that 
occur prior to study drug administration will be treated as 0, BLQ values at all other timepoints 
will be treated as one-half of the lower limit of quantitation (LLOQ). 
Laboratory data that are continuous in nature but are less than the LLOQ or above the upper limit 
of quantitation will be imputed to the value of the lower or upper limit minus or plus 1 
significant digit, respectively (e.g., if the result of a continuous laboratory test is < 30, a value of 
29 will be assigned; if the result of a continuous laboratory test is < 30.0, a value of 29.9 will be 
assigned). 


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9.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using standard descriptive 
statistics including sample size, mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum for continuous variables and numbers and of subjects for 
categorical variables. 
9.5. 
Safety Analysis 
All safety analyses will be performed using the Safety Analysis Set. Safety will be evaluated by 
assessment of clinical laboratory tests, physical examinations, ECGs, vital signs measurements at 
various timepoints during the study, and by the documentation of AEs. 
All safety data collected up to 12 weeks after the last study drug administration will be 
summarized by cohort for each VIR-2218 dose and placebo.  
9.5.1. 
Adverse Events 
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), High-
Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be attached to the 
clinical database. 
Treatment-Emergent Adverse Events (TEAEs) are defined as any AEs with an onset date of on 
or after the study drug start date and no later than 30 days after permanent discontinuation of 
study drug. 
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided by 
cohort. TEAEs will also be summarized by relationship to study drug and severity.  
9.5.2. 
Laboratory Evaluations 
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by cohort and study visit along with corresponding change from baseline. 
Graded laboratory abnormalities will be defined using CTCAE Version 5.0 grading scale. 
The incidence of treatment-emergent laboratory abnormalities, defined as values that increase at 
least 1 toxicity grade from baseline at any postbaseline timepoint up to 30 days after permanent 
discontinuation of study drug will be summarized by treatment group. If the relevant baseline 
laboratory data are missing, then any abnormality of at least Grade 1 will be considered as 
treatment-emergent.   
 
9.5.3. 
Other Safety Evaluations 
Individual data for physical examination findings, prior and concomitant medications and 
medical history will be provided. Twelve-lead ECGs and vital signs measurements will be listed 


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by subject and summarized by incidence of events/abnormalities or descriptive statistics as 
appropriate. 
9.6. 
Pharmacokinetic/Pharmacodynamic Analysis 
Plasma PK parameters of VIR-2218 and possible metabolites will be computed using standard 
noncompartmental methods. Parameters may include, but not be limited to maximum 
concentration, time to reach maximum concentration, area under the concentration versus time 
curve (to the last measurable timepoint and to infinity), percent of area extrapolated, apparent 
terminal elimination half-life, clearance, and volume of distribution. Other parameters may be 
calculated, if deemed necessary.  
PK/pharmacodynamic analyses will be conducted to explore exposure-response relationships 
between PK parameters and selected antiviral variables. These analyses may include graphical 
plots, tabular summaries, and various linear and/or nonlinear analyses. Details of the analysis 
will be provided in the Statistical Analysis Plan. 
9.7. 
Antiviral Activity Analysis 
Selected data relating to the antiviral activity of VIR-2218, such as HBsAg, HBeAg,
 
anti-HBs, anti-HBe, 
 and HBV DNA levels, will be summarized (n, mean, SD, 
median, Q1, Q3, minimum, and maximum) by cohort and study visit along with corresponding 
change from baseline. Summaries (number and percentage of subjects) of HBsAg loss, anti-HBs 
seroconversion, HBeAg loss, and anti-HBe seroconversion will be provided by cohort and study 
visit. 
9.8. 
Sample Size 
No formal sample size calculation was conducted. Up to 30 subjects with chronic HBV infection 
are planned to complete the study. 
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10. 
RESPONSIBILITIES 
10.1. 
Investigator and Sponsor Responsibilities 
10.1.1. 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval 
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB or IEC. Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
10.1.2. 
Informed Consent 
The investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Subjects must also 
be notified that participation is completely voluntary and that they are free to discontinue from 
the study at any time. The subject should be given the opportunity to ask questions and allowed 
time to consider the information provided.  
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures.  
The investigator must maintain the original, signed Informed Consent Form (ICF). A copy of the 
signed ICF must be given to the subject. 
10.1.3. 
Confidentiality 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials and date of birth (where 
local regulations allow) and an identification code (ie, not names) should be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the study. 
The investigator agrees that all information received from the Sponsor, including but not limited 
to the Investigator’s Brochure, this protocol, CRFs, the investigational new drug, and any other 
study information, remain the sole and exclusive property of the Sponsor during the conduct of 
the study and thereafter. This information is not to be disclosed to any third party (except 
employees or agents directly involved in the conduct of the study or as required by law) without 
prior written consent from the Sponsor. The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the clinical investigative site 
to any third party or otherwise into the public domain. 


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In compliance with local and/or regional regulations, this clinical study may be registered and 
study results may be posted on public registries, such as ClinicalTrials.gov.  
10.1.4. 
Study Files and Retention of Records 
All documentation relating to the study should be retained for the period of time required by 
applicable local law. If it becomes necessary for the Sponsor or designee, applicable IRB/IEC, or 
applicable regulatory authorities to review or audit any documentation relating to the study, the 
investigator must permit direct access to all source documents/data. Records will not be 
destroyed without informing the Sponsor in writing and giving the Sponsor the opportunity to 
store the records for a longer period of time at the Sponsor’s expense.  
10.1.5. 
Electronic Case Report Forms (eCRF) 
Study data must be recorded on electronic CRFs (eCRFs) provided by the Sponsor or designee 
on behalf of the Sponsor. eCRFs must be completed only by the investigator or person 
designated by the investigator. eCRF data must be entered by trained clinical investigative site 
personnel with access to a valid and secure eCRF system. All data entered into the eCRF must 
also be available in the source documents. Correction on source documents must be made so as 
to not obliterate the original data and must be initialed and dated by the person who made the 
correction.  
10.1.6. 
Good Clinical Practice 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the guidelines of Good Clinical Practice (GCP). Compliance with 
GCP provides public assurance that the rights, safety, and well-being of study subjects are 
protected consistent with the principles that have their origin in the Declaration of Helsinki 
(revised version of Edinburgh, Scotland, 2000), International Conference on Harmonisation 
(ICH) guidelines, or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the study subject.  
10.1.7. 
Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational product and placebo. Refer to the Pharmacy Manual for 
further information.  
10.1.8. 
Quality Control and Assurance 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core study process and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reports according to the 
protocol, GCP guidelines of ICH, an any applicable regulatory requirements. A regulatory 
authority, an IEC or an IRB may visit the clinical investigative site to perform audits or 
inspections, including source data verification. The investigator should contact the Sponsor, or 
its designee, immediately if contacted by a regulatory agency about an inspection.  


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10.1.9. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.1.10. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by the Sponsor. All protocol modifications must be submitted to the IRB or IEC in 
accordance with local requirements. Approval must be obtained before changes can be 
implemented. 
10.1.11. 
Study Report and Publications 
A clinical study report will be prepared and provided to the regulatory agency(ies).  
The Sponsor 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. 
After conclusion of the study and without prior written approval from the Sponsor, investigators 
in this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
 the results of the study in their entirety have been publicly disclosed by or with the 
consent of the Sponsor in an abstract, manuscript, or presentation form; or 
 the study has been completed at all clinical investigative sites for at least 2 years 
No such communication, presentation, or publication will include the Sponsor’s confidential 
information (Section 10.1.3). 
The investigator will submit any proposed publication or presentation along with the respective 
scientific journal or presentation forum at least 30 days before submission of the publication or 
presentation. The investigator will comply with the Sponsor’s request to delete references to its 
confidential information (other than the study results) in any paper or presentation and agrees to 
withhold publication or presentation for an additional 60 days to obtain patent protection if 
deemed necessary. 
10.2. 
Study Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have access to the 
investigator’s source documentation to verify the data recorded in the CRFs for consistency. 
The monitor is responsible for routine review of the CRFs 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 subject records needed to 


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verify the entries on the CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved.  
10.2.1. 
Study Discontinuation 
The Sponsor reserves the right to terminate the overall study at any time. The investigator 
reserves the right to discontinue the study at their institution at any time. Should this be 
necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, the Sponsor and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests. 


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11. 
REFERENCES 
1. Allweiss L, Dandri M. The Role of cccDNA in HBV Maintenance. Viruses. 2017;9: 156. doi: 
10.3390/v9060156 
2. Burton AR, Pallett LJ, McCoy L, Suveizdyte K, Amin OE, Froghi F, Davidson BR, Gill US, 
Kennedy PTF, Blair PA, Mauri C, Pelletier N, and Maini MK Dysfunctional surface antigen-
specific memory B cells accumulate in chronic hepatitis B infection. EASL International 
Liver Congress, Paris, France 2018 
3. Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. Journal of Hepatology. 2016; 
64(1): S71 - S83. doi: 10.1016/j.jhep.2016.01.026 
4. EASL. Recommendations for the treatment of hepatitis B in 2017. Clin Exp Hepatol. 2017 
Jun; 3(2): 35–46. doi: 10.5114/ceh.2017.67626 
5. Konerman MA, Lok AS. Interferon Treatment for Hepatitis B. Clinics in Liver Disease. 
2016;20(4): 645-665. doi: 10.1016/j.cld.2016.06.002 
6. Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. 
Journal of Hepatology. 2016;64(1): S84 - S101. doi: 10.1016/j.jhep.2016.02.021 
7. Li Y, Si L, Zhai Y, et al. Genome-wide association study identifies 8p21.3 associated with 
persistent hepatitis B virus infection among Chinese. Nature Communications. 2016; 
7:11664. doi:10.1038/ncomms11664. 
8. Liang TJ, Block TM, McMahon BJ, et al. Present and Future Therapies of Hepatitis B: From 
Discovery to Cure. Hepatology. 2015; 62(6):1893-1908. doi:10.1002/hep.28025. 
9. Lucifora J, Protzer U. Attacking hepatis B virus cccDNA—The holy grail to hepatitis B cure. 
Journal of Hepatology. 2016;64(1): S41-S48. doi: 10.1016/j.jhep.2016.02.009 
10. Maini MK, Gehring AJ. The role of innate immunity in the immunopathology and treatment 
of HBV infection. Journal of Hepatology. 2016;64(1): S60-S70. 10.1016/j.jhep.2016.01.028 
11. Nair, JK, Willoughby JL, Chan A, Charisse K, Alam MR, Wang Q, et al. Multivalent N 
acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi 
mediated gene silencing. J Am Chem Soc. 2014 Dec 10;136(49):16958-61. 
12. Protzer U, Maini MK, Knoelle PA. Living in the liver: hepatic infections. Nature Reviews 
Immunology. 2012;12: 201-213. doi:10.1038/nri3169 
13. Schweitzer A, Horn J, Mikolajczyk RT, Kraus G, Ott JJ. Estimations of worldwide 
prevalence of chronic hepatitis B virus infection: a systematic review of data published 
between 1965 and 2013. The Lancet. 2015;387(10003):1546-1555. doi: 10.1016/S0140-
6736(15)61412-X 


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14. Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology. 2015; 479-
480:672-686. doi: 10.1016/j.virol.2015.02.031. 
15. Stanaway JD, Flaxman AD, Naghavi M, et al. The global burden of viral hepatitis from 1990 
to 2013: findings from the Global Burden of Disease Study 2013. Lancet (London, England). 
2016;388(10049):1081-1088. doi:10.1016/S0140-6736(16)30579-7. 
16. Tong S, Revill P. Overview of viral replication and genetic variability. Journal of 
hepatology. 2016;64(1):S4-S16. doi:10.1016/j.jhep.2016.01.027. 
17. Trepo C. A brief history of hepatitis milestones. Liver International. 2014;34(1):29-37.doi: 
10.1111/liv.12409 
18. Willoughby JLS, Chan A, Sehgal A, Butler JS, Nair JK, Racie T, Shulga-Morskaya S, 
Nguyen T, Qian K, Yucius K, Charisse K, van Berkel TJC, Manoharan M, Rajeev KG, Maier 
MA, Jadhav V, Zimmermann TS. Evaluation of GalNAc-siRNA Conjugate Activity in Pre-
clinical Animal Models with Reduced Asialoglycoprotein Receptor Expression. Mol Ther. 
2018 Jan 3;26(1):105-114. doi: 10.1016/j.ymthe.2017.08.019. Epub 2017 Sep 7. 
19. WHO. “WPRO New Hepatitis B treatment guidelines released in China.” WHO Website. 
http://www.wpro.who.int/china/mediacentre/releases/2015/20150515/en/. May 15, 2015. 
20. WHO. Hepatitis B Fact sheet. WHO Website. 
http://www.who.int/mediacentre/factsheets/fs204/en/ . Updated July 2019. 


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12. 
APPENDICES 
Appendix 1. 
Investigator Signature Page 
Appendix 2.  
Part One/Two Schedule of Study Assessments (SoA) for Planned and 
Optional Cohorts in Subjects with Chronic HBV Infection 
Appendix 3. 
Part One/Two Pharmacokinetic Assessment Timepoints 
Appendix 4. 
Cohort Dose Schedule of the Regional Study and the China Study 
Appendix 5 
Protocol Amendment History 
 


VIR-2218-1005 
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Appendix 1. Investigator Signature Page 
Sponsor: 
Brii Biosciences Ltd. 
Room 301, 3/F, 
Building 7, 
No. 1 Yongtaizhuang North Street, 
Haidian District, Beijing 100192, China 
 
 
 
STUDY ACKNOWLEDGMENT 
 A Phase 2 Randomized, Placebo-Controlled Study in Mainland China to Evaluate the 
Safety, Tolerability, Pharmacokinetics and Antiviral activity of VIR-2218 
VIR-2218-1005, Amendment 2, 23 September 2020 
This protocol has been approved by Brii Biosciences Ltd. The following signature documents this 
approval.  
 
 
 
 
 
Printed Name 
 
Signature and 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 Brii Biosciences Ltd. I will discuss this material with them to ensure they are 
fully informed about the drugs and the study.  
 
 
 
 
Principal Investigator Printed Name 
 
Signature 
 
 
 
 
 
Date 
CCI


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Appendix 2.  Part One/Two Schedule of Study Assessments (SoA) for Planned and Optional Cohorts in Subjects with Chronic 
HBV Infection 
Study Stage 
Screening 
Dosing Period 
Post-dose Follow-up Period b 
Extended Follow-up 
Period c 
Study Visit Week 
 
 
 
W1 
W2 
W3 
W4a 
W5 
W6 
W7 
W8 
W12 
W16/ET 
W20 
W24 
Study Visit Day 
±Visit Window 
D-28 to -1 
D1a 
D2 
D8 
±2 
D15 
±2 
D22 
±2 
D29a 
±2 
D36 
±2 
D43 
±2 
D50 
±2 
D57 
±2 
D85 
±7 
D113 
±7/ET 
D141 
±7 
D169 
±7 
Q28D 
±7 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
including HBV 
genotyped
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
examinationf
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Symptom-directed 
physical examination 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Alcohol intake 
assessmentg
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Safety ECGi 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy testj 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
 
FibroScank 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening viral 
serologyl
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Stage 
Screening 
Dosing Period 
Post-dose Follow-up Period b 
Extended Follow-up 
Period c 
Study Visit Week 
 
 
 
W1 
W2 
W3 
W4a 
W5 
W6 
W7 
W8 
W12 
W16/ET 
W20 
W24 
Study Visit Day 
±Visit Window 
D-28 to -1 
D1a 
D2 
D8 
±2 
D15 
±2 
D22 
±2 
D29a 
±2 
D36 
±2 
D43 
±2 
D50 
±2 
D57 
±2 
D85 
±7 
D113 
±7/ET 
D141 
±7 
D169 
±7 
Q28D 
±7 
Laboratory 
assessmentm
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
Xn 
Urinalysism 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine for drugs 
abuseo
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administrationp
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Blood samples for PK 
analysisq
 
X 
X 
X 
 
 
Xr 
X 
 
 
X 
 
X 
 
X 
 
Blood sample for 
HBsAg
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for 
anti-HBs
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Xs 
Blood sample for 
HBeAg qualitative
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
HBeAg quantitative 
for Part Two onlyt
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
X 
Xs 
Blood sample for 
anti-HBe for Part 
Two only
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Xs 
Blood sample for 
HBV DNA 
quantitationu
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
Xs 


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Study Stage 
Screening 
Dosing Period 
Post-dose Follow-up Period b 
Extended Follow-up 
Period c 
Study Visit Week 
 
 
 
W1 
W2 
W3 
W4a 
W5 
W6 
W7 
W8 
W12 
W16/ET 
W20 
W24 
Study Visit Day 
±Visit Window 
D-28 to -1 
D1a 
D2 
D8 
±2 
D15 
±2 
D22 
±2 
D29a 
±2 
D36 
±2 
D43 
±2 
D50 
±2 
D57 
±2 
D85 
±7 
D113 
±7/ET 
D141 
±7 
D169 
±7 
Q28D 
±7 
Review/record AEsx 
X 
 
Concomitant 
Medications
X 
 
NrtI medication 
adherence
X 
AE = adverse event; ECG = electrocardiogram; ET = early termination; 
HBeAg = hepatitis e-antigen; HBsAg = hepatitis B 
surface antigen; HBV = Hepatitis B Virus; NrtI = nucleoside/nucleotide; PK = pharmacokinetics 
Note: When scheduled at the same timepoints, the assessments of vital signs and 12-lead ECGs must be performed before blood sample collections. 
a 
Assessments performed predose unless otherwise specified. 
b 
If a subject withdraws prematurely from the study prior to their Week 16 visit, ET assessments should be performed. 
c 
Additional HBsAg monitoring is required for subjects with a ≥ 1 1og10 change from baseline (Day 1 predose level) decrease in HBsAg achieved by the Week 16 
visit. Extended follow-up visits will occur every 4 weeks starting at Week 20, and subjects will be followed until the HBsAg level returns to > 90% of the Day 1 
predose level or Week 48, whichever comes earlier. Additional HBsAg monitoring may be discontinued at the Sponsor’s discretion based on emerging data.  
d 
A complete medical history will be taken at screening including HBV genotype if available. Any changes should be updated prior to dosing. 
e 
Evaluation of inclusion and exclusion criteria related to pregnancy testing, urine drug screen, medical history and concomitant medications prior to dosing. 
f 
See Section 7.2.1 for assessments to be performed during a full physical examination. 
g 
Subjects’ alcohol intake will be recorded while on study. 
h 
Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured in the supine position after the subject has rested comfortably for 
approximately 10 minutes. On Day 1, vital signs should be measured within 2 hours predose and 4 hours (± 30 minutes) post-dose. On all other visit days, vital 
signs are only required to be recorded once during the visit. 
i 
12-lead safety ECGs should be measured in the supine position after the subject has rested comfortably for 10 minutes. 
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Amendment 2 
 
CONFIDENTIAL 
Page 66 
23 September 2020 
j 
WOCBP are required to have pregnancy tests. A blood pregnancy test will be performed at screening and urine pregnancy tests will be performed thereafter. Urine 
pregnancy test results from local laboratories are acceptable. Negative pregnancy test must be confirmed prior to study drug administration. 
k 
Does not need to be performed if the subject has had a FibroScan in the 6 months prior to screening or liver biopsy in the year prior to screening that confirmed the 
absence of Metavir F3 fibrosis or F4 cirrhosis. 
l 
See Section 7.1.3 for viral serology parameters. 
m 
Clinical laboratory and urinalysis parameters are described in Section 7.2.7.  
n 
Liver function tests only. 
o 
Drugs of abuse included in the screen are described in the inclusion/exclusion criteria. Screening results for drugs of abuse must be reviewed prior to dosing. 
p 
Study drug will be administered via SC injection as described in Section 6.2.4. 
q 
Blood samples for PK analysis will be collected at the timepoints listed in Appendix 3.  
r 
As a part of the Week 4 visit, subjects will return to the study center 24-hours after their initial post dose Week 4 PK sample is drawn to have a 24-hour post dose 
PK sample drawn. 
s 
Testing should occur again only at Week 36 and Week 48. 
t 
For subjects in Part Two, if HBeAg has become undetectable for 2 consecutive assessments, no further quantitative testing is needed. 
u 
If a subject experiences ALT flare (as defined by ALT > 2x ULN) additional HBV DNA quantitation sample(s) may be collected 
v 
 
 
w 
. 
x 
All AEs related to screening activities must be collected from the time of consent onwards; any other events occurring during the screening period should be 
reported as medical history. All SAEs must be collected from the time of consent onwards. 
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VIR-2218-1005 
Clinical Study Protocol 
Amendment 2 
CONFIDENTIAL 
Page 69 
23 September 2020 
 
Appendix 5 Protocol Amendment History 
The Protocol Amendment Summary of Changes for the current amendment is located directly 
before the Table of Contents (TOC). 
Amendment 1: 07 April 2020 
Overall Rationale for the Amendment 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.2 Inclusion Criteria 
and the relevant sections 
Women of child-bearing 
potential (WOCBP) will be 
assessed by urine pregnancy 
test on Day 1 instead of by 
serum pregnancy test by 
central laboratory. 
Changes allow for same day 
confirmation of pregnancy 
status prior to dosing on 
Day 1 of the study. 
Table 4 Study Drug Dose and 
Administration; 
Table 5 Clinical Laboratory 
Tests 
Remove unessential 
footnotes concerning the 
injection volume per 
administration and Creatine 
Kinase testing. 
Changes eliminate 
confusion concerning 
related topics. 
Appendix 2 Schedule of 
Assessments 
Removal of inappropriate 
time points of the 
exploratory endpoints. 
Changes reflect adequate 
time points to assess the 
exploratory endpoints. 
Section 8.3.2 Serious 
Adverse Events; 
Section 8.5.2 Reporting 
Other Special Situations 
Correct the contact 
information for reporting 
SAEs and other special 
situations. 
Changes reflect correct 
contact information. 
 
Document History Table for Protocol Amendments 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2 
23 September 2020 
Amendment 1 
07 April 2020 
Original Protocol 
06 September 2019 
 

SAP_001.pdf: 
A Phase 2 Randomized, Placebo-Controlled Study in Mainland China to 
Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Activity 
of VIR-2218 
NCT04507269 
Statistical Analysis Plan V1.0 
19 November 2021 
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STATISTICAL ANALYSIS PLAN 
A Phase 2 Randomized, Placebo-Controlled Study in Mainland China to Evaluate 
the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of VIR-2218 
PROTOCOL NO.: 
VIR-2218-1005 
PRODUCT CODE: 
VIR-2218 
PREPARED FOR: 
Brii Biosciences 
Room 301, 3/F, 
Building 7, 
No. 1 Yongtaizhuang North Street, 
Haidian District, Beijing 100192,  
China 
 
 
DATE OF ISSUE: 
19 November 2021 
VERSION/STATUS: 
Final Version 1.0 
VERSION HISTORY: Version 1.0 (19 November 2021) 
 
 
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Table of contents 
 
1. 
INTRODUCTION 
7 
2. 
PROJECT OVERVIEW 
8 
2.1 
Study Design 
8 
2.2 
Objectives 
10 
2.3 
Endpoints 
10 
2.4 
Sample Size 
11 
2.5 
Randomization 
11 
3. 
STATISTICAL CONSIDERATIONS 
12 
3.1 
General Considerations 
12 
3.2 
Key Definitions 
13 
3.3 
Hypothesis Testing and Inferential Analyses 
14 
3.4 
Multiple Comparisons and Multiplicity Adjustments. 
14 
3.5 
Coding of Events and Medications 
14 
3.6 
Cohorts (Treatment Groups) 
14 
4. 
ANALYSIS SETS 
15 
4.1 
Analysis Set Descriptions 
15 
5. 
SUBJECT DISPOSITION AND ANALYSIS SETS 
16 
6. 
PROTOCOL DEVIATIONS 
16 
7. 
DEMOGRAPHIC AND BASELINE INFORMATION 
17 
7.1 
Demographics 
17 
7.2 
Screening Viral Serology 
17 
7.3 
Medical History 
17 
7.4 
Urine Drug Test 
17 
7.5 
Cirrhosis Status 
17 
8. 
TREATMENT EXPOSURE 
18 
9. 
PHARMACOKINETICS (PK) 
18 
10. 
PHARMACODYNAMICS (PD) 
18 
11. 
EFFICACY 
18 
12. 
SAFETY 
19 
12.1 Adverse Events 
19 
12.2 Safety Laboratory Assessments 
20 
12.3 Vital Signs Measurements 
22 
12.4 12-Lead Safety Electrocardiogram (ECG) 
23 
12.5 Physical Examinations 
24 
12.6 Substance Use 
24 
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12.7 Pregnancy Test Results 
24 
12.8 Prior and Concomitant Medications 
24 
13. 
ANTIVIRAL ACTIVITY 
25 
13.1 Definition of variables 
25 
13.2 Biostatistical methods 
25 
14. 
HANDLING OF MISSING DATA 
26 
Algorithm for Treatment Emergence of Adverse Events: 
26 
Algorithm for Prior / Concomitant Medications: 
27 
15. 
CHANGES TO THE PLANNED ANALYSIS 
28 
16. 
INTERIM AND FINAL ANALYSIS 
28 
16.1 Interim Analysis 
28 
16.2 Final Analysis (End of Study) 
28 
17. 
SOFTWARE 
28 
18. 
REFERENCES 
28 
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List of Abbreviations 
 
Abbreviation 
Description 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
CS 
Clinically Significant   
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
 
 
HBV 
Hepatitis B Virus 
HBeAg 
Hepatitis B e-Antigen 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
INR 
International Normalized Ratio 
IWRS 
Interactive Web Response System 
LDH 
Lactic Acid Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not Clinically Significant 
NK 
Not Known 
NrtI 
Nucleos(t)ide reverse transcriptase inhibitor 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
S.I. 
International System of Units 
SRC 
Safety Review Committee 
SOC 
System Organ Class 
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Abbreviation 
Description 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment Emergent Adverse Event 
WHO-DD 
World Health Organization Drug Dictionary 
 
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1. 
INTRODUCTION 
The following Statistical Analysis Plan (SAP) provides the outline for the statistical analysis of 
the data collected from the VIR-2218-1005 phase 2 study 
 
 focusing on safety, tolerability and antiviral activity of VIR-2218. For PK 
statistical analysis a separate SAP will be prepared. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. 
 
 
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2. 
PROJECT OVERVIEW   
2.1 
Study Design 
This is a phase 2 randomized, double-blind, placebo-controlled study of VIR-2218 
administered subcutaneously to adult subjects with chronic Hepatitis B Virus (HBV) infection 
without cirrhosis on nucleos(t)ide reverse transcriptase inhibitor (NrtI) therapy. The study is 
designed to evaluate the safety, tolerability, PK and antiviral activity of VIR-2218.  
This study will be conducted in close collaboration with an ongoing phase 1/2 regional study 
being conducted in multiple sites in the Asia-Pacific region. 
This study will include two Parts: 
• 
Part One: adult subjects with Hepatitis B e-Antigen (HBeAg)-negative chronic HBV 
infection without cirrhosis on NrtI therapy for ≥ 6 months and HBV DNA < 90 IU/mL at 
screening (by central laboratory)  
• 
Part Two: adult subjects with HBeAg-positive chronic HBV infection without cirrhosis 
on NrtI therapy for ≥ 6 months and HBV DNA < 90 IU/mL at screening (by central 
laboratory)  
Each cohort in Part One/Two will be composed of 5 subjects randomized 4:1 to VIR-2218 or 
placebo, respectively. There are two planned cohorts (50 mg dose-level and 100 mg dose-
level) and 1 optional cohort (≤ 200 mg dose-level) for each of Part One and Part Two of the 
study. Enrollment of the Part One/Two optional cohorts will be according to the same 
randomization scheme and eligibility criteria as the Part One/Two planned cohorts. The 
optional cohorts may be initiated after Safety Review Committee (SRC) review of a minimum 
of 6 weeks of available safety and antiviral activity data from the 200 mg cohorts of the VIR-
2218-1001 regional study. 
The estimated total duration for each subject is up to 52 weeks, including screening period (4 
weeks), dosing period (4 weeks), post-second dose follow-up period (12 weeks) and extended 
follow-up period (up to 48 weeks) (Figure 1). Additional HBsAg monitoring is required for 
subjects with a ≥ 1 log10 change from baseline (Day 1 pre-dose level) decrease in HBsAg 
achieved by the Week 16 visit. Extended follow-up visits will occur every 4 weeks starting at 
Week 20, and subjects will be followed until the HBsAg level returns to > 90% of the Day 1 
pre-dose level or Week 48, whichever comes earlier. Additional HBsAg monitoring may be 
discontinued at the Sponsor’s discretion based on emerging data. 
Figure 1.  Study Design for Cohorts 
 
Screening period 
Screening will be performed no more than 4 weeks before the Day 1 visit and will include 
written informed consent, determination of eligibility, collection of demographics and medical 
history as well as physical examination (including vitals), laboratory tests, 12-lead 
Electrocardiogram (ECG) and other assessments per the schedule of assessments.  To 
exclude the presence of cirrhosis, screening will include a mandatory noninvasive assessment 
of liver fibrosis such as a FibroScan evaluation, unless the subject has results from a 
FibroScan evaluation performed within 6 months prior to screening or a liver biopsy performed 
within 1 year prior to screening that confirms the absence of Metavir F3 fibrosis or F4 cirrhosis. 
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Adverse events related to screening activities must be collected from the time of consent 
onwards; any other events occurring during the screening period should be reported as 
medical history. All SAEs must be collected from the time of consent onwards.  
Dosing period 
Subjects enrolled will remain outpatient. Subjects will be randomized 4:1 to receive VIR-2218 
or placebo within 48 hours prior to study drug administration on Day 1. Subject eligibility must 
be confirmed prior to study drug administration on Day 1. Subjects will return to the clinical 
investigative site at Week 4 to receive a second dose of the same study drug administered on 
Day 1. The decision to administer a second dose will be made based on Week 3 laboratory 
values in accordance with dose suspension/stopping criteria in Protocol Amendment 2 section 
4.6. Additional blood samples for possible analyses to elucidate VIR-2218 antiviral activity 
and/or host responses to infection and treatment will be collected. 
Subjects enrolled into the optional cohorts will receive VIR-2218 or placebo on Day 1 and 
Week 4 at a maximum dose-level of 200 mg. 
Post-dose follow-up period 
Subjects will return to the clinical investigative site on an outpatient basis for safety, tolerability, 
PK, and antiviral activity monitoring at specified timepoints during this Post dose Follow up 
period (Week 5 to Week 16). Additional HBsAg monitoring is required for subjects with a ≥ 1 
log10 change from baseline (Day 1 pre-dose level) decrease in HBsAg achieved by the Week 
16 visit. 
Extended follow-up period 
Subjects who require additional HBsAg monitoring will return to the clinical investigational site 
for in-person assessments. Extended follow-up visits will occur every 4 weeks starting at Week 
20, and subjects will be followed until the HBsAg level returns to > 90% of the Day 1 pre-dose 
level or Week 48, whichever comes earlier. Additional HBsAg monitoring may be discontinued 
at the Sponsor’s discretion based on emerging data. 
Discontinuations 
Subjects who discontinue prematurely will be followed for safety, and under certain 
circumstances, subjects who discontinue study drug (as described in Protocol Amendment 2 
section 4.3) may be replaced. If a subject discontinues from the study post-dose but before 
completion of the Week 16 visit, an early termination visit should be performed. 
Replacement of Subjects 
Replacement subjects may be enrolled to ensure that the minimum data requirements for SRC 
decisions and study progression are met, as described in Protocol Amendment 2 section 4.5. 
Subjects who do not receive the full planned dose, do not receive a second dose, discontinue 
due to an Adverse event (AE) that does not meet study progression and dose 
suspension/stopping rules (Protocol Amendment 2 section 4.6), or who withdraw from the 
study, may be replaced with confirmation by the SRC. Subjects who are discontinued from 
treatment for reasons other than experiencing an AE may be replaced following discussion 
between the Sponsor and investigator. 
The replacement subject will be assigned a unique study identification number and will receive 
the same study drug assignment and dose level as the subject who is being replaced and in 
the same blinded fashion. 
Safety Review Committee 
An SRC will perform ongoing reviews of safety, tolerability, and available study data collected 
throughout the study with the primary purpose of protecting the safety of subjects participating 
in this clinical study. The SRC will be governed by an SRC Charter that will be finalized prior 
to screening the first subject. 
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The SRC will undertake safety data review prior to initiation of dosing the optional cohorts of 
the study in accordance with the SRC Charter. In addition, ad hoc SRC meetings may take 
place as needed, e.g., for a significant safety event such as a subject or cohort stopping 
criterion being reached (Protocol Amendment 2 section 4.6). 
Decisions to suspend dosing or discontinue individual subjects from study drug will be made 
according to predetermined stopping rules (Protocol Amendment 2 section 4.6). Additionally, 
the SRC may recommend discontinuation of the study to the Sponsor. The SRC membership 
composition is described in detail in the SRC Charter. 
2.2 
Objectives 
2.2.1 Primary objective 
The primary objective of this study is: 
To evaluate the safety and tolerability of multiple doses of VIR-2218 in subjects with HBeAg-
negative and HBeAg-positive chronic HBV infection without cirrhosis on NrtI therapy. 
2.2.2 Secondary objectives 
The secondary objectives of this study are: 
• 
To characterize the PK of VIR-2218 in subjects with chronic HBV infection without 
cirrhosis on NrtI therapy. 
• 
To assess the antiviral activity of VIR-2218 in subjects with chronic HBV infection without 
cirrhosis on NrtI therapy. 
 
 
 
 
 
 
2.3 
Endpoints 
2.3.1 Primary endpoints 
• 
Incidence of treatment-emergent adverse events (TEAEs). 
• 
Clinical assessments including but not limited to laboratory test results. 
2.3.2 Secondary endpoints 
• 
PK parameters of VIR-2218 and possible metabolites (may include, but not limited to, 
maximum plasma concentration, time to reach maximum concentration, area under the 
concentration versus time curve [to last measurable timepoint and to infinity], percent of 
area extrapolated, apparent terminal elimination half-life, clearance, and volume of 
distribution). 
• 
Maximum reduction of serum HBsAg from Day 1 until 12 weeks post last dose. 
• 
Number of subjects with serum HBsAg loss at any timepoint. 
• 
Number of subjects with sustained serum HBsAg loss for greater than or equal to 6 
months. 
• 
Number of subjects with anti-HBs seroconversion at any timepoint. 
• 
For HBeAg-positive subjects (Part Two only): number of subjects with HBeAg loss 
and/or anti-HBe seroconversion at any timepoint. 
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2.4 
Sample Size 
No formal sample size calculation was conducted. Up to 30 subjects with chronic HBV 
infection are planned to complete the study. 
2.5 
Randomization 
An Interactive Web Response System (IWRS) will be employed to manage subject 
randomization and treatment assignments. 
For each of the planned 50 and 100 mg dose-level cohorts, 5 subjects will be randomized 4:1 
to VIR-2218 or placebo administered 4 weeks apart on Day 1 and Week 4.  
One optional cohort may be added to each study part (Part One and Part Two), wherein 5 
subjects will be randomized 4:1 to VIR-2218 or placebo administered 4 weeks apart on Day 1 
and Week 4 at a dose-level of up to 200 mg. 
Blinding of study treatment will be managed by the clinical investigative site’s pharmacy in 
accordance with the Pharmacy Manual. In the event of a medical emergency where breaking 
the blind is required to provide medical care to the subject, the investigator may obtain 
treatment assignment for that subject. IWRS should be used as the primary method of 
breaking the blind. If IWRS cannot be accessed, the investigator should contact the Sponsor 
medical monitor to break the blind. Treatment assignment should remain blinded unless that 
knowledge is necessary to guide subject emergency medical care. The investigator is 
requested to contact the Sponsor medical monitor promptly in case of any treatment 
unblinding. 
Blinding of study treatment is critical to the integrity of this clinical study and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to 
do so is specifically withdrawn by the subject. 
The Sponsor or designee may independently unblind cases for expedited reporting of 
suspected unexpected serious adverse reactions (SUSARs) as required by regulators. 
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3. 
STATISTICAL CONSIDERATIONS 
Data will be handled and processed per the sponsor’s representative 
Standard 
Operating Procedures (SOPs), which are written based on the principles of good clinical 
practice (GCP).   
3.1 
General Considerations 
All data collected on the electronic case report form (eCRF) will be presented in the data 
listings and will be listed and sorted by treatment arm, subject number and visit, where 
applicable. All summaries will be presented by treatment arm. 
When reporting descriptive statistics, the following rules will apply: 
• 
Continuous variables: Descriptive statistics for observed data or log10-transformed 
observed values, where applicable, will include the number of non-missing values (n), 
arithmetic mean, standard deviation (SD), median, first quartile (Q1), third quartile (Q3), 
minimum and maximum values. The minimum and maximum are the smallest and 
largest arithmetic values, respectively, unless specified otherwise. 
The Q1, Q3, minimum and maximum values will be displayed to the same decimal 
precision as the source data; the arithmetic mean and median values will be displayed 
to one more decimal than the source data; SD value will be displayed to two more 
decimal than the source data for the specific variable. 
The appropriate precision for derived variables will be determined based on the 
precision of the data on which the derivations are based, and statistics will be presented 
in accordance with the abovementioned rules. 
n will be an integer. If no subjects have data at a given time point, then only n=0 will be 
presented. 
All data will be presented to a maximum of 3 decimal places. 
• 
Categorical variables: Descriptive statistics will include counts and percentages per 
category. The denominator in all percentage calculations will be the number of subjects 
in the relevant analysis set with non-missing data, unless specifically stated otherwise. 
Percentages will be displayed to one decimal place.  
Percentage change from baseline values will be calculated and displayed to 1 decimal 
place in the listings. In the summaries, the mean and median percentage change from 
baseline values will be presented to 2 decimal places, the minimum and maximum 
values will be presented to 1 decimal place and the SD value will be presented to 3 
decimal places. 
For categories where all subjects fulfill certain criteria, the percentage value will be 
displayed as 100. For categories where zero subjects fulfill certain criteria, there will be 
no percentage displayed. All other percentage displays will use 1 decimal place. Data 
listings will contain all reported and derived data.  
Unless otherwise stated, the following methods will be applied: 
• 
Repeat/unscheduled assessments: Only values collected at scheduled study visits/time 
points will be presented in summary tables. Repeat and unscheduled assessments will 
be included in the derivation of the baseline values and minimum/maximum values post 
baseline. If a repeat assessment was performed, the result from the original assessment 
will be presented as the result at the specific visit/time point. For screening visits, there 
are some repeated lab results because the original results may be errors. Then the 
repeated results will be presented as screening results for these cases. All collected 
data will be included in the data listings. 
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• 
Assessment windows: All assessments will be included in the data listings and no visit 
windows will be applied to exclude assessments that were performed outside of the 
protocol specified procedure windows. 
• 
Result display convention: Results will be center aligned in all summary tables and 
listings. Subject identifiers visit and parameter labels may be left-aligned if required. 
• 
Date and time display conventions: The following display conventions will be applied in 
all outputs where dates and/or times are displayed: 
▪ 
Date only: YYYY-MM-DD 
▪ 
Date and time: YYYY-MM-DD HH:MM 
If only partial information is available, unknown components of the date or time will be 
presented as ‘NK’ (not known), i.e., ‘2016-NK-NK’. Times will be reported in military time. 
3.2 
Key Definitions 
The following definitions will be used: 
• 
Baseline: The baseline value is defined as the last available valid (quantifiable 
continuous or categorical value), non-missing observation for each subject prior to first 
study drug administration. Repeat and unscheduled assessments will be included in the 
derivation of the baseline values. 
• 
Change from Baseline: The change from baseline value is defined as the difference 
between the result collected/derived at a post-baseline visit/time point and the baseline 
value. 
The change from baseline value at each post-baseline visit/time point will be calculated 
for all continuous parameters using the following formula: 
Change from Baseline Value = Result at Visit/Time Point – Baseline Value 
The change from baseline value will only be calculated if the specific post-baseline 
visit/time point result and the baseline value for the parameter are both available and 
will be treated as missing otherwise. 
• 
Study day: The study day of an event is defined as the relative day of the event starting 
with the date of the first study drug administration (reference date) as Day 1 (there will 
be no Day 0). 
The study day of events occurring before the first study drug administration will be 
calculated as: 
Study Day = (Date of Event - Date of First Study Drug Administration) 
For events occurring on or after Day 1, study day will be calculated as: 
Study Day = (Date of Event - Date of First Study Drug Administration) + 1 
Study days will only be calculated for events with complete dates and will be undefined 
for events that are ‘Ongoing’ at the end of the study. 
Relative days compared to an alternative reference point will be calculated similarly, 
but the alternative starting reference start date will be used instead of the date of the 
first study drug dosing. 
• 
HBsAg loss: quantitative HBsAg < 0.05 IU/mL at two or more consecutive 
measurements. 
• 
Sustained HBsAg loss: quantitative HBsAg < 0.05 IU/mL at all visits (scheduled and 
unscheduled) for ≥ 6 months. 
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• 
HBsAg Seroconversion: HBsAg loss plus anti-HBs positivity at two or more 
consecutive measurements 
• 
HBeAg loss (HBeAg+ subjects only): quantitative HBeAg < 0.14 IU/mL at two or more 
consecutive measurements 
• 
HBeAg Seroconversion (HBeAg+ subjects only): HBeAg loss plus anti-HBe positivity at 
two or more consecutive measurements  
3.3 
Hypothesis Testing and Inferential Analyses 
Descriptive statistics will be used to summarize all data. No formal hypothesis testing is 
planned. 
3.4 
Multiple Comparisons and Multiplicity Adjustments. 
Not applicable for this study. 
3.5 
Coding of Events and Medications 
Adverse event verbatim terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 23.0 or the latest version in use. Terms will be coded to the full 
MedDRA hierarchy, but the system organ class (SOC) and preferred terms (PT) will be of 
primary interest for the analysis. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD, 01MAR2020 Enhanced) or the latest version in use. Medications will be 
mapped to the full WHO-DD Anatomical Therapeutic Chemical (ATC) class hierarchy, but PTs 
will be of primary interest in this analysis. 
3.6 
Cohorts (Treatment Groups) 
Part One (HBeAg-): 
• 
VIR-2218 50 mg 
• 
VIR-2218 100 mg 
• 
VIR-2218 optional cohort, up to 200 mg 
• 
VIR-2218 Overall, for safety data 
• 
Placebo 
• 
Overall 
Part Two (HBeAg+): 
• 
VIR-2218 50 mg 
• 
VIR-2218 100 mg 
• 
VIR-2218 optional cohort, up to 200 mg 
• 
VIR-2218 Overall, for safety data  
• 
Placebo 
• 
Overall 
For summaries using Safety Analysis Set, the VIR-2218 Overall group will be presented.  
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4. 
ANALYSIS SETS 
In this SAP, 4 analysis sets are defined: The screened, all randomized, safety, and antiviral 
analysis sets. 
Furthermore, any additional exploratory analysis not identified in the SAP will be identified in 
the final Clinical Study Report (CSR) as exploratory post hoc analyses, including analyses for 
additional study populations or subgroups of interest.  
The number and percentage of subjects in each analysis set will be summarized by cohort 
and overall by study part. 
4.1 
Analysis Set Descriptions 
4.1.1 Screened Analysis Set 
The Screened Analysis Set will consist of all subjects that sign the informed consent form. The 
listing of Eligibility Criteria will be based on this population. 
4.1.2 All Randomized Analysis Set 
The All Randomized Analysis Set will include all randomized subjects, irrespective of whether 
they received any study treatment. Subjects will be summarized by the treatment to which 
they were randomized, regardless of treatment actually received. 
Important protocol deviations, demographic and baseline characteristics will be summarized 
by the All Randomized Analysis Set.  
4.1.3 Safety Analysis Set 
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes all 
randomized subjects who received at least 1 dose of study treatment. The Safety Analysis Set 
will be based on actual treatment received if different from the treatment to which they were 
randomized. 
All safety analyses will be based on the Safety Analysis Set. 
4.1.4 Antiviral Activity Set 
The primary analysis set for antiviral activity analyses will be the Antiviral Analysis Set, which 
includes all subjects in the Safety Analysis Set who have at least 1 non-missing data to provide 
interpretable results for the specific antiviral activity parameters of interest. 
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5. 
SUBJECT DISPOSITION AND ANALYSIS SETS 
Outcomes will be summarized by cohort, by study part and overall. All outcomes will be 
listed by study part and cohort. 
5.1.1 Subject Disposition 
Subject disposition will be summarized using counts and percentages and will be based on 
the Screened Analysis Set. The number and percentage of subjects who completed the study 
as planned, subjects discontinued early from the study, as well as the primary reason for early 
discontinuation will be presented.  
All disposition information collected will be listed together with the date that the subject 
provided informed consent and the date and time of study drug administration. 
5.1.2 Analysis Sets 
The number of subjects included in each of the defined analysis sets will be summarized using 
counts and percentages and will be based on the Screened Analysis Set. 
In addition, each subject’s inclusion into/exclusion from each of the defined analysis sets will 
be listed by the Screened Analysis Set. 
 
6. 
PROTOCOL DEVIATIONS 
Important protocol deviations will be presented for each subject in the by-subject data listings 
by study part and cohort. 
Important protocol deviations will be decided prior to database lock, and may include the 
deviations from the following, depending on the timing and nature of the deviation: 
• 
Informed Consent Criteria 
• 
Eligibility and Entry Criteria 
• 
Concomitant Medication Criteria 
• 
Laboratory Assessment Criteria 
• 
Study Procedures Criteria 
• 
Serious Adverse Event Criteria 
• 
Randomization Criteria 
• 
Visit Schedule Criteria 
• 
Investigation Product (IP) Compliance 
• 
Efficacy Criteria 
• 
Administrative Criteria 
• 
Source Document Criteria 
• 
Regulatory or Ethics Approvals Criteria 
• 
Other Criteria 
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7. 
DEMOGRAPHIC AND BASELINE INFORMATION 
Demographic and baseline information will be analyzed using the All Randomized Analysis 
Set. All summarized information will be presented by cohort, by study part and overall. All 
demographic information will be listed by cohort and study part. 
7.1 
Demographics 
7.1.1 Definition of variables 
• 
Age (years) 
• 
Sex 
• 
Childbearing Potential 
• 
Race 
• 
Ethnicity 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body Mass Index (BMI) (kg/m2) 
• 
HBeAg Baseline Status 
• 
Baseline log10 HBsAg (IU/mL) 
• 
Baseline Alanine Aminotransferase (U/L) 
• 
Baseline HBV DNA Categories (IU/mL) (<10, >=10 and <90, and >=90) 
7.1.2 Biostatistical methods 
Continuous and categorical summaries will be presented for demographic variables as 
discussed in section 3.1 by cohort, by study part and overall. 
7.2 
Screening Viral Serology  
Viral serology results (Active infection with HIV infection, HCV infection, chronic HBV infection 
and hepatitis Delta virus infection. Chronic HBV infection is defined as serum HBsAg for > 6 
months. In cases of occult HBV, chronic HBV infection is defined as serum HBV DNA positive 
for > 6 months.) at screening will be listed. 
7.3 
Medical History 
Medical history will be summarized by cohort, by study part and overall if coding using 
MedDRA® is available. All medical history data will be listed.  
HBV Genotype data will be listed. 
7.4 
Urine Drug Test 
Urine drug test results obtained at screening will be listed. 
7.5 
Cirrhosis Status 
Cirrhosis status (FibroScan results and Cirrhosis status) at screening will be summarized by 
cohort, by study part and overall, and all cirrhosis data collected will be listed. 
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8. 
TREATMENT EXPOSURE 
Treatment exposure information will be summarized by cohort, by study part and overall using 
safety population. Duration of Treatment (Days) is calculated as Date of Last Dose - Date of 
First Dose + 1.  
All exposure information will be listed by cohort and study part. 
9. 
PHARMACOKINETICS (PK) 
Pharmacokinetic analysis falls outside the scope of the SAP. There will be a sperate SAP for 
PK analyses. 
10. 
PHARMACODYNAMICS (PD) 
No PD analysis is planned for this study. 
11. 
EFFICACY 
No efficacy analysis is planned for this study. 
 
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12. 
 SAFETY  
Safety endpoints will be analyzed using the safety analysis set. All information will be 
presented by cohort, by study part and overall, unless otherwise specified. All safety data will 
be listed by cohort and study part. 
12.1 Adverse Events  
12.1.1 Definition of variables 
• 
AE 
• 
Serious adverse event (SAE) 
• 
Treatment emergent adverse event (TEAE) 
AEs and SAEs are defined in the study protocol. TEAEs are defined as any AEs with an onset 
date of on or after the study drug start date and no later than 30 days after permanent 
discontinuation of study drug. If a subject experiences an AE before dosing and after dosing, 
this AE will be considered as TEAE only if it has worsened in severity. Adverse events that 
have missing onset dates will be considered treatment-emergent, unless the stop date is 
known to be prior to the first administration of the study medication. Related AEs are adverse 
events with relationship as “Related” collected in CRF or missing relationship. 
Please refer to section 14 for handling of partial dates for AEs. 
12.1.2 Biostatistical methods 
All AEs will be coded using MedDRA. 
AE summary tables will be provided. Summary tables will include the number of subjects (%) 
experiencing an event and the number of events. Subjects will be counted only once at each 
SOC and PT level of summary. 
The AE, SAE and TEAE summaries will include: 
• 
Overall Summary of all AEs including SAEs  
• 
Overall Summary of TEAEs 
• 
TEAE summary by SOC and PT 
• 
TEAE of Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 3 
summary by SOC and PT  
• 
Drug related TEAE summary by SOC and PT  
• 
TEAE leading to study withdrawal summary by SOC and PT  
• 
TEAE leading to treatment withdrawal summary by SOC and PT 
• 
Serious TEAE summary by SOC and PT  
• 
Serious TEAE of CTCAE Grade ≥ 3 summary by SOC and PT  
• 
Drug related serious TEAE summary by SOC and PT  
• 
Serious TEAE leading to study withdrawal summary by SOC and PT  
• 
Serious TEAE leading to treatment withdrawal summary by SOC and PT 
• 
SAE summary by SOC and PT  
• 
SAE of CTCAE Grade ≥ 3 summary by SOC and PT  
• 
Drug related SAE summary by SOC and PT  
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• 
SAE leading to study withdrawal summary by SOC and PT  
• 
SAE leading to treatment withdrawal summary by SOC and PT 
• 
TEAE leading to death summary by SOC and PT 
• 
Death 
• 
TEAE summary by CTCAE Grade, SOC and PT 
• 
Serious TEAE summary by CTCAE Grade, SOC and PT 
• 
SAE summary by CTCAE Grade, SOC and PT 
All AEs will be listed and will include verbatim term, PT, SOC, treatment, severity, causal 
relationship to the study drug, seriousness, outcome, and action taken with regards to the 
study drug. Separate listings will be created for AEs leading to study withdrawal and SAEs. 
12.2 Safety Laboratory Assessments 
Blood and urine samples will be collected at the time points specified in the Schedule of 
Assessments (refer to the protocol) to conduct hematology, chemistry, liver function tests, 
coagulation, urinalysis, pregnancy testing, and serology analyses. 
The following tests will be performed within each of the specified test panels: 
Hematology: 
• 
Complete blood count with differential 
Chemistry: 
• 
Albumin 
• 
Creatinine clearance 
• 
Blood urea nitrogen (BUN) 
• 
Gamma glutamyl transferase (GGT) 
• 
Calcium 
• 
Glucose 
• 
Carbon dioxide/bicarbonate 
• 
Lactate dehydrogenase (LDH) 
• 
Chloride 
• 
Potassium 
• 
Creatine kinase 
• 
Sodium 
• 
Creatinine 
• 
Uric acid 
Liver Function Tests: 
• 
Alkaline phosphatase (ALP) 
• 
Aspartate aminotransferase (AST) 
• 
Alanine aminotransferase (ALT) 
• 
Bilirubin (total and direct) 
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Coagulation: 
• 
International normalized ratio (INR) time 
• 
Prothrombin 
Urinalysis & Microscopic Urinalysis: 
• 
Bilirubin  
• 
Proteins 
• 
Glucose 
• 
Red Blood Cells 
• 
Ketones 
• 
Screen for drugs of abuse 
• 
Leukocytes 
• 
Specific gravity 
• 
Microscopy (if clinically indicated) 
• 
Urobilinogen 
• 
Nitrite 
• 
Visual inspection for appearance and color 
• 
pH 
Pregnancy Testing: 
• 
Beta-human chorionic gonadotropin (WOCBP) 
• 
Urine pregnancy test 
Serology 
• 
Hepatitis B, C, and Delta 
• 
Human immunodeficiency virus I and II 
12.2.1 Biostatistical Methods 
All laboratory data collected at scheduled and unscheduled visits will be included in the 
listings, but only results collected as scheduled visits will be included in the summary tables.  
Repeated and unscheduled assessments will be included in the derivation of the baseline 
values and minimum/maximum values post baseline. All information will be presented by 
cohort and study part. 
Results for individual parameters may be reported in different units depending on the 
analyzing laboratory. If required, the results (and the corresponding normal range cut-off 
values) for individual parameters may be converted to International System of Units (S.I.) units 
to summarize the data. 
For all the parameters where a unit value has been reported, the parameter names that will 
be used in the outputs will comprise the test name and the unit of measure, for example, 
‘Albumin (g/L)’. Parameters will be sorted alphabetically within tables and listings. 
For all parameters where a normal range limit value is reported, the normal range will be 
derived based on the available lower and upper limit values and any reported mathematical 
symbols. If both a lower and upper limit value is available, the normal range will be presented 
as ‘(Lower, Upper)’. 
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The reported results for each parameter with a defined normal range will be classified (‘Low’, 
‘Normal’ or ‘High’) in relation to the defined normal range limits. If a result is equal to the normal 
range cut-off value, the result will be considered normal. 
The change from baseline values at each post-baseline visit will be calculated for all 
parameters with continuous results.  
The minimum/maximum post baseline value will be the minimum/maximum non-missing value 
after baseline and during the reference period. Scheduled visits, unscheduled visits, and 
repeated measurements will be included to derive the minimum/maximum post baseline 
values. 
The decimal precision to which the summaries for each parameter will be based on the 
maximum number of decimals to which the reported result or the normal range limits are 
presented to in the raw data. The results and normal ranges will be displayed to the same 
decimal precision in the listings. 
The hematology and chemistry results tables will present summary statistics for each 
laboratory parameter within the specific test panel. For each parameter, summaries will be 
presented for the baseline and each scheduled post-baseline visit. In addition, summaries will 
be presented for the change from baseline values at each scheduled post-baseline visit.  
The incidence of treatment-emergent laboratory abnormalities, defined as values that increase 
at least 1 toxicity grade from baseline at any postbaseline timepoint will be summarized by 
cohort. 
The worst post baseline value will be the worst non-missing value after baseline and during 
the reference period. Scheduled visits, unscheduled visits, and repeat measurements will be 
included to derive the worst post baseline values. 
Additionally, shift tables from baseline in CTCAE grade (version 5) by visit plus worst post-
baseline will be summarized by counts and percentages. 
The urinalysis table will present counts and percentages for the reported results at baseline 
and each post-baseline visit within each test parameter. Result categories will be order 
alphabetically, or in ascending order. 
The listings of laboratory parameters will include all the information (fields) collected (including 
CTCAE derived values). In addition, the observations that are used as the baseline record 
(value) for each parameter will be flagged, and the change from baseline values at each post-
baseline visit will be presented. 
12.3 Vital Signs Measurements 
The following vital signs measurements will be taken at the time points specified in the 
Schedule of Assessments (refer to the protocol): 
• 
Systolic blood pressure (SBP) (mmHg) 
• 
Diastolic blood pressure (DBP) (mmHg) 
• 
Pulse rate (beats/min) 
• 
Respiratory rate (breaths/min) 
• 
Temperature (ºC) 
12.3.1 Biostatistical Methods 
All vital signs data collected at scheduled and unscheduled visits will be included in the listings, 
but only results collected as scheduled visits will be included in the summary tables. Repeated 
and unscheduled assessments will be included in the derivation of the baseline values and 
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minimum/maximum values post baseline. All information will be presented by cohort and study 
part. 
The parameter names that will be used in the outputs will comprise the test name and the unit 
of measure, for example, ‘Systolic Blood Pressure (mmHg)’. Parameters will be sorted in the 
order that the measurements were collected in on the Vital Signs eCRF page within the tables 
and listings: Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, Respiratory Rate, 
and Temperature. 
The change from baseline to the pre-dose assessment at each post-baseline visit will be 
calculated for all parameters. If unscheduled pre-dose assessments are recorded on Day 1, 
the average of the pre-dose Day 1 and unscheduled pre-dose assessments will be used as 
baseline for all change from baseline calculations. 
The minimum/maximum post baseline value will be the minimum/maximum non-missing value 
after baseline and during the reference period. Scheduled visits, unscheduled visits, and 
repeat measurements will be included to derive the minimum/maximum post baseline values. 
The decimal precision to which the summaries for each parameter will presented will be based 
on the maximum number of decimals to which the results were reported on the eCRF. 
Vital signs measurements will present summary statistics for the results at the baseline and 
each scheduled post-baseline visit for each of the parameters. In addition, summaries will be 
presented for the change from baseline values at each scheduled post-baseline visit. 
The listings of vital signs measurements will include all the information collected. In addition, 
the observations that are used as the baseline record (value) for each parameter will be 
flagged, and the change from baseline values at each post-baseline visit will be presented. 
12.4 12-Lead Safety Electrocardiogram (ECG) 
12-lead safety ECGs interpretations will be recorded and reviewed on-site by the investigator 
as outlined in the Schedule of Assessments (refer to the protocol). This 12-lead safety ECGs 
will be measured in the supine position after the subject has rested comfortably for 10 minutes. 
12.4.1 Biostatistical Methods 
All ECG data collected at scheduled and unscheduled visits will be included in the listings, but 
only results collected as scheduled visits will be included in the summary tables. All information 
will be presented by cohort and study part. 
The summary of overall interpretation findings table will present counts and percentages for 
the reported results at baseline and each post-baseline visit/time point. Result categories will 
be ordered as ‘Normal’, ‘Abnormal - Not Clinically Significant (NCS)’ and ‘Abnormal - Clinically 
Significant (CS)’. 
The worst post baseline value will be the worst non-missing value after baseline and during 
the reference period. Scheduled visits, unscheduled visits, and repeat measurements will be 
included to derive the worst post baseline values (Abnormal CS is the worst, Abnormal NCS 
is next, then normal). 
Additionally, shift tables from baseline in categories as ‘Normal’, ‘Abnormal - Not Clinically 
Significant (NCS)’, ‘Abnormal - Clinically Significant (CS)’ and ‘Missing’, will be summarized 
by counts and percentages. 
The listings of ECG measurements will include all the information collected. In addition, the 
observations that are used as the baseline record (value) for each parameter will be flagged, 
and the change from baseline values at each post-baseline visit will be presented. 
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12.5 Physical Examinations 
Physical Examination assessments will be listed for all time points. 
12.6 Substance Use 
Alcohol intake during the study will be recorded. 
12.6.1 Biostatistical Methods 
All alcohol intake data collected at scheduled and unscheduled visits will be included in the 
listings. 
The parameter names that will be used in the outputs will comprise the test name and the unit 
of measure, for example, ‘Amount of alcohol consumed (unit)’.  
The listings of alcohol intake assessment will include all the information collected.  
12.7 Pregnancy Test Results 
Pregnancy testing are performed per Schedule of Assessments (refer to the protocol) and any 
time pregnancy is suspected. A serum pregnancy test is performed at screening and urine 
pregnancy tests are to be performed thereafter.  
All information related to pregnancy testing (urine and serum based - beta-human chorionic 
gonadotropin) will be listed. This listing will include all pregnancy test results collected during 
the study. 
12.8 Prior and Concomitant Medications 
Prior medications are defined as any medication which started and stopped prior to the first 
dose of study medication. 
Concomitant medications are defined as any medication (other than the study drug) that was 
used at least once after the first administration of the study medication and before end of 
study. Medications that were stopped on the same date as the first study drug administration 
will be analyzed as concomitant medications. If a clear determination cannot be made (partial 
medication end dates) the medication will be classified as concomitant.  
Please refer to section 14 for handling of partial dates for medications. 
12.8.1 Biostatistical Methods 
Concomitant medications will be summarized by ATC class Level 3 and PT. Within each 
category, the number of subjects who used the medication (count and percentage) will be 
presented. Subject who used the same medication on multiple occasions will only be counted 
once in the specific category (PT). PTs will be sorted alphabetically. In addition to the 
summaries by the coded terms, the number of subjects who used at least one concomitant 
medication during the study will be presented. 
Prior medications will be summarized similarly with concomitant medications. 
All information that was collected on the Concomitant Medication eCRF as well as the coded 
WHO-DD terms will be included in the listings.  
All prior and concomitant medications will be listed. 
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13. 
ANTIVIRAL ACTIVITY 
Antiviral activity endpoints will be analyzed using the Antiviral Analysis Set. All information will 
be presented by cohort, by study part and overall. All antiviral activity data will be listed by 
cohort and study part. 
13.1 Definition of variables 
• 
Maximum reduction of serum HBsAg from Day 1 until Week 16. 
o Serum log10 HBsAg levels by timepoint 
o Serum log10 HBsAg Nadir level per subject 
• 
Number of subjects with serum HBsAg loss. 
• 
Number of subjects with sustained serum HBsAg loss for ≥ 6 months. 
• 
Number of subjects with anti-HBs seroconversion. 
• 
For HBeAg-positive subjects (Part Two only): number of subjects with HBeAg loss 
and/or anti-HBe seroconversion.  
13.2 Biostatistical methods 
All antiviral data collected at scheduled and unscheduled visits will be included in the listings. 
The results collected as scheduled visits will be included in the summary tables. 
The parameter names that will be used in the outputs will comprise the test name and the unit 
of measure, for example, HBsAg (IU/mL). Parameters will be sorted within parameter class (if 
present) in alphabetical order within the tables and listings. 
Measurements will present summary statistics for the results at the baseline and each 
scheduled post-baseline visit for each of the parameters. In addition, summaries w ll be 
presented for the change from baseline of the antiviral measure to that assessed at baseline 
values at each scheduled post-baseline visit. See section 3.1 for more detail with regards 
continuous data representation. Spaghetti plots of log10-transformed observed values and 
change from baseline values in HBsAg, HBeAg (Part Two only), 
HBV DNA and 
 
 will be provided. 
Categorical summaries (% of subjects) will present counts and percentages for the reported 
results at baseline and each post-baseline time point. 
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14.
HANDLING OF MISSING DATA
All data will be analyzed as collected and missing values will not be imputed nor replaced. 
Laboratory data that are continuous in nature but are less than the LLOQ or above the upper 
limit of quantitation will be imputed to the value of the lower or upper limit minus or plus 1 
significant digit, respectively (e.g., if the result of a continuous laboratory test is < 30, a value 
of 29 will be assigned; if the result of a continuous laboratory test is < 30.0, a value of 29.9 will 
be assigned). 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known/Partial/ 
Missing 
If start date < study med start date, then not 
TEAE 
If start date >= study med start date and start 
date <= study med end date + 30, then TEAE 
Partial, but known 
components show that it 
cannot be on or after 
study med start date 
Known/Partial/ 
Missing 
Not TEAE 
Partial, could be on or 
after study med start 
date 
OR Missing 
Known 
If stop date < study med start date, then not 
TEAE 
If stop date >= study med start date, then TEAE 
Partial 
Impute stop date as latest possible date (i.e. last 
day of month if day unknown or 31st December if 
day and month are unknown), then: 
If stop date < study med start date, then not 
TEAE 
If stop date >= study med start date, then TEAE 
Missing 
Assumed TEAE 
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ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS: 
START 
DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of 
study, assign as concomitant  
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
study, assign as concomitant 
Missing 
If stop date is missing could never be assumed a prior 
medication 
If start date <= end of study, assign as concomitant 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
study, assign as concomitant 
Partial 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown) and impute stop date as latest possible date (i.e. last 
day of month if day unknown or 31st December if day and 
month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
study, assign as concomitant 
Missing 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown), then: 
If stop date is missing could never be assumed a prior 
medication 
If start date <= end of study, assign as concomitant 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
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START 
DATE 
STOP 
DATE 
ACTION 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Missing 
Assign as concomitant 
Imputed dates will not be presented in the listings. 
15.
CHANGES TO THE PLANNED ANALYSIS
Not applicable. 
16.
INTERIM AND FINAL ANALYSIS
16.1 
Interim Analysis
No planned interim analysis for this study.
16.2 Final Analysis (End of Study) 
After all subjects have completed the study, outstanding data queries have been 
resolved/closed, and the data have been cleaned and finalized, and database has been 
locked, the sponsor will authorize breaking of the study blind and the final analysis of the data 
will be performed.  
The final SAP and analysis sets must be approved and signed by the sponsor before the 
database is locked and treatment assignment unblinded. Any deviations from the planned 
analysis will be documented in the CSR. 
17.
SOFTWARE
•
The following software will be used to perform the statistical analyses: SAS® Version
9.4 or higher (SAS Institute, Cary, North Carolina, USA).
18.
REFERENCES
1)
VIR-2218-1005 protocol amendment 2 dated 23 September 2020.
2)
VIR-2218-1001, ClinicalTrials.gov Identifier: NCT03672188.
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
PK Statistical Analysis Plan 
 
        Final Version 1 
 
CONFIDENTIAL 
Page 1 
 12 November 2021 
 
STATISTICAL ANALYSIS PLAN for PHARMACOKINETICS  
A Phase 2 Randomized, Placebo-Controlled Study in Mainland China to Evaluate 
the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of VIR-2218 
 
PROTOCOL NO.: 
VIR-2218-1005 
 
PRODUCT CODE: 
VIR-2218 
 
 
DATE OF ISSUE: 
12 NOV 2021 
 
 
VERSION/STATUS: 
Fina Version 1 
 
SPONSER: 
Brii Biosciences Ltd. 
Room 301, 3/F, 
Building 7, 
No. 1 Yongtaizhuang North Street, 
Haidian District, Beijing 100192, China 
 
 
 
 
 
DocuSign Envelope ID: 9FD8BBA4-4657-4FE3-AD25-8FF5BC14B193
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PPD


Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
PK Statistical Analysis Plan 
 
        Final Version 1 
 
CONFIDENTIAL 
Page 2 
 12 November 2021 
SAP APPROVAL 
 
By my signature, I confirm that this SAP has been reviewed and has been approved for use for 
the VIR-2218-1005 study: 
 
DocuSign Envelope ID: 9FD8BBA4-4657-4FE3-AD25-8FF5BC14B193
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
PK Statistical Analysis Plan 
 
        Final Version 1 
 
CONFIDENTIAL 
Page 3 
 12 November 2021 
Table of contents 
 
1. 
INTRODUCTION 
5 
2. 
PROJECT OVERVIEW 
6 
2.1 
Study Design 
6 
2.2 
Pharmacokinetic Assessments 
7 
2.3 
Pharmacokinetic Objective 
8 
3. 
PHARMACOKINETIC EVALUATION/ANALYSIS 
8 
3.1 
Pharmacokinetic Concentration Population 
8 
3.2 
Pharmacokinetic Analysis Population 
8 
3.3 
Summary Statistics for PK Data 
8 
3.4 
CONCENTRATION-TIME PROFILES 
9 
3.5 
Estimation of Pharmacokinetic Parameters 
10 
3.6 
Other important PK considerations 
12 
4. 
SOFTWARE 
13 
5. 
SAP Revision 
14 
6. 
Proposed Tables, Figures, and Listings 
14 
6.1 
Tables 
14 
6.2 
Figures 
14 
6.3 
Listings 
15 
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
PK Statistical Analysis Plan 
 
        Final Version 1 
 
CONFIDENTIAL 
Page 4 
 12 November 2021 
List of Abbreviations 
 
Abbreviation 
Description 
HBV 
Hepatitis B Virus 
HBeAg 
Hepatitis B e-Antigen 
HBsAg 
Hepatitis B Surface Antigen 
PK 
Pharmacokinetic 
Q1 
First Quartile 
Q3 
Third Quartile 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
 
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
PK Statistical Analysis Plan 
 
        Final Version 1 
 
CONFIDENTIAL 
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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides the outline for the statistical analysis of the 
pharmacokinetic data collected from the VIR-2218-1005 phase 2 study 
 
 should be used in conjunction with the separate SAP focusing on 
safety, tolerability, and antiviral activity of VIR-2218. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. 
 
 
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
PK Statistical Analysis Plan 
 
        Final Version 1 
 
CONFIDENTIAL 
Page 6 
 12 November 2021 
2. 
PROJECT OVERVIEW   
2.1 
Study Design 
This is a phase 2 randomized, double-blind, placebo-controlled study of VIR-2218 administered 
subcutaneously to adult subjects with chronic Hepatitis B Virus (HBV) infection without cirrhosis 
on nucleos(t)ide reverse transcriptase inhibitor (NrtI) therapy. The study is designed to evaluate 
the safety, tolerability, PK and antiviral activity of VIR-2218.  
This study will include two Parts: 
 
Part One: adult subjects with Hepatitis B e-Antigen (HBeAg)-negative chronic HBV 
infection without cirrhosis on NrtI therapy for ≥ 6 months and HBV DNA < 90 IU/mL at 
screening (by central laboratory)  
 
Part Two: adult subjects with HBeAg-positive chronic HBV infection without cirrhosis on 
NrtI therapy for ≥ 6 months and HBV DNA < 90 IU/mL at screening (by central laboratory)  
Each cohort in Part One/Two will be composed of 5 subjects randomized 4:1 to VIR-2218 or 
placebo, respectively. There are two planned cohorts (50 mg dose-level and 100 mg dose-level) 
and 1 optional cohort (≤ 200 mg dose-level) for each of Part One and Part Two of the study. 
Enrollment of the Part One/Two optional cohorts will be according to the same randomization 
scheme and eligibility criteria as the Part One/Two planned cohorts. The optional cohorts may be 
initiated after Safety Review Committee (SRC) review of a minimum of 6 weeks of available safety 
and antiviral activity data from the 200 mg cohorts of the VIR-2218-1001 regional study. 
The estimated total duration for each subject is up to 52 weeks, including screening period (4 
weeks), dosing period (4 weeks), post-second dose follow-up period (12 weeks) and extended 
follow-up period (up to 48 weeks) (Figure 1).  
Figure 1.  Study Design for Cohorts 
 
 
 
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
PK Statistical Analysis Plan 
 
        Final Version 1 
 
CONFIDENTIAL 
Page 7 
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2.2 
Pharmacokinetic Assessments 
Blood samples will be collected to assess concentrations of VIR-2218 and its metabolite (A-
312327) , as applicable. Timepoints for the collection of samples for VIR-2218 PK analysis of 
the study are provided Table 1.  
 
Table 1: Part One/Two Pharmacokinetic Assessment Timepoints 
Study Day/Week 
Protocol Time (Time Window) 
PK Blood 
Screening 
 
 
Day 1 
Predose  
Xa 
Dose 
 
1 hour ± 5 minutes 
X 
2 hours ± 10 minutes 
X 
4 hours ± 30 minutes 
X 
8 hours ± 30 minutes 
X 
Day 2 
24 hours ± 2 hours 
X 
Week 1 
 
X 
Week 4 
Predose  
Xa 
 
Dose 
 
 
1 hour ± 5 minutes 
X 
 
2 hours ± 10 minutes 
X 
 
4 hours ± 30 minutes 
X 
 
8 hours ± 30 minutes 
X 
 
24 hours ± 2 hours 
X 
Week 5 
 
X 
Week 8 
 
X 
Week 16 
 
X 
Week 24b 
 
X 
a At ≤ 15 minutes prior to dosing 
b  Collected only from subjects in extended follow up.
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
PK Statistical Analysis Plan 
 
        Final Version 1 
 
 
 
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2.3 
Pharmacokinetic Objective 
 
To characterize the PK of VIR-2218 in subjects with chronic HBV infection without 
cirrhosis on NrtI therapy. 
 
3. 
PHARMACOKINETIC EVALUATION/ANALYSIS 
3.1 
Pharmacokinetic Concentration Population 
The pharmacokinetic (PK) concentration population is defined as all randomized subjects 
who have at least 1 dose of VIR-2218 and at least 1 measurable (>LLOQ) concentration 
value. 
 
3.2 
Pharmacokinetic Analysis Population 
The PK Analysis Set includes all randomized subjects who have at least 1 dose of VIR-2218 
and 1 post-baseline PK parameter of interests. 
3.3 
Summary Statistics for PK Data 
3.3.1 General Consideration 
 
Due to the short plasma half-life of VIR-2218 and its metabolite (A-312327), pharmacokinetic 
parameters will be generated separately for day-1 dose and day-29 dose for patients in PK 
analysis population. 
All analyses, including summary for plasma concentration data, summary for plasma PK 
parameter data, and concentration vs. time plots, will be summarized by Part, Dose Level, 
and Dosing Day as listed below.  In addition, subjects received the same dose level (ie, VIR-
2218 50 mg or VIR-2218 100 mg) from Parts One and Two will be pooled together for 
summary purpose. 
 
Part One: VIR-2218 50 mg, Day X 
 
Part One: VIR-2218 100 mg, Day X 
 
Part Two: VIR-2218 50 mg, Day X 
 
Part Two: VIR-2218 100 mg, Day X 
 
Part One & Two: VIR-2218 50 mg, Day X 
 
Part One & Two: VIR-2218 100 mg, Day X 
.     
3.3.2 Summary statistics for plasma concentration data 
The concentration and associated unit will be presented as they are received from the 
analytical laboratories.  
The actual sampling date and time and elapsed time relative to dosing time for plasma and 
urine data will be listed by subject and nominal sampling time, with time deviation (difference 
in minutes between nominal and actual sampling times) calculated, for all subjects with 
available concentration data, including subjects excluded from the PK analysis set.  
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
PK Statistical Analysis Plan 
 
        Final Version 1 
 
 
 
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Summary statistics of PK concentration data of VIR-2218 and its metabolite (A-312327)  (n, 
arithmetic mean, standard deviation [SD], coefficient of variation [CV%], geometric mean, 
geometric CV%, median, minimum and maximum) will be calculated for each time point and 
summarized by dose day and dose level from each part and in combination (ie, subjects 
received the same dose level from part one and two will be pooled together), respectively. 
Geometric CV% calculated as the square root of the exponentiated SD of the natural log 
transformed data (SQRT(exp(sln2 )-1), where appropriate.  
When reporting individual values and descriptive statistics for VIR-2218 and its metabolite 
(A-312327) plasma concentration data, the following rules will apply regarding rounding and 
precision:  
 
Descriptive statistics for PK concentration data will be reported to the same level of 
precision as the individual data for the minimum and maximum, and to 1 additional 
decimal place - for the mean (arithmetic and geometric), median and standard 
deviation. 
 
Between-subject CV% and geometric CV% will be reported as a percentage to 1 
decimal place.  
 
Subjects with dosing deviations will be listed but excluded from the summary tables.  
3.3.3 Summary statistics for plasma PK parameters  
MR (metabolite to parent ratio) for a selected PK parameter is defined as the ratio of VIR-
2218 metabolite(A-312327) PK parameter divided by the corresponding VIR-2218 PK 
parameter, for example MR of AUCinf (%) = AUCinf of A-312327 / AUCinf of VIR-2218 * 100%. 
Summary tables with MR in PK parameters of AUC0-8, AUC0-12, AUCinf and Cmax will be 
tabulated. 
Calculated PK parameters will be listed and summarized descriptively, including n, arithmetic 
mean, SD, minimum, median, maximum, coefficient of variation [CV(%)], geometric mean, 
geometric SD, geometric CV%; For time-related PK parameters (ie., Tmax, Tlast and t1/2 ) only 
n, minimum, median, and maximum will be reported. When reporting individual values and 
descriptive statistics for PK parameters of VIR-2218 and its metabolite (A-312327), the 
following rules will apply to rounding and precision:  
 
Individual values for PK parameters will be reported to 3 significant figures.   
 
Descriptive statistics for PK parameters will be reported to 3 significant figures.  
 
Between-subject CV% and geometric CV% will be reported as a percentage to 1 
decimal place.  
 
Data listings containing all documented data and all derived data will be generated. 
Missing data will not be imputed.  
 
Subjects with dosing deviations will be reported in the listings but excluded from the 
summary tables.  
3.4 
CONCENTRATION-TIME PROFILES  
Individual (for each subject) and mean plasma VIR-2218 and metabolite (A-312327) 
concentrations will be displayed graphically in linear and semi-logarithmic plots versus 
time (hour) Part, Dose Level, and Dosing Day l and Day 29. The actual collection time will 
be used for plots of individual plasma concentrations and nominal time will be used for 
plots of mean plasma concentrations. Below the plots, the number of quantifiable 
concentrations per timepoint will be displayed. Subjects with dosing deviations will be 
excluded from the mean plots. They will be displayed in the individual plots with footnote. 
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
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3.5 
Estimation of Pharmacokinetic Parameters 
Pharmacokinetic (PK) parameters will be estimated using Phoenix WinNonlin® software 
using standard noncompartmental methods. The linear/log trapezoidal rule will be used in 
conjunction with the appropriate noncompartmental model, with input values for dose level, 
dosing time, PK concentration, and corresponding real time values, based on drug dosing 
times whenever possible. 
All predose sample times before time-zero will be converted to zero. 
For area under the curve (AUC), samples below the limit of quantitation (BLQ) of the 
bioanalytical assays occurring prior to the achievement of the first quantifiable concentration 
will be assigned a concentration value of zero 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 (e.g., plasma collection) or dosing interval (τ) may be 
used to permit direct calculation of AUC over specific time intervals.  
Pharmacokinetic parameters such as AUCinf, λz, and t1/2 are dependent on an accurate 
estimation of the terminal elimination phase of drug. The appropriateness of calculating these 
parameters will be evaluated upon inspection of PK data on a profile-by-profile basis by the 
PK scientist. 
The following parameters will be used to evaluate the PK objectives of the study: Tmax, Cmax, 
Tlast, Clast, t1/2, AUC0- t, AUC0-8hr, AUC0-12hr, AUC0-24hr, AUCinf, z, CL/F, Vz/F. 
 
Tmax: The time to attain Cmax. If the same Cmax concentration occurs at different time 
points, tmax is assigned to the first occurrence of Cmax. 
 
Cmax: Individual maximum concentration (Cmax) values are directly determined from 
the plasma concentration time profiles for each subject. 
 
Tlast: Time of last measurable (positive) observed concentration. 
 
Clast: Observed concentration corresponding to Tlast.  
 
t1/2: The terminal half-life will be calculated from the terminal rate constant using the 
equation: 
𝑡1/2 = 𝐿𝑛(2)
𝜆𝑧
 
 
 
AUC0-t: The areas under the curve spanning time interval from 0 to t (up to the last 
time point with measurable concentration. AUC0-t will be calculated using the linear-
up /logarithmic-down trapezoidal rule. Linear trapezoidal rule: The area of the 
trapezoid between the two data points (t1, C1) and (t2, C2) where C2≥C1 will be 
computed by: 
𝐴𝑈𝐶𝑡1−𝑡2 = 0.5(𝑡2 −𝑡1)(𝐶1 + 𝐶2) 
Logarithmic trapezoidal rule: The area of the trapezoid between the two data points 
(t1, C1) and (t2, C2) where C2<C1 will be computed by 
𝐴𝑈𝐶𝑡1−𝑡2 = ((𝑡2 −𝑡1)(𝐶1 −𝐶2))
𝑙𝑛𝐶1 −𝑙𝑛𝐶2
 
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
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 
When a partial AUC(e.g. AUC0-12hr) is requested at time points not included in the 
scheduled measurements scheme, Interpolation will be used to estimate the 
concentration of these time points.  
1) Additional point before last observed data point 
Depending on the choice of the “Integral method” setting, this can be done using 
a linear or log formula to find the added concentration C* at requested time t*, 
given that the previous and following measurements are C1 at t1 and C2 at t2.  
Linear interpolation formula: 
 
𝐶∗= 𝐶1 + |𝑡∗−𝑡1
𝑡2 −𝑡1
| × (𝐶2 −𝐶1) 
Logarithmic interpolation formula: 
 
𝐶∗= 𝑒𝑥𝑝(𝑙𝑛(𝐶1) + |𝑡∗−𝑡1
𝑡2 −𝑡1
| × (𝑙𝑛(𝐶2) −ln(𝐶1))) 
 
If the logarithmic interpolation rule fails in an interval because C1 or C2 are null or 
negative, then the linear interpolation rule will apply for that interval. 
 
2) Additional point after last observed data point 
If z  is not estimable, the partial area will not be calculated. Otherwise, z  is used 
to calculate the additional Concentration C* 
 
C*=exp(Lambda_z_intercept-z×tlast) 
 
Where Lambda_z_intercept is the intercept on log scale estimated via linear 
regression of time vs. log concentration in estimating z  
 
 
AUC0-8hr: The area under the plasma concentration-time curve over the time interval 
from 0 to 8 hr using the linear-up /logarithmic-down trapezoidal rule.  
 
AUC0-12hr: The area under the plasma concentration-time curve over the time 
interval from 0 to 12 hr using the linear-up /logarithmic-down trapezoidal rule. AUC0-
24hr: The area under the plasma concentration-time curve over the time interval from 
0 to 24 hr using the linear-up /logarithmic-down trapezoidal rule.  
 
 AUCinf: The area under the plasma concentration-time curve over the time interval 
from 0 extrapolated to infinity will be calculated according to the following equation: 
𝐴𝑈𝐶0−∞= 𝐴𝑈𝐶0−𝑡+ 𝐶𝑡
′
𝜆𝑧
 
where C't is the predicted concentration at the time t (last time point with a 
measurable plasma concentration above the quantification limit) at which 
quantification was still possible, the calculation of z is given below.  
 
AUC%extrap: The percentage of the AUC that has been extrapolated beyond the last 
observed data point, calculated as: 
𝐴𝑈𝐶%𝑒𝑥𝑡𝑟𝑎𝑝= (𝐴𝑈𝐶0−∞−𝐴𝑈𝐶0−𝑡
𝐴𝑈𝐶0−∞
) ∗100 
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
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 
z: The apparent terminal rate constant z will be estimated from a regression of ln(C) 
versus time over the terminal log-linear drug disposition portion of the concentration-
time profiles. To calculate the elimination rate constant, the terminal data from a 
concentration-time curve will be used. Starting with the final non-BLQ data point and 
moving backwards, toward time zero, at least 3 data points not included Cmax are fit to a 
linear regression. The number of data points used can be determined by maximizing 
the value adjusted-r2 which defines the “best-fit” of the data. The first order rate 
constant associated with the terminal (log-linear) portion of the curve will be estimated 
via linear regression of time vs. log concentration. The rules are that a minimum of 
three points is needed to define the terminal (log-linear) portion of the curve, z must be 
positive, and the selection is based on the best adjusted square coefficient of 
regression (r2 ). Additionally, if the adjusted r2 does not improve, but is within 0.0001 of 
the largest adjusted R2 value, the regression with the larger number of points is used. 
The “adjusted” r2 is calculated using the following equation: 
𝐴𝑑𝑗𝑢𝑠𝑡𝑒𝑑 𝑟2 = 1 −(1 −𝑟2) ∗(𝑛−1)
(𝑛−2) 
where n = the number of data points used in the regression. The slope of the line is 
equal to -z (i.e., the slope will be negative, but z is a positive value). 
 If terminal concentration-time point(s) increases, this time point may be included if 
the t1/2 estimate is reasonable. If z is not determinable (for example, adjusted-r2 
value <0.8) then consequently only parameters not requiring z will be reported. In 
addition, the lower (Rstart) and upper (Rend) limit on time (h) for values to be included 
in the calculation of z will be listed. 
 
CL/F: The total clearance will be calculated as following: 
𝐶𝐿𝐹
⁄
=
𝐷
𝐴𝑈𝐶0−∞
 
where D is dose 
 
Vz/F: The apparent volume of distribution based on terminal phase will be calculated 
according to the follow equation: 
𝑉𝑧𝐹
⁄
=
𝐶𝐿𝐹
⁄
𝜆𝑧
 
 
3.6 
Other important PK considerations 
 
 
The value of AUC%extrap will be less than or equal to 20% for the AUC0-∞ to be 
considered well estimated. If this proportion is > 20%, then the values of AUC0-∞ will be 
treated with caution, and emphasis will be placed on AUC0-t values (i.e. in subsequent 
statistical analyses).  
 
If AUC%extrap >20%, all elimination related parameters (z, AUC0-∞, t1/2, CL/F or CL/F,ss, 
and Vz/F or Vz/F,ss) will be presented in the listings but excluded from the calculation of 
summary statistics. All values excluded from the summaries should be flagged in the 
individual listings with an explanation for the exclusion. 
 
If data permits, the other PK parameters may be reported. 
 
If tlast = tmax; Cmax will not be reported for that subject in the listings. It will be footnoted to 
indicate that sampling timepoints were not appropriate for that subject.  
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
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 
If tlast<24hr, AUC0-24hr will only be reported when AUC%extrap<20%; it will be presented 
in the listing with footnote to indicate that AUC0-24hr was extrapolated. In the summary 
tables, the cohort will be footnoted to indicate that subjects with extrapolated AUC0-24hr  
were included in the calculation of summary statistics. 
 
If tlast<8hr, AUC0-8hr will only be reported when AUC%extrap <20%; it will be presented in 
the listing with footnote to indicate that AUC0-8hr was extrapolated. In the summary 
tables the cohort will be footnoted to indicate that subjects with extrapolated AUC0-8hr  
were included in the calculation of summary statistics. 
 
4. 
SOFTWARE 
 
The following software will be used to perform the statistical analyses: SAS® Version 9.4 
or higher (SAS Institute, Cary, North Carolina, USA). Phoenix WinNonlin® software 
(version 8.1 or higher). 
 
 
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
PK Statistical Analysis Plan 
 
        Final Version 1 
 
 
 
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5. 
SAP REVISION 
Revision Date 
(dd month, yyyy) 
Section 
Summary of Revision 
Reason for Revision 
 
 
 
 
 
 
 
 
 
6. 
PROPOSED TABLES, FIGURES, AND LISTINGS 
6.1 
Tables 
 
Title 
Analysis Set 
Notes 
1.1.1 
Individual and Summary of VIR-2218 and A-312327 
Plasma Concentrations by Timepoint, Dosing Day, and 
Dose Level 
PK Analysis 
Population 
 
1.1.2 
Individual and Summary of VIR-2218 Plasma 
Pharmacokinetic Parameter by Dosing Day and Dose 
Level  
PK Analysis 
Population 
 
1.1.3 
Individual and Summary of A-312327 Plasma 
Pharmacokinetic Parameter by Dosing Day and Dose 
Level 
PK Analysis 
Population 
 
1.1.4 
Individual and Summary of MR metabolite to parent 
ratio by Dosing Day and Dose Level 
PK Analysis 
Population 
 
6.2 
Figures 
 
Title 
Analysis Set 
Notes 
1.1.1.1 
Individual VIR-2218 Plasma PK Concentration vs 
Time by Dosing Day and Dose Level (Linear) 
PK Concentration 
Population 
 
2.2.2.1 
Individual A-312327 Plasma PK Concentrations vs 
Time by Dosing Day and Dose Level (Linear) 
PK Concentration 
Population 
 
2.2.2.2 
Individual VIR-2218 Plasma Concentration vs Time 
by Dosing Day and Dose Level (Semi-Logarithmic)  
PK Concentration 
Population 
 
2.2.3.1 
Individual A-312327 Plasma PK Concentrations vs 
Time by Dosing Day and Dose Level (Semi-
Logarithmic) 
PK Concentration 
Population 
 
3.2.1.1 
Mean VIR-2218 Plasma Concentration vs time by 
Dose Day and Dose Level (Linear) 
PK Concentration 
Population 
 
3.2.1.2 
Mean A-312327 Plasma Concentration vs time by 
Dose Day and Dose Level (Linear) 
PK Concentration 
Population 
 
3.2.1.1 
Mean VIR-2218 Plasma Concentration vs time by 
Dose Day and Dose Level (Semi-Logarithmic)  
PK Concentration 
Population 
 
3.2.1.2 
Mean A-312327 Plasma Concentration vs time by 
Dose Day and Dose Level  (Semi-Logarithmic)  
PK Concentration 
Population 
 
 
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Protocol Number: VIR-2218-1005                                                               12 NOV 2021 
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6.3 
Listings 
 
Title 
Analysis Set 
Notes 
11 
Plasma Concentrations of VIR-2218 and A-312327  
PK Concentration 
Population 
  
 
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