A Phase 1, Open-label, Parallel-group, Multiple-dose Study to Evaluate the Pharmacokinetics of Bulevirtide in Participants With Normal and Impaired Hepatic Function
Phase: PHASE1
Conditions: Hepatic Impairment, Healthy
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1, Open-label, Parallel-group, Multiple-dose Study to 
Evaluate the Pharmacokinetics of Bulevirtide in Participants With 
Normal and Impaired Hepatic Function
Plain Language Short 
Title:
A Multiple-dose Study of Bulevirtide in Participants Who Have 
Normal or Impaired Liver Function
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EU CT Number:
ClinicalTrials.gov 
Identifier:
125159
Not Applicable
NCT05765344
Indication:
Chronic Hepatitis D Infection
Protocol ID:
GS-US-589-6162
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List
Amendment History:
Original:
22 November 2022
Amendment 1:
13 February 2023
Amendment 2: 
30 September 2024
A high-level summary of the history of amendment is provided in 
Appendix 11.6.
Country-specific 
Requirements:
Not applicable
This study will be conducted under United States Food and Drug Administration investigational 
new drug application regulations (21 Code of Federal Regulations Part 312).
This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, and that are consistent with 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
regulatory requirements.
(r) GILEAU 

CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in 
the protocol. You will not disclose any of the information to others without written 
authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered.

Bulevirtide 
Protocol GS-US-589-6162 
Gilead Sciences, Inc. 
Final 
Amendment2 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................................................ 3 
LIST OF IN-TEXT TABLES ......................................................................................................................................... 6 
LIST OF IN-TEXT FIGURES ........................................................................................................................................ 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................................... 7 
PROTOCOL SYNOPSIS ................................................................................................................................................ 9 
STUDY SCHEMA ........................................................................................................................................................ 15 
STUDY PROCEDURES TABLE ................................................................................................................................ 16 
1. 
INTRODUCTION ................................................................................................................................................ 21 
1.1. 
Background .............................................................................................................................................. 21 
1.2. 
Background on Study Interventions ........................................................................................................ 22 
1.2.1. 
Bulevi.tt ide ............................................................................................................................. 22 
1.2.2. 
Info1mation About Comparator ............................................................................................. 24 
1.2.3. 
Info1mation About Auxilia1y Medicmal Products ................................................................ 24 
1.3. 
Rationale for This Study .......................................................................................................................... 24 
1.4. 
Rationale for the Dose Selection of Bulevi.ttide ...................................................................................... 26 
1.5. 
Risk/Benefit Assessment for the Study ................................................................................................... 26 
1.6. 
Coinpliance .............................................................................................................................................. 26 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................................................... 27 
3. 
STUDY DESIGN ................................................................................................................................................. 28 
3.1. 
StudyDesign ........................................................................................................................................... 28 
3.1.1 
Dose Selection ......................................................................................................................... 29 
3.2. 
Duration of Dosing .................................................................................................................................. 30 
3.3. 
Protocol-Specific Discontmuation Criteria ............................................................................................. 30 
3.3.1. 
Criteria for Early Discontmuation for the Individual Prut icipant.. ........................................ 30 
3.3.2. 
Criteria for Eru·ly Discontmuation of an Individua.l Coh011 .................................................. 31 
3 .3 .3. 
Criteria for Eru·ly Discontmuation of the Study .................................................................... 31 
3.3.4. 
Loss to Follow-Up ................................................................................................................. 31 
3.4. 
Clmic Confine1nent ................................................................................................................................. 32 
3.5. 
Definitions for Ti.tne of Prima1y Endpomt and End of Study ................................................................. 32 
3.5.1. 
Pri1nruy Endpomt. .................................................................................................................. 32 
3.5.2. 
End ofStudy .......................................................................................................................... 32 
3.6 
Source Data .............................................................................................................................................. 32 
4. 
PARTICIPANTPOPULATION .......................................................................................................................... 33 
4.1. 
Number of Pa11icipants and Part icipant Selection ................................................................................... 33 
4.1.1. 
Participant Replacement ........................................................................................................ 33 
4.2. 
Inclusion Criteria ..................................................................................................................................... 33 
4.3. 
Exclusion Criteria .................................................................................................................................... 35 
5. 
STUDY INTERVENTIONS AND CONCOMITANT MEDICATIONS ........................................................... 38 
5.1. 
Enrollment, Blmdmg, and Treatment Code Access ................................................................................ 38 
5.1.1. 
Enrolhnent ............................................................................................................................. 38 
5.1.2. 
Blmdmg ................................................................................................................................. 38 
5.2. 
Description and Handling ofBuleviitide ................................................................................................ 38 
5.2.1. 
Fo1mulation ........................................................................................................................... 38 
5.2.2. 
Packagmg and Labelmg ........................................................................................................ 39 
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5.2.3.
Storage and Handling ............................................................................................................39
5.3.
Dosage and Administration .....................................................................................................................39
5.3.1.
Administration Site Reactions...............................................................................................40
5.4.
Fasting and Meals....................................................................................................................................40
5.5.
Dispensing, Accountability, and Disposal or Return of Study Drug ......................................................41
5.6.
Concomitant Medications and Other Protocol Restrictions ....................................................................42
5.6.1.
Concomitant Medications......................................................................................................42
5.6.2.
Other Protocol Restrictions ...................................................................................................44
6.
STUDY ASSESSMENTS....................................................................................................................................45
6.1.
Informed Consent ....................................................................................................................................45
6.2.
Participant Enrollment and Treatment Assignment ................................................................................46
6.3.
Instructions for Study Procedures ...........................................................................................................46
6.3.1.
Adverse Events......................................................................................................................46
6.3.2.
Screening Assessments..........................................................................................................46
6.3.3.
Admission Assessments ........................................................................................................47
6.3.4.
Treatment Assessments .........................................................................................................47
6.3.5.
Pharmacokinetic and Pharmacodynamics Assessments........................................................47
6.3.6.
Plasma Collection for Immunogenicity Evaluation ..............................................................49
6.4.
Safety Assessments .................................................................................................................................49
6.4.1.
Electrocardiogram Assessment .............................................................................................49
6.4.2.
Physical Examination ............................................................................................................49
6.4.3.
Vital Signs .............................................................................................................................50
6.4.4.
Body Mass Index...................................................................................................................50
6.4.5.
Clinical Laboratory Tests/Assessments.................................................................................50
6.4.6.
Creatinine Clearance .............................................................................................................52
6.4.7.
Concomitant Medications/Protocol Restrictions...................................................................52
6.5.
Posttreatment Assessments......................................................................................................................52
6.6.
Assessments for Early Discontinuation From Study Intervention or From the Study............................52
6.6.1.
Assessments for Early Discontinuation From Study Intervention ........................................52
6.6.2.
Assessments for End of Study...............................................................................................52
6.7.
Sample Storage........................................................................................................................................53
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT................................................................................54
7.1.
Definitions of Adverse Events and Serious Adverse Events...................................................................54
7.1.1.
Adverse Events......................................................................................................................54
7.1.2.
Serious Adverse Events.........................................................................................................54
7.1.3.
Study Drugs and Gilead Concomitant Therapy Special Situation Reports...........................55
7.2.
Assessment of Adverse Events and Serious Adverse Events..................................................................56
7.2.1.
Assessment of Causality for Study Drugs and Procedures ...................................................56
7.2.2.
Assessment of Severity..........................................................................................................56
7.3.
Investigator Reporting Requirements and Instructions ...........................................................................57
7.3.1.
Requirements for Collection Prior to Study Drug Initiation .................................................57
7.3.2.
Adverse Events......................................................................................................................57
7.3.3.
Serious Adverse Events.........................................................................................................57
7.3.4.
Study Drug Special Situations Reports .................................................................................57
7.3.5.
Concomitant Therapy Reports...............................................................................................57
7.4.
Reporting Process for Serious Adverse Events and Special Situations Reports.....................................58
7.4.1.
Serious Adverse Event Reporting Process ............................................................................58
7.4.2.
Special Situations Reporting Process ....................................................................................59
7.5.
Gilead Reporting Requirements ..............................................................................................................60
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events...........................................................................................................................61
CCI

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7.7.
Toxicity Management..............................................................................................................................61
7.7.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event ..................................................62
7.7.2.
Grade 3 or Grade 4 Laboratory Abnormality or Clinical Event............................................62
8.
STATISTICAL CONSIDERATIONS.................................................................................................................63
8.1.
Analysis Objectives and Endpoints.........................................................................................................63
8.2.
Planned Analyses.....................................................................................................................................63
8.2.1.
Interim Analysis ....................................................................................................................63
8.2.2.
Final Analysis........................................................................................................................63
8.3.
Analysis Conventions..............................................................................................................................63
8.3.1.
Analysis Sets .........................................................................................................................63
8.3.2.
Data Handling Conventions ..................................................................................................64
8.4.
Demographic Data and Baseline Characteristics ....................................................................................64
8.5.
Safety Analysis........................................................................................................................................65
8.5.1.
Extent of Exposure ................................................................................................................65
8.5.2.
Adverse Events......................................................................................................................65
8.5.3.
Laboratory Evaluations .........................................................................................................65
8.5.4.
Other Safety Evaluations.......................................................................................................65
8.6.
Pharmacokinetic and Pharmacodynamic Analysis..................................................................................65
8.7.
Immunogenicity Analysis........................................................................................................................66
8.8.
Biomarker Analysis.................................................................................................................................66
8.9.
Sample Size .............................................................................................................................................66
9.
RESPONSIBILITIES...........................................................................................................................................67
9.1.
Investigator Responsibilities ...................................................................................................................67
9.1.1.
Good Clinical Practice...........................................................................................................67
9.1.2.
Financial Disclosure ..............................................................................................................67
9.1.3.
Institutional Review Board or Independent Ethics Committee Review and 
Approval................................................................................................................................67
9.1.4.
Informed Consent ..................................................................................................................67
9.1.5.
Confidentiality.......................................................................................................................68
9.1.6.
Study Files and Retention of Records ...................................................................................68
9.1.7.
Case Report Forms ................................................................................................................70
9.1.8.
Investigator Inspections.........................................................................................................70
9.1.9.
Protocol Compliance .............................................................................................................70
9.2.
Sponsor Responsibilities .........................................................................................................................70
9.2.1.
Protocol Modifications ..........................................................................................................70
9.2.2.
Study Reports and Publications.............................................................................................71
9.3.
Joint Investigator/Sponsor Responsibilities ............................................................................................71
9.3.1.
Payment Reporting ................................................................................................................71
9.3.2.
Access to Information for Monitoring...................................................................................71
9.3.3.
Access to Information for Auditing or Inspections ...............................................................71
9.3.4.
Study Discontinuation ...........................................................................................................71
10.
REFERENCES.....................................................................................................................................................72
11.
APPENDICES......................................................................................................................................................75
11.1.
Investigator Signature Page.....................................................................................................................76
11.2.
Pandemic Risk Assessment and Mitigation Plan ....................................................................................77
11.3.
Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive Requirements ..........79
11.4.
Toxicity Grading Scale for Severity of Adverse Events and Laboratory Abnormalities........................82
11.5.
Country-Specific Requirements ..............................................................................................................83
11.6.
Amendment History ................................................................................................................................84
11.6.1.
Amendment 2 (30 September 2024)......................................................................................84

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11.6.2.
Amendment 1 (13 February 2023) ........................................................................................85
LIST OF IN-TEXT TABLES
Table 1.
Study Procedures Table...........................................................................................................16
Table 2.
Study Objectives and Endpoints..............................................................................................27
Table 3.
Laboratory Analytes ................................................................................................................50
LIST OF IN-TEXT FIGURES
Figure 1.
Study Schema ..........................................................................................................................15

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
ADA
antidrug antibodies
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC0-24h
partial area under the concentration versus time curve from time zero to time 24 hours
AUCtau
area under the concentration versus time curve over the dosing interval
BA
bile acids
BLV
bulevirtide
BMI
body mass index
CFR
Code of Federal Regulations
CHB
chronic hepatitis B infection
CHD
chronic hepatitis D infection
CHO
Chinese hamster ovary
CI
confidence interval
CK
creatine kinase
CL
clearance
CLcr
creatinine clearance
CLss/F
apparent oral clearance at steady state
Cmax
maximum observed concentration of drug
COVID-19
coronavirus disease 2019
CPT
Child-Pugh-Turcotte
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
concentration at the end of the dosing interval
DDI
drug-drug interaction
DNA
deoxyribonucleic acid
EASL
European Association for the Study of the Liver
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EFD
embryofetal development
ET
early termination
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase

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Gilead
Gilead Sciences
GLSM
geometric least-squares mean
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDV
hepatitis D virus
HEK293
human embryonic kidney 293 cell line
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
IB
investigator’s brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
IEC
independent ethics committee
IND
investigational new drug
IRB
institutional review board
IRT
Interactive Response Technology
Ki
kinetic inhibition constant
MedDRA
Medical Dictionary for Regulatory Activities
NTCP
sodium-taurocholate cotransporting polypeptide
OATP
organic anion transporting polypeptide
PD
pharmacodynamic(s)
Peg-IFNα
pegylated interferon alpha
PK
pharmacokinetic(s)
PopPK
population pharmacokinetic
PS
Patient Safety
QT (interval)
electrocardiographic interval between the beginning of the Q wave and termination of 
the T wave, representing the time for both ventricular depolarization and 
repolarization to occur
RNA
ribonucleic acid
SAE
serious adverse event
SC
subcutaneous(ly)
SSR
special situation report
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal elimination half-life
Tmax
time (observed time point) of Cmax
ULN
upper limit of normal
US
United States
Vss/F
apparent steady-state volume of distribution of the drug

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
Study Title: A Phase 1, Open-label, Parallel-group, Multiple-dose Study to Evaluate the 
Pharmacokinetics of Bulevirtide in Participants With Normal and Impaired Hepatic Function
Plain Language Short Title: A Multiple-dose Study of Bulevirtide in Participants Who Have 
Normal or Impaired Liver Function
Regulatory Agency Identifier Numbers:
IND Number: 125159
EU CT Number: Not Applicable
ClinicalTrials.gov Identifier: NCT05765344
Study Sites Planned: Multiple sites in US
Objectives and Endpoints:
Primary Objective
Primary Endpoint 
•
To evaluate the steady-state plasma 
pharmacokinetics (PK) of bulevirtide (BLV) in 
non-hepatitis D virus/hepatitis B virus-infected 
participants with hepatic impairment compared to 
matched controls with normal hepatic function
•
BLV steady-state plasma PK parameters AUCtau 
and Cmax,ss 
Secondary Objectives
Secondary Endpoints
•
To further characterize the plasma PK of BLV in 
participants with hepatic impairment compared 
with matched controls with normal hepatic 
function
•
To evaluate the pharmacodynamic (PD) effect of 
BLV on plasma bile acids (BA) in participants 
with hepatic impairment compared with matched 
controls with normal hepatic function
•
To evaluate the safety and tolerability of BLV 
following multiple dose administration in 
participants with hepatic impairment compared 
with matched controls with normal hepatic 
function
•
Plasma PK parameters for BLV, as applicable: 
AUC0-24h, Cmax, Tmax, t1/2, CLss/F, and Vss/F 
•
Total BA concentrations in plasma and exposure 
parameters for total BA, as applicable: Ctrough, 
Cmax, AUC0-24h, and Tmax
•
The incidences of adverse events (AEs) and 
laboratory abnormalities
Study Design: This protocol describes an open-label, multicenter, multiple-dose, parallel-group, 
Phase 1 study to evaluate the steady-state plasma PK following exposure to BLV in participants 
with hepatic impairment compared with matched controls with normal hepatic function. An 
overview of the study design is described below and shown in Figure 1. Participants will be 
enrolled into 1 of 4 study groups:

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•
Group A (BLV 2 mg in moderate hepatic impairment): 20 participants (10 with moderate 
hepatic impairment and 10 matched controls with normal hepatic function)
•
Group B (BLV 2 mg in severe hepatic impairment): Approximately 16 participants (8 with 
severe hepatic impairment and 8 matched controls with normal hepatic function)
•
Group C (Optional; BLV 10 mg in moderate hepatic impairment): 20 participants (10 with 
moderate hepatic impairment and 10 matched controls with normal hepatic function)
•
Group D (Optional; BLV 10 mg in severe hepatic impairment): Approximately 16 
participants (8 with severe hepatic impairment and 8 matched controls with normal hepatic 
function)
Classification of hepatic impairment will be assigned at screening as follows:
•
Group A and Group C: Moderate hepatic impairment, Class B, Child-Pugh-Turcotte (CPT) 
score of 7 to 9
•
Group B and Group D: Severe hepatic impairment, Class C, CPT score of 10 to 15
The control group will consist of matched participants with normal hepatic function. Each 
control participant (normal hepatic function) will be matched for age, sex, and body mass index 
(BMI) with a participant in the hepatic impairment group.
Study procedures will include safety assessments and PK assessments for all participants. 
Clinical procedures in all groups will be identical to those described for Group A.
Number of Participants Planned: Up to 72 participants will be enrolled, with a goal of 
obtaining approximately 56 evaluable participants.
Study Population: Participants should have no history of hepatitis D virus or hepatitis B virus 
infection and either have hepatic impairment based upon the CPT classification system for 
moderate or severe hepatic impairment (CPT Class B or C, respectively) or normal hepatic 
function.
Diagnosis and Main Eligibility Criteria:
Key Inclusion Criteria
All Participants:
•
Be aged 18 through 79 years, inclusive, at screening.
•
Have a calculated BMI 18 ≤ BMI ≤ 40 kg/m2at screening.
•
Have a calculated creatinine clearance (CLcr) of at least 60 mL/minute (using the 
Cockcroft-Gault method {Cockcroft 1976}) based on serum creatinine and actual body 
weight as measured at screening.
•
12-lead electrocardiogram (ECG) evaluations at screening must be without clinically 
significant abnormalities as assessed by the investigator.

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•
Aside from hepatic impairment among the participants with hepatic impairment, the 
participant must, in the opinion of the investigator, be sufficiently healthy for study 
participation based upon medical history, physical examination, vital signs, and screening 
laboratory evaluations.
Participants With Hepatic Impairment:
•
Have a diagnosis of chronic (> 6 months), stable hepatic impairment (moderate or severe 
based upon the CPT classification system [CPT Class B or C, respectively]) with no 
clinically significant change in hepatic status (as determined by the investigator) within the 
2 months (60 days) prior to screening.
Participants with moderate or severe hepatic impairment must have a score of 7 to 9 or 
10 to 15, respectively, on the CPT classification system at screening. If a participant’s 
score changes during the study, the score at screening will be used for classification.
•
Must meet all of the following laboratory parameters at screening:
alanine aminotransferase (ALT) ≤ 10 × upper limit of normal (ULN)
aspartate aminotransferase (AST) ≤ 10 × ULN
platelets ≥ 25,000/mm3
hemoglobin ≥ 9 g/dL
Matched Control Participants With Normal Hepatic Function:
•
Have ALT, AST, alkaline phosphatase, international normalized ratio, and total bilirubin at 
or below the ULN; and albumin above the lower limit of normal at screening and at 
admission.
•
Must be matched for age (± 10 years), sex (assigned at birth), and BMI (± 20%, 18 ≤ BMI 
≤ 40 kg/m2) with a participant in the hepatic impairment group.
Key Exclusion Criteria
All Participants:
•
Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic 
agents within 3 months prior to screening or is expected to receive these agents during the 
study (eg, corticosteroids, immunoglobulins, other immune or cytokine-based therapies).
•
Have a history of any of the following:
Significant serious skin disease, such as but not limited to rash, food allergy, eczema, 
psoriasis, or urticaria.
Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity).
Known hypersensitivity to the study drugs, their metabolites, or to formulation 
excipients.

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Significant cardiac disease (including history of myocardial infarction based on ECG 
and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or 
dilated cardiomyopathy with left ventricular ejection fraction ≤ 40%); or a family history 
of long QT syndrome, or unexplained death in an otherwise healthy individual between 
the ages of 1 and 30 years.
Syncope, palpitations, or unexplained dizziness.
Implanted defibrillator or pacemaker.
•
Have any serious or active medical or psychiatric illness (including depression) that, in the 
opinion of the investigator, would interfere with participant treatment, assessment, or 
compliance with the protocol. This would include renal, cardiac, hematological, hepatic, 
pulmonary (including chronic asthma), endocrine (including diabetes), central nervous, 
gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), 
immunodeficiency disorders, autoimmune disorders, active infection, or malignancy (except 
basal cell carcinoma or squamous cell carcinoma localized to the skin) that are clinically 
significant or requiring treatment, with the exception of hepatic impairment-related 
symptoms in participants within the hepatic impairment group.
Participants With Hepatic Impairment:
•
Have a positive test result for HIV antibody, hepatitis B virus surface antigen, or hepatitis C 
virus (HCV) antibody with detectable HCV RNA at screening. Note: any previous treatment 
for an HCV infection must have been completed at least 12 weeks before screening.
•
Prior placement of a transjugular intrahepatic portosystemic shunt, unless the most recent 
vascular imaging indicates the shunt has no current blood flow.
•
Suspicion of hepatocellular carcinoma (ie, if alpha-fetoprotein > 20 ng/mL at screening, 
enrollment is only allowed if results of appropriate diagnostic imaging studies are 
inconsistent with a diagnosis of hepatocellular carcinoma and after discussion with the 
medical monitor).
•
Participants with hepatic impairment with comorbid diseases not associated with hepatic 
impairment requiring medications must be taking the medications without a change in dose 
for at least 4 weeks (or 5 half-lives, whichever is longer) prior to screening. Any change in 
the dosage during this timeframe should be reviewed and approved by the sponsor.
Matched Control Participants With Normal Hepatic Function:
•
Have a positive test result for HIV antibody, HBsAg, or HCV antibody.
•
Have taken any prescription medications or over-the-counter medications, including herbal 
products, within 28 days prior to start of study drug dosing, with the exception of vitamins 
and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications.

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Test Product, Dose, and Mode of Administration: Participants will be administered BLV 
administered by subcutaneous injection once daily:
•
Group A: BLV 2 mg in participants with moderate hepatic impairment and in participants 
who are matched controls with normal hepatic function
•
Group B: BLV 2 mg in participants with severe hepatic impairment and in participants who 
are matched controls with normal hepatic function
•
Group C: BLV 10 mg in participants with moderate hepatic impairment and in participants 
who are matched controls with normal hepatic function
•
Group D: BLV 10 mg in participants with severe hepatic impairment and in participants who 
are matched controls with normal hepatic function
Reference Therapy, Dose, and Mode of Administration: Not applicable.
Duration of Dosing and Duration of Study:
•
Duration of Dosing: 6 days
•
Duration of Study: 14 days (± 2 days)
Following the completion of screening procedures and study enrollment at admission, eligible 
participants will remain in the clinic for a period of 9 days, beginning on Day −1 until the 
completion of assessments on Day 8. Participants will be administered daily injections of BLV 
Day 1 through Day 6. A follow-up telephone call to collect safety data will be made on Day 13 
(± 2 days).
Study Procedures/Frequency: Following the completion of screening procedures and study 
enrollment at admission, eligible participants will be administered study drug and undergo the 
following assessments as summarized in Table 1:
•
Adverse event reporting
•
Physical examinations
•
Vital signs
•
12-lead ECGs
•
Safety laboratory
•
Other laboratory assessments (eg intensive PK, trough PK, BA for PD, protein binding, 
immunogenicity)
Statistical Methods:
Pharmacokinetics and Pharmacodynamics: Plasma concentrations of BLV and PK parameters, 
and plasma concentrations of total BA and PD parameters, will be listed and summarized by 
hepatic function group and dose level using descriptive statistics. In addition, concentrations of 
individual BA may be measured and PD parameters may be summarized. Percent of plasma 
protein binding may be estimated based on the plasma sample data collected on Day 1.

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For the primary objective analysis, a one-way analysis of variance model appropriate for a 
parallel design with hepatic function group as a fixed effect will be fit to the natural logarithmic 
transformation of PK parameters (AUCtau and Cmax,ss) for BLV. The 90% CIs will be constructed 
for the geometric least-squares mean (GLSM) ratio of PK parameters for BLV in the hepatic 
impairment group versus the matched control (normal hepatic function) group. The same 
analysis will be conducted for PD parameters of total BA, as applicable.
Safety: Adverse event data will be listed by participant. Treatment-emergent AEs, serious AEs, 
and AEs leading to permanent study drug discontinuation will be summarized by hepatic 
function group, dose, system organ class, and preferred term using the current version of 
MedDRA.
Listings of individual participant laboratory results will be provided. Laboratory results and 
changes from baseline values for selected laboratory tests will be summarized by hepatic 
function group and dose at scheduled visits. The incidence of treatment-emergent laboratory 
abnormalities will be summarized by hepatic function group and dose.
Vital signs and ECG data will be summarized by hepatic function group and dose.
Sample Size: For Group A and Group C (if conducted), with 16 (8 hepatic impairment and 
8 matched control [normal hepatic function]) evaluable participants, the estimated upper limit of 
1-sided 95% CIs of the GLSM ratio of hepatic impairment group versus matched control, with 
regards to AUCtau and Cmax,ss of BLV, would be less than 200% with at least 80% probability if 
the expected GLSM ratio is 1.0. This assumes a percentage coefficient of variation of no more 
than 51%, which is supported by the results from the previously conducted Gilead Sciences 
(Gilead) Study MYR102. Accounting for a 20% dropout rate, a total sample size of 20 participants 
(10 hepatic impairment and 10 matched control each) will be required. Furthermore, given the 
lower variability in BA concentrations compared with BLV concentrations observed in Study 
MYR102 {Blank 2018}, this sample size will also provide an at least 80% probability that the 
estimated upper limit of the 1-sided 95% CIs of the GLSM ratio of hepatic impairment group 
versus matched control, with regards to AUCtau and Cmax ss of plasma total BA, would be less 
than 200% if the expected GLSM ratio is 1.0.
For Group B and Group D (if conducted), given the challenges with enrolling participants with 
severe decompensated hepatic dysfunction, up to 16 participants (8 hepatic impairment and 
8 matched control) will be enrolled in each conducted study group with a target of at least 
12 (6 hepatic impairment and 6 matched control) evaluable participants. This may be lower than 
the power from the moderate groups but should provide sufficient characterization of BLV in the 
severe population. Note that based on the known metabolic pathway of linear peptides such as 
BLV, significant changes in the BLV PK are not expected in this population.

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STUDY SCHEMA
Figure 1.
Study Schema
BA = bile acids; BLV = bulevirtide; CPT = Child-Pugh-Turcotte; PK = pharmacokinetics; QD = once daily; SC = subcutaneous; TC = telephone call
Screening 
(up to 28 
days) 
Participants 
with Hepatic 
Impairment~ 
N = 8 to 10 
Matched 
Healthy 
Controls 
N = 8 to 10 
Day -1 
Admission/labs 
~Participants with Hepatic Impairment defined as: 
Day 1 
Days 2 to 5 
Baseline safety 
Trough PK and 
tabs 
BA sampling 
Intensive BLV 
PK and BA 
sampling 
Groups A and C: Moderate; CPT Class B, Score of 7 to 9 
Groups B and D: Severe; CPT Class C, Score of 10 to 15 
Day 6 
Intensive BLV 
PK and BA 
sampling 
Day 7 
Trough PK and 
BA sampling 
Day 8 
Day 13 (± 2) 
Trough PK and 
Follow-up TC 
BA sampling 
Discharge 

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STUDY PROCEDURES TABLE
Table 1.
Study Procedures Table
Study Procedure
Screening
Admission
Evaluation Period
Dischargea
Follow-upb
ETc
Study Day:
−1
1
2-5
6
7
8
13
Window:
≤ 28 Days 
Prior to 
Dosing
± 2 Days
Notes
Written informed 
consent
X
Clinic confinement
X
X
X
X
X
X
Review study 
restrictions
X
X
X
X
Complete medical 
history 
X
Complete physical 
examination
X
X
X
X
Symptom-driven physical examination may occur at 
any other visits if clinically indicated.
Weight, height, 
and BMI
X
X
COVID-19 testing
X
Must receive a negative PCR result for enrollment. If 
study site cannot obtain results from the local 
laboratory in time for Day 1 dosing, then COVID-19 
rapid antigen test/rapid PCR is acceptable.
Vital signs
X
X
X
X
X
X
X
X
Vital signs include resting blood pressure, heart rate, 
and body temperature at: screening, admission 
(Day −1), Day 1 (predose and approximately 2 hours 
postdose), Day 6 (predose and approximately 
2 hours postdose), then once in the morning of 
following days/before blood PK sampling: Day 2 
through Day 5, Day 7, discharge (Day 8), and at the 
ET visit (if applicable).

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Study Procedure
Screening
Admission
Evaluation Period
Dischargea
Follow-upb
ETc
Study Day:
−1
1
2-5
6
7
8
13
Window:
≤ 28 Days 
Prior to 
Dosing
± 2 Days
Notes
12-Lead ECG
X
X
X
X
X
X
X
12-Lead ECG will be performed at screening, 
admission (Day −1), Day 1 (4 hours postdose), 
Day 3 (4 hours postdose), Day 6 (4 hours postdose), 
discharge (Day 8), and at the ET visit (if applicable).
HIV, HBV, and 
HCV testing
X
Fourth generation HIV antibody/antigen test, 
hepatitis B surface antibody, hepatitis B surface 
antigen, HCV antibody, and HCV RNA testing (at 
screening only).
Creatinine 
clearance
X
X
X
X
X
X
X
X
Creatinine clearance will only be calculated via 
Cockcroft-Gault method (Section 4.2) on days 
chemistry is performed.
Hematologyd,e
X
X
X
X
X
X
X
X
8-hour fasting required.
Chemistryd,e
X
X
X
X
X
X
X
X
8-hour fasting required
Urinalysisd,e
X
X
X
X
X
X
X
X
8-hour fasting required.
Urine drug and 
alcohol screene
X
X
If study site cannot perform urine alcohol or receive 
results from the local laboratory in time for 
enrollment on Day 1, then an alcohol breathalyzer 
test is acceptable.
Coagulatione,f
X
X
X
X
X
X
X
Prothrombin time, partial thromboplastin time, and 
INR.
Alpha-fetoprotein
X
Immunogenicity
X
X
Collected predose (≤ 30 minutes before dose).

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Study Procedure
Screening
Admission
Evaluation Period
Dischargea
Follow-upb
ETc
Study Day:
−1
1
2-5
6
7
8
13
Window:
≤ 28 Days 
Prior to 
Dosing
± 2 Days
Notes
Serum pregnancy 
test
X
X
Required for participants assigned female at birth 
and of childbearing potential only. 
Point of care (urine) pregnancy test may be used at 
site if serum test result is not available prior to 
dosing.
FSH testing
X
FSH testing required for participants assigned female 
at birth who are younger than 54 years, not on 
hormonal contraception, and who have stopped 
menstruating for at least 12 months but do not have 
documentation of ovarian hormonal failure. 
Enrollment
X
Participants will be considered enrolled after 
eligibility is confirmed and a participant number is 
assigned on Day 1 prior to dosing.
Study drug 
administration
X
X
X
See Section 5.3
Intensive plasma 
PK and BA 
sampling for PD
X
X
X
Intensive PK and total BA sampling will occur 
relative to the dosing of BLV at the following time 
points: Day 1 and Day 6 at predose (≤ 30 minutes 
before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, and 12 hours 
postdose, and at the ET visit (if applicable).

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Study Procedure
Screening
Admission
Evaluation Period
Dischargea
Follow-upb
ETc
Study Day:
−1
1
2-5
6
7
8
13
Window:
≤ 28 Days 
Prior to 
Dosing
± 2 Days
Notes
Trough plasma PK 
and BA for PD
X
X
X
X
Trough PK and total BA sampling will occur 
predose (≤ 30 minutes before dose) on Day 2 
through Day 5 and at 24 hours post Day 6 dose 
(Day 7) and 48 hours post Day 6 dose (Day 8), and 
the ET visit (as applicable). The Day 2 predose 
trough sample of plasma PK and plasma BA will 
serve as the 24 hours post Day 1 dose sample for 
intensive plasma PK and plasma BA, respectively, 
and would be interpolated programmatically at the 
time of PK analysis.
Plasma sample for 
protein binding
X
On Day 1, at predose, and 2 and 12 hours postdose.
Meal monitoring
X
X
X
X
X
X
Record the percentage of meal consumed (0%-25%, 
25%-50%, > 50%). See Section 5.4 for meal intervals.
Review AEs and 
concomitant 
medications
X
X
X
X
X
X
X
X
X
From the time of obtaining informed consent 
through the first administration of study drug, record 
all SAEs, as well as any nonserious AEs related to 
protocol-mandated procedures, on the AE eCRF. All 
other untoward medical occurrences observed during 
the screening period, including exacerbation or 
changes in medical history, are to be captured on the 
medical history eCRF. See Section 7, Adverse 
Events and Toxicity Management, for additional 
details.
CCI

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AE = adverse event; BA = bile acids; BLV = bulevirtide; BMI = body mass index; ECG = electrocardiogram; eCRF = electronic case report form; ET = early termination; 
FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; INR = international normalized ratio; 
PCR = polymerase chain reaction; PD = pharmacodynamics; PK = pharmacokinetics; SAE = serious adverse event
a.
Participants will be discharged from the clinic on Day 8 per investigator’s discretion, following all morning assessments.
b.
Participants will be contacted for evaluation of AEs by telephone on Day 13 ± 2 days, 7 days (± 2 days) following the last administration of study drug.
c.
ET assessments will be performed within 24 hours of prematurely discontinuing from the study (prior to Day 8). 
d.
Performed at screening, admission (Day −1), Day 1 (predose), Day 3 (predose), Day 6 (predose), Day 7, at discharge on Day 8, and at the ET visit, if applicable. Predose 
collections are to be performed ≤ 30 minutes before study drug administration.
e.
Safety laboratory tests will be performed upon study site admission (Day −1) and will be evaluated at the site’s local laboratory to obtain results for participant’s eligibility 
prior to dosing on Day 1. Results of the Day −1 safety laboratory tests will be maintained with the source documents and will not be entered in the electronic data capture at 
the site. Baseline safety laboratory assessments will be performed on Day 1 and then participants will be administered daily injections of BLV.
f.
Coagulation tests will be performed at screening, admission (Day −1), Day 1 (predose), Day 3 (predose), Day 6 (predose), at discharge on Day 8, and at the ET visit, if 
applicable. Predose collections are to be performed ≤ 30 minutes before study drug administration. 

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1.
INTRODUCTION
1.1.
Background
Hepatitis D virus (HDV) infection is the most severe form of viral hepatitis, affecting as many as 
10 to 20 million people globally {Stockdale 2020}. Hepatitis D is caused by the HDV, a 
defective RNA virus that requires the presence of hepatitis B surface antigen (HBsAg) for its 
complete replication and transmission {Rizzetto 2009, Sureau 1993, Taylor 2015}, and, as such, 
this form of hepatitis only occurs in individuals also infected with the hepatitis B virus (HBV). 
Prevalence rates vary widely; however, HDV infections are mostly concentrated in low- and 
middle-income countries, with the highest rates reported in Brazil, Mongolia, and parts of Africa 
{Lempp 2016}. In the United States (US) and European Union (EU), HDV infection is 
considered an orphan disease, with an estimated prevalence of 100,000 and 130,000 patients, 
respectively {Rizzetto 2009, Romeo 2018, Wedemeyer 2010b}.
Among patients with chronic hepatitis D infection (CHD), higher rates of disease progression, 
including liver-related events, cirrhosis, hepatocellular carcinoma, and death, have been reported 
than among patients with chronic hepatitis B infection (CHB) monoinfection {Heidrich 2014}. 
Several cohort studies have found that this risk may indeed be as much as 9 times higher than in 
patients with HBV monoinfection {Beguelin 2017}. Collectively, available data support the 
conclusion that CHD is the most severe form of viral hepatitis in humans {Wedemeyer 2010a}, 
with a more rapid progression to fibrosis and cirrhosis, earlier onset of hepatic complications, 
and greater likelihood of liver transplantation than other forms of viral hepatitis {Ni 2014, Yan 
2012}.
The therapeutic options for patients with HDV coinfection are very limited. Nucleos(t)ide 
analogues, while effective in patients with CHB have not been shown to have a meaningful 
therapeutic effect on HDV RNA levels in patients with CHD {European Association for the 
Study of the Liver 2017}. Currently in the US, there is no approved treatment available for CHD. 
Based on clinical studies conducted over the past few decades, the current guidelines of the 
American Association for the Study of Liver Diseases, the Asian Pacific Association for the 
Study of the Liver, and the European Association for the Study of the Liver (EASL) recommend 
the off-label use of pegylated interferon alpha (Peg-IFNα) for 12 months {Cornberg 2020, 
European Association for the Study of the Liver 2017, Terrault 2018}. Response rates with 
Peg-IFNα have been variable, ranging from 17% to 35%, and treatment is frequently associated 
with adverse effects such as flu-like symptoms, anemia, neutropenia, and thrombocytopenia that 
result in poor tolerability and subsequent high rates of discontinuation {Alavian 2012, Wranke 
2017}. Furthermore, among patients who achieve a response (undetectable HDV RNA 
posttreatment) when treated with Peg-IFNα, approximately 50% relapse in long-term follow-up 
{Heidrich 2014}. Overall, Peg-IFNα therapy is estimated to provide a long-lasting benefit for 
approximately 10% of patients {Heidrich 2014}. Recent advances in the field of HDV drug 
development include novel antiviral therapies with mechanisms of action such as those that 
target viral entry or impact assembly and release of viral particles, and treatments that work 
directly by activating the host immune response {Urban 2021}. Development of therapies that 

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effectively target critical aspects of the HDV replication cycle and are also well tolerated is 
needed to improve treatment outcomes and the long-term prognosis of those chronically infected 
with HDV.
1.2.
Background on Study Interventions
1.2.1.
Bulevirtide
1.2.1.1.
General Information
Bulevirtide (BLV; GS-4438), formerly known as Myrcludex B, is a novel 47-amino acid, 
N-terminally myristoylated, HBV large envelope protein–derived, synthesized lipopeptide that 
binds specifically to the sodium-taurocholate cotransporting polypeptide (NTCP) and acts as a 
potent, highly selective entry inhibitor of HDV into hepatocytes {Ni 2014, Yan 2012}. By 
blocking the essential entry receptor, the de novo infection of liver cells is decreased, viral 
spread is inhibited, and the life cycle of HDV is disrupted {Urban 2021}.
Bulevirtide is approved under the brand name Hepcludex® in the European Economic Area, the 
United Kingdom, Switzerland, and Australia and approved as Myrcludex B® in Russia. 
Bulevirtide as a 2-mg lyophilized powder for injection is to be administered subcutaneously (SC) 
once daily for the treatment of CHD in adults with compensated liver disease.
For further information on BLV, refer to the investigator’s brochure (IB) for BLV, including 
information on the company core data sheet and the reference safety information.
1.2.1.2.
Nonclinical Pharmacology, Pharmacokinetics, and Toxicology
Nonclinical Pharmacology
In vitro, BLV specifically binds to NTCP in mouse, rat, rabbit, dog, and human hepatocytes and 
the receptor structure and function are highly conserved between these species. No binding to 
cynomolgus monkey hepatocytes was observed, which is in line with recent studies showing that 
the cynomolgus monkey expresses an altered form of NTCP. The in vitro functional activity of 
myristoylated HBVpreS1 peptides (similar to the BLV molecule) to inhibit NTCP transporter 
function was assessed in a transporter inhibition uptake assay in cells overexpressing human 
NTCP. The half-maximal inhibitory concentration (IC50) value of 190 nM for bile acid (BA) 
uptake was obtained in human embryonic kidney 293 cell line (HEK293)-NTCP cells and an 
IC50 of 9.7 nM was obtained in primary human hepatocytes. Inhibition of rat NTCP function was 
assessed using Chinese hamster ovary (CHO)-K1 cells overexpressing the rat NTCP and a 
dose-dependent inhibition with an IC50 value of 0.068 μM was demonstrated. Consistently, an 
increase in total bile salts was observed in rats treated with 2.5 mg/kg body weight/day BLV for 
12 days during pregnancy as part of the embryofetal development (EFD) toxicity study. The 
increase in total bile salts was also observed in the EFD study in rabbits treated with BLV 
2.5 mg/kg body weight/day, thus confirming the functional inhibition of NTCP by BLV. In 
safety pharmacology studies, no BLV-related influence was observed on pulmonary, 
neuropharmacological, cardiovascular, renal, hepatic, ophthalmologic, or auditory parameters.

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Nonclinical Pharmacokinetics
An extensive program of nonclinical absorption and distribution studies with BLV was 
conducted in animals. Bulevirtide is a highly target-specific drug that was found exclusively 
distributed to the liver in all tested animals beside the cynomolgus monkey. It is rapidly absorbed 
after SC administration with Cmax being reached within 4 to 6 hours. Area under the curve 
generally increased in approximate proportion to dose in rats and dogs (0.25-2.5 mg/kg dose). 
After a single SC dose, the bioavailability of BLV was 81% in rats. Bulevirtide is highly plasma 
protein bound. In dogs, binding to plasma proteins was investigated by size exclusion 
chromatography. The radioactivity peak of BLV-y-123I overlapped with the main plasma protein 
peak showing BLV binding. In vitro, the plasma protein binding of BLV has been additionally 
evaluated using rat, dog, rabbit, and human plasmas by cross filtration demonstrating that the 
bound fraction percentage ranges from > 99.90% to > 99.92%. Given that BLV is a 47-amino 
acid peptide, it is likely eliminated via peptide catabolism by peptidases in systemic circulation 
and tissues, and no active metabolite is to be expected. Finally, the potential of drug-drug 
interactions (DDIs) for BLV were evaluated in vitro, and overall a low DDI risk was predicted.
Nonclinical Toxicology
A comprehensive toxicology program was conducted in accordance with the regulatory 
guidelines. Toxicology studies included a single-dose study in rats, and repeated-dose studies up 
to 13 weeks in dogs and 6 months in rats, as well as antigenicity studies in rats. No BLV-related 
toxicity was noted. Developmental and reproductive toxicology studies conducted in rats and 
rabbits showed no embryofetal and reproductive toxicity in either species. Within the rabbit 
embryofetal toxicity study, a maternal toxicity in the form of minimal reduction in body weight 
and food intake in dams administered BLV 2.5 mg/kg/day was observed. There were no effects 
on the male and female fertility parameters in fertility and early embryonic development studies 
and no effects on prenatal or postnatal development in rats up to 2.5 mg/kg/day, the highest dose 
tested.
1.2.1.3.
Additional Clinical Studies of Bulevirtide
The pharmacokinetic (PK) profile of BLV has been evaluated in a total of 7 clinical studies, of 
which 2 were Phase 1 studies (MYR101 and MYR102), 1 was a Phase 1/2 study (MYR201 
[HBV]), 3 were Phase 2 studies (MYR202, MYR203, and MYR204), and 1 was a Phase 3 study 
(MYR301). Bulevirtide exhibited dose-dependent, nonlinear PK following IV and SC 
administration. Following single and multiple dose SC administration, absorption was rapid and 
Tmax occurred between 0.5 to 3 hours postdose across all doses tested. After reaching peak 
concentrations, plasma levels declined with a t1/2 of 3 to 7 hours. With increasing doses greater 
than 2 mg daily, exposure to BLV was greater than dose proportional with an estimated increase 
in AUC0-24h of 3.9-fold and 10.9-fold, respectively, for 5 mg and 10 mg doses compared with the 
2 mg reference dose. There was also a corresponding reduction in apparent clearance (CL) and 
volume of distribution, suggesting saturation of binding of BLV to its target receptor, NTCP, in 
the liver with the excess BLV within the circulation resulting in higher than dose proportional 
plasma concentrations.

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Following single and multiple doses in Study MYR102 {Blank 2018, Blank 2016}, no 
full-length peptide was detected in urine samples of healthy participants, demonstrating that 
renal elimination of BLV is unlikely. Considering that BLV is a linear peptide, it is also not 
expected that hepatic metabolism would contribute to BLV elimination. In an integrated 
population PK (PopPK) modeling analysis, participants (N = 154) with cirrhosis 
(Child-Pugh-Turcotte [CPT] Class A; mild hepatic impairment) were found to have slightly 
lower CL (14% decrease), higher AUC0-24h (16.6%), and higher Cmax (13.3%) than participants 
without cirrhosis, resulting in no clinically relevant impact on exposure to BLV (BLV PopPK 
report CTRA-2021-1057). Therefore, no dose adjustment is recommended for participants with 
mild hepatic impairment. The PK of BLV has not been evaluated in participants with moderate 
and severe hepatic impairment (CPT Classes B and C, respectively), as these participants were 
excluded from the BLV clinical development program per protocol.
The molecular target of BLV is the NTCP receptor in the liver, which is inhibited by BLV as a 
direct result of its mechanism of action against HDV. Dose-dependent asymptomatic bile salt 
elevations were consistently observed across studies, as an expected consequence of the 
blockage of NTCP by BLV in accordance with its mechanism of action. Importantly, the bile salt 
elevations resolved upon discontinuation of BLV treatment and were asymptomatic.
The safety of BLV was assessed in participants with CHD without cirrhosis or with compensated 
cirrhosis from 3 Phase 2 studies and 1 Phase 3 study. Bulevirtide was generally safe and well 
tolerated when assessed in the combined and the separated dose analyses, with a low frequency 
of Grade 3 or 4 adverse events (AEs), serious adverse events (SAEs), and AEs leading to 
discontinuation of BLV; no SAEs were assessed as related to BLV while on treatment. The AE 
profile was generally similar between the BLV monotherapy groups and the control group, with 
the exception of higher rates of total BA increased, injection site reactions, headache, and 
pruritus that were very commonly reported with BLV treatment but not reported in the control 
group.
1.2.2.
Information About Comparator
This is a match-controlled, open-label study. No comparator drug is provided.
1.2.3.
Information About Auxiliary Medicinal Products
Auxiliary medicinal products are not planned for this study.
1.3.
Rationale for This Study
Hepatic impairment has been associated with changes in drug absorption, plasma protein 
binding, transport, and tissue distribution. These changes are prominent in patients with severely 
impaired  hepatic function. As chronic HDV is associated with development of fibrosis and 
cirrhosis, there is a need to characterize the PK and tolerability of BLV in people with impaired 
hepatic function. As a linear peptide, it is not expected that hepatic metabolism would contribute 
to BLV elimination. As described in Section 1.2.1.3, in the PopPK modeling analysis, 
participants with cirrhosis (Child-Pugh A mild hepatic impairment) were found to have slightly 

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lower CL than participants without cirrhosis, resulting in no clinically relevant impact on 
exposure to BLV exposure. Given this, this proposed study will be conducted in participants with 
moderate and severe hepatic impairment only. The results from this study will inform any dose 
adjustments needed at both dose levels of interest (2 mg and 10 mg) for patients infected with 
HDV who have moderate and/or severe hepatic impairment.
Up to 4 total groups are planned for this study, each enrolling 8 to 10 participants with reduced 
hepatic function. Each participant with hepatic impairment will have a matched control 
participant enrolled with normal hepatic function (matched for age, sex, and body mass index 
[BMI]). Pharmacokinetic data from participants with normal hepatic function may serve as 
matched controls for multiple participants across multiple groups, if the BLV dose is the same 
and the matching criteria are met.
Classification of hepatic impairment will be based upon the CPT classification system:
•
Groups A and C: Moderate hepatic impairment, Class B, CPT score of 7 to 9
•
Groups B and D: Severe hepatic impairment, Class C, CPT score of 10 to 15
The control group will consist of participants with normal hepatic function, and creatinine 
clearance (estimated using Cockcroft-Gault formula) ≥ 60 mL/minute.
Bulevirtide has a dose-dependent effect of elevating plasma BA concentrations, as a 
consequence of its mechanism of action (inhibition of the NTCP receptor responsible for uptake 
of BA into hepatocytes). Studies of participants with chronic hepatic impairment have shown 
that cirrhosis associated with viral hepatitis is associated with elevated serum BA, with a 
progressive increase as CPT score advances {Farooqui 2022}. Given this, there is the potential 
that BA concentrations may be further elevated in participants treated with BLV with hepatic 
impairment, thus this study will evaluate plasma BA concentrations.
Participants in Groups A and B will be administered BLV 2 mg once daily for 6 days and 
participants in Groups C and D will be administered BLV 10 mg once daily for 6 days. 
Administration of BLV with multiple dosing (once daily) is being utilized in this study as BLV 
has demonstrated dose- and time-dependent PK, with approximately a 2-fold accumulation after 
once-daily multiple dosing despite a short apparent terminal half-life (3 to 7 hours). A previous 
study, MYR102, demonstrated that steady state is achieved within 6 days of BLV dosing {Blank 
2016}. Hepatic impairment may also be associated with changes in protein binding, and thus 
plasma protein binding of BLV may also be evaluated in this study.
Intensive PK assessments will be conducted to ensure sufficient characterization of terminal 
elimination phase of BLV. To ensure participant safety, a minimum confinement until Day 8 will 
be required.
Non-HDV/HBV-infected participants are selected for this study to remove potential confounding 
effects of the target disease and/or therapies in participants with HDV infection. In addition, this 
study design, conducted at a Phase 1 unit, provides comparisons of PK and generates safety data 
for the expected therapeutic range of drug exposures planned for evaluation in subsequent 
studies.

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1.4.
Rationale for the Dose Selection of Bulevirtide
The 2 BLV doses for this study were chosen based on the following factors: 1) the 2 mg dose in 
Group A is the approved dose in some regions such as the EU and is a dose that has resulted in 
efficacy for the treatment of CHD in Phase 2 and 3 studies; 2) the 10 mg dose was selected as 
this dose has been evaluated throughout the clinical development program and continues to be 
investigated in ongoing Phase 2 and Phase 3 studies. Given the lack of dose linearity observed 
with BLV, whereby an approximately 11-fold increase in exposure is observed with the 10 mg 
dose compared with the 2 mg dose, and the corresponding dose-dependent effect on elevations of 
plasma BA, this dose needs to be independently characterized to enable future dose 
recommendations.
1.5.
Risk/Benefit Assessment for the Study
In addition to the established risks associated with SC injection of BLV (see IB), potential risks 
of a participant’s study involvement include unknown AEs, laboratory abnormalities, and 
general risks associated with clinic visits and laboratory blood draws. Strategies to mitigate these 
risks include close monitoring of participants’ clinical status, laboratory values, and AEs. 
Parameters for discontinuation of the study drug due to AEs will be well defined and closely 
followed.
There is no direct benefit to participants in this study; however, data from this study will support 
the development of BLV for the treatment of hepatitis D infection.
An infectious disease pandemic may pose additional risks to study drug availability, study visit 
schedule, and adherence to protocol-specified safety monitoring or laboratory assessments. Refer 
to Appendix 11.2 for further details on pandemic risks and risk mitigation strategy.
Considering the above, the benefit-risk balance for this study is considered positive.
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice, and all 
applicable regulatory requirements.

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2.
OBJECTIVES AND ENDPOINTS
The study objectives and endpoints are presented in Table 2.
Table 2.
Study Objectives and Endpoints
Primary Objective
Primary Endpoint 
•
To evaluate the steady-state plasma PK of BLV in 
non-HDV/HBV-infected participants with hepatic 
impairment compared with matched controls with 
normal hepatic function
•
BLV steady-state plasma PK parameters: AUCtau 
and Cmax,ss 
Secondary Objectives
Secondary Endpoints
•
To further characterize the plasma PK of BLV in 
participants with hepatic impairment compared 
with matched controls with normal hepatic 
function
•
To evaluate the pharmacodynamic (PD) effect of 
BLV on plasma BA in participants with hepatic 
impairment compared with matched controls with 
normal hepatic function
•
To evaluate the safety and tolerability of BLV 
following multiple dose administration in 
participants with hepatic impairment compared 
with matched controls with normal hepatic 
function
•
Plasma PK parameters for BLV, as applicable: 
AUC0-24h, Tmax, Cmax, t1/2, CLss/F, and Vss/F 
•
Total BA concentrations in plasma and exposure 
parameters for total BA, as applicable: Ctrough, 
Cmax, AUC0-24h, and Tmax
•
The incidences of AEs and laboratory 
abnormalities
Exploratory Objective
Exploratory Endpoint
•
To evaluate the plasma protein binding of BLV
•
Percent of plasma protein binding may be 
estimated

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3.
STUDY DESIGN
3.1.
Study Design
This protocol describes an open-label, multicenter, multiple-dose, parallel-group, Phase 1 study 
to evaluate the steady state plasma PK following exposure to BLV in participants with hepatic 
impairment compared with matched controls with normal hepatic function. Up to 72 participants 
will be enrolled, with a goal of obtaining approximately 56 evaluable participants.
An approximately even distribution of participants assigned male at birth and nonpregnant, 
nonlactating participants assigned female at birth, aged 18 through 79 years will be enrolled into 
the study.
An overview of the study design is described below and shown in Figure 1. Participants will be 
enrolled into 1 of 4 study groups:
•
Group A (BLV 2 mg in moderate hepatic impairment): 20 participants (10 with moderate 
hepatic impairment and 10 matched controls with normal hepatic function for a target of 
8 evaluable participants per group)
•
Group B (BLV 2 mg in severe hepatic impairment): Approximately 16 participants (8 with 
severe hepatic impairment and 8 matched controls with normal hepatic function for a target 
of 6 evaluable participants per group)
•
Group C (Optional; BLV 10 mg in moderate hepatic impairment): 20 participants (10 with 
moderate hepatic impairment and 10 matched controls with normal hepatic function for a 
target of 8 evaluable participants per group)
•
Group D (Optional; BLV 10 mg in severe hepatic impairment): Approximately 
16 participants (8 with severe hepatic impairment and 8 matched controls with normal 
hepatic function for a target of 6 evaluable participants per group)
Classification of hepatic impairment will be assigned at screening as follows:
•
Group A and Group C: Moderate hepatic impairment, Class B, CPT score of 7 to 9
•
Group B and Group D: Severe hepatic impairment, Class C, CPT score of 10 to 15
The matched control group will consist of matched participants with normal hepatic function. 
Each control participant (normal hepatic function) will be matched for age (± 10 years), sex 
(assigned at birth), and BMI (± 20%, 18 ≤ BMI ≤ 40 kg/m2) with a participant in the hepatic 
impairment group.
Study procedures will include safety assessments and PK assessments for all participants. 
Clinical procedures in all groups will be identical to those described for Group A.

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3.1.1.
Dose Selection
Participants will be administered BLV administered by SC injection once daily for 6 days:
•
Group A: BLV 2 mg in participants with moderate hepatic impairment
•
Group B: BLV 2 mg in participants with severe hepatic impairment
•
Group C: BLV 10 mg in participants with moderate hepatic impairment
•
Group D: BLV 10 mg in participants with severe hepatic impairment
Groups A and B will begin enrollment simultaneously. Once the safety and PK data from all 
participants in Group A (2 mg moderate hepatic impairment) have been reviewed, Group C 
(10 mg moderate hepatic impairment) may be opened. Once the safety and PK data from all 
participants in Group B (2 mg severe hepatic impairment) have been reviewed, Group D (10 mg 
severe hepatic impairment) may be opened.
Within each group, once a participant with hepatic impairment is enrolled, a matched control to 
that participant will be allowed to enroll. Dosing of matched participant with normal hepatic 
function may begin after the corresponding participant with hepatic impairment in that group has 
completed the last PK assessment.
A matching control may serve as a matched control participant only once per study group. A 
participant with normal hepatic function may have their PK and BA data reused just once to 
serve as a matched control for another group, if the BLV dose is the same and the matching 
criteria are met. Participants who have completed the study from previous groups can be 
re-enrolled in subsequent groups provided they meet all the inclusion and none of the exclusion 
criteria. 
3.1.1.1.
Safety Review Team and Charter
A safety review team will review all PK and safety data from completed Group A before opening 
Group C and from completed Group B before opening Group D.
A safety review team charter defining the team membership, meeting conduct, and 
decision-making process will be agreed upon by all team members before the first meeting. The 
data reviewed at the team meetings to make decisions to allow proceeding to subsequent cohorts 
will be defined in the charter. The quality control checks performed on the data reviewed and 
used for making dose selection and/or modification decisions will also be described in the 
charter.
Source data verification may not be performed before safety review team meetings. Alternative 
data quality control checks that are performed on data used to make dose escalation decisions 
will be described in the safety review team and/or dose escalation team charter (or similar 
document).

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3.2.
Duration of Dosing
The study will be conducted in 5 parts: screening, admission, evaluation, discharge, and 
follow-up. Study participation will be approximately 14 days, excluding the screening period, 
and dosing with BLV will occur once daily for 6 days on Day 1 through Day 6.
3.3.
Protocol-Specific Discontinuation Criteria
3.3.1.
Criteria for Early Discontinuation for the Individual Participant
3.3.1.1.
Criteria for Early Discontinuation for the Individual Participant From the Study 
Intervention
Study interventions will be discontinued in the following instances:
•
Any treatment-emergent study drug-related Grade 3 or higher AE 
•
Any treatment-emergent Grade 3 or higher confirmed laboratory abnormality suspected to be 
related to study drug by the investigator (with the exception of asymptomatic BA elevations 
and clinically insignificant Grade 3 or 4 cholesterol, triglyceride, glucose, creatine kinase 
[CK] elevations)
•
Unacceptable toxicity, as defined in Section 7.7, or toxicity that, in the judgment of the 
investigator, compromises the ability to continue study-specific procedures or is considered 
not to be in the participant’s best interest
•
Adverse event that would, in the judgment of the investigator, affect assessments of clinical 
status to a significant degree
•
Participant request to discontinue for any reason
•
Participant noncompliance
•
Pregnancy during the study (refer to Appendix 11.3)
•
Lost to follow-up
•
Discontinuation of the study at the request of Gilead or a regulatory agency/institutional 
review board (IRB)/independent ethics committee (IEC)
3.3.1.2.
Criteria for Early Discontinuation for the Individual Participant From the Study
The participant will be discontinued from the study early in the following instances:
•
Participant noncompliance
•
Investigator discretion

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•
Lost to follow-up
•
Discontinuation of the study at the request of Gilead or an IRB/IEC
•
Withdrawal of consent
•
Death
3.3.2.
Criteria for Early Discontinuation of an Individual Cohort
Cohort-Specific Discontinuation Criteria
Study drug dosing of a group and/or progression to optional Groups C and D will be suspended 
when:
•
The number and/or severity of AEs justifies discontinuation of the study or if 2 or more 
participants experience the same or similar SAE following administration of study drug
•
The sponsor unilaterally requests it
•
Discontinuation of the study at the request of Gilead or an IRB/IEC
Decisions to reinitiate the cohort will be made in consultation with the sponsor and pending a 
safety review. In the event of a participant death, safety reports will be submitted to the 
appropriate regulatory authority for review and approval prior to reinitiating the cohort.
3.3.3.
Criteria for Early Discontinuation of the Study
The study will be discontinued in the following instance:
•
Discontinuation of the study at the request of Gilead or an IRB
3.3.4.
Loss to Follow-Up
Should the participant fail to return to the study site for a scheduled protocol-specified visit (eg, 
repeat laboratory assessments if the participant was discontinued early) or the participant fails to 
respond to the safety follow-up telephone call (7 days [± 2 days] following last administration of 
study drug), the site will need to make at least 3 attempts by telephone or email to contact the 
participant. After the third unsuccessful contact attempt, the site will send a letter to the 
participant via registered courier/mail and the participant must sign for the letter. The site must 
document all attempts to contact the participant. If a participant does not respond within 10 days 
after the letter is received, the participant will be considered lost to follow-up and no additional 
contact will be required.

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3.4.
Clinic Confinement
Following the completion of screening procedures and study enrollment at admission, eligible 
participants will remain in the clinic for a period of 9 days, beginning on Day −1 until the 
completion of assessments on Day 8. Baseline safety laboratory assessments will be performed 
on Day 1 and then participants will be administered daily injections of BLV and will undergo 
blood sampling for PK and BA assessments from Day 1 through Day 6. Additional sampling will 
be performed on Day 7 and Day 8 and participants will be discharged on Day 8. A follow-up 
telephone call to collect safety data will be made on Day 13 (± 2 days).
3.5.
Definitions for Time of Primary Endpoint and End of Study
3.5.1.
Primary Endpoint
The date for the last participant last visit for the primary endpoint is the date of the last visit to 
perform assessments for the primary analysis.
3.5.2.
End of Study
The end of this study will be the last participant’s last observation (or visit/telephone call).
3.6.
Source Data
The source data for this study will be obtained from medical records, local laboratory, and/or 
specialty laboratory (for PK data).

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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection
Approximately 72 participants will be enrolled in the study, aged 18 through 79 years, inclusive. 
Every effort will be made to encourage participation from both genders, with an approximately 
even distribution of participants assigned male at birth and nonpregnant, nonlactating 
participants assigned female at birth. The collection of race, ethnicity, gender, and age data 
allows for the analysis and reporting of safety and efficacy data by demographic subgroups as 
required by certain health authorities. Participants should have no history of HDV/HBV infection 
and either have hepatic impairment based upon the CPT classification system for moderate or 
severe hepatic impairment (CPT Class B or C, respectively) or normal hepatic function.
4.1.1.
Participant Replacement
If necessary, replacement participants may be enrolled after discussion and approval from Gilead 
if participants do not complete all intensive PK procedures or the participant is considered 
nonevaluable. Replacement participants will not be enrolled for participants who discontinue the 
study due to study drug-related AEs.
4.2.
Inclusion Criteria
Participants must meet all of the following inclusion criteria to be eligible for participation in this 
study:
All Participants:
1) Have the ability to understand and sign a written informed consent form (ICF), which must 
be obtained prior to initiation of study procedures.
2) Be aged 18 through 79 years, inclusive, at screening.
3) Have a calculated BMI 18 ≤ BMI ≤ 40 kg/m2at screening.
4) Have a calculated creatinine clearance (CLcr) of at least 60 mL/minute (using the 
Cockcroft-Gault method {Cockcroft 1976}) based on serum creatinine and actual body 
weight as measured at screening:
•
Participant assigned male at birth:
(140  ―  Age [years]) × Weight [kg] 
72  ×  Serum Creatinine [mg/dL]  = CLcr (mL/minute)
•
Participant assigned female at birth:
(140  ―  Age [years]) × Weight [kg] 
72  ×  Serum Creatinine [mg/dL]  × 0.85 = CLcr (mL/minute)
5) Participants assigned male at birth and participants assigned female at birth and of 
childbearing potential who engage in heterosexual intercourse must agree to use 
protocol-specified methods of contraception as described in Appendix 11.3.

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6) Participants have not donated blood within 56 days of study entry or plasma within 7 days of 
study entry and must refrain from blood donation from clinic admission, throughout the study 
period, and continuing for at least 30 days following the last dose of study drug.
7) 12-lead electrocardiogram (ECG) evaluations at screening must be without clinically 
significant abnormalities as assessed by the investigator.
8) Aside from hepatic impairment among the participants with hepatic impairment, the 
participant must, in the opinion of the investigator, be sufficiently healthy for study 
participation based upon medical history, physical examination, vital signs, and screening 
laboratory evaluations. 
9) Must be willing and able to comply with all study requirements.
Participants With Hepatic Impairment:
10) Have a diagnosis of chronic (> 6 months), stable hepatic impairment (moderate or severe 
based upon the CPT classification system for moderate or severe hepatic impairment [CPT 
Class B or C, respectively]) with no clinically significant change in hepatic status (as 
determined by the investigator) within the 2 months (60 days) prior to screening.
a) Participants with moderate or severe hepatic impairment must have a score of 7 to 9 or 
10 to 15, respectively, on the CPT classification system at screening. If a participant’s 
score changes during the study, the score at screening will be used for classification.
11) Must meet all of the following laboratory parameters at screening:
a) alanine aminotransferase (ALT) ≤ 10 × upper limit of normal (ULN)
b) aspartate aminotransferase (AST) ≤ 10 × ULN
c) platelets ≥ 25,000/mm3
d) hemoglobin ≥ 9 g/dL
12) Participants with hepatic impairment who have not been on a stable dose of concomitant 
medications for at least 4 weeks prior to screening (or 5 half-lives, whichever is longer) 
and/or for whom dose changes are likely to occur during the study should have their 
medications reviewed and approved by the sponsor.

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Matched Control Participants With Normal Hepatic Function:
13) Have ALT, AST, alkaline phosphatase, international normalized ratio, and total bilirubin at 
or below the ULN; and albumin above the lower limit of normal at screening and at 
admission.
14) Must be matched for age (± 10 years), sex (assigned at birth), and BMI (± 20%, 18 ≤ BMI 
≤ 40 kg/m2) with a participant in the hepatic impairment group.
4.3.
Exclusion Criteria
Participants who meet any of the following exclusion criteria will not be enrolled in this study:
All Participants:
1) Positive serum pregnancy test at screening and at admission (Appendix 11.3).
2) Breastfeeding participant
3) Have received any study drug within 30 days prior to study dosing.
4) Have current alcohol or substance abuse judged by the investigator to potentially interfere 
with participant compliance or participant safety, or a positive drug or alcohol test at 
screening or admission.
5) Have poor venous access that limits phlebotomy.
6) Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic 
agents within 3 months prior to screening or is expected to receive these agents during the 
study (eg, corticosteroids, immunoglobulins, other immune- or cytokine-based therapies).
7) Have a history of any of the following:
a) Significant serious skin disease, such as but not limited to rash, food allergy, eczema, 
psoriasis, or urticaria.
b) Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity).
c) Known hypersensitivity to the study drugs, their metabolites, or to formulation excipients 
(see Section 5).
d) Significant cardiac disease (including history of myocardial infarction based on ECG 
and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or 
dilated cardiomyopathy with left ventricular ejection fraction ≤ 40%); or a family history 
of long QT syndrome, or unexplained death in an otherwise healthy individual between 
the ages of 1 and 30 years.
e) Syncope, palpitations, or unexplained dizziness.
f)
Implanted defibrillator or pacemaker.

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8) Have any serious or active medical or psychiatric illness (including depression) that, in the 
opinion of the investigator, would interfere with participant treatment, assessment, or 
compliance with the protocol. This would include renal, cardiac, hematological, hepatic, 
pulmonary (including chronic asthma), endocrine (including diabetes), central nervous, 
gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), 
immunodeficiency disorders, active infection, or malignancy (except basal cell carcinoma or 
squamous cell carcinoma localized to the skin) that are clinically significant or requiring 
treatment, with the exception of hepatic impairment-related symptoms in participants within 
the hepatic impairment group.
9) Requirement for ongoing therapy with or prior use of any prohibited medications listed in 
Section 5.6.1.
Participants With Hepatic Impairment:
10) Have a positive test result for HIV antibody, HBsAg, or hepatitis C virus (HCV) antibody 
with detectable HCV RNA at screening. Note: any previous treatment for an HCV infection 
must have been completed at least 12 weeks before screening.
11) Prior placement of a transjugular intrahepatic portosystemic shunt, unless the most recent 
vascular imaging indicates the shunt has no current blood flow.
12) Suspicion of hepatocellular carcinoma (ie, if alpha-fetoprotein > 20 ng/mL at screening, 
enrollment is only allowed if results of appropriate diagnostic imaging studies are 
inconsistent with a diagnosis of hepatocellular carcinoma and after discussion with the 
medical monitor).
13) Anticipated changes in concomitant medications or dosage used to treat symptoms of hepatic 
impairment or associated comorbid conditions that could lead to clinically significant 
changes in medical conditions during the study.
14) Use of known hepatotoxic medications, clinical organic anion transporting polypeptide 
(OATP)1B1/3 inhibitors, or NTCP inhibitors (IC50 or kinetic inhibition constant [Ki] 
< 20 μM) (Section 5.6.1).
15) Positive test for drugs of abuse, including alcohol at screening or admission, with the 
exception of opioids and tetrahydrocannabinol (marijuana) under prescription and verified by 
the investigator as for pain management. Participants who screen positive for 
benzodiazepines may be allowed if prescribed under the care of a physician and after review 
by the investigator and sponsor.

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Matched Control Participants With Normal Hepatic Function:
16) Have a positive test result for HIV antibody, HBsAg, or HCV antibody.
17) Have a history of liver disease including Gilbert’s disease
18) Have taken any prescription medications or over-the-counter medications, including herbal 
products, within 28 days prior to start of study drug dosing, with the exception of vitamins 
and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications.

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5.
STUDY INTERVENTIONS AND CONCOMITANT 
MEDICATIONS
5.1.
Enrollment, Blinding, and Treatment Code Access
5.1.1.
Enrollment
Study participants will be assigned a screening number in the Interactive Response Technology 
(IRT) system at the time of consent and they will be assigned to a treatment group (A, B, C, or 
D). Once eligibility has been confirmed following completion of the admission study procedures, 
eligible participants will be entered in the IRT system and assigned a participant number to 
enroll in the study.
All screening and admission (Day −1) tests and procedures must be completed and reviewed by 
the investigator prior to the administration of the first dose of study drug on Day 1. It is the 
responsibility of the investigator to ensure that the participant is eligible for the study prior to 
enrollment. Once a participant number has been assigned to a participant, it will not be 
reassigned to another participant. If necessary, replacement participants may be enrolled after 
discussion and approval from sponsor. A new unique participant number will be assigned to any 
replacement participant.
5.1.2.
Blinding
Blinding to treatment assignments or data will not be performed in this study.
5.2.
Description and Handling of Bulevirtide
5.2.1.
Formulation
Bulevirtide for injection, 2 mg, is a preservative-free, white to off-white lyophilized powder 
containing 2 mg BLV that is to be reconstituted with 1 mL of sterile water for injection prior to 
SC injection. In addition to the active ingredient, BLV for injection, 2 mg, contains the following 
inactive ingredients: mannitol, sodium carbonate, sodium bicarbonate, water for injection, 
sodium hydroxide, and hydrochloric acid.
Bulevirtide for injection, 10 mg, is a preservative-free, white to off-white to yellow lyophilized 
solid containing 10 mg BLV that is to be reconstituted with 1 mL of sterile water for injection 
prior to SC injection. In addition to the active ingredient, BLV for injection, 10 mg, contains the 
following inactive ingredients: mannitol, histidine, sucrose, water for injection, sodium 
hydroxide, and hydrochloric acid.

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5.2.2.
Packaging and Labeling
Bulevirtide for injection, 2 mg, is supplied as a sterile product in a single-use, 2R Type I clear 
glass vial. Each vial is sealed with an elastomeric stopper and an aluminum overseal with a blue, 
plastic flip-off cap.
Bulevirtide for injection, 10 mg, is supplied as a sterile product in a single-use, 2R Type I clear 
glass vial. Each vial is sealed with an elastomeric stopper and an aluminum overseal with a 
green, plastic flip-off cap.
Study drug to be distributed to sites in the US shall be labeled to meet applicable requirements of 
the US FDA, and/or other local regulations.
Gilead or designated distribution depots will distribute study drug to sites according to Good 
Manufacturing Practices requirements.
5.2.3.
Storage and Handling
Bulevirtide for injection, 2 and 10 mg, will be provided by Gilead. Store BLV for injection vials 
(2 mg and 10 mg) in a refrigerator between 2 to 8 °C (36 to 46 °F) prior to use. Keep BLV for 
injection vials (2 mg and 10 mg) in the original carton to protect from light. Storage conditions 
are specified on the label. Until dispensed to the participants, all vials of study drugs should be 
stored in a securely locked area, accessible only to authorized site personnel.
To ensure the sterility, stability, and proper identification, study drug should not be stored in a 
container other than the container in which they were supplied. Keep the vials tightly closed to 
protect from moisture.
Measures that minimize drug contact with the body should always be considered during 
handling, preparation, and disposal procedures.
Bulevirtide for injection must be reconstituted with sterile water for injection prior to use. 
Reconstituted BLV for injection must be used right away and should not be saved for later use. 
The total storage time of reconstituted solution containing BLV for injection should not exceed 
2 hours at room temperature.
Refer to the pharmacy manual for detailed instructions.
5.3.
Dosage and Administration
Following completion of screening and admission assessments, eligible participants will be 
administered BLV by SC injection once daily for 6 days starting on Day 1, at the doses described 
in Section 3.1.1.
During each study treatment, each dose will be administered by assigned study staff at 
approximately the same time each morning on Days 1 through 6 following an overnight fast (no 
food or drinks, except water) for at least 8 hours prior to dosing.

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To prepare study drug for injection, the contents of each BLV vial assigned for administration on 
the day of dosing will be reconstituted with 1 mL of the supplied diluent and administered with 
the supplied syringe. Study drug should be reconstituted on the day of dosing and within 2 hours 
of administration.
The injection site will be the anterolateral surface of the abdominal wall with developed SC fat. 
During the treatment period, study staff will avoid reinjection at the same abdominal skin sites as 
previous injections.
5.3.1.
Administration Site Reactions
Bulevirtide is intended for SC injection that is associated with risks for injection site reactions 
such as swelling, redness, irritation, pruritus, infection, hematoma, and local pain. Any instances 
of injection site reactions are to be reported as AEs and graded using the Common Terminology 
Criteria for Adverse Events (CTCAE) toxicity grading scale, Version 5 (Appendix 11.4).
5.4.
Fasting and Meals
An overnight fast (no food or drinks, except water) for at least 8 hours prior to dosing will be 
required on Days 1 through 8.
The extent of food consumption during in-clinic days will be monitored.
On the days of intensive PK sampling (Day 1 and Day 6), participants will continue to fast until 
after collection of the 4-hour PK sample, relative to study drug dosing. Additionally, participants 
will be restricted from water consumption from 1 hour before until 2 hours after dose 
administration. A standardized lunch (meal calories and fat content will be prespecified) will be 
provided to participants after the 4-hour postdose blood draw (when relevant), and a standardized 
dinner (meal calories and fat content will be prespecified) will be provided at approximately 
10 hours postdose on each day that the participants are in the clinic. Water may be consumed ad 
libitum.
A standardized breakfast will be provided on Days 2 to 5 after collection of trough PK and BA 
samples and dosing, and on Day 7 after collection of trough PK and BA samples. Water may be 
consumed ad libitum.
Participants with comorbidities can take their concomitant medications with the first meal of the 
day if the medication is to be administered with food or fasting if needed as guided by the 
prescribing physician and approved by the medical monitor.
As BA are being monitored in this study, the caloric count of meals associated with BA 
collection will be standardized and the timing and consumption of meals will be monitored.

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All meals and/or snacks given to participants during their stay in the clinical study facility will be 
standardized for all matched control participants and should be similar in calorie and fat content 
and taken at approximately the same time each day. All meals and/or snacks given to participants 
with hepatic impairment will follow local recommendations regarding fasting and diet. All meals 
provided must be approved by the sponsor. Components of meals (eg, margarine, jelly, bread) 
should be given to participants in individual portions (eg, 1 tablespoon) per the approved meal 
schedule. The provision of meal components in bulk (eg, a jar of jelly for participants to share) 
should not be practiced. All meals should be given at approximately the same time each day.
5.5.
Dispensing, Accountability, and Disposal or Return of Study Drug
The investigator (or designee, eg, study site pharmacist) will acknowledge receipt of the study 
drug (after reviewing the shipment’s content and condition) from Gilead (or designee). The 
investigator will maintain an accurate inventory of all study drug. Each dose of the study drug 
administered at the study site will be administered by qualified study site staff. The dose of study 
drug administered to participants in the clinic under the supervision of staff will be accurately 
recorded on the Study Drug Accountability form provided by Gilead (or on equivalent 
documentation maintained by the study site), which indicates the date and quantity of each 
dosage formulation dispensed to individual participants.
Gilead recommends that used study drugs should be destroyed at the site. If the site has an 
appropriate standard operating procedure for study drug destruction as determined by Gilead, the 
site may destroy used (empty or partially empty) study drug in accordance with that site’s 
approved procedural documents. A copy of the site’s approved procedural document will be 
obtained for electronic trial master file. If study drugs are destroyed on site, the investigator must 
maintain accurate records for all study drugs destroyed. Records must show the identification 
and quantity of each unit destroyed, the method of destruction, and the person who disposed of 
the study drug. Upon study completion, copies of the study drug accountability records must be 
filed at the site. Another copy will be returned to Gilead.
If the site does not have an appropriate procedural document for study drug destruction, used 
study drugs are to be sent to the designated disposal facility for destruction. The study monitor 
will provide instructions for return.
For both disposal options listed above, the study monitor must first perform drug accountability 
during an on-site monitoring visit. The study monitor will review study drug supplies and 
associated records at periodic intervals.
Unused study drug should be stored at the site, pending further instructions from Gilead.

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5.6.
Concomitant Medications and Other Protocol Restrictions
5.6.1.
Concomitant Medications
Participants With Impaired Hepatic Function:
Concomitant use of certain medications or herbal/natural supplements with study drug may 
result in PK or PD interactions resulting in increases or decreases in exposure of study drug or 
these medications, or alterations in PD effects of study drug or these medications; thus, 
concomitant medications taken within 30 days of the screening visit through the follow-up visits 
must be recorded in the source documents and case report form (CRF)/electronic case report 
forms (eCRFs).
All prior medications with long-lasting biologic effect even after discontinuation, such as 
systemic corticosteroids, must be reviewed by the medical monitor to determine the participant’s 
eligibility.
Participants with hepatic impairment who have not been on a stable dose of concomitant 
medications for at least 4 weeks prior to screening (or 5 half-lives, whichever is longer) and/or 
for whom dose changes are likely to occur during the study should have their medications 
reviewed and approved by the sponsor.
All concomitant medications, including over-the-counter and herbal products, must be 
approved by the investigator and medical monitor prior to study enrollment and study drug 
administration. Any changes in concomitant medications during the study should be reviewed 
and approved by the medical monitor. The following medications are excluded during the study 
(from screening until discharge) for participants with hepatic impairment:
•
Any and all illegal or illicit drug use, including use of prescription drugs outside the care of 
the prescribing physician (excluding prescribed benzodiazepines, opioids, and 
tetrahydrocannabinol [marijuana] verified by the investigator, and with the investigator and 
sponsor review and approval)
•
Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (eg, infliximab) or other immune or cytokine based therapies within 
3 months prior to screening
•
Investigational agents or devices for any indication
•
Drugs that are reported to be clinical inhibitors of OATP1B1/3 {Food and Drug 
Administration (FDA) 2022, University of Washington School of Pharmacy 2022}:
Atazanavir, clarithromycin, cyclosporin, elbasvir, enasidenib, fostemsavir, gemfibrozil, 
grazoprevir, lopinavir, ritonavir, rifampin, roxadustat, sofosbuvir, velpatasvir, 
voxilaprevir

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•
Drugs that have been reported in vitro to be inhibitors of NTCP function (IC50 or Ki < 20 μM 
from NTCP transfected cells) {University of Washington School of Pharmacy 2022}:
Aprocitentan, bosentan, cyclosporine, fluvastatin, furosemide, glyburide (glibenclamide), 
itraconazole, irbesartan, macitentan, piroxicam, propranolol, rifamycin, ritonavir, 
rosiglitazone, saquinavir, simeprevir, simvastatin, sulindac, sulfasalazine, tolvaptan, 
zafirlukast
Note: Fluvastatin and simvastatin are not allowed due to being both NTCP substrates and 
weak inhibitors. 
Note: In scenarios where potential participants are receiving these medications, 
exploration by the medical monitor and investigator into alternative medications of the 
same therapeutic class and/or for the same indication is encouraged.
•
Drugs reported to have an increased risk of hepatotoxicity in patients with liver disease with 
adequate evidence {Lewis 2013, Suzuki 2010}: 
Amoxicillin-clavulanate, flucloxacillin, erythromycin, diclofenac, 
sulfamethoxazole/trimethoprim, disulfiram, ibuprofen, flutamide, antituberculosis drugs 
(eg, isoniazid, pyrazinamide, rifampin/rifampicin, rifapentine), nevirapine, efavirenz, 
methimazole, methotrexate, nefazodone, propoxyphene, valproate, and Vitamin A 
Note: Use of acetaminophen should be limited to 2 g/day or less. 
Note: In scenarios where potential participants are receiving these medications, 
exploration by the medical monitor and investigator into alternative medications of the 
same therapeutic class and/or for the same indication is encouraged.
•
Medications to treat disease conditions that are excluded from the protocol are not listed 
under this concomitant medication section and are disallowed in the study.
Matched Control Participants With Normal Hepatic Function:
The following medications are excluded while participants with normal hepatic function are 
participating in the study (from screening until discharge):
•
Any prescription medications and over-the-counter medications, including herbal products 
and antacids, with the exception of vitamins, and/or acetaminophen and/or ibuprofen and/or 
hormonal contraceptive medications. However, the short-term use of topical hydrocortisone 
cream or A&D ointment to treat minor skin irritation due to ECG leads will be allowed. If a 
participant requires use of a disallowed medication, a request for such use must be reviewed 
by the sponsor and if approved, participants may continue to participate in the study.
•
Any and all illegal or illicit drug use, including use of prescription drugs outside the care of 
the prescribing physician.
•
Recreational or medical cannabinoids or derivatives.

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Any Participant:
There are no substantial safety data regarding the concomitant administration of the COVID-19 
vaccines and BLV. Participants are allowed to receive the COVID-19 vaccine, and study visits 
should continue as planned if vaccination occurs while the participant is on the study. 
Investigators should follow local guidelines for concomitant administration of the COVID-19 
vaccines with the study drug.
Should participants have the need to initiate treatment with any excluded concomitant 
medication, the investigator should make every effort to consult the medical monitor and seek 
approval prior to initiation of the new medication. In an instance where an excluded medication 
must be initiated prior to discussion with the medical monitor (eg, a medical emergency), the 
investigator must notify Gilead as soon as he/she is aware of the use of the medication.
5.6.2.
Other Protocol Restrictions
•
Participants will be required to refrain from the consumption of beverages containing alcohol 
products 72 hours prior to the first dose of study drug and during the study through the 
follow-up visit.
•
Participants must agree to limit the use of nicotine-containing products while confined in the 
clinic to ≤ 5 cigarettes per day, or its nicotine equivalent. 
•
Participants will be required to refrain from consumption of grapefruit juice, grapefruits, and 
Seville orange juice 72 hours prior to the first dose of study drug and during the study 
through the end of study drug administration period.
•
While confined at the study site, tea, coffee, chocolate, and other foods and beverages 
containing caffeine and other methyl xanthines will be prohibited on each dosing day. At all 
other times, caffeine-containing beverages and foodstuffs may be served or withheld in 
accordance with normal practice at the site. Caffeine-containing beverages and foodstuffs 
will not be restricted while participants are outside of the clinic.
•
Participants will be encouraged to avoid strenuous or prolonged exercise, as well as saunas, 
steambaths, and sunbathing or other prolonged ultraviolet exposure (eg, in a tanning salon) 
from the screening evaluation until completion of the follow-up visit, as these activities are 
known to affect certain clinical laboratory test parameters (eg, CK) and will provide false 
indicators of a potentially treatment-related toxicity.
Upon admission to the clinic, each participant will be questioned as to their compliance with the 
above protocol restrictions. If a participant is unable to comply with any of the restrictions 
described above, the participant’s continued participation in the study will be reevaluated by the 
investigator in consultation with the sponsor.

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STUDY ASSESSMENTS 
Final 
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The study procedures to be conducted for each paiticipant emolled in the study are presented in 
tabulai· f01m in Table 1 and detailed below. 
Any deviation from protocol procedures should be noted in the paiticipant's clinical chart and 
appropriate eCRFs. In addition, the sponsor should be promptly notified of any protocol 
deviations. 
The study site will not initiate dosing until the following have all been met: 
• 
The IRB/IEC/other applicable regulato1y agencies have reviewed and approved the study and 
the info1m ed consent document. 
• 
All requested regulato1y documents have been submitted to and approved by Gilead. 
• 
A master services agreement and/or study agreement is executed. 
• 
The study initiation meeting has been conducted by the Gilead (or designee). 
The initiation meeting will include but is not limited to a review of the protocol, the IB, study 
diug, and investigator responsibilities. 
Documentation of the personally signed and dated ICF for each participant, using the 
study-specific, IRB/IEC-approved ICF, is required before initiating the screening process. 
6.1. 
Informed Consent 
Written info1m ed consent (Section 9 .1.4) must be obtained from each paiticipant before initiation 
of any screening procedure. After a paiticipant has provided infonned consent, the investigator 
and other study personnel will dete1mine if the paiticipant is eligible for paiticipation in the 
study (Section 6.3.2). 
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6.2. 
Participant Enrollment and Treatment Assignment 
Final 
Amendment2 
En1:Iy into screening does not guarantee enrollment into the study. In order to manage the total 
study enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or study-wide at any time. 
It is the responsibility of the investigator to ensure that participants are eligible to paiticipate in 
the study prior to enrollment and continue to remain eligible throughout the study. 
Once the ICF has been obtained, all screening and admission tests and assessments have been 
assessed, and study eligibility has been confnmed, paiticipants will be enrolled to receive study 
drng on Day 1. 
Paiticipants will be administered the study 1:I'eatments as described in Section 5.3. 
6.3. 
6.3.1. 
Instructions for Study Procedures 
Adverse Events 
From the time info1med consent is obtained through the first adminis1:I'ation of study drng, record 
all SAEs, as well as any nonserious AEs related to protocol-required procedures, on the AE 
eCRF. All other untowai·d medical occunences observed during the screening period, including 
exacerbation or changes in medical histo1y, ai·e to be considered medical histo1y. After study 
diug adminisu·ation, repo1t all AEs and SAEs. Evaluation of AEs will occur at the visits shown 
in Table 1. See Section 7 for additional details. 
6.3.2. 
Screening Assessments 
Prospective pait icipants should be screened no more than 28 days prior to adminisu·ation of the 
first dose of study diug. If a paiticipant does not begin the u·eatment phase within this 28-day 
window, all screening evaluation procedures must be repeated. Screening laborato1y assessments 
may be repeated once within 28 days prior to adminisu·ation of study diug for exclusiona1y 
laborato1y values if, in the investigator's opinion, 1 of the following ai·e met: there is reason to 
believe the retest value will be within accepted parameters, if the initial value was deemed to be 
inaccurate or inconsistent with the paiticipant's previous result(s), if the initial value was 
generated in enor (eg, mishandled sample), or there is another relevant extenuating 
circUillstance. In any instance, the site should obtain approval from the sponsor prior to repeating 
the laborato1y assessment. 
A sufficient nlllllber of paiticipants will be screened to identify planned number of participants 
for enrollment. 
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Participants should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the screening visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
The screening assessment will include a review of the inclusion/exclusion criteria and 
completion of all screening procedures as outlined in Table 1 and described in the following text.
Eligible participants meeting all of the inclusion criteria and none of the exclusion criteria will be 
instructed on all protocol requirements, including the restrictions on concomitant medication 
usage and other substances as well as consumption of food or beverages containing alcohol, 
caffeine, or xanthine. Participants will be asked to arrive at the study site on Day −1 for 
admission assessments.
6.3.3.
Admission Assessments
Participants should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the admission visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection.
Participants meeting all eligibility criteria following the screening evaluation will return to the 
site for admission assessments on Day −1. The admission evaluations and/or procedures are 
outlined in Table 1.
Prior to dosing on Day 1, the results of the clinical and laboratory evaluations (as described in 
Table 1) must be reviewed by the investigator to confirm the continued eligibility of each 
participant to participate in the study, including have received a negative COVID-19 polymerase 
chain reaction test on admission. At the time of enrollment, participants will be assigned a 
participant number as described in Section 5.1.1. Participants will remain confined to the study 
clinic for the duration as described in Section 3.4 and Table 1.
6.3.4.
Treatment Assessments
Study procedures and assessments are outlined in Table 1.
6.3.5.
Pharmacokinetic and Pharmacodynamics Assessments
6.3.5.1.
Plasma Sample Collection for Pharmacokinetics and Pharmacodynamics
Plasma concentrations of BLV and plasma concentrations of total BA will be determined, and 
BLV PK and BA exposure parameters will be estimated. The following plasma PK parameters 
will be calculated for BLV, as applicable: Primary PK parameters, AUCtau, Cmax,ss; and 
secondary PK parameters, AUC0-24h, Tmax, t1/2, Cmax, CLss/F, and Vss/F. The following exposure 
parameters in plasma for total BA will be calculated, as applicable: Cmax, Ctrough, AUC0-24h, and 
Tmax. Additional PK parameters may be analyzed and reported as necessary. In addition, 
concentrations of individual plasma BA may be measured and exposure parameters may be 
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Phaimacokinetic sampling and PD of total BA sampling will occur relative to the dosing of BL V 
at the following time points: 
• 
Day 1 at predose (:S 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, and 12 hours postdose; 
Day 2 at predose (:S 30 minutes before dose); Day 3 at predose (:S 30 minutes before dose); 
Day 4 at predose (:S 30 minutes before dose); Day 5 at predose (:S 30 minutes before dose); 
Day 6 at predose (:S 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24 (Day 7), and 
48 hours (Day 8) postdose, and at the eai·ly te1mination (ET) visit, as applicable (Table 1). A 
time window of± 10% will be allowed for samples collected through 4 hours postdose. All 
other samples collected beyond 4 hours postdose will have a± 30-minute window. Clinical 
staff should make eve1y effo1i to ensure that the sampling time is as close as possible to 
nominal time. The exact time and date of the blood draw must be recorded in the electronic 
data capture (EDC) system. For all plasma BA and plasma PK samples, a prima1y and 
backup sample will be collected and the backup sample will be stored for potential fmi her 
analysis or reanalysis. 
6.3.5.2. 
Plasma Protein Binding 
On Day 1, a blood sample will be collected predose ( < 30 minutes prior to BL V dosing), and at 
2 hours and 12 hours postdose. These samples in addition to other predose and postdose PK 
samples may be utilized for plasma protein binding evaluation, and percent plasma protein 
binding may be detennined. A single blood sample for PK analysis will also be collected at the 
ET visit (if applicable) and may be analyzed. 
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6.3.6. 
Plasma Collection for Immunogenicity Evaluation 
Final 
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The presence of antibodies to BL V will be assessed in plasma samples collected Day 1 and 
Day 6 at the time points (:S 30 minutes before dose) shown in Table 1. Antidmg antibodies 
(ADAs) may be further characterized (eg, for neutralizing activity). 
6.4. 
Safety Assessments 
Safety will be evaluated throughout the study. Refer to Table 1 for a schedule of assessments. 
Safety assessments will include physical examination ( complete or symptom-driven), vital signs, 
height, weight, clinical laborato1y tests, urine diug and alcohol assessments, 12-lead ECG, 
pregnancy testing, and assessment of AEs. 
All safety assessments will be completed predose unless othe1wise specified. 
6.4.1. 
Electrocardiogram Assessment 
Paiiicipants should rest quietly in the supine position for a minimum of 10 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete. 
There should be no environmental distractions (including TV, radio, video games, and 
conversation) while the paiiicipants ai·e resting prior to and during the recordings. 
Electrocai·diograms will be recorded using the site's standai·d ECG equipment. All ECGs will be 
obtained using instnnnents that analyze data using the same algoritlnns and produce the same 
data for inte1pretation. Electrode placement will be perfonned according to the method of 
Wilson, Goldberger, and Einthoven with a check to confnm that the a VR lead is not inverted. 
The investigator or other qualified individuals at the study site will review ECGs to assess for 
changes in ECG intervals and mo1phology as compai·ed with pretreatment ECGs. The ECG 
interval measurements output by the machine will be used for bedside safety monitoring. 
Collection of additional ECGs for routine safety monitoring at additional time points or days is at 
the discretion of the investigator based on Good Clinical Practice (GCP). 
6.4.2. 
Physical Examination 
Physical examinations conducted throughout the study will be a complete physical examination 
or a symptom-di·iven physical examination if clinically indicated, as outlined in Table 1. The 
complete physical examination conducted at screening will also include the following 
assessments: 
• 
Review medical histo1y, including histo1y of allergies, prior and cmTent use of nicotine or 
nicotine-containing products, alcohol and illegal diug use, and prior (within 30 days) and 
cmTent medication use. 
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6.4.3.
Vital Signs
Vital sign measurements include blood pressure, heart rate, and body temperature and should be 
taken once participants have been seated or in the supine position. Participant position for 
measurement should be kept consistent throughout the study. Refer to Table 1 for vital signs 
collection time points.
6.4.4.
Body Mass Index
Height and weight will be collected at screening for calculation of BMI for inclusion criteria and 
upon admission for the purpose of subsequent creatinine clearance calculation.
6.4.5.
Clinical Laboratory Tests/Assessments
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Table 1 and Table 3.
Table 3.
Laboratory Analytes
Safety Laboratory Measurements
Chemistry 
(Serum or 
Plasma)
Hematology
Urinalysis
Coagulation
Virological 
Measurements
Other Laboratory 
Measurements
• AST
• ALT
• Albumin
• Total protein
• Alkaline 
phosphatase
• Creatine kinase
• Serum creatinine
• BUN
• Total bilirubin
• Direct bilirubin
• Indirect bilirubin
• GGT 
• Glucose
• Lipase
• Calcium
• Bicarbonate 
• Sodium 
• Potassium
• Chloride
• Uric acid 
(serum) 
• Total bile acids
• Vitamin D
• RBC (count and 
morphology)
• Hemoglobin
• Hematocrit
• MCH
• MCHC
• MCV
• RDW
• Platelets
• WBC total
• WBC 
differential
• ANC
• Eosinophils
• Basophils
• Monocytes
• Lymphocytes
• Neutrophils
• Reticulocytes
• pH
• Specific gravity
• Color
• Protein
• Glucose
• Ketones
• Hemoglobin 
(erythrocytes) 
• Leukocytes
• Microscopic 
analysis, if urine 
is positive for 
protein, 
leukocytes, or 
hemoglobin
• Prothrombin 
time
• Partial 
thromboplastin 
time
• INR
• HIV 
antibody/antigen 
test
• HBsAb
• HBsAg
• HCV antibody 
(reflex to HCV 
RNA if positive)
• Serum/urine 
pregnancy test
• FSH
• Antidrug 
antibodies to 
BLV
• Alpha-
fetoprotein
• Urine drug and 
alcohol testing
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BLV = bulevirtide; 
BUN = blood urea nitrogen; FSH = follicle-stimulating hormone; GGT = gamma-glutamyl transferase; HBsAb = hepatitis B 
surface antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; INR = international normalized ratio; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; RBC = red blood cell; RDW = red blood cell distribution width; WBC = white blood cell 
Refer to Table 1 for collection time points.

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6.4.5.1.
Blood Sampling
Blood samples will be collected for the following laboratory analyses:
•
Hematology: hematocrit, hemoglobin, platelet count, red blood cell count, red blood cell 
morphology, mean corpuscular hemoglobin; mean corpuscular hemoglobin concentration, 
mean corpuscular volume, red blood cell distribution width, white blood cell count total, 
white blood cell count with differential (absolute and percentage), including reticulocytes, 
lymphocytes, monocytes, absolute neutrophil count, neutrophils, eosinophils, and basophils 
•
Coagulation panel: international normalized ratio, prothrombin time, and partial 
thromboplastin time
•
Chemistry (fasting): alkaline phosphatase, AST, ALT, total bilirubin, direct bilirubin, indirect 
bilirubin, gamma-glutamyl transferase (GGT), albumin, total protein, CK, serum creatinine, 
bicarbonate, blood urea nitrogen, calcium, chloride, creatinine (see below), glucose, lipase, 
potassium, sodium, uric acid, vitamin D, and total BA 
•
Alpha-fetoprotein testing will be performed at screening only
•
Serum pregnancy test (participants assigned female at birth who are younger than 54 years, 
not on hormonal contraception, and who have stopped menstruating for at least 12 months 
but do not have documentation of ovarian hormonal failure)
•
Follicle-stimulating hormone testing (screening only): participants assigned female at birth 
who are younger than 54 years, not on hormonal contraception, and who have stopped 
menstruating for at least 12 months but do not have documentation of ovarian hormonal 
failure
•
Fourth generation HIV antibody/antigen test, hepatitis B surface antigen, hepatitis B surface 
antibody, HCV antibody, HCV RNA (screening only)
6.4.5.2.
Urine Samples
Urine samples will be collected for the following laboratory analyses: pH, specific gravity, color, 
protein, glucose, ketones, hemoglobin (erythrocytes), leukocytes, microscopic analysis if urine is 
positive for protein, leukocytes, or hemoglobin
Urine samples will also be collected for urinalysis and alcohol and drug screen assessments, 
which include: amphetamines/3,4-methylenedioxy-methamphetamine, tricyclic antidepressants, 
barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, methadone, and phencyclidine.

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On admission on Day −1, safety laboratory assessments (hematology, chemistry, urinalysis and 
urine drug and alcohol assessment) will be collected upon study site admission and will be sent 
to the site’s local laboratory to obtain results in time for enrollment on Day 1. If study site cannot 
perform urine alcohol or receive results from the local laboratory in time for enrollment on 
Day 1, then an alcohol breathalyzer test is acceptable.
Urine pregnancy testing (point-of-care pregnancy test) may be used at the site on admission 
(Day −1) if a serum test result is not available prior to dosing.
6.4.6.
Creatinine Clearance
Weight will be collected at screening and upon admission. The Cockcroft-Gault method 
{Cockcroft 1976} based on serum creatinine and actual body weight will be used to calculate 
CLcr for the inclusion criteria.
6.4.7.
Concomitant Medications/Protocol Restrictions
Review of concomitant medications, and review of protocol restrictions will occur at the times 
shown in Table 1. See Sections 4.3 and 5.6.1 for more information about concomitant 
medications.
6.5.
Posttreatment Assessments
All participants will be contacted for a safety follow-up on Day 13 ± 2 days, 7 days following 
last administration of study drug.
6.6.
Assessments for Early Discontinuation From Study Intervention or From the 
Study
If a participant discontinues study treatment dosing (see Sections 3.3), for example as a result of 
an AE, every attempt should be made to keep the participant and continue to perform procedures 
for stabilization per the investigator.
6.6.1.
Assessments for Early Discontinuation From Study Intervention
A participant who discontinues study drug early will undergo ET assessments and procedures 
within 24 hours of termination, as specified in Table 1. Evaluations indicating abnormal results 
believed to be possibly or probably related to study treatment at the ET visit should be repeated 
weekly or as often as deemed appropriate by the investigator until the abnormality resolves, 
returns to baseline visit levels, or is otherwise explained.
6.6.2.
Assessments for End of Study
A participant who completes the study will undergo assessments and procedures for discharge on 
Day 8 as specified in Table 1. Additionally, as described in Section 6.5, a safety follow-up visit 
at end of study will be conducted by telephone on Day 13 ± 2 days.

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6.7.
Sample Storage
Stored biological samples may be used by Gilead or its research partner for future testing to 
provide additional data to answer questions that relate to the main study. At the end of this study, 
these samples may be retained in storage by Gilead for a period up to 15 years or per country 
requirements. If participants provide additional specific consent for optional future research, 
biologic samples may be destroyed no later than 15 years after the end of the study or per 
country requirements.

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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events and Serious Adverse Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study participant administered a study 
drug that does not necessarily have a causal relationship with the treatment. An AE can, 
therefore, be any unfavorable and/or unintended sign, symptom, or disease temporally associated 
with the use of a study drug, whether or not considered related to the study drug. Adverse events 
may also include pretreatment or posttreatment complications that occur as a result of 
protocol-specified procedures, or special situations (Section 7.1.3).
An AE does not include the following:
•
Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an AE and must be reported.
•
Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen.
•
Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions).
•
Overdose without clinical sequelae (see Section 7.1.3).
•
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed and not related to a protocol-associated procedure is not an AE but 
rather considered to be preexisting and should be documented medical history.
Preexisting events that increase in severity or change in nature after study drug initiation or 
during or as a consequence of participation in the clinical study will also be considered AEs.
7.1.2.
Serious Adverse Events
An SAE is defined as an event that, at any dose, results in the following:
•
Death.
•
A life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the participant was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death if it were more severe.)
•
Inpatient hospitalization or prolongation of existing hospitalization.

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•
Persistent or significant disability/incapacity.
•
A congenital anomaly/birth defect.
•
A medically important event or reaction; such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent 1 of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse.
7.1.3.
Study Drugs and Gilead Concomitant Therapy Special Situation Reports
Special situations reports (SSRs) include all reports of medication error, abuse, misuse, overdose, 
occupational exposure, drug interactions, exposure via breastfeeding, unexpected benefit, 
transmission of infectious agents via the product, counterfeit of falsified medicine, and 
pregnancy regardless of an associated AE.
Medication error is any unintentional error in the prescribing, dispensing, preparation for 
administration or administration of a study drug while the medication is in the control of a health 
care professional, patient, or consumer. Medication errors may be classified as a medication error 
without an AE, which includes situations of missed dose, medication error with an AE, 
intercepted medication error, or potential medication error.
Abuse is defined as persistent or sporadic intentional excessive use of a study drug by a 
participant.
Misuse is defined as any intentional and inappropriate use of a study drug that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a study 
drug given per administration or cumulatively that is above the maximum recommended dose as 
per protocol or in the product labelling (as it applies to the daily dose of the participant in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the participant has taken the excess dose(s). Overdose cannot be established 
when the participant cannot account for the discrepancy, except in cases in which the 
investigator has reason to suspect that the participant has taken the additional dose(s).
Occupational exposure is defined as exposure to a study drug as a result of one’s professional or 
nonprofessional occupation.
Drug interaction is defined as any drug/drug, drug/food, drug/alcohol, or drug/device interaction.

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Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial.
Transmission of infectious agents is defined as any suspected transmission of an infected agent 
through a Gilead study drug.
Counterfeit or falsified medicine is defined as any study drug with a false representation of (a) its 
identity, (b) its source, or (c) its history.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship for each 
study drug using clinical judgment and the following considerations:
•
No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, concomitant medication).
•
Yes: There is reasonable possibility that the AE may have been caused by the study drug.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:
•
No: Evidence exists that the AE has an etiology other than the study procedure.
•
Yes: The AE occurred as a result of protocol procedures (eg, venipuncture).
7.2.2.
Assessment of Severity 
The severity of AEs will be graded using the CTCAE toxicity grading scale, Version 5. For each 
episode, the highest grade attained should be reported as defined in the toxicity grading scale 
(Appendix 11.4).

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7.3.
Investigator Reporting Requirements and Instructions
7.3.1.
Requirements for Collection Prior to Study Drug Initiation
After informed consent, but prior to initiation of study medication, the following types of events 
must be reported on the applicable eCRFs: all SAEs and any AEs related to protocol-mandated 
procedures.
7.3.2.
Adverse Events
Following initiation of study treatment, collect all AEs, regardless of cause or relationship, until 
the end of study, including the protocol-defined posttreatment follow-up period and report them 
on the eCRFs as instructed.
All AEs and clinically significant laboratory abnormalities should be followed until resolution or 
stability of the abnormality has been demonstrated, if possible. Gilead may request that certain 
AEs be followed beyond the protocol-defined follow-up period.
7.3.3.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the participant first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the posttreatment follow-up visit, must be reported on the applicable eCRFs and 
Patient Safety (PS) as instructed below in this section. This also includes any SAEs resulting 
from protocol-associated procedures performed after informed consent is signed.
Investigators are not obligated to actively seek SAEs after the protocol-defined follow-up period; 
however, if an investigator learns of any SAEs that occur after the protocol-defined follow-up 
period has concluded and the event is deemed relevant to the use of the study drug, the 
investigator should promptly document and report the event to PS.
Instructions for reporting SAEs are described in Section 7.4.1.
7.3.4.
Study Drug Special Situations Reports
All study drug SSRs that occur from study drug initiation and throughout the duration of the 
study, including the posttreatment follow-up visit, must be reported to PS (Section 7.4.2). 
Adverse events and SAEs resulting from SSRs must be reported in accordance to the AE and 
SAE reporting guidance (Section 7.3).
7.3.5.
Concomitant Therapy Reports
7.3.5.1.
Gilead Concomitant Therapy Special Situations Report
Special situation reports involving a Gilead concomitant therapy (not considered study drug), 
that occurs after the participant first consents to participate in the study (ie, signing the informed 
consent) and throughout the duration of the study, including the posttreatment follow-up visit, 
must be reported to PS utilizing the paper SSR form (Section 7.4.2.2).

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7.3.5.2.
Non-Gilead Concomitant Therapy Report
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the SSR form; however, for special situations that result in AEs due to a non-Gilead concomitant 
medication, the AE should be reported on the AE form.
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
All clinical sequelae in relation to these SSRs will be reported as AEs or SAEs at the same time 
using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available.
7.4.
Reporting Process for Serious Adverse Events and Special Situations Reports
7.4.1.
Serious Adverse Event Reporting Process
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be transmitted by email or fax when requested and applicable. 
Transmission of such documents should occur without personal participant identification, 
maintaining the traceability of a document to the participant identifiers.
Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the participant’s eCRF and the SAE narrative section of the Safety Report 
Form.
7.4.1.1.
Paper Serious Adverse Event Reporting Process
All SAEs will be recorded on the paper Initial SAE Report Form and transmitted by emailing or 
faxing the report form using the contact information below within 24 hours of the investigator’s 
knowledge of the event from the time of ICF signature throughout the duration of the study 
including the protocol-required posttreatment follow-up period. Any follow-up information for a 
previously reported SAE (including updates to the reported event term[s]) will be submitted to 
PS using the paper Follow-up SAE Report Form within 24 hours of the investigator’s knowledge 
of the follow-up/updated information using the contact information below. Additionally, the 
SAE must be captured on the applicable CRFs.
Gilead PS 
Email: Safety_FC@gilead.com 
or
Fax: +1-650-522-5477

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7.4.2.
Special Situations Reporting Process
7.4.2.1.
Paper Special Situations Reporting Process for Study Drug
All SSRs will be recorded on the SSR form and transmitted by emailing or faxing the report 
form within 24 hours of the investigator’s knowledge of the event to the attention of Gilead PS 
from study drug initiation throughout the duration of the study, including the protocol-required 
posttreatment follow-up period.
Gilead PS 
Email: Safety_FC@gilead.com 
or
Fax: +1-650-522-5477
7.4.2.2.
Reporting Process for Gilead Concomitant Medications
Special situations that involve Gilead concomitant medications that are not considered study 
drug must be reported within 24 hours of the investigator’s knowledge of the event to Gilead PS 
utilizing the paper SSR form to:
Gilead PS 
Email: Safety_FC@gilead.com 
or
Fax: +1-650-522-5477
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the SSR form; however, special situations that result in AEs due to a non-Gilead concomitant 
medication, must be reported as an AE.
7.4.2.3.
Pregnancy Reporting Process
The investigator should report pregnancies identified after initiation of study drug and 
throughout the study, including the protocol-required posttreatment follow-up period in 
participants in the study period in which contraceptive measures are needed. Pregnancies should 
be reported to Gilead PS using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy. Contact details for transmitting the pregnancy report form are as follows:
Gilead PS 
Email: Safety_FC@gilead.com 
or
Fax: +1-650-522-5477

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The pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
All other premature terminations of pregnancy (eg, a spontaneous abortion, an induced 
therapeutic abortion due to complications or other medical reasons) must be reported within 
24 hours as an SAE, as described in Section 7.4.1. The underlying medical reason for this 
procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.4.1. Furthermore, any SAE occurring as an adverse pregnancy outcome poststudy must 
be reported to the Gilead PS.
The participant should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome of the pregnancy should be reported to Gilead PS using the pregnancy 
outcome report form. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Gilead PS. Gilead PS contact information is as follows: 
email: Safety_FC@gilead.com and fax: +1-650-522-5477.
Refer to Appendix 11.3 for Pregnancy Precautions, Definition for Childbearing Potential, and 
Contraceptive Requirements.
7.5.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable FDA CFR, the 
European Union Clinical Trials Directive (2001/20/EC)/EU Regulation 536/2014 and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, which may be in the form of line-listings, 
serious adverse drug reactions, or suspected unexpected serious adverse reactions (SUSARs). In 
accordance with the European Union Clinical Trials Directive (2001/20/EC)/EU Regulation 
536/2014, Gilead or a specified designee will notify worldwide regulatory agencies and the 
relevant IEC in concerned member states of applicable SUSARs as outlined in current 
regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable.
All investigators will receive 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.

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7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, urinalysis) that require 
medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, ECG, X-rays, vital signs) that are associated with 
signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE 
or SAE as described in Sections 7.1.1 and 7.1.2, respectively. If the laboratory abnormality is 
part of a syndrome, record the syndrome or diagnosis (eg, anemia) not the laboratory result 
(ie, decreased hemoglobin).
Note: In accordance with the mechanism of action of BLV, asymptomatic elevation of BA 
occurring with BLV dosing in this study will not be documented as a laboratory toxicity.
Severity should be recorded and graded according to CTCAE toxicity grading scale, Version 5 
(Section 7.2.2) and Appendix 11.4. For AEs associated with laboratory abnormalities, the event 
should be graded on the basis of the clinical severity in the context of the underlying conditions; 
this may or may not be in agreement with the grading of the laboratory abnormality.
7.7.
Toxicity Management
Bulevirtide injection will be administered to participants at the site under close supervision. 
Healthcare professionals administering the SC injections should have the appropriate medication 
available for immediate use in case of hypersensitivity or injection-related reactions. The 
participant should be treated according to the standard of care for management of 
hypersensitivity reaction or injection-related reactions.
All clinical and clinically significant laboratory toxicities will be managed as outlined below.
•
Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing as soon as possible, and preferably within 3 calendar days after receipt of the original 
test results. The study drug may be continued without dose interruption for a clinically 
insignificant Grade 3 and 4 laboratory abnormality (eg, CK elevation after strenuous 
exercise, triglyceride elevation that is nonfasting or that can be medically managed). 
Recurrence of laboratory abnormalities considered unrelated to the study drug may not 
require permanent discontinuation.
•
Grade 3 or 4 clinical events if considered unrelated to the study drug may not require dose 
interruption and continuation of the investigational product is at the discretion of the 
investigator.
The Gilead medical monitor should be consulted prior to study drug discontinuation when 
medically feasible.

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7.7.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
•
Continue study drug at the discretion of the investigator.
7.7.2.
Grade 3 or Grade 4 Laboratory Abnormality or Clinical Event
•
For a Grade 3 or Grade 4 clinical event or clinically significant laboratory abnormality 
confirmed by repeat testing considered to be related to the study drug, study drug should be 
permanently discontinued and the participant managed according to local practice. The 
participant should be followed as clinically indicated until the laboratory abnormality returns 
to baseline or is otherwise explained, whichever occurs first. A clinically significant Grade 3 
or Grade 4 laboratory abnormality that is not confirmed by repeat testing should be managed 
according to the algorithm for the new toxicity grade.
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead medical monitor, and the appropriate course of action will be discussed and decided. 
Whether or not considered treatment related, all participants experiencing AEs must be 
monitored periodically until symptoms subside, any abnormal laboratory values have resolved or 
returned to baseline levels or they are considered irreversible, or until there is a satisfactory 
explanation for the changes observed.
Any questions regarding toxicity management should be directed to the Gilead medical monitor.

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8.
STATISTICAL CONSIDERATIONS
Details of the statistical methods will be provided in the statistical analysis plan, including any 
deviations from the original statistical analyses planned.
8.1.
Analysis Objectives and Endpoints
Objectives and endpoints are listed in Section 2.
8.2.
Planned Analyses
8.2.1.
Interim Analysis
Prior to the final analysis, a formal interim analysis and interim clinical study report (CSR) are 
planned following completion of Group A and Group B. These analyses may be submitted to 
regulatory agencies to seek guidance for the overall clinical development program.
8.2.1.1.
Dose Escalation Planned Internal Analysis
Group A and B will begin enrollment simultaneously. For the purpose of making the decision to 
proceed to the subsequent cohorts, interim analyses of relevant safety and PK data will be 
conducted by the Gilead safety review team. Once the safety and PK data from all participants in 
Group A (2 mg moderate hepatic impairment) are available and reviewed, Group C (10 mg 
moderate hepatic impairment) may be opened. Once the safety and PK data from all participants 
in Group B (2 mg severe hepatic impairment) are available and reviewed, Group D (10 mg 
severe hepatic impairment) may be opened. Safety assessments (eg, AEs, ECG, laboratory 
results) will be displayed by hepatic function group to facilitate the decision to proceed to the 
next dose level or cohort.
8.2.2.
Final Analysis
The final analysis will be performed after all participants have completed the study, outstanding 
data queries have been resolved or adjudicated as unresolvable, and the data have been cleaned 
and finalized. The analyses of the primary endpoints will be conducted at the time of the final 
analysis.
8.3.
Analysis Conventions
8.3.1.
Analysis Sets
8.3.1.1.
All Enrolled
The All Enrolled Analysis Set includes all participants enrolled into the study after screening. 
This is the primary analysis set for safety listings.

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8.3.1.2.
Safety
The Safety Analysis Set will include all enrolled participants who received at least 1 dose of 
BLV. Participants who received treatment other than that to which they were assigned will be 
analyzed according to the treatment received.
8.3.1.3.
Pharmacokinetics
The PK Analysis Set will include all enrolled participants who received at least 1 dose of BLV 
and had at least 1 nonmissing PK concentration datum reported by PK laboratory for each 
respective analyte.
8.3.1.4.
Immunogenicity
The Immunogenicity Analysis Set will include all enrolled participants who received at least 
1 dose of BLV and had at least 1 blood sample collected for immunogenicity evaluation before 
any BLV administration and at least 1 blood sample collected after administration of BLV.
8.3.1.5.
Pharmacodynamics
The PD Analysis Set will include all enrolled participants who received at least 1 dose of BLV 
and had at least 1 nonmissing PD concentration value reported for their respective PD analyte.
8.3.2.
Data Handling Conventions
For summary statistics, PK and PD concentration values below the limit of quantitation will be 
treated as zero at predose and missing for postdose time points.
Laboratory data that are continuous in nature but are less than the lower limit of quantitation 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 (eg, if the result of a continuous laboratory test is 
less than 20, a value of 19 will be assigned; if the result of a continuous laboratory test is less 
than 20.0, a value of 19.9 will be assigned).
Missing data can have an impact upon the interpretation of the study data. As this study is of 
short duration, it is anticipated that missing data will be minimal. In general, values for missing 
data will not be imputed. However, a missing pretreatment laboratory result would be treated as 
normal (ie, no toxicity grade) for the laboratory abnormality summary.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized and descriptive statistics will be 
provided.
Demographic summaries will include sex, race/ethnicity, and age.

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Baseline data will include a summary of height, weight, BMI, and estimated glomerular filtration 
rate by the Cockcroft-Gault method.
8.5.
Safety Analysis
All safety data collected on or after the date that study drug was first administered up to the date 
of last dose of study drug plus 7 days will be summarized by hepatic function group and dose 
using the Safety Analysis Set.
8.5.1.
Extent of Exposure
A participant’s extent of exposure to study drug data will be generated from the study drug 
administration data. Exposure data will be listed.
8.5.2.
Adverse Events
Adverse event data will be listed by participant. Treatment-emergent AEs, SAEs, and AEs 
leading to permanent discontinuation of study drug will be summarized by hepatic function 
group, dose, system organ class, and preferred term using the current version of MedDRA.
8.5.3.
Laboratory Evaluations
Listings of individual participant laboratory results will be provided. Laboratory results and 
changes from baseline values for selected laboratory tests will be summarized by hepatic 
function group and dose at scheduled visits. The incidence of treatment-emergent laboratory 
abnormalities will be summarized by hepatic function group and dose.
8.5.4.
Other Safety Evaluations
Vital signs and ECG data will be summarized by hepatic function group and dose at scheduled 
visits.
8.6.
Pharmacokinetic and Pharmacodynamic Analysis
Plasma concentrations of BLV and PK parameters, and plasma concentrations of total BA and 
PD parameters, will be listed and summarized by hepatic function group and dose level using 
descriptive statistics. In addition, plasma concentrations of individual BA may be measured and 
PD parameters may be summarized. Percent of plasma protein binding may be estimated based 
on the plasma data collected on Day 1 (Section 6.3.5.1).
For the primary objective analysis, a one-way analysis of variance model appropriate for a 
parallel design with hepatic function group as a fixed effect will be fit to the natural logarithmic 
transformation of PK parameters (AUCtau and Cmax ss) for BLV. The 90% CIs will be constructed 
for the geometric least-squares mean (GLSM) ratio of PK parameters for BLV in the hepatic 
impairment group versus the matched control (normal hepatic function) group. The same 
analysis will be conducted for PD parameters of total BA, as applicable.

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8.7.
Immunogenicity Analysis
Plasma will be evaluated for the presence of ADA to BLV. Antidrug antibodies may be further 
characterized (eg, for neutralizing activity).
8.8.
Biomarker Analysis
Details of the statistical methods used for potential future biomarker analysis (Section 6.3.5.3) 
may be provided in a separate biomarker analysis plan.
8.9.
Sample Size
For Group A and Group C (if conducted), with 16 (8 hepatic impairment and 8 matched control 
[normal hepatic function]) evaluable participants, the estimated upper limit of the 1-sided 95% 
CIs of the GLSM ratio of hepatic impairment group versus matched control, with regards to 
AUCtau and Cmax ss of BLV, would be less than 200% with ≥ 80% probability if the expected 
GLSM ratio is 1.0. This assumes a percentage coefficient of variation of no more than 51%, 
which is supported by the results from the previously conducted Gilead Study MYR102. 
Accounting for a 20% dropout rate, a total sample size of 20 participants (10 hepatic impairment 
and 10 matched control each) will be required. Furthermore, given the lower variability in BA 
concentrations compared with BLV concentrations observed in Study MYR102, this sample size 
will also provide a ≥ 80% probability that the estimated upper limit of the 1-sided 95% CIs of the 
GLSM ratio of hepatic impairment group versus matched control, with regards to AUCtau and 
Cmax ss of plasma total BA, would be less than 200% if the expected GLSM ratio is 1.0.
For Group B and Group D (if conducted), given the challenges with enrolling participants with 
severe decompensated hepatic dysfunction, up to 16 participants (8 hepatic impairment and 
8 matched control) will be enrolled in each conducted study group with a target of at least 
12 (6 hepatic impairment and 6 matched control) evaluable participants. This may be lower than 
the power from the moderate groups but should provide sufficient characterization of BLV in the 
severe population. Note that based on the known metabolic pathway of linear peptides such as 
BLV, significant changes in the BLV PK are not expected in this population.

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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with International Council 
for Harmonisation (ICH) E6(R2) GCP and applicable laws and regulations.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide prompt and accurate documentation of their 
financial interest or arrangements with the sponsor or proprietary interests in the study drug. This 
documentation must be provided prior to the investigator’s (and any subinvestigator’s) 
participation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last participant completes the protocol-defined 
activities.
9.1.3.
Institutional Review Board or Independent Ethics Committee Review and 
Approval
The investigator (or Gilead as appropriate according to local regulations) will submit this 
protocol, ICF, and any accompanying material to be provided to the participant (such as 
advertisements, participant information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB or IEC. The investigator will not begin any study participant 
activities until approval from the IRB or IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB or IEC for any modifications made to the protocol or any accompanying material to be 
provided to the participant after initial IRB or IEC approval, with the exception of those 
necessary to reduce immediate risk to study participants.
9.1.4.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study before undertaking any study-related procedures. The investigator 
must use the most current IRB- or IEC-approved ICF for documenting written informed consent. 
Each ICF will be appropriately signed and dated by the participant, the person conducting the 
consent discussion, and also by an impartial witness if required by the IRB or IEC or local 
requirements.

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The ICF will inform participants about genomic testing and/or planned sample retention. In 
addition to the study-specific ICF to be signed by each participant in the study, participants will 
be required to document additional consent to provide additional samples and/or to allow the use 
of the remainder of their already-collected specimens for optional future research, in accordance 
with applicable regulations. In addition to the study-specific ICF to be signed by each participant 
in the study, participants will be required to document additional consent to provide additional 
samples for optional genomic research. The results of the tests done on the samples will not be 
given to the participant or the investigator. The stored biological samples will be destroyed no 
later than 15 years after the end of study or per country requirements, but participants may at any 
time request that their stored samples be destroyed.
9.1.5.
Confidentiality
The investigator must ensure that participants’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to Gilead, IRB or IEC, or the laboratory. Laboratory specimens 
must be labeled in such a way as to protect participant identity while allowing the results to be 
recorded to the proper participant. Refer to specific laboratory instructions or in accordance with 
local regulations. NOTE: The investigator must keep a screening log with details for all 
participants screened and enrolled in the study. Participant data will be processed in accordance 
with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
IB, this protocol, CRFs, study drug information, and any other study information, remain the sole 
and exclusive property of Gilead 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 Gilead. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the investigational site to any third party or otherwise into the public 
domain.
9.1.6.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file and 
(2) participant clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRFs, IRBs or IECs, and 
governmental approval with correspondence, ICF, drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence.

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The required source data should include sequential notes containing at least the following 
information for each participant:
•
Participant identification (name, date of birth, gender)
•
Documentation that participant meets eligibility criteria, ie, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria)
•
Documentation of the reason(s) a consented participant is not enrolled
•
Participation in study (including study number)
•
Study discussed and date of informed consent
•
Dates of all visits
•
Documentation that protocol-specific procedures were performed
•
Start and end dates (including dose regimen) of study drug, including dates of dispensing and 
return
•
Record of all AEs and other safety parameters (start and end date; causality and severity), 
and documentation that adequate medical care has been provided for any AE
•
Concomitant medication (including start and end dates, dose if relevant, and dose changes)
•
Date of study completion and reason for early discontinuation, if it occurs
All clinical study documents must be retained by the investigator for at least 2 years or according 
to local laws, whichever is longer, after the last approval of a marketing application in an ICH 
region (ie, US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, for 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Gilead. The investigator 
must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
participant, appropriate copies should be made for storage away from the site.

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

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9.2.2.
Study Reports and Publications
A CSR will be prepared and provided to the regulatory agency(ies) when applicable and in 
accordance with local regulatory requirements. Gilead will ensure that the report meets the 
standards set out in the ICH Guideline for Structure and Content of Clinical Study Reports 
(ICH E3). Note that an abbreviated report may be prepared in certain cases..
Investigators in this study may communicate, orally present, or publish study data in scientific 
journals or other scholarly media in accordance with the Gilead clinical trial agreement.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol (eg, attendance at investigator's meetings). If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to federal and state agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal 
and/or travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation and any participant records in order to verify the adherence 
to the protocol and accuracy of the data recorded in the CRFs or eCRFs. The study monitor is 
responsible for routine review of the CRFs or eCRFs 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 investigator agrees to cooperate with the study monitor to ensure that 
any problems detected through any type of monitoring (central, off-site, on-site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead study monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Gilead reserves the right to terminate the study at any time, and the investigator has the right to 
terminate the study at his or her site. Should this be necessary, both parties will arrange 
discontinuation procedures and notify the participants, appropriate regulatory authority(ies), and 
IRB or IEC. In terminating the study, Gilead and the investigator will ensure that adequate 
consideration is given to the protection of the participants’ interests.

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10.
REFERENCES
Alavian SM, Tabatabaei SV, Behnava B, Rizzetto M. Standard and pegylated interferon therapy 
of HDV infection: A systematic review and meta- analysis. J Res Med Sci 
2012;17 (10):967-74.
Beguelin C, Moradpour D, Sahli R, Suter-Riniker F, Luthi A, Cavassini M, et al. Hepatitis delta-
associated mortality in HIV/HBV-coinfected patients. J Hepatol 2017;66 (2):297-
303.
Blank A, Eidam A, Haag M, Hohmann N, Burhenne J, Schwab M, et al. The NTCP-inhibitor 
Myrcludex B: Effects on Bile Acid Disposition and Tenofovir Pharmacokinetics. 
Clin Pharmacol Ther 2018;103 (2):341-8.
Blank A, Markert C, Hohmann N, Carls A, Mikus G, Lehr T, et al. First-in-human application of 
the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol 
2016;65 (3):483-9.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Cornberg M, Lok AS, Terrault NA, Zoulim F, Easl-Aasld Hbv Treatment Endpoints Conference 
Faculty. Guidance for design and endpoints of clinical trials in chronic hepatitis B 
- Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference. J 
Hepatol 2020;71 (3):1070-92.
European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the 
Management of Hepatitis B Virus Infection. J Hepatol 2017;67 (2):370-98.
Farooqui N, Elhence A, Shalimar. A Current Understanding of Bile Acids in Chronic Liver 
Disease. J Clin Exp Hepatol 2022;12 (1):155-73.
Food and Drug Administration (FDA). Drug Development and Drug Interactions | Table of 
Substrates, Inhibitors and Inducers. Available at: https://www.fda.gov/drugs/drug-
interactions-labeling/drug-development-and-drug-interactions-table-substrates-
inhibitors-and-inducers. Accessed: 03 October 2022. Last Updated: 24 August. 
2022.
Heidrich B, Yurdaydin C, Kabacam G, Ratsch BA, Zachou K, Bremer B, et al. Late HDV RNA 
relapse after peginterferon alpha-based therapy of chronic hepatitis delta. 
Hepatology 2014;60 (1):87-97.
Lempp FA, Ni Y, Urban S. Hepatitis delta virus: insights into a peculiar pathogen and novel 
treatment options. Nature reviews. Gastroenterology & hepatology 2016;13 
(10):580-9.

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Lewis JH, Stine JG. Review article: prescribing medications in patients with cirrhosis - a 
practical guide. Aliment Pharmacol Ther 2013;37 (12):1132-56.
Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C, Falth M, et al. Hepatitis B and D viruses 
exploit sodium taurocholate co-transporting polypeptide for species-specific entry 
into hepatocytes. Gastroenterology 2014;146 (4):1070-83.
Rizzetto M. Hepatitis D: thirty years after. J Hepatol 2009;50 (5):1043-50.
Romeo R, Petruzziello A, Pecheur EI, Facchetti F, Perbellini R, Galmozzi E, et al. Hepatitis delta 
virus and hepatocellular carcinoma: an update. Epidemiol Infect 2018;146 
(13):1612-8.
Stockdale AJ, Kreuels B, Henrion MYR, Giorgi E, Kyomuhangi I, de Martel C, et al. The global 
prevalence of hepatitis D virus infection: Systematic review and meta-analysis. J 
Hepatol 2020;73 (3):523-32.
Sureau C, Guerra B, Lanford RE. Role of the large hepatitis B virus envelope protein in 
infectivity of the hepatitis delta virion. J Virol 1993;67 (1):366-72.
Suzuki A, Andrade RJ, Bjornsson E, Lucena MI, Lee WM, Yuen NA, et al. Drugs associated 
with hepatotoxicity and their reporting frequency of liver adverse events in 
VigiBase: unified list based on international collaborative work. Drug Saf 
2010;33 (6):503-22.
Taylor JM. Hepatitis D Virus Replication. Cold Spring Harbor perspectives in medicine 2015;5 
(11):a021568.
Terrault NA, Lok AS, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on 
Prevention, Diagnosis, and Treatment and of Chronic Hepatitis B: AASLD 2018 
Hepatitis B Guidance. Hepatology 2018;67:1560-99.
University of Washington School of Pharmacy. Human In vitro Drug Metabolism Dataset. 
Available at: https://www.druginteractionsolutions.org/wp-
content/uploads/Human-In-Vitro-Drug-Metabolism-Dataset.pdf.  2022:
Urban S, Neumann-Haefelin C, Lampertico P. Hepatitis D virus in 2021: virology, immunology 
and new treatment approaches for a difficult-to-treat disease. Gut 2021;70 
(9):1782-94.
Wedemeyer H. Re-emerging interest in hepatitis delta: new insights into the dynamic interplay 
between HBV and HDV. J Hepatol 2010a;52 (5):627-9.
Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update 
and challenges ahead. Nature reviews. Gastroenterology & hepatology 2010b;7 
(1):31-40.

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Wranke A, Serrano BC, Heidrich B, Kirschner J, Bremer B, Lehmann P, et al. Antiviral 
treatment and liver-related complications in hepatitis delta. Hepatology 2017;65 
(2):414-25.
Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, et al. Sodium taurocholate cotransporting 
polypeptide is a functional receptor for human hepatitis B and D virus. eLife 
2012;1:e00049.

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11.
APPENDICES

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11.1.
Investigator Signature Page
GILEAD SCIENCES, INC.
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
USA
STUDY ACKNOWLEDGEMENT
A Phase 1, Open-label, Parallel-group, Multiple-dose Study to Evaluate the 
Pharmacokinetics of Bulevirtide in Participants With Normal and Impaired Hepatic 
Function
Amendment 2, 30 September 2024
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval.
[See appended electronic signature]
Director, Clinical Development
Signature
[See appended electronic signature]
Date
INVESTIGATOR STATEMENT
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated.
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study.
Principal Investigator Name (Printed)
Signature
Date
Site Number
PPD

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11.2.
Pandemic Risk Assessment and Mitigation Plan
During an ongoing pandemic, potential risks associated with participants being unable to attend 
study visits have been identified for this study. 
These risks can be summarized as follows:
1) Participant safety monitoring and follow-up:
a) Participants may be unable or unwilling to come to the investigational site for their 
in-clinic stay or other requested visits as required per protocol.
Mitigation plan: Participants who may be unable or unwilling to visit the investigational 
site for their in-clinic stay as required per protocol, will not be able to receive treatment 
and will be discontinued. Participants who have received treatment and have been 
discharged either at the end of treatment or early as the result of a pandemic, will receive 
a follow-up telephone call to collect safety data as specified in the protocol follow-up 
procedures. During the follow-up telephone call, the following information at minimum 
will be reviewed: 
i)
Confirm if participant has experienced any adverse events (AEs)/serious adverse 
events (SAEs)/special situations (including pregnancy) and follow up on any 
unresolved AEs/SAEs.
ii) Review the current list of concomitant medications and document any new 
concomitant medications.
b) Participants may be unable or unwilling to travel to the investigational site for unplanned 
laboratory assessments (eg, safety blood draws); hence samples may not be sent for 
central laboratory analyses.
Mitigation plan: Local laboratories or other vendors may be utilized as appropriate to 
monitor safety until the participant can return to the site for their follow-up assessment. 
Any changes in the party conducting laboratory assessments for the study because of the 
pandemic will be documented accordingly. Pregnancy testing may be performed using a 
home urine pregnancy test if local laboratory pregnancy testing is not feasible.
c) Participants may be unable or unwilling to attend a study visit to sign an updated 
informed consent form version.
Mitigation plan: The site staff will follow their approved consent process and remain in 
compliance with the local ethics committee/institutional review board and national laws 
and regulations. Remote consent will be allowed if has been approved by the local ethics 
committee/institutional review board. The consent process will be documented and 
confirmed by normal consent procedure at the earliest opportunity.

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2) Protocol and monitoring compliance:
a) Protocol deviations may occur in case scheduled visits cannot be conducted as planned 
per protocol.
Mitigation plan: If it is not possible to complete a required procedure, an unscheduled 
visit should be conducted as soon as possible when conditions allow. The situation should 
be recorded and explained as a protocol deviation. Any missed participant visits or 
deviation to the protocol because of the pandemic must be reported in the electronic case 
report form and described in the clinical study report. Any remote study visits that are 
conducted in lieu of clinic visits because of the pandemic will be documented as a 
protocol deviation related to the pandemic.
b) Study monitors may be unable to carry out source data review or source data verification, 
or study drug accountability or assess protocol and Good Clinical Practice compliance. 
This may lead to delays in source data verification, an increase in protocol deviations, or 
underreporting of AEs.
Mitigation plan: The study monitor is to remain in close communication with the site to 
ensure data entry and query resolution. Remote source data verification may be arranged 
if allowed by local regulation and the Study Monitoring Plan. The study monitor is to 
reference the Study Monitoring Plan for guidance on how to conduct an off-site 
monitoring visit. The study staff is to save and document all relevant communication in 
the study files. The status of sites that cannot accept monitoring visits and/or participants 
on site, must be tracked centrally and updated on a regular basis.
3) Missing data and data integrity:
There may be an increased amount of missing data because of participant missing 
visits/assessments. This could have an impact on the analysis and the interpretation of 
clinical study data.
Mitigation plan: Implications of a pandemic on methodological aspects for the study will be 
thoroughly assessed and documented, and relevant actions will be taken as appropriate (eg, 
modification of the statistical analysis plan) and in compliance with regulatory authorities’ 
guidance. Overall, the clinical study report will describe the impact of the pandemic on the 
interpretability of study data.
Risks will be assessed continuously, and temporary measures will be implemented to 
mitigate these risks as part of a mitigation plan, as described above. These measures will be 
communicated to the relevant stakeholders as appropriate and are intended to provide 
alternate methods that will ensure the evaluation and assessment of the safety of participants 
who are enrolled in this study.
Since these potential risks are considered mitigated with the implementation of these measures, 
the expected benefit-risk assessment of BLV in study participants remains unchanged.

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11.3.
Pregnancy Precautions, Definition of Childbearing Potential, and 
Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a participant assigned female at birth is considered of childbearing 
potential following the initiation of puberty (Tanner stage 2) until becoming postmenopausal 
unless the participant is permanently sterile or has medically documented ovarian failure.
Participants assigned female at birth are considered to be in a postmenopausal state when they 
are at least 54 years of age with cessation of previously occurring menses for at least 12 months 
without an alternative cause. In addition, participants assigned female at birth younger than 
54 years with amenorrhea of at least 12 months also may be considered postmenopausal if their 
follicle-stimulating hormone level is in the postmenopausal range and they are not using 
hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a participant assigned female at birth of any age.
b. Definition of Fertility in a Participant Assigned Male at Birth
For the purposes of this study, a participant assigned male at birth is considered fertile after the 
initiation of puberty unless the participant is permanently sterile by bilateral orchidectomy or 
medical documentation.
2) Contraception Requirements for Female Participants Assigned Female at Birth and of 
Childbearing Potential
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Bulevirtide data on pregnant participants are limited or not available. Data from nonclinical 
toxicity studies of bulevirtide have demonstrated no adverse effect on fertility or embryofetal 
development. Available data indicate that bulevirtide is not anticipated to reduce the clinical 
efficacy of hormonal contraception. Please refer to the latest version of the investigator’s 
brochure for additional information.
b. Contraception Requirements for Female Participants of Childbearing Potential
The inclusion of participants assigned female at birth and of childbearing potential requires using 
at least an acceptable effective contraceptive measure. They must have a negative serum 
pregnancy test at screening and a negative pregnancy test on the admission (Day −1) visit before 
enrollment. In the event of a delayed menstrual period (over 1 month between menstruations), a 
pregnancy test must be performed to rule out pregnancy. This is applicable also for participants 
assigned female at birth and of childbearing potential with infrequent or irregular periods.
Duration of required contraception for participants assigned female at birth and of childbearing 
potential enrolled in this clinical study should start from the screening visit until end of study.

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Participants assigned female at birth and of childbearing potential must agree to 1 of the 
following contraceptive methods:
•
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the participant’s preferred and usual 
lifestyle.
Or
Consistent and correct use of 1 of the following methods of birth control listed below:
•
Hormonal and nonhormonal intrauterine device (IUD) 
•
Bilateral tubal occlusion (upon medical assessment of surgical success)
•
Vasectomy in the partner assigned male at birth (upon medical assessment of surgical 
success)
Or
Participants assigned female at birth and of childbearing potential who initiate use of a hormonal 
contraceptive greater than 5 days after onset of menses as their method of birth control should 
use additional backup contraception (eg, condoms) for 7 days or avoid sexual intercourse for 
7 days. Hormonally-based contraceptives or barrier methods permitted for use in this protocol 
are as follows:
•
Hormonal methods
Oral contraceptives (either combined or progesterone only)
Injectable progesterone
Subdermal contraceptive implant
Transdermal contraceptive patch
Contraceptive vaginal ring
•
Barrier methods
Male condom (with or without spermicide)
Female condom (with or without spermicide)
Diaphragm with spermicide

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Cervical cap with spermicide
Sponge with spermicide
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved. 
Participants assigned female at birth and of childbearing potential must also refrain from egg 
donation and in vitro fertilization during treatment and until the end of the contraception 
requirement.
3) Contraception Requirements for Participants Assigned Male at Birth
No contraception measures are needed.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together.
5) Procedures to Be Followed in the Event of Pregnancy
Participants assigned female at birth will be instructed to notify the investigator if they become 
pregnant or suspect they are pregnant at any time from start of the study to the end of the study. 
Study drug must be discontinued immediately.

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11.4.
Toxicity Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities
The severity of AEs will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) toxicity grading scale, Version 5 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_refer
ence_8.5x11.pdf).

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11.5.
Country-Specific Requirements
Not applicable.

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11.6.
Amendment History
A high-level summary of this amendment is provided in tabular form in the subsection below, 
with changes listed in order of importance. Minor changes such as the correction of typographic 
errors, grammar, or formatting are not detailed.  
A separate tracked change (red-lined) document comparing the original protocol to this 
amendment will be made available upon the publication of this protocol.
11.6.1.
Amendment 2 (30 September 2024)
Rationale for Key Changes Included in Amendment 2
Affected Sections
NCT number added
Title page and Synopsis
Country-specific requirements for sites in European Union and EU CT number 
was deleted as the study will be conducted only in US. 
Title page, Protocol 
Synopsis, and Section 9.2.2.
Sites revised from global to US as the study will be only conducted in US. 
Protocol Synopsis
Text updated from conditionally approved to approved status for bulevirtide 
(BLV) and included Switzerland and Australia to list of countries with approved 
status.
Section 1.2.1.1 and Section 
1.4
Sections updated per latest protocol template 
Section 4.1 and Section 
7.4.1.1
Updated discrepancy regarding Baseline safety laboratory assessments performed 
on Day 1 prior to dosing and to keep the language consistent between Study 
Schema and Section 3.4 Clinic Confinement.
Study Procedures Table and 
Section 3.4 
Section updated to ensure re-enrollment of participants was allowed. 
Section 3.1.1
Exclusion criterion “severe peptic ulcer disease, gastroesophageal reflux disease, 
or other gastric acid, hypersecretory conditions requiring prolonged (≥ 6 months) 
medical treatment” was deleted as change in the BLV pharmacokinetics based on 
mode of administration is not expected and treatment associated with those 
conditions are unlikely to include medication on the prohibited list.
Protocol synopsis and 
Section 4.3
Body mass index (BMI) was updated to 18 ≤ BMI ≤ 40 kg/m2 throughout the 
protocol, to address inconsistencies in text.
Protocol Synopsis, Section 
4.2 
Alpha-fetoprotein was removed from inclusion criterion for matched control 
participants with normal hepatic function, to align with the other sections of 
protocol and to maintain consistency
Protocol Synopsis and 
Section 4.2 
Appendix 11.2 and its reference was removed as this study is intended to be 
conducted only in US. 
Section 1.2 and Appendix 
11.2 
Minor changes to correct typographic errors. 
Throughout, as needed

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11.6.2.
Amendment 1 (13 February 2023)
Rationale for Key Changes Included in Amendment 1
Affected Sections
Gamma-glutamyl transferase and red blood cell morphology were added as 
additional safety laboratory assessments.
Sections 6.4.5 (Table 3) and 
6.4.5.1
Timing of creatinine clearance calculations clarified in notes and footnote “f” was 
added to clarify timing of coagulation collections.
Study Procedures Table 
Minor changes to correct typographic errors. 
Throughout, as needed

protocol GS-US-589-6162 Amd-2
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Development
eSigned
27-Sep-2024
18:00:39
PPD