A Phase 1 Open-Label, Parallel-Design, Multiple-Dose Study to Evaluate the Pharmacokinetics, Pharmacodynamics, and Safety of Bulevirtide in Participants With Normal and Impaired Renal Function
Phase: PHASE1
Conditions: Chronic Hepatitis D Infection
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1 Open-Label, Parallel-Design, Multiple-Dose Study to 
Evaluate the Pharmacokinetics, Pharmacodynamics, and Safety of 
Bulevirtide in Participants with Normal and Impaired Renal 
Function
Plain Language Short 
Title:
A Multiple-Dose Study of Bulevirtide in Participants with Normal 
and Impaired Renal Function
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EU CT Number:
ClinicalTrials.gov 
Identifier:
125159
2022-502054-13-00
Not applicable
Indication:
Chronic Hepatitis Delta Infection
Protocol ID:
GS-US-589-6160
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List
Protocol Version/Date:
Amendment History:
Original:
22 November 2022
Amendment 1:      02 February 2023
A high-level summary of the history of amendment is provided in 
Appendix 11.7
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); however, sites 
located in the European Economic Area, the United Kingdom, and Switzerland are not included 
under the investigational new drug application and are not considered to be investigational new 
drug application sites.
(r) GILEAU 

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This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, and that are consistent with 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
regulatory requirements.
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in 
the protocol. You will not disclose any of the information to others without written 
authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered.

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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 3 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 6 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................................... 7 
PROTOCOL SYNOPSIS ............................................................................................................................................ 10 
STUDY SCHEMA ...................................................................................................................................................... 18 
STUDY PROCEDURES TABLE ............................................................................................................................... 20 
1. 
INTRODUCTION .............................................................................................................................................. 25 
1.1. 
Background ............................................................................................................................................ 25 
1.2. 
Background on Study Interventions ....................................................................................................... 26 
1.2.1. 
Bulevirtide ............................................................................................................................ 26 
1.2.2. 
Information About Comparator ............................................................................................ 29 
1.2.3. 
Information About Auxiliary Medicinal Products ................................................................ 29 
1.3. 
Rationale for This Study ........................................................................................................................ 29 
1.4. 
Rationale for the Dose Selection of Bulevirtide ..................................................................................... 30 
1.5. 
Risk/Benefit Assessment for the Study .................................................................................................. 30 
1.6. 
Compliance ............................................................................................................................................ 31 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................................................... 32 
3. 
STUDY DESIGN ................................................................................................................................................ 33 
3.1. 
Study Design .......................................................................................................................................... 33 
3.1.1. 
Dose Selection ...................................................................................................................... 34 
3.2. 
Duration of Dosing ................................................................................................................................. 36 
3.3. 
Protocol-Specific Discontinuation Criteria ............................................................................................ 36 
3.3.1. 
Criteria for Early Discontinuation for the Individual Participant ......................................... 36 
3.3.2. 
Criteria for Early Discontinuation of an Individual Group................................................... 37 
3.3.3. 
Criteria for Early Discontinuation of the Study .................................................................... 38 
3.3.4. 
Loss to Follow-Up ................................................................................................................ 38 
3.3.5. 
Early Termination ................................................................................................................ 38 
3.4. 
Clinic Confinement ................................................................................................................................ 38 
3.5. 
Definitions for Time of Primary Endpoint and End of Study ................................................................ 39 
3.5.1. 
Primary Endpoint ................................................................................................................. 39 
3.5.2. 
End of Study ......................................................................................................................... 39 
3.6. 
Source Data ............................................................................................................................................ 39 
4. 
PARTICIPANT POPULATION ......................................................................................................................... 40 
4.1. 
Number of Participants and Participant Selection .................................................................................. 40 
4.1.1. 
Participant Replacement ....................................................................................................... 40 
4.2. 
Inclusion Criteria .................................................................................................................................... 40 
4.3. 
Exclusion Criteria................................................................................................................................... 42 
5. 
STUDY INTERVENTIONS AND CONCOMITANT MEDICATIONS .......................................................... 45 
5.1. 
Enrollment and Blinding ........................................................................................................................ 45 
5.1.1. 
Enrollment ............................................................................................................................ 45 
5.1.2. 
Blinding ................................................................................................................................ 45 
5.2. 
Description and Handling of Bulevirtide ............................................................................................... 45 
5.2.1. 
Formulation .......................................................................................................................... 45 

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5.2.2. 
Packaging and Labeling ....................................................................................................... 46 
5.2.3. 
Storage and Handling ........................................................................................................... 46 
5.3. 
Dosage and Administration .................................................................................................................... 47 
5.3.1. 
Administration Site Reactions .............................................................................................. 47 
5.4. 
Fasting and Meals .................................................................................................................................. 47 
5.5. 
Dispensing, Accountability, and Disposal or Return of Study Drug ...................................................... 48 
5.6. 
Concomitant Medications and Other Protocol Restrictions ................................................................... 49 
5.6.1. 
Concomitant Medications ..................................................................................................... 49 
5.6.2. 
Other Protocol Restrictions .................................................................................................. 51 
6. 
STUDY ASSESSMENTS ................................................................................................................................... 53 
6.1. 
Informed Consent ................................................................................................................................... 53 
6.2. 
Participant Enrollment and Treatment Assignment................................................................................ 54 
6.3. 
Instructions for Study Procedures .......................................................................................................... 54 
6.3.1. 
Adverse Events ..................................................................................................................... 54 
6.3.2. 
Screening Assessments......................................................................................................... 54 
6.3.3. 
Admission Assessments ....................................................................................................... 55 
6.3.4. 
Treatment Assessments ........................................................................................................ 55 
6.3.5. 
Pharmacokinetic and Pharmacodynamic Assessments ........................................................ 55 
6.3.6. 
Plasma Collection for Immunogenicity Evaluation .............................................................. 58 
6.4. 
Safety Assessments ................................................................................................................................ 58 
6.4.1. 
Electrocardiogram Assessment ............................................................................................ 58 
6.4.2. 
Physical Examination ........................................................................................................... 59 
6.4.3. 
Vital Signs ............................................................................................................................ 59 
6.4.4. 
Body Mass Index .................................................................................................................. 59 
6.4.5. 
Clinical Laboratory Tests/Assessments ................................................................................ 59 
6.4.6. 
Estimated Glomerular Filtration Rate .................................................................................. 62 
6.4.7. 
Concomitant Medications/Protocol Restrictions .................................................................. 62 
6.5. 
Posttreatment Assessments .................................................................................................................... 62 
6.6. 
Assessments for Early Discontinuation from Study Intervention and from the Study ........................... 62 
6.6.1. 
Assessments for Early Discontinuation from Study Intervention......................................... 62 
6.6.2. 
Assessments for End of Study .............................................................................................. 63 
6.7. 
Sample Storage....................................................................................................................................... 63 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 64 
7.1. 
Definitions of Adverse Events and Serious Adverse Events .................................................................. 64 
7.1.1. 
Adverse Events ..................................................................................................................... 64 
7.1.2. 
Serious Adverse Events ........................................................................................................ 64 
7.1.3. 
Study Drugs and Gilead Concomitant Therapy Special Situation Reports .......................... 65 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 66 
7.2.1. 
Assessment of Causality for Study Drug and Procedures .................................................... 66 
7.2.2. 
Assessment of Severity ........................................................................................................ 66 
7.3. 
Investigator Reporting Requirements and Instructions .......................................................................... 67 
7.3.1. 
Requirements for Collection Prior to Study Drug Initiation................................................. 67 
7.3.2. 
Adverse Events ..................................................................................................................... 67 
7.3.3. 
Serious Adverse Events ........................................................................................................ 67 
7.3.4. 
Study Drug Special Situations Reports ................................................................................ 67 
7.3.5. 
Concomitant Therapy Reports .............................................................................................. 68 
7.4. 
Reporting Process for Serious Adverse Events and Special Situations Reports .................................... 68 
7.4.1. 
Serious Adverse Event Reporting Process ........................................................................... 68 
7.4.2. 
Special Situations Reporting Process ................................................................................... 69 
7.5. 
Gilead Reporting Requirements ............................................................................................................. 70 
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7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events...........................................................................................................................71
7.7.
Toxicity Management..............................................................................................................................71
7.7.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event ..................................................72
7.7.2.
Grade 3 and Grade 4 Laboratory Abnormality or Clinical Event .........................................72
8.
STATISTICAL CONSIDERATIONS.................................................................................................................73
8.1.
Analysis Objectives and Endpoints.........................................................................................................73
8.2.
Planned Analyses.....................................................................................................................................73
8.2.1.
Interim Analysis ....................................................................................................................73
8.2.2.
Final Analysis........................................................................................................................73
8.3.
Analysis Conventions..............................................................................................................................73
8.3.1.
Analysis Sets .........................................................................................................................73
8.3.2.
Data Handling Conventions ..................................................................................................74
8.4.
Demographic Data and Baseline Characteristics ....................................................................................74
8.5.
Safety Analysis........................................................................................................................................74
8.5.1.
Extent of Exposure ................................................................................................................74
8.5.2.
Adverse Events......................................................................................................................75
8.5.3.
Laboratory Evaluations .........................................................................................................75
8.5.4.
Other Safety Evaluations.......................................................................................................75
8.6.
Pharmacokinetic and Pharmacodynamic Analysis..................................................................................75
8.7.
Immunogenicity Analysis........................................................................................................................76
8.8.
Sample Size .............................................................................................................................................76
9.
RESPONSIBILITIES...........................................................................................................................................77
9.1.
Investigator Responsibilities ...................................................................................................................77
9.1.1.
Good Clinical Practice...........................................................................................................77
9.1.2.
Financial Disclosure ..............................................................................................................77
9.1.3.
Institutional Review Board or Independent Ethics Committee Review and 
Approval................................................................................................................................77
9.1.4.
Informed Consent ..................................................................................................................77
9.1.5.
Confidentiality.......................................................................................................................78
9.1.6.
Study Files and Retention of Records ...................................................................................78
9.1.7.
Case Report Forms ................................................................................................................79
9.1.8.
Investigator Inspections.........................................................................................................80
9.1.9.
Protocol Compliance .............................................................................................................80
9.2.
Sponsor Responsibilities .........................................................................................................................80
9.2.1.
Protocol Modifications ..........................................................................................................80
9.2.2.
Study Reports and Publications.............................................................................................80
9.3.
Joint Investigator/Sponsor Responsibilities ............................................................................................81
9.3.1.
Payment Reporting ................................................................................................................81
9.3.2.
Access to Information for Monitoring...................................................................................81
9.3.3.
Access to Information for Auditing or Inspections ...............................................................81
9.3.4.
Study Discontinuation ...........................................................................................................81
10.
REFERENCES.....................................................................................................................................................82
11.
APPENDICES......................................................................................................................................................85
11.1.
Investigator Signature Page.....................................................................................................................86
11.2.
Authorization Status of Study Interventions ...........................................................................................87
11.3.
Pandemic Risk Assessment and Mitigation Plan ....................................................................................88
11.4.
Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive Requirements ..........90
11.5.
Toxicity Grading Scale for Severity of Adverse Events and Laboratory Abnormalities........................93
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11.6.
Country-Specific Requirements ..............................................................................................................94
11.7.
Amendment History ................................................................................................................................95
11.7.1.
Amendment 1 (02 February 2023) ........................................................................................95
LIST OF IN-TEXT TABLES
Table 1.
Study Procedures Table...........................................................................................................20
Table 2.
Study Objectives and Endpoints..............................................................................................32
Table 3.
Laboratory Analytes ................................................................................................................60
LIST OF IN-TEXT FIGURES
Figure 1-a.
Study Schema ..........................................................................................................................18
Figure 1-b.
PK Decision Criteria for Progression to Subsequent Study Groups .......................................19

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
Ae
amount of unchanged drug excreted in urine calculated either over a specific interval (Ae 
(interval)) or cumulatively over all collection intervals, calculated as (concentration of 
unchanged drug in urine) × (volume of urine collected)
ADA
antidrug antibodies 
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUCtau
area under the concentration versus time curve over the dosing interval
BA
bile acids
BMI
body mass index
BLA
biologic license application 
BLV
bulevirtide
CCDS
company core data sheet 
CDER
Center for Drug Evaluation and Research
CHB
chronic hepatitis B infection
CHD 
chronic hepatitis D infection
CHO
Chinese hamster ovary
CI
confidence interval
CK
creatine kinase
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration
CL/F 
apparent clearance 
CLcr
creatinine clearance 
CLss/F
apparent clearance at steady state
CLr
renal clearance of unchanged drug in a specific interval (CLr (interval)) or cumulatively 
over all collection intervals
Cmax
maximum observed concentration of drug
Cmax ss
maximum observed concentration of drug at steady state
COVID-19
Coronavirus disease 2019
CPK
creatine phosphokinase
CSR
clinical study report
Ctrough
concentration at the end of the dosing interval 
CTCAE
Common Terminology Criteria for Adverse Events
CV%
percentage coefficient of variation
CYP
cytochrome
DDI 
drug-drug interactions 
DNA
deoxyribonucleic acid
ECG
electrocardiogram

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eCRF
electronic case report form
EASL
European Association for the Study of the Liver
EDC
electronic data capture
EFD 
embryofetal development 
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
ET
early termination
EU
European Union
FDA
US Food and Drug Administration
Fe
excreted fraction of administered drug
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
Gilead
Gilead Sciences, Inc.
GMP
Good Manufacturing Practices
PS
Patient Safety
GLSM
geometric least-squares mean
GMR
geometric mean ratio
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
high density lipoprotein
HDV
hepatitis D virus
HEK293
human embryonic kidney 293 cell line
HIV
human immunodeficiency virus
IB
investigator’s brochure
IBW
ideal body weight 
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 
IRB
institutional review board
IUD
intrauterine device
LDL
low density lipoprotein
LLOQ
lower limit of quantitation
MDMA 
3,4-methylenedioxymethamphetamine 
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute

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NTCP
sodium-taurocholate cotransporting polypeptide
OATP
organic anion transporting polypeptide
PCR
polymerase chain reaction
PD
pharmacodynamic
PI
principal investigator
PK
pharmacokinetic
PopPK
population pharmacokinetic
PT
preferred term
QD
once-daily
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
RI
renal impairment
RNA
ribonucleic acid
RSI
reference safety information
SAE
serious adverse event
SC
subcutaneous
SDV
source data verification
SOC
system organ class
SOP
standard operating procedure
SRT
safety review team
SSR
special situations reports
SUSAR
suspected unexpected serious adverse reaction
TAF 
tenofovir alafenamide 
TDF
tenofovir disoproxil fumarate
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
Tmax
time (observed time point) of Cmax
t1/2 
terminal elimination half-life
ULN
upper limit of normal
US, USA
United States, United States of America
V/F 
apparent volume of distribution 
Vss/F
apparent volume of distribution at steady state

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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-Design, Multiple-Dose Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of Bulevirtide in Participants with Normal 
and Impaired Renal Function
Plain Language Short Title: A Multiple-Dose Study of Bulevirtide in Participants with Normal 
and Impaired Renal Function
Regulatory Agency Identifier Number(s):
IND Number: 125159
EU CT Number: 2022-502054-13-00
ClinicalTrials.gov Identifier: Not applicable
Study Sites Planned: Multiple sites globally
Objectives and Endpoints:
Primary Objective
Primary Endpoint(s)

To evaluate the steady-state plasma 
pharmacokinetics (PK) of BLV in non-
HDV/HBV-infected participants with renal 
impairment (RI) and in matched control 
participants with normal renal function

BLV steady-state plasma PK parameters: AUCtau 
and Cmax ss
Secondary Objective(s)
Secondary Endpoint(s)

To further characterize the plasma PK of BLV in 
participants with RI and in matched control 
participants with normal renal function

Plasma PK parameters for BLV, as applicable: 
AUC0-24, Cmax, Tmax, t1/2, CLss/F, and Vss/F

To evaluate the pharmacodynamic (PD) effect of 
BLV on plasma bile acids (BA) in participants 
with RI to matched control participants with 
normal renal function

Total bile acids concentrations in plasma and 
exposure parameters for total BA, as applicable: 
Ctrough, Cmax, AUC0-24, Tmax

To evaluate the safety and tolerability of BLV 
following multiple-dose administration in 
participants with RI and matched control 
participants with normal renal function

The incidences of AEs and laboratory 
abnormalities

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ADA = antidrng antibodies; AE = adverse event; BA = bile acids; BL V = bulevirtide; HBV = hepatitis B vims; HDV = hepatitis 
• 
• 
okinetic; RI = renal impainuent 
Study Design: Phase 1, open-label, multiple-dose, parallel-group study ofbulevi1iide (BL V) 
phannacokinetic (PK), phannacodynamic (PD), and safety in paiiicipants with renal impainnent 
(RI) and matched control paiiicipants with nonnal renal function. An overview of the study 
design is described below and in Figure 1-a. The study will begin with Group A and following 
com letion and evaluation of PK and safe 
data from all aitici ants in Grou A 
• 
Group A (BLV 2 mg severe RI): A total ofup to 20 paiiicipants (10 paiiicipants with 
severe RI and 10 matched control paiiicipants) will be emolled to obtain at least 16 evaluable 
paiiicipants (8 paiiicipants with severe RI and 8 matched control participants) 
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Classification of renal function will be assessed using the estimated glomerular filtration rate 
(eGFR) based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
(expressed for serum creatinine, sex, and age) {Inker 2021} at screening as follows:

Group A (BLV 2 mg severe RI): Participants with severe RI (eGFR ≥15 to 
≤ 29 mL/min/1.73 m²) and normal renal function (eGFR ≥ 90 mL/min/1.73 m²) at screening. 
Participants with severe RI requiring or anticipated to require dialysis within 90 days of study 
entry will not be eligible.
The matched control group will consist of participants with normal renal function matched for 
age, sex, and BMI with a participant in the RI group. Within each group, once a participant with 
RI is enrolled a matched control to that participant will be allowed to enroll. Dosing of matched 
participant with normal renal function may begin after the corresponding participant with RI in 
that group has completed the last PK assessment.
A matching control may serve as a matched control only once per study group. A participant 
with normal renal function may have their PK and BA data reused just once to serve as a match 
for an another group, if the BLV dose is the same and the matching criteria are met.
Study Population: Male and nonpregnant/nonlactating female participants who have no history 
of hepatitis D virus (HDV) or hepatitis B virus (HBV) infection. The participants will be 
classified based on renal function using the eGFR CKD-EPI equation with either severe, 
moderate, or mild RI, or normal renal function (controls).
Number of Participants Planned: For Group A, a total of up to approximately 20 enrolled 
(10 non-HDV/HBV participants with severe renal impairment and 10 matched control 
participants with normal renal function) with a goal of obtaining approximately 16 evaluable 
participants (8 severe RI and 8 matched controls).
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Diagnosis and Main Eligibility Criteria:
Key Inclusion Criteria
All Participants:

Be aged 18 through 79 years, inclusive, at screening.

Have a calculated body mass index (BMI) of at least 18.0 kg/m² and no greater than 
40.0 kg/m² at screening.

12-lead electrocardiogram (ECG) evaluations at screening and admission must be without 
clinically significant abnormalities as assessed by the investigator.

Have no known liver disease with hepatic transaminases (aspartate aminotransferase [AST] 
and ALT) ≤ 3  upper limit of normal (ULN) at screening.
Participants with RI:

Have RI classification at screening that has been unchanged (based on medical history, 
physical examination, and clinical laboratory results with no clinically significant change) 
during the 90 days prior to study drug dosing, as determined by the investigator.

eGFR must be the following (using the CKD-EPI equation {Inker 2021}) based on serum 
creatinine as measured at the screening evaluation:
Severe RI (Groups A and B): eGFR ≥ 15 to ≤ 29 mL/min/1.73 m²
Moderate RI (Group C): eGFR ≥ 30 to ≤ 59 mL/min/1.73 m²
Mild RI (Group D): eGFR ≥ 60 to ≤ 89 mL/min/1.73 m²

Hemoglobin ≥ 9 g/dL at screening.

Participants with diseases/conditions associated with RI (eg, cardiovascular disease, 
hypertension, diabetes mellitus, hyperlipidemia, etc) and participants with other concomitant 
diseases not related to RI (eg, hypothyroidism, osteoporosis, and many others) may be 
included provided that these diseases/conditions are clinically stable (as judged by the 
investigator, and in consultation with the medical monitor) and without impact on the study 
outcome.

For participants with RI 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:

Have an eGFR of at least 90 mL/min/1.73 m² (using the CKD-EPI equation) based on serum 
creatinine as measured at screening evaluation.

Matched for sex, age (± 10 years), and BMI (± 20%, 18.0 ≤ BMI ≤ 40.0 kg/m²) with the 
respective participant in the RI group.
Key Exclusion Criteria
All Participants:

Have a positive test result for the fourth generation HIV antibody/antigen test, HBsAg, or 
hepatitis C virus (HCV) antibody with detectable HCV viral RNA at screening.
Note: Any previous treatment for an HCV infection must have been completed at least 
12 weeks before screening.

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 uncontrolled or unstable cardiovascular, 
hematologic, hepatic, pulmonary, endocrine, gastrointestinal, metabolic, neurological 
disease, or active infection.
Participants with RI:

Recent history of reception of any blood or blood products or history of major bleeding 
within 4 weeks of dosing.

Positive test for drugs of abuse, including alcohol at screening or admission, with the 
exception of opioids and tetrahydrocannabinol (THC, 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.

Received treatment with trimethoprim or cimetidine or tenofovir prodrugs (tenofovir 
disoproxil fumarate [TDF] or tenofovir alafenamide [TAF]) (affects elimination of 
creatinine) or with competitors of renal tubular excretion (eg, probenecid, chronic high-dose 
nonsteroidal anti-inflammatory drugs) within 28 days of Day –1.

Received known nephrotoxic drugs (eg, aminoglycosides, amphotericin B, vancomycin, 
cidofovir, foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus, herbal remedies 
[eg, compounds with aristolochic acid]) within 28 days of Day –1.

Participants requiring or anticipated to require dialysis within 90 days of study entry.

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
Serum albumin concentration <25 g/L.

Uncontrolled treated/untreated hypertension (defined as a mean of 3 repeated measurements 
for systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg); current 
or documented history of repeated clinically significant hypotension or severe episodes of 
orthostatic hypotension (systolic blood pressure <90 mmHg and/or diastolic blood pressure 
<50 mmHg).
Matched Control Participants:

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.
Test Product, Dose, and Mode of Administration: For each study group, participants will be 
administered BLV by SC injection by assigned study staff, once-daily (QD) at approximately the 
same time (± 30 minutes) each morning on Days 1-6 following an overnight fast (no food or 
drinks, except water) for at least 8 hours prior to dosing. The study will begin with Group A and 
additional optional groups (Groups B, C, and D) may be evaluated. The Figure 1-b outlines the 
PK decision criteria for dose selection and renal population for the subsequent study groups.

Group A: BLV 2 mg in participants with severe RI and matched control participants

Optional Group B: BLV 10 mg in participants with severe RI and matched control 
participants

Optional Group C: BLV 2 mg or 10 mg (dose to be determined) in participants with 
moderate RI and matched control participants

Optional Group D: BLV 2 mg or 10 mg (dose to be determined) in participants with mild 
RI and matched control participants
Reference Therapy, Dose, and Mode of Administration: Not applicable
Duration of Dosing and Duration of Study:

Duration of Dosing: 6 days for each study group

Duration of Study: 14 days (± 2 days) for each study group
The study will start with Group A (BLV 2 mg and severe RI with matched controls). 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 SC injection of BLV by assigned 
study staff, Day 1 through Day 6. A follow-up telephone call to collect adverse event (AE) data 
will be made on Day 13 (± 2 days).

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e the safety and PK 
(refer to PK criteria in Fioure 1-b) from all 
• • 
• 
. 
. 
. 
Study Procedures/Frequency: Following the completion of screening procedures and study 
emollment at admission, eligible participants will be administered study chu g and undergo the 
following PK, PD and safety assessments as outlined in Table 1. 
• 
AE repo1iing 
• 
Physical examinations 
• 
Vital signs 
• 
12-lead ECGs 
• 
Safety laborato1y 
• 
Other assessments ( eg intensive plasma BL V PK inte • 
Statistical Methods: 
Phaimacokinetics and Phaim acodynainics: Plasma concentrations and PK pai·ameters of BLV; 
and plasma concentrations and PD biomai·ker parameter of total BA, will be listed and 
smnmai·ized by renal function group and dose level using descriptive statistics. In addition, 
concentrations of individual BA may be measured and PD pai·ameters may be smnmarized. 
In addition, a one-way analysis of vai·iance (ANOV A) model appropriate for a parallel-design 
with renal function group as a fixed effect will be fit to the natural logarithmic transfonnation of 
PK parameters (AUCtau and Cmax ss) for BL V. The 90% Cls will be constrncted for the geometric 
least-squai·es mean (GLSM) ratio of PK pai·ameters for BLV in the RI group versus the matched 
control (no1mal renal function) group. The same analysis will be conducted for PD pai·ameters of 
total BA, as applicable. 
The PK-PD relationship using plasma BLV PK concentrations/pai·ameters and plasma BA 
concentrations/parameters may be explored using a graphic approach and coITelation coefficients 
as appropriate. Additional PK and PD pai·ameters may be estimated as necessa1y . 
If dete1mined, BL V and BA urine concentrations and pai·ameters will be listed and smnmai·ized 
b renal function ·ou and dose level usin descri tive statistics. 
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Urine samples may be analyzed for detennining the 6 beta-hydroxyco1iisol to c01iisol ratio as a 
marker of CYP3A4 metabolic activity at Day 1 predose and at steady state (Day 6). 
Plasma will be evaluated for the presence of antidmg antibodies (ADA) to BL V for 
immunogenicity analysis as applicable. ADA may be fmiher characterized for neutralizing 
activity. 
Safety: The AE data will be listed by paiiicipant. The treatment-emergent AEs (TEAEs), serious 
AEs (SAEs), and AEs leading to pe1manent study diug discontinuation will be Slllllffiai·ized by 
renal function group, dose, system organ class, and prefe1Ted te1m using the cunent version of 
Medical Dictiona1y for Regulato1y Activities (MedDRA). 
Listings of individual pa1i icipant laborato1y results will be provided. Laborato1y results and 
changes from baseline values for selected laborato1y tests will be Sllffilnai·ized by renal function 
group and dose at scheduled visits. The incidence of treatment-emergent laborato1y 
abno1malities will be Slllllffiai·ized by renal function group and dose. 
Vital signs and ECG data will be summarized by renal function group and dose. 
Sainple Size: For study Group A, with 16 (8 RI and 8 matched control [ n01mal renal function]) 
evaluable paiiicipants, the estimated upper limit of the one-sided 95% Cls of the GLSM ratio of 
RI group versus matched control group with regai·ds to AUCtau and Cma.x 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 (CV%) of no more than 51 %, which is suppo1ied by previously 
conducted Study MYR102. Accounting for a 20% di·opout rate, a total sainple size of 
20 paiiicipants (10 RI and 10 matched control each) will be required. 
Furthe1more, given the lower degree of vai·iability in BA concentrations compai·ed to BL V 
plasma concentrations observed in Study MYR102 {Blank 2018}, this sainple size will also 
provide :::: 80% probability that the estimated upper limit of the one-sided 95% Cls of the GLSM 
ratio of RI group versus matched control group with regards to AUCiau and Cma.x of total lasma 
BA would be less than 200% if the ex ected GLSM ratio is 1.0. 
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STUDY SCHEMA
Figure 1-a.
Study Schema
BA = bile acids; BLV = bulevirtide; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; eGFR = estimated glomerular filtration rate; N = number of participants; 
PK = pharmacokinetics; QD = once-daily; SC = subcutaneous; TC = telephone call
Note: Refer to Figure 1-b for PK criteria for dose selection and renal population of the subsequent study groups.
Screening 
(up to 28 days) 
Participants 
with Renal 
Impairment* 
= 10 
Matched 
Control 
Participants 
(eGFRe: 90 
mL/min/ 
1.73m2 ) 
= 10 
Day-1 
Admission 
/ labs 
*Participants with Renal Impairment (CKD-EPI equation) 
defined as: 
Groups A aod B: Severe; eGFR 2:: 15 to ::; 29 ml/min/I. 73 
Group C: Moderate; eGFR 2:: 30 to::; 59 mL/min/1.73 m2 
Group D: Mild; eGFR 2:: 60 to::; 89 mL/min/1.73 m2 
Day 1 
Baseline 
safety labs 
Intensive 
BLV PK 
andBA 
sampling 
Urine 
collected 
Days 2 to 5 
Day6 
Trough PK 
Intensive 
and BA 
sampling 
BLV 2 mg SC QD (Group A) 
BLV 10mg SC QD (Group B) 
BLV PK 
and BA 
sampling 
Urine 
collected 
BLV 2 mg or 10 mg SC QD (Groups C and D) 
Day7 
Day8 
Day 13 
Trough PK 
Trough PK 
(± 2 days) 
and BA 
andBA 
Follow-up 
sampling 
sampling 
TC 
Urine 
Urine 
collected 
collected 
Discharge 

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Figure 1-b.
PK Decision Criteria for Progression to Subsequent Study Groups
BLV = bulevirtide; GMR = geometric mean ratio; PK = pharmacokinetic; QD = once-daily; RI = renal impairment
Boxes in bold and shaded indicate the most likely scenario to be pursued.
PK criteria based on the geometric mean ratio (GMR) of AUCtau of renal 
impairment (RI) participants compared to participants with normal renal function 
Start of Study 
GMR > 4 
GroupB 
GMR S2 
Group A 
GMR > 4 
Group C 
Severe RI 
Severe RI 
Moderate RI 
10 mg QD 
2mgQD 
2 mg QD 
GMR > 2to:,; 4 
GMR:52 
GMR > 4 
End of Study 
GMR > 2to:,; 4 
GMR :,;4 
-
Group D 
Group C 
Group D 
Mild RI 
Moderate RI 
Mild RI 
10 mg QD 
GMR > 2 to:,; 4 
10 mg QD 
GMR > 4 
2 mgQD 
GMR :5 2 
' 
End of Stud y 

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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, and discharge (Day 8), and at 
ET visit (if applicable).
I 
I 

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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: screening, admission (Day –1), Day 1 (4 hours 
postdose), Day 3 (4 hours postdose), Day 6 (4 hours 
postdose) and discharge (Day 8), and at ET visit (if 
applicable).
HIV, HBV, and 
HCV testing
X
Fourth generation HIV antibody/antigen test, HBsAg, 
HBsAb, HCV antibody, and HCV RNA testing.
eGFRe
X
X
X
X
X
X
X
X
eGFR will be estimated at screening, admission (Day –1), 
predose Day 1 to 6, Day 7, and at discharge (Day 8), and at 
ET visit if applicable. eGFR will be calculated using the 
CKD-EPI equation (2021) for allocation to the RI group 
based on serum creatinine as measured at screening.
Hematologyd,e
X
X
X
X
X
X
X
X
8 hours fasting required.
Chemistryd,e
X
X
X
X
X
X
X
X
8 hours fasting required. Assessment of total BA for safety.
Urinalysisd,e
X
X
X
X
X
X
X
X
8 hours fasting required.
Urine drug and 
alcohol screen
X
X
If study site cannot perform urine alcohol or obtain results 
from the local laboratory in time for enrollment on Day 1, 
then an alcohol breathalyzer test is acceptable.
Coagulationd,e
X
X
X
X
X
X
X
Prothrombin time, partial thromboplastin time, and 
international normalized ratio. 
Serum pregnancy 
test
X
X
Required for participants assigned female at birth and of 
childbearing potential only. Point of care pregnancy test may 
be used at site if serum test result is not available prior to 
dosing.

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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
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
Day 1 to Day 6, BLV SC injection, QD. See Section 5.3.
Intensive plasma 
BLV PK and 
plasma BA for PD
X
X
X
Intensive BLV PK and total plasma BA for PD biomarker 
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) at 0.5, 1, 1.5, 2, 3, 4, 6, 9, and 12 hours 
postdose; and, at ET visit (as applicable).
Trough plasma 
PK and trough 
plasma BA for PD
X
X
X
X
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 at 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.

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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
Immunogenicity
X
X
ADA to BLV. Collected predose (≤ 30 minutes before dose).
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 & 
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.
ADA = antidrug antibodies; AE = adverse events; BA = bile acids; BLV = bulevirtide; BMI = body mass index; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; 
ECG = electrocardiogram; eCRF = electronic case report forms; eGFR = estimated glomerular filtration rate; ET = early termination; FSH = follicle-stimulating hormone; 
HBsAb= hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; PCR = 
polymerase chain reaction; PK = pharmacokinetics; QD = once-daily; RI = renal impairment; SAE = serious adverse event; SC = subcutaneous
CCI

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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 ie, 7 days (± 2 days) following last administration of study drug.
c
ET assessments will be performed within 24 hours of prematurely discontinuing from the study (prior to Day 8), if possible.
d
Performed at screening, admission (Day −1), predose on Days 1 to 6, Day 7, at discharge (Day 8), and at ET visit, if applicable. Predose collections are to be performed ≤ 30 
minutes before dose. Coagulation tests will not be performed on Day 7.
e
Safety laboratory tests will be collected upon study site admission (Day –1); 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 labs will be maintained with the source documents and will not be entered in the electronic data capture at the site. Day 1 safety 
labs will be used for baseline values.

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1.
INTRODUCTION
1.1.
Background
Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis, affecting as many 
as 10 to 20 million people globally {Stockdale 2020}. Delta hepatitis 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 (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 (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 co-infection 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 (EASL) 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 (EASL) 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 effectively target critical aspects of the HDV replication 

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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
A list of study interventions and their authorization status is provided in Appendix 11.2.
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 (and HBV) 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 conditionally approved under the brand name Hepcludex® in the European 
Economic Area and the United Kingdom and approved as Myrcludex B® in Russia. Bulevirtide 
as a 2-mg lyophilized powder for injection is to be administered subcutaneously once-daily (QD) 
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 (CCDS) and the reference safety information (RSI).
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 acids (BA) 
uptake was obtained in HEK293-NTCP cells and an IC50 of 9.7 nM was obtained in primary 
human hepatocytes. Inhibition of rat NTCP function was assessed using 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 besides the cynomolgus monkey. It is rapidly 
absorbed after subcutaneous (SC) administration with maximum plasma concentrations (Cmax) 
being reached within 4 to 6 hours. Area under the curve (AUC) 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 plasma 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 (DDI) for BLV were evaluated in 
vitro and overall a low DDI risk was predicted. The renal excretion of BLV is likely very low as 
indicated by an observed lack of renal excretion of radiolabeled peptides in nonclinical species.
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 pre- or post-natal development in rats up to 2.5 mg/kg/day, the highest dose 
tested.
1.2.1.3.
Additional Clinical Experience with 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, BLV exposure 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/F) and 
volume of distribution (V/F), 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 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 BLV exposure (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 severely hepatic impairment (Child-Pugh B and C, 
respectively).
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 
BA 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 
BA elevations resolved upon discontinuation of BLV treatment and were asymptomatic.
Population PK modeling (n=60) found no impact of mild renal impairment (RI) (creatinine 
clearance [CLcr] ≥ 60 and < 90 mL/min) on BLV PK. The safety and PK of BLV has not been 
evaluated in patients with moderate and severe RI (CLcr < 60 mL/min), or in patients with 
end-stage renal disease, including those on dialysis. As BLV is > 99.9% protein bound, dialysis 
is not expected to alter exposures of BLV. No dosage adjustment of BLV is required in patients 
with mild RI. This Phase 1 study is being conducted to determine whether study drug PK 
parameters are altered in participants with impaired renal function as compared to participants 
with normal renal function to an extent that dose adjustments of study drug in participants with 
RI may be warranted.
In a clinical PK DDI study in healthy volunteers, there was no significant effect of BLV on the 
PK of tenofovir disoproxil fumarate (TDF), a potential concomitant medication for the treatment 
of HBV infection. No CYP or transporter inhibition or induction by BLV was observed in vitro 
at clinically relevant concentrations.
The safety of BLV was assessed in participants with CHD without cirrhosis or with compensated 
cirrhosis from three Phase 2 studies and one Phase 3 study. BLV 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.
Bulevirtide has the potential to induce antidrug antibodies (ADA), as detected in clinical studies 
using an enzyme-linked immunosorbent assay (ELISA). In Studies MYR203 and MYR301, a 
total of 64 patients who were treated with BLV 2 mg monotherapy for 48 weeks were eligible for 

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assessment of ADA prevalence; 18 of these patients (28.1%) were positive for ADA prevalence, 
of which 3 patients (4.7%) were positive for ADA at baseline. Similar ADA findings were 
observed at the BLV 10 mg dose level. There is no evidence that the pharmacokinetics, safety, or 
effectiveness of BLV were altered in these patients.
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
Renal 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 
renal function. In healthy participants the lack of full-length peptide was detected in urine PK 
with 24-hour urine collection after single doses and at steady state with BLV 10 mg QD therapy. 
Therefore, RI is not expected to substantially affect the exposure of BLV. Accordingly, a 
reduced study design at the “extremes” of renal function will be used, in accordance with 
regulatory guidance from the Food and Drug Administration (FDA) “Pharmacokinetics in 
Patients with Impaired Renal Function-Study Design, Data Analysis, and Impact on Dosing and 
Labeling” {U.S. Department of Health and Human Services 2020}. The results from this study 
(Groups A and B) will inform the decision to evaluate the PK of BLV in participants with 
moderate and/or mild RI in additional optional groups of this study (Groups C and D).
The RI categorization for entry criteria in this study will be based on the CKD-EPI (2021) 
equation to estimate GFR, as this is recommended by the National Kidney Foundation and the 
American Society of Nephrology {Delgado 2022}. This study will evaluate the multiple-dose PK 
of BLV in participants with severe RI, not requiring dialysis (eGFR ≥ 15 to ≤ 29 mL/min/1.73 
m²) as compared to matched control participants with normal renal function (eGFR ≥ 90 
mL/min/1.73 m²) with a goal to provide appropriate dosing recommendations in patients with RI. 
The matched control group will be composed of participants with normal renal function and 
matched for age, body weight, and sex.
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). Bile acids are eliminated in the urine, with increases in urine BA 
observed in a previous healthy participant study (MYR102) following BLV treatment. Given 
this, there is the potential that BA concentrations may be further elevated in patients with RI, 
thus this study will evaluate plasma BA concentrations and may explore urine BA 
concentrations.

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Administration of BLV with multiple dosing (QD) will be utilized in this study as BL V has 
demonstrated dose- and time-dependent PK, with approximately a 2-fold accumulation after QD 
multiple dosing despite a sho1i apparent tenninal half-life (3-7 hours). A previous study, 
MYR102 {Blank 2016}, demonstrated that steady-state accumulation can be achieved within 6 
days of dosing and that effects on elevations of plasma and urine BA appeared to plateau within 
this time frame. Renal impaiiment may also be associated with changes in protein binding, and 
thus plasma protein binding ofBLV may also be evaluated in this study. 
Intensive PK and BA assessments will be conducted to ensure sufficient characterization of 
tenninal eliinination phase ofBLV. To ensure paiiicipant safety, a minimum confinement until 
Day 8 will be requii·ed. 
Non-HDV/HBV-infected paiiicipants (paiiicipants with RI and matched control paiiicipants with 
n01m al renal function) ai·e selected for this study to remove potential confounding effects of the 
tai·get disease and/or therapies in participants with hepatitis D infection. In addition, this study 
design, conducted at Phase 1 units will provide compai·isons of PK and PD data and generate 
safety data to provide appropriate dosing recommendations in patients with RI. 
1.4. 
Rationale for the Dose Selection of Bulevirtide 
The 2 doses for this study were chosen based on the following factors: 1) the 2 mg in Group A is 
the conditionally approved dose in some regions such as the EU, administered as a SC QD dose 
for the treatment of CHD in adults with compensated liver disease and a dose that has resulted in 
efficac for the treatment of CHD in Phase 2 and 3 studies. 2 
1.5. 
Risk/Benefit Assessment for the Study 
In addition to the established risks associated with SC injection of BLV, potential risks of a 
paiiicipant's study involvement include unknown AEs, laborato1y abno1malities, and general 
risks associated with frequent clinic visits and laborato1y blood draws. Strategies to mitigate 
these risks include close monitoring of paiiicipants' clinical status, laborato1y values, and AEs. 
Pai·ameters for discontinuation of the study dmg due to AEs will be well defined and closely 
followed. 
Dose-dependent elevations of sennn bile salts has been ve1y commonly observed with BL V 
which are typically asymptomatic. It is possible that BA concentrations may be fmiher elevated 
in participants with RI. 
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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 CHD in adults with compensated liver disease.
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 11.3 for further details on the 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 (GCP), 
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(s)

To evaluate the steady-state plasma PK of 
BLV in non-HDV/HBV-infected participants 
with RI and in matched control participants 
with normal renal function

BLV steady-state plasma PK parameters 
AUCtau and Cmax ss 
Secondary Objective(s)
Secondary Endpoint(s)

To further characterize the plasma PK of 
BLV in participants with RI and in matched 
control participants with normal renal 
function

To evaluate the PD effect of BLV on plasma 
BA in participants with RI to matched 
control participants with normal renal 
function

To evaluate the safety and tolerability of 
BLV following multiple-dose administration 
in participants with RI and matched control 
participants with normal renal function

Plasma PK parameters for BLV, as 
applicable: AUC0-24, Cmax, Tmax, t1/2, CLss/F, 
and Vss/F

Total BA concentrations in plasma and 
exposure parameters for total BA, as 
applicable: Ctrough, Cmax, AUC0-24, Tmax

The incidences of AEs and laboratory 
abnormalities
ADA = antidrug antibodies; AE = adverse event; BA = bile acids; BLV = bulevirtide; HBV = hepatitis B virus; HDV = hepatitis 
D virus; PD = pharmacodynamic; PK = pharmacokinetic; RI = renal impairment
CCI
CCI

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3.
STUDY DESIGN
3.1.
Study Design
The study adheres to the guidelines for studies with renally impaired participants according to 
the recommendations given by the FDA {U.S. Department of Health and Human Services 
2020}.
This protocol describes a Phase 1, open-label, multiple-dose, parallel-group study to evaluate 
multiple-dose PK, PD, and safety of BLV in participants with severe RI and matched control 
participants with normal renal function. Additional groups of participants with mild and/or 
moderate RI (and with matched control participants) may be included pending evaluation of 
safety and PK results in severe RI participants.
Non-HDV/HBV-infected participants assigned male at birth and nonpregnant, nonlactating 
participants assigned female at birth, aged 18 through 79 years inclusive with a body mass index 
(BMI) from 18.0 kg/m² to 40.0 kg/m² will be enrolled in the study.
The matched control group will consist of matched participants with normal renal function. Each 
match participant (normal renal function ie, eGFR ≥ 90 mL/min/1.73 m²) will be matched for age 
(± 10 years), sex (assigned at birth), and BMI (± 20%, 18.0 ≤ BMI ≤ 40.0 kg/m²) with a 
participant in the RI group.
An overview of the study design is described below and shown in Figure 1-a. In accordance with 
the objectives, a reduced study design starting in participants with severe RI was selected. The 
study will begin with Group A. Following completion and evaluation of PK and safety data from 
all participants in Group A, additional optional groups (Groups B, C, and D) may be evaluated as 
per the criteria detailed in Section 3.1.1.1 and Figure 1-b.

Group A (BLV 2 mg severe RI): A total of up to 20 participants (10 participants with 
severe RI and 10 matched control participants) will be enrolled to obtain at least 16 evaluable 
participants (8 participants with severe RI and 8 matched control participants)

Optional Group B (BLV 10 mg severe RI): A total of up to 20 participants (10 participants 
with severe RI and 10 matched control participants) will be enrolled to obtain at least 
16 evaluable participants (8 participants with severe RI and 8 matched control participants)

Optional Group C (BLV 2 mg or 10 mg moderate RI): A total of up to 20 participants 
(10 participants with moderate RI and 10 matched control participants) will be enrolled to 
obtain at least 16 evaluable participants (8 participants with moderate RI and 8 matched 
control participants)

Optional Group D (BLV 2 mg or 10 mg mild RI): A total of up to 20 participants 
(10 participants with mild RI and 10 matched control participants) will be enrolled to obtain 
at least 16 evaluable participants (8 participants with mild RI and 8 matched control 
participants)

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Classification of renal function will be assessed using the eGFR based on the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation (expressed for serum creatinine, sex, 
and age) {Inker 2021} at screening (Refer to Section 4.1 for equation) as follows:

Group A (BLV 2 mg severe RI): Participants with severe RI (eGFR ≥15 to 
≤ 29 mL/min/1.73 m²) and normal renal function (eGFR ≥ 90 mL/min/1.73 m²) at screening. 
Participants with severe RI requiring or anticipated to require dialysis within 90 days of study 
entry will not be eligible.

Optional Group B (BLV 10 mg severe RI): Same target participant population as Group A.

Optional Group C (BLV 2 mg or 10 mg moderate RI): Participants with moderate RI 
(eGFR ≥ 30 to ≤ 59 mL/min/1.73 m²) and normal renal function (eGFR ≥ 90 mL/min/1.73 m²) 
at screening.

Optional Group D (BLV 2 mg or 10 mg mild RI): Participants with mild RI (eGFR ≥ 60 to 
≤ 89 mL/min/1.73 m²) and normal renal function (eGFR ≥ 90 mL/min/1.73 m²) at screening.
Study procedures will include safety, PK, and PD assessments for all participants. Clinical 
procedures in all groups will be identical to those described for Group A.
3.1.1.
Dose Selection
Participants will be administered BLV by SC injection by assigned study staff, QD for 6 days:

Group A: BLV 2 mg in participants with severe RI and matched control participants

Optional Group B: BLV 10 mg in participants with severe RI and matched control 
participants

Optional Group C: BLV 2 mg or 10 mg (dose to be determined) in participants with 
moderate RI and matched control participants

Optional Group D: BLV 2 mg or 10 mg (dose to be determined) in participants with mild 
RI and matched control participants
Additional optional groups (Groups B, C, and D) may be evaluated as per the safety and 
PK criteria for dose selection and renal population outlined in Figure 1-b and Section 3.1.1.1. 
Once the safety and PK data from all participants in Group A (2 mg severe RI) has been 
reviewed, Group B (10 mg severe RI) or Group C (2 or 10 mg moderate RI) may be opened. 
Once the data from all participants in Group B has been reviewed, Group C may be opened. 
Once the data from all participants in Group C has been reviewed, Group D (2 or 10 mg mild RI) 
may be opened.

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Within each group, once a participant with RI is enrolled, a matched control to that participant 
will be allowed to enroll. Dosing of matched participant with normal renal function may begin 
after the corresponding participant with RI 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 renal function may have their PK and BA data reused just once to serve 
as a matched control for an another group, if the BLV dose is the same and the matching criteria 
are met.
3.1.1.1.
Criteria for Proceeding to Optional Groups (Groups B, C, and D)
The decision to proceed to enrollment for optional groups will be based on review of safety and 
PK data from Day 1 through Day 8 from all participants enrolled in any previously conducted 
groups as detailed below. Available BA data will be reviewed from the safety perspective. Based 
on the PK properties of BLV, a significant increase in exposure in renal impaired participants is 
not expected. Thus, a reduced study design starting in participants with severe RI was selected. 
The study design also includes the option of two dose levels of 2 mg and 10 mg for 
characterization in this population.
The individual group will be discontinued if 2 or more participants in that group experience the 
same or similar SAE following administration of the study drug. The severity of 
treatment-emergent adverse events (TEAEs) will be graded using the Common Terminology 
Criteria for Adverse Events (CTCAE), Version 5.0. NOTE: conditions that exist before 
enrollment (eg, alanine aminotransferase [ALT] elevation before study drug administration) are 
not to be reported as TEAEs unless a notable deterioration occurs, or SAE occurs after BLV 
dosing. The investigator will assess all results of laboratory tests that deviate from normal ranges 
and decide whether or not these deviations qualify as AEs. Dose-dependent asymptomatic BA 
elevations were consistently observed across studies, as an expected consequence of the 
blockage of NTCP by BLV in accordance with its mechanism of action. Given this, 
asymptomatic elevation of BA with BLV dosing in this study should not be documented as AEs. 
Furthermore, the decision to conduct Group B will consider safety data including any AEs as 
reviewed at an internal safety review meeting held by the sponsor. The decision to conduct 
Group C and/or Group D and the selection of the dose in each group will consider safety data 
from all previously completed groups, including any AEs as reviewed at an internal safety 
review meeting held by the sponsor.
In addition to safety and tolerability assessment, PK criteria will be used to select the dose and 
population of the remainder of the study. The flowchart in Figure 1-b outlines the PK decision 
criteria for progression to subsequent study groups. The area under the concentration versus time 
curve (AUC) over the dosing interval (AUCtau) was selected to represent the exposure metric for 
decision making. In general, a nominal increase (ie, ≤ 2-fold) in PK exposure, as measured by 
the geometric mean ratio (GMR) of AUCtau in participants with RI compared to participants with 
normal renal function, would allow escalation of the dose to 10 mg QD in the severe RI 
population. Similarly a GMR of > 2 to ≤ 4 will also allow dose escalation to 10 mg for the 
subsequent study groups. In contrast, while not anticipated, a large increase in PK exposure 
(ie, GMR > 4) in participants with RI would trigger further investigation in additional groups of 

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participants with moderate (Group C) and/or mild (Group D) impaired renal function. This 
follows the FDA RI guidance - Pharmacokinetics in Patients with Impaired Renal 
Function-Study Design, Data Analysis, and Impact on Dosing and Labeling {U.S. Department of 
Health and Human Services 2020}.
3.1.1.2.
Safety Review Team and Charter
A safety review team (SRT) will review all PK and safety data from completed Group A before 
opening Group B or Group C; and from completed Group B before opening Group C; and from 
completed Group C before opening Group D (refer to PK criteria in Figure 1-b).
A SRT charter defining the team membership, meeting conduct, and decision making process 
will be agreed upon by all team members before the first SRT meeting. The data reviewed at the 
team meetings to make decisions to allow proceeding to subsequent optional groups 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 SRT meetings. Alternative data quality 
control checks that are performed on data used to make dose escalation decisions will be 
described in the SRT and/or dose escalation team charter (or similar document).
3.2.
Duration of Dosing
The study will be conducted in 5 parts for each group: screening, admission, evaluation, 
discharge, and follow-up. Study participation for each group will be approximately 16 days, 
excluding the screening period, and dosing with BLV will occur QD for 6 days from 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:

Adverse event that would, in the judgment of the investigator, affect assessments of clinical 
status to a significant degree

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

Any treatment-emergent study drug-related Grade 3 or higher AE

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
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) (Refer to Section 7.7 for toxicity management)
Note: As per the mechanism of action of BLV, asymptomatic elevation of BA with BLV 
dosing in this study will not be documented as AEs.

Participant request to discontinue for any reason

Participant noncompliance

Pregnancy during the study (refer to Appendix 11.4)

Lost to follow-up

Discontinuation of the study at the request of Gilead, regulatory agency, or an 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

Lost to follow-up

Discontinuation of the study at the request of Gilead or an IRB/IEC

Withdrawal of consent

Death
CCI

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3.3.3. 
Criteria for Early Discontinuation of the Study 
The study will be discontinued in the following instances: 
• 
The number and/or severity of AEs justifies discontinuation of the study 
• 
Discontinuation of the study at the request of Gilead or an IRB/IEC 
3.3.4. 
Loss to Follow-Up 
Final 
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Should the paiiicipant fail to return to the study site for a scheduled protocol-specified visit 
(eg, repeat laborato1y assessments if the paiiicipant was discontinued eai·ly) or the participant 
fails to respond to the safety follow-up telephone call (7 days [ ± 2 days] following last 
administration of study diug), the site will need to make at least 3 attempts by telephone or email 
to contact the paiiicipant. After the third unsuccessful contact attempt, the site will send a letter 
to the paiiicipant via registered courier/mail and the pa1iicipant must sign for the letter. The site 
must document all attempts to contact the paiiicipant. If a paiiicipant does not respond within 
10 days after the letter is received, the paiiicipant will be considered lost to follow-up and no 
additional contact will be required. 
3.3.5. 
Early Termination 
Early tennination (ET) assessments will be perfo1med within 24 hours of prematurely 
discontinuing the study, if possible as outlined in Table 1 and in Section 6.6.1. 
3.4. 
Clinic Confinement 
Following the completion of screening procedures and study emolhnent at adinission, eligible 
paiiicipants will remain in the clinic for a period of 9 days, beginning on Day - 1 until the 
completion of assessments on Day 8. Safety laborato1y tests will be collected upon study site 
adinission (Day -1); will be evaluated at the site's local laborato1y to obtain results for 
paiiicipant's eligibility prior to dosing on Day 1. Baseline safety laborato1y assessments will be 
perfo1med on Day 1 and then paiiicipants will be adininistered daily injections of BL V and will 
undergo blood sampling for plasma PK and plasma BA PD assessments from Day 1 through 
Day 6. Additional sampling will be perfonned on Day 7 and Day 8 and pai·ticipants will be 
discharged on Day 8. A follow-up telephone call to collect safety data will be made at 
7 days (± 2 days) following last adininistration of study di11g. 
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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
For each group, up to approximately 20 non-HDV/HBV-infected male and 
nonpregnant/nonlactating female participants (10 participants with RI and a maximum of 
10 matched control participants with normal renal function), aged 18 through 79 years inclusive, 
will be enrolled. Each participant with RI will have a matched control participant with a goal of 
obtaining approximately 16 evaluable participants (8 renal impaired and 8 matched controls) in 
each group.
The study will begin with the enrollment of Group A (10 severe renal impaired and 10 matched 
control participants). Following completion and evaluation of PK and safety data from Group A, 
additional optional groups (Groups B, C, and D) may or may not be initiated.
At screening, participants will have their eGFR measured and classified based on the CKD-EPI 
equation for renal function (expressed for serum creatinine, sex, and age) {Inker 2021}.
The CKD-EPI Creatinine equation (2021) is:
eGFR = 142 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.200 × 0.9938Age × 1.012 [if female]
where:
eGFR (estimated glomerular filtration rate) expressed in mL/min/1.73 m²
Scr (standardized serum creatinine) in mg/dL
κ is 0.7 for females and 0.9 for males
α is -0.241 for females and -0.302 for males
min indicates the minimum of Scr/κ or 1.0
max indicates the maximum of Scr/κ or 1.0
age is expressed in years
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.

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2) Be aged 18 through 79 years, inclusive, at screening.
3) Have a calculated BMI of at least 18.0 kg/m² and no greater than 40.0 kg/m² at screening.
4) 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 method(s) of contraception as described in Appendix 11.4.
5) 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.
6) 12-lead electrocardiogram (ECG) evaluations at screening and admission must be without 
clinically significant abnormalities as assessed by the investigator.
7) Have no known liver disease with hepatic transaminases (aspartate aminotransferase [AST] 
and ALT) ≤ 3  upper limit of normal (ULN) at screening.
8) Must be willing and able to comply with all study requirements.
Participants with RI:
Participants with RI must also meet the following additional inclusion criteria to be eligible for 
participation in this study:
9) Have RI classification at screening that has been unchanged (based on medical history, 
physical examination and clinical laboratory results with no clinically significant change) 
during the 90 days prior to study drug dosing, as determined by the investigator.
10) eGFR must be the following (using the CKD-EPI equation {Inker 2021}) based on serum 
creatinine as measured at the screening evaluation:
a) Severe RI (Groups A and B): eGFR ≥ 15 to ≤ 29 mL/min/1.73 m²
b) Moderate RI (Group C): eGFR ≥ 30 to ≤ 59 mL/min/1.73 m²
c) Mild RI (Group D): eGFR ≥ 60 to ≤ 89 mL/min/1.73 m²
11) Hemoglobin ≥ 9 g/dL at screening.
12) Participants with diseases/conditions associated with RI (eg, cardiovascular disease, 
hypertension, diabetes mellitus, hyperlipidemia, etc) and participants with other concomitant 
diseases not related to RI (eg, hypothyroidism, osteoporosis and many others) may be 
included provided that these diseases/conditions are clinically stable (as judged by the 
investigator, and in consultation with the medical monitor) and without impact on the study 
outcome.

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13) For participants with RI 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.
Matched Control Participants:
In addition to the criteria listed for all participants, matched control participants must also meet 
the following additional inclusion criteria to be eligible for participation in this study:
14) Have an eGFR of at least 90 mL/min/1.73 m² (using the CKD-EPI equation) based on serum 
creatinine as measured at screening evaluation.
15) Matched for sex, age (± 10 years), and BMI (± 20%, 18.0 ≤ BMI ≤ 40.0 kg/m²) with the 
respective participant in the RI group.
16) Must, in the opinion of the investigator, be in good health based upon medical history, 
physical examination, vital signs, and screening laboratory evaluations.
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 upon admission in participants assigned 
female at birth. (Appendix 11.4).
2) Lactating/breastfeeding participant.
3) Participants assigned female at birth and of childbearing potential who plan egg donation and 
in vitro fertilization during study drug dosing and until end of contraception requirement.
4) Have received any study drug within 30 days (or 5 half-lives whichever is longer) prior to 
study dosing.
5) 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.
6) Have a positive test result for the fourth generation HIV antibody/antigen test, HBsAg, or 
hepatitis C virus (HCV) antibody with detectable HCV viral RNA at screening.
Note: Any previous treatment for a HCV infection must have been completed at least 
12 weeks before screening.
7) Have poor venous access that limits phlebotomy.

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8) 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).
9) Have previous diagnosis of malignancy with the exception of basal cell carcinoma or 
squamous cell carcinoma localized to the skin.
10) Acute illness within 14 days prior to study drug administration unless mild in severity and 
approved by the investigator and sponsor’s medical representative.
11) 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 or 
nephrotoxicity).
c) Known hypersensitivity to the study drugs, their metabolites, or to formulation excipients 
(see Section 5.2).
d) Significant cardiac disease in the past 2 years (including history of myocardial infarction 
based on ECG and/or clinical history, any history of ventricular tachycardia, congestive 
heart failure [New York Heart Association Class III or IV], or dilated cardiomyopathy 
with left ventricular ejection fraction ≤ 40%); or a family history of long QT syndrome, 
or unexplained death in the family, in an otherwise healthy individual between the ages 
of 1 and 30 years that in the clinical judgment of the investigator, may not be an 
appropriate candidate to participate in the study.
e) Syncope, palpitations, or unexplained dizziness.
f)
Implanted defibrillator or pacemaker.
g) Liver disease, including Gilbert syndrome.
12) 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 uncontrolled or unstable cardiovascular, 
hematologic, hepatic, pulmonary, endocrine, gastrointestinal, metabolic, neurological 
disease, or active infection.
13) Are unable to comply with study requirements or are otherwise believed, by the study 
investigator, to be inappropriate for study participation for any reason.
14) Requirement for ongoing therapy with or prior use of any prohibited medications listed in 
Section 5.6.

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Participants with RI:
15) Recent history of reception of any blood or blood products or history of major bleeding 
within 4 weeks of dosing.
16) Positive test for drugs of abuse, including alcohol at screening or admission, with the 
exception of opioids and tetrahydrocannabinol (THC, 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.
17) Received treatment with trimethoprim or cimetidine or tenofovir prodrugs (TDF or tenofovir 
alafenamide or [TAF]) (affects elimination of creatinine) or with competitors of renal tubular 
excretion (eg, probenecid, chronic high-dose nonsteroidal anti-inflammatory drugs) within 
28 days of Day –1.
18) Received known nephrotoxic drugs (eg, aminoglycosides, amphotericin B, vancomycin, 
cidofovir, foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus, herbal remedies 
[eg, compounds with aristolochic acid]) within 28 days of Day –1.
19) Participants requiring or anticipated to require dialysis within 90 days of study entry.
20) Anticipated changes in concomitant medications or dosage used to treat symptoms of RI or 
associated comorbid conditions that could lead to clinically significant changes in medical 
conditions during the course of the study.
21) Acute renal failure (as judged by the investigator).
22) History of transplant (eg, kidney, liver) regardless of functionality.
23) History of nephrectomy.
24) Serum albumin concentration <25 g/L.
25) Uncontrolled treated/untreated hypertension (defined as a mean of 3 repeated measurements 
for systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg); current 
or documented history of repeated clinically significant hypotension or severe episodes of 
orthostatic hypotension (systolic blood pressure <90 mmHg and/or diastolic blood pressure 
<50 mmHg).
Matched Control Participants:
26) 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 and Blinding
5.1.1.
Enrollment
It is the responsibility of the investigator to ensure that the participant is eligible for the study 
prior to enrollment.
The study will begin with Group A (severe RI and with matched control participants). Additional 
groups of participants with severe, moderate and/or mild RI (and with matched control 
participants) may be included pending evaluation of PK and safety results in participants with 
severe RI (Group A).
At screening, study participants will be assigned a screening number at the time of consent. The 
renal function of all participants will be assessed, and the participants will be allocated into the 
respective renal function group.
Once eligibility has been confirmed following completion of the admission procedures on Day –
 1, eligible participants will be enrolled and assigned a participant number.
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. 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 
by the sponsor. A new unique participant number will be assigned to the replacement participant.
5.1.2.
Blinding
Blinding to treatment assignments or data will not be performed in this study.
Study drug will be dispensed by the study pharmacist, or designee, in an open-label fashion to 
participants.
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.

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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.
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(s) to be distributed to study 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 (GMP) requirements.
5.2.3.
Storage and Handling
Bulevirtide for injection, 2 and 10 mg, will be provided by Gilead. Bulevirtide for injection vials 
(2 mg and 10 mg) should be stored in a refrigerator between 2°C to 8°C (36°F to 46°F) prior to 
use. Bulevirtide for injection vials (2 mg and 10 mg) should be kept 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(s) 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.

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5.3.
Dosage and Administration
The study will begin with the dosing of Group A and proceed to optional groups (Groups B, C, 
or D) if applicable. For each group, following completion of screening and admission 
assessments, eligible participants will be administered BLV by SC injection QD for 6 days 
starting on Day 1 by assigned study staff, 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 (± 30 minutes) each morning on Days 1 to 6 following an overnight fast (no food or 
drinks, except water) for at least 8 hours prior to dosing.
Refer to Pharmacy manual for BLV injection and administration instructions.
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 immediately before 
dosing. The total storage time of reconstituted solution containing BLV for injection should not 
exceed 2 hours at room temperature.
5.3.1.
Administration Site Reactions
Bulevirtide is intended for SC injection, and has been associated with the risk for injection site 
reactions such as swelling, redness, irritation, itchiness, infection, hematoma and local pain. Any 
instances of injection site reactions are to be reported as AEs and graded using the CTCAE 
toxicity grading scale, Version 5.0.
5.4.
Fasting and Meals
Each dose will be administered via SC injection at approximately the same time (± 30 minutes) 
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.
The extent of food consumption during in-clinic days will be monitored.
On the days of intensive PK and BA PD sampling, and urine collection (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 after dosing on Days 2 to 5 and after collection of 
trough PK and BA samples on Day 7 and Day 8. Water may be consumed ad libitum, however 
participants with RI should observe the restriction on fluid consumption related to their 
underlying disease.

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Participants with RI having 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 bile acids 
collection will be standardized and the timing and consumption of meals will be monitored.
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 RI 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 drug should be destroyed at the site. If the site has an 
appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead, 
the site may destroy used (empty or partially empty) study drug supplies in accordance with that 
site’s approved SOP. A copy of the site’s approved SOP will be obtained for the electronic Trial 
Master File (eTMF). If study drug is destroyed onsite, the investigator must maintain accurate 
records for all study drugs destroyed. Records must show the identification and quantity of each 
unit destroyed, the method of destruction, and the person who disposed of the study drug. Upon 
study completion, copies of the study drug accountability records must be filed at the site. 
Another copy will be returned to Gilead.
If the site does not have an appropriate SOP for drug destruction, used study drug supplies 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 onsite 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 RI:
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. Concomitant 
medications taken within 30 days of screening through the follow-up visits must be recorded in 
the source documents and case report form (CRF)/electronic case report forms (eCRFs).
All prior medication(s) with long-lasting biologic effect even after discontinuation, such as 
systemic corticosteroid, immunosuppressant therapies, or chemotherapeutic agents must be 
reviewed by the medical monitor to determine the participant’s eligibility.
Participants with RI 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 RI:

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 [THC, 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)
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

Use of any of the following medications:
Drugs that affect elimination of creatinine (trimethoprim, cimetidine, tenofovir prodrugs 
[TDF or TAF])
Competitors of renal tubular excretion (probenecid, chronic high-dose nonsteroidal 
anti-inflammatory drugs)
Known nephrotoxic drugs (eg, aminoglycosides, amphotericin B, vancomycin, cidofovir, 
foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus, herbal remedies 
[eg, compounds with aristolochic acid]).

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.
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.
Matched Control Participants:
The following medications are excluded from screening until discharge for participants with 
normal renal function:

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
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.
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 course of the study 
through the follow-up visit.

Participants will be required to refrain from the use of nicotine or nicotine-containing 
products while confined in the clinic to ≤ 5 cigarettes per day, or its nicotine equivalent.

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 required to refrain from consumption of grapefruit juice, grapefruits, and 
Seville orange and juice from 72 hours prior to the first dose of study drug and during the 
course of the study through the end of study drug administration period.

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.

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
There are no substantial safety data regarding the concomitant administration of the 
coronavirus disease 2019 (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.
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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6.
STUDY ASSESSMENTS
The study procedures to be conducted for each participant enrolled in the study are detailed in 
Table 1.
Any deviation from protocol procedures should be noted in the participant’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 regulatory agencies have reviewed and approved the study and 
the informed consent document.

All requested regulatory 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 Gilead (or designee).
The initiation meeting will include but is not limited to a review of the protocol, the IB, study 
drug(s), 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 informed consent must be obtained from each participant before initiation of any 
screening procedure. After a participant has provided informed consent, the investigator and 
other study personnel will determine if the participant is eligible for participation in the study 
(Section 6.3.2).
CCI

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6.2.
Participant Enrollment and Treatment Assignment
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
study enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or study-wide at any time.
It is the responsibility of the investigator to ensure that participants are eligible to participate 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 confirmed, participants will be enrolled to receive study 
drug on Day 1.
Participants will be administered the study treatments as described in Section 5.3.
6.3.
Instructions for Study Procedures
6.3.1.
Adverse Events
From the time informed consent is obtained through the first administration of study drug, all 
SAEs, as well as any AEs related to protocol-required procedures will be recorded on the AE 
eCRF. All other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history, are to be considered medical history.
After study drug administration, all AEs and SAEs will be reported. Evaluation of AEs will 
occur at the visits shown in Table 1. See Section 7 for additional details.
6.3.2.
Screening Assessments
Prospective participants should be screened no more than 28 days prior to administration of the 
first dose of study drug. If a participant does not begin the treatment phase within this 28-day 
window, all screening evaluation procedures must be repeated. Screening laboratory assessments 
may be repeated once within 28 days prior to administration of study drug for exclusionary 
laboratory values if, in the investigator’s opinion, one of the following are 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 participant’s previous result(s), if the initial value was 
generated in error (eg, mishandled sample), or there is another relevant extenuating 
circumstance. In any instance, the site should obtain approval from Gilead prior to repeating the 
laboratory assessment.
A sufficient number of participants will be screened to identify planned number of participants 
for enrollment.
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.

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Written informed consent must be obtained from each participant before initiation of any 
screening procedure. After a participant has provided informed consent, the investigator and 
other study personnel will determine if the participant is eligible for participation in the study. 
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 (PCR) test at Day –1 admission. 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.
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.
The study will be initiated with dosing of participants in Group A. Following completion of all 
participants and evaluation of all safety and PK data from Group A, an internal safety review 
meeting will be held by the sponsor to determine if the study should proceed to any optional 
groups (Groups B, C, and D).
6.3.4.
Treatment Assessments
Study procedures and assessments are outlined in Table 1.
6.3.5.
Pharmacokinetic and Pharmacodynamic Assessments
6.3.5.1.
Plasma Sample Collection for Pharmacokinetics and Pharmacodynamics
Intensive plasma PK and total plasma BA sampling for PD will occur relative to the dosing of 
BLV at the following time points:

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Day 1 at predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 hours postdose, and at 
the ET visit, as applicable.
Day 6 at predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 hours postdose, and at 
the ET visit, as applicable.
A trough (predose) PK and PD biomarker BA sample (≤ 30 minutes before dose) will be 
collected 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).
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 every effort to ensure that sampling time is as close as possible to 
nominal time. The exact time and date of the blood draw must be recorded. For all plasma BA 
and plasma PK samples, a primary and backup sample will be collected and the backup sample 
will be stored for potential further analysis or reanalysis.
Plasma concentrations of BLV and plasma concentrations of total BA will be determined, and 
BLV PK and bile acids PD parameters will be estimated.
Plasma Protein Binding Evaluation: On Day 1, additional blood samples will be collected 
predose (≤ 30 minutes prior to BLV 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 determined. 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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Immunogenicity sampling will occur on Days 1 and 6 at predose (~ 30 minutes before dose). 
Plasma will be evaluated for the presence of ADA to BLV. ADA may be further characterized 
for neutralizing activity. 
6.4. 
Safety Assessments 
Safety assessments will include physical examination ( complete or symptom-driven), vital signs, 
height, weight, clinical laborato1y tests, urine drng and alcohol assessments, 12-lead ECG, 
pregnancy testing, fomth generation HIV antibody/antigen test, HBsAb, HBsAg, HCV antibody, 
and HCV RNA testing, and assessment of AEs. 
All safety assessments will be completed predose unless othe1wise specified. The Day 1 safety 
labs will be used for baseline values. Safety will be evaluated throughout the study. Refer to 
Table 1 for a schedule of assessments. 
6.4.1. 
Electrocardiogram Assessment 
Paiticipants 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 paiticipants 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 interpretation. 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 inve1ied. 
The investigator or other qualified individuals at the study site will review ECGs to assess for 
changes in ECG intervals and morphology as compai·ed with pretreatment ECGs. 
Collection of additional ECGs for routine safety monitoring at additional time points or days is at 
the discretion of the investigator based on GCP. 
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6.4.2.
Physical Examination
Physical examinations conducted throughout the study will be a complete physical examination 
or a symptom-driven physical examination, as outlined in Table 1. The complete physical 
examination conducted at screening will also include the following assessments:

Review medical history, including history of allergies, prior and current use of nicotine or 
nicotine-containing products, alcohol and illegal drug use, and prior (within 30 days) and 
current medication use.
6.4.3.
Vital Signs
Vital sign measurements include resting blood pressure, heart rate, and body temperature and 
should be taken once participants are 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.
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.

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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
Triglycerides
Total cholesterol
High density 
lipoprotein
Low density 
lipoprotein
Creatine kinase
Serum creatinine
eGFRa
Lactic acid 
dehydrogenase
BUN
Total bilirubin
Direct bilirubin
Indirect bilirubin
GGT
Glucose
Lipaseb
Calcium
Inorganic phosphate
Bicarbonate
Sodium
Potassium
Chloride
Uric acid (serum)
Total BA
RBC (count 
and 
morphology)
Hemoglobin
Hematocrit
MCH
MCHC
MCV
RDW
Platelets
WBC total
WBC 
differential
ANC
Eosinophils
Basophils
Lymphocytes
Monocytes
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
Urine drug and 
alcohol testing
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BA = bile acids; 
BLV = bulevirtide; BUN = blood urea nitrogen; CK = creatine kinase; CKD-EPI = Chronic Kidney Disease Epidemiology 
Collaboration; eGFR = estimated glomerular filtration rate; FSH = follicular stimulating hormone; GGT = gamma glutamyl 
transferase; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCV = hepatitis C virus; INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RDW = red blood cell distribution width; 
RNA = ribonucleic acid; ULN = upper limit of normal; WBC = white blood cell
Refer to Table 1 for collection time points.
a
eGFR will be calculated using the CKD-EPI equation (expressed for serum creatinine, sex. and age)
b
Reflex lipase testing will be performed in participants with total amylase greater than 1.5 × ULN

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6.4.5.1.
Blood Samples
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 with 
differential (absolute and percentage), including reticulocytes, lymphocytes, monocytes, 
absolute neutrophil count, neutrophils, eosinophils, and basophils

Coagulation panel: prothrombin time, partial thromboplastin time, and international 
normalized ratio

Chemistry (fasting): alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total BA (for safety assessments; total BA for PD assessments will be drawn 
separately), gamma glutamyl transferase (GGT), total protein, albumin, triglycerides, total 
cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), lactic acid 
dehydrogenase, CK, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine (see 
below Section 6.4.6 for eGFR), glucose, inorganic phosphate, potassium, sodium, uric acid, 
and amylase (reflex lipase testing is performed in participants with total amylase greater than 
1.5 × ULN)

Serum pregnancy test (females of childbearing potential only) at screening and admission 
Day –1

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, HBsAb, HBsAg, HCV antibody, and 
HCV RNA testing (screening only)
Upon study site admission (Day –1), safety laboratory tests will be collected and will be sent to 
the site’s local laboratory to obtain results in time for enrollment on Day 1. Eligibility will be 
determined based on local laboratory results. The Day 1 safety labs will be used for baseline 
values.
6.4.5.2.
Urine Samples
Urine samples will be collected for urinalysis and alcohol and drug screen assessments which 
include: amphetamines/3,4-methylenedioxymethamphetamine (MDMA), tricyclic 
antidepressants, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, methadone, and 
phencyclidine.

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
 If study site cannot perform urine alcohol or obtain results from the local laboratory in time 
for enrollment on Day 1, then an alcohol breathalyzer test is acceptable.

Point of care pregnancy test may be used at site if serum pregnancy test result is not available 
prior to dosing.
6.4.6.
Estimated Glomerular Filtration Rate
Serum creatinine will be collected at screening to calculate eGFR for inclusion criteria. The 
eGFR will be calculated using the CKD-EPI creatinine equation (expressed for sex and age) for 
allocation to the RI group based on serum creatinine as measured at screening (refer to 
Section 4.1 for CKD-EPI creatinine equation).
In addition, eGFR values will be estimated at admission (Day –1), predose Day 1 to 6, Day 7, 
and at discharge (Day 8), and at ET visit if applicable.
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 for more information about concomitant medications.
6.5.
Posttreatment Assessments
Participants will be discharged from the clinic on Day 8, following all morning assessments as 
outlined in Table 1.
All participants will be contacted for evaluation of AEs, by follow-up telephone call at 
Day 13 (± 2 days) ie, 7 days (± 2 days) following last administration of study drug.
6.6.
Assessments for Early Discontinuation from Study Intervention and from the 
Study
6.6.1.
Assessments for Early Discontinuation from Study Intervention
If a participant discontinues study treatment dosing (see Section 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.
If the participant withdraws consent from the study, the ET evaluations and/or procedures 
outlined in Table 1 should be performed within 24 hours of permanently discontinuing the study 
if possible.
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.

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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 at end 
of study will be conducted by telephone on Day 13 ± 2 days.
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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 in which an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, or 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
A 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 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 or 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 labeling (as it applies to the daily dose of the participant in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the participant has taken the excess dose(s). Overdose cannot be established 
when the participant cannot account for the discrepancy, except in cases in which the 
investigator has reason to suspect that the participant has taken the additional dose(s).
Occupational exposure is defined as exposure to a study drug as a result of one’s professional or 
nonprofessional occupation.
Drug interaction is defined as any drug-drug, drug-food, or drug-alcohol 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 Drug 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, SC injection 
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, Version 5.0. For each episode, the highest 
grade attained should be reported as defined in the Toxicity Grading Scale (Appendix 11.5).

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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, all AEs will be collected, regardless of cause or 
relationship, throughout the duration of the study until the end of study including the 
protocol-defined posttreatment follow-up period and will be reported on the eCRFs as instructed.
All AEs and clinically significant laboratory abnormalities will 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 Gilead PS.
Instructions for reporting SAEs are described in Section 7.4.1.
7.3.4.
Study Drug Special Situations Reports
All study drug SSRs that occur from study drug initiation and throughout the duration of the 
study, including the posttreatment follow-up visit, must be reported to Gilead’s PS 
(Section 7.4.2).
Adverse events and SAEs resulting from SSRs must be reported in accordance with the AE and 
SAE reporting guidance (Section 7.3).

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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 Gilead’s PS utilizing the paper SSR (Section 7.4.2.2).
7.3.5.2.
Non-Gilead Concomitant Therapy Report
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the SSR form; however, for special situations that result in AEs due to a non-Gilead concomitant 
medication, the AE should be reported on the AE form.
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
All clinical sequelae in relation to these SSRs will be reported as AEs or SAEs at the same time 
using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available.
7.4.
Reporting Process for Serious Adverse Events and Special 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 eCRF.
7.4.1.1.
Paper Serious Adverse Event Reporting Process
All SAEs will be recorded on the SAE report 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 ICF signature throughout the duration of the study, including the 
protocol-required follow-up period. Additionally, the SAE must be captured on the applicable 
eCRF.

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Gilead PS
Email: Safety_FC@gilead.com
or
Fax: +1-650-522-5477
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 special situations report 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 and transmitted 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 because of a non-Gilead 
concomitant medication, must be reported as an AE.
7.4.2.3.
Pregnancy Reporting Process
The investigator should report pregnancies in female study participants who are identified after 
initiation of study drug and throughout the study, including the protocol required follow-up 
period to Gilead PS using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy. Contact details for transmitting the pregnancy report form are as follows:

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Gilead PS
Email: Safety_FC@gilead.com
or
Fax: +1-650-522-5477
The pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
All other premature terminations of pregnancy (eg, a spontaneous abortion, an induced 
therapeutic abortion due to complications or other medical reasons) must be reported within 
24 hours as an SAE, as described in Section 7.4.1. The underlying medical reason for this 
procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.4.1. Furthermore, any SAE occurring as an adverse pregnancy outcome 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 11.4 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 Code of 
Federal Regulations, 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 IRB or IEC in concerned member states of applicable 
SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using RSI 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, the syndrome or diagnosis (eg, anemia) will be recorded and not the 
laboratory result (ie, decreased hemoglobin).
Note: In accordance with the mechanism of action of BLV, asymptomatic elevation of BA with 
BLV dosing in this study will not be documented as laboratory toxicities.
Severity should be recorded and graded according to the CTCAE, toxicity grading scale, 
Version 5.0 (Section 7.2.2 and Appendix 11.5). 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 toxicities 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 and 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, interim analyses may be conducted and the analyses may be submitted 
to regulatory agencies to seek guidance for the overall clinical development program.
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 analysis 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 Analysis Set
The All Enrolled Analysis Set includes all participants enrolled into the study after screening. 
This is the primary analysis set for safety listings.
8.3.1.2.
Safety Set
The Safety Analysis Set will include all enrolled participants who received at least 1 dose of 
study drug BLV.
8.3.1.3.
Pharmacokinetics Set
The plasma PK Analysis Set will include all enrolled participants who received at least 1 dose of 
BLV and had at least 1 measurable plasma PK concentration data reported by PK laboratory for 
the respective analyte. The urine PK Analysis Set will include all enrolled participants who 
received at least 1 dose of BLV and had at least 1 measurable urine PK concentration data 
reported by PK laboratory for BLV.

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8.3.1.4.
Pharmacodynamics Set
The plasma PD Biomarker Analysis Set will include all enrolled participants who received at 
least 1 dose of study drug BLV and had at least 1 measurable plasma PD concentration value 
reported for each respective analyte. The urine PD Analysis Set will include all enrolled 
participants who received at least 1 dose of study drug BLV and had at least 1 measurable urine 
PD concentration value reported for BA.
8.3.1.5.
Immunogenicity Set
The Immunogenicity Analysis Set will include all enrolled participants who received at least 
1 dose of BLV, had at least 1 blood sample collected for immunogenicity evaluation before any 
BLV administration and had at least 1 blood sample collected after administration of BLV.
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 
(LLOQ) or above the upper limit of quantitation will be imputed to the value of the lower or 
upper limit minus or plus 1 significant digit, respectively (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. Baseline data will 
include a summary of height, weight, BMI, and eGFR by the CKD-EPI equation.
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 (± 2 days) will be summarized by renal function group and 
dose level (according to the study drug dose received) 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.

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8.5.2.
Adverse Events
Clinical and laboratory AEs will be coded using the current version of the Medical Dictionary 
for Regulatory Activities (MedDRA). System organ class (SOC), high-level group term, 
high-level term, preferred term (PT), and lower-level term will be attached to the clinical 
database.
Adverse event data will be listed by participant. Treatment-emergent AEs (TEAEs), serious 
TEAEs, and TEAEs leading to permanent study drug discontinuation will be summarized by 
renal function group, dose, and SOC and PT 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 renal function 
group and dose at scheduled visits. The incidence of treatment-emergent graded laboratory 
abnormalities will be summarized by renal function group and dose.
8.5.4.
Other Safety Evaluations
Vital signs and ECG data will be summarized by renal function group and dose.
8.6.
Pharmacokinetic and Pharmacodynamic Analysis
The following plasma PK parameters will be calculated for BLV, as applicable: AUCtau, Cmax ss, 
AUC0-24, Cmax, Tmax, t1/2, CLss/F, and Vss/F.
The following PD parameters in plasma for total BA will be calculated, as applicable: Ctrough, 
Cmax, AUC0-24, and Tmax. In addition, concentrations of individual BA may be measured and 
exposure parameters may be summarized.
Plasma concentrations and PK parameters of BLV, and plasma concentrations and PD 
parameters of total BA, will be listed and summarized by renal function group and dose level 
using descriptive statistics.
In addition, a one-way analysis of variance (ANOVA) model appropriate for a parallel-design 
with renal function group as a fixed effect will be fit to the natural logarithmic transformation of 
plasma 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 RI group versus 
the matched control (normal renal function) group.
The same analysis will be conducted for plasma PD parameters of total BA, as applicable.
The PK-PD relationship using plasma BLV PK concentrations/parameters and plasma BA 
concentrations/parameters may be explored using a graphical approach and correlation 
coefficients as appropriate. Additional PK and PD parameters may be estimated as necessary.

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8.7.
Immunogenicity Analysis
Plasma will be evaluated for the presence of ADA to BLV as applicable. ADA may be further 
characterized for neutralizing activity.
8.8.
Sample Size
For study Group A, with 16 (8 RI and 8 matched control [normal renal function]) evaluable 
participants, the estimated upper limit of the one-sided 95% CIs of the GLSM ratio of RI group 
versus matched control group with regards to AUCtau and Cmax 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 (CV%) of no more than 51%, which is supported by previously conducted Study 
MYR102. Accounting for a 20% dropout rate, a total sample size of 20 participants (10 RI and 
10 matched control each) will be required.
Furthermore, given the lower degree of variability in BA concentrations compared to BLV, 
plasma concentrations observed in Study MYR102 {Blank 2018}, this sample size will also 
provide ≥ 80% probability that the estimated upper limit of the one-sided 95% CIs of the GLSM 
ratio of RI group versus matched control group with regards to AUCtau and Cmax of total plasma 
BA would be less than 200% if the expected GLSM ratio is 1.0. If additional optional groups 
(Groups B, C, and D) are conducted, a total of up to 20 participants (10 RI and 10 matched 
controls with normal renal function) will be enrolled in each conducted study group in order to 
adequately power each subgroup.
CCI

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9. 
9.1. 
9.1.1. 
RESPONSIBILITIES 
Investigator Responsibilities 
Good Clinical Practice 
Final 
Amendment 1 
The investigator will ensure that this study is conducted in accordance with 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 anangements with the sponsor or proprietaiy interests in the study diug. This 
documentation must be provided prior to the investigator's (and any subinvestigator's) 
paiiicipation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in repo1iable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last paiiicipant 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 pa1iicipant (such as 
advertisements, paiiicipant infonnation sheets, or descriptions of the study used to obtain 
info1med consent) to an IRB/IEC. The investigator will not begin any study participant activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator. 
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC for any modifications made to the protocol or any accompanying material to be 
provided to the paiiicipant after initial IRB/IEC approval, with the exception of those necessa1y 
to reduce immediate risk to study pa1iicipants. 
9.1.4. 
Informed Consent 
The investigator is responsible for obtaining written infonned consent from each individual 
paiiicipating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazai·ds of the study before unde1iaking any study-related procedures. The investigator 
must use the most cunent !RB-approved ICF for documenting written infonned consent. Each 
ICF will be appropriately signed and dated by the paiiicipant, the person conducting the consent 
discussion, and also by an impaiiial witness if required by the IRB/IEC or local requirements. 
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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/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. 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, eCRFs, 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, eCRFs, IRB/IEC, and 
governmental approval with correspondence, ICF, drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each participant:

Participant identification (name, date of birth, gender)
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
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.
9.1.7.
Case Report Forms
An eCRF casebook will be completed by an authorized study p rsonnel member whose training 
for this function is completed in the electronic data capture (EDC) system unless otherwise 
directed. The eCRF casebook will only capture the data required per the protocol schedule of 
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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 (clinical research associate) may perform source data verification (SDV). 
System-generated or manual queries will be issued in the EDC system as data discrepancies are 
identified by the study monitor or Gilead personnel who routinely review the data for 
completeness, correctness, and consistency. The site investigator, site coordinator, or other 
designee is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (eg, data entry error). Original entries as well as any changes to data fields will be 
stored in the audit trail of the system. Regular oversight by the 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 after database lock, ICON will provide the site with a 
read-only archive copy of the data entered by that site. 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 IRB/IEC, 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 the 
IRB/IEC in accordance with local requirements and receive documented IRB/IEC approval 
before modifications may be implemented.
9.2.2.
Study Reports and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies) when 
applicable and in accordance with local regulatory requirements. Gilead will ensure that the 
report meets the standards set out in the ICH Guideline for Structure and Content of Clinical 
Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain cases. For 

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studies with sites in countries following the EU Regulation No. 536/2014, a CSR will be 
submitted within 1 year (6 months for pediatric studies, in accordance with Regulation [EC] 
No. 1901/2006) after the global end of study (as defined in Section 3.5.2).
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 eCRFs. The study monitor is responsible 
for routine review of the 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, onsite) 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/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
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Wranke A, Serrano BC, Heidrich B, Kirschner J, Bremer B, Lehmann P, et al. Antiviral 
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2012;1:e00049.

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11.
APPENDICES
Appendix 11.1.
Investigator Signature Page
Appendix 11.2.
Authorization Status of Study Interventions
Appendix 11.3.
Pandemic Risk Assessment and Mitigation Plan
Appendix 11.4.
Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive Requirements
Appendix 11.5.
Toxicity Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 11.6.
Country-Specific Requirements
Appendix 11.7.
Amendment History

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Protocol GS-US-589-6160
Final
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Amendment 1
CONFIDENTIAL
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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-Design, Multiple-Dose Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of Bulevirtide in Participants with 
Normal and Impaired Renal Function
Amendment 1: 02 February 2023
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

Bulevirtide
Protocol GS-US-589-6160
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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02 February 2023
11.2.
Authorization Status of Study Interventions
Study 
Intervention 
Name
Category
Authorized in at Least 
1 Country Following 
EU Regulation 
No. 536/2014
Authorized in 
at Least 1 ICH 
Country
Authorized by 
Swissmedic
Bulevirtide
Study drug
No
Yes
No
EU = European Union, ICH = International Council for Harmonisation of Technical Requirements for Pharmaceuticals

Bulevirtide
Protocol GS-US-589-6160
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 88
02 February 2023
11.3.
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 AEs/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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Protocol GS-US-589-6160
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Amendment 1
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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 eCRF 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 SDV, or study drug 
accountability or assess protocol and Good Clinical Practice compliance. This may lead 
to delays in SDV, 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 SDV 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 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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Protocol GS-US-589-6160
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 90
02 February 2023
11.4.
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 
FSH level is in the postmenopausal range and they are not using hormonal contraception or 
hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a 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 male born participant is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Participants
a. Investigational Product Effects on Pregnancy, Lactation and Hormonal Contraception
There are no adequate and well-controlled studies with BLV in pregnant women. Bulevirtide 
should be used during pregnancy only if the potential benefit justifies the potential risk to the 
fetus. In nonclinical reproductive toxicity studies, BLV demonstrated no adverse effect on 
embryofetal development when administered to pregnant rats and rabbits at systemic exposures 
(AUC) 12- and 124-fold relative to exposure in humans at the recommended human dose.
It is not known whether BLV is secreted in human milk. In nonclinical pre- and post-natal 
developmental rat studies, BLV was not measured in the plasma of pups or in the milk of nursing 
animals. However, due to its high protein binding, liver tropism, and high specificity for the 
NTCP, BLV is not likely to be secreted in milk.
Available data indicate that BLV is not anticipated to reduce the clinical efficacy of hormonal 
contraception. Please refer to the latest version of the IB for additional information.
b. Assigned Female at Birth and 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 at the admission (Day –1) visit before 

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Protocol GS-US-589-6160
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Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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02 February 2023
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 in this clinical study should start from the screening visit until the end of study.
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 or nonhormonal intrauterine device (IUD)

Bilateral tubal occlusion (upon medical assessment of surgical success)

Vasectomy in the male partner (upon medical assessment of surgical success)
Or
Female participants who initiate use of a hormonal contraceptive greater than 5 days after onset 
of menses as one of their birth control methods should use additional backup contraception 
(eg, condoms) or avoid sexual intercourse for 7 days. Hormonally-based contraceptives and 
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)

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Protocol GS-US-589-6160
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 92
02 February 2023
Female condom (with or without spermicide)
Diaphragm with spermicide
Cervical cap with spermicide
Sponge with spermicide
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved.
Participants assigned female at birth and of childbearing potential must also refrain from egg 
donation and in vitro fertilization during study drug dosing and until end of 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 at any time during the study, or if they become pregnant within 7 days of last study 
drug dose. Participants who become pregnant or who suspect that they are pregnant during the 
study must report the information to the investigator and discontinue study drug immediately.
Instructions for reporting pregnancy and pregnancy outcome are outlined in Section 7.4.2.3.

Bulevirtide
Protocol GS-US-589-6160
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 93
02 February 2023
11.5.
Toxicity Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities
The CTCAE toxicity grading scale Version 5.0 dated 27 November 2017 is available at the 
following location:
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_refer
ence_8.5x11.pdf).

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Protocol GS-US-589-6160
Final
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Amendment 1
CONFIDENTIAL
Page 94
02 February 2023
11.6.
Country-Specific Requirements
Not applicable.

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Protocol GS-US-589-6160
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 95
02 February 2023
11.7.
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.
11.7.1.
Amendment 1 (02 February 2023)
Rationale for Key Changes Included in Amendment 1
Affected Sections
Footnote “d” was modified to specify and correctly mention the schedule of 
collection for safety laboratory tests during the study.
Study Procedures Table 
(footnote “d”)
Red blood cell morphology was added as a hematology parameter applicable for 
each scheduled hematology laboratory assessment during the study.
Sections 6.4.5 (Table 3) and 
6.4.5.1
Minor changes to correct typographic errors. 
Throughout, as needed

PPD 
CONFIDENTIAL 
Amend 1-Protocol_ GS-US-589-6160 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
I 
Clinical Research eSigned 
Page 96 
Server Date 
(dd-MMM-
yyyy hh:mm:ss) 
03-Feb-2023 
16:59:18 
02 Febrna1y 2023