Clinical trial NCT03365947
Conditions: Hepatitis B
Sponsor: Arrowhead Pharmaceuticals
Start date: 2018-03-27; Completion date: 2020-04-23
Enrollment: 114 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single- and multiple-ascending doses of ARO-HBV in healthy adult volunteers and participants with hepatitis B virus (HBV).

Detailed description:

Arms: arm 1: Single dose of ARO-HBV 35 mg subcutaneous (sc) injection in normal healthy volunteers arm 2: Single dose of ARO-HBV 100 mg sc injection in normal healthy volunteers arm 3: Single dose of ARO-HBV 200 mg sc injection in normal healthy volunteers arm 4: Single dose of ARO-HBV 300 mg sc injection in normal healthy volunteers arm 5: Single dose of ARO-HBV 400 mg sc injection in normal healthy volunteers arm 6: Sterile normal saline (0.9% NaCl) sc injection in normal healthy volunteers arm 7: ARO-HBV 25 mg sc injection every 28 days (Q28D) in participants with chronic hepatitis B arm 8: ARO-HBV 50 mg sc injection Q28D in participants with chronic hepatitis B arm 9: ARO-HBV 100 mg sc injection Q28D in participants with chronic hepatitis B arm 10: ARO-HBV 200 mg sc injection Q28D in participants with chronic hepatitis B arm 11: ARO-HBV 300 mg sc injection Q28D in participants with chronic hepatitis B arm 12: ARO-HBV 400 mg sc injection Q28D in participants with chronic hepatitis B arm 13: ARO-HBV 100 mg sc injection every 14 days (Q14D) in participants with chronic hepatitis B arm 14: ARO-HBV 100 mg sc injection every 7 days (Q7D) in participants with chronic hepatitis B arm 15: ARO-HBV 300 mg sc injection Q28D in hepatitis B e antigen positive/treatment naïve (HBeAg+/Trt Naïve) participants with chronic hepatitis B arm 16: ARO-HBV 300 mg sc injection Q28D in HBeAg+/nucleotide or nucleoside analog treated (HBeAg+/NUC) participants with chronic hepatitis B arm 17: ARO-HBV 200 mg sc injection Q7D in participants with chronic hepatitis B arm 18: ARO-HBV 300 mg sc injection Q7D in participants with chronic hepatitis B arm 19: ARO-HBV 200 mg sc injection Q28D plus JNJ-56136379 250 mg in participants with chronic hepatitis B
Interventions: intervention 1: ARO-HBV intervention 2: Sterile Normal Saline (0.9% NaCl) intervention 3: JNJ-56136379
Intervention descriptions: intervention 1: sc injection intervention 2: sc injection intervention 3: oral tablets

Protocol documents:
SAP_002.pdf: 
Protocol Number: AROHBV1001 
 
03 July 2020 
Document status: Final SAP Version 4.0 
 
Novotech - Strictly Confidential 
 
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STATISTICAL ANALYSIS PLAN 
 
A PHASE 1/2A SINGLE DOSE-ESCALATING STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY AND PHARMACOKINETIC EFFECTS OF ARO-HBV IN 
NORMAL ADULT VOLUNTEERS AND MULTIPLE ESCALATING DOSES 
EVALUATING SAFETY, TOLERABILITY AND PHARMACODYNAMIC EFFECTS IN 
HBV PATIENTS 
 
Protocol No.: AROHBV1001 
Product Code: ARO-HBV, JNJ-56136379 
 
PREPARED FOR:   Arrowhead Pharmaceuticals, Inc. 
                                 177 E Colorado Blvd., Suite 700 
       Pasadena, CA  91105 
                                 USA 
 
PREPARED BY:      Novotech (Australia) Pty Ltd 
 
Level 3, 235 Pyrmont Street 
 
Pyrmont, NSW, 2009  
 
Australia  
 
DATE OF ISSUE:     03 July 2020 (Final Version 4.0) 
 
 
VERSION/STATUS: Final Version 4.0 
 
 
      VERSION DATE:      03 July 2020 
 
      AUTHOR:         




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Table of contents 
 
1. 
INTRODUCTION .................................................................................................................... 5 
2. 
PROJECT OVERVIEW ............................................................................................................ 6 
2.1 
Study Design ............................................................................................................................. 6 
2.2 
Objectives ................................................................................................................................. 9 
2.3 
Study Endpoints ...................................................................................................................... 10 
2.4 
Sample Size ............................................................................................................................. 11 
2.5 
Randomisation ........................................................................................................................ 11 
3. 
STATISTICAL CONSIDERATIONS ......................................................................................... 12 
4. 
ANALYSIS POPULATIONS .................................................................................................... 15 
5. 
SUBJECT DISPOSITION ........................................................................................................ 16 
6. 
PROTOCOL DEVIATIONS..................................................................................................... 17 
7. 
DEMOGRAPHIC AND BASELINE INFORMATION ................................................................ 18 
7.1 
Demographics ......................................................................................................................... 18 
7.2 
Medical history ....................................................................................................................... 18 
7.3 
Informed Consent and Eligibility ............................................................................................ 18 
7.4 
Pregnancy Test (Urine) ........................................................................................................... 18 
7.5 
Serology Screen (Hepatitis/HIV) ............................................................................................. 18 
7.6 
Urine Drug Screen .................................................................................................................. 18 
7.7 
Hepatic Fibrosis Measure ....................................................................................................... 18 
8. 
TREATMENT EXPOSURE ..................................................................................................... 19 
9. 
PHARMACOKINETICS (PK) .................................................................................................. 20 
9.1 
Definition of variables ............................................................................................................ 20 
9.2 
Biostatistical methods ............................................................................................................ 21 
10. 
SAFETY ............................................................................................................................ 23 
10.1 
Adverse Events ....................................................................................................................... 23 
10.2 
Concomitant medication ........................................................................................................ 25 
10.3 
Laboratory .............................................................................................................................. 26 
10.4 
Vital Signs ............................................................................................................................... 27 
10.5 
Physical examination .............................................................................................................. 28 
10.6 
12-lead ECG ............................................................................................................................ 28 
11. 
VIROLOGY ....................................................................................................................... 30 
12. 
CELLULAR IMMUNOLOGY .............................................................................................. 35 
13. 
IMMUNOGENICITY ......................................................................................................... 36 


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14. 
CYTOKINES AND COMPLEMENT ..................................................................................... 37 
15. 
HANDLING OF MISSING DATA........................................................................................ 38 
16. 
CHANGES TO THE PLANNED ANALYSIS .......................................................................... 39 
17. 
INTERIM AND FINAL ANALYSIS ...................................................................................... 40 
17.1 
Dose Escalation, Data Safety Committee (DSC) Analyses ...................................................... 40 
17.2 
Interim Analyses ..................................................................................................................... 40 
17.3 
Final Analysis (End of Study) ................................................................................................... 40 
18. 
SOFTWARE ..................................................................................................................... 41 
19. 
TABLES ............................................................................................................................ 42 
20. 
LISTINGS ......................................................................................................................... 45 
21. 
FIGURES .......................................................................................................................... 48 
22. 
REFERENCES ................................................................................................................... 53 
 
 
 


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1. 
INTRODUCTION 
The following Statistical Analysis Plan (SAP) provides the outline for the statistical analysis of 
the data from AROHBV1001 study. 
 
This Statistical Analysis Plan (SAP) is an adjunct to the Arrowhead Pharmaceuticals protocol 
number AROHBV1001 (Version 6.0, 28 February 2020). The planned analyses identified in 
this SAP may be included in clinical study reports (CSRs), regulatory submissions, or future 
manuscripts. Also, post hoc analyses not necessarily identified in this SAP may be performed 
to further examine study data.  Any post hoc, or unplanned, exploratory analyses performed 
will be clearly identified as such in the final CSR. 


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2. 
PROJECT OVERVIEW 
2.1 
Study Design 
This is a phase 1/2a single dose-escalating study to evaluate the safety, tolerability and 
pharmacokinetic effects of ARO-HBV in Normal Healthy Volunteers (NHV) and multiple 
escalating doses to evaluate safety, tolerability and pharmacodynamic effects in HBV patients. 
ARO-HBV is a drug candidate developed by Arrowhead Pharmaceuticals, Inc. to treat chronic 
HBV infection. ARO-HBV is administered through subcutaneous injection.  
This study will include the following cohorts, with the dose escalation schedule plotted as below. 
Dose escalation and start of new cohort are subject to Data Safety Committee (DSC) approval 
based on the evaluation of all available safety data.  
 
Normal Healthy Volunteers (NHV): Cohorts 1, 2, 3, 4 and 5.  
Each NHV cohort will recruit 6 healthy volunteers, with subjects randomized to receive 
placebo (2 subjects) or active ARO-HBV (4 subjects) in a double blinded fashion. The 
first two subjects in each cohort serve as sentinel participants (one ARO-HBV and one 
placebo). NHV cohorts will be single dosed as follows:  
 Cohort 1: 35 mg ARO-HBV, at Day 1 
 Cohort 2: 100 mg ARO-HBV, at Day 1   
 Cohort 3: 200 mg ARO-HBV, at Day 1  
 Cohort 4: 300 mg ARO-HBV, at Day 1  
 Cohort 5: 400 mg ARO-HBV, at Day 1  
 
 
Chronic Hepatitis B (CHB) Patients: Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 
and 12. 
CHB cohorts 1b, 1c, 2b, 3b, 4b and 5b will each enroll a minimum of 4 and a maximum 
of 8 subjects and the remaining CHB cohorts (except Cohort 12) will each recruit a 
maximum of 4 chronic hepatitis B patients, with all subjects receiving three doses of 
ARO-HBV at dose intervals ranging from once every week to once every 4 weeks in an 
open label fashion. All CHB cohorts except Cohorts 8 and 9 will include CHB patients 
regardless of NUC or HBeAg status. Cohort 8 will include HBeAg(+) and treatment 
naïve patients, and Cohort 9 will include HBeAg(+) and entecavir or tenofovir 
experienced patients. CHB patients on current nucleos(t)ide (NUC) therapy (entecavir 
or tenofovir) will stay on NUC therapy for the study duration. CHB patients not on NUC 
therapy (NUC naïve) will be started on either entecavir or tenofovir (selection between 
entecavir and tenofovir based on site Principal Investigator (PI) discretion) on Day 1.  
Cohort 12 will enroll 12 CHB patients who will either enter the study on NUCs or start 
NUCs on Day 1. Cohort 12 patients will also initiate daily JNJ-56136379 (JNJ-6379) 
250 mg on Day 1 and continue through Day 84. 
 
CHB cohorts will be multi-dosed as follows: 
 Cohort 1b: 25 mg ARO-HBV, at Days 1, 29 and 57 
 Cohort 1c: 50 mg ARO-HBV, at Days 1, 29 and 57 
 Cohort 2b: 100 mg ARO-HBV, at Days 1, 29 and 57 






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2.2 
Objectives 
2.2.1 Primary objective 
 
To determine the incidence and frequency of adverse events possibly or probably 
related to treatment as a measure of the safety and tolerability of ARO-HBV using 
escalating single doses in healthy volunteers (NHV) and escalating multiple doses 
in patients chronically infected with hepatitis B virus (CHB). 
2.2.2 Secondary objective(s) 
 
To evaluate the single-dose pharmacokinetics of ARO-HBV in healthy volunteers 
 
To determine the reduction from Day 1 pre-dose baseline to post-dose nadir of 
HBsAg in response to ARO-HBV in CHB patients as a measure of activity 
2.2.3 Exploratory objective 
 
To determine the reduction from Day 1 pre-dose baseline to post-dose nadir of 
HBcrAg, HBsAg, HBV DNA, HBV RNA (if scientifically feasible) and HBeAg (e+ 
only), in response to ARO-HBV (alone or in combination with JNJ-6379) in CHB 
patients as a measure of activity. The following categories will be considered for 
HBV DNA: >LLQ, <LLQ target detected and <LLQ target not detected. 
 
To evaluate the effect of single doses of ARO-HBV on cytokines (Cytokine panel A: 
interleukin-6 [IL-6], monocyte chemoattractant protein-1 [MCP-1], tumor necrosis 
factor-alpha [TNF-alpha], interleukin-8 [IL-8], interleukin-1beta [IL-1beta], interferon 
alpha [IFN-alpha], IL-10, IL-12 [p40], IL-12 [p70], macrophage inflammatory protein-
1alpha [Mip-1alpha]) in healthy volunteers. 
 
To evaluate the effect of single escalating doses of ARO-HBV on complement 
factors Bb, CH50, C5a, C4a, and C3a in healthy volunteers. 
 
To collect plasma samples in healthy volunteers for subsequent metabolite 
identification (reported in a separate report outside of this study)  
 
To collect urine samples in healthy volunteers for subsequent determination of 
urinary excretion and metabolite identification (reported in a separate report outside 
of this study) 
 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with 
JNJ-6379) on cytokines (Cytokine panel B: TNF-alpha, IFN-gamma, CXCL-9, and 
CXCL-10) in CHB patients 
 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with 
JNJ-6379) on HBV patient immune cell profile including T-cells, NK cells, B cells 
and monocytes (if scientifically feasible) 
 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with 
JNJ-6379) on HBV antigen specific T-cell response (if scientifically feasible). 
 
To evaluate the effect of interferon response gene single nucleotide polymorphisms 
(SNPs) including IL28B on response to ARO-HBV (alone or in combination with 
JNJ-6379). 


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To determine the incidence and frequency of adverse events possibly or probably 
related to treatment as a measure of the safety and tolerability of ARO-HBV in 
combination with JNJ-6379 in patients chronically infected with hepatitis B virus 
(CHB) (Cohort 12 only). 
 
To determine plasma concentration of ARO-HBV, JNJ-6379, and NUCs at 
specified timepoints in HBV patients (Cohort 12 only). 
 
2.3 
Study Endpoints 
Safety endpoints 
 
Monitoring of AEs/SAEs  
 
Physical examinations  
 
Vital signs  
 
ECG measurements  
 
Injection Site Reactions (Mild, Moderate or Severe)  
 
Clinical laboratory tests (hematology, biochemistry, coagulation, urinalysis)  
 
Concomitant medications/therapy, and  
 
Reasons for treatment discontinuation due to toxicity 
 
Cellular Immunologic Endpoints (CHB Cohorts in New Zealand only) 
 
Patient immune cell profile: T cell subsets (activation and exhaustion state), NK cell 
subsets (activation and exhaustion state), B cell subset, monocyte subsets. To be 
conducted if scientifically feasible. 
 
HBV antigen specific T cell response (including HBcAg, HBsAg). To be conducted if 
scientifically feasible. 
 
Virology Endpoints (CHB Cohorts only) 
 
Qualitative assessments: HBsAg, HBeAg, anti-HBsAg, anti-HBeAg 
 
Quantitative assessments: HBV DNA, qHBsAg, qHBeAg, qHBcrAg, qHBV RNA (if 
feasible), anti-HBsAg and ratio of bound/free anti-HBsAg 
 
HBV genotyping and HBV sequencing 
 
Immunogenicity (CHB Cohorts only) 
 
Anti-drug antibodies 
 
Pharmacokinetics (NHV Cohorts and limited PK in Cohort 12) 
 
Plasma PK blood samples will be collected at Day 1 
 
Plasma concentrations of ARO-HBV, NUC and JNJ-6379 will be measured at a single 
post-dose time point in Cohort 12 only  
 


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Cytokines  
 
Cytokine panel A (NHV Cohorts): interleukin-6 [IL-6], monocyte chemoattractant 
protein-1 [MCP-1], tumor necrosis factor-alpha [TNF-alpha], interleukin-8 [IL-8], 
interleukin-1beta [IL-1beta], interferon alpha [IFN alpha], IL-10, IL-12 [p40], IL-12 [p70], 
macrophage inflammatory protein-1alpha [Mip-1alpha] 
 
Cytokine panel B (CHB Cohorts): TNF-alpha, IFN gamma, CXCL-9, and CXCL-10 
 
Complement (NHV Cohorts) 
 
Bb, CH50, C5a, C4a, and C3a 
 
Genetic Testing (consenting CHB patients only) 
 
Interferon response gene SNP analysis testing  
 
Excretion and Metabolism Parameters  
 
Samples for metabolic analyses will be stored and reported outside of this study 
 
Urine collections will be collected per the Schedule of Assessments.  
2.4 
Sample Size 
No formal statistical calculation of sample size will be used for this Phase 1/2a study. The 
sample size is empirical. The small numbers per cohort in this study are not intended for 
statistical hypothesis inference analysis. Results from this study will be utilized in sample size 
calculations for subsequent studies. 
 
This study will involve approximately 30 eligible normal healthy volunteers in NHV cohorts and 
a minimum of 60 and a maximum of 84 CHB patients in CHB cohorts. Each of the 5 NHV 
cohorts will recruit 6 healthy volunteers. CHB cohorts 1b, 1c, 2b, 3b, 4b and 5b will recruit a 
minimum of 4 and a maximum of 8 patients, and CHB cohorts 6, 7, 8, 9, 10, 11 will recruit a 
maximum of 4 CHB patients.  Cohort 12 will recruit 12 CHB patients.  
 
2.5 
Randomisation 
 
NHV Cohorts 
 
The six (6) healthy volunteers in each of the five (5) NHV cohorts will be randomized at a ratio 
of 2:1 (active: placebo) to receive ARO-HBV or Placebo in a double-blind fashion. Therefore 4 
subjects will be randomized to receive ARO-HBV and 2 subjects to receive placebo in each of 
the NHV cohorts. 
 
CHB Cohorts 
 
All CHB patients in each of the 13 CHB cohorts will receive ARO-HBV (alone or in combination 
with JNJ-6379) and daily NUC, and no randomization is applied.  
 


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3. 
STATISTICAL CONSIDERATIONS 
 
Data will be handled and processed according to the 
 representative (Novotech 
(Australia) Pty Ltd) Standard Operating Procedures (SOPs), which are written based on the 
principles of GCP. 
 
All data collected on the eCRFs will be presented in the data listings and will be listed and 
sorted by subject number and visit, where applicable. All summaries will present the data by 
ARO-HBV dose level/cohort and overall (total subjects), as applicable. 
 
Data collected during the main study (up to the Day 29 or Day 113 EOS visits) and at the 
additional follow-up visits (CHB cohorts only) will be presented in the same summary table, as 
appropriate. The first part of each table will present the main study results for the specific 
analysis. The second part of each table will include all data collected during the study, including 
data collected during the follow-up period, for the subset of CHB patients that consented to 
participate in the follow-up. All data will be included in the listings, and data collected during 
the follow-up period will be flagged in all event/medication-based listings. Separate figures that 
include all data will be presented for the subset of patients that participated in the follow-up 
period. 
 
Unless otherwise stated, the following statistical approaches will be taken: 
 
Continuous variables: Descriptive statistics will include the number of non-missing 
values (N), mean, standard deviation (SD), median, minimum, maximum.  
 
Categorical variables: Descriptive statistics will include frequency counts and 
percentages per category. Percentages will be rounded to one decimal place, with the 
denominator being the number of subjects in the relevant population with non-missing 
data, unless otherwise specified.  
 
Imputation: No missing data will be imputed generally.  
 
Confidence intervals (CIs): CIs will be two-sided and will use 95% confidence levels 
unless specified otherwise. 
 
Baseline: Baseline values will be defined as the last non-missing observation (pre-dose 
value closest to the first dose) for each subject prior to the dosing of study medication 
(i.e. start of injection on Day 1). 
 
Repeat assessments (Safety): If there is a repeat test, the repeat result will be used in 
the analysis table and the original result will only be listed in the data listing.  
 
Repeat assessments (Virology): Certain virologic assessments such as qHBsAg may 
be batch analyzed per patient at the end of study. In cases where both batch-analyzed 
and non-batch analyzed data are available, batch analyzed data with be used in the 
analysis table and all other results will be listed. In other instances, repeat tests may 
have been performed for other reasons than batch-analysis. If there is a repeat test, the 
repeat result will be used in the analysis table and the original result will only be listed 
in the data listing.  
 
Continuous safety variables will be reported to the same precision as the source data. Derived 
variables will be reported using the same precision to the value(s) from which they were 
derived. For the reporting of descriptive statistics, the mean (95% CI) and median will be 
reported to 1 decimal place more than the source data; the minimum, and the maximum values 
will be presented to the same precision as the source data; and standard deviation will be 


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reported to 2 decimal places more than the source data. Rounding is not allowed in the middle 
of the calculation. It only takes place at the last step to report the final result. Post-dose time 
points/visits will be calculated relative to start time of injection on Day 1.  Study day will be 
defined as assessment date minus dosing day +1. 
 
The NHV cohorts (Cohorts 1, 2, 3, 4, and 5) will be summarized separately from the CHB 
cohorts (Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10,11 and 12). The dose levels (cohorts) will 
be referred to in the text, tables and listings as follows. 
NHV Cohorts: 
 
Coh1: ARO-HBV (35 mg) 
 
Coh2: ARO-HBV (100 mg) 
 
Coh3: ARO-HBV (200 mg) 
 
Coh4: ARO-HBV (300 mg) 
 
Coh5: ARO-HBV (400 mg) 
 
Combined ARO-HBV 
 
Combined Placebo 
 
Total (including all ARO-HBV and 
Placebo)   
 
CHB Cohorts: 
 
Coh1b: ARO-HBV (25 mg, Q28D) 
 
Coh1c: ARO-HBV (50 mg, Q28D) 
 
Coh2b: ARO-HBV (100 mg, Q28D) 
 
Coh3b: ARO-HBV (200 mg, Q28D) 
 
Coh4b: ARO-HBV (300 mg, Q28D) 
 
Coh5b: ARO-HBV (400 mg, Q28D) 
 
Coh6: ARO-HBV (100 mg, Q14D) 
 
Coh7: ARO-HBV (100 mg, Q7D) 
 
Coh8: ARO-HBV (300 mg, Q28D, 
HBeAg+/Trt Naive) 
 
Coh9: ARO-HBV (300 mg, Q28D, 
HBeAg+/NUC) 
 
Coh10: ARO-HBV (200 mg, Q7D) 
 
Coh11: ARO-HBV (300 mg, Q7D) 
 
Coh12: ARO-HBV (200 mg, Q28D) 
+ JNJ-6379 250mg 
 
Combined ARO-HBV 
 
Pooled ARO-HBV (300 mg, Q28D) 
 
 
where Q7D: dosing once every 7 days,  
           Q14D: dosing once every 14 days, 
           Q28D: dosing once every 28 days 
  
Summary tables and listings will be produced separately for NHV cohorts (Cohorts 1, 2, 3, 4 
and 5) and CHB cohorts (Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10,11 and 12).  The 
Pooled ARO-HBV (300 mg, Q28D) group will only be presented for the safety outputs. 
 
Due to the large number of treatment columns that will be displayed in the outputs, the results 
for a specific parameter/visit could span multiple pages. Summaries will be presented by 
groups of treatments, i.e., if only CHB Coh1b to Coh7 can be fit onto a page, all of the results 
for these cohorts will be presented on the subsequent pages before the results for the initial 
visits of the next group of cohorts are presented.  Where appropriate, the outputs may also be 


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transposed to present the treatment information in rows instead of columns to facilitate the 
review process. 
 
 


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4. 
ANALYSIS POPULATIONS 
In this study, three analysis populations are defined: Safety Population, Pharmacokinetic 
Population, and Pharmacodynamic population.  Data for Screen Failures will not be included 
in any summary tables, figures, or data listings. Subjects included in the defined (various) 
analysis populations will be decided at the blinded data review meeting prior to unblinding of 
NHV cohorts. The same process will be applied to the CHB cohorts as well even if there is no 
blinding for these cohorts.    
 
Furthermore, any additional analysis populations not identified in the SAP will be identified in 
the final CSR as post hoc analyses. This may include the addition of additional study 
populations or subgroups of interest.  
 
The number and percentage of subjects in each analysis population will be summarized. 
 
Safety Population 
All subjects who receive at least one dose of study treatment (ARO-HBV or JNJ-6379) will be 
included in the Safety Population. Subjects will be summarized according to the treatment they 
received. 
 
All safety, treatment exposure, demographic and baseline characteristic data will be listed and 
summarized using the Safety Population. 
 
Pharmacokinetic (PK) Population 
Subjects who have received the active treatment (ARO-HBV) and have adequate PK data to 
characterize PK profile will be included in the PK Population. This includes NHV Cohorts 1, 2, 
3, 4 and 5 and CHB Cohort 12 subjects that received at least one dose of active study treatment 
(ARO-HBV). 
 
Subjects who prematurely discontinue from the study will be included in the Safety Population 
but may not be included in the PK Population if they do not have PK data to contribute to the 
analyses. Subjects with missing sample concentrations will be included in the PK analyses 
provided their PK parameters can be adequately characterized based upon the remaining data. 
Subjects who received only placebo will be excluded from the PK population. The PK 
population will be used for the summaries of all PK data. 
 
Subjects with protocol violations will be assessed on a subject-by-subject basis for inclusion in 
the PK Population. The determination of study populations will be made, prior to unblinding the 
PK data, at the blinded data review meeting before the final analyses for NHV Cohorts 1, 2, 3, 
4, 5, and 12. 
 
Pharmacodynamic (PD) Population 
Subjects who received at least one dose of study treatment (ARO-HBV, JNJ-6379, or 
placebo) and had PD assessment from baseline and 
 assessment from post-baseline will 
be included in the PD population. Subjects will be summarized according to the treatment 
they received. 
 
Subjects with protocol violations will be assessed on a subject-by-subject basis for inclusion in 
the PD Population. The determination of study populations will be made, prior to unblinding the 
PD data, at the blinded data review meeting before the final analyses. The PD population will 
be used for the summaries of all immunologic endpoints, virology endpoints, cytokines and 
complement. 
 
 


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5. 
SUBJECT DISPOSITION 
All subjects who provide informed consent and are randomized (NHV Cohorts 1, 2, 3, 4 and 
5)/enrolled (CHB Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10,11 and 12) will be accounted for 
in this study. Subject disposition will be summarized using the Safety Population. 
 
By-subject data listings for subject disposition will be generated, including informed consent 
date, randomization date/number (NHV cohorts), completion status, date of withdrawal and 
reason for withdrawal from the study, if applicable. The listing will also include the date of 
informed consent for CHB subjects that consented to participate in the follow-up period and the 
date of consent to single nucleotide polymorphisms (SNP) genetic testing and optional 
sampling. 
 
The number of subjects randomized (NHV cohorts)/enrolled (CHB cohorts), as well as the 
number and percentage of subjects completing the study and withdrawn from the study will be 
presented by dose level (cohort) and overall. The reason for withdrawal will also be 
summarized for all subjects who do not complete the study. The table will also show the number 
of CHB subjects that participated in the follow-up period.  Patients who participated in the 
follow-up period will be deemed to have completed the main part of the study (up to Day 113). 
 
 


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6. 
PROTOCOL DEVIATIONS 
In case protocol deviations are reported, protocol deviations will be presented for each subject 
in the by-subject data listings.  
 
Prior to database lock, all protocol deviations will be reviewed by medical monitors and 
assigned a category (see below). 
 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action 
or inaction of the patient, investigator, or site staff. All deviations will be tracked and should be 
reported to IRBs in accordance with their reporting policy. Examples of deviations include, but 
are not limited to:  
 
Failure to adhere to study exclusion and inclusion criteria; 
 
Failure to comply with dispensing or dosing requirements; 
 
Use of medications, food, drink, herbal remedies, or supplements that are specifically 
prohibited in the protocol; 
 
Missed or out-of-window visits; 
 
Drug dosing not administered within the time frame specified in the protocol; 
 
Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, blood draws, medical history, etc.  either tests not done, incorrect tests 
done, or not done within the time frame specified in the protocol; 
 
Procedural deviations such as incorrect storage of study drug, failure to update the ICF 
when new risks become known, failure to obtain IRB/EC approvals for the protocol and 
ICF revisions. 


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7. 
DEMOGRAPHIC AND BASELINE INFORMATION 
Demographic and baseline body measurements will be summarized using the Safety 
Population.  
7.1 
Demographics 
Demographic data, including age, gender, race, weight, height and BMI, will be summarized 
by dose level (cohort) and overall. The table will also be repeated for the subset of CHB 
subjects that participated in the Additional Follow-up period. A by-subject data listing for 
demographic characteristics will be generated. 
 
Baseline disease characteristics including, baseline alanine aminotransferase (ALT), baseline 
Fibroscan score, prior nucleos(t)ide (NUC) treatment status and the type of prior treatments 
and the log-transformed quantitative HBV DNA, genotype (if available), qHBsAg, qHBeAg,
qHBcrAg, qHBV RNA (if feasible), and anti-HBsAg values and the and ratio of bound/free anti-
HBs (untransformed, subset of patients only) at baseline will be summarized for the CHB 
cohorts as well as for the subset of CHB subjects that participated in the follow-up period.  The 
table will also be repeated for the PD Population.  A by-subject data listing for baseline disease 
characteristics will be generated. 
7.2 
Medical history 
Past medical history will be coded using the Medical Dictionary for Regulatory Activities, 
MedDRA® with the latest available version. Medical history data, including the MedDRA codes, 
will be presented in the by-subject data listings. 
7.3 
Informed Consent and Eligibility 
Informed consent date, and inclusion/exclusion eligibility criteria information, including any 
criteria not met, will be listed for each subject. 
7.4 
Pregnancy Test (Urine) 
Child-bearing potential (yes/no), and if No, the reason (post menopause, surgically sterile, and 
other), and pregnancy test results will be included in the by-subject data listings. This includes 
the urine dipstick pregnancy test results assessed regularly at the scheduled study visits. 
Screening Follicle-Stimulating Hormone (FSH) will also be listed. 
7.5 
Serology Screen (Hepatitis/HIV) 
Data for Hepatitis B, Hepatitis C and HIV assessment at screening will be listed for each 
subject. 
7.6 
Urine Drug Screen 
Urine Drug Screen results at Screening will be listed for each subject. 
7.7 
Hepatic Fibrosis Measure 
The score of hepatic fibrosis at Screening will be listed for each subject. 
 
 


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8. 
TREATMENT EXPOSURE 
Study drug administration results will be presented using the Safety Population. Study drugs 
include drug administration for ARO-HBV or placebo (Placebo is only applicable for NHV 
Cohorts 1, 2, 3, 4 and 5), NUC and JNJ-6379 (CHB Cohort 12 only).  
 
Each single dose of either active drug (ARO-HBV) or Placebo will be administered by 
subcutaneous injection (either one or two subcutaneous injections per dose as required for 
each dose level). Injections will be made into the subcutaneous tissue at an appropriate site 
(e.g. abdomen, thigh, upper arm, etc.). The abdomen is the preferred site. Injection site is to 
be varied (no multiple injections into the same exact site). Alternating various locations on the 
abdomen is acceptable, and injection site location is to be recorded in the eCRF. 
 
A by-subject data listing will be generated for study drug (ARO-HBV or Placebo) 
administrations. This listing will include study drug administration date, time, dose, and injection 
site. If study drug was not administered, the reason why the drug was not administered will be 
reported.  Separate listings will be created for the NUC and JNJ-6379 treatment compliance 
and dosing deviation data. 
 
 




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Parameter 
Description 
DN_AUC0-inf 
Dose-normalized AUC0-inf, calculated as AUC0-inf divided by dose 
DN_AUC0-t 
Dose-normalized AUC0-t, calculated as AUC0-t divided by dose 
DN_Cmax 
Dose-normalized Cmax, calculated as Cmax divided by dose 
 
9.2 
Biostatistical methods 
The two ARO-HBV analytes, JNJ 73763976 (AD04872) and JNJ 73763924 (AD05070) will be 
analyzed and presented separately (as appropriate). 
 
ARO-HBV plasma concentrations will be listed by subject, dose level/treatment, and nominal 
(scheduled) sampling time. ARO-HBV concentrations will be summarized by dose 
level/treatment and nominal sampling time for the PK Analysis Population. Plasma 
concentrations that are below the limit of quantitation (BLQ) will be set to 0 for calculation of 
summary statistics for concentration data at each time point, except geometric statistics 
(geometric mean and geometric CV%). For the calculation of the geometric statistics they will 
be treated as equal to the Lower Limit of Quantification (LLQ). Missing values will be omitted 
from the calculation of descriptive statistics.   
 
The actual blood sampling dates and times relative to dosing time will be listed by study group 
(dose level/treatment), subject and nominal sampling time, with time deviation calculated, for 
all subjects with available plasma concentration data, including subjects receiving placebo or 
subjects excluded from the PK Analysis Population. 
 
Figures of individual plasma concentration vs. actual time profiles for ARO-HBV will be 
produced on both linear and semi-log scales for the PK Analysis Population. Mean and median 
plasma blood concentration vs. nominal time curves for all dose levels/treatments in the PK 
Analysis Population will be plotted together on both linear and semi-log scales for ARO-HBV.  
 
Pharmacokinetic parameters for each dose level will be calculated from the concentrations of 
ARO-HBV measured in pre-dose and post-dose plasma samples. For the calculation of the PK 
parameters, all plasma concentrations that are BLQ prior to the first measurable concentration 
will be set to zero. The BLQ values that are between measurable concentrations will be set to 
missing. The BLQ values that occur at the end of the profile (after the last quantifiable 
concentration) will be set to missing and will not be used for the estimation of parameter values. 
Dose normalized PK parameters (DN_AUC0-24, DN_AUC0-inf, DN_AUC0-t, and DN_Cmax) will be 
calculated as well.  
 
For each dose level, descriptive statistics will be provided for the PK parameters. Summary 
tabulations will display the number of observations, mean, SD, CV%, median, minimum and 
maximum. Geometric means and geometric CV% will be calculated for AUCs and Cmax. PK 
parameters will be displayed by treatment. AUC0-24, AUC0-inf, AUC0-t, and Cmax will also be 
presented in scatter plots by treatment.  
 
The dose proportionality of ARO-HBV over the dose range 35 400 mg (NHV Cohorts 1-5) will 
be assessed by fitting a simple unweighted linear regression model with the natural log-
transformed pharmacokinetic parameters (AUC0-24, AUC0-t, and Cmax) and dependent and the 
natural log-transformed dose values as independent variables.    


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Dose proportionality will be declared if the 95% CI for the slope of the regression line (
1) 
contains the value 1. AUC0-24, AUC0-t, and Cmax will be assessed separately. 
 
The CHB Cohort 12 ARO-HBV, NUC and JNJ-6379 concentrations data will be summarized 
and presented graphically. The data will also be listed.  PK parameters will not be calculated 
for Cohort 12.
 
 


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10. 
SAFETY  
Statistical methods for the safety analyses will be primarily descriptive in nature. Each dose 
level (cohort) will be summarized separately.  
 
Safety endpoints included in the analysis are AEs, concomitant medications, clinical laboratory 
assessments, vital signs, physical examination, and 12-lead ECG. 
 
Safety endpoints will be analyzed separately for the main study (up to Day 113 EOS) and for 
the overall study duration, including the follow-up period, for the subset of CHB patients that 
consented to participate in the follow-up. Endpoints will be derived separately for each analysis 
taking into consideration all the applicable data for the specific period.  
 
Safety endpoints will be analyzed using the Safety Population. 
10.1 
Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®, the latest available version), and data will be summarized by System Organ Class 
(SOC) and Preferred Term (PT). The number and percent of subjects reporting each AE will 
be summarized for each dose level (cohort) and overall. A subject with two or more AEs within 
the same level of summarization (i.e., SOC or PT) will be counted only once in that level. 
Percentages will be based on the number of subjects in the Safety Population within each dose 
level (cohort). The number of AEs reported will also be presented.  
 
Treatment-emergent AEs (TEAEs) are defined as pre-treatment existing conditions that worsen 
after study drug administration, or events that occur during the course of the study during or 
after administration of study drug. Only TEAEs will be included in the AE summary tables which 
will present data by dose level (NHV/CHB cohorts) for active treatment versus pooled placebo 
subjects (NHV cohorts). In the case of a missing AE start date or stop date, the most 
conservative approach will be followed to classify AE into TEAE unless it is not possible that 
the AE could be treatment emergent. AEs that occurred during the follow-up period will only be 
included in the follow-up table. 
 
A table providing an overall summary of AEs will be produced which will include the number of 
TEAEs; the number and % of subjects reporting at least one: TEAE, serious TEAE, grade 3 
(severe) or higher TEAE, TEAE related to study treatment (related to ARO-HBV or JNJ-6379 
[Cohort 12 only]: possibly/probably), serious TEAE related to study treatment, grade 3 or higher 
TEAE related to the study drug, TEAEs by severity and TEAEs by relationship, drug or study 
discontinuations due to TEAEs. The table will also be repeated for related (ARO-HBV or 
placebo) TEAEs. 
 
Additional AE tables will be generated as follows: 
 
TEAEs by SOC and PT 
 
TEAEs by decreasing incidence of the PTs in the Combined ARO-HBV group 
 
Study Drug (ARO-HBV or placebo) Related TEAEs by SOC and PT 
 
Study Drug (ARO-HBV or placebo) Related TEAEs by decreasing incidence of the PTs 
in the Combined ARO-HBV group 
 
Study Drug (JNJ-6379) Related TEAEs by SOC and PT (Cohort 12 only) 


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Study Drug (JNJ-6379) Related TEAEs by decreasing incidence of the PTs in the 
Combined ARO-HBV group (Cohort 12 only) 
 
TEAEs by Severity 
 
TEAEs by Relationship to Study Drug (ARO-HBV) 
 
Treatment Emergent SAEs 
 
Study Drug (ARO-HBV or placebo) Related SAEs by SOC and PT 
 
Study Drug (JNJ-6379) Related SAEs by SOC and PT (Cohort 12 only) 
 
TEAEs Leading to Study Drug or Study Withdrawn 
 
TEAEs occurring at the treatment injection site by SOC (General disorders and 
 
 
TEAEs fitting the definition of LISR by SOC and PT 
 
A by-subject AE data listing, including verbatim term, MedDRA SOC and PT, severity, outcome 
and relationship to study treatment, will be provided. Separate listings will be generated for 
SAEs. AEs that started during the follow-up period will be flagged.  Cohort 12 data will be listed 
separately. 
 
Local Injection Site Reactions (LISR) 
Local Injection Site Reactions will be reviewed based on description of symptoms, level of 
severity (mild, moderate or severe) and outcome of the reactions as well as other relevant data 
elements such as de/re-challenge, medical history, and possible confounding variables.  Based 
on the review, the reactions will be specifically categorized and collated for the analysis.  
The results will be summarised by cohort across all dose levels and percentages for the 
reported LISR by using the MedDRA coding system by System Organ Class (SOC), General 
disorders and administration site conditions and Preferred Terms that are associated with local 
injection site reactions.  
 
personnel represent the local injection site reaction: 
 
Injection site discomfort 
Injection site abscess 
Injection site discoloration 
Injection site abscess sterile 
Injection site erythema 
Injection site atrophy 
Injection site irritation 
Injection site calcification 
Injection site inflammation  
Injection site cellulitis 
Injection site induration 
Injection site dermatitis 
Injection site pain 
Injection site erosion 
Injection site oedema 
Injection site fibrosis 
Injection site pruritus 
Injection site indentation 
Injection site rash 
Injection site necrosis 
Injection site urticaria 
Injection site nodule 
Injection site reaction 
Injection site ulcer 
Injection site swelling 
 
 
Those summaries will only include events that start on the day of injection and persist for at 
least 2 days (48 hours) post injection (i.e., event onset date on the day of injection and 


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resolution date not on the day of injection or the day after the injection) will be included. Events 
with onset date on the day of injection and missing resolution date will also be included in the 
summary. 
 
The percentage of injections leading to local injection site reactions will be summarized using 
descriptive statistics.  
 
The following calculation will be utilized to determine the percentage of injections leading to 
local injection site reactions for each subject: 
 
(A/B) *, where A = number of injections with a local injection site reaction, and B = total number 
of injections.  
 
The results of local injections site reactions will be provided in summary tabulation. 
10.2 
Concomitant medication 
Concomitant medications and non-drug therapies will be coded using World Health 
Organization Drug Dictionary (WHO-DD, the latest available version). Concomitant 
medications are medications taken at least once after the start of first study-drug administration. 
Medications stopped prior to the day of the start of first study-drug administration will not be 
considered concomitant medication. The prior medication will not be summarized, but they will 
be listed along with concomitant medications. Only concomitant medications will be 
summarized. Medications that started during the follow-up period will only be included in the 
follow-up concomitant summary table and will be flagged in the listing. 
 
Individual data listings will be presented for each subject and summarized by WHO-DD 
Anatomical Therapeutic Chemical (ATC) anatomical group, and preferred term using frequency 
counts and percentages. Subjects who take the same medication more than once will be 
counted only once for that preferred term. 
 
Dispensing of Nucleos(t)ide (NUC) will be listed for CHB cohorts, as appropriate. 


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10.3 
Laboratory 
10.3.1 Definition of variables  
Hematology Parameters 
 
Hemoglobin 
 
Red Blood Cell Count 
 
Hematocrit 
 
Mean Cell Volume (MCV) 
 
Mean Cell Hemoglobin (MCH) 
 
Mean Cell Hemoglobin 
Concentration (MCHC) 
 
Platelets 
 
White Blood Cell Count 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
 
Chemistry Parameters 
 
Sodium 
 
Potassium 
 
Chloride 
 
Bicarbonate 
 
Glucose 
 
Urea 
 
Creatinine (including calculated 
creatinine clearance)  
 
Creatine kinase 
 
Uric acid 
 
Phosphate 
 
Total calcium 
 
Anion gap 
 
Cholesterol 
 
Albumin 
 
Globulins 
 
Protein 
 
Total bilirubin 
 
Conjugated bilirubin 
 
Gamma glutamyltransferase 
(GGT) 
 
Alkaline phosphatase (ALP) 
 
Alanine aminotransferase (ALT) 
 
Aspartate transaminase (AST) 
 
Lactate dehydrogenase (LD) 
 
Triglycerides 
 
Amylase 
 
Lipase 
 
C-reactive protein 
 
Troponin I 
 
 Coagulation Parameters 
 
Partial Thromboplastin Time (PTT) 
 
Prothrombin Time (PT) 
 
INR  
 
Urinalysis Parameters 
 
Leukocytes 
 
Nitrites 
 
Urobilinogen 
 
Protein 
 
pH 
 
Blood 
 
Specific Gravity 
 
Ketone 
 
Bilirubin 
 
Glucose 
 
Microscopic urinalysis will be performed if indicated: White blood cells, red blood cells, 
epithelial cells, and bacteria. 
 


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10.3.2 Biostatistical methods 
All hematology, chemistry, coagulation and urinalysis parameters will be summarized using 
descriptive statistics for each dose level (cohort) for all time points assessed, including change 
from baseline (last pre-dose value) for all post-dose assessments. All continuous parameters 
will be summarized using the units reported from the laboratory. 
 
Laboratory values will be compared to normal range of the single local laboratory and values 
that fall outside of the normal ranges will be flagged as: H (High) and L (Low) in the data listings.  
Results that were flagged as 
 will be reported as 
 and results flagged as 
 will be 
reported 
 Shift tables from Day 1 (pre-dose) to all follow-up visits will also be generated for 
each hematology, chemistry and coagulation laboratory parameter with values of Within 
Normal Limits (WNL), High, and Low used for the shift categories. 
 
To assess the liver function of CHB patients, number of subjects with ALT above the upper limit 
of normal over time will be summarized for CHB cohorts. 
 
All laboratory data will be included in the by-subject data listings. Microscopic urinalysis will 
only be listed.
 
Time series of mean values for the following safety assessments will be plotted by NHV and 
CHB Cohorts.  
 
Creatinine 
 
Creatine Kinase 
 
AST 
 
ALT 
 
Total Bilirubin 
 
10.4 
Vital Signs 
10.4.1 Definition of variables 
 
Systolic Blood Pressure (SBP) (mmHg) 
 
Diastolic Blood Pressure (DBP) (mmHg) 
 
Pulse Rate (beats/min) 
 
Body Temperature (°C) 
 
Respiratory rate (breaths/minute) 
10.4.2 Biostatistical methods 
All vital sign parameters will be summarized using descriptive statistics for each dose level 
(cohort) for all time points assessed, including change from baseline (last pre-dose value) for 
all post-dose assessments. Pre-dosing vital signs on Day 1 will be used as baseline data. If the 
baseline value is missing, then the data from screening will be used as baseline data as 
appropriate. 
 
All vital sign parameters will be listed for each dose level (cohort) for all time points assessed. 


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10.5 
Physical examination 
10.5.1 Definition of variables 
The following body systems will be assessed: 
 
General Appearance 
 
HEENT (Head, Eyes, Ears, Nose 
and Throat) 
 
Cardiovascular  
 
Lungs 
 
Abdomen 
 
Lymph nodes 
 
Genitourinary 
 
Extremities 
 
Neurological 
 
Skin 
 
Musculoskeletal  
 
Other 
 
For abnormal result of physical examination: 
o Abnormal NCS (Not Clinically Significant) 
o Abnormal CS (Clinically Significant). 
 
10.5.2 Biostatistical methods 
Physical examination will be summarized by study visit and treatment cohort. The frequency 
counts and percentages of subjects with different physical examination results and their clinical 
significance (for abnormal) will be summarized.  
 
According to the schedule of assessment, a complete physical exam will be performed at 
Screening. Symptom-directed physical examinations will only be conducted at other visits as 
necessary. Only complete exams (screening) will be summarized. 
 
By-subject data listings will be generated for all the physical examination data, including the 
Investigator assessment of clinical significance for abnormal findings, for all time points 
assessed.  
 
10.6 
12-lead ECG 
10.6.1 Definition of variables 
 
Heart Rate (beats/min) 
 
PR interval (msec) 
 
QRS interval (msec) 
 
QT interval (msec) 
 
QTcF interval (msec) 
 
Overall interpretation of 12-lead ECG: 
o Normal 
o Abnormal NCS (Not Clinically Significant) 
o Abnormal CS (Clinically Significant). 
 


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10.6.2 Biostatistical methods 
Descriptive statistics will be calculated for heart rate, PR interval, QRS interval, QT interval, 
and QTcF interval, including change from baseline (last pre-dose value on Day 1) for each 
dose level (cohort) for all time points assessed.  
 
12-lead ECG measurements will be obtained at the scheduled time points after the participant 
is semi-supine for at least 3 minutes. Any abnormal ECGs will be repeated in triplicate, with 
each measurement approximately 1 minute apart. If triplicate ECG parameters are available, 
the average of the triplicate ECG parameters will be used. Unscheduled visits will be excluded 
from summary tables. However, the findings from the unscheduled will be listed. 
 
In addition, the overall interpretation of 12-lead ECG results will be classified using frequency 
counts and percentages for the categories of Normal, Abnormal - Not Clinically Significant 
(NCS) and Abnormal - Clinically Significant (CS) for each treatment group for all time points 
assessed. 
 
All ECG data will be presented in the by-subject data listings. 
 


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11. 
VIROLOGY  
Virology endpoints are only collected for CHB cohorts across the study period according to 
the protocol schedule of assessment. The analysis population for virology data is PD.  
 
Virology endpoints will be analyzed separately for the main study (up to Day 113 EOS) and for 
the overall study duration, including the follow-up period, for the subset of patients that 
consented to participate in the follow-up. Endpoints will be derived separately for each analysis 
taking onto consideration all the applicable data for the specific period.  
 
Data Handling Rules 
 
The units and lower limit of quantitation (LLQ) cut-off and imputed values in the table below will 
be used in all derivations and outputs.  
 
Parameter
Qualitative / 
Quantitative 
LLQ 
Unit 
Values for Imputation 
< LLQ 
< LLQ  
Detected 
< LLQ  
Not Detected 
HBeAg 
Qualitative 
0.22 
PEIU/mL 
N/A 
N/A 
N/A 
qHBeAg 
Quantitative 
0.11 
PEIU/mL 
0.055 
0.055 
0.055 a) 
HBV DNA 
Quantitative 
20 
IU/mL 
N/A 
15 
5 
HBV RNA 
Quantitative 
1.65 
Log10 U/mL 
N/A 
0.825 
0.4125 
qHBcrAg 
Quantitative 
1 
kU/mL 
0.5 
N/A 
N/A 
qHBsAg 
Quantitative 
0.05 
IU/mL 
0.025 
N/A 
N/A 
a) Values below 0.11 PEIU/mL may have been reported as not detected  
 
All reported qHBsAg and qHBcrAg results below the LLQ cut-off values will be treated as below 
LLQ and included in the 
 
 category counts.  
 
qHBeAg results will be imputed based on the reported HBeAg (qualitative) results provided by 
the analyzing laboratory: 
 
Positive: All reported qHBeAg results equal to or above the LLQ cut-off value (0.11 
PEIU/mL) 
 
 
 All results below the LLQ cut-off value where the HBeAg result is any outcome 
other than Not 
 
 
Negative: All results below the LLQ cut-off value where the HBeAg result is 
 
 
 
HBV DNA results reported as 
 
 will be imputed as 5 IU/mL. Results reported as 
 or results below the LLQ cut-off value where the status is not specified ( Detect  or 
Not Detected ) will be imputed as 15 IU/mL.  
 
The quantitative HBV RNA results will be imputed based on the HBV RNA interpretation 
provided by the analyzing laboratory. If the interpretation is reported as 
 and the result 
is below the LLQ cut-off value, the result will be imputed as 0.825 Log10 U/mL. Interpretations 


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reported as 
 or results below the LLQ cut-off value where the status is not specified 
( LLOQ  or Negative ) will be imputed as 0.4125 Log10 U/mL. 
 
Screening and baseline results below LLQ will not be imputed for any of the parameters and 
patients with results below the LLQ value at baseline will not be included in any of the post-
dose summaries or the figures for the specific parameter. 
 
Results equal to or above the LLQ cut-off value will be analyzed as reported, except where the 
result has been reported as a range 
  or 
 
 in which case the result will be imputed to 
one significant digit above or below the reported cut-off value (i.e., 
 will be analyzed as 29 
and 
 will be analyzed as 30.1). 
 
All results (except for HBV RNA) will be log transformed (base 10) for analysis purposes. 
 
Imputed results will be identified in the data listings.   
 
HBV genotyping and HBV sequencing 
 
HBV genotyping and HBV sequencing will be summarised descriptively using frequency count 
and percentage by study cohort. Emergence of HBV mutations (sequencing of ARO-HBV target 
site, Core/pre-core, HBsAg epitope, NUC resistant mutations any other mutations by deep 
sequencing) will be summarized accordingly, depending on the available HBV mutation data. 
It should be noted that the HBV sequencing data could be missing for HBeAg negative subjects 
and subjects on NUCs, as they may have HBV DNA that is too low to sequence.  
 
Quantitative assessments: HBV DNA, qHBsAg, qHBeAg, qHBcrAg, qHBV RNA, anti-HBsAg 
and ratio of bound/free anti-HBsAg (if available) 
  
Quantitative HBV DNA, qHBsAg (overall and by IL28B genotype mutation [rs12979860 and 
rs8099917]), qHBeAg qHBcrAg and qHBV RNA will be logarithm (log 10) transformed, and the 
observed log transformed value and change from baseline of the log transformed value will be 
summarised descriptively for all time points assessed. In addition, for HBV DNA, qHBsAg, 
qHBeAg, qHBcrAg, and qHBV RNA, the change to the maximum post-dose decline (nadir) 
from baseline will be pooled for a nadir 
 and summarized by cohort as well. The nadir 
values will also be calculated based on the overall study period (including the follow-up visits). 
The ratio of bound/free anti-HBsAg will be summarized descriptively without log transformation.  
The change from baseline values at each post-baseline visit will also be categorized 
 log 
 
-<1.5 log 
 
.5-< 3 log 
 
 3 log 
 and summarized.  Only 
patients with a baseline result above the LLQ for the specific parameter will be included in the 
post-baseline summaries.  
 
The summary table will also be repeated for the following subgroups (based on the categories 
described for the qualitative assessments below): 
 
Baseline HBV DNA: 
o Baseline HBV DNA Not Detected 
o Baseline HBV DNA Detected 
 
 


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Baseline HBeAg: 
o Baseline qHBeAg Negative 
o Baseline qHBeAg Positive 
 
The quantitative HBV DNA, qHBsAg, qHBeAg, qHBcrAg and qHBV RNA over time (up to Day 
113) will be plotted for mean and individual subject values, based on log transformed data, by 
cohort. The log transformed results will be plotted on a linear scale (y-axis). The log transformed 
LLQ values will be added as a horizontal reference line. The change from baseline values will 
also be presented. The plots will also be presented for the subset of CHB patients that 
participated in the follow-up period and will include all available data. Only patients with a 
baseline result above the LLQ for the specific parameter will be included in the plots. 
 
Qualitative assessments: HBV DNA, HBV RNA, HBsAg Loss, anti-HBsAg, HBeAg and anti-
HBeAg  
 
The quantitative HBV DNA results will be categorized as follows for the qualitative HBV DNA 
summary: 
 
Target Detected: All results that are equal to or above the LLQ cut-off value and results 
below the LLQ that have been classified as 
 (for example, 
 
 
 
20 Detected , etc.) by the analyzing laboratory. 
 
Target Not Detected: Results below the LLQ cut-off values that have been classified as 
 
 by the analyzing laboratory. 
 
The HBV RNA interpretation provided by the analyzing laboratory will be categorized as follows 
for the qualitative HBV RNA summary: 
 
Target Detected: All results where the interpretation provided by the analyzing 
laboratory is 
 or 
 
 
Target Not Detected: All results where the interpretation provided by the analyzing 
laboratory is 
 
 
Loss of HBsAg ( Not Detected ) is defined as HBsAg of less than 0.05 IU/mL. Post-baseline 
qHBsAg results will be classified as follows for the qualitative HBsAg summary: 
 
Loss of HBsAg: Reported qHBsAg result is below the LLQ cut-off value. 
 
HBsAg Present: Reported qHBsAg result is equal to or above the LLQ cut-off value. 
 
The qualitative HBeAg results will be categorized as follows for the qualitative HBeAg 
summary: 
 
Positive: Qualitative results reported as 
 by the analyzing laboratory. 
 
Negative: Qualitative results reported as 
 
 by the analyzing laboratory. 
 
Anti-HBsAg and anti-HBeAg will be reported as Detected  or Not Detected  by the analyzing 
laboratory. Anti-HBsAg and anti-HBeAg will only be assessed if there was a HBsAg or HBeAg 
loss during the study and may not be available at all timepoints. 
 


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Virology Responses 
 
The following virology responses are also defined based on the qualitative response data: 
 
Anti-HBsAg seroconversion is defined as the absence of HBsAg (i.e. a 
 
 
result for HBsAg which is defined as a value less than 0.05 IU/mL) and the presence of 
Anti-HBsAg (i.e. a 
 result for Anti-HBsAg). Patients will be analyzed as non-
responders (seroconversion = 
 at a specific time point if the HBsAg result at that 
time point is reported as equal to or greater than 0.05 IU/mL 
.     
 
Anti-HBeAg seroconversion is defined as the change from HBeAg 
 to HBeAg 
 
 and the presence of anti-HBeAg (i.e. a 
 result for anti-HBeAg). 
Patients will be analyzed as non-responders (seroconversion = 
 at a specific time 
point if the HBeAg result at that time point is reported as 
 Anti-HBeAg 
seroconversion is only applicable to HBeAg positive patients.  
 
For each of the response endpoints, frequent count and percentage will be summarised for 
each category of qualitative HBsAg, anti-HBsAg, anti-HBsAg seroconversion, HBeAg, anti-
HBeAg and anti-HBeAg seroconversion response by cohort for all the assessed study visits. 
The exact (Clopper-Pearson) 95% confidence interval for each category (response) will be 
reported as well. 
 
Time to Event Endpoints 
 
Time to HBsAg Loss is defined as the duration from first dosing to the date of HBsAg 
 
 (HBsAg loss defined as HBsAg < 0.05 IU/mL). Subjects without HBsAg 
loss will be censored at the end of study (or the end of follow-up period). 
 
 
Time to anti-HBsAg seroconversion is defined as the duration from first dosing to the 
date of anti-HBsAg seroconversion. Subjects without anti-HBsAg seroconversion will 
be censored at the end of study (or the end of follow-up period). 
 
 
Duration of Response (for HBV DNA, qHBsAg, qHBeAg, qHBcrAg, qHBV RNA): 
defined as the duration from post dose nadir back to within 20% of baseline value. The 
analysis will only be performed for the overall study period (including the follow-up 
period) and only patients with baseline values above the LLQ for the specific parameter 
will be included in the analysis. Subjects with the endpoint not returning to within 20% 
of baseline value will be censored at the end of the follow-up period. 
 
The time to event endpoints will be analyzed by survival analysis method. Survival analysis will 
only be conducted if there are at least some responders within a cohort. The survival functions 
of the time to event endpoints will be summarized for 25th percentile, median, and 75th 
percentile and their 95% confidence intervals. The rates of HBsAg Loss and anti-HBsAg 
seroconversion at Day 60 and Day 113 post dosing (and also at Days 169, 225, 281, 337 and 
393 for the subset of CHB subjects that participated in the follow-up), the response rates (for 
HBV DNA, qHBsAg, qHBeAg, qHBcrAg, qHBV RNA) at Day 30 and Day 60 (and additional 
time points at 30 days intervals as appropriate) post nadir, and their respective 95% confidence 
intervals will be derived based on their survival functions estimated by Kaplan-Meier method. 
In addition, the graphs of Kaplan-Meier estimates of survival functions (survival plots) will be 
presented.  Histograms will also be presented showing the response rates for each cohort over 
30-day intervals. 


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All the above analyses will be conducted by CHB cohorts. In addition, separate subgroup 
analyses might be completed for all CHB patients receiving at least one dose, all HBeAg 
negative patients and all HBeAg positive patients, all treatment naïve and all entecavir or 
tenofovir experienced patients. As the sample size is small for each CHB cohort, the subgroup 
analysis might be conducted as post hoc basis, after reviewing the data from the overall by 
CHB cohort  analyses.    
 
All virology data will be presented in the by-subject data listings.  Imputed values will be 
flagged. Separate listings that includes only patients that had results below LLQ at baseline 
and that had a post-
will be presented for all the parameters with quantitative results. 
 
 


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12. 
CELLULAR IMMUNOLOGY  
For CHB cohorts in New Zealand, if feasible, cellular immunology data will be collected at 
Days 1 (pre-dose), 43 and 113. 
 
Cellular immunology data will be analyzed using the PD Population. Descriptive statistics will 
be used for the summary. For continuous antibody measurement data, the observed value and 
change from baseline (last pre-dose value on Day 1) for each dose level (cohort) for all time 
points assessed will be summarised descriptively. In addition to other descriptive statistics, the 
summary statistics will also include geometric mean in the table. If categorical data 
(negative/positive) are reported, these values will be summarised as well for frequent count 
and percentage. Post-hoc exploratory data analyses maybe conducted depending on the data 
available. 
 
All cellular immunology data will be presented in the by-subject data listings. 
 
 


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13. 
IMMUNOGENICITY 
For CHB cohorts (Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10,11 and 12) blood samples for 
anti-drug antibodies testing will be collected at pre-dose, day 57 and at the end of study visit 
(Day 113) or at early termination as per Schedule of Assessments. Anti-drug antibodies will be 
analyzed using the Safety Population. 
 
Descriptive statistics will be summarised for anti-drug antibodies. For continuous antibody 
measurement data, the observed assay value and change from baseline (last pre-dose value 
on Day 1) for each dose level (cohort) for all time points assessed will be summarised 
descriptively. In addition to other descriptive statistics, the summary statistics will also include 
geometric mean in the table. If categorical data (negative/positive) are reported for antibody 
measurement data, these values will be summarised as well for frequent count and percentage.  
 
All anti-drug antibodies measures will be presented in the by-subject data listings. 
 
 


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14. 
CYTOKINES AND COMPLEMENT 
Cytokines Panel A (whole blood, NHV cohorts only) will be collected at the time of 0 (pre-dose), 
15 min, 0.5, 1, 2, 3, 6, 24 and 48 hours post-dose. Cytokines Panel B (whole blood, CHB 
cohorts only) will be collected across the study period according the protocol schedule of 
assessment,  
Complement (serum and plasma, NHV cohorts only) will be collected at the time of 0 (pre-
dose), 0.5, 2, 6 and 24 hours post-dose. 
Cytokines (Panels A/B) and complement data will be analyzed using the PD Population. 
Descriptive statistics will be summarised for cytokines and complement parameters, including 
the observed value, change from baseline (last pre-dose value on Day 1) and percentage 
change from baseline for each dose level (cohort) for all time points assessed. In addition to 
other descriptive statistics, the summary statistics will also include geometric mean in the table. 
Mean and individual subject assessment values of cytokines and complement parameters over 
time will be plotted.  
 
All cytokines and complement data will be presented in the by-subject data listings. 
 
 


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15. 
HANDLING OF MISSING DATA 
Missing values will not be imputed. 
 


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16. 
CHANGES TO THE PLANNED ANALYSIS 
Any changes to the analyses outlined in the approved SAP will be detailed in the Clinical 
Study Report (CSR). 
 
 


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17. 
INTERIM AND FINAL ANALYSIS 
17.1 
Dose Escalation, Data Safety Committee (DSC) Analyses 
Dose escalation will require approval by the DSC based on a review of all cumulative available 
safety data for prior cohorts. Based on observations for all NHV subjects in a cohort through 
Day 8, and experience from any prior cohorts, dosing will begin for the next NHV cohort and 
as applicable the next CHB cohort at the discretion of the DSC. 
 
Escalation to the next highest dose level will proceed in cohorts of 6 until the dose level of 400 
mg is completed, or the trial is halted prematurely by the PI, DSC or Sponsor due to safety or 
other concerns. Blinding will be preserved to the extent possible for the NHVs; however, 
treatment un-blinding may occur, at the 
 discretion, where deemed necessary for treatment 
of an AE or for a decision to be made regarding trial continuation. 
 
A formal charter will be in place prior to study start and will establish the rules, meeting 
frequency and scope of responsibilities of the DSC. 
17.2 
Interim Analyses 
 
An interim analysis of the safety and PD data was planned and performed in May 2019 (data 
cut-off 27Mar2019). This interim analysis was conducted to assist with the planning of future 
studies and Health Authority interactions and did not impact the conduct of this study. The 
Sponsor was unblinded to selected summary data only.  
 
A second interim analysis based on all study data up to Day 113 for all cohorts, was 
completed in February 2020 (data cut-off 14Nov2019). 
17.3 
Final Analysis (End of Study) 
The final end of study analysis will be based on the final version of the SAP. If feasible, Clinical 
Study Report analysis of quantitative HBsAg through EOS (Day 113) and Additional Follow-Up 
(Day 393) will be based on a final batched analysis of samples. PD analyses will be completed 
at EOS (Day 113) and at the end of additional follow up period only in subjects entering into 
the additional follow up period.  
 
 


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18. 
SOFTWARE 
The following software will be used to perform the statistical analyses: SAS® Version 9.4 or 
higher (SAS Institute, Cary, North Carolina, USA). 
 


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19. 
TABLES 
Tables will be produced separately for NHV cohorts (Cohorts 1, 2, 3, 4 and 5), CHB cohorts 
(Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12), and the subset of CHB patients that 
participated in the follow up period. 
 
No. 
Title 
Analysis 
Population 
Day 113: 
Interim 
Analysis
14.1.1.1 
Summary of Disposition 
Safety 
X 
14.1.1.2 
Summary of Demographics 
Safety 
X 
14.1.1.3.1 
Summary of Baseline Disease Characteristics 
Safety 
X 
14.1.1.3.2 
Summary of Baseline Virology Characteristics 
PD 
X 
14.2.1.1 
Summary of Plasma Concentrations of ARO-HBV 
(ng/mL) by Dose 
[NHV Cohorts 1, 2, 3, 4 and 5 only] 
PK 
X 
14.2.2.1 
Summary of Plasma Pharmacokinetic Parameters 
of ARO-HBV by Dose  
[NHV Cohorts 1, 2, 3, 4 and 5 only] 
PK 
X 
14.2.2.2 
Analysis of Dose Proportionality for ARO-HBV  
[NHV Cohorts 1, 2, 3, 4 and 5 only] 
PK 
X 
14.2.3.1 
Summary of Plasma Concentrations of ARO-HBV 
(ng/mL), Nucleos(t)ide and JNJ-6397 Plasma 
Concentrations (Cohort 12) 
[CHB Cohort 12 only] 
PK 
 
14.2.4.1 
Summary of Anti-drug Antibodies  
[CHB cohorts only] 
Safety 
 
14.2.4.2.1 
Summary of Quantitative HBV Assessments and 
Change from Baseline    
[CHB cohorts only] 
PD 
X 
14.2.4.2.1.1 
Summary of Quantitative HBV Assessments and 
Change from Baseline by Baseline HBV DNA 
Group   
[CHB cohorts only] 
PD 
X 
14.2.4.2.1.2 
Summary of Quantitative HBV Assessments and 
Change from Baseline by Baseline HBeAg Group   
[CHB cohorts only] 
PD 
X 
14.2.4.2.2 
Summary of Quantitative HBsAg (IU/mL) by 
IL28B Genotype and Change from Baseline [CHB 
cohorts only] 
PD 
 
14.2.4.2.3 
Summary of Quantitative HBV Assessments 
Change from Baseline Categories 
[CHB cohorts only] 
PD 
X 
14.2.4.2.4 
Summary of Qualitative HBV Assessments    
[CHB cohorts only] 
PD 
X 
14.2.4.3 
Summary of HBV Virology Response    
[CHB cohorts only] 
PD 
X 
14.2.4.4 
Summary of Time to HBsAg Loss   
[CHB cohorts only] 
PD 
X 
14.2.4.5 
Summary of Time to Anti-HBsAg Seroconversion  
[CHB cohorts only] 
PD 
X 
14.2.4.6 
Summary of Duration of Response for HBV DNA  
[CHB cohorts only] 
PD 
X 
14.2.4.7 
Summary of Duration of Response for HBsAg  
PD 
X 


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No. 
Title 
Analysis 
Population 
Day 113: 
Interim 
Analysis
[CHB cohorts only] 
14.2.4.8 
Summary of Duration of Response for HBeAg  
[CHB cohorts only] 
PD 
X 
14.2.4.9 
Summary of Duration of Response for HBcrAg  
[CHB cohorts only] 
PD 
X 
14.2.4.10 
Summary of Duration of Response for HBV RNA  
[CHB cohorts only] 
PD 
X 
14.2.4.11 
Summary of Cellular Immunology Parameters 
[CHB cohorts in New Zealand only] 
PD 
 
14.2.5.1 
Summary of Cytokine Parameters 
[Panel A for NHV cohorts, Panel B for CHB 
cohorts] 
PD 
X 
14.2.6.1 
Summary of Complement Parameters 
[NHV cohorts] 
PD 
X 
14.3.1.1 
Summary of Concomitant Medications and Non-
Drug Therapies 
Safety 
X 
14.3.3.1 
Overall Summary of Treatment Emergent 
Adverse Events 
Safety 
X 
14.3.3.2 
Summary of Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term 
Safety 
X 
14.3.3.3 
Summary of Treatment Emergent Adverse Events 
in Descending Order of Frequency by Preferred 
Term 
Safety 
X 
14.3.3.4 
Overall Summary of Related Treatment Emergent 
Adverse Events 
Safety 
X 
14.3.3.5.1 
Summary of Related Treatment Emergent 
Adverse Events by System Organ Class and 
Preferred Term 
Safety 
X 
14.3.3.5.2 
Summary of JNJ-6379 Related Treatment 
Emergent Adverse Events by System Organ 
Class and Preferred Term (Cohort 12) 
[CHB Cohort 12 only] 
Safety 
X 
14.3.3.6.1 
Summary of Related Treatment Emergent 
Adverse Events in Descending Order of 
Frequency by Preferred Term 
Safety 
X 
14.3.3.6.2 
Summary of JNJ-6379 Related Treatment 
Emergent Adverse Events in Descending Order of 
Frequency by Preferred Term (Cohort 12) 
[CHB Cohort 12 only] 
Safety 
X 
14.3.3.7 
Summary of Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term and 
by Severity 
Safety 
X 
14.3.3.8 
Summary of Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term and 
by Relationship to Study Drug 
Safety 
X 
14.3.3.9 
Summary of Serious Treatment Emergent 
Adverse Events by System Organ Class and 
Preferred Term 
Safety 
X 
14.3.3.10.1 
Summary of Serious Study Drug Related 
Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety 
X 


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No. 
Title 
Analysis 
Population 
Day 113: 
Interim 
Analysis
14.3.3.10.2 
Summary of Serious JNJ-6379 Related Treatment 
Emergent Adverse Events by System Organ 
Class and Preferred Term (Cohort 12) 
[CHB Cohort 12 only] 
Safety 
X 
14.3.3.11 
Summary of Treatment Emergent Adverse Events 
Leading to Study Drug or Study Withdrawn  
Safety 
X 
14.3.3.12 
Summary of Treatment Emergent Adverse Events 
Occurring at the Treatment Injection Site 
Safety 
X 
14.3.3.13 
Summary of Treatment Emergent Adverse Events 
Fitting the Definition of Local Injection Site 
Reactions (LISR)  
(See LISR definition in Section 10.1) 
Safety 
X 
14.3.3.14 
Summary of Treatment Emergent Adverse Events 
Fitting the Definition of Local Injection Site 
Reactions (LISR) by System Organ Class and 
Preferred Term and by Severity 
Safety 
X 
14.3.4.1 
Laboratory  Hematology: Summary and Change 
from Baseline 
Safety 
X 
14.3.4.2 
Laboratory - Chemistry: Summary and Change 
from Baseline 
Safety 
X 
14.3.4.3 
Laboratory  Coagulation: Summary and Change 
from Baseline 
Safety 
X 
14.3.4.4 
Laboratory - Urinalysis: Summary and Change 
from Baseline 
Safety 
X 
14.3.4.5 
Summary of Haematology Shifts from Baseline 
Safety 
X 
14.3.4.6 
Summary of Biochemistry Shifts from Baseline 
Safety 
X 
14.3.4.7 
Summary of Coagulation Shifts from Baseline 
Safety 
X 
14.3.4.8 
Summary of Subjects with ALT above Upper Limit 
of Normal Over Time  
[CHB cohorts only] 
Safety 
X 
14.3.5.1 
Summary of Vital Signs 
Safety 
X 
14.3.6.1 
Summary of Physical Examination 
Safety 
X 
14.3.7.1 
Summary of ECG Values 
Safety 
X 
14.3.7.2 
Summary of ECG Findings 
Safety 
X 
 
 
 


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20. 
LISTINGS 
Listings will be produced separately for NHV cohorts (Cohorts 1, 2, 3, 4 and 5) and CHB 
cohorts (Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10,11 and 12). 
 
No. 
Title 
Analysis 
Population
Day 113: 
Interim 
Analysis 
16.2.1.1 
Listing of Enrolment 
Safety 
X 
16.2.1.2 
Listing of Eligibility Criteria 
Safety 
X 
16.2.2.1 
Listing of Protocol Deviations 
Safety 
X 
16.2.3.1.1 
Listing of Disposition 
Safety 
X 
16.2.3.1.2 
Listing of Disposition (Follow-Up) 
Safety 
X 
16.2.3.2 
Listing of Randomization 
[NHV Cohorts 1, 2, 3, 4 and 5 only] 
Safety 
X  
16.2.4.1 
Listing of Demographics 
Safety 
X 
16.2.4.2 
Listing of Medical History 
Safety 
X 
16.2.4.3 
Listing of Child-bearing Potential, Follicle-
Stimulating Hormone (FSH) Results and 
Pregnancy Test 
Safety 
X 
16.2.4.4 
Listing of Serology Screen 
Safety 
X 
16.2.4.5 
Listing of Drug Screen 
Safety 
X 
16.2.4.6 
Listing of Hepatic Fibrosis Measure 
Safety 
X 
16.2.4.7 
Listing of Baseline Disease Characteristics 
[CHB cohorts only] 
Safety 
X 
16.2.5.1 
Listing of Study Drug Administrations 
Safety 
X 
16.2.5.2 
Listing of Concomitant/Prior Medications and 
Non-Drug Therapies 
Safety 
X 
16.2.5.3 
Listing of Dispensing of Nucleos(t)ide 
[CHB cohorts only] 
Safety 
X 
16.2.5.4 
Listing of JNJ-6397 Compliance (Cohort 12) 
[CHB Cohort 12 only] 
Safety 
X 
16.2.5.5 
Listing of JNJ-6397 Dosing Deviations 
(Cohort 12) 
[CHB Cohort 12 only] 
Safety 
X 
16.2.6.1.1 
Listing of Individual ARO-HBV Plasma 
Concentration (ng/mL) 
[NHV cohorts only] 
Safety 
X 
16.2.6.1.2 
Listing of Individual ARO-HBV, Nucleos(t)ide 
and JNJ-6397 Plasma Concentrations 
(Cohort 12) 
[CHB Cohort 12 only] 
PK 
 
16.2.6.2 
Listing of Individual ARO-HBV Plasma 
Pharmacokinetic Parameters 
[NHV cohorts only] 
PK 
X 
16.2.6.3 
Listing of Anti-drug Antibodies   
[CHB cohorts only] 
Safety 
 
16.2.6.4.1 
Listing of HBV Genotyping and HBV 
Sequencing    
[CHB cohorts only] 
PD 
X 
16.2.6.4.2.1.1 
Listing of Quantitative HBV Serology: HBV 
DNA     
[CHB cohorts only] 
PD 
X 


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No. 
Title 
Analysis 
Population
Day 113: 
Interim 
Analysis 
16.2.6.4.2.1.2 
Listing of Quantitative HBV Serology: HBV 
DNA  Baseline Result Below LLQ     
[CHB cohorts only] 
PD 
X 
16.2.6.4.2.2.1 
Listing of Quantitative HBV Serology: HBsAg   
[CHB cohorts only] 
PD 
X 
16.2.6.4.2.2.2 
Listing of Quantitative HBV Serology: HBsAg 
 Baseline Result Below LLQ         
[CHB cohorts only] 
PD 
X 
16.2.6.4.2.3.1 
Listing of Quantitative HBV Serology: HBeAg  
[CHB cohorts only] 
PD 
X 
16.2.6.4.2.3.2 
Listing of Quantitative HBV Serology: HBeAg 
 Baseline Result Below LLQ         
[CHB cohorts only] 
PD 
X 
16.2.6.4.2.4.1 
Listing of Quantitative HBV Serology: HBcrAg 
[CHB cohorts only] 
PD 
X 
16.2.6.4.2.4.2 
Listing of Quantitative HBV Serology: HBcrAg 
 Baseline Result Below LLQ         
[CHB cohorts only] 
PD 
X 
16.2.6.4.2.5.1 
Listing of Quantitative HBV Serology: HBV 
RNA     
[CHB cohorts only] 
PD 
X 
16.2.6.4.2.5.2 
Listing of Quantitative HBV Serology: HBV 
RNA  Baseline Result Below LLQ         
[CHB cohorts only] 
PD 
X 
16.2.6.4.2.6 
Listing of Quantitative HBV Serology: Ratio of 
Bound/Free Anti-HBsAg     
[CHB cohorts only] 
PD 
X 
16.2.6.4.3 
Listing of HBV Virology Responses 
[CHB cohorts only] 
PD 
X 
16.2.6.4.4 
Listing of HBV Virology Time to Event 
Endpoints 
[CHB cohorts only] 
PD 
X 
16.2.6.4.5 
Listing of HBV Virology Time to Event 
Endpoints (Follow-Up) 
[CHB cohorts only] 
PD 
X 
16.2.6.5 
Listing of Cellular Immunology Parameters 
[CHB cohorts in New Zealand] 
PD 
 
16.2.6.6 
Listing of Cytokine Parameters 
[Panel A for NHV cohorts, Panel B for CHB 
cohorts] 
PD 
X 
16.2.6.7 
Listing of Complement Parameters 
[NHV cohorts only] 
PD 
X 
16.2.7.1.1 
Listing of Adverse Events 
Safety 
X 
16.2.7.1.2 
Listing of Adverse Events (Cohort 12) 
[CHB Cohort 12 only] 
Safety 
X 
16.2.7.2 
Listing of Serious Adverse Events 
Safety 
X 
16.2.7.3 
Listing of Adverse Events Leading to Study 
Drug Withdrawn or Study Withdrawn 
Safety 
X 
16.2.7.4 
Listing of Adverse Events Occurring at the 
Treatment Injection Site 
Safety 
X 


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No. 
Title 
Analysis 
Population
Day 113: 
Interim 
Analysis 
16.2.7.5 
Listing of Adverse Events Fitting the 
Definition of LISR 
Safety 
X 
16.2.8.1 
Listing of Haematology 
Safety 
X 
16.2.8.2 
Listing of Biochemistry  
Safety 
X 
16.2.8.3 
Listing of Coagulation 
Safety 
X 
16.2.8.4 
Listing of Urinalysis 
Safety 
X 
16.2.8.5 
Listing of Microscopic Urinalysis 
Safety 
X 
16.2.9.1 
Listing of Vital Signs 
Safety 
X 
16.2.10.1 
Listing of Physical Examination 
Safety 
X 
16.2.11.1 
Listing of ECG Values 
Safety 
X 
16.2.11.2 
Listing of ECG Findings 
Safety 
X 
14.2.2.2 
Analysis of Dose Proportionality for ARO-
HBV  
PK 
X 
 


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21. 
FIGURES 
PK Figures will be produced for NHV cohorts (Cohorts 1, 2, 3, 4 and 5). Others will be produced 
separately for NHV cohorts (Cohorts 1, 2, 3, 4 and 5), CHB cohorts (Cohorts 1b, 1c, 2b, 3b, 
4b, 5b, 6, 7, 8, 9, 10,11 and 12), and the subset of CHB patients that participated in the follow 
up period. 
 
No. 
Title 
Analysis 
Population
Day 113: 
Interim 
Analysis 
14.2.1.1.1a 
Mean (+/-SD) Plasma Concentrations of ARO-
HBV versus Time by Dose (Linear Scale)  
PK 
X 
14.2.1.1.1b 
Mean (+/-SD) Plasma Concentrations of ARO-
HBV versus Time by Dose (Semilogarithmic 
Scale)  
PK 
X 
14.2.1.2.1a 
Median Plasma Concentrations of ARO-HBV 
versus Time by Dose (Linear Scale)  
PK 
X 
14.2.1.2.1b 
Median Plasma Concentrations of ARO-HBV 
versus Time by Dose (Semilogarithmic Scale)  
PK 
X 
14.2.2.1.1a 
Individual Plasma Concentrations of ARO-HBV 
versus Time (Linear Scale) 
PK 
X 
14.2.2.1.1b 
Individual Plasma Concentrations of ARO-HBV 
versus Time (Semilogarithmic Scale) 
PK 
X 
14.2.1.1.2a 
Mean (+/-SD) Plasma Concentrations of ARO-
HBV, Nucleos(t)ide and JNJ-6397 versus Time 
by Dose (Linear Scale) (Cohort 12) 
[CHB Cohort 12 only] 
PK 
X 
14.2.1.1.2b 
Mean (+/-SD) Plasma Concentrations of ARO-
HBV, Nucleos(t)ide and JNJ-6397 versus Time 
by Dose (Semilogarithmic Scale) (Cohort 12) 
[CHB Cohort 12 only] 
PK 
X 
14.2.1.2.2a 
Median Plasma Concentrations of ARO-HBV, 
Nucleos(t)ide and JNJ-6397 versus Time by 
Dose (Linear Scale) (Cohort 12) 
[CHB Cohort 12 only] 
PK 
X 
14.2.1.2.2b 
Median Plasma Concentrations of ARO-HBV, 
Nucleos(t)ide and JNJ-6397 versus Time by 
Dose (Semilogarithmic Scale) (Cohort 12) 
[CHB Cohort 12 only] 
PK 
X 
14.2.2.1.2a 
Individual Plasma Concentrations of ARO-HBV, 
Nucleos(t)ide and JNJ-6397 versus Time 
(Linear Scale) 
PK 
X 
14.2.2.1.2b 
Individual Plasma Concentrations of ARO-HBV, 
Nucleos(t)ide and JNJ-6397 versus Time 
(Semilogarithmic Scale) (Cohort 12) 
[CHB Cohort 12 only] 
PK 
X 
14.2.3.1 
Scatterplot of Individual and Mean Plasma 
AUC0-24 versus Dose for ARO-HBV 
PK 
X 
14.2.3.2 
Scatterplot of Individual and Mean Plasma 
AUC0-inf versus Dose for ARO-HBV 
PK 
X 
14.2.3.3 
Scatterplot of Individual and Mean Plasma 
AUC0-t versus Dose for ARO-HBV 
PK 
X 
14.2.3.4 
Scatterplot of Individual and Mean Plasma Cmax 
versus Dose for ARO-HBV 
PK 
X 


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No. 
Title 
Analysis 
Population
Day 113: 
Interim 
Analysis 
14.2.4.1 
Scatterplot of Individual and Mean Plasma 
Dose Normalized AUC0-24 versus Dose for 
ARO-HBV 
PK 
X 
14.2.4.2 
Scatterplot of Individual and Mean Plasma 
Dose Normalized AUC0-inf versus Dose for 
ARO-HBV 
PK 
X 
14.2.4.3 
Scatterplot of Individual and Mean Plasma 
Dose Normalized AUC0-t versus Dose for ARO-
HBV 
PK 
X 
14.2.4.4 
Scatterplot of Individual and Mean Plasma 
Dose Normalized Cmax versus Dose for ARO-
HBV 
PK 
X 
14.2.5.1 
Mean (+/-SD) of Creatinine versus Time by 
Cohort 
Safety 
X 
14.2.5.2 
Mean (+/-SD) of Creatine Kinase versus Time 
by Cohort 
Safety 
X 
14.2.5.3 
Mean (+/-SD) of AST versus Time by Cohort 
Safety 
X 
14.2.5.4 
Mean (+/-SD) of ALT versus Time by Cohort 
Safety 
X 
14.2.5.5 
Mean (+/-SD) of Total Bilirubin versus Time by 
Cohort 
Safety 
X 
14.2.6.1.1 
Mean (+/-SD) of Logarithm Transformed 
Quantitative HBV DNA versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.6.1.2 
Mean (+/-SD) Change from Baseline in 
Logarithm Transformed Quantitative HBV DNA 
versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.6.2.1 
Mean (+/-SD) of Logarithm Transformed 
Quantitative HBsAg versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.6.2.2 
Mean (+/-SD) Change from Baseline in 
Logarithm Transformed Quantitative HBsAg 
versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.6.3.1 
Mean (+/-SD) of Logarithm Transformed 
Quantitative HBeAg versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.6.3.2 
Mean (+/-SD) Change from Baseline in 
Logarithm Transformed Quantitative HBeAg 
versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.6.4.1 
Mean (+/-SD) of Logarithm Transformed 
Quantitative HBcrAg versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.6.4.2 
Mean (+/-SD) Change from Baseline in 
Logarithm Transformed Quantitative HBcrAg 
versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.6.5.1 
Mean (+/-SD) of Logarithm Transformed 
Quantitative HBV RNA versus Time by Cohort 
[CHB cohorts only] 
PD 
X 


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No. 
Title 
Analysis 
Population
Day 113: 
Interim 
Analysis 
14.2.6.5.2 
Mean (+/-SD) Change from Baseline in 
Logarithm Transformed Quantitative HBV RNA 
versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.7.1.1 
Individual Logarithm Transformed Quantitative 
HBV DNA versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.7.1.2 
Individual Change from Baseline in Logarithm 
Transformed Quantitative HBV DNA versus 
Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.7.2.1 
Individual Logarithm Transformed Quantitative 
HBsAg versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.7.2.2 
Individual Change from Baseline in Logarithm 
Transformed Quantitative HBsAg versus Time 
by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.7.3.1 
Individual Logarithm Transformed Quantitative 
HBeAg versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.7.3.2 
Individual Change from Baseline in Logarithm 
Transformed Quantitative HBeAg versus Time 
by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.7.4.1 
Individual Logarithm Transformed Quantitative 
HBcrAg versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.7.4.2 
Individual Change from Baseline in Logarithm 
Transformed Quantitative HBcrAg versus Time 
by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.7.5.1 
Individual Logarithm Transformed Quantitative 
HBV RNA versus Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.7.5.2 
Individual Change from Baseline in Logarithm 
Transformed Quantitative HBV RNA versus 
Time by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.8.1 
Kaplan-Meier Plot of Time to HBsAg Loss by 
Cohort 
[CHB cohorts only] 
PD 
X 
14.2.8.2 
Kaplan-Meier Plot of Time to Anti-HBsAg 
Seroconversion by Cohort 
[CHB cohorts only] 
PD 
X 
14.2.8.3 
Kaplan-Meier Plot of Duration of Response for 
Quantitative HBV DNA by Cohort (Follow-Up) 
[CHB cohorts only] 
PD 
X 
14.2.8.4 
Kaplan-Meier Plot of Duration of Response for 
Quantitative HBsAg by Cohort (Follow-Up) 
[CHB cohorts only] 
PD 
X 


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Page 51 of 53
 
 
No. 
Title 
Analysis 
Population
Day 113: 
Interim 
Analysis 
14.2.8.5 
Kaplan-Meier Plot of Duration of Response for 
Quantitative HBeAg by Cohort (Follow-Up) 
[CHB cohorts only] 
PD 
X 
14.2.8.6 
Kaplan-Meier Plot of Duration of Response for 
Quantitative HBcrAg by Cohort (Follow-Up) 
[CHB cohorts only] 
PD 
X 
14.2.8.7 
Kaplan-Meier Plot of Duration of Response for 
Quantitative HBV RNA by Cohort (Follow-Up) 
[CHB cohorts only] 
PD 
X 
14.2.8.8 
Histogram of Duration of Response for 
Quantitative HBV DNA by Cohort (Follow-Up) 
[CHB cohorts only] 
PD 
X 
14.2.8.9 
Histogram of Duration of Response for 
Quantitative HBsAg by Cohort (Follow-Up) 
[CHB cohorts only] 
PD 
X 
14.2.8.10 
Histogram of Duration of Response for 
Quantitative HBeAg by Cohort (Follow-Up) 
[CHB cohorts only] 
PD 
X 
14.2.8.11 
Histogram of Duration of Response for 
Quantitative HBcrAg by Cohort (Follow-Up) 
[CHB cohorts only] 
PD 
X 
14.2.8.12 
Histogram of Duration of Response for 
Quantitative HBV RNA by Cohort (Follow-Up) 
[CHB cohorts only] 
PD 
X 
14.2.9.1 
Mean (+/-SD) of Cytokine Parameter Levels 
versus Time by Dose 
PD 
X 
14.2.9.2 
Mean (+/-SD) of Cytokine Parameter Change 
from Baseline versus Time by Dose 
PD 
X 
14.2.9.3 
Mean (+/-SD) of Cytokine Parameter 
Percentage Change from Baseline versus Time 
by Dose 
PD 
X 
14.2.10.1 
Individual Cytokine Parameter Levels versus 
Time 
PD 
X 
14.2.10.2 
Individual Cytokine Parameter Change from 
Baseline versus Time 
PD 
X 
14.2.10.3 
Individual Cytokine Parameter Percentage 
Change from Baseline versus Time 
PD 
X 
14.2.11.1 
Mean (+/-SD) of Complement Parameter Levels 
versus Time by Dose 
PD 
X 
14.2.11.2 
Mean (+/-SD) of Complement Parameter 
Change from Baseline versus Time by Dose 
PD 
X 
14.2.11.3 
Mean (+/-SD) of Complement Parameter 
Percentage Change from Baseline versus Time 
by Dose 
PD 
X 
14.2.12.1 
Individual Complement Parameter Levels 
versus Time 
PD 
X 
14.2.12.2 
Individual Complement Parameter Change from 
Baseline versus Time 
PD 
X 
14.2.12.3 
Individual Complement Parameter Percentage 
Change from Baseline versus Time 
PD 
X 


Protocol Number: AROHBV1001 
 
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Novotech - Strictly Confidential 
 
Page 52 of 53
 
 
Notes: Each cytokine and complement parameter will be plotted separately. Therefore, each 
PD output above could have multiple plots. 
 
 


Protocol Number: AROHBV1001 
 
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Page 53 of 53
 
 
22. 
REFERENCES 
1) AROHBV1001 Clinical Study Protocol, Version 4.0, 01Oct2018 
2) AROHBV1001 Clinical Study Protocol, Version 5.0, 04Jan2019 
3) AROHBV1001 Clinical Study Protocol, Version 6.0, 28Feb2019 
 
 

Prot_000.pdf: 
Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 1 of 93 
Protocol No.: AROHBV1001 
 
Version 6.0 February 28, 2020 FINAL  
 
PROTOCOL 
NUMBER: 
AROHBV1001 
STUDY TITLE: 
A Phase 1/2a Single Dose-Escalating Study to Evaluate the Safety, 
Tolerability and Pharmacokinetic Effects of ARO-HBV in Normal 
Adult Volunteers and Multiple Escalating Doses Evaluating Safety, 
Tolerability and Pharmacodynamic Effects in HBV Patients 
 
 
DRUG (Active): 
ARO-HBV 
 
ROUTE: 
Subcutaneous Injection  
 
STUDY DESIGN: 
Double blind, escalating single dose administrations to normal adult 
volunteers assessing safety, tolerability and pharmacokinetics and 
open label, escalating multiple dose administrations assessing safety, 
tolerability and pharmacodynamic effects in patients with chronic 
HBV infection 
 
SPONSOR: 
Arrowhead Pharmaceuticals, Inc. 
177 E. Colorado Blvd., Suite 700 
Pasadena, CA 91105 
Telephone: +1 626 304 3400     Facsimile: +1 626 304 3401 
 
 
 
 
 
 
 
 
 
 
 
 
This amendment, specific to Hong Kong only, reduces the 
protocol required follow-up period to Day 337 (±5 days) 
for the open-label CHB Cohort 12 patients only. All 
previously enrolled CHB cohorts will continue with follow-
up visits until Day 393 (±5 days). 
 
Confidential 
Information contained in this protocol includes trade secrets and commercial information that is privileged or 
confidential and should not be disclosed, other than to those directly involved in the execution or ethical review of the 
study, without written authorization from Arrowhead Pharmaceuticals, Inc. It is, however, permissible to provide 
information to a volunteer to obtain consent. In any event, persons to whom the information is disclosed must be informed 
that the information is privileged or confidential and may not be further disclosed by them. 
 
 
 


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Protocol No.: AROHBV1001 
 
Version 6.0 February 28, 2020 FINAL  
1 
PROTOCOL SYNOPSIS 
 
Study Title:  A Phase 1/2a Single Dose-Escalating Study to Evaluate the Safety, Tolerability and Pharmacokinetic 
Effects of ARO-HBV in Normal Adult Volunteers and Multiple Escalating Doses Evaluating Safety, Tolerability and 
Pharmacodynamic Effects in HBV Patients 
Study Number:  AROHBV1001 
Phase:  Phase 1 First-in-Human, Phase 2a First-in-Patient 
Number of Sites:  Healthy volunteers: Single site in New Zealand  
                               Patients chronically infected with Hepatitis B: multiple sites in New Zealand, Australia and 
Hong Kong 
Study Treatments:   
There will be up to three study treatments (depending on the cohort); two active (Test Formulation) ARO-HBV 
and JNJ-56136379 (JNJ-6379) and one placebo (Reference Formulation).   
Test Formulation:   
The test formulation is active ARO-HBV Injection (also referred to as ARO-HBV).  The active pharmaceutical 
ingredient (API) contained in ARO-HBV is composed of a 2:1 molar mixture of two synthetic, double-stranded, 
small interfering RNA (siRNA) duplexes each separately conjugated to a N-acetyl-galactosamine targeting ligand 
to facilitate hepatocyte delivery. 
Cohort 12 only will add JNJ-56136379 (JNJ-6379) as a study treatment to be evaluated in CHB patients in 
combination with ARO-HBV. JNJ-6379 is a capsid assembly modulator (CAM) being developed for the treatment 
of hepatitis B infection. JNJ-6379 binds to the HBV core protein and interferes with the viral capsid assembly 
process and resulting in the formation of empty viral capsids devoid of HBV-DNA. JNJ-6379 also acts at an early 
stage of the viral life cycle by inhibiting the de novo formation of cccDNA. 
Reference Formulation:   
The reference formulation is placebo (PBO): normal saline (0.9%) administered subcutaneously, volume matched 
to the corresponding ARO-HBV dose volume. 
 
Study Objectives:   
Primary Objectives:   
• 
To determine the incidence and frequency of adverse events possibly or probably related to treatment as a 
measure of the safety and tolerability of ARO-HBV using escalating single doses in healthy volunteers 
(NHV) and escalating multiple doses in patients chronically infected with hepatitis B virus (CHB). 
Secondary Objectives:    
• 
To evaluate the single-dose pharmacokinetics of ARO-HBV in NHVs 
• 
To determine the reduction from Day 1 pre-dose baseline to post-dose nadir of HBsAg in response to 
ARO-HBV in patients chronically infected with HBV (CHB) as a measure of activity. 
Exploratory Objectives 
• 
To determine the reduction from Day 1 pre-dose baseline to post-dose nadir of HBcrAg, HBsAg, HBV 
RNA (if scientifically feasible) and HBeAg (e+ patients only), in response to ARO-HBV (alone or in 
combination with JNJ-6379) in CHB patients as a measure of activity. 


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Protocol No.: AROHBV1001 
 
Version 6.0 February 28, 2020 FINAL  
• 
To evaluate the effect of single doses of ARO-HBV on cytokines (Cytokine panel A: interleukin-6 [IL-6], 
monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-alpha [TNF-alpha], interleukin-8 
[IL-8], interleukin-1beta [IL-1beta], interferon alpha [IFN alpha], IL-10, IL-12 [p40], IL-12 [p70], 
macrophage inflammatory protein-1alpha [Mip-1alpha]) in NHVs. 
• 
To evaluate the effect of single escalating doses of ARO-HBV on complement factors Bb, CH50, C5a, 
C4a, and C3a in NHVs. 
• 
To collect plasma samples in NHVs for subsequent metabolite identification (reported in a separate report 
outside of this study) 
• 
To collect urine samples in NHVs for subsequent determination of urinary excretion and metabolite 
identification (reported in a separate report outside of this study).  
• 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with JNJ-6379) on 
cytokines (Cytokine panel B: TNF alpha, IFN gamma, CXCL-9, and CXCL-10) in CHB patients 
• 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with JNJ-6379) on HBV 
patient immune cell profile including T-cells, NK cells, B cells and monocytes (if scientifically feasible). 
• 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with JNJ-6379) on HBV 
antigen specific T-cell response (if scientifically feasible).  
• 
To evaluate the effect of interferon response gene single nucleotide polymorphisms (SNPs) including 
IL28B on response to ARO-HBV (alone or in combination with JNJ-6379). 
• 
To determine the incidence and frequency of adverse events possibly or probably related to treatment as a 
measure of the safety and tolerability of ARO-HBV in combination with JNJ-6379 in patients chronically 
infected with hepatitis B virus (CHB) (Cohort 12 only). 
 
Study Population/Patient Number:  This study will be conducted in NHVs, adult males and females, aged 18-55 
years with BMI between 19.0 and 35.0 kg/m² (Cohorts 1 – 5) and in HBeAg negative or HBeAg positive CHB 
patients, aged 18-65 years with BMI between 19.0 and 38.0 kg/m² (Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 
11and 12). Cohort 8 will enroll HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or 
Interferon) and Cohort 9 will enroll HBeAg positive NUC experienced patients (on entecavir or tenofovir for at 
least 12 months). Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10, 11 and 12 will enroll either HBeAg positive or negative 
patients regardless of previous NUC or PEG IFN treatment experience. Only Cohort 12 patients will start JNJ-
6379 on Day 1 and continue until Day 84. All patients will be started on entecavir or tenofovir on Day 1. Patients 
currently on PEG IFN will not be allowed.   
 
Summary of Participant Profile by Cohort: 
• 
Cohorts 1-5: NHVs, adult males and females, aged 18-55 years 
• 
Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10, 11 and 12: Any CHB patient regardless of HBeAg or prior therapy 
status (as long as other Inclusion and Exclusion criteria are met).  
• 
Cohort 8: HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or Interferon). 
• 
Cohort 9: HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 months). 
 
NHV subjects will enroll sequentially into a total of 5 cohorts (comprised of 6 subjects each), randomized to 
receive ARO-HBV or placebo (4 active: 2 placebo) at single escalating doses of 35, 100, 200, 300 and 400 mg 
administered as a single subcutaneous injection.  
CHB cohorts 1b, 1c, 2b, 3b, 4b and 5b will each enroll a minimum of 4 and a maximum of 8 subjects in an open 


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label fashion to receive escalating multiple doses of ARO-HBV. Cohorts 6, 7, 8, 9, 10 and 11 will each enroll a 
maximum of 4 subjects. Cohort 12 will enroll 12 CHB patients to each receive 250 mg daily oral JNJ-
6379+NUCs+200mg ARO-HBV Q28 days X3 doses. 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially into a total of 11 
open label cohorts (Cohorts 2b through 7, Cohorts 10, 11, 12, 1b and 1c). Cohorts 1b, and 1c through 5b will enroll 
at planned dose levels of 25 mg (Cohort 1b), 50 mg (Cohort 1c), 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg 
(Cohort 4b) and 400 mg (Cohort 5b) to receive three doses (Q28 days) of active treatment in an open label fashion. 
Cohort 6 will enroll CHB subjects (after Cohort 5b has completed enrollment) to receive three doses two weeks 
apart. Cohorts 7, 10 and 11 will enroll CHB patients sequentially (after Cohort 6 has completed enrollment) to 
receive three doses a week apart at increasing dose levels starting with a dose equal to Cohort 6. Cohorts 5b 
through 7 and Cohorts 10 and 11 will enroll sequentially (after being opened at the final planned DSC meeting) 
with enrollment and dosing in a later cohort not initiating until all subjects in the earlier cohort have received at 
least their first scheduled dose. Cohort 8 will enroll HBeAg positive treatment naïve CHB patients to receive three 
monthly doses of ARO-HBV. Cohort 9 will enroll HBeAg positive entecavir or tenofovir experienced CHB 
patients to receive three monthly doses of ARO-HBV. Cohorts 8 and 9 may enroll in parallel with Cohort 5b once 
opened by the DSC. Cohorts 6 through 12 will enroll at planned dose levels of 100 mg (Cohorts 6 and 7), 200 mg 
(Cohorts 10 and 12), and 300 mg (Cohorts 8, 9, and 11). CHB patient screening for all CHB cohorts may start 
when Cohort 1 opens for enrollment. However, no CHB patients may be dosed until their respective cohort is 
approved for dosing by the DSC (not including Cohorts 1b, 1c and 12). CHB dosing may begin and NHV dose 
escalation may occur based on DSC approval which can occur by vote after cumulative data through Day 8 from 
the current NHV cohort is available. See Figure 1 for dose escalation schedule). CHB patients on current NUC 
therapy (entecavir or tenofovir) will stay on NUC therapy for the study duration. CHB patients not on NUC 
therapy (NUC naïve) will be started on either entecavir or tenofovir (selection between entecavir and tenofovir 
based on site Principal Investigator (PI) discretion) on Day 1.  Either tenofovir disoproxil fumarate (including 
generic) or tenofovir alafenamide are acceptable. 
Cohort 12 will enroll 12 CHB patients to receive ARO-HBV 200 mg on Days 1, 29 and 57. Like all other CHB 
cohorts, patients enrolling in Cohort 12 will either enter the study on NUCs or start NUCs on Day 1. Cohort 12 
patients will also initiate daily JNJ-6379 250 mg on Day 1 and continue through Day 84. 
NHV subjects who withdraw from the study prior to collection of the final pharmacokinetic blood sample, for 
reasons other than an adverse event, may be replaced.  CHB patients who are withdrawn or discontinue prior to the 
End-of-Study visit (EOS/Day 113) for reasons other than an adverse event, may be replaced.  
A total of approximately 30 NHV and a minimum of 60 or a maximum of 84 CHB participants (not including 
potential replacements) may be enrolled in the study.   
Number of Doses per Treatment:  Single dose (Healthy Volunteer Cohorts 1 through 5) or three doses of ARO-
HBV ranging in frequency from once weekly to once every 4 weeks (CHB patients).  
Daily dose of JNJ-6379 250 mg from Day 1 through Day 84 (Cohort 12 CHB patients only). 
Study Duration:  For each NHV subject in the single dose cohorts, the duration of the study clinic visits is a 
maximum of 13 weeks from the beginning of the screening period to the Day 29 EOS examination.  
For each CHB patient in the multi-dose Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12 the duration of 
the study clinic visits is approximately 25 weeks from screening to the Day 113 EOS examination.  With the 
exception of Cohort 12 patients, all other CHB patients consenting to additional follow up will be followed as 
per Additional Follow-Up Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits 
after Day 113. Only Cohort 12 patients will require follow-up until the Day 337 (±5 days) visit. Subjects 
consenting to additional follow up will continue on NUCs. Subjects not consenting to additional follow up will 
be followed per protocol based on Schedule of Assessment Tables 1.2, 1.3 and 1.4.  
All CHB patients and NHV subjects will be contacted by phone 90 days after the EOS visit (post Day 29 for 
NHVs and post Day 113 for CHB patients) to confirm pregnancy status.  
Study Confinement:  For NHVs, clinical facility confinement will be approximately 2 days for single dose 
administration (Day -1 through 24-hour assessments).  Subjects will return to the clinical facility for out-patient 


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visits.  
For CHB patients, clinical facility confinement will be approximately 2 hours on dosing days unless additional 
monitoring at PI discretion is needed for safety reasons.  Patients will return to the clinical facility for outpatient 
visits.    
Study Design/Methods:   
Healthy volunteers: 
For NHVs, cohorts of 6 eligible subjects (2 placebo, 4 active ARO-HBV) will be evaluated at each dose level 
starting at dose level 1 (35 mg). Participants who have signed an HDEC (or local equivalent) approved informed 
consent form and have met all of the protocol eligibility criteria during screening, will be randomized at a ratio of 
2:1 (active:PBO) to receive ARO-HBV or PBO in a double blind fashion.  NHV cohorts will receive a single dose 
only.   
Each cohort will begin with administration of ARO-HBV or PBO to two sentinel participants (one ARO-HBV, one 
PBO). Following the Day 3 evaluation in these participants, if there are no significant safety concerns based on 
PI’s judgement, the remaining participants in the cohort will be treated. Dosing of participants will be staggered by 
at least 15 minutes such that no two participants will be dosed simultaneously. 
Clinical facility confinement will be approximately 2 days for single dose administration (Day -1 through 24-hour 
assessments). Blood samples will be drawn pre-dose on Day 1 for baseline measurements.  Height and weight will 
be measured at Screening only to calculate BMI.   
Based on observations for all NHV subjects in a cohort through Day 8, and experience from any prior cohorts, 
dosing will begin for the next NHV cohort and as applicable the next CHB cohort at the discretion of the DSC. 
Escalation to the next highest dose level will proceed in cohorts of 6 until the dose level of 400 mg is completed, or 
the trial is halted prematurely by the PI, DSC or Sponsor due to safety or other concerns. Blinding will be 
preserved to the extent possible for the NHVs; however, treatment un-blinding may occur, at the PI’s discretion, 
where deemed necessary for treatment of an AE or for a decision to be made regarding trial continuation.  
After all subjects in a cohort have completed an EOS visit (Day 29), Sponsor may be unblinded at Sponsor’s request. 
PI and study participants will remain blinded.  
 
CHB patients: 
In Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12, eligible CHB patients who have signed an HDEC (or 
local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose intervals ranging 
from once every week to once every 4 weeks in an open label fashion. In addition, Cohort 12 patients will also 
initiate daily JNJ-6379 250 mg on Day 1 and continue through Day 84. Screening for the CHB cohorts can begin 
once Cohort 1 dosing has commenced. These cohorts (not including Cohorts 1b, 1c and 12) will be opened for 
accrual once the corresponding NHV cohort receiving the same single dose level has reached Day 8, based on 
agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8, 9, 10 and 11 can be opened for enrollment any 
time after Cohort 5 has reached Day 8 (and DSC has approved opening of such cohorts) and there is sufficient viral 
antigen response data from CHB patients to determine a dose level for these cohorts (at the discretion of the DSC). 
Dose levels for Cohorts 6-12 is between 100 and 300 mg.   Cohorts 2b through Cohort 7 and Cohorts 10 and 11, 
will be enrolled in sequence (as shown in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other CHB 
cohorts after the DSC has voted post Cohort 5 to open the remaining CHB patient cohorts and the specified dose (≤ 
300 mg) has been identified. Cohort 12 is open for enrollment in Hong Kong only. Cohorts 1b and 1c are open for 
enrollment with the addition of a protocol amendment and may enroll in parallel. For clarity, after Cohort 5 is 
through Day 8, the DSC will review all available safety data and vote to open Cohorts 5b, 6, 7, 8, 9, 10 and 11. 
Cohorts 5b, 8 and 9 may enroll and dose patients in parallel. Cohorts 5b through 7 and Cohorts 10 and 11 must 
enroll sequentially, meaning that Cohort 5b must be fully enrolled with each subject receiving at least a first dose 
before Cohort 6 can enroll. Cohort 6 must be fully enrolled with each subject receiving at least a first dose before 
Cohort 7 can enroll. Cohort 7 must be fully enrolled with each subject receiving at least a first dose before Cohort 
10 can enroll and Cohort 10 must be fully enrolled with each subject receiving at least a first dose before Cohort 11 
can enroll. It is the intent that Cohorts 7, 10 and 11 will be treated at increasing dose levels starting with a dose 
equal to Cohort 6. 


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Enrollment in Cohort 12 can begin once enrollment is full in Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11. The ARO-
HBV dose level for Cohort 12 is 200 mg Q28 days (Days 1, 29, 57). Cohort 12 patients will also initiate daily JNJ-
6379 250 mg on Day 1 and continue through Day 84. 
 
On dosing days, clinical facility confinement will be approximately 2 hours. Blood samples will be drawn pre-dose 
on Day 1 for baseline measurements.  Height and weight will be measured at Screening only to calculate BMI. 
Participants will undergo evaluations at screening and at regular intervals during the study as described in the 
Schedule of Assessments. 
With the exception of Cohort 12 patients, all other CHB patients consenting to additional follow up will be 
followed as per Additional Follow-Up Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 
additional visits after Day 113. Only Cohort 12 patients will require follow-up until the Day 337 (±5 days) 
visit. Subjects consenting to additional follow up will continue on NUCs. Subjects not consenting to additional 
follow up will be followed per protocol based on Schedule of Assessment Tables 1.2, 1.3 and 1.4.  
Single doses of ARO-HBV will be evaluated in normal healthy volunteers (NHVs) and multiple doses of ARO-
HBV will be evaluated in patients with chronic hepatitis B (CHB) in a sequential manner as shown in Figure 1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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     Figure 1: Dose Escalation Schedule 
Healthy Volunteers (double blind) * 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose Regimen 
Cohort 1 
 
35 mg 
 
Cohort 1b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
ARO-HBV 25 mg 
dosed on Day 1, 
29, 57 
 
 
 
Cohort 1c (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
ARO-HBV 50 mg 
dosed on Day 1, 
29, 57 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
ARO-HBV 100 
mg dosed on Day 
1, 29, 57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
ARO-HBV 200 
mg dosed on Day 
1, 29, 57 
Cohort 4 
300 mg 
 
Cohort 4b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
ARO-HBV 300 
mg dosed on Day 
1, 29, 57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
ARO-HBV 400 
mg dosed on Day 
1, 29, 57 
 
 
  
 
Cohort 6 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
ARO-HBV 100 
mg dosed on Day 
1, 15, 29 
 
 
 
Cohort 7 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
ARO-HBV 100 
mg dosed on Day 
1, 8, 15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
ARO-HBV 300 
mg dosed on Day 
1, 29, 57  
 
 
 
Cohort 9 HBeAg+, 
entecavir or tenofovir 
experienced  
ARO-HBV 300 
mg dosed on Day 
1, 29, 57  
 
 
 
Cohort 10 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
ARO-HBV 200 
mg dosed on Day 
1, 8, 15 
 
 
 
Cohort 11 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
ARO-HBV 300 
mg dosed on Day 
1, 8, 15  
 
 
 
Cohort 12 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
JNJ-6379 daily 
250mg + ARO-
HBV 200 mg dosed 
on Day 1, 29, 57 


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* All NHV Cohorts use 2 sentinel subjects 
Unblinding of NHV cohorts may occur at Sponsor discretion on a cohort by cohort basis after all subjects in a 
cohort have completed their last on-site study visit. Study participants as well as sites will remain blinded.  
Open label anti-viral response data may be disclosed to investigators by the Sponsor at Sponsor’s discretion. There 
is no requirement for Sponsor to disclose anti-viral response data while the study is ongoing unless required for 
safety reasons.  
Adverse Event Monitoring 
Safety assessments will include: AEs/SAEs, physical examinations, vital sign measurements (blood pressure, heart 
rate, temperature, and respiratory rate), ECGs, clinical laboratory tests, concomitant medications/therapy, and 
reasons for treatment discontinuation. Safety assessments will be performed at specified time points and prior to 
study completion.  
The AE/SAE reporting period for an enrolled participant begins when the participant provides informed consent. 
Treatment-emergent AEs/SAEs are defined as those following study drug administration or pre-existing condition 
exacerbated by study drug. All AEs that occur during the AE reporting period specified in the protocol must be 
reported to Arrowhead via electronic case report forms within approximately 48 hours. All SAEs that occur during 
the reporting period, in addition to reporting via electronic case report forms, must also be reported to Arrowhead 
via the SAE report form within 24 hours of awareness. All AE/SAEs will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the participant is lost to follow-up. If the PI 
learns of any SAE, including a death, at any time after a patient has been discharged from the study, and he/she 
considers the event reasonably related to the investigational product, the PI will promptly notify the Sponsor.  
Laboratory abnormalities will be reported as AEs if considered clinically significant by the PI. Laboratory 
abnormalities not reported as AEs are not to be reported as Clinically Significant (CS) in the study database. 
 
Treatment Stopping Rules:   
Escalation to the next cohort will proceed according to the study design through the 400 mg dose level and until all 
subsequent cohorts are completed unless the trial is stopped early by the DSC or Sponsor. A decision to stop the 
trial early or discontinue drug in an individual subject or group of subjects may (following a case-by-case decision 
based on consultation between the sponsor, DSC and the PI) be indicated based on any of the following:  
 
1. A single Serious Adverse Event (SAE, defined in Section 9.1) considered at least possibly related to 
ARO-HBV or JNJ-6379 
2. One of the following abnormal results at least possibly related to ARO-HBV or JNJ-6379: 
• 
In NHVs, treatment emergent ALT or AST > 3X ULN, which must be confirmed by repeat blood 
draw within 48 hours of initial results.  
• 
In CHB patients, treatment emergent ALT or AST > 3X Day 1 pre-dose baseline, confirmed by 
repeat blood draw within 48 hours of initial results AND ALT > 10X ULN AND any one of the 
following: 
o 
Total Bilirubin newly elevated to 2X ULN AND 2X Day 1 pre-dose baseline (confirmed on 
repeat lab draw within 48 hours) or 
o 
Decrease in serum albumin of 0.5 g/dL or greater confirmed on repeat lab draw within 48 
hours 
 
• 
Treatment emergent platelet count < 70,000 per microliter in NHVs or < 50,000 in CHB patients, 
confirmed on repeat measure within 48 hours of initial results 
• 
Treatment emergent serum creatinine > 180 μmol/L confirmed by repeat blood draw within 48 hours 
of initial results 
 
Sponsor or PI can discontinue any subject at any time with or without DSC consultation. If such events (as 
described above) occur and the subject is not discontinued from the study the reason for not discontinuing the 
subject will be included in DSC meeting minutes. Including, but not limited to the events listed above, the DSC 
may pause the study to additional dosing or dose escalation to provide time to evaluate safety data and recommend 
the action to be taken, which may include, but is not limited to one of the following: 


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• Discontinuation of a subject or group of subjects from the study  
• The study is stopped immediately with no further dosing 
• The study will continue until the current cohort is completed 
• The study will continue, but the next dose escalation will be to a level midway between the current level 
and the next level specified in Section 8.3  
• The study will continue as planned  
 
Study Assessments:  
 
Safety Assessments: 
Safety assessments will be performed at specified time points per the Schedule of Assessments and will include the 
following:  
• 
Vital signs: Resting heart rate, semi-supine systolic/diastolic blood pressure, respiratory rate and 
temperature  
• 
Clinical laboratory measurements (e.g., biochemistry, hematology, coagulation and urinalysis) 
• 
Resting ECG measurements (measured after participant is semi-supine for at least 3 minutes). 
• 
At each visit, participants will be asked about concomitant medications/therapy and will be instructed to 
volunteer any information regarding AEs and SAEs that he/she may have experienced. Any known 
untoward event that occurs beyond the AE reporting period that the PI considers an SAE possibly related 
to study treatment will be reported as an SAE.  
• 
Injection site reactions: Injection site reactions will be defined and graded as mild, moderate or severe 
(based on clinical findings). ISRs will be photographed at time of reporting and at time of resolution. 
• 
90-day post-EOS pregnancy follow up call.  
 
 
Immunologic Assessments (limited number of HBV patients in New Zealand only) 
• 
Patient immune cell profile: T cell subsets (activation and exhaustion state), NK cell subsets (activation 
and exhaustion state), B cell subset, monocyte subsets. To be conducted if scientifically feasible.  
• 
HBV antigen specific T cell response (including HBcAg, HBsAg). To be conducted if scientifically 
feasible.   
 
Virology assessments (CHB patients only) 
Virology assessments will be performed at specified time points per the Schedule of Assessments and will include 
the following: 
• 
Qualitative assessments:  HBsAg, HBeAg, anti-HBs, anti-HBe 
• 
Quantitative assessments: HBV DNA, qHBsAg, qHBeAg, qHBcrAg, qHBV RNA (if feasible), anti-HBs 
and ratio of bound/free anti-HBs  
• 
HBV genotyping and HBV sequencing 
Immunogenicity: 
For Cohorts 1b, 1c, 2b, 3b, 4b, 5b, and 6-12 blood samples for the anti-drug antibodies test will be collected at 
screening, Day 57 and Day 113 or at the end of study visit.  
 
Pharmacokinetics (NHVs only and limited PK in Cohort 12): 
Blood samples will be collected from each subject for pharmacokinetic analysis after dose 1 (Cohorts 1-5) per the 
Schedule of Assessments and for Cohort 12 patients per the Schedule of Assessments. 
Genetic Testing (CHBs only): 
If subject consents to genetic testing while actively participating in the study, one whole blood sample will be 


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collected on Day 1 or any time thereafter for SNP analysis for IFN response genes.  
Cytokines:  
Blood samples will be collected from each NHV participant for cytokine analysis per the Schedule of Assessments.  
The resultant serum will be analyzed for the following cytokine panel A:  IL-6, MCP-1, TNF-alpha, IL-8, IL-
1beta, IFN alpha, IL-10, IL-12 (p40), IL-12 (p70), and Mip-1alpha. CHB patients will have cytokine panel B (TNF 
alpha, IFN gamma, CXCL-9, and CXCL-10) measured as per Schedule of Assessments.  In Cohorts 1-5 (Panel A), 
initially the 0 (pre-) and 2-hour post-dose samples will be analyzed, with the remaining samples analyzed only if a 
change from pre-dose baseline is observed at 2 hours.   
Complement:  
Blood samples will be collected from each NHV (Cohorts 1-5) participant during the study for Complement 
analysis after dose 1 (all cohorts).  Two blood samples will be collected at each collection time.  One sample will 
be processed to produce serum for complement CH50 analysis, and one sample will be processed to produce 
plasma, which will be analyzed to determine the level of split products Bb, C5a, C4a, and C3a.  Initially the 0 (pre-
) and 2-hour post-dose samples will be analyzed, with the remaining samples analyzed only if a change from pre-
dose baseline is observed at 2 hours.   
 
Excretion and Metabolism: 
Seven blood samples will be collected from each subject for metabolic analysis after dose 1 (Cohorts 2-5) per the 
Schedule of Assessments. Samples will be frozen at -80ºC for analysis outside of this study.   
Urine collections will be performed after dosing per the Schedule of Assessments.  
 
Data Analysis: 
 
Two separate data analyses will be performed, one for all subjects through EOS (Day 29 for NHVs and Day 113 
for CHB patients), and one additional and separate analysis for CHB patients who consent to the additional follow 
up through Day 337 (Cohort 12 only) or Day 393. Separate analyses including and excluding Cohort 12 may also 
be completed. 
 
Screening, Compliance, Tolerability and Safety Data: 
In general, safety analyses will be performed and the results summarized by cohort. Post-treatment safety 
assessments will be compared with measurements recorded at baseline. Treatment emergent AEs will be 
summarized using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) by System 
Organ Class (SOC) and Preferred Term (PT). The incidence and frequency of AEs, SAEs, related AEs, related 
SAEs, and AEs leading to discontinuation, will be summarized by cohort per SOC, PT, and severity. All Adverse 
Events will also be presented in listings. The duration of AEs will be determined and included in listings, along 
with the action taken and outcome. The incidence of laboratory abnormalities will be assessed using descriptive 
summary statistics and shift tables. Vital sign measurements will be summarized at each scheduled time point 
using descriptive statistics. Abnormal physical examination findings will be summarized by time point and 
presented in subject listings. ECG parameters, changes from baseline, and qualitative assessments will be 
summarized. Pregnancy and FSH test results will be listed separately by time point. 
 
Safety population:  All participants (NHV and CHB patients) that received at least one dose of ARO-HBV or JNJ-
6379. 
 
Unless otherwise specified, for data analysis purposes baseline will be defined as pre-dose on Day 1.  
 
Immunology Assessments (limited number of CHB patients in New Zealand only) 
Immunology parameters will be summarized by cohort for the following: 
• 
Changes in profile from pre-dose to post-dose time points for: T cell subsets (activation and exhaustion 
state), NK cell subsets (activation and exhaustion state), B cell subset, monocyte subsets. To be conducted 
if scientifically feasible. 
• 
Changes from pre-dose to post-dose time points for: HBV antigen specific T cell response (including 


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HBcAg, HBsAg). To be conducted if scientifically feasible.   
 
Virology assessments (CHB patients only) 
Virologic parameters will be summarized by cohort for the following: 
• 
Quantitative HBsAg (qHBsAg: Log change from baseline to nadir and duration of response from nadir 
back to approximately 20% of baseline or EOS  
• 
Percent of patients with loss of HBsAg (defined as HBsAg < 0.05 IU/mL) at EOS and time to occurrence 
(Kaplan Meier) 
• 
Percent of patients with anti-HBS seroconversion at EOS and time to occurrence (Kaplan Meier). 
• 
Change in Anti-HBs (quantitative) over time  
• 
Quantitative HBV DNA (when quantifiable at baseline): Log change from baseline to EOS 
• 
Quantitative HBV RNA: Log change from baseline to nadir and duration of response from baseline to 
EOS (if scientifically feasible) 
• 
Quantitative HBcrAg: Log change from baseline to nadir and duration of response from baseline to EOS 
• 
Quantitative HBeAg (where applicable): Log change from baseline to nadir and duration of response from 
baseline to EOS 
• 
Emergence of HBV mutations (sequencing of ARO-HBV target site, Core/pre-core, HBsAg epitope, any 
other mutations by deep sequencing) 
 
Descriptive statistics of virologic parameters will include mean, median, count, SD, minimum, and maximum. 
Additional details will be provided in the statistical analysis plan. 
 
Separate analysis will be completed for all CHB patients receiving at least one dose, all HBeAg negative patients 
and all HBeAg positive patients, all treatment naïve and all entecavir or tenofovir experienced patients.   
 
Pharmacokinetics (NHV subjects and limited PK in Cohort 12): 
Plasma concentrations of ARO-HBV product constituents will be used to calculate the following PK parameters: 
maximum observed plasma concentration (Cmax), area under the plasma concentration time curve (AUC) from time 
0 to 24 hours (AUC0-24), AUC from time 0 extrapolated to infinity (AUCinf), and terminal elimination half-life (t½). 
Pharmacokinetic parameters will be determined using non-compartmental methods. Descriptive statistics of PK 
parameters will include mean, standard deviation (SD), coefficient of variation, median, minimum, and maximum. 
PK results will be analyzed for dose proportionality, and sex differences.  
 
Plasma concentrations of ARO-HBV, NUC and JNJ-6379 will be measured at a single post-dose time point in 
Cohort 12 only. 
 
PK population:  All NHV subjects and Cohort 12 patients that received at least one dose of active study treatment 
(ARO-HBV). 
 
Genetic Testing (CHB patients only): 
Evaluate mean and maximum nadir HBsAg decline in relationship to patient variants in interferon response genes 
(e.g. IL28B).  
 
Pharmacodynamics:  
Pharmacodynamic results, percent change, and duration of response from baseline to 24 hours post-dose will be 
analyzed and summarized by cohort and number of doses administered.   
 
Immunogenicity (Anti-Drug Antibodies): 
Changes from assay negative to positive will be summarized by dose and number of doses administered. 
Descriptive statistics of immunogenicity parameters will include mean, SD, minimum, and maximum.  
 
Additional details will be provided in the statistical analysis plan. 
 


















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TABLE OF CONTENTS  
 
1 
PROTOCOL SYNOPSIS ............................................................................................................. 2 
2 
STUDY INFORMATION AND SIGNATURES ...................................................................... 23 
3 
LIST OF ABBREVIATIONS AND TERMS ........................................................................... 24 
4 
INTRODUCTION ...................................................................................................................... 26 
4.1 
Background Information ........................................................................................................ 26 
4.2 
ARO-HBV and JNJ-6379 Pre-clinical Pharmacology and Toxicology Studies .................... 27 
4.3 
ARO-HBV Clinical Studies ................................................................................................... 28 
4.4 
JNJ-6379 Clinical Studies ...................................................................................................... 30 
4.5 
ARO-HBV and JNJ-6379 Pre-Clinical Pharmacokinetic and Product Metabolism Studies . 32 
4.6 
Rationale for the Study .......................................................................................................... 33 
4.7 
Risk Assessment for Participants ........................................................................................... 34 
4.8 
Justification for Dose of ARO-HBV and JNJ-6379 ............................................................... 36 
5 
OBJECTIVES ............................................................................................................................. 38 
5.1 
Primary Objectives ................................................................................................................. 38 
5.2 
Secondary Objectives ............................................................................................................. 38 
5.3 
Exploratory Objectives .......................................................................................................... 38 
6 
STUDY PLAN ............................................................................................................................. 39 
6.1 
Study Design .......................................................................................................................... 39 
6.2 
Rationale for Study Design .................................................................................................... 44 
6.3 
Criteria for Dose-escalation and Stopping Rules ................................................................... 46 
6.4 
Duration of the Study ............................................................................................................. 47 
7 
SUBJECT SELECTION ............................................................................................................ 48 
7.1 
Number of Subjects ................................................................................................................ 48 
7.2 
Inclusion Criteria .................................................................................................................... 48 
7.3 
Exclusion Criteria .................................................................................................................. 50 
7.4 
Participant Withdrawal Criteria ............................................................................................. 54 
7.5 
Restrictions and Concomitant Medications ........................................................................... 55 
8 
INVESTIGATIONAL PRODUCT ........................................................................................... 56 
8.1 
ARO-HBV Description, Identification and Dosage ............................................................... 56 
8.2 
Supply, Preparation, Storage and Labelling of ARO-HBV ................................................... 57 
8.3 
JNJ-6379 Physical Description of Study Drug(s) .................................................................. 58 
8.4 
Packaging and Storage ........................................................................................................... 58 
8.5 
Study Drug Handling ............................................................................................................. 58 
8.6 
Accountability of Study Supplies........................................................................................... 59 
8.7 
Retention of Investigational Product Vials ............................................................................ 60 
8.8 
Allocation to Treatment ......................................................................................................... 60 
8.9 
Blinding and Code-break ....................................................................................................... 61 


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9 
STUDY METHODS AND SCHEDULES ................................................................................. 62 
9.1 
Overview of Procedures ......................................................................................................... 62 
9.2 
Selection and Screening ......................................................................................................... 63 
9.3 
On-Study Procedures/Assessments ........................................................................................ 64 
9.3.1 
Study Procedures: Clinical Facility Confinement ....................................................... 64 
9.3.2 
Demographics/Medical History................................................................................... 64 
9.3.3 
Physical Exam ............................................................................................................. 65 
9.3.4 
Electrocardiogram ....................................................................................................... 65 
9.3.5 
Vital Sign Assessments ............................................................................................... 65 
9.3.6 
Clinical Laboratory Tests & Pharmacodynamic Values ............................................. 65 
9.3.7 
Pharmacokinetics ......................................................................................................... 67 
9.3.8 
Concomitant Medications/Therapies ........................................................................... 67 
9.3.9 
Follow-Up Procedures ................................................................................................. 67 
9.3.10 
Early Termination Procedures ..................................................................................... 68 
9.4 
Allocation of Formulations .................................................................................................... 68 
9.5 
Study Formulation Administration ........................................................................................ 69 
9.6 
Timing of Treatments and Procedures ................................................................................... 69 
9.7 
Safety Endpoints .................................................................................................................... 70 
9.8 
Blood Sampling for Pharmacokinetic and Pharmacodynamic Analysis ................................ 71 
10 
ADVERSE EVENTS .................................................................................................................. 72 
10.1 
Definitions .............................................................................................................................. 72 
10.2 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs ..................... 73 
10.3 
Timing, Frequency, and Method of Detecting AEs ............................................................... 74 
10.4 
Recording of AEs ................................................................................................................... 74 
10.5 
Evaluating AEs ...................................................................................................................... 74 
10.6 
Follow-up of AEs ................................................................................................................... 76 
10.7 
Prompt Reporting of SAEs .................................................................................................... 77 
10.8 
Regulatory Requirements for Reporting of SAEs .................................................................. 78 
10.9 
Post-study AEs ....................................................................................................................... 78 
10.10 SAEs Related to Study Participation ...................................................................................... 78 
11 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ........................................... 79 
11.1 
Data analysis through EOS and Additional follow-up ........................................................... 79 
11.2 
Sample Size Considerations ................................................................................................... 79 
11.3 
Screening Data ....................................................................................................................... 79 
11.4 
Safety/Tolerability Data ......................................................................................................... 79 
11.5 
Pharmacokinetic Data ............................................................................................................ 80 
11.6 
Pharmacodynamic Data ......................................................................................................... 81 
11.7 
Data Recording and Quality Control ...................................................................................... 83 
12 
STUDY APPROVAL AND CONDUCT ................................................................................... 83 
12.1 
Regulatory Approval .............................................................................................................. 83 
12.2 
Institutional Review Board/Ethics Committee (HDEC or local equivalent) Approval ......... 83 
12.3 
Ethical Considerations ........................................................................................................... 84 


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12.4 
Written Informed Consent ..................................................................................................... 84 
12.5 
Emergency Contact with Principal Investigator .................................................................... 85 
12.6 
Notification of General Practitioner ....................................................................................... 85 
12.7 
Clinical Laboratory Certification and Reference Ranges ...................................................... 85 
12.8 
Protocol Deviations ................................................................................................................ 85 
12.9 
Termination of the Study ....................................................................................................... 86 
13 
STUDY ADMINISTRATION ................................................................................................... 87 
13.1 
Study Monitoring ................................................................................................................... 87 
13.2 
Quality Assurance .................................................................................................................. 88 
13.3 
Records Retention .................................................................................................................. 88 
14 
INFORMATION DISCLOSURE AND INVENTIONS .......................................................... 89 
14.1 
Ownership .............................................................................................................................. 89 
14.2 
Confidentiality ....................................................................................................................... 90 
14.3 
Publication ............................................................................................................................. 90 
15 
REFERENCES ........................................................................................................................... 92 
16 
APPENDIX 1: ALT FLARE GUIDELINES ............................................................................ 93 
 


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2 
STUDY INFORMATION AND SIGNATURES 
 
 
Investigator’s Statement: 
I have read and understood the information in this protocol and agree to conduct the trial according 
to the protocol (subject to any amendments) and in accordance with the principles of Good Clinical 
Practice. I have read and agree to comply with the Investigator obligations stated in this protocol. 
Any changes in procedure will only be made if necessary to protect the safety, rights or welfare of 
participants. 
I agree to conduct in person or to supervise the trial. 
I agree to ensure that all that assist me in the conduct of the study are aware of their obligations. 
 
 
 
 
 
Principal Investigator: 
 
 
 
 _______________________________  
________________________________ 
 
 Signature 
Date 
 
 
 
 
 
 
 
 _______________________________  
 
 
 Printed Name 
 
 
 
 
 


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3 
LIST OF ABBREVIATIONS AND TERMS 
 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
API 
Active Pharmaceutical Ingredient 
AST 
aspartate transaminase 
ARO-HBVAPI 
Solution for Injection 
Vial containing sterile, liquid API 
ARO-HBV 
Clinical drug product solution ready for SC injection 
AUC 
Area Under Curve 
B cell 
Lymphocyte not processed by the thymus and producing antibodies 
BMI 
Body Mass Index 
BP 
Blood Pressure 
cGMP 
current Good Manufacturing Practice 
CAM 
Capsid Assembly Modulator 
cccDNA 
Covalently Closed Circular DNA 
CDM 
Carboxy Dimethyl Maleic anhydride 
CHB 
Chronic hepatitis B 
Cmax 
Concentration maximum (peak) 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTN  
Clinical Trial Notification 
CVA 
Cerebrovascular Accident 
DSC  
Data Safety Committee 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
HBcAg 
HBV core antigen 
HBcrAg 
HBV core related antigen 
HBeAg 
HBV E (envelope) antigen 
HBsAg 
HBV S (surface) antigen 
HBV 
Hepatitis B virus 
HDEC 
Health and Disabilities Ethics Committee 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonisation  
IFN 
Interferon 
IFNalpha 
Interferon alpha 
IL-6 
Interleukin-6 
IL-8 
Interleukin-8 
IL-1beta 
Interleukin-1beta 
IL-10 
Interleukin-10 
IL-12p40 
Interleukin-12p40 


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IL-12p70 
Interleukin-12p70 
JNJ-6379 
JNJ-56136379, a capsid assembly modulator (CAM) 
MCP-1 
Monocyte chemoattractant protein-1 
MDMA 
3,4-Methylenedioxymethamphetamine 
MLP 
Melittin-like peptide 
MLP-(CDM-NAG) 
MLP chemically modified with CDM-NAG  
mmHg 
millimeters of mercury 
NAG 
N-acetyl galactosamine 
NHV 
Normal healthy volunteer 
NK cell 
Natural Killer Cell 
NUC 
Nucleos(t)ide inhibitors 
NYHA 
New York Heart Association 
OTC 
Over-the-counter 
PD 
Pharmacodynamic 
PBO 
PK 
Placebo 
Pharmacokinetic 
PR 
PR interval - measured from the beginning of the P wave to the 
beginning of the QRS complex 
PT 
Prothrombin time 
QRS 
QRS duration (complex) - a structure on the ECG that corresponds to the 
depolarization of the ventricles 
QT 
QT interval - a measure of the time between the start of the Q wave and 
the end of the T wave in the heart's electrical cycle 
QTc 
QT interval corrected for heart rate 
RNAi 
SAD 
RNA interference 
Single Ascending Dose 
SAE 
Serious Adverse Event  
siRNA 
Short interfering RNA oligonucleotides  
SNP 
Single Nucleotide Polymorphism 
T cell 
Lymphocyte produced or processed by thymus gland 
TIA 
Transient Ischemic Attack 
TNF alpha 
Tumor Necrosis Factor 
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
UNA 
Unlocked Nucleobase Analog containing RNAi trigger molecule  
 
 
 
 
 
 


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4 
INTRODUCTION 
4.1 
Background Information 
Globally, an estimated 360 million people are chronically infected with hepatitis B virus (HBV) and 
up to 1 million a year die because of hepatocellular carcinoma, cirrhosis of the liver, or liver failure 
caused by HBV. When drug treatment is deemed appropriate, the current treatment for chronic HBV 
infection is a daily oral dose of nucleotide/nucleoside analogs (NUC) (depending on renal function) or 
a regimen of interferon injections 1 to 7 times weekly for a year or longer. Nucleotide/nucleoside 
analogs effectively reduce viral deoxyribonucleic acid (DNA) production by inhibiting the viral 
polymerase, but patients can expect to take these antivirals for life because viral replication quickly 
rebounds upon cessation of treatment in more than half of patients who are HBeAg (+) at baseline and 
more than 80% in patients who are HBeAg (-) with Chronic Hepatitis B (CHB). A more desirable 
outcome would be HBV surface antigen (HBsAg) loss with or without S-antigen seroconversion, 
which is an effective antibody response to the envelope protein that is also called HBsAg. S-antigen 
loss (with or without seroconversion to Anti-HBsAg) represents immune mediated viral clearance and 
is considered a functional cure, if HBV DNA is also undetectable. Nucleotide/nucleoside analog 
treatment has very little effect, if any on the level of HBsAg that is produced, nor on production of the 
other viral proteins. The highly abundant HBsAg produced in the infected patient, as high as 
1012 particles/mL of blood, is believed to counteract virus-neutralizing Anti-HBsAg antibodies, 
allowing the virus to spread cell to cell and to be maintained in the host. The large quantities of 
secreted HBsAg also lead to T-cell exhaustion and anergy. Thus, even on NUC therapy, the rate of 
HBsAg loss in CHB patients is only about 1% annually, even after many years of NUC treatment. The 
rate of HBsAg clearance is similarly low from interferon treatment, and these therapeutics cause 
significant side effects, including severe flu-like symptoms, bone marrow suppression, and 
autoimmune disorders. The lack of satisfactory therapeutics for treatment of chronic HBV infection 
highlights the need for a different approach to this disease. 
Arrowhead Pharmaceuticals, Inc. has developed a product candidate, ARO-HBV to treat chronic HBV 
infection. ARO-HBV is designed to produce interference with HBV ribonucleic acid (RNA) 
translation into viral proteins, and also to knock down reverse transcription of HBV RNA into viral 
DNA, necessary for production of infectious viral particles. This novel product should allow testing of 
the hypothesis that significantly reducing circulating viral proteins, principally HBsAg, will allow for 
reconstitution of an effective host immune response and ultimately seroclearance. Seroclearance in 


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HBV patients, whether spontaneous or drug-induced, is associated with persistent absence of viremia 
and a reversal of hepatic inflammation off therapy. 
ARO-HBV is a RNA interference (RNAi) based therapy. RNAi is a naturally-occurring phenomenon 
by which short interfering RNA oligonucleotides (siRNAs) trigger a sequence-specific down-
modulation of gene expression. By delivering the siRNAs targeting HBV sequences to hepatocytes, it 
is possible to knock down expression of viral RNAs. This results in a reduction in viral load and viral 
proteins that result in disease and are believed to hinder the immune system’s ability to eliminate the 
virus. Reawakening the immune system could allow a chronically infected patient to mount an 
effective antiviral response, resulting in a functional cure.  
JNJ-6379 is a capsid assembly modulator (CAM) being developed for the treatment of hepatitis B 
infection. JNJ-6379 binds to the HBV core protein and interferes with the viral capsid assembly 
process and resulting in the formation of empty viral capsids devoid of HBV-DNA. JNJ-6379 also acts 
at an early stage of the viral life cycle by inhibiting the de novo formation of cccDNA. It is thought 
that by using an siRNA approach to silence production of viral antigen in combination with NUCs to 
inhibit viral replication and JNJ-6379 which inhibits capsid assembly and cccDNA formation the 
response to treatment and potentially the rate of functional cure could be enhanced.  
4.2 
ARO-HBV and JNJ-6379 Pre-clinical Pharmacology and Toxicology Studies 
ARO-HBV has been studied in rats and in monkeys in single and multi-dose toxicity studies up to 
doses of 300 mg/kg. Further details regarding the nonclinical safety results are provided in the 
Investigator’s Brochure. The human JNJ-6379 exposure at 28 days of 250 mg oral dose and the 
observed NOAEL in 6 month rat and 9 month dog exposure studies are described in Table 1.  Details 
regarding nonclinical safety results using JNJ-6379 are provided in the JNJ-56136379 Investigator’s 
Brochure.  
 
 
 
 
 


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Table 1. 
 
Sex 
NOAEL 
(mg 
eq./kg/day) 
Cmax 
(ng/mL) 
AUC0-24h 
(ng.h/mL) 
Ratio Total 
Concentration 
Ratio 
Concentration 
Corrected for 
Plasma Protein 
Bindingb 
Cmax 
A/H 
Ratio 
AUC0-24h 
A/H 
Ratio 
Cmax 
A/H 
Ratio 
AUC0-24h 
A/H 
Ratio 
Human exposurea 
13,798 
265,384 
- 
- 
 
 
6M rat 
M 
30 
7,540 
93,100 
0.6 
0.4 
0.9 
0.6 
M 
100c 
13,600d 
180,000d 
1.0 
0.7 
1.7 
1.1 
F 
100 
19,900 
233,000  
1.4 
0.9 
2.4 
1.5 
9M dog 
M 
25 
30,000 
606,000 
2.2 
2.3 
3.3 
3.5 
F 
12.5 
22,500 
383,000 
1.6 
1.4 
2.5 
2.2 
250 mg JNJ-56136379 once daily for 28 days (Study 56136379HPB1001). 
b Ratio of the total Cmax or AUC corrected for species difference in plasma unbound fraction. Calculation: [animal 
Cmax or AUC0-24h x animal free fraction] / [human Cmax or AUC0-24h x human free fraction]. 
c A dose of 100 mg eq./kg/day in male rats is considered to be above the NOAEL due to kidney findings in male 
rats, which are likely not relevant for human.  
d The plasma Cmax of 13,600 ng/mL and AUC0-24h of 180,000 ng h/mL in male rats at 100 mg eq./kg/day corresponds 
to an unbound Cmax of 1,754 ng/mL and AUC0-24h of 23,220 ng h/mL (fraction unbound rat plasma=12.9%). This 
unbound plasma exposure will be achieved in humans at a total plasma Cmax of 22,784 ng/ml and AUC0-24h of 
301,558 ng.h/mL (fraction unbound in human plasma=7.7%). 
 
4.3 
ARO-HBV Clinical Studies 
Sponsor has conducted extensive clinical evaluation of other anti-HBV compounds using an siRNA 
mechanism including ARC-520 Injection and ARC-521 Injection. The critical difference between 
ARO-HBV and ARC-520/521 is that ARO-HBV is a conjugate of siRNA to a hepatocyte specific 
targeting ligand, N-acetyl-galactosamine which can be administered subcutaneously. ARC-520/521 
used a separate delivery excipient (ARC-EX1) which was co-injected intravenously with the siRNA 
API. ARO-HBV requires no delivery excipient. ARC-EX1 is no longer being developed. In a Phase 
1a/b study of ARC-521 conducted using escalating single doses in healthy volunteers up to a dose of 6 
mg/kg and using a multiple escalating dose regimen in HBV patients, ARC-521 was well tolerated and 
demonstrated anti-viral activity (See Investigator Brochure for details). Thirty-six NHVs and 11 HBV 
patients received ARC-521 in this study. 
Similarly, ARC-520 has been evaluated in a Phase 1, first in human, single ascending dose study in 
healthy subjects (Heparc-1001). Fifty-four subjects were successfully dosed in the Phase 1 study with 
36 having received active drug. All dosing cohorts were completed without dose adjustment. There 
were no serious AEs or drug related AEs rated as severe, no discontinuations due to adverse events 


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(AEs) and a modest occurrence rate of AEs. A similar single dose healthy volunteer study (Heparc-
1002 study) was conducted in 40 subjects using doses of either 4 mg/kg, 5 mg/kg or 6 mg/kg with 
similar favorable safety findings. Overall, it was concluded that a single IV administration of ARC-
520 appeared to be safe and well-tolerated up to a single dose of 6.0 mg/kg in a healthy volunteer 
population. ARC-520 has also been evaluated in a Phase 2a, single ascending dose study in HBeAg 
negative and HBeAg positive, chronic hepatitis B patients to evaluate safety and tolerability as well as 
depth and duration of HBsAg knockdown (Heparc-2001) which was extended into a multi-dose study 
in select HBV patients. In the Heparc-2001 study, patients were randomized to receive a single dose of 
PBO (0.9% Normal Saline) or ARC-520 in cohorts of four escalating doses (1, 2, 3 and 4 mg/kg). A 
total of 58 patients were enrolled of which 48 received active treatment at doses between 1 and 4 
mg/kg and 10 received PBO. In Heparc-2001 were no premature discontinuations, no serious or severe 
adverse events, no clinically relevant changes in physical exam, ECG or vital signs and no dose-
limiting toxicities. An interim analysis of pharmacodynamic results showed that ARC-520 can 
produce deep (up to 1.9 log) and sustained reductions of multiple antigens (HBsAg, HBeAg, and 
HBcrAg) derived from cccDNA. Reductions in HBsAg in NUC experienced and HBeAg negative 
patients were less pronounced, consistent with lower levels of cccDNA derived mRNA transcripts in 
these patients.  Additional multiple dose studies of ARC-520 including the Heparc-2002, 2003, 2004, 
2007 and 2008 studies (which in aggregate exposed a total of 264 HBV patients to various doses of 
ARC-520) all demonstrated similar safety profiles. Across all clinical studies, both ARC-520 and 
ARC-521 were safe and well tolerated in a healthy volunteer and HBV patient populations.  
The ARC-520 and ARC-521 programs were terminated early due to toxicity findings related to high 
doses of ARC-EX1 in a non-human primate study.  Non-human primate toxicity findings were specific 
to the use of the ARC-EX1 excipient which is not used with ARO-HBV. Toxicity findings were not 
related to the siRNA API.  
The potent reductions in viral antigens seen using ARC-520/521 and as described in the Investigator 
Brochure provides strong proof of concept for testing of next generation siRNA compounds like ARO-
HBV in HBV patients. Additionally, the human safety profile seen with ARC-520/521 across several 
multi-dose clinical studies in HBV patients and two SAD healthy volunteer studies is encouraging. 
Updated interim clinical safety and pharmacologic activity data for ARO-HBV from the  ongoing 
AROHBV1001 study are presented in the Investigator’s Brochure 2nd Edition. These data indicate that 
ARO-HBV has been well tolerated and has demonstrated promising pharmacologic activity against the 
HBV virus based on reductions of viral antigens and HBV DNA. Pharmacodynamic data to date 


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justify the further clinical development of ARO-HBV with the goal of developing finite regimens 
aimed at HBsAg clearance in patients with chronic HBV.  
4.4 
JNJ-6379 Clinical Studies 
Antiviral Activity 
Interim data of the ongoing clinical study 56136379HPB1001 (Sessions 8 to 11), in CHB-infected 
subjects show that JNJ-6379 administration at doses of 25- to 250-mg leads to reduction in HBV 
DNA. A mean (±SD) reduction in plasma HBV DNA levels of 2.16 (0.49) log10 IU/mL (25 mg), 2.89 
(0.48) log10 IU/mL (75 mg), 2.70 (0.53) log10 IU/mL (150 mg), and 2.70 (0.33) log10 IU/mL (250 
mg) from baseline was observed at Day 29. In the 250-mg dosing group, 5 out of 12 subjects achieved 
HBV DNA levels below the LLOQ of the HBV DNA assay, while 3 out of 12 subjects in both the 75-
mg and 150-mg dosing groups and none (out of 12) of the subjects in the 25-mg dosing group 
achieved this. A more pronounced and consistent decline in HBV DNA levels was observed across 
subjects in the 75-mg, 150-mg, and 250-mg group compared with the 25-mg group. 
In line with HBV DNA levels, reductions in HBV RNA levels were observed with JNJ‑56136379 
treatment. Baseline levels of HBV RNA were generally low and sometimes undetectable, especially in 
the higher dose groups, limiting the HBV RNA decline observable in this study. No notable changes in 
HBsAg or HBeAg were observed. 
Safety 
Healthy Subjects 
In a pooled analysis of 123 adult healthy subjects, 98 subjects received at least one dose of JNJ-6379. 
Eleven subjects did not complete their treatment: due to withdrawal by subject (such as withdrawal of 
consent or withdrawal due to personal reasons) (4 [3.3%] subjects), lost to follow-up (1 [0.8%] 
subject), other reasons (2 [1.6%] subjects) or due to adverse events (AEs) (4 [3.3%] subjects, see 
below). 
There were no deaths and 2 subjects experienced a serious adverse event (SAE), both considered not 
related to JNJ-6379: one during the screening phase (spontaneous abortion; moderate) in study 
5636379HPB1004, and the other (wrist fracture right; severe) in study 563679HPB1002, 24 days after 
the last single dose of JNJ-56136379. Apart from the severe wrist fracture, no severe AEs were 
reported. In most cases AEs were mild and not considered related to JNJ-56136379.  


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Two subjects in study 56136379HPB1001 Part 1, single dose escalation phase, discontinued from 
further dosing with JNJ-56136379 in subsequent sessions due to an AE. One subject in study 
56136379HPB1001 Part 2, multiple dose phase, discontinued JNJ-6379 treatment after administration 
of JNJ-6379 150 mg bid for 2 days, followed by JNJ-6379 100 mg for 9 days due to the AEs 
abdominal pain lower and dizziness postural. These AEs were considered by the investigator of mild 
severity and possibly related to JNJ-6379 and resolved after discontinuation. 
Overall, the most common treatment-emergent AEs, experienced by >10% of all subjects treated with 
JNJ-6379 was headache (27 [27.6%] subjects on JNJ-56136379 versus 3 [12.0%] subjects on placebo). 
Most graded laboratory abnormalities were grade 1 or 2, except for a grade 3 amylase and grade 4 
lipase elevation in 1 subject in study 56136379HPB1002 (both observed during follow-up), a grade 3 
lipase elevation in another subject in study 56136379HPB1002 (observed when subject on treatment), 
and 2 grade 3 LDL cholesterol elevations in one subject each from study 56136379HPB1002 and 
study 56136379HPB1003 (both observed when subjects on treatment). Based on these cases, lipase 
and amylase have been identified as laboratory abnormalities of interest. The pooled data show that 5 
(5.1%) and 6 (6.1%) subjects on JNJ-6379 had lipase and amylase elevations, respectively versus none 
on placebo.  
CHB Infected Subjects 
In the unblinded 25-250 mg sessions of Part 2 of study 56136379HPB1001 in CHB-infected subjects, 
no deaths were reported. No other SAEs, AEs leading to discontinuation or grade 4 AEs were 
observed in the 25, 75 and 250 mg treatment groups. 
One subject in the JNJ-6379 150 mg treatment group experienced several grade 3 SAEs (idiopathic 
intracranial hypertension, headache, epilepsy, gliosis, brain edema, brain neoplasm, brain 
compression) 2 days after completing treatment with JNJ-6379. The subject was withdrawn from the 
study. All SAEs were considered not related to study drug with outcome unknown. Despite several 
attempts to reach the patient, the patient was lost to follow-up. 
One subject experienced the grade 3 AE AST increased and grade 4 AE ALT increased during JNJ-
6379 150 mg treatment. Both AEs were considered probably related to study drug, which was 
withdrawn, due to the protocol defined stopping criteria. The AEs were considered resolved after end 
of treatment. The subject also had the AEs liver tenderness (grade 1, possibly related, resolved before 


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end of treatment) and abdominal distension (grade 1, not related, resolved after end of treatment) for 
which study drug was withdrawn. 
Other grade 3 AEs were reported for 1 subject during JNJ-56136379 25 mg treatment (amylase 
increased, possibly related, resolved before end of treatment), for 1 subject during JNJ-6379 75 mg 
treatment (ALT increased, possibly related, resolved after end of treatment) and 1 subject after JNJ-
6379 150 mg treatment (AST increased, probably related, resolved). 
The most frequently reported treatment-emergent AEs across all doses (>1 subject) on JNJ-6379 were 
headache (4 [11.8%] subjects on JNJ-6379 versus 6 [42.9%] subjects on placebo), nausea 
(2 [5.9%] subjects versus 0 subjects, respectively), dyspepsia (2 [5.9%] subjects versus 0 subjects, 
respectively), ALT increased (2 [5.9%] subjects versus 1 [7.1%] subject, respectively), amylase 
increased (2 [5.9%] subjects versus 0 subjects, respectively), and hypophosphatemia (2 [5.9%] 
subjects versus 0 subjects, respectively). All other AEs were reported in 1 subject at most. No dose-
related trend in AEs was observed. The majority of AEs were grade 1. 
The majority of laboratory abnormalities were grade 1 or 2. No grade 3 or 4 laboratory abnormalities 
were observed in the 250 mg treatment group. Grade 4 ALT elevations were observed in 1 subject 
each in the 75 and 150 mg treatment groups and were related to the AEs discussed above (for the 
subject in the 75 mg treatment group, this was observed during follow-up). Grade 3 pancreatic 
amylase (discussed above as AE) and grade 3 triglycerides (observed during follow-up) were observed 
in 1 subject each in the 25 mg treatment group. Grade 3 AST elevation was observed in 1 subject in 
the 75 mg treatment group (observed during follow-up) and in 2 subjects in the 150 mg group (for 1 
subject observed during follow-up) (discussed as AE above). Grade 3 hyperkalemia was observed in 1 
subject in the 150 mg treatment group. 
No ECG-related or vital sign-related AEs were reported. No clinically relevant changes from baseline 
in ECG or vital signs values were observed. 
Further details regarding clinical safety results using JNJ-6379 are provided in the JNJ-56136379 
Investigator’s Brochure. 
4.5 
ARO-HBV and JNJ-6379 Pre-Clinical Pharmacokinetic and Product Metabolism Studies 
PK parameters for ARO-HBV have been evaluated in both rats and monkeys. Results of these studies 
can be found in the Investigator’s Brochure.  In general, ARO-HBV will be unmeasurable in the 


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circulation within 1-2 days following a single dose. In healthy subjects, JNJ-6379 is rapidly absorbed 
from the oral tablets, with a median tmax ranging between 1.26 and 3 hours in fasting conditions, and 
around 4 hours in fed conditions. Mean terminal half-life (t1/2term) was comparable between studies 
56136379HPB1001 and 56136379HPB1003, ranging between 93.3 and 116 hours across the dose 
levels in both studies, suggesting no significant difference in clearance between Asian and non-Asian 
subjects. In study 56136379HPB1003, approximately 18% of the administered dose was excreted via 
the kidney, resulting in a mean renal clearance of 0.161 L/h. No significant difference was observed in 
healthy volunteers when compared to patients with CHB. Details regarding pharmacokinetics and 
metabolism of JNJ-6379 are provided in the latest ARO-HBV and JNJ-56136379 Investigator’s 
Brochure. 
4.6 
Rationale for the Study  
Treatment with ARO-HBV is expected to reduce all HBV proteins and replicative intermediates via 
RNAi. The magnitude of the reduction and duration of effect will depend on the dose and dosing 
schedule. Since to date there has been no human clinical exposure to ARO-HBV, an effective 
therapeutic dose and optimal dosing schedule to administer to patients with chronic HBV infection is 
unknown. Accordingly, this single-ascending dose /multi-ascending-dose study has been designed to 
determine the tolerability of increasing doses in a healthy volunteer population as well as activity of 
ARO-HBV in patients with chronic HBV. Additionally, three separate dosing schedules from weekly 
to monthly dosing intervals will be evaluated.  This strategy of evaluating monthly, bi-weekly and 
weekly dosing strategies is derived from published data in CHB patients receiving PEG-IFN alpha, 
where those patients experiencing a more rapid initial HBsAg response were more likely to eventually 
seroconvert for HBsAg. These studies imply that a faster HBsAg response (short time till HBsAg 
nadir) may be beneficial in driving future seroconversions. Additionally, it is likely that a longer 
period of lower viral antigen levels is more likely to prove clinically beneficial. For these reasons, two 
loading dose strategies (weekly and bi-weekly for three doses) will be tested in addition to monthly 
dosing. The purpose of these varied initial dosing regimens is to optimize for a rapid initial HBsAg 
decline. 
CHB patients currently on entecavir or tenofovir for at least twelve months will be studied as well as 
CHB patients naive to NUCs or Interferon. These separate patient populations may respond differently 
to ARO-HBV. Safe and effective doses of ARO-HBV will then be studied in subsequent clinical trials 
aimed at producing HBsAg seroclearance (functional cure). Functional cure may allow patients to 


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discontinue their anti-viral medication in the future, and may prevent additional long-term liver 
damage or risk of developing hepatocellular carcinoma caused by chronic HBV infection.    
The 25 and 50 mg dose levels (Cohorts 1b and 1c) are being added after the initial enrollment and 
dosing of Cohorts 2b through 5b (dose levels of 100 mg through 400 mg) have been completed to 
better understand dose response at lower doses.  
Cohort 12 uses a combination of NUCs + ARO-HBV + JNJ-6379. Throughout the study all patients 
have been treated with the combination of NUCs + ARO-HBV in all other cohorts (Cohorts 1b 
through 11). It is thought that by using an siRNA approach to silence production of viral antigens in 
combination with NUCs to inhibit viral replication and JNJ-6379 which inhibits capsid assembly and 
cccDNA formation the response to treatment and potentially the rate of functional cure could be 
enhanced. ARO-HBV + NUCs has been well tolerated throughout the AROHBV1001 study. JNJ-6379 
in combination with NUCs has also been well tolerated in CHB clinical studies. In vitro, JNJ-6379 
does not inhibit phosphorylation of tenofovir or entecavir. Based on results from GLP toxicology 
studies and in vitro assessments of drug metabolism and transport for both JNJ-6379 and ARO-HBV, 
as well as safety and tolerability results from prior human studies in healthy volunteers and CHB, there 
is no indication that JNJ-6379 and ARO-HBV will have overlapping or additive toxicity. As such, the 
benefit of this combination “triple” therapy is expected to outweigh risk of toxicity.  
4.7 
Risk Assessment for Participants 
4.7.1 ARO-HBV: 
• 
Embryo-fetal toxicity: Limited GLP toxicology as well as preliminary non-GLP embryo-fetal 
studies have been conducted. Accordingly, eligible participants enrolled in this study, both 
male and female (including partners), must agree to use two effective methods of 
contraception (double barrier contraception or hormonal contraception along with a barrier 
contraceptive) during the study and for 3 months post-dose, or agree to abstinence (acceptable 
only if this method is in alignment with the normal life style of the patient).  
• 
Injection Site Reaction Risk: Other subcutaneously administered modified siRNA drug 
candidates evaluated in clinical studies have been associated with mild to moderate injection 
site reactions (e.g. pain, erythema). This study includes a protocol for evaluation and grading 
of injection site reactions based on pre-defined criteria for mild, moderate and severe 
reactions. Injection site reactions will be photographed for tracking resolution and/or 
progression. Additionally, steps will be taken to minimize injection site reactions such as 


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rotating injection sites and allowing the ARO-HBV solution to come to room temperature 
prior to injecting. 
• 
Hepatic Toxicity (theoretical risk): ARO-HBV targets the liver. Arrowhead has not seen 
meaningful drug induced transaminase changes with a previously studied liver targeted RNAi-
based therapeutic (ARC-520/521) targeting HBV. However, another company (Alnylam 
Therapeutics) developing an siRNA for AATD has seen evidence of mild to moderate 
elevations in transaminases using hepatocyte targeted siRNA conjugates similar to those used 
by Arrowhead. Alnylam has described that these ALT changes were due to off- target effects 
of the siRNA seed region on microRNAs in the hepatocyte (Vaishnaw et al, 2017; Schlegel et 
al, 2017). The siRNA sequence of the ARO-HBV sense and antisense molecules have been 
screened for potential mRNA and microRNA off-target effects. No such off-target effects are 
anticipated. Multi-dose (3 weekly doses) GLP toxicity studies with ARO-HBV in rats and 
monkeys demonstrate no evidence of hepatic toxicity up to doses of 300 mg/kg. To mitigate 
this risk, the proposed study has built in stopping rules for ALT and AST elevation. Labs to 
evaluate liver injury and liver function will be drawn frequently.  The Drug Safety Committee 
will include a hepatologist member with extensive clinical trial experience and significant 
experience in evaluation of liver targeted therapeutics, including siRNAs. Additionally, the 
planned starting dose of 35 mg is approximately 1/50th (assuming weight based conversion 
and a 60-kg subject) of the lowest dose of 30 mg/kg used in both the multi-dose rat and 
monkey GLP toxicity studies. This starting dose provides a safety margin of over 500-fold 
from the monkey NOAEL.     
• 
Host or viral induced ALT flares (theoretical risk): Fluctuations in ALT are part of the natural 
history of CHB infection. In fact, many experts believe that ALT increase represents innate 
immune responses against infected hepatocytes and is required for HBsAg seroclearance. ALT 
elevation can also be seen in the setting of rebounding (such as with NUC discontinuation) 
HBV DNA levels or fluctuations of HBV DNA such as with NUC non-compliance.  It is 
likely that host induced ALT flares will be seen in ARO-HBV studies as part of the normal 
sequelae associated with HBV. This risk will be mitigated by starting all patients NUCs 
(entecavir or tenofovir) upon entering the study, or kept on NUCs if NUC experienced. 
Measures of liver injury (ALT, AST) and of liver function (bilirubin, albumin and coagulation 
factors) will be measured frequently. Stopping rules for adverse changes in liver function are 


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included. Additionally, “ALT Flare Guidelines” are specified in Appendix 1 to help 
investigators evaluate ALT elevations during the study. 
4.7.2. JNJ-6379: 
• 
Changes in amylase, lipase, cholesterol: Based on data from Study 56136379HPB1002, lipase 
and amylase elevations were identified as laboratory abnormalities of interest. In addition, 
based on preclinical findings in rats and dogs, increased cholesterol was identified as 
laboratory abnormality of interest. Serum lipase, amylase and cholesterol will be monitored in 
patients.  
• 
Emergence of Resistance: Treatment with JNJ-56136379 may lead to emergence of viral 
variants with reduced susceptibility or resistance to JNJ-56136379. Based on pre-clinical data, 
these variants remain susceptible to TDF and ETV but might affect treatment options with 
CAMs in the future. 
4.7.3. ARO-HBV and JNJ-6379 combined 
• 
Overlapping drug toxicity (theoretical risk): Cohort 12 proposes the addition of JNJ-6379 to 
the treatment regimen of ARO-HBV+NUC which has been used throughout the study. Based 
on available clinical and pre-clinical experience with each compound as well as combination 
clinical studies of ARO-HBV with NUCs and JNJ-6379 with NUCs, clinically significant 
overlapping toxicity is not expected in Cohort 12. 
4.8 
 Justification for Dose of ARO-HBV and JNJ-6379  
Regulatory guidance for calculation of starting dose in healthy volunteer studies indicates that the No-
Observed-Adverse-Effect-Level (NOAEL) in the most relevant animal species should be used (EMA, 
July 2017). FDA guidance also recommends calculation of human starting dose based on the NOAEL 
in the most relevant animal model (FDA Guidance, July 2005). The most pharmacologically relevant 
animal model for calculating the NOAEL is the monkey. This is supported by consensus statements 
regarding appropriate pharmacologically relevant animal models in toxicology studies of 
oligonucleotide therapeutics. (Marlowe et al, 2017). 
Reported pharmacokinetic properties for several oligonucleotide subclasses across species, including 
humans (Geary et al, 2001, 2003; Yu et al, 2001), indicate that the most appropriate method for 
extrapolating animal doses to human equivalent doses is the comparison of dose per unit body weight 
(mg/kg), rather than dose per surface area (mg/m2) or plasma exposure (AUC or Cmax). The human 
equivalent dose for oligonucleotide therapeutics can be extrapolated directly from monkeys to humans 
with a scaling factor of 1.0 on mg/kg dose administrations (Yu et al, 2015). Arrowhead has historically 


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used 1:1 mg/kg scaling factor based on monkey NOAELs to determine starting dose in other siRNA 
first-in-human studies (ARC-520, ARC-521, both studied for hepatitis B, and ARC-AAT first in 
human studies). 
Extrapolated based on body weight, the proposed starting dose of 35 mg will be administered to 
healthy volunteers in Cohort 1, the first dose level. The 35 mg starting dose is approximately 1/50th of 
the lowest dose of 30 mg/kg used in the monkey multi-dose GLP toxicity study (using a weight-based 
animal to human conversion and assuming a 60-kg human subject). The starting dose is equal to less 
than 1/500th of the 300 mg/kg NOAEL in monkeys. The maximum proposed dose in the study of 400 
mg is 1/45th of the monkey NOAEL. After dose escalation through 400 mg, to better understand dose 
response at low doses, protocol amendment 4.0 added a 25 and 50 mg X3 Q28 days cohort (Cohorts 
1b and 1c). 
For cohort 12, the dose of ARO-HBV administered will be 200mg on Days 1, 29, and 57. ARO-HBV 
has been shown to be well tolerated and and effective at reducing viral antigens at doses up to 400mg 
dosed on Days 1, 29 and 57 (see Investigator’s Brochure 2nd Edition). Since there was no obvious dose 
response observed between 100mg and 400mg ARO-HBV dosed on Days 1, 29, and 57, the second 
lowest dose level of 200 mg was chosen for cohort 12. The JNJ-6379 dose to be administered will be 
250 mg given once daily. This dose is currently tested for up to 48 weeks in the ongoing Phase 2a 
study 56136379HPB2001 and has been selected based on all safety, PK, and antiviral activity data 
available following completion of the highest JNJ-6379 dose group (who received 250 mg once daily) 
in the Phase 1 study 56136379HPB1001 in treatment-naïve CHB-infected subjects treated for 28 days. 
No SAEs or AEs leading to treatment discontinuation were reported for CHB-infected subjects who 
received 250 mg JNJ-6379 once daily for 28 days, and all AEs were grade 1. In addition, no treatment-
emergent laboratory abnormalities of >grade 2, ECG or vital signs abnormalities of ≥grade 2 were 
reported for these subjects, and no abnormalities were reported as AEs. The dose of 250 mg once daily 
has been selected to efficiently inhibit HBV DNA replication across a broad spectrum of patients and 
viral variants. In addition, 250 mg is expected to increase the potential to trigger the secondary mode 
of action (MoA) (i.e., inhibition of de novo cccDNA formation) which requires about 10-fold higher 
concentrations of JNJ-6379 than the primary MoA of inhibition, ie, interfering with capsid assembly 
(EC90 primary MoA=376 nM and EC90 secondary MoA=4019 nM).  


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5 
OBJECTIVES 
5.1 
Primary Objectives 
To determine the incidence and frequency of adverse events possibly or probably related to treatment 
as a measure of the safety and tolerability of ARO-HBV using escalating single doses in healthy 
volunteers and escalating multiple doses in CHB patients.  
5.2 
Secondary Objectives 
• 
To evaluate the single-dose pharmacokinetics of ARO-HBV in healthy volunteers 
• 
To determine the reduction of HBsAg in response to ARO-HBV in CHB patients as a measure 
of activity 
5.3 
Exploratory Objectives 
• 
To determine the reduction of HBcrAg, , HBsAg, HBV RNA (if scientifically feasible) and 
HBeAg (e+ only), in response to ARO-HBV (alone or in combination with JNJ-6379) in CHB 
patients as a measure of activity 
• 
To evaluate the effect of single doses of ARO-HBV on cytokines (Cytokine panel A: 
interleukin-6 [IL-6], monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-
alpha [TNF-alpha], interleukin-8 [IL-8], interleukin-1beta [IL-1beta], interferon alpha [IFN 
alpha], IL-10, IL-12 [p40], IL-12 [p70], macrophage inflammatory protein-1alpha [Mip-
1alpha]) in healthy volunteers. 
• 
To evaluate the effect of single escalating doses of ARO-HBV on complement factors Bb, 
CH50, C5a, C4a, and C3a in healthy volunteers. 
• 
To collect plasma samples in healthy volunteers for subsequent metabolite identification 
(reported in a separate report outside of this study) 
• 
To collect urine samples in healthy volunteers for subsequent determination of urinary 
excretion and metabolite identification (reported in a separate report outside of this study).  


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• 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with JNJ-
6379)  on cytokines (Cytokine panel B: TNF alpha, IFN gamma, CXCL-9, and CXCL-10) in 
CHB patients 
• 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with JNJ-
6379)  on HBV patient immune cell profile including T-cells, NK cells, B cells and monocytes 
in a limited number of HBV patients in New Zealand only (if scientifically feasible). 
• 
To evaluate the effect of multiple doses of ARO-HBV on HBV antigen specific T-cell 
response in a limited number of HBV patients in New Zealand only (if scientifically feasible).  
• 
To evaluate the effect of interferon response gene single nucleotide polymorphisms (SNPs) 
including IL28B on response to ARO-HBV (alone or in combination with JNJ-6379). 
• 
To determine the incidence and frequency of adverse events possibly or probably related to 
treatment as a measure of the safety and tolerability of ARO-HBV in combination with JNJ-
6379 in patients chronically infected with hepatitis B virus (CHB) (Cohort 12 only). 
6 
STUDY PLAN 
6.1 
Study Design 
Healthy volunteers: 
The study will be conducted in NHVs, adult males and females, aged 18-55 years with BMI between 
19.0 and 35.0 kg/m² (Cohorts 1 – 5). For NHVs, cohorts of 6 eligible subjects (2 placebo, 4 active 
ARO-HBV) will be evaluated at each dose level starting at dose level 1 (35 mg). Participants who 
have signed an HDEC (or local equivalent) approved informed consent form and have met all of the 
protocol eligibility criteria during screening, will be randomized at a ratio of 2:1 (active:PBO) to 
receive ARO-HBV or PBO in a double-blind fashion.  NHV cohorts will receive a single dose only.   
Each cohort will begin with administration of ARO-HBV or PBO to two sentinel participants (one 
ARO-HBV, one PBO). Following the Day 3 evaluation in these participants, if there are no significant 
safety concerns based on PI’s judgement, the remaining participants in the cohort will be treated. 
Dosing of participants will be staggered by at least 15 minutes such that no two participants will be 
dosed simultaneously. 


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Clinical facility confinement will be approximately 2 days for single dose administration (Day -1 
through 24-hour assessments). Blood samples will be drawn pre-dose on Day 1 for baseline 
measurements.  Height and weight will be measured at Screening only to calculate BMI.   
Based on observations for all NHV subjects in a cohort through Day 8, dosing will begin for the next 
NHV cohort and as applicable the next CHB cohort at the discretion of the DSC.  Escalation to the 
next highest dose level will proceed in cohorts of 6 until the dose level of 400 mg is completed, or the 
trial is halted prematurely by the PI, DSC or Sponsor due to safety or other concerns. Blinding will be 
preserved to the extent possible for the NHVs; however, treatment un-blinding will occur, at the PI’s 
discretion, where deemed necessary for treatment of an AE or for a decision to be made regarding trial 
continuation.  
After all subjects in a cohort have completed an End-of-Study visit (Day 29), Sponsor may be 
unblinded at Sponsor’s request. PI and study participants will remain blinded.  
CHB patients: 
HBeAg negative or HBeAg positive CHB patients, aged 18-65 years with BMI between 19.0 and 38.0 
kg/m² (Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12) will be enrolled. Cohort 8 will enroll 
HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or Interferon) and 
Cohort 9 will enroll HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 
12 months). Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10, 11 and 12 will enroll either HBeAg positive or 
negative patients regardless of previous NUC or PEG IFN treatment experience. All patients will be 
started on entecavir or tenofovir on Day 1. Cohort 12 will start on JNJ-6379 on Day 1 and continue 
oral 250 mg QD through Day 84. Patients currently on PEG IFN will not be allowed.   
Summary of Participant Profile by Cohort and Cohort Size: 
• 
Cohorts 1-5: NHVs, adult males and females, aged 18-55 years 
o 6 NHV subjects per cohort 
• 
Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10, 11 and 12: Any CHB patient regardless of HBeAg or 
prior therapy status (as long as other Inclusion and Exclusion criteria are met).  
o Cohorts 1b, 1c, 2b, 3b, 4b and 5b will enroll a minimum of 4 and a maximum of 8 
patients per cohort. 


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o Cohorts 6, 7, 10 and 11 will enroll a maximum of 4 patients per cohort. 
o Cohort 12 will enroll 12 patients. 
• 
Cohort 8: HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or 
Interferon) 
o Cohort 8: Maximum of 4 patients per cohort 
• 
Cohort 9: HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 
months). 
o Cohort 9: Maximum of 4 patients per cohort 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially in 
Cohorts 2b through 7, Cohorts 10 and 11, and Cohorts 1b and 1c into a total of 10 open label cohorts. 
Cohorts 1b, and 1c through 5b will enroll at planned dose levels of 25 mg (Cohort 1b), 50 mg (Cohort 
1c), 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) and 400 mg (Cohort 5b) to receive 
three doses (Q28 days) of active treatment in an open label fashion. Cohorts 6 through 12 will enroll at 
planned dose levels of 100 mg (Cohorts 6 and 7), 200 mg (Cohort 10, 12), and 300 mg (Cohorts 8, 9, 
and 11). Cohort 6 will enroll CHB subjects (after Cohort 5b has completed enrollment) to receive three 
doses two weeks apart. Cohorts 7, 10 and 11 will enroll CHB patients sequentially (after Cohort 6 has 
completed enrollment) to receive three doses a week apart at increasing dose levels starting with a 
dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially (after 
being opened at the final planned DSC meeting) with enrollment and dosing in a later cohort not 
initiating until all subjects in the earlier cohort have received at least their first scheduled dose. Cohort 
8 will enroll HBeAg positive treatment naïve CHB patients to receive three monthly doses of ARO-
HBV. Cohort 9 will enroll HBeAg positive entecavir or tenofovir experienced CHB patients to receive 
three monthly doses of ARO-HBV.  CHB patient screening for all CHB cohorts may start when 
Cohort 1 opens for enrollment. However, no CHB patients may be dosed until their respective cohort 
is approved for dosing by the DSC (not including Cohorts 1b,1c and 12). CHB dosing may begin and 
NHV dose escalation may occur based on DSC approval which can occur by vote after cumulative 
data through Day 8 from the current NHV cohort is available. (See Figure 1 for dose escalation 
schedule).  


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CHB patients on current NUC therapy (entecavir or tenofovir) will stay on NUC therapy for the study 
duration. CHB patients not on NUC therapy (NUC naïve) will be started on either entecavir or 
tenofovir (selection between entecavir and tenofovir based on site Principal Investigator (PI) 
discretion) on Day 1.  Either tenofovir disoproxil fumarate (including generic) or tenofovir 
alafenamide are acceptable. During the extended follow up period after Day 113, NUCs may be 
discontinued at investigator discretion if subject becomes HBsAg undetectable (< 0.05 IU/mL). 
Cohort 12 will enroll 12 CHB patients in an open label fashion to receive 200 mg ARO-HBV on Days 
1, 29 and 57 as well as JNJ-6379 250 mg oral once daily starting on Day 1 and continuing through 
Day 84. Like all other cohorts, patients enrolling in Cohort 12 will either enter the study on NUCs or 
start NUCs on Day 1. Enrollment in Cohort 12 can begin once enrollment is full in Cohorts 2b, 3b, 4b, 
5b, 6, 7, 8, 9, 10, 11. The ARO-HBV dose level for Cohort 12 is 200 mg Q28 days (Days 1, 29, 57). 
Cohort 12 is open for enrollment in Hong Kong only. 
In Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12, eligible CHB patients who have signed an 
HDEC (or local equivalent) approved informed consent form will receive three doses of ARO-HBV at 
dose intervals ranging from once every week to once every 4 weeks in an open label fashion. 
Screening for the CHB cohorts can begin once Cohort 1 dosing has commenced. These cohorts (not 
including Cohorts 1b and 1c) will be opened for accrual once the corresponding NHV cohort receiving 
the same dose level has reached Day 8, based on agreement of the DSC that it is safe to proceed. 
Cohorts 6, 7, 8, 9, 10 and 11 can be opened for enrollment any time after Cohort 5 has reached Day 8 
(and DSC has approved opening of such cohorts) and there is sufficient viral antigen response data 
from CHB patients to determine a dose level for these cohorts. Dose levels for Cohorts 6 through 11 is 
between 100 and 300 mg.   Cohorts 2b through Cohort 7 and Cohorts 10 and 11 will be enrolled in 
sequence (as shown in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts 
after the DSC has voted post Cohort 5 to open the remaining CHB patient cohorts and once a specified 
dose (≤ 400 mg) has been identified. Cohorts 1b, 1c and Cohort 12 are open for enrollment with the 
addition of applicable protocol amendments and may enroll in parallel. 
For clarity, after Cohort 5 is through Day 8, the DSC will review all available safety data and vote to 
open Cohorts 5b, 6, 7, 8, 9, 10 and 11. Cohorts 5b, 8 and 9 may enroll and dose patients in parallel. 
Cohorts 5b through 7 and Cohorts 10 and 11 must enroll sequentially, meaning that Cohort 5b must be 
fully enrolled with each subject receiving at least a first dose before Cohort 6 can enroll. Cohort 6 
must be fully enrolled with each subject receiving at least a first dose before Cohort 7 can enroll. 
Cohort 7 must be fully enrolled with each subject receiving at least a first dose before Cohort 10 can 


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enroll and Cohort 10 must be fully enrolled with each subject receiving at least a first dose before 
Cohort 11 can enroll. It is the intent that Cohorts 7, 10 and 11 will be treated at increasing dose levels 
starting with a dose equal to Cohort 6. 
On dosing days, clinical facility confinement will be approximately 2 hours unless a longer period of 
post-dose observation is needed based on PI discretion. Blood samples will be drawn pre-dose on Day 
1 for baseline measurements.  Height and weight will be measured at Screening only to calculate BMI. 
Participants will undergo evaluations at screening and at regular intervals during the study as 
described in the Schedule of Assessments. 
With the exception of Cohort 12 patients, all other CHB patients consenting to additional follow up 
will be followed as per Additional Follow-Up Schedule of Assessments (Table 1.5), every 56 days (± 
5 days) for 5 additional visits after Day 113. Only Cohort 12 patients will require follow-up until the 
Day 337 (±5 days) visit. Subjects consenting to additional follow up will continue on NUCs and may 
have NUCs discontinued at the investigator’s discretion if patients become HBsAg undetectable (< 
0.05 IU/mL). Subjects not consenting to additional follow up will be followed per protocol based on 
Schedule of Assessment Tables 1.2, 1.3 and 1.4.  
 
Single doses of ARO-HBV will be evaluated in normal healthy volunteers (NHVs) and multiple doses 
of ARO-HBV will be evaluated in patients with chronic hepatitis B (CHB) in a sequential manner as 
shown in Figure 1.          
  
  Figure 1. Dose Escalation Schedule 
Healthy Volunteers (double blind)* 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose Regimen 
Cohort 1 
 
35 mg 
 
Cohort 1b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 25 mg dosed 
on Day 1, 29, 57 
 
 
 
Cohort 1c (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 50 mg dosed 
on Day 1, 29, 57 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 100 mg 
dosed on Day 1, 29, 57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 200 mg 
dosed on Day 1, 29, 57 


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Cohort 4 
300 mg 
 
Cohort 4b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 300 mg 
dosed on Day 1, 29, 57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 400 mg 
dosed on Day 1, 29, 57 
 
 
  
 
Cohort 6 (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 100 mg 
dosed on Day 1, 15, 29 
 
 
 
Cohort 7 (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 100 mg 
dosed on Day 1, 8, 15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
ARO-HBV 300 mg 
dosed on Day 1, 29, 57  
 
 
 
Cohort 9 HBeAg+, entecavir 
or tenofovir experienced  
ARO-HBV 300 mg 
dosed on Day 1, 29, 57  
 
 
 
Cohort 10 (all eligible CHB 
patients regardless of NUC 
or HBeAg status)  
ARO-HBV 200 mg 
dosed on Day 1, 8, 15 
 
 
 
Cohort 11 (all eligible CHB 
patients regardless of NUC 
or HBeAg status)  
 
ARO-HBV 300 mg 
dosed on Day 1, 8, 15  
 
 
 
Cohort 12 (all eligible CHB 
patients regardless of NUC 
or HBeAg status)  
JNJ-6379 250mg QD + 
ARO-HBV 200 mg 
dosed on Day 1, 29, 57 
*All NHV cohorts will start with two sentinel subjects 
 
Unblinding of NHV cohorts may occur at Sponsor discretion on a cohort by cohort basis after all 
subjects in a cohort have completed their last on-site study visit. Study participants (CHB patients and 
NHVs) as well as sites will remain blinded.  
Open label anti-viral response data may be disclosed to investigators by the Sponsor at Sponsor’s 
discretion. There is no requirement for Sponsor to disclose anti-viral response data while the study is 
ongoing.   
6.2 
Rationale for Study Design  
This first-in-human study plans to investigate ARO-HBV in adult healthy volunteers (NHVs) and 
HBV patients to evaluate the drug’s safety and tolerability as well as its pharmacokinetics in healthy 
volunteers and pharmacodynamics in HBV patients, following a single (or multiple subcutaneous 
doses in HBV patients).  The study initiates in NHVs because the single dose risk is considered low. 
Additionally, this population will be otherwise healthy without co-morbidities that may increase risk 


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for toxicity. The siRNA triggers in ARO-HBV are targeted against the mRNA transcripts generated by 
HBV viral cccDNA and integrated DNA. Since NHVs will not have HBV infection the potential for 
toxicity due to pharmacodynamic (e.g. “on-target”) effect is very low. After a period of post-dose 
safety evaluation in NHVs at each dose level, multi-dose (3 dose) cohorts in HBV patients at the same 
dose levels are planned (See Figure 1). Multiple doses of ARO-HBV are employed in the HBV patient 
cohorts as it is highly likely that prolonged reduction of viral antigens will be required to elicit 
functional cures. It is also important to note that this study excludes patients with excessive co-
morbidities. HBV patients enrolled will not have other co-morbid conditions which could increase 
their risk of adverse effects to ARO-HBV. The anticipated safety profile in NHVs and HBV patients is 
likely to be very similar. This is supported by Sponsor’s experience with ARC-521 Injection and 
ARC-520 Injection, which were siRNA therapeutics studied in single and multi-dose studies in NHV 
and CHB patient populations. Both ARC-521 Injection and ARC-520 Injection demonstrated a 
favorable safety profile in NHVs and HBV patients. Variation of dose frequency in the HBV patient 
cohorts (See Figure 1) is important to understand the dosing regimen that produces the deepest and 
most rapid reduction in viral antigen.   
This study is similar to the ARC5211001 study which was executed successfully at the same site in 
New Zealand in NHVs and HBV patients.  
The study is double-blind to limit the occurrence of conscious and unconscious bias in trial conduct 
and interpretation. Blinding will be achieved using a PBO product (0.9% normal saline).  Inclusion of 
participants receiving PBO will reduce bias in the assessment of drug safety and tolerability. The study 
is randomized with a 2:1 (active:PBO) ratio to reduce bias. 
Cohort 12 uses a combination of NUCs + ARO-HBV + JNJ-6379. Throughout the study all patients 
have been treated with the combination of NUCs + ARO-HBV. It is thought that by using an siRNA 
approach to silence production of viral antigen in combination with NUCs to inhibit viral replication 
and JNJ-6379 which inhibits capsid assembly and cccDNA formation the response to treatment and 
potentially the rate of functional cure could be enhanced. ARO-HBV + NUCs has been well tolerated 
throughout the AROHBV1001 study. JNJ-6379 in combination with NUCs has also been well 
tolerated in CHB clinical studies. In vitro, JNJ-6379 does not inhibit phosphorylation of tenofovir or 
entecavir. It is not expected that JNJ-6379 and ARO-HBV will have overlapping or additive toxicity. 
As such, the benefit of this combination “triple” therapy is expected to outweigh risk of toxicity.  


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6.3 
Criteria for Dose-escalation and Stopping Rules 
Escalation to the next cohort will proceed according to the study design until the 400 mg dose level 
and all subsequent cohorts are completed unless the trial is stopped early by the Data Safety 
Committee (DSC) or Sponsor. Dose escalation will require approval by the DSC based on all 
cumulative available safety data through Day 8 of the current cohort.  Dose escalation will proceed 
until all cohorts are fully enrolled or until the study is stopped or the DSC votes to not escalate to the 
next dose.  
A decision to stop the trial early or discontinue drug in an individual subject or group of subjects may 
(following a case-by-case decision based on consultation between the sponsor, DSC and the PI) be 
indicated based on any of the following:  
1. A single Serious Adverse Event(SAE) (defined in Section 9.1) considered at least possibly 
related to ARO-HBV and/or JNJ-6379 
2. One of the following abnormal results at least possibly related to ARO-HBV and/or JNJ-6379: 
o In NHVs, treatment emergent ALT or AST > 3X ULN which must be confirmed by 
repeat blood draw within 48 hours of initial results. 
o In CHB patients, treatment emergent ALT or AST > 3X Day 1 pre-dose baseline 
confirmed by repeat blood draw within 48 hours of initial results AND ALT > 10X 
ULN AND any one of the following: 
 
Total Bilirubin newly elevated to 2X ULN AND 2X Day-1 pre-dose baseline 
(confirmed on repeat lab draw within 48 hours) or 
 
Decrease in serum albumin of 0.5 g/dL or greater (confirmed on repeat lab 
draw within 48 hours) 
o Treatment emergent platelet count < 70,000 per microliter in NHVs or < 50,000 in 
CHB patients, confirmed on repeat measure within 48 hours of initial results 
o Treatment emergent serum creatinine > 180 μmol/L confirmed by repeat blood draw 
within 48 hours of initial results 


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Sponsor or PI can discontinue any subject at any time with or without DSC consultation. If such 
events (as described in #1, #2 above) occur and the subject is not discontinued from the study the 
reason for not discontinuing the subject will be included in DSC meeting minutes. Including, but not 
limited to the events listed above, the DSC may pause the study to additional dosing or dose escalation 
to provide time to evaluate safety data and recommend the action to be taken, which may include, but 
is not limited to one of the following: 
• 
Discontinuation of a subject or group of subjects from the study  
• 
The study is stopped immediately with no further dosing 
• 
The study will continue until the current cohort is completed 
• 
The study will continue, but the next dose escalation will be to a level midway between the 
current level and the next level specified in Section 8.3  
• 
The study will continue as planned  
If a serious adverse event (SAE) at least possibly related to study drug should occur for a single 
participant, subsequent dosing within that cohort may be put on hold pending a complete review of 
safety data by the DSC to determine if participant enrollment at the same dose may proceed, or if 
additional enrollment/dosing should stop.  If following the DSC safety review it is deemed appropriate 
to restart dosing/enrollment, subject enrollment, dosing and dose escalation may proceed as planned.  
6.4 
Duration of the Study 
For each NHV subject in the single dose cohorts, the duration of the study clinic visits is a maximum 
of 13 weeks from the beginning of the screening period to the Day 29 End-of-Study (EOS) 
examination.  
For each CHB patient in the multi-dose cohorts the duration of the study clinic visits is approximately 
25 weeks from screening to the Day 113 EOS examination.  With the exception of Cohort 12 patients, 
all other CHB patients consenting to additional follow up will be followed as per Additional Follow-
Up Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 
113. Only Cohort 12 patients will require follow-up until the Day 337 (±5 days) visit. Subjects 
consenting to additional follow up will continue on NUCs. Subjects not consenting to additional 
follow up will be followed per protocol based on Schedule of Assessment Tables 1.2, 1.3 and 1.4.  


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All CHB subjects who complete the study until Day 113 EOS examination are considered to complete 
the study and may continue to attend the Additional Follow-Up visits per the Schedule of Assessments 
(Table 1.5) if re-consent is obtained. If a subject withdraws from the Additional Follow-Up visits 
before the Day 337 (Cohort 12 only) or 393 visit, he or she will still be considered as a completed 
subject and reason for not continuing with the Additional Follow-Up visits per protocol will be 
recorded.   
All CHB patients and NHV subjects will be contacted by phone 90 days after the EOS visit (Day 29 
for NHVs and Day 113 for CHB patients) to confirm pregnancy status. 
7 
SUBJECT SELECTION 
7.1 
Number of Subjects 
A total of approximately 30 NHV and a minimum of 50 or a maximum of 84 CHB participants (not 
including potential replacements) may be enrolled in the study.   
7.2 
Inclusion Criteria 
Inclusion Criteria for Healthy Volunteer Cohorts  
To be eligible for enrollment, subjects must meet all the following inclusion criteria: 
1. Male or female, 18 to 55 years of age inclusive, at the time of informed consent 
2. Able to provide written informed consent prior to the performance of any study specific 
procedures 
3. Body mass index (BMI) between 19.0 and 35.0 kg/m2, inclusive 
BMI = weight (kg)/(height [m])2 
4. A 12-lead ECG at Screening and pre-dose assessment that, in the opinion of the PI, has no 
abnormalities that compromise participant’s safety in this study 
5. Participants using two effective methods of contraception (double barrier contraception or 
hormonal contraception along with a barrier contraceptive, both male and female partners) during 
the study and for 3 months following the dose of ARO-HBV.  Males must not donate sperm for at 
least 3 months after the last study treatment. Male partners of female subjects and female partners 
of male subjects must also use contraception, if they are of childbearing potential. Females of 
childbearing potential must have a negative urine pregnancy test at Screening and on Day 1, pre-
dose. Females not of childbearing potential must be post-menopausal (defined as cessation of 
regular menstrual periods for at least 12 months), confirmed by follicle-stimulating hormone 
(FSH) level in the post-menopausal range.  


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• 
Using twice the normal protection of birth control by using a condom AND one other form 
of the following (abstinence is acceptable at PI’s discretion): 
• 
Birth control pills (The Pill) 
• 
Depot or injectable birth control 
• 
IUD (Intrauterine Device) 
• 
Birth Control Patch (e.g., Ortho Evra) 
• 
NuvaRing® 
• 
Surgical sterilization. i.e., tubal ligation or hysterectomy for women or vasectomy for 
men or other forms of surgical sterilization 
Requirement for contraception can be waived in certain circumstances (i.e. same sex 
relationships) if approved by PI. 
6. Willing and able to comply with all study assessments and adhere to the protocol schedule 
7. Have suitable venous access for blood sampling 
8. No abnormal finding of clinical relevance at the Screening evaluation 
9.  AST, ALT and Creatinine levels ≤ upper limit of normal at Screening 
 
Inclusion Criteria for CHB Patient Cohorts 
To be eligible for enrollment, patients must meet all the following inclusion criteria: 
1. 
Male or female, 18 to 65 years of age, inclusive, at the time of informed consent 
2. Able to provide written informed consent prior to the performance of any study specific 
procedures 
3. Body mass index (BMI) between 19.0 and 38.0 kg/m2, inclusive. Patients with BMI above or 
below the cutoff may be enrolled at the discretion of the PI based on risks and co-morbidities. 
BMI = weight (kg)/(height [m])2 
4. A 12-lead ECG at Screening and pre-dose assessment that, in the opinion of the PI, has no 
abnormalities that compromise participant’s safety in this study  
5. Participants using two effective methods of contraception (double barrier contraception or 
hormonal contraception along with a barrier contraceptive, both male and female partners) during 
the study and for 3 months following the dose of ARO-HBV.  Males must not donate sperm for at 
least 3 months after the last study treatment. Male partners of female patients and female partners 
of male patients must also use contraception, if they are of childbearing potential. Females of 
childbearing potential must have a negative urine pregnancy test at Screening and on Day 1, 
predose. Females not of childbearing potential must be post-menopausal (defined as cessation of 
regular menstrual periods for at least 12 months), confirmed by follicle-stimulating hormone 
(FSH) level in the post-menopausal range.  


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• 
Using twice the normal protection of birth control by using a condom AND one other form 
of the following (abstinence is acceptable at PI’s discretion): 
• 
Birth control pills (The Pill) 
o Cohort 12 Only: Female subjects of childbearing potential who are on a stable 
treatment regimen with hormonal contraceptives (i.e., same dose and not 
starting or stopping hormonal contraceptive use) for ≥3 months prior to 
screening should continue the same dose regimen until 12 weeks after EOT. 
Ethinylestradiol-containing 
contraceptives 
are 
only 
allowed 
if 
the 
ethinylestradiol content is ≤20 µg. For female subjects of childbearing 
potential who will start a hormonal contraceptive treatment during the study, 
ethinylestradiol-containing contraceptives are not allowed. 
• 
Depot or injectable birth control 
• 
IUD (Intrauterine Device) 
• 
Birth Control Patch (e.g., Ortho Evra) 
• 
NuvaRing® 
• 
Surgical sterilization. i.e., tubal ligation or hysterectomy for women or vasectomy for 
men or other forms of surgical sterilization 
Requirement for contraception can be waived in certain circumstances (i.e. same sex relationships) 
if approved by PI. 
6. Willing and able to comply with all study assessments and adhere to the protocol schedule 
7. Have suitable venous access for blood sampling 
8. Have a diagnosis of HBeAg positive or HBeAg negative chronic (> 6 months) HBV infection. 
9. HBeAg positive at Screening and experienced to entecavir or tenofovir therapy defined as 
consistently on any entecavir or tenofovir for at least the most recent 12 months (Cohort 9 only).  
10. HBeAg positive at Screening and naïve (has never received) any NUC or Interferon therapy 
(Cohort 8 only).  
11. HBsAg at screening ≥ 5 IU/mL 
12.  Patients with liver Elastography (i.e. FibroScan®) score ≤ 10.5 at or within 3 months of 
Screening (for Cohort 12 patients must have FibroScan < 9.0 kPa). 
13.  No prior use of capsid assembly modulators 
 
7.3 
Exclusion Criteria  
Exclusion Criteria for Healthy Volunteer Cohorts 
A potential subject will be excluded from the study if any of the following criteria apply: 
1. 
Female subjects have a positive pregnancy test or are lactating. 


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2. 
Acute signs of hepatitis/other infection (e.g., moderate fever, jaundice, nausea, vomiting, 
abdominal pain) at Screening or at baseline 
3. 
Use within the last 14 days or an anticipated requirement for anticoagulants (aspirin is 
acceptable), systemic (oral, depot or intravenous) corticosteroids, immunomodulators, or 
immunosuppressants (other than those used in study treatment regimens)  
4. 
Use of prescription medication within 14 days prior to administration of study treatment that 
in the opinion of the PI or the Sponsor would interfere with study conduct. Topical products 
without systemic absorption, statins, hypertensive medications, OTC and prescription pain 
medication or hormonal contraceptives (females) are acceptable.  
5. 
A history of poorly controlled autoimmune disease or any history of autoimmune hepatitis 
6. 
Human immunodeficiency virus infection, as shown by the presence of anti-HIV antibody 
(sero-positive) 
7. 
Seropositive for HBV or HCV or a history of delta virus hepatitis  
8. 
 Has uncontrolled hypertension defined as blood pressure > 170/100 mmHg at screening 
confirmed by repeat  
9. 
 A history of torsades de pointes, ventricular rhythm disturbances (eg, ventricular tachycardia 
or fibrillation), pathologic symptomatic bradycardia (heart rate < 45 bpm), 2nd degree or 3rd 
degree heart block, congenital long QT syndrome, prolonged QT interval due to medications, 
or new elevation or depression in the part of an ECG immediately following the QRS complex 
and merging into the T wave (ST segment) or new pathologic inverted T waves, or new 
pathologic Q waves on ECG that are deemed clinically significant in the opinion of the PI. 
Subjects with a history of atrial arrhythmias should be discussed with the Sponsor Medical 
Monitor and CRO Medical Monitor.  
10.  A family history of congenital long QT syndrome, Brugada syndrome or unexplained sudden 
cardiac death 
11.  Is taking medications known to prolong the QTc interval (the length of washout from a 
medication know to prolong the QTc interval will be determined by the PI depending on the 
medication’s half-life) 
12.  Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial infarction, 
severe cardiovascular disease (ejection fraction < 20%, transient ischemic attack (TIA) or 
cerebrovascular accident (CVA) within 6 months prior to study entry 
13.  History of malignancy within the last 5 years except for adequately treated basal cell 
carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. 
Participants with other curatively treated malignancies who have no evidence of metastatic 
disease and >2 years disease-free may be entered following approval by the Sponsor Medical 
Monitor 
14.  History of major surgery within 3 months of Screening 


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15.  Regular use of alcohol within one month prior to the Screening visit (i.e., more than fourteen 
units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% 
alcohol]) 
16.  Has evidence of severe systemic acute inflammation, sepsis, or hemolysis 
17. Recent (within 3 months) use of illicit drugs (such as cocaine, phencyclidine [PCP], MDMA,) 
or positive test for such drugs of abuse at screening. Subjects who are on prescription 
medications that cause a positive result on urine drug screen are eligible based on PI 
discretion. Subjects with a positive urine drug screen for opioids, cannabinoids or 
benzodiazepines may be eligible based on PI discretion.   
18. Use of an investigational agent or device within 30 days prior to dosing or current 
participation in an investigational study 
19. Has any clinically significant history or presence of poorly controlled or decompensated 
neurological, endocrine, cardiovascular, pulmonary, hematological, immunologic, psychiatric, 
metabolic, or other uncontrolled systemic disease, that may affect participation in the study 
20.  Blood donation (500 mL) within 7 days prior to study treatment administration.  
21. Any concomitant medical or psychiatric condition or social situation that would make it 
difficult to comply with protocol requirements or put the participant at additional safety risk 
22. Has a history of coagulopathy (including deep vein thrombosis and pulmonary embolism) or 
stroke within 6 months of baseline, and/or concurrent anticoagulant medication(s). 
23. Subjects with any of the following laboratory abnormalities: 
a. International normalized ratio (INR) > 1.5 × ULN 
b. Platelets < 100,000 cells per microliter 
24. Participants who are unable to return for all scheduled study visits 
25. Has any other condition that, in the opinion of the PI, would render the subject unsuitable for 
enrolment, or could interfere with his/her participation in the study 
Note: The PI has the sole right to enroll a subject for the study.  The Sponsor may discuss with 
the PI the suitability of enrolment based upon the subject’s medical history or screening results, if 
it is felt that a subject’s safety may be at risk. 
 
Exclusion Criteria for CHB Patient Cohorts 
A potential patient will be excluded from the study if any of the following criteria apply: 
1. Female patients have a positive pregnancy test or are lactating. 
2. Acute signs of hepatitis (e.g., combination of moderate fever, jaundice, nausea, vomiting, 
abdominal pain) within 4 weeks of Screening and/or at baseline 


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3. Use within the last 14 days or an anticipated requirement for anticoagulants (aspirin and other 
antiplatelet agents are acceptable), systemic (oral, depot or intravenous) corticosteroids, 
immunomodulators, or immunosuppressants (other than those used in study treatment 
regimens) 
4. Use of prescription medication within 14 days prior to administration of study treatment that 
in the opinion of the PI or the Sponsor would interfere with study conduct. Topical products 
without systemic absorption, statins, hypertensive medications, OTC and prescription pain 
medication or hormonal contraceptives (females) are acceptable 
5. A history of poorly controlled autoimmune disease or any history of autoimmune hepatitis 
6. Human immunodeficiency virus infection, as shown by the presence of anti-HIV antibody 
(sero-positive) 
7. Is sero-positive for HCV (defined by positive test for HCV RNA), or a history of delta virus 
hepatitis  
8. A history of torsades de pointes, ventricular rhythm disturbances (eg, ventricular tachycardia 
or fibrillation), pathologic symptomatic bradycardia (heart rate < 45 bpm), 2nd degree or 3rd 
degree heart block, congenital long QT syndrome, prolonged QT interval due to medications, 
or new clinically significant elevation or depression in the part of an ECG immediately 
following the QRS complex and merging into the T wave (ST segment) or new clinically 
significant pathologic inverted T waves, or new pathologic Q waves on ECG that is deemed 
clinically significant in the opinion of the PI. Patients with a history of atrial arrhythmias 
should be discussed with the Sponsor Medical Monitor and CRO Medical Monitor  
9.  A family history of congenital long QT syndrome, Brugada syndrome or unexplained sudden 
cardiac death 
10. Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial infarction, 
severe cardiovascular disease (ejection fraction < 20%, transient ischemic attack (TIA) or 
cerebrovascular accident (CVA) within 6 months prior to study entry 
11. History of malignancy within the last 5 years except for adequately treated basal cell 
carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. 
Participants with other curatively treated malignancies who have no evidence of metastatic 
disease and >1 year disease-free may be entered following approval by the Sponsor Medical 
Monitor 
12. History of major surgery within 3 months of Screening 
13. Regular use of alcohol within one month prior to the Screening visit (i.e., more than fourteen 
units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% 
alcohol]) 
14. Recent (within 3 months) use of illicit drugs (such as cocaine, phencyclidine [PCP], MDMA) 
or positive test for such drugs of abuse at screening. Subjects who are on prescription 
medications that cause a positive result on urine drug screen are eligible based on PI 
discretion. Subjects with a positive urine drug screen for opioids, cannabinoids or 
benzodiazepines may be eligible based on PI discretion.   


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15. Use of an investigational agent or device within 30 days prior to dosing or current 
participation in an investigational study 
16. Has any clinically significant history or presence of poorly controlled or decompensated 
neurological, endocrine, cardiovascular, pulmonary, hematological, immunologic, psychiatric, 
metabolic, or other uncontrolled systemic disease, that may affect participation in the study 
17. Any concomitant medical or psychiatric condition or social situation that would make it 
difficult to comply with protocol requirements or put the participant at additional safety risk 
18. Has a history of coagulopathy (including deep vein thrombosis and pulmonary embolism) or 
stroke within 6 months of baseline, and/or concurrent anticoagulant medication(s). 
19. Patients with any of the following laboratory abnormalities at screening: 
a. Serum creatinine > 1.5 mg/dL (132.6 µmol/L) 
b. International normalized ratio (INR) > 1.5 × ULN 
c. Platelets < 70,000 cells per microliter 
d. Hepatic transaminases (ALT or AST) > 5X ULN 
20. Participants who are unable to return for all scheduled study visits 
21. Has any other condition that, in the opinion of the PI, would render the patient unsuitable for 
enrolment, or could interfere with his/her participation in the study 
Note: The PI has the sole right to enroll a patient for the study.  The Sponsor may discuss with the 
PI the suitability of enrolment based upon the patient’s medical history or screening results, if it is 
felt that a patient’s safety may be at risk 
7.4 
Participant Withdrawal Criteria 
Participants will be advised that they are free to withdraw from the study at any time for any reason 
or, if necessary, the PI, or medically trained designee, may withdraw a participant from the study, 
per the following criteria, to protect the participant's health: 
• 
the need to take medication which may interfere with study measurements; 
• 
intolerable/unacceptable adverse experiences; 
• 
major violation of or deviation from study protocol procedures; 
• 
non-compliance of participant with protocol; 
• 
participant unwilling to proceed and/or consent is withdrawn; or 
• 
withdrawal from the study if, in the PI’s judgement, it is in the participant’s best interest. 


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The reasons for withdrawal will be recorded on the case report form (CRF) and included in the 
final clinical study report, along with any adverse events and any necessary medical treatment.  
If a participant is withdrawn from the study due to significant AE or SAE, the PI, or medically 
trained designee, will evaluate the urgency of the event. If the situation warrants, the PI, or 
medically trained designee, will take appropriate diagnostic and therapeutic measures. If the 
situation is not an immediate emergency, the PI, or medically trained designee, at the clinical study 
facility will attempt to contact the Arrowhead Pharmaceuticals, Inc. Medical Monitor or medically 
qualified designee for consultation. No medical help, diagnosis, or advice will be withheld from the 
participant due to an inability to contact the Medical Monitor. The participant will be encouraged 
to remain available for follow-up medical monitoring. The Sponsor will be notified as soon as 
possible of any participant withdrawals. 
Participants who are withdrawn or discontinue prior to EOS visit for reasons other than an adverse 
event, may be replaced. 
7.5 
Restrictions and Concomitant Medications 
1. Confinement: For each NHV participant, clinical facility confinement will be approximately 2 
days, starting on Day -1, with discharge on Day 2 (after the 24-hour post-dose assessments) and 
dosing on Day 1. Participants will return to the clinical facility for out-patient visits as per 
Schedule of Assessments. For CHB patients confinement is limited to approximately 2 hours 
post-dose administration.  
2. Fasting: On the day of dosing, patients will fast from food for at least 2 hours prior to study 
treatment administration and 2 hours post dose.  
3. Recreational Drugs & Alcohol:  Participants will be instructed to abstain from consuming 
alcohol for at least 48 hours prior to admission, and whilst confined to the clinical facility. In 
addition, participants will be instructed to refrain from regular use of alcohol (i.e., more than 
fourteen units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% 
alcohol]) for the study duration. Participants should abstain from use of recreational drugs 
throughout the study.  
4. Concomitant Medications Healthy Volunteers:  Subjects will be instructed not to take any 
prescription medication (other than medications used as part of the study) for 7 days prior to 
admission and for the duration of the study. Oral or other hormonal contraceptives are acceptable. 
Subjects will be instructed to inform the PI of the details (indication, dose and dates of 
administration) if they do take any medication, and these details will be recorded in the CRF.  If 
necessary, paracetamol may be used during the study as necessary. Any other medication or 
therapy other than blood pressure medication must be approved by the Medical Monitor or PI 
prior to administration.   


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5. Concomitant Medications CHB Patients: Use of concomitant medications during the study is at 
the discretion of the PI unless otherwise specified. However, participants should not be on 
medications that would interfere with study evaluations. Topical or inhaled steroids, statins, 
hypertensive medications, and birth control (where appropriate), and oral analgesics are 
acceptable. Participants will be instructed not to take any anticoagulants (aspirin and antiplatelet 
agents are acceptable), systemic (oral, depo or intramuscular) corticosteroids, immunomodulators 
(other than those specified in the study), or immunosuppressants 14 days prior to dosing and for 
the duration of the study. Participants will be instructed to inform the PI of the details (indication, 
dose, and dates of administration) if they do take any medication, and these details will be 
recorded in the eCRF. CHB patients entering the study on entecavir or tenofovir will continue 
their NUC therapy at the prescribed dose and frequency throughout the study. All treatment naïve 
CHB patients entering the study will start on entecavir or tenofovir on Day 1.  
Based on results from drug-drug interaction study 56136379HPB1004 investigating the potential 
effect of co-administration of JNJ-6379 with oral contraceptives, it is not anticipated that the 
efficacy of oral contraceptives will be impacted during co-administration with JNJ-6379 since the 
exposure of a progestin sensitive to CYP3A4 induction was not significantly affected by co-
administration of JNJ-56136379. In contrast, it is anticipated that co-administration with ethinyl-
estradiol-containing contraceptives will result in an increased exposure to ethinyl-estradiol. In the 
current study, female subjects of childbearing potential who are on a stable treatment regimen 
with hormonal contraceptives (ie, same dose and not starting or stopping hormonal contraceptive 
use) for ≥3 months prior to screening, should continue the same dose regimen until 12 weeks 
after EOT. Ethinyl-estradiol-containing contraceptives are only allowed if the ethinyl-estradiol 
content is ≤20 µg. For female subjects of childbearing potential who will start a hormonal 
contraceptive treatment during the study, ethinyl-estradiol-containing contraceptives are not 
allowed, given the observed increase in ethinyl-estradiol in study 56136379HPB1004. Co-
administration of JNJ-6379 170 mg qd with oral midazolam as a CYP3A4 probe showed a 
reduction of 41.7% in Cmax and 53.9% in AUC (study 56136379HPB1004), implying that JNJ-
6379 may induce the metabolism of CYP3A4 sensitive substrates. Questions regarding use of 
ARO-HBV or JNJ-6379 concomitantly with other medications should be discussed with Sponsor 
medical monitor.  
8 
INVESTIGATIONAL PRODUCT 
Arrowhead Pharmaceuticals, Inc. is responsible for the supply to the clinical site of active drug 
supplies together with detailed instructions (in a pharmacy manual) describing preparation and 
administration of ARO-HBV and of JNJ-6379.  The PBO (normal saline 0.9%) will be supplied by the 
clinical site. 
8.1 
ARO-HBV Description, Identification and Dosage 
ARO-HBV will be supplied as single sterile 2-mL vials containing ARO-HBV, with the correct dose 
of ARO-HBV prepared by the Pharmacy prior to dosing participants. 
The placebo (PBO) will be 0.9% normal saline administered subcutaneously.  


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Doses administered per Dose Level:   
Each single dose of either active drug (ARO-HBV) or PBO (normal saline 0.9%), will be administered 
by subcutaneous injection (either one or two subcutaneous injections per dose as required for each 
dose level). Injections will be made into the subcutaneous tissue at an appropriate site (e.g. abdomen, 
thigh, upper arm, etc.) using a 25-30 Gauge, ½ inch needle. The abdomen is the preferred site. 
Injection site is to be varied (no multiple injections into the same exact site. Alternating various 
locations on the abdomen is acceptable, and injection site location is to be recorded in the eCRF. Prior 
to dose administration, the ARO-HBV vial must be allowed sufficient time to come to room 
temperature. Do not inject into areas of active skin disease or injury such as ecchymosis, sunburns, 
skin rashes, inflammation or skin infections.  
8.2 
Supply, Preparation, Storage and Labelling of ARO-HBV 
ARO-HBV Injection is an aqueous solution in a sterile, 2-mL type I glass vial with a fluorocarbon-
lined butyl stopper and a blue flip-off seal. Each vial contains a nominal volume of 1.15 mL to provide 
a full 1 mL withdrawable volume.    
Strength: 200 mg/mL 
Volume: 1.15 mL 
Appearance: Clear, colorless to light yellow solution 
Inactive ingredients: 0.5 mM sodium phosphate monobasic, 0.5 mM sodium phosphate dibasic in 
water for injection 
Shipment and storage: Refrigerated, 2-8 ºC 
ARO-HBV Injection syringes will be prepared, per the Pharmacy Manual, by a pharmacist or qualified 
staff at the clinical sites. Aseptic technique will be used to ensure sterility of the solution to be 
injected.  The time of preparation for active drug must be documented and tracked. Please refer to the 
pharmacy manual for more detailed instructions 
The final study doses will be labeled per Good Manufacturing Practice (cGMP)/Good Clinical Practice 
(cGCP).  
Study drug supplies will be stored at clinical sites securely under the appropriate conditions. 


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8.3 
JNJ-6379 Physical Description of Study Drug(s) 
JNJ-56136379 supplied for this study is formulated as oral tablets containing 25 mg and 100 mg JNJ-
56136379-AAA. Refer to the IB for a list of excipients. 
8.4 
 Packaging and Storage 
JNJ-56136379 will be packaged in bottles. All study drugs will be dispensed in child-resistant 
packaging. No study drugs can be repacked without prior approval from the sponsor. 
JNJ-56136379 must be stored on site in the original package at controlled temperatures ranging from 
15°C to 30°C. The NUCs ETV (Baraclude®) and TDF (Viread®) must be stored on site in the original 
package at controlled temperatures ranging from 15°C to 25°C. Refer to the pharmacy manual/study 
site investigational product and procedures manual for additional guidance on study drug preparation, 
handling, and storage. 
8.5 
Study Drug Handling  
The Sponsor will provide the PI with a sufficient quantity of clinical drug supplies. The PI must ensure 
that deliveries of investigational product from the Sponsor are correctly received by a responsible 
person, that all receipts of drug shipments are recorded on the appropriate Drug Accountability forms 
prepared by the pharmacy at the clinical site and that the products are stored in a secure area under 
recommended storage conditions.  It is also the responsibility of the PI to ensure that the integrity of 
packaged study product not be jeopardized prior to dispensing.   
Only participants enrolled in the study may receive study drug, in accordance with all applicable 
regulatory requirements. Only authorized site staff may supply or administer study drug. The study 
drug must be stored in a secure area with access limited to the PI and authorized staff and under the 
physical conditions that are consistent with the study drug-specific requirements.  
An authorized and trained staff member at each clinical trial site will dispense the study drug per pre-
defined drug dispensing requirements. The dispensing and administration will be verified by a second 
member of site staff.  
ARO-HBV and JNJ-6379 will be supplied by Arrowhead Pharmaceuticals, Inc. and labeled with the 
drug name, batch number, expiration date (as applicable) and storage conditions. Individual doses will 


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be dispensed by clinical trial site staff members at the time of dosing and recorded in the drug 
accountability records. A Pharmacy Manual will be prepared to define the procedures for dispensing. 
Instructions provided in the Pharmacy Manual will be followed for the receipt, handling and 
accountability of the study formulations. 
8.6 
Accountability of Study Supplies 
All material supplied is for use only in this clinical study and should not be used for any other purpose. 
The PI is responsible for the investigational product accountability, reconciliation and record 
maintenance at the investigational site. In accordance with all applicable regulatory requirements, the 
PI or designated site staff must maintain investigational product accountability records throughout the 
course of the study. This person will document the amount of investigational product received from 
Arrowhead Pharmaceuticals, Inc., the amount supplied and/or administered to and returned by 
participants, if applicable.  A non-blinded Clinical Research Associate (CRA) will perform initial and 
ongoing study drug kit and placebo accountability. The non-blinded CRA will protect the integrity of 
the assignment blind and will not participate in data review for study participants.  Used vials of ARO-
HBV will be retained sequestered per participant and cohort and made available to the non-blinded 
CRA during study drug and placebo reconciliation, where allowable by local policy. Used bottles of 
JNJ-6379 will be retained sequestered per participant and made available to the CRA for study drug 
reconciliation. 
A Drug Dispensing Log must be kept current and will contain the following information: 
• 
the identification of the participant to whom the drug was dispensed; and 
• 
the date(s) and quantity of the drug dispensed to the participant. 
The date and time of ARO-HBV/placebo dose preparation and release will be maintained to support 
administration of study drug/PBO. The authorized pharmacist or qualified staff will be un-blinded to 
the doses. The pharmacy will dispense ARO-HBV/placebo and the study center will administer ARO-
HBV only to participants included in this study following the procedures set out in the study protocol.  
The pharmacy will dispense JNJ-6379 to the site staff who will provide it to the patients who will take 
their daily dose of 250 mg (oral) at home.  Patients will record taking their daily dose of JNJ-6379 on a 
diary provided to the clinical site.  Patients will bring their used bottles of JNJ-6379 and diaries with 
them to each subsequent visit so that the study staff may count the remaining tablets, compare the 
count to the patient’s recorded diary and ascertain the level of patient compliance with study 
treatment.  Patients will be provided with additional JNJ-6379 at each visit to cover the period of time 


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until their next clinic visit.  The pharmacy/clinical site will dispense JNJ-6379 only to participants 
included in this study following the procedures set out in the study protocol. 
Each participant will be given only the study medication carrying his/her study number.  Study drug 
administration will be documented on the CRFs and/or other study drug record.  
The study drug inventory must be available for inspection by the non-blinded monitor during the 
study. Drug supplies, excluding partially used or empty containers, will either be collected at the end 
of the study by the study monitor or returned by the PI or designee to Arrowhead Pharmaceuticals Inc. 
or its designee. When requested in writing by the Sponsor, following drug accountability and 
reconciliation, unused drug supplies may be destroyed by the PI or designee provided such disposition 
does not expose humans to risks from the drug and is permitted per the site’s Standard Operating 
Procedures. Records shall be maintained by the PI of any such alternate disposition of the test drug. 
These records must show the identification and quantity of each unit disposed of, the method of 
destruction (considering the requirements of local law), and the person who disposed of the test 
substance. Such records must be submitted to the Sponsor. 
8.7 
Retention of Investigational Product Vials 
For this study, used and partially used drug vials and bottles will be retained for an adequate period to 
allow accountability by the non-blinded CRA. No additional study drug samples will be retained. 
8.8 
Allocation to Treatment 
All potential participants who sign an informed consent at Screening will receive a unique 6-digit 
number (i.e., a Screening Number).  The first 3 digits will be the assigned site number and will be the 
same for each participant that screens at an individual site.  The next 3 digits will be assigned 
sequentially (starting with 001).  For patients who are deemed eligible, this 6-digit screening number 
will become the subject’s permanent study ID number. 
Once screened, eligible participants will be allocated to a sequentially numbered treatment and 
assigned a unique randomization number in accordance with the randomization schedule. Each 
participant will be assigned to either active (ARO-HBV) or PBO treatment. The allocation of active 
treatment or PBO will be performed using a block randomization algorithm. Randomization 
assignment can be requested up to 5 days prior to a scheduled Day -1 visit.  Final confirmation of 
eligibility will be checked prior to dosing on Day 1. 


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Participants who drop out or are removed from the study prior to their final onsite study visit for 
reasons other than AEs may be replaced. 
Only patients enrolled into Cohort 12 will received JNJ-6379.  
8.9 
Blinding and Code-break 
Blinding of study drug (ARO-HBV)/PBO assignment is critical to the integrity of this clinical trial.  It 
is expected that in most cases, AEs can be properly managed without the need for unblinding.  
However, in the event of a medical emergency in which knowledge of an individual participant’s 
assignment is considered critical to the participant’s well-being and management, the PI or 
documented designated treating physician may request permission to unblind the treatment assignment 
from the Sponsor Medical Monitor.  If the situation is not an immediate emergency, the PI should 
contact the responsible Medical Monitor to discuss the participant and circumstances requiring the 
unblinding.  The blind will be broken only for the specific participant under discussion.  Unblinding in 
situations that are not an immediate emergency may only take place with the notification and 
agreement of the responsible Sponsor Medical Monitor.  The randomization schedules will be 
maintained under controlled access. The personnel involved in the dispensing of investigational 
products will be accountable for ensuring compliance to randomization schedules. The non-blinded 
CRA will review the randomization schedule in comparison to the dispensing log to verify correct 
randomization.  
As the NHV component of the study is double-blinded, sealed subject -specific code break envelopes 
will be produced by the Sponsor or Sponsor designee and will be retained at the clinical study site in a 
secure, accessible location. If the PI considers an adverse event to be of such severity as to require 
immediate specific knowledge of the identity and dose of the relevant product, the PI may break the 
study code for that participant only. A record, including date, time, name and signature of person 
opening the envelope and reason, must be made both on the opened envelope and in the participant’s 
medical records. The study monitor should be informed promptly. 
After the completion of the final study visit (not including 90-day follow up phone call) for each NHV 
cohort, unblinding for Sponsor analysis will occur at Sponsor discretion. However, the site will remain 
blinded to treatment assignment.  


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9 
STUDY METHODS AND SCHEDULES  
9.1 
Overview of Procedures  
For NHVs, cohorts of 6 eligible subjects (2 placebo, 4 active ARO-HBV) will be evaluated at each 
dose level starting at dose level 1 (35 mg). Participants who have signed an HDEC (or local 
equivalent) approved informed consent form and have met all of the protocol eligibility criteria during 
screening, will be randomized at a ratio of 2:1 (active:PBO) to receive ARO-HBV or PBO in a double 
blind fashion.  NHV cohorts will receive a single dose only.   
Each cohort will begin with administration of ARO-HBV or PBO to two sentinel participants (one 
ARO-HBV, one PBO). Following the Day 3 evaluation in these participants, if there are no significant 
safety concerns based on PI’s judgement, the remaining participants in the cohort will be treated. 
Dosing of participants will be staggered by at least 15 minutes such that no two participants will be 
dosed simultaneously. 
Clinical facility confinement for NHVs will be approximately 2 days for single dose administration 
(Day -1 through 24 hour assessments). Blood samples will be drawn pre-dose on Day 1 for baseline 
measurements.  Height and weight will be measured at Screening only to calculate BMI.   
Based on observations for all NHV subjects in a cohort through Day 8, dosing will begin for the next 
NHV cohort and as applicable the next CHB cohort at the discretion of the DSC (not including 
Cohorts 1b and 1c).  Escalation to the next highest dose level will proceed in cohorts of 6 until the 
dose level of 400 mg is completed, or the trial is halted prematurely by the PI, DSC or Sponsor due to 
safety or other concerns. Blinding will be preserved to the extent possible for NHVs; however, 
treatment un-blinding may occur, at the PI’s discretion, where deemed necessary for treatment of an 
AE or for a decision to be made regarding trial continuation.  
After all subjects in a cohort have completed an End-of-Study (EOS) visit, Sponsor may be unblinded 
at Sponsors request. PI and study participants will remain blinded.  
For CHB patients in Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12, eligible CHB patients 
who have signed an HDEC (or local equivalent) approved informed consent form will receive three 
doses of ARO-HBV at dose intervals ranging from once every week to once every 4 weeks in an open 
label fashion. Screening for the CHB cohorts can begin once Cohort 1 dosing has commenced. These 
cohorts (not including Cohorts 1b and 1c) will be opened for accrual once the corresponding NHV 
cohort receiving the same dose level has reached Day 8, based on agreement of the DSC that it is safe 


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to proceed. Cohorts 6, 7, 8, 9, 10 and 11 can be opened for enrollment any time after Cohort 5 has 
reached Day 8 (and DSC has approved opening of such cohorts) and there is sufficient safety and viral 
antigen response data from CHB patients to determine a dose level for these cohorts. It is the intent 
that Cohorts 7, 10 and 11 will be treated at increasing dose levels starting with a dose equal to Cohort 
6.  Dose levels for Cohorts 6-11 is ≤ 300 mg.   Cohorts 2b through Cohort 7 and Cohorts 10 and 11 
will be enrolled in sequence (as shown in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with 
other CHB cohorts after the DSC has voted post Cohort 5 to open the remaining CHB patient cohorts 
and once a specified dose (≤ 400 mg) has been identified. Cohorts 1b and 1c are open for enrollment 
with the addition of this protocol amendment and may enroll in parallel. 
On dosing days, clinical facility confinement for CHB patients will be approximately 2 hours unless a 
prolonged period of post-dose observation is needed based on PI discretion. Blood samples will be 
drawn pre-dose on Day 1 for baseline measurements.  Height and weight will be measured at 
Screening only to calculate BMI. Participants will undergo evaluations at screening and at regular 
intervals during the study as described in the Schedule of Assessments. 
With the exception of Cohort 12 patients, all other CHB patients consenting to additional follow up 
will be followed as per Additional Follow-Up Schedule of Assessments (Table 1.5), every 56 days 
(± 5 days) for 5 additional visits after Day 113. Only Cohort 12 patients will require follow-up until 
the Day 337 (±5 days) visit. Subjects consenting to additional follow up will continue on NUCs. 
Subjects not consenting to additional follow up will be followed per protocol based on Schedule of 
Assessment Tables 1.2, 1.3 and 1.4.  
Single doses of ARO-HBV will be evaluated in NHVs and multiple doses of ARO-HBV will be 
evaluated in CHB patients in a sequential manner as shown in Figure 1.  
Cohort 12 will enroll 12 CHB patients in an open label fashion to receive 200 mg ARO-HBV on Days 
1, 29 and 57 as well as JNJ-6379 250 mg oral once daily starting on Day 1 and continuing through 
Day 84. Like all other cohorts, patients enrolling in Cohort 12 will either enter the study on NUCs or 
start NUCs on Day 1.   Enrollment in Cohort 12 can begin once enrollment is full in Cohorts 2b, 3b, 
4b, 5b, 6, 7, 8, 9, 10, 11.  
9.2 
Selection and Screening  
Prior to commencement of any screening procedures, the PI, or designee, will inform the participant 
about the nature and purpose of the study, including the risks and benefits involved, possible AEs, the 


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fact that their participation is voluntary and provide a copy of the HDEC (or local equivalent)-
approved Informed Consent Form for review. Each participant will acknowledge receipt of this 
information by giving written informed consent for their involvement in the study in the presence of 
the PI, or qualified designee, who will also sign and date the Informed Consent Form. Time of consent 
will be recorded on the Informed Consent Form. The original signed consent form will be retained by 
the PI and a copy of the original will be given to the participant. Informed consent will be performed 
per the Principles of the International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) procedures.    
Having given Informed Consent, potential participants will undergo procedures outlined in the 
Schedule of Assessments, to be performed within 60 days of the scheduled dosing date, to determine 
that he/she meets the inclusion/exclusion criteria specified in Sections 7.2 and 7.3.  
9.3 
On-Study Procedures/Assessments 
9.3.1 Study Procedures: Clinical Facility Confinement 
Eligible participants will present at the Clinical Facility on Day -1, the day prior to dosing.  Note that 
study dose administration is on Day 1, which must occur within 60 days of screening.  NHV 
participants only will be confined to the clinical facility until after the 24-hour post-dose (Day 2) 
assessments.  
On arrival at the clinical facility on Day -1, the PI, or appropriately trained designee, will meet with 
participants to reiterate all study procedures and encourage participants to ask any questions. All 
participants shall undergo a check-in procedure during which questions will be asked regarding 
protocol compliance and safety monitoring.  
Documentation of the participant’s fulfillment of the entry criteria, for all participants considered for 
the study and subsequently included or excluded, is to be completed by the PI, or medically qualified 
designee. Documentation of screening failure details will be recorded using eligibility screening forms 
or a participant screen failure log. Procedures outlined in the Schedule of Assessments will be 
performed. Meals and water will be provided while participants are confined at the clinical facility.  
Timing will abide by fasting restrictions outlined in Section 7.5. 
9.3.2 Demographics/Medical History 
Medical History will include medication use over the previous 30 days, including vitamins, over-the-
counter, prescription drugs, recreational drugs or supplements and alcohol and tobacco use. 


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9.3.3 Physical Exam 
A complete physical exam will be performed at Screening and as per Schedule of Assessments.  
At Screening, height (centimetres, without shoes) and weight (kilograms, without shoes) will be 
obtained to determine BMI.   
At all other time points outlined in the Schedule of Assessments, a symptom-directed physical exam 
will be performed if indicated.  
9.3.4 Electrocardiogram 
A single 12-lead ECG measurement will be obtained at time points outlined in the Schedule of 
Assessments after the participant is supine for at least 3 minutes. Any abnormal ECGs will be repeated 
in triplicate, with each measurement approximately 1 minute apart. ECGs will be performed prior to 
venipuncture and other invasive procedures. 
9.3.5 Vital Sign Assessments 
Systolic/diastolic blood pressure, temperature, heart rate, respiratory rate (breaths/min) will be 
obtained at time points outlined in the Schedule of Assessments after the participant is seated or semi-
supine for at least 3 minutes. Vitals signs will be obtained prior to venipuncture and other invasive 
procedures.  
9.3.6 Clinical Laboratory Tests & Pharmacodynamic Values 
Blood and urine samples will be collected to perform clinical laboratory tests run at a central 
laboratory. Participants will be required to fast for the Screening sample collections. 
At the Screening visit, up to 60 days prior to the first dose of study medication, a blood and urine 
sample will be collected for the laboratory tests detailed below, to establish eligibility for enrolment. 
Baseline values will be the values from Day 1 pre-dose labs. If this sample is not available Screening 
values will be considered baseline. The results will be assessed by the PI, or medically qualified 
designee, before study enrolment. Any abnormality in laboratory values (that are confirmed on repeat) 
deemed clinically significant by the PI, or medically qualified designee (i.e., those that would 
jeopardize the safety of the participant or impact on the validity of the study results), will result in 
exclusion of that participant. Up to two retests for inclusionary or exclusionary labs are allowed. 
Clinical laboratory tests will be performed on participants’ blood and urine at specified time-points 
listed in the Schedule of Assessments. 
Biochemistry: Sodium, potassium, chloride, bicarbonate, glucose, urea, creatinine (including 
calculated creatinine clearance), creatine kinase, uric acid, phosphate, total calcium, anion gap, 
cholesterol, albumin, globulins, protein, total bilirubin, conjugated bilirubin, gamma 


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glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate 
transaminase (AST), lactate dehydrogenase (LD), triglycerides, amylase, lipase, C-reactive protein 
and Troponin l. 
Hematology: Hemoglobin, red blood cell count (RBC), hematocrit, mean cell volume (MCV), 
mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), platelets, white cell 
count, neutrophils, lymphocytes, monocytes, eosinophils and basophils.  
Coagulation: Partial thromboplastin time (PTT), Prothrombin time (PT) with INR. 
Urinalysis: Leucocytes, nitrites, urobilinogen, protein, pH, blood, specific gravity, ketone, bilirubin 
and glucose. 
Reflex microscopic urinalysis will be performed if indicated: White Blood Cells, Red Blood Cells, 
Epithelial cells, Bacteria. 
Serology: HBV genotyping, HBV-RNA (if scientifically feasible), HBV-DNA, HBsAg (qualitative 
and quantitative), Anti-HBsAg (qualitative and quantitative), HBeAg (qualitative and quantitative), 
Anti-HBeAg (qualitative and quantitative), HBcrAg (quantitative), Hepatitis C antibody and HIV 
antibody screen. If necessary, participants will be counseled by the PI, or medically trained 
designee, concerning the blood tests for Hepatitis B surface antigen, Hepatitis C and HIV 
antibodies, and their subsequent results.  
HBV DNA sequencing: To be analyzed only if HBV DNA serum levels are above 60 IU/mL for 
ARO-HBV target site, HBsAg epitope shift, and core/pre-core mutation tests, and above 1,900 IU/mL 
for HBV deep sequencing.  An additional sample will be collected if resistance is suspected (defined 
as a > 1.0 log IU/mL increase in HBV DNA from NADIR from Day 1 through day 71, confirmed by 
repeat test). 
 
FSH:  Post-menopausal status will be confirmed by follicle-stimulating hormone (FSH) level 
consistent with post-menopausal state. 
Drugs Screen: Urine drug screen for Benzodiazepines, Amphetamines, Barbiturates, 
Methamphetamines, Methadone, Opiates, Phencyclidine, Cannabinoids, Ecstasy and Cocaine.  
Pregnancy:  Females of childbearing potential will have a urine pregnancy test.  If urine pregnancy 
test is positive, patient will be referred to their primary care provider for follow up.  
Cytokines & Complement: Samples for analysis of Cytokine Panel A: IL-6, MCP-1, TNFalpha, IL-8, 
IL-1beta, IFNalpha, IL-10, IL-12 (p40), IL-12 (p70), Mip-1alpha) and Complement factors (Bb and 
CH50, C5a, C4a, C3a) and Cytokine Panel B: TNF alpha, IFN gamma, CXCL-9, and CXCL-10 will 
be obtained as indicated at time points outlined in the Schedule of Assessments. Collected cytokine 
Panel B samples will only be analyzed at discretion of and with notification by Sponsor. 
Anti-Drug Antibodies: For Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and11 blood samples for the anti-drug 
antibodies test will be collected at Screening, Day 57 and Day 113 or at EOS.  
Cellular Immunology Studies: For all CHB patient cohorts, blood samples to evaluate changes in 
anti-viral host immunologist profile will be collected on Day 1 (pre-dose), 43 and 113. This will 
include T cell subsets (activation and exhaustion state), NK cell subsets (activation and exhaustion 
state), B cell subset, monocyte subsets and HBV antigen specific T cell response (including HBcAg, 


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HBsAg). Cellular immunology studies will be conducted if scientifically feasible in New Zealand 
only.  
Interferon Response Gene SNP testing: Patient’s interferon response gene SNPs will be evaluated (if 
patient consents to limited genetic testing). A blood sample for pharmacogenomics (DNA) research is 
optional and will only be collected from subjects who consent separately to this component of the 
study. Subjects who are enrolled in the study at the time of this amendment will be contacted to ask for 
their consent for this component of the study. Sample can be collected any time after the consent has 
been signed. This sample can be used to assess impact of IL28B polymorphism on efficacy of ARO-
HBV treatment. In addition, samples can be used to investigate the potential association of genetic 
factors with efficacy, safety, or pharmacokinetics of ARO-HBV, CHB infection, or HBV-related 
disease or may be used to develop tests/assays related to ARO-HBV or HBV. These analyses will be 
performed at the sponsor’s discretion, will always be under the sponsor's supervision, and may be 
reported separately. 
9.3.7 Pharmacokinetics 
Samples for analysis of circulating AD04872 and AD05070 will be obtained at time points following 
the end of injection outlined in the Schedule of Assessments. 
Plasma concentrations of ARO-HBV, NUC and JNJ-6379 will be measured at a single post-dose time 
point in Cohort 12 only. 
 
9.3.8 Concomitant Medications/Therapies 
Participants will be instructed to inform the PI of the details (indication, dose and dates of 
administration) if they do take any medication, and these details will be recorded in the eCRF.  If 
necessary, paracetamol may be used during the study as necessary. Any other medication or therapy 
other than blood pressure medication must be approved by the Medical Monitor or PI prior to 
administration.   
9.3.9 Follow-Up Procedures  
Day 90 (± 5 days) Telephone Call   
Documented telephone contact with each participant to verify compliance with contraceptive measures 
and absence of any known pregnancy at 90 days post EOS (Day 29 for NHVs and Day 113 for CHB 
patients). 
Additional CHB Follow-up 
With the exception of Cohort 12 patients, all other CHB patients consenting to additional follow up 
will be followed as per Additional Follow-Up Schedule of Assessments (Table 1.5), every 56 days 
(± 5 days) for 5 additional visits after Day 113. Only Cohort 12 patients will require follow-up until 
the Day 337 (±5 days) visit. Subjects consenting to additional follow up will continue on NUCs. 
Subjects not consenting to additional follow up will be followed per protocol based on Schedule of 
Assessment Tables 1.2, 1.3 and 1.4.  


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9.3.10 Early Termination Procedures 
The reason for Early Termination will be documented in source documents and eCRF. Procedures as 
outlined in the Schedule of Assessments will be completed.  
9.4 
Allocation of Formulations 
Four NHV participants will receive active treatment and 2 participants will receive PBO in each dose 
level. Treatments will be administered per the randomized sequence kept by the pharmacy or in a 
secure place at the clinical site, under control of the un-blinded staff member.   All CHB patients will 
receive active treatment.  CHB patients in Cohort 12 will receive daily oral JNJ-6379 + ARO-HBV 
Q28 x 3. 


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9.5 
Study Formulation Administration 
Appropriately trained employees of the clinical site will administer ARO-HBV/PBO. Each dose will 
be administered as a subcutaneous injection. Doses of 400 mg will be administered as two injections 
per dose with each injection administered into separate a site.  The date, time and location of 
administration will be recorded in the source notes and witnessed by a second person from the clinical 
facility. The preferred site of injection is the abdomen. Optional additional sites are the upper arms 
and thighs or other sites based on PI clinical judgement.  
Table 2: Injection number and volume per cohort 
Cohort 
Dose 
Concentration Total Injection Volume # Injections per planned dose 
1 
35 mg 
200 mg/mL 
0.175 mL 
Single 
1b 
25 mg 
200 mg/mL 
0.125 mL 
Single 
1c 
50 mg 
200 mg/mL 
0.25 mL 
Single 
2, 2b, 6, 7 
100 mg 200 mg/mL 
0.5 mL 
Single 
3, 3b, 10, 12 
200 mg 200 mg/mL 
1.0 mL 
Single 
4, 4b, 8, 9, 11 300 mg 200 mg/mL 
1.5 mL 
Single 
5, 5b 
400 mg 200 mg/mL 
2.0 mL 
Two (at separate sites) 
JNJ-6379 will be dispensed to patients in Cohort 12 only who will take their daily dose (250 mg oral) 
at home.  Patients will bring all remaining tablets to their subsequent visits for compliance assessment, 
and receive additional tablets to cover their daily doses until the next subsequent visit. 
9.6 
Timing of Treatments and Procedures 
Actual times of procedures for each participant will vary depending on scheduling and will be 
recorded in the eCRF. 
Post-dose time points will be determined based on time of injection.   


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In the event of multiple procedures scheduled at the same time, non-invasive procedures (i.e. ECGs, 
AE assessment) will be conducted prior to invasive procedures (i.e., blood sample collection). Timing 
of activities may be adjusted slightly to accommodate all procedures. 
The following windows are allowed for study assessments/visits: 
Pre-dose:  
 
 
 
Within 60 minutes prior to dosing  
PK/PD through 6 hours:  
 
± 2 minutes                                                                
All other procedures through 6 hours:  ± 10 minutes                                                         
PK/PD from 8 to 48 hours:  
 
± 5 minutes                                                                
All other procedures from 8 to 48 hours: ± 15 minutes                                                             
Day 8:  
 
 
 
± as per SOA 
Day 15 to Day 29: 
 
 
± as per SOA 
Visits beyond Day 29:  
 
± as per SOA 
9.7 
Safety Endpoints  
The safety of ARO-HBV (alone or in combination with JNJ-6379) will be evaluated by collection 
of the following measurements performed at specified time points: 
• Monitoring of AEs/ SAEs 
• Physical examinations 
• Vital signs  
• ECG measurements  
• Injection Site Reactions (Mild, Moderate or Severe): Photographic images will be taken of all 
injection site reactions at the time of reporting and at the time of resolution.  
• Clinical laboratory tests (hematology, biochemistry, coagulation, urinalysis) 
• Concomitant medications/therapy, and  
• Reasons for treatment discontinuation due to toxicity 
The AE/SAE reporting period for an enrolled participant will begin when the participant provides 
informed consent. Treatment-Emergent AEs/SAEs will be those defined as following dose 
administration. All AEs/SAEs that occur during the AE reporting period specified in the protocol must 
be reported to Arrowhead Pharmaceuticals, Inc., regardless of the relationship of the AE to study 


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treatment.  Any known untoward event that occurs beyond the AE reporting period that the PI 
considers an SAE and possibly related to study treatment will be reported to Arrowhead. 
9.8 
Blood Sampling for Pharmacokinetic and Pharmacodynamic Analysis 
Blood samples will be collected from participants through an indwelling cannula or through a fresh 
vein puncture.  The actual blood collection time will be recorded in the source documents. All 
deviations outside the range allowed above will be documented as protocol deviations. In all such 
cases, appropriate time corrections, for the actual time of sample collection will be incorporated at the 
time of data analysis. Blood samples for pharmacokinetic and pharmacodynamic analyses will be 
collected at time points outlined in the Schedule of Assessments.  
The target sample times will be printed in the eCRF. The actual sample times (times samples taken) 
will be recorded alongside the nominal times in the eCRF and will be entered at the time of or as soon 
as possible after sampling. All times must be recorded in the 24-hour format. An explanation must be 
given for any blood sample taken outside of the set sampling times. 
9.8.1 Sample Processing and Analysis for Pharmacokinetic Samples 
Blood samples will be collected and processed per the Laboratory Manual. 
Plasma samples will be assayed by a validated hybridization-ligation method. The criteria for repeat 
analysis, as defined in the respective in-house procedure, will be followed.  
The validation study conducted by the appointed bioanalytical laboratory to establish validity 
including accuracy, precision, reproducibility, specificity, recovery and frozen stability of the 
analytical method will be appended to the final report. 
9.8.2 Sample Processing and Analysis for Pharmacodynamic, Cytokine and Complement 
Samples 
Whole blood will be collected at specified time points for analysis of cytokines and complement.   
Cytokines:  Whole blood samples will be collected and processed per the Laboratory Manual. Initially 
the pre-dose and 2-hour post-dose samples will be analyzed, with the remaining samples analyzed if a 
change from baseline is observed at 2 hours. 


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Complement: Venous blood samples will be collected and processed per the Laboratory Manual at 
each time point.  Initially the 0 (pre-) and 2-hour post-dose samples will be analyzed, with the 
remaining samples analyzed if a change from baseline is observed at 2 hours. 
Results, percent change, and duration of response from baseline to 4 weeks (or longer as necessary) 
will be analyzed and summarized by dose cohort and treatment group. 
10 
ADVERSE EVENTS 
The PI and clinical facility staff are responsible for detection, recording and reporting of events that 
meet the criteria and definition of various adverse events as listed below. Adverse events will be 
recorded from time of signed consent through to end of study; only AEs that occur post-dose will be 
considered treatment-emergent.  The PI and clinical facility staff are responsible for detection, 
recording and reporting of pregnancy and appropriate follow up. 
10.1 
Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding or diagnostic test), symptom, or disease temporally 
associated with the use of a medicinal (investigational/experimental) product, whether related to this 
product or not. (Refer to International Conference on Harmonisation [ICH] E2a: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, 27 October 1994). 
Treatment emergent AEs will be defined as AEs with onset after administration of the study drug, or 
when a preexisting medical condition increases in severity or frequency after study drug 
administration.  
AEs will not include: 
• 
A medical or surgical procedure such as surgery, endoscopy, tooth extraction, or transfusion 
(although the condition that leads to the procedure may be an AE) 
• 
A pre-existing disease or condition present at the start of the study that does not worsen during 
the study 
• 
Any situation where an untoward medical occurrence has not occurred (for example, 
hospitalizations for cosmetic elective surgery or “social” admissions) 


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• 
An overdose of either the investigational product or a concurrent medication without any 
resulting signs or symptoms. 
A Serious Adverse Event (SAE) is an AE that: 
• 
Results in death, 
• 
Is life-threatening, (NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers to an 
event/reaction in which the participant was at immediate risk of death at the time of the 
event/reaction; it does not refer to an event/reaction which hypothetically might have caused 
death, if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization,  
• 
Results in persistent or significant disability/incapacity,  
• 
Is a congenital anomaly/birth defect, 
• 
Is a medically important event or reaction.  
Medical and scientific judgment should be exercised in deciding whether other situations, should be 
considered serious such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but might jeopardize the participant or might require medical or 
surgical intervention to prevent one of the other serious outcomes listed in the above definition. These 
should also be considered serious. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
10.2 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
AEs 
Abnormal assessments (e.g. ECGs and vital signs) that are judged by the PI as clinically significant or 
result in clinical sequelae will be recorded as AEs. Laboratory abnormalities will be reported by the PI 
as AEs if the abnormality is considered clinically significant or results in clinical sequelae.  Laboratory 
abnormalities not reported as AEs are not to be reported as Clinically Significant (CS) in the study 
database.   
Clinically significant abnormal laboratory findings or other abnormal assessments that are detected 
during the study or are present at baseline and significantly worsen following the start of the study will 
be reported as AEs.  


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The PI (or medically qualified designee) will exercise his or her medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.   
10.3 
Timing, Frequency, and Method of Detecting AEs 
Any pre-existing conditions or signs and/or symptoms present in a participant prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical/Surgical History.  
All AEs occurring after informed consent and on or before the final visit must be reported as AEs; 
only AEs that occur post-dose will be considered treatment-emergent.  All AEs must be recorded 
irrespective of whether they are considered drug-related. 
At each visit/assessment in the period defined above, AEs will be evaluated by the PI (or medically 
qualified designee) and recorded. 
10.4 
Recording of AEs  
When an AE occurs, it is the responsibility of the PI or medically qualified designee to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event. 
The PI or medically qualified designee will then record the AE on the AE CRF. Additional reporting 
requirements for an AE meeting serious criteria are discussed in Section 10.7 below. 
The PI or medically qualified designee will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. In all cases, when available, the diagnosis should 
be reported as the event and not the individual signs/symptoms.  It is not acceptable for the PI to send 
photocopies of the subject’s medical records to the Sponsor in lieu of completion of the appropriate 
AE CRF pages. 
10.5 
Evaluating AEs  
10.5.1 Assessment of Intensity 
The PI or medically qualified designee will assess intensity for each AE reported during the study. The 
assessment will be based on the PI’s (or medically qualified designee’s) clinical judgment. The 
intensity should be assigned to one of the following categories: 


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Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities. 
Severe: An event that prevents normal everyday activities. 
An AE that is assessed as severe should not be confused with a SAE. Severity is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. An event is defined 
as ‘serious’ when it meets one of the pre-defined outcomes as described in Section 10.1.  
10.5.2 Injection site reactions  
Injection site reactions will be graded as either Mild, Moderate or Severe. An injection site reaction is 
defined as an adverse reaction (usually immunologic) developing at the site of injection. Injection site 
reactions are graded Mild, Moderate or Severe based on symptoms. Photographs of local reactions 
around injection site should be obtained at the time of reporting and at the approximate time of 
resolution.  
• 
Mild: Tenderness with or without associated symptoms (e.g., warmth, erythema, itching), mild 
pain or mild edema.  
• 
Moderate: Pain with associated phlebitis or lipodystrophy 
• 
Severe: Tissue ulceration or necrosis with associated severe tissue damage or if operative 
intervention is indicated 
10.5.2 Assessment of Causality 
The PI (or medically qualified designee) is obligated to assess the relationship between investigational 
product and the occurrence of each AE. The PI (or medically qualified designee) will use clinical 
judgment to determine the relationship. Alternative causes, such as natural history of the underlying 
diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the 
investigational product will be considered and investigated. The PI (or medically qualified designee) 
will also consult the Investigator’s Brochure in the determination of his/her assessment. 
There may be situations when an SAE has occurred and the PI has minimal information to include in 
the initial SAE report. However, it is very important that the PI (or medically qualified designee) 


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always assess causality for every event prior to transmission of the SAE report form. The PI (or 
medically qualified designee) may change his/her opinion of causality considering follow-up 
information, amending the SAE report form accordingly. The causality assessment is one of the 
criteria used when determining global regulatory reporting requirements. 
The PI (or medically qualified designee) will provide the assessment of causality utilizing three 
possible categories:  Not Related, Possibly Related and Probably Related. 
An AE will be considered “not related” to the use of the product if any of the following tests are met: 
An unreasonable temporal relationship between administration of the product and the 
onset of the AE (e.g., the event occurred either before, or too long after administration 
of the product for it to be considered product-related); 
A causal relationship between the product and the AE is biologically implausible (e.g., 
death as a passenger in an automobile accident) 
A clearly more likely alternative explanation for the AE is present (e.g., typical 
adverse reaction to a concomitant drug and/or typical disease-related event) 
An AE will be considered “Possibly related” when there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the product under investigation. 
An AE will be considered “Probably related” when there are facts, evidence, or arguments to suggest 
that the event is related to the product under investigation. 
10.6 
Follow-up of AEs 
After the initial AE, the PI is required to proactively follow each participant and provide further 
information on the participant’s condition as deemed appropriate.  
All AEs will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the participant is lost to follow-up. Once resolved, the appropriate AE CRF page 
and SAE report form (if event is serious) will be updated. The PI, or medically qualified designee, will 
ensure that follow-up includes any supplemental investigations as may be indicated to elucidate the 
nature and/or causality of the AE or SAE. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals.  In 


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the event of a fatal outcome in an SAE, the PI, or medically qualified designee, will attempt to obtain 
postmortem findings, including histopathology, and provide all additional information in a follow up 
SAE report. 
New or updated information regarding an SAE will be recorded on a new SAE report form marked as 
follow-up with the appropriate follow-up number added to the report. The follow-up report will be 
signed and dated by the PI.  
10.7 
Prompt Reporting of SAEs  
AEs meeting serious criteria MUST be reported promptly to the designated Pharmacovigilance CRO, 
and the HDEC or local equivalent. 
10.7.1 Completion and Transmission of the SAE reports  
Once the PI becomes aware that an SAE has occurred in a study participant, she/he will report the 
information on an SAE report form to the designated Pharmacovigilance CRO within 24 hours. The 
SAE report form will always be completed as thoroughly as possible with all available details of the 
event and signed by the PI or medically qualified designee. If the PI, or medically qualified designee, 
does not have all information regarding an SAE, he/she will not wait to receive additional information 
before reporting the event. The SAE report form will be updated when additional information is 
received. 
The PI (or medically qualified designee) will always provide an assessment of causality at the time of 
the initial report as described in Section 10.5.2. 
Facsimile or email transmission of the SAE report form are the preferred methods to transmit this 
information to the designated Pharmacovigilance CRO. In rare circumstances, notification by 
telephone is acceptable, with a copy of the SAE CRF sent by overnight mail. Initial notification via the 
telephone does not replace the need for the PI, or medically qualified designee, to complete and sign 
the SAE report form within the outlined time frames. 
The Sponsor will provide a list of project contacts for SAE receipt, fax numbers, telephone numbers, 
and mailing addresses. Any event that in the opinion of the PI, or medically qualified designee, may be 
of immediate or potential concern for the participant’s health or well-being will be reported to the 
Sponsor emergency contact listed below.  
 


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Sponsor Emergency Contact 
 
10.7.2 Serious Adverse Event Reports to the HDEC (or local equivalent) 
The PI, or responsible person per local requirements, will comply with the applicable local regulatory 
requirements related to the reporting of SAEs to regulatory authorities and the HDEC or local 
equivalent.   
10.8 
Regulatory Requirements for Reporting of SAEs  
The PI (or medically qualified designee) will promptly report all SAEs in accordance with the 
procedures detailed in Section 10.7.  Prompt notification of SAEs by the PI is essential so that the 
Sponsor may comply with its regulatory obligations.  
10.9 
Post-study AEs 
A post-study AE is defined as any event that occurs outside of the AE detection period defined in 
Section 10.3. 
The PI is not obligated to actively seek AEs in former study participants. However, if the PI learns of 
any SAE, including a death, at any time after a participant has been discharged from the study, and 
he/she considers the event at least possibly related to the investigational product, the PI will promptly 
notify Arrowhead.  
10.10 
SAEs Related to Study Participation 
An SAE considered related to study participation (e.g., procedures, invasive tests, a change in existing 
therapy), even if it occurs during the pre- or post-treatment period, will be reported promptly (refer 
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11 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
11.1 
Data analysis through EOS and Additional follow-up 
Two separate data analyses will be performed, one for all subjects through EOS (Day 29 for NHVs 
and Day 113 for CHB patients), and one additional and separate analysis for CHB patients who 
consent to the additional follow up.   
11.2 
Sample Size Considerations 
This study represents a proof of principle study, and as such no formal sample size calculation was 
performed.  Results from this study will be utilized in sample size calculations for subsequent studies. 
11.3 
Screening Data 
Demographics will be tabulated by participant and summarized by cohort and treatment group. 
Eligibility assessments at baseline, including medical/surgical history data and physical examination 
data (including height and weight), will be listed for each participant.  
11.4 
Safety/Tolerability Data 
In general, safety analyses will be performed and the results summarized by-cohort and treatment 
group.   
Treatment-emergent AEs will be summarized using the latest version of MedDRA by System Organ 
Class (SOC) and Preferred Term (PT), classified from verbatim terms. The incidence and percentage 
of participants with at least 1 occurrence of a PT will be included, per the most severe grade using a 3-
point scale (mild, moderate, severe). The number of events per Preferred Term will also be 
summarized.  Causality (relationship to study treatment) will be summarized separately. 
The incidence and frequency of AEs, SAEs, related AEs, related SAEs and AEs leading to withdrawal, 
dose modification, or treatment discontinuation will be summarized by dose and treatment group per 
SOC and Preferred Terms. AEs will also be summarized in listings. The duration of AEs will be 
determined and included in listings, along with the action taken and outcome. 
The incidence of laboratory abnormalities will be summarized. Results for variables that are not coded 
will be presented in the listings as “below, within, and above” the normal limits of the laboratory. 
Pregnancy test results will be summarized separately by time point. 


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Vital sign measurements will be summarized at each scheduled time point using descriptive statistics.  
Physical examination findings will be summarized by time point and presented in subject listings.  
ECG parameter changes overall, changes from baseline and qualitative assessments will be 
summarized.  
The whole blood collected for analysis following a single dose of ARO-HBV at different dose levels 
will undergo analysis for cytokines (Panel A) and complement changes. Results, percent change, and 
duration of response from baseline to 24 hours (or 48 hours, as necessary) will be analyzed where 
indicated by initial testing at pre-dose and at 2-hours post-administration. If cytokine or complement 
levels are elevated from pre-dose to 2-hours post-dose then all other specified timepoints (See 
Schedule of Assessments) will also be analyzed. Whole blood collected following multiple doses of 
ARO-HBV for cytokine Panel B samples will only be analyzed at discretion of and with notification 
by Sponsor. Results, percent change, and duration of response from baseline will be analyzed where 
indicated. Results for cytokines and complement will be summarized by dose cohort and treatment 
group.  
11.5 
Pharmacokinetic Data 
Plasma concentrations of ARO-HBV collected at specified time points post-dose from all participants 
at different dose levels will be used to calculate the following single dose pharmacokinetic parameters: 
AUC0–24:   
The area under the plasma concentration versus time curve from the zero to 24 hours.  
AUCinf: 
 
The area under the plasma concentration versus time curve from zero to infinity. 
Cmax: 
 
The maximum plasma concentration will be obtained directly from the plasma 
concentration time profile. 
tmax:  
 
The time to maximum plasma concentration will be obtained by inspection.  
t½:  
 
The half-life will be calculated by the equation t½ = ln(2)/kel. 
 
The pharmacokinetic parameters will be determined using non-compartmental method(s).  Descriptive 
statistics of pharmacokinetic parameters will include mean, standard deviation (SD), and coefficient of 
variation (CV), minimum and maximum. Dose-related trends in pharmacokinetic parameters will be 
assessed. 
Plasma concentrations of ARO-HBV, NUC and JNJ-6379 will be measured at a single 2 hour post-
dose time point in Cohort 12 only. 


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Pharmacokinetic parameters will be tabulated and summarized by dose level where applicable. The 
concentration-time profiles for each participant and the mean concentration-time profiles by dose level 
will be plotted with concentration presented on both linear and logarithmic scales. Cohort 12 CHB 
patient limited PK data will be evaluated separately from NHV PK data. 
Statistical analysis will be performed on the pharmacokinetic parameters using validated statistical 
software.  
11.6 
Pharmacodynamic Data 
The whole blood collected for pharmacodynamic analysis following multiple doses of ARO-HBV at 
different dose levels will undergo analysis for changes in HBV-DNA, HBV-RNA (if scientifically 
feasible) and viral antigens based on reference laboratory (VIDRL) generated values. Cellular 
immunologic assessments will also be conducted (if scientifically feasible) at University of Auckland.  
Immunology assessments (CHB patients in New Zealand only) 
• 
Changes in profile from pre-dose to post-dose time points for: T cell subsets (activation and 
exhaustion state), NK cell subsets (activation and exhaustion state), B cell subset, monocyte 
subsets. To be conducted if scientifically feasible. 
• 
Changes from pre-dose to post-dose time points for: HBV antigen specific T cell response 
(including HBcAg, HBsAg). To be conducted if scientifically feasible.    
Virology assessments (CHB patients only) 
• 
Virologic parameters will be summarized by cohort for the following: 
• 
Quantitative HBsAg (qHBsAg): Log change from baseline to nadir and duration of response 
from nadir back to approximately 20% of baseline or EOS. In CHB patients who consent to 
additional follow up, HBsAg will be followed until the end of the additional follow-up period 
or early termination and summarized separately.   
• 
Percent of patients with loss of HBsAg (defined as quantitative HBsAg < 0.05 IU/mL) at EOS 
and time to occurrence (Kaplan Meier). In CHB patients who consent to additional follow up, 


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HBsAg loss will be monitored until the end of the additional follow-up period or early 
termination and summarized separately.   
• 
Percent of patients with anti-HBS seroconversion at EOS and time to occurrence (Kaplan 
Meier). In CHB patients who consent to additional follow up, anti-HBS seroconversion will be 
monitored until the end of the additional follow-up period or early termination and 
summarized separately.   
• 
Change in Anti-HBs (quantitative) to EOS. In CHB patients who consent to additional follow 
up, change in Anti-HBs (quantitative) will be monitored until the end of the additional follow-
up period or early termination and summarized separately.   
• 
Quantitative HBV DNA (when quantifiable at baseline): Log change from baseline to EOS. In 
CHB patients who consent to additional follow up, HBV DNA will be monitored until the end 
of the additional follow-up period or early termination and summarized separately.   
• 
Quantitative HBV RNA: Log change from baseline to nadir and duration of response from 
baseline to EOS (if scientifically feasible). In CHB patients who consent to additional follow 
up, HBV RNA will be monitored until the end of the additional follow-up period or early 
termination and summarized separately. 
• 
Quantitative HBcrAg: Log change from baseline to nadir and duration of response from 
baseline to EOS. In CHB patients who consent to additional follow up, HBcrAg will be 
monitored until the end of the additional follow-up period or early termination and 
summarized separately. 
• 
Quantitative HBeAg (HBeAg positive only):  Log change from baseline to nadir and duration 
of response from baseline to EOS. In CHB patients who consent to additional follow up, 
HBeAg will be monitored until the end of the additional follow-up period or early termination 
and summarized separately. 
• 
Emergence of HBV mutations (sequencing of ARO-HBV target site, Core/pre-core, HBsAg 
epitope, any other mutations by deep sequencing) to EOS. In CHB patients who consent to 
additional follow up, HBV mutations will be monitored until the end of the additional follow-
up period or early termination and summarized separately. 


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• 
Virologic response parameters may be summarized based on presence of interferon response 
gene SNPs (e.g. IL28B). 
Descriptive statistics of virologic parameters will include mean, median, count, SD, minimum, and 
maximum. Additional details will be provided in the statistical analysis plan. If feasible, Clinical Study 
Report analysis of, quantitative HBsAg through EOS will be based on a final batched analysis of 
samples.  
Separate analysis will be completed for all CHB patients receiving at least one dose, all HBeAg 
negative patients and all HBeAg positive patients, all treatment naïve and all entecavir or tenofovir 
experienced patients.   
11.7 
Data Recording and Quality Control 
Source documents must be maintained for each participant in the study, consisting of all demographic 
and medical information, including clinical laboratory data, etc.  A copy of the signed informed 
consent form must be retained.  All information on the e-CRFs must be traceable to these source 
documents in the participant's file.  Data recorded in all participants’ eCRFs will be subjected to a 
quality control review.   
12 
STUDY APPROVAL AND CONDUCT 
The following conditions will be met. 
12.1 
Regulatory Approval 
The requirements for the conduct of clinical trials in accordance with local applicable regulations will 
be met before commencement of this study. 
12.2 
Institutional Review Board/Ethics Committee (HDEC or local equivalent) 
Approval 
Prior to initiation of the study, written HDEC (or local equivalent) approval of the Protocol and 
Informed Consent Forms, based on the principles of ICH GCP procedures, will be received. A copy of 
the signed and dated letter of approval will be provided to the clinical site and Arrowhead 
Pharmaceuticals, Inc. prior to study commencement. Any written information and/or advertisements to 
be used for volunteer recruitment will be approved by the HDEC (or local equivalent) prior to use. A 


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list of the HDEC (or local equivalent) voting members, their titles or occupations, FWA number 
(where applicable) and their institutional affiliations will be requested before study initiation.  
Protocol modifications that may impact subject safety or the validity of the study will be approved by 
the HDEC (or local equivalent), following written agreement from the Sponsor. 
12.3 
Ethical Considerations 
This study will be carried out per the Declaration of Helsinki 1964, as modified by the 64th World 
Medical Assembly, Fortaleza, Brazil, October 2013, the Notes for Guidance on Good Clinical Practice 
(GCP) (2000) (CPMP/ICH/135/95), and the Principles of the ICH GCP. The protocol will be 
submitted for approval to the appropriate HDEC (or local equivalent), and written approval obtained 
before patients are enrolled. The composition of the HDEC (or local equivalent) will also be provided 
to the Sponsor. If approval is suspended or terminated by an HDEC (or local equivalent), the PI will 
notify the Sponsor immediately 
Where applicable, the clinical site and Arrowhead Pharmaceuticals, Inc. agree to abide by the local 
compensation guidelines for injury resulting from participating in a company-sponsored research 
project. Compensation will only be provided on the understanding that the provision of compensation 
does not amount to an admission of legal liability, and is subject to the proposed recipient signing a 
full and complete release of the company from all claims, damages and costs. 
12.4 
Written Informed Consent 
Informed consent will be obtained before the volunteer can participate in the study. The contents and 
process of obtaining informed consent will be in accordance with all applicable regulatory 
requirements. Study participation includes all screening procedures, as well as any wash-out of 
excluded medications. 
It is the responsibility of the PI (or medically qualified designee) to obtain a written informed consent 
from everyone participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study. The PI (or medically qualified designee) must also explain to the 
volunteers that they are completely free to refuse to enter the study or to withdraw from it at any time. 
Appropriate forms for documenting a written consent will be provided by the PI or by Arrowhead 
Pharmaceuticals, Inc. 


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For this study, each eligible participant will be required to provide written informed consent before 
participation in the study.  
All eligible participants will have the study explained by the PI or designee. They will receive a full 
explanation, in lay terms, of the aims of the study, the discomforts, risks and benefits in taking part as 
well as of insurance and other procedures for compensation in case of injury. It will be explained that 
the study is for research purposes only and is not expected to provide any therapeutic benefit to the 
individual. It will be pointed out that they can withdraw from the study at any time without prejudice. 
Each participant will acknowledge receipt of this information by giving written informed consent for 
participation in the study. The volunteer will be given a copy of the signed Informed Consent Form to 
retain. 
12.5 
Emergency Contact with Principal Investigator 
Suitable arrangements will be made for participants to contact the PI or medically trained designee in 
the event of an emergency. 
12.6 
Notification of General Practitioner 
It is the responsibility of the PI or designee, to notify, where applicable, with the consent of the 
participant, the general practitioner of the subject’s participation in the trial, by sending a letter stating 
the nature of the trial, treatments, expected benefits or adverse events and concomitant drugs to be 
avoided. 
12.7 
Clinical Laboratory Certification and Reference Ranges 
Before the initiation of this study, the PI, or designee, will obtain a copy of the certification form, with 
certification number and expiration date for all clinical laboratories (excluding central laboratories) 
used in the study. Reference ranges for each clinical laboratory test used in this study will be obtained 
from the appropriate laboratory, which will perform the test for the study. 
12.8 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance with, 
the approved protocol procedures or requirements. The PI will conduct the study in compliance with 
the approved protocol and will not implement any deviation from or changes to the protocol without 
prior agreement by the Sponsor and review and documented approval from the HDEC (or local 


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equivalent) of an amendment, except where necessary to eliminate an immediate hazard to study 
subjects. 
Deviations may result from the action or inaction of the participant, PI, or site staff. Examples of 
deviations include, but are not limited to: 
• 
Failure to adhere to study exclusion and inclusion criteria 
• 
Failure to comply with dispensing or dosing requirements 
• 
Use of medications, food, drink, herbal remedies, or supplements that are specifically 
prohibited in the protocol 
• 
Missed or out-of-window visits 
• 
Drug dosing not administered within the time frame specified in the protocol 
• 
Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc. – either tests not done, incorrect tests 
done, or not done within the time frame specified in the protocol 
• 
Procedural deviations such as incorrect storage of study drug, failure to update the ICF when 
new risks become known, failure to obtain IRB/EC approvals for the protocol and ICF 
revisions 
Protocol deviations impacting subject safety or eligibility will be reported to the Sponsor or CRO 
within 2 business days of occurrence and to the HDEC (or local equivalent) /competent regulatory 
authority per local regulatory requirements.  
The PI is responsible for ensuring that any known protocol deviations are recorded and reported as 
agreed. The nature and reasons for protocol deviations will be recorded in each participant’s CRF. 
12.9 
Termination of the Study 
The Sponsor reserves the right to discontinue the trial at any time. Reasons will be provided in the 
event of this happening. The PI reserves the right to discontinue the study for safety reasons at any 
time in collaboration with the Sponsor. 


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13 
STUDY ADMINISTRATION 
13.1 
Study Monitoring 
Arrowhead Pharmaceuticals, Inc. is responsible for assuring the proper conduct of the study about 
protocol adherence and validity of the data recorded on the CRFs. Participant confidentiality will be 
maintained. 
In accordance with applicable regulations, GCP, and Arrowhead Pharmaceuticals, Inc. procedures, 
Arrowhead Pharmaceuticals, Inc. or its designee will be responsible for assigning a study monitor 
(CRA) who will contact the site to organize a visit prior to participant enrolment to review the 
protocol and data collection procedures with site staff. In addition, the assigned study monitor will 
periodically contact the site, including conducting on-site visits. The extent, nature and frequency of 
on-site visits will be based on such considerations as the study objective and/or endpoints, the purpose 
of the study, study design complexity, and enrolment rate. 
During these site visits, the study monitor will: 
• 
Check the progress of the study. 
• 
Review study data collected. 
• 
Conduct source document verification. 
• 
Identify any issues and address their resolution. 
• 
Check investigational product accountability 
• 
Review blood and urine samples and ensure they are labeled and stored correctly. 
This will be done to verify that the: 
• 
Data are authentic, accurate and complete. 
• 
Safety and rights of participants are being protected. 
• 
Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP and all applicable regulatory requirements. 
The PI agrees to allow the monitor direct access to all relevant documents and to allocate his/her time 
and the time of his/her staff to the monitor to discuss findings and any relevant issues. 
At study closure, a study monitor will conduct the following activities in conjunction with the PI or 
site staff as appropriate: 


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• 
Return of all study data to Arrowhead Pharmaceuticals, Inc. 
• 
Data queries. 
• 
Accountability, reconciliation and arrangements for unused investigational product(s). 
• 
Inventory and final disposition (e.g., destruction, shipping to repository, etc.). 
• 
Review of site study records for completeness. 
Because the study is blinded, an unblinded study monitor will be assigned to visit the site pharmacy 
during, and at study completion to review the randomization schedule in comparison to the dispensing 
log to verify correct randomization of study drug. 
13.2 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, Arrowhead 
Pharmaceuticals, Inc. may conduct a quality assurance audit of the study site. Regulatory agencies 
may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any time 
during or after completion of the study. If an audit or inspection occurs, the PI and clinical site agree 
to notify Sponsor as soon as possible following awareness of an impending regulatory inspection.  The 
PI and clinical site agree to allow the auditor/inspector direct access to all relevant documents and 
allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and any 
relevant issues. 
13.3 
Records Retention 
Following closure of the study, the PI must maintain all site study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit 
or inspection) and whenever feasible, to allow any subsequent review of data in conjunction with 
assessment of the facility, supporting systems and staff. When permitted by local laws/regulations or 
institutional policy, some or these records can be maintained in a format other than hard copy (e.g., 
microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. 
The PI must assure that all reproductions are legible and are a true and accurate copy of the original 
and meet accessibility and retrieval standards, including re-generating a hard copy, if required. 
Furthermore, the PI must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions. 


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Arrowhead Pharmaceuticals, Inc. will inform the PI of the time period for retaining these records to 
comply with all applicable regulatory requirements. The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional requirements or 
local laws or regulations, or Arrowhead Pharmaceuticals, Inc. standards/procedures; otherwise, the 
retention period will default to 15 years. 
The material to be stored shall include, but is not limited to, the following: 
• 
Signed and dated copy of the final study protocol and any amendments. 
• 
Signed and dated letter of IRB/EC approval, letter of constitution of the HDEC (or local 
equivalent) and copies of any other correspondence relevant to the study with the HDEC (or 
local equivalent) or regulatory authorities. 
• 
The HDEC (or local equivalent) approved Informed Consent Form. 
• 
Current curriculum vitae (signed and dated) of the PI and co-workers with major 
responsibilities in the trial. 
• 
Site Signature and Delegation of Responsibility Log 
• 
FDA Form 1572 (where applicable)  
• 
Financial Disclosure Form(s) 
• 
Blank CRF/eCRF. 
• 
Signed participant informed consent forms. 
• 
Laboratory reference ranges (signed and dated). 
• 
The completed CTN Application Form (where applicable). 
• 
The Final Study Report. 
• 
Clinical raw data including the Source Data Forms, all clinical laboratory report forms, 
subject CRFs, drug accountability forms, and dispensing records, etc. 
14 
INFORMATION DISCLOSURE AND INVENTIONS 
14.1 
Ownership 
 
 
 


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14.2 
Confidentiality 
 
 
 
 
 
 
 
 
 
 
14.3 
Publication 
 
 
 
 
 
 
  
 
 
 
 


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Protocol No.: AROHBV1001 
 
  
 
 
 


Arrowhead Pharmaceuticals, Inc.  
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Protocol No.: AROHBV1001 
 
Version 6.0 February 28, 2020 FINAL  
 
15 
REFERENCES 
 
European Medicines Agency: Guideline on strategies to identify and mitigate risks for first-in-human 
and early clinical trials with investigational medicinal products. EMEA/CHMP/SWP/28367/07 Rev. 1, 
20 July 2017. 
FDA Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers (July 2005) 
Geary RS, Yu, RZ, Watanabe T, Herny SP, Hardee GE, Chappell A, Matson J, Sasmor H, Cummins 
L, Levin AA. Pharmacokinetics of a tumor necrosis factor-alpha phophorothioate 2’ –O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispo 
(2003) 31(11):1419-28. 
Marlowe JL, Akopian V, Karmali P, Kornbrust D, Lockridge J, Semple S. Recommendations of the 
Oligonucleotide Safety Working Group's Formulated Oligonucleotide Subcommittee for the Safety 
Assessment of Formulated Oligonucleotide-Based Therapeutics. Nucleic Acid Therapeutics. 2017; 27: 
183-196. 
Schlegel M, Janas M, Babu R, Blair L, Brown C, Castoreno A, Harbison C, Hinkle G, Jayaraman M, 
Jiang Y, Kel’in A, Kretschmer P, Manoharan M, Matsuda S, Milstein S, Parmar R, Rajeev K, 
Schofield S, Morskaya S, Theile C, Yilmaz V, Zlatev I, Jadhav V, Maier M. Improved Specificity and 
Therapeutic Index with ESC+ siRNA Conjugates Utilizing Seed-Pairing Destabilization via Novel 
Chemical Modifications. Presented as a poster at The 13th Annual Meeting of the Oligonucleotide 
Therapeutics Society; September 24-27, 2017, Bordeaux, France. 
Vaishnaw A, Jadhav V, Janas M, Schlegel M. Platform Advances in RNAi Therapeutics, Alnylam 
Therapeutics Corporate Presentation, August, 2017. 
Yu RZ, Geary RS, Leeds JM, Watanabe T, Moore M, Fitchett J, Matson J, Burckin T, Templin MV, 
Levin AA. Comparison of pharmacokinetics and tissue disposition of an antisense phosphorothioate 
oligonucleotide targeting human Ha-ras mRNA in mouse and monkey J Pharm Sci (2001) 90(2):182-
93. 
Yu RZ, Grundy JS, Henry SP, Kim TW, Norris DA, Burkey J, Wang Y, Vick A, Geary RS. Predictive 
Dose-Based Estimation of Systemic Exposure Multiples in Mouse and Monkey Relative to Human for 
Antisense Oligonucleotides With 2'-O-(2-Methoxyethyl) Modifications. Mol Ther Nucleic Acids. 
2015; 4: 2018. 
 
 
 
 
 
 


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Protocol No.: AROHBV1001 
 
Version 6.0 February 28, 2020 FINAL  
16 
APPENDIX 1: ALT FLARE GUIDELINES 
 
Fluctuations and elevations above ULN in ALT and AST are a normal part of CHB natural history. In fact, it is 
commonly believed that an elevation in ALT in the setting of undetectable or falling HBV-DNA, or in the 
setting of a decline in HBsAg may be a favorable prognosticator, representing immune system reconstitution 
against HBV. This is often referred to as an host induced flare. Similarly, elevated ALT in the setting of rising 
HBV-DNA may be a virus induced flare. In a first in human/first in patient clinical trial involving subjects 
infected with HBV, it is critically important to differentiate such causes of elevated ALT from drug induced 
liver injury which should inform the decision of whether to continue a subject with elevated ALT in the study. 
To facilitate this interpretation of ALT elevations the following guideline is provided.  
 
Close monitoring and intercurrent diagnostic evaluations for any patient on study treatment (or 
placebo in blinded studies) who fits the following “ALT flare” definition: 
 
• A rise in a patient’s serum ALT to a value that is > 3-fold above the patient’s Baseline ALT value 
(confirmed on repeat), and ALT value that is at least 10x ULN (confirmed on repeat) 
• patient management should include a prompt clinic visit (and further follow-up visits when 
needed) 
o Drawn serum chemistry, hematology and cytokine Panel B and serially monitor if 
indicated. Immediately check and serially monitor albumin and direct bilirubin levels, to 
determine if liver functions are stable or deteriorating. 
o evaluate patient for potential causes of the ALT elevation, e.g.:  intercurrent HAV, HEV, 
HCV or other infection; toxin exposures including acetaminophen, alcohol use,  
hepatotoxic herbal supplements or concomitant medicines. 
o patient’s recent HBV DNA levels should be checked for pattern of change. If HBV DNA 
is declining the ALT flare is presumptively not due to viral breakthrough (resistance) and 
could be a `beneficial’ (host immune system induced) flare if no intervening causes are 
found. 
 
Study treatment interruption (pending diagnostic tests) or discontinuation for an ALT flare with 
biochemical evidence of hepatic decompensation should be considered as per protocol stopping rules.   
 
 
 
 
 
 
 
 


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Page 1 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
PROTOCOL 
NUMBER: 
AROHBV1001 
STUDY TITLE: 
A Phase 1/2a Single Dose-Escalating Study to Evaluate the Safety, 
Tolerability and Pharmacokinetic Effects of ARO-HBV in Normal 
Adult Volunteers and Multiple Escalating Doses Evaluating Safety, 
Tolerability and Pharmacodynamic Effects in HBV Patients 
VERSION/DATE: 
Version 2.0, 13 June 2018  
 
 
OVERVIEW/RATIONALE:   
This amendment: 
1. Adds two additional CHB cohorts with all subjects in each cohort scheduled to receive three weekly 
doses. 
2. Adds Immunologic Assessments to be performed in CHB patients in New Zealand 
3. Clarifies that any patient volunteering for inclusion in cohort 5b (in addition to 8 or 9) that has 
signed an informed consent at the time that the fourth patient in that cohort is enrolled, may also be 
enrolled if enrolment can be accomplished within 14 days of the fourth patient being dosed 
4. Incorporates the following administrative changes submitted by Note to File dated 24May2018: 
 
A ±2 day window applied to assessments performed on Days 71 & 85 in Cohort 7 
 
A symptom directed physical exam added on Day 113/EOS for Cohort 7 
 
A pregnancy test for females of child bearing potential added at Day 113/EOS for Cohort 6 
5. Corrects any administrative, grammatical, formatting errors and inconsistencies; rewording for 
clarity. 
 
 
SUMMARY OF CHANGES: 
1. Section/page:  Title Page, page 1 
  
Added:  
This amendment adds two additional CHB cohorts with all subjects in each cohort scheduled to 
receive three weekly doses. 
 
This amendment also adds Immunologic Assessments to be performed in CHB patients in New 
Zealand only.   


Arrowhead Pharmaceuticals  
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Page 2 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
2. Section/page:  1 Protocol Synopsis, Exploratory Objectives, p. 3 
  
Added:  
 
To evaluate the effect of multiple doses of ARO-HBV on HBV patient immune cell profile including T-
cells, NK cells, B cells and monocytes (if scientifically feasible). 
 
To evaluate the effect of multiple doses of ARO-HBV on HBV antigen specific T-cell response (if 
scientifically feasible).    
 
3. Section/page:  1 Protocol Synopsis, Study Population/Patient Number, p. 3 
 
From: 
This study will be conducted in NHVs, adult males and females, aged 18-55 years with BMI between 
19.0 and 35.0 kg/m² (Cohorts 1 – 5) and in HBeAg negative or HBeAg positive CHB patients, aged 
18-65 years with BMI between 19.0 and 38.0 kg/m² (Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, and 9). Cohort 8 
will enroll HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or 
Interferon) and Cohort 9 will enroll HBeAg positive NUC experienced patients (on entecavir or 
tenofovir for at least 12 months). Cohorts 2b, 3b, 4b, 5b, 6 and 7 will enroll either HBeAg positive or 
negative patients regardless of previous NUC or PEG IFN treatment experience. All patients will be 
started on entecavir or tenofovir on Day 1. Patients currently on PEG IFN will not be allowed. 
 
To: 
This study will be conducted in NHVs, adult males and females, aged 18-55 years with BMI between 
19.0 and 35.0 kg/m² (Cohorts 1 – 5) and in HBeAg negative or HBeAg positive CHB patients, aged 
18-65 years with BMI between 19.0 and 38.0 kg/m² (Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11). 
Cohort 8 will enroll HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or 
Interferon) and Cohort 9 will enroll HBeAg positive NUC experienced patients (on entecavir or 
tenofovir for at least 12 months). Cohorts 2b, 3b, 4b, 5b, 6, 7, 10 and 11 will enroll either HBeAg 
positive or negative patients regardless of previous NUC or PEG IFN treatment experience. All 
patients will be started on entecavir or tenofovir on Day 1. Patients currently on PEG IFN will not be 
allowed. 
 
From: 
Summary of Participant Profile by Cohort: 
 
Cohorts 2b, 3b, 4b, 5b, 6, 7: Any CHB patient regardless of HBeAg or prior therapy status (as 
long as other Inclusion and Exclusion criteria are met. 
 


Arrowhead Pharmaceuticals  
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Page 3 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
To: 
Summary of Participant Profile by Cohort: 
 
Cohorts 2b, 3b, 4b, 5b, 6, 7, 10 and 11: Any CHB patient regardless of HBeAg or prior 
therapy status (as long as other Inclusion and Exclusion criteria are met). 
 
From: 
CHB cohorts will each enroll 4 subjects in an open label fashion to receive escalating multiple doses 
of ARO-HBV. In addition, any patient volunteering for inclusion in cohort 8 or 9 that has signed an 
informed consent at the time that the fourth patient in that cohort is enrolled, may also be enrolled if 
enrolment can be accomplished within 14 days of the fourth patient being dosed. 
 
To: 
CHB cohorts will each enroll 4 subjects in an open label fashion to receive escalating multiple doses 
of ARO-HBV. In addition, any patient volunteering for inclusion in Cohort 5b, 8 or 9 that has signed 
an informed consent at the time that the fourth patient in that cohort is enrolled, may also be enrolled 
if enrolment can be accomplished within 14 days of the fourth patient being dosed. 
4. Section/page:  1 Protocol Synopsis, Study Population/Patient Number, pp. 3-4 
 
From: 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially in 
cohorts 2b through 7) into a total of 6 open label cohorts (4 patients per cohort) at planned dose levels 
of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4B) and 400 mg (Cohort 5b) to receive 
three doses (Q28 days) of active treatment in an open label fashion. Cohort 6 will enroll 4 CHB 
subjects (after cohort 5b has completed enrollment) to receive three doses two weeks apart. Cohort 7 
will enroll 4 CHB patients (after Cohort 6 has completed enrollment) to receive three doses a week 
apart. Cohort 8 will enroll 4 HBeAg positive treatment naïve CHB patients to receive three monthly 
doses of ARO-HBV. Cohort 9 will enroll 4 HBeAg positive entecavir or tenofovir experienced CHB 
patients to receive three monthly doses of ARO-HBV. The dose used for Cohorts 6, 7, 8 and 9 will be 
≤ 400 mg with an expected dose level of 400 mg. 
 


Arrowhead Pharmaceuticals  
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Page 4 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
To: 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially into 
a total of 8 open label cohorts (Cohorts 2b through 7 and Cohorts 10 and 11, 4 patients per cohort) 
at planned dose levels of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) and 400 mg 
(Cohort 5b) to receive three doses (Q28 days) of active treatment in an open label fashion. Cohort 6 
will enroll 4 CHB subjects (after Cohort 5b has completed enrollment) to receive three doses two 
weeks apart. Cohorts 7, 10 and 11 will enroll 4 CHB patients sequentially (after Cohort 6 has 
completed enrollment) to receive three doses a week apart at increasing dose levels starting with a 
dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially (after 
being opened at the final planned DSC meeting) with enrollment and dosing in a later cohort not 
initiating until all subjects in the earlier cohort have received at least their first scheduled dose. 
Cohort 8 will enroll 4 HBeAg positive treatment naïve CHB patients to receive three monthly doses 
of ARO-HBV. Cohort 9 will enroll 4 HBeAg positive entecavir or tenofovir experienced CHB 
patients to receive three monthly doses of ARO-HBV. Cohorts 8 and 9 may enroll in parallel with 
Cohort 5b once opened by the DSC. The dose used for Cohorts 6, 7, 8, 9, 10 and 11 will be ≤ 400 mg 
with an expected dose level of between 100 mg to 400 mg.  
5. Section/page:  1 Protocol Synopsis, Study Population/Patient Number, p. 4 
From: 
A total of approximately 30 NHV and 32 CHB participants (not including potential replacements) 
may be enrolled in the study. 
To: 
A total of approximately 30 NHV and 40 CHB participants (not including potential replacements) 
may be enrolled in the study.     
6. Section/page:  1 Protocol Synopsis, Study Duration, p. 4 
From: 
For each CHB patient in the multi-dose cohorts 2b, 3b, 4b, 5b, 6, 7, 8 and 9 the duration of the study 
clinic visits is approximately 25 weeks from screening to the Day 113 EOS examination. 
To: 
For each CHB patient in the multi-dose Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11 the duration of 
the study clinic visits is approximately 25 weeks from screening to the Day 113 EOS examination. 


Arrowhead Pharmaceuticals  
Confidential 
Page 5 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
7. Section/page:  1 Protocol Synopsis, Study Design/Methods, p. 5 
From: 
 
CHB patients: 
In Cohorts 2b, 3b, 4b, 5b, 6, 7, 8 and 9, 4 eligible CHB patients per cohort who have signed an HDEC 
(or local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose 
intervals ranging from once every week to once every 4 weeks in an open label fashion. Screening for 
the CHB cohorts can begin once cohort 1 dosing has commenced. These cohorts will be opened for 
accrual once the corresponding NHV cohort receiving the same dose level has reached Day 8, based 
on agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8 and 9 can be opened for enrollment 
concurrently with or any time after Cohort 5 has reached Day 8 (and DSC has approved opening of 
such cohorts) and there is sufficient viral antigen response data from CHB patients to determine a 
dose level for these cohorts (at the discretion of the DSC). The planned dose level for Cohorts 6-9 is ≤ 
400 mg.   Cohorts 2b through Cohort 7 will be enrolled in sequence (as shown in Figure 1). Cohorts 8 
and 9 may be enrolled in parallel with other CHB cohorts after the DSC has voted post cohort 5 to 
open the remaining CHB patient cohorts and once a specified dose (≤ 400 mg) has been identified. 
To: 
 
CHB patients: 
In Cohorts 2b, 3b, 4b, 5b, 6, 7, 8,  9, 10 and 11, 4 eligible CHB patients per cohort who have signed 
an HDEC (or local equivalent) approved informed consent form will receive three doses of ARO-
HBV at dose intervals ranging from once every week to once every 4 weeks in an open label fashion. 
Screening for the CHB cohorts can begin once Cohort 1 dosing has commenced. These cohorts will 
be opened for accrual once the corresponding NHV cohort receiving the same single dose level has 
reached Day 8, based on agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8, 9, 10 and 11 
can be opened for enrollment any time after Cohort 5 has reached Day 8 (and DSC has approved 
opening of such cohorts) and there is sufficient viral antigen response data from CHB patients to 
determine a dose level for these cohorts (at the discretion of the DSC). The planned dose level for 
Cohorts 6-11 is between 100 and  400 mg.   Cohorts 2b through Cohort 7 and Cohorts 10 and 11, 
will be enrolled in sequence (as shown in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with 
other CHB cohorts after the DSC has voted post Cohort 5 to open the remaining CHB patient cohorts 
and once a specified dose (≤ 400 mg) has been identified. For clarity, after Cohort 5 is through Day 
8, the DSC will review all available safety data and vote to open Cohorts 5b, 6, 7, 8, 9, 10 and 11. 
Cohorts 5b, 8 and 9 may enroll and dose patients in parallel. Cohorts 5b through 7 and Cohorts 10 
and 11 must enroll sequentially, meaning that Cohort 5b must be fully enrolled with each subject 
receiving at least a first dose before Cohort 6 can enroll. Cohort 6 must be fully enrolled with each 
subject receiving at least a first dose before Cohort 7 can enroll. Cohort 7 must be fully enrolled 
with each subject receiving at least a first dose before Cohort 10 can enroll and Cohort 10 must be 
fully enrolled with each subject receiving at least a first dose before Cohort 11 can enroll. It is the 
intent that Cohorts 7, 10 and 11 will be treated at increasing dose levels starting with a dose equal 
to Cohort 6. 


Arrowhead Pharmaceuticals  
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Page 6 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
 
8. Section/page:  1 Protocol Synopsis, Figure 1, p. 6, pp. 34-35 
From: 
 
Figure 1: Dose Escalation Schedule 
Healthy Volunteers (double blind) 
CHB Patients (open label) 
Cohort* 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose 
Regimen 
Cohort 1 
 
35 mg 
 
N/A 
N/A 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 29, 
57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 29, 
57 
Cohort 4 
300 mg
 
Cohort 4b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 29, 
57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
400 mg dosed 
on Day 1, 29, 
57 
 
 
  
 
Cohort 6 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 15, 29 
 
 
 
Cohort 7 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 8, 15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve 
Dose TBD** 
Day 1, 29, 57 
 
 
 
Cohort 9 
HBeAg+, entecavir or 
tenofovir experienced  
 
Dose TBD** 
Day 1, 29, 57 
* All Cohorts use 2 sentinel subjects 
**Dose for Cohort 6, 7, 8 and 9 to be determined based on safety and viral antigen response seen in 
Cohorts 2b, 3b, 4b and 5b.  The planned dose level for Cohorts 6-9 is ≤ 400 mg.  Cohorts 6-9 may be 
opened for enrollment any time after Cohort 5 Day 8 safety evaluation with a vote from the DSC.  
Cohorts 2b through Cohort 7 will be enrolled in sequence (as shown in Figure 1).  Cohorts 8 and 9 may 
be enrolled in parallel with other CHB cohorts after the DSC has voted post cohort 5 to open the 
remaining CHB patient cohorts and once a specified dose (≤ 400 mg) has been identified. 


Arrowhead Pharmaceuticals  
Confidential 
Page 7 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
To: 
 
        Figure 1: Dose Escalation Schedule 
Healthy Volunteers (double blind) * 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose 
Regimen 
Cohort 1 
 
35 mg 
 
N/A 
N/A 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 29, 
57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 29, 
57 
Cohort 4 
300 mg
 
Cohort 4b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 29, 
57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
400 mg dosed 
on Day 1, 29, 
57 
 
 
  
 
Cohort 6 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 15, 29 
 
 
 
Cohort 7 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 8, 15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
Dose TBD** 
Day 1, 29, 57 
 
 
 
Cohort 9 HBeAg+, 
entecavir or tenofovir 
experienced  
Dose TBD** 
Day 1, 29, 57 
 
 
 
Cohort 10 (all eligible 
CHB patients regardless 
of NUC or HBeAg 
status) 
Dose TBD** 
Day 1, 8, 15 
 
 
 
Cohort 11 (all eligible 
CHB patients regardless 
of NUC or HBeAg 
status) 
Dose TBD** 
Day 1, 8, 15  
* All Cohorts use 2 sentinel subjects 
** Dose for Cohort 6, 7, 8,  9, 10 and 11 to be determined based on safety and viral antigen response seen in 
Cohorts 2b, 3b, 4b, and 5b. The planned dose level for Cohorts 6-11 is ≤ 400 mg.  Cohorts 6-11 may be opened 
for enrollment any time after Cohort 5 Day 8 safety evaluation with a vote from the DSC. Cohorts 2b through 
Cohort 7 and Cohorts 10 and 11 will be enrolled in sequence (as shown in Figure 1). Cohorts 8 and 9 may be 
enrolled in parallel with other CHB cohorts after the DSC has voted post Cohort 5 to open the remaining CHB 
patient cohorts and once a specified dose (≤ 400 mg) has been identified. 


Arrowhead Pharmaceuticals  
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Page 8 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
9. Section/page:  1 Protocol Synopsis, Study Assessments, p. 8 
  
Added:  
Immunologic Assessments (limited number of HBV patients in New Zealand only) 
 
Patient immune cell profile: T cell subsets (activation and exhaustion state), NK cell subsets 
(activation and exhaustion state), B cell subset, monocyte subsets. To be conducted if scientifically 
feasible.  
 
HBV antigen specific T cell response (including HBcAg, HBsAg). To be conducted if scientifically 
feasible.   
 
10. Section/page:  1 Protocol Synopsis, Study Assessments, p. 8 
From: 
 
Immunogenicity: 
For Cohorts 2b, 3b, 4b, 5b, and 6-9 blood samples for the anti-drug antibodies test will be collected at 
screening, Day 57 and Day 113 or at the end of study visit.  
To: 
 
Immunogenicity: 
For Cohorts 2b, 3b, 4b, 5b, and 6-11 blood samples for the anti-drug antibodies test will be collected 
at screening, Day 57 and Day 113 or at the end of study visit. 
 
11. Section/page:  1 Protocol Synopsis, Data Analysis, p. 9 
      Added:  
Immunology Assessments (limited number of CHB patients in New Zealand only) 
Immunology parameters will be summarized by cohort for the following: 
 
Changes in profile from pre-dose to post-dose time points for: T cell subsets (activation and 
exhaustion state), NK cell subsets (activation and exhaustion state), B cell subset, monocyte subsets. 
To be conducted if scientifically feasible. 
 
Changes from pre-dose to post-dose time points for: HBV antigen specific T cell response (including 
HBcAg, HBsAg). To be conducted if scientifically feasible.   
 
 
 
12. Section/page:  Schedule of Assessments, Table 1.2, pp. 12-13 
 
 From:  
 
Table 1.2: Cohorts 2b, 3b, 4b, 5b, 8 and 9 (CHB patients, three Q28 day doses) 


Arrowhead Pharmaceuticals  
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Page 9 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
 
Assessment 
Screen 
(Days  
-60 to -
1) 
 
Day
1 
Day 
2 
Day 
8  
 
Day 
15 
(±  2)
 
Day  
29, 57
(± 2)  
Day 
43, 
71 
(± 2) 
Day 
85 (± 
2) 
Day  
113 
(± 2) 
EOS 
Early 
Termination
 
Informed Consent 
X 
RANDOMIZE 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X9 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X* 
 
 
 
 
 
 
 
 
Drug Screen 
X 
 
 
 
 
 
 
 
 
 
Hepatitis/HIV Serology 
Screen 
X 
 
 
 
 
 
 
 
 
 
Physical Exam1 
X 
X* 
X1 
X1 
X1 
X1 
X1 
X1 
X 
X1 
FSH 
X8 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X5 
X5 
 
 
 
X5 
 
 
X 
X 
ECG  
X 
X2 
 
 
 
X2 
 
 
X 
X 
Vital Signs (BP, temp, RR, 
heart rate) 
X 
X4 
X 
X 
X 
X4 
X 
X 
X 
X 
Hepatic Fibrosis Measure 
(FibroScan®) 
X 
 
 
 
 
 
 
 
 
 
Clinical Labs (heme, coag, 
chem, UA) 
X 
X7 
X 
X 
X 
X7 
X 
X 
X 
X 
HBeAg qualitative 
X 
 
 
 
 
 
 
 
 
 
Quantitative HBsAg, 
HBcrAg, HBeAg (e+ only) 
HBV DNA, HBV RNA 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Quantitative anti-HBs, 
qualitative anti-HBe (e+ 
only) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
HBV genotyping 
X 
 
 
 
 
 
 
 
 
 
HBV sequencing  
X 
 
 
 
 
 
 
 
X 
X 
Cytokines (Panel B)  TNF 
alpha, IFN gamma, CXCL-
9, and CXCL-103 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Meds/Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Treatment 
 
X 
 
 
 
X 
 
 
 
 
Anti-drug antibodies9 
X 
 
 
 
 
 
X9 
 
 
X 
X 
Start NUCs (naïve patients 
only) 
 
 
X 
 
 
 
 
 
 
 
 
* Repeat if > 2 weeks from Screening  
1. Symptom-directed PEs to be performed by visit as necessary. 
 
 
 
 
 


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Page 10 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
2. ECGs: Measured pre-dose and at 1 and 2 hours post-dose; more frequently per hour if necessary. Performed prior to other 
invasive procedures. 
3. Cytokines Panel B: (whole blood).  Venous blood samples collected pre-dose on dosing days then as indicated. Collected 
samples will only be analyzed at discretion of and with notification by Sponsor.  
4. Vitals: Measured pre-dose and at 5 min, 0.5, 1, and 2 hours post-dose. 
5. Urine pregnancy test for females of childbearing potential only. Complete pre-dose on dosing days. 
6. AE/SAE data capture begins from time of informed consent. 
7. Clinical Chemistry, Hematology, Coagulation and Urinalysis pre-dose only on dosing days. 
8. Performed for females not of childbearing potential to confirm postmenopausal status. 
9. Anti-drug antibodies collected pre-dose, Day 57 and on Day 113 or EOS. 
 
To: 
Table 1.2: Cohorts 2b, 3b, 4b, 5b, 8 and 9 (CHB patients, three Q28 day doses) 
 
Assessment 
Screen 
(Days  
-60 to -
1) 
 
Day
1 
Day 
2 
Day 
8  
 
Day 
15 
(±  2)
 
Day  
29, 57
(± 2)  
Day 
43, 
71 
(± 2) 
Day 
85 (± 
2) 
Day  
113 
(± 2) 
EOS 
Early 
Termination
 
Informed Consent 
X 
RANDOMIZE 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X9 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X* 
 
 
 
 
 
 
 
 
Drug Screen 
X 
 
 
 
 
 
 
 
 
 
Hepatitis/HIV Serology 
Screen 
X 
 
 
 
 
 
 
 
 
 
Physical Exam1 
X 
X* 
X1 
X1 
X1 
X1 
X1 
X1 
X 
X1 
FSH 
X8 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X5 
X5 
 
 
 
X5 
 
 
X 
X 
ECG  
X 
X2 
 
 
 
X2 
 
 
X 
X 
Vital Signs (BP, temp, RR, 
heart rate) 
X 
X4 
X 
X 
X 
X4 
X 
X 
X 
X 
Hepatic Fibrosis Measure 
(FibroScan®) 
X 
 
 
 
 
 
 
 
 
 
Clinical Labs (heme, coag, 
chem, UA) 
X 
X7 
X 
X 
X 
X7 
X 
X 
X 
X 
HBeAg qualitative 
X 
 
 
 
 
 
 
 
 
 
Quantitative HBsAg, 
HBcrAg, HBeAg (e+ only) 
HBV DNA, HBV RNA 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Quantitative anti-HBs, 
qualitative anti-HBe (e+ 
only) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
HBV genotyping 
X 
 
 
 
 
 
 
 
 
 
HBV sequencing  
X 
 
 
 
 
 
 
 
X 
X 


Arrowhead Pharmaceuticals  
Confidential 
Page 11 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
Cytokines (Panel B)  TNF 
alpha, IFN gamma, CXCL-
9, and CXCL-103 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Cellular Immunology10  
 
X 
 
 
 
 
X 
 
X 
 
Concomitant 
Meds/Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Treatment 
 
X 
 
 
 
X 
 
 
 
 
Anti-drug antibodies9 
X 
 
 
 
 
 
X9 
 
 
X 
X 
Start NUCs (naïve patients 
only) 
 
 
X 
 
 
 
 
 
 
 
 
* Repeat if > 2 weeks from Screening  
1. Symptom-directed PEs to be performed by visit as necessary. 
 
 
 
 
 
2. ECGs: Measured pre-dose and at 1 and 2 hours post-dose; more frequently per hour if necessary. Performed prior to other 
invasive procedures. 
3. Cytokines Panel B: (whole blood).  Venous blood samples collected pre-dose on dosing days then as indicated. Collected 
samples will only be analyzed at discretion of and with notification by Sponsor.  
4. Vitals: Measured pre-dose and at 5 min, 0.5, 1, and 2 hours post-dose. 
5. Urine pregnancy test for females of childbearing potential only. Complete pre-dose on dosing days. 
6. AE/SAE data capture begins from time of informed consent. 
7. Clinical Chemistry, Hematology, Coagulation and Urinalysis pre-dose only on dosing days. 
8. Performed for females not of childbearing potential to confirm postmenopausal status. 
9. Anti-drug antibodies collected pre-dose, Day 57 and on Day 113 or EOS. 
10. T cell subsets (activation and exhaustion state), NK cell subsets (activation and exhaustion state), B cell subset, monocyte 
subsets. To be conducted if scientifically feasible. HBV antigen specific T cell response (including HBcAg, HBsAg). To be 
conducted if scientifically feasible.  Cellular immunology studies to be conducted on Days 1 (pre-dose), 43 and 113 in New 
Zealand only. 
 
13. Section/page:  Schedule of Assessments, Table 1.3, pp. 13-14 
 
From:  
Table 1.3 Cohort 6 (CHB 3 doses Q14 days) 
 
Assessment 
Screen 
(Days  
-60 to -1) 
 
Day 
1 
Day 
2 
Day 
8  
 
Day 15
(± 2) 
 
Day 29, 
(± 2)  
Day 43, 57, 
71, 85, 113 
(EOS) 
(± 2) 
Early 
Termination 
 
Informed Consent 
X 
RANDOMIZE 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X9 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
X* 
 
 
 
 
 
 
Drug Screen 
X 
 
 
 
 
 
 
 
Hepatitis/HIV 
Serology Screen 
X 
 
 
 
 
 
 
 
Physical Exam1 
X 
X* 
X1 
X1 
X1 
X1 
X1 
X1 
FSH 
X8 
 
 
 
 
 
 
 


Arrowhead Pharmaceuticals  
Confidential 
Page 12 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
Pregnancy test 
X5 
X5 
 
 
X5 
X5 
 
X 
ECG  
X 
X2 
 
 
X2 
X2 
 
X 
Vital Signs (BP, temp, 
RR, heart rate) 
X 
X4 
X 
X 
X4 
X4 
X 
X 
Hepatic Fibrosis 
Measure (FibroScan®) 
X 
 
 
 
 
 
 
 
Clinical Labs (heme, 
coag, chem, UA) 
X 
X7 
X 
X 
X 
X7 
X 
X 
HBeAg qualitative 
X 
 
 
 
 
 
 
 
Quantitative HBsAg, 
HBcrAg, HBV DNA, 
HBV RNA, HBeAg 
(e+ only 
X 
X 
 
X 
X 
X 
X 
X 
Quantitative anti-HBs, 
qualitative anti-HBe 
(e+ only) 
 
X 
 
X 
X 
X 
X 
X 
HBV genotyping 
X 
 
 
 
 
 
 
 
HBV sequencing  
X 
 
 
 
 
 
 
X 
Cytokines (Panel B) – 
TNF alpha, IFN 
gamma, CXCL-9, and 
CXCL-103 
 
X 
 
X 
X 
X 
X 
X 
Concomitant 
Meds/Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events6 
 
X 
X 
X 
X 
X 
X 
X 
Study Treatment 
 
X 
 
 
X 
X 
 
 
Anti-drug antibodies9 
X 
 
 
 
 
 
 
X9 
X 
Start NUCs (naïve 
patients only) 
 
 
X 
 
 
 
 
 
 
 
* Repeat if > 2 weeks from Screening  
1. Symptom-directed PEs to be performed by visit as necessary. 
 
 
 
 
 
2. ECGs: Measured pre-dose and at 1 and 2 hours post-dose; more frequently per hour if necessary. Performed prior to other 
invasive procedures. 
3. Cytokines Panel B: (whole blood).  Venous blood samples collected pre-dose on dosing days then as indicated. Collected 
samples will only be analyzed at discretion of and with notification by Sponsor. 
4. Vitals: Measured pre-dose and at 5 min, 0.5, 1, and 2 hours post-dose. 
5. Urine pregnancy test for females of childbearing potential only. Pre-dose on dosing days. 
6. AE/SAE data capture begins from time of informed consent. 
7. Clinical Chemistry, Hematology, Coagulation and Urinalysis pre-dose  
8. Performed for females not of childbearing potential to confirm postmenopausal status 
9. Anti-drug antibodies collected pre-dose, Day 57 and on Day 113 or EOS. 
 
 
 
 
 


Arrowhead Pharmaceuticals  
Confidential 
Page 13 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
To: 
Table 1.3 Cohort 6 (CHB 3 doses Q14 days) 
 
Assessment 
Screen 
(Days  
-60 to -1) 
 
Day 
1 
Day 
2 
Day 
8  
 
Day 15
(± 2) 
 
Day 29, 
(± 2)  
Day 43, 57, 
71, 85, 113 
(EOS) 
(± 2) 
Early 
Termination 
 
Informed Consent 
X 
RANDOMIZE 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X9 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
X* 
 
 
 
 
 
 
Drug Screen 
X 
 
 
 
 
 
 
 
Hepatitis/HIV 
Serology Screen 
X 
 
 
 
 
 
 
 
Physical Exam1 
X 
X* 
X1 
X1 
X1 
X1 
X1 
X1 
FSH 
X8 
 
 
 
 
 
 
 
Pregnancy test 
X5 
X5 
 
 
X5 
X5 
X11 
X 
ECG  
X 
X2 
 
 
X2 
X2 
 
X 
Vital Signs (BP, temp, 
RR, heart rate) 
X 
X4 
X 
X 
X4 
X4 
X 
X 
Hepatic Fibrosis 
Measure (FibroScan®) 
X 
 
 
 
 
 
 
 
Clinical Labs (heme, 
coag, chem, UA) 
X 
X7 
X 
X 
X 
X7 
X 
X 
HBeAg qualitative 
X 
 
 
 
 
 
 
 
Quantitative HBsAg, 
HBcrAg, HBV DNA, 
HBV RNA, HBeAg 
(e+ only 
X 
X 
 
X 
X 
X 
X 
X 
Quantitative anti-HBs, 
qualitative anti-HBe 
(e+ only) 
 
X 
 
X 
X 
X 
X 
X 
HBV genotyping 
X 
 
 
 
 
 
 
 
HBV sequencing  
X 
 
 
 
 
 
 
X 
Cytokines (Panel B) – 
TNF alpha, IFN 
gamma, CXCL-9, and 
CXCL-103 
 
X 
 
X 
X 
X 
X 
X 
Cellular 
Immunology10 
 
X 
 
 
 
 
X10 
 
Concomitant 
Meds/Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events6 
 
X 
X 
X 
X 
X 
X 
X 


Arrowhead Pharmaceuticals  
Confidential 
Page 14 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
Study Treatment 
 
X 
 
 
X 
X 
 
 
Anti-drug antibodies9 
X 
 
 
 
 
 
 
X9 
X 
Start NUCs (naïve 
patients only) 
 
 
X 
 
 
 
 
 
 
 
* Repeat if > 2 weeks from Screening  
1. Symptom-directed PEs to be performed by visit as necessary. 
 
 
 
 
 
2. ECGs: Measured pre-dose and at 1 and 2 hours post-dose; more frequently per hour if necessary. Performed prior to other 
invasive procedures. 
3. Cytokines Panel B: (whole blood).  Venous blood samples collected pre-dose on dosing days then as indicated. Collected 
samples will only be analyzed at discretion of and with notification by Sponsor. 
4. Vitals: Measured pre-dose and at 5 min, 0.5, 1, and 2 hours post-dose. 
5. Urine pregnancy test for females of childbearing potential only. Pre-dose on dosing days. 
6. AE/SAE data capture begins from time of informed consent. 
7. Clinical Chemistry, Hematology, Coagulation and Urinalysis pre-dose  
8. Performed for females not of childbearing potential to confirm postmenopausal status 
9. Anti-drug antibodies collected pre-dose, Day 57 and on Day 113 or EOS. 
10.   T cell subsets (activation and exhaustion state), NK cell subsets (activation and exhaustion state), B cell subset, monocyte 
subsets. To be conducted if scientifically feasible. HBV antigen specific T cell response (including HBcAg, HBsAg). To be 
conducted if scientifically feasible.  Cellular immunology studies to be conducted on Days 1 (pre-dose), 43 and 113 in New 
Zealand only. 
11.  Pregnancy test on Day 113 
14. Section/page:  Schedule of Assessments, Table 1.4, pp. 15-16 
  
From:  
 
Table 1.4 Cohort 7 (CHB three weekly doses) 
 
Assessment 
Screen 
(Days  
-60 to -1) 
 
Day
1 
Day 
2 
Day 
8  
 
Day 15
(± 2) 
 
Day 
29 
(± 2) 
Day 43, 
57 
(± 2) 
Day 71, 
85  
 
Day 113 
(± 2) 
(EOS) 
Early 
Termination
 
Informed Consent 
X 
RANDOMIZE 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X* 
 
 
 
 
 
 
 
 
Drug Screen 
X 
 
 
 
 
 
 
 
 
 
Hepatitis/HIV Serology 
Screen 
X 
 
 
 
 
 
 
 
 
 
Physical Exam1 
X 
X* 
X1 
X1 
X1 
X1 
X1 
X1 
 
X1 
FSH 
X8 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X5 
X5 
 
X5 
X5 
 
 
 
X 
X 
ECG  
X 
X2 
 
X2 
X2 
 
 
 
 
X 
Vital Signs (BP, temp, RR, 
heart rate) 
X 
X4 
X 
X4 
X4 
X 
X 
X 
X 
X 
Hepatic Fibrosis Measure 
(FibroScan®) 
X 
 
 
 
 
 
 
 
 
 


Arrowhead Pharmaceuticals  
Confidential 
Page 15 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
Clinical Labs (heme, coag, 
chem, UA) 
X 
X7 
X 
X7 
X7 
X 
X 
X 
X 
X 
HBeAg qualitative 
X 
 
 
 
 
 
 
 
 
 
Quantitative HBsAg, 
HBcrAg, HBV DNA, HBV 
RNA, HBeAg (e+ only) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Quantitative anti-HBs, 
qualitative anti-HBe (e+ 
only) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
HBV genotyping 
X 
 
 
 
 
 
 
 
 
 
HBV sequencing 
X 
 
 
 
 
 
 
 
X 
X 
Cytokines (Panel B) – TNF 
alpha, IFN gamma, CXCL-
9, and CXCL-103 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Meds/Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Treatment 
 
X 
 
X 
X 
 
 
 
 
 
Anti-drug antibodies9 
X 
 
 
 
 
 
 
X9 
 
X 
X 
Start NUCs (naïve patients 
only) 
 
 
X 
 
 
 
 
 
 
 
 
* Repeat if > 2 weeks from Screening  
1. Symptom-directed PEs to be performed by visit as necessary. 
 
 
 
 
 
2. ECGs: Measured pre-dose and at 1 and 2 hours post-dose; more frequently per hour if necessary. Performed prior to other 
invasive procedures. 
3. Cytokines Panel B: (whole blood).  Venous blood samples collected pre-dose on dosing days then as indicated. Collected 
samples will only be analyzed at discretion of and with notification by Sponsor.    
4. Vitals: Measured pre-dose and at 5 min, 0.5, 1, and 2hours post-dose. 
5. Urine pregnancy test for females of childbearing potential only. Pre-dose on dosing days. 
6. AE/SAE data capture begins from time of informed consent. 
7. Clinical Chemistry, Hematology, Coagulation and Urinalysis pre-dose. 
8. Performed for females not of childbearing potential to confirm postmenopausal status. 
9. Anti-drug antibodies collected pre-dose, Day 57 and on Day 113 or EOS. 
 
 
To: 
Table 1.4 Cohort 7, 10 and 11 (CHB three weekly doses) 
 
Assessment 
Screen 
(Days  
-60 to -1) 
 
Day
1 
Day 
2 
Day 
8  
 
Day 15
(± 2) 
 
Day 
29 
(± 2) 
Day 43, 
57 
(± 2) 
Day 71, 
85 (±2) 
 
Day 113 
(± 2) 
(EOS) 
Early 
Termination
 
Informed Consent 
X 
RANDOMIZE 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X* 
 
 
 
 
 
 
 
 
Drug Screen 
X 
 
 
 
 
 
 
 
 
 


Arrowhead Pharmaceuticals  
Confidential 
Page 16 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
Hepatitis/HIV Serology 
Screen 
X 
 
 
 
 
 
 
 
 
 
Physical Exam1 
X 
X* 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
FSH 
X8 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X5 
X5 
 
X5 
X5 
 
 
 
X 
X 
ECG  
X 
X2 
 
X2 
X2 
 
 
 
 
X 
Vital Signs (BP, temp, RR, 
heart rate) 
X 
X4 
X 
X4 
X4 
X 
X 
X 
X 
X 
Hepatic Fibrosis Measure 
(FibroScan®) 
X 
 
 
 
 
 
 
 
 
 
Clinical Labs (heme, coag, 
chem, UA) 
X 
X7 
X 
X7 
X7 
X 
X 
X 
X 
X 
HBeAg qualitative 
X 
 
 
 
 
 
 
 
 
 
Quantitative HBsAg, 
HBcrAg, HBV DNA, HBV 
RNA, HBeAg (e+ only) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Quantitative anti-HBs, 
qualitative anti-HBe (e+ 
only) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
HBV genotyping 
X 
 
 
 
 
 
 
 
 
 
HBV sequencing 
X 
 
 
 
 
 
 
 
X 
X 
Cytokines (Panel B) – TNF 
alpha, IFN gamma, CXCL-
9, and CXCL-103 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Cellular Immunology10 
 
X 
 
 
 
 
X 
 
X 
 
Concomitant 
Meds/Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Treatment 
 
X 
 
X 
X 
 
 
 
 
 
Anti-drug antibodies9 
X 
 
 
 
 
 
 
X9 
 
X 
X 
Start NUCs (naïve patients 
only) 
 
 
X 
 
 
 
 
 
 
 
 
* Repeat if > 2 weeks from Screening  
1. Symptom-directed PEs to be performed by visit as necessary. 
 
 
 
 
 
2. ECGs: Measured pre-dose and at 1 and 2 hours post-dose; more frequently per hour if necessary. Performed prior to other 
invasive procedures. 
3. Cytokines Panel B: (whole blood).  Venous blood samples collected pre-dose on dosing days then as indicated. Collected 
samples will only be analyzed at discretion of and with notification by Sponsor.    
4. Vitals: Measured pre-dose and at 5 min, 0.5, 1, and 2hours post-dose. 
5. Urine pregnancy test for females of childbearing potential only. Pre-dose on dosing days. 
6. AE/SAE data capture begins from time of informed consent. 
7. Clinical Chemistry, Hematology, Coagulation and Urinalysis pre-dose. 
8. Performed for females not of childbearing potential to confirm postmenopausal status. 
9. Anti-drug antibodies collected pre-dose, Day 57 and on Day 113 or EOS. 
10. T cell subsets (activation and exhaustion state), NK cell subsets (activation and exhaustion state), B cell subset, monocyte 
subsets. To be conducted if scientifically feasible. HBV antigen specific T cell response (including HBcAg, HBsAg). To be 
conducted if scientifically feasible.  Cellular immunology studies to be conducted on Days 1 (pre-dose), 43 and 113 in New 
Zealand only. 


Arrowhead Pharmaceuticals  
Confidential 
Page 17 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
15. Section/page: 3, List of Abbreviations, pp. 21-22 
Added: 
B-cell 
Lymphocyte not processed by the thymus and producing 
antibodies 
HBcAg 
HBV core antigen 
HBcrAg 
HBV core related antigen 
HBeAg 
HBV E (envelope) antigen 
HBsAg 
HBV S (surface) antigen 
NHV 
Normal Healthy Volunteer 
NK cell 
Natural Killer Cell 
T-cell 
Lymphocyte produced or processed by thymus gland 
 
16. Section/page: 5.3, Exploratory Objectives, pp. 29-30 
Added:   
 
To evaluate the effect of multiple doses of ARO-HBV on HBV patient immune cell profile including 
T-cells, NK cells, B cells and monocytes in a limited number of HBV patients in New Zealand only 
(if scientifically feasible). 
 
To evaluate the effect of multiple doses of ARO-HBV on HBV antigen specific T-cell response in a 
limited number of HBV patients in New Zealand only (if scientifically feasible). 
 
 
17. Section/page:  6.1, Study Design, pp. 31-33 
 
From: 
HBeAg negative or HBeAg positive CHB patients, aged 18-65 years with BMI between 19.0 and 38.0 
kg/m² (Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, and 9) will be enrolled. Cohort 8 will enroll HBeAg positive 
treatment naïve patients (no prior chronic exposure to NUCs or Interferon) and Cohort 9 will enroll 
HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 months). Cohorts 
2b, 3b, 4b, 5b, 6 and 7 will enroll either HBeAg positive or negative patients regardless of previous 


Arrowhead Pharmaceuticals  
Confidential 
Page 18 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
NUC or PEG IFN treatment experience. All patients will be started on entecavir or tenofovir on Day 1. 
Patients currently on PEG IFN will not be allowed.   
Summary of Participant Profile by Cohort: 
 
Cohorts 1-5: NHVs, adult males and females, aged 18-55 years 
 
Cohorts 2b, 3b, 4b, 5b, 6, 7: Any CHB patient regardless of HBeAg or prior therapy status (as 
long as other Inclusion and Exclusion criteria are met.  
 
Cohort 8: HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or 
Interferon) 
 
Cohort 9: HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 
months). 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially in 
cohorts 2b through 7) into a total of 6 open label cohorts (4 patients per cohort) at planned dose levels 
of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4B) and 400 mg (Cohort 5b) to receive 
three doses (Q28 days) of active treatment in an open label fashion. Cohort 6 will enroll 4 CHB 
subjects (after cohort 5b has completed enrollment) to receive three doses two weeks apart. Cohort 7 
will enroll 4 CHB patients (after Cohort 6 has completed enrollment) to receive three doses a week 
apart. Cohort 8 will enroll 4 HBeAg positive treatment naïve CHB patients to receive three monthly 
doses of ARO-HBV. Cohort 9 will enroll 4 HBeAg positive entecavir or tenofovir experienced CHB 
patients to receive three monthly doses of ARO-HBV. The dose used for Cohorts 6, 7, 8 and 9 will be 
≤ 400 mg with an expected dose level of 400 mg. An additional cohort using an intermediate dose 
level and dose frequency may be added with approval of the HDEC (or local equivalent) and DSC. 
CHB patient Screening for all CHB cohorts may start when Cohort 1 opens for enrollment. However, 
no CHB patients may be dosed until their respective cohort is approved for dosing by the DSC. CHB 
dosing may begin and NHV dose escalation may occur based on DSC approval which can occur by 
vote after cumulative data through Day 8 from the current NHV cohort is available. See Figure 1 for 
dose escalation schedule). 
To: 
HBeAg negative or HBeAg positive CHB patients, aged 18-65 years with BMI between 19.0 and 38.0 
kg/m² (Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11) will be enrolled. Cohort 8 will enroll HBeAg 
positive treatment naïve patients (no prior chronic exposure to NUCs or Interferon) and Cohort 9 will 
enroll HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 months). 


Arrowhead Pharmaceuticals  
Confidential 
Page 19 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
Cohorts 2b, 3b, 4b, 5b, 6, 7, 10 and 11 will enroll either HBeAg positive or negative patients regardless 
of previous NUC or PEG IFN treatment experience. All patients will be started on entecavir or tenofovir 
on Day 1. Patients currently on PEG IFN will not be allowed.   
Summary of Participant Profile by Cohort: 
 
Cohorts 1-5: NHVs, adult males and females, aged 18-55 years 
 
Cohorts 2b, 3b, 4b, 5b, 6, 7, 10 and 11: Any CHB patient regardless of HBeAg or prior therapy 
status (as long as other Inclusion and Exclusion criteria are met).  
 
Cohort 8: HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or 
Interferon) 
 
Cohort 9: HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 
months). 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially in 
Cohorts 2b through 7 and Cohorts 10 and 11) into a total of 8 open label cohorts (4 patients per 
cohort) at planned dose levels of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) and 
400 mg (Cohort 5b) to receive three doses (Q28 days) of active treatment in an open label fashion. 
Cohort 6 will enroll 4 CHB subjects (after Cohort 5b has completed enrollment) to receive three 
doses two weeks apart. Cohorts 7, 10 and 11 will enroll 4 CHB patients sequentially (after Cohort 6 
has completed enrollment) to receive three doses a week apart at increasing dose levels starting with 
a dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially 
(after being opened at the final planned DSC meeting) with enrollment and dosing in a later cohort 
not initiating until all subjects in the earlier cohort have received at least their first scheduled dose. 
Cohort 8 will enroll 4 HBeAg positive treatment naïve CHB patients to receive three monthly doses 
of ARO-HBV. Cohort 9 will enroll 4 HBeAg positive entecavir or tenofovir experienced CHB 
patients to receive three monthly doses of ARO-HBV. The dose used for Cohorts 6, 7, 8, 9, 10 and 11 
will be ≤ 400 mg with an expected dose level of between 100 mg to 400 mg. 
From:  
Any patient volunteering for inclusion in cohort 8 or 9 that has signed an informed consent at the time 
that the fourth patient in that cohort is enrolled, may also be enrolled if enrolment can be 
accomplished within 14 days of the fourth patient being dosed. 
 
 


Arrowhead Pharmaceuticals  
Confidential 
Page 20 of 24 
Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
To: 
Any patient volunteering for inclusion in Cohort 5b, 8 or 9 that has signed an informed consent at the 
time that the fourth patient in that cohort is enrolled, may also be enrolled if enrolment can be 
accomplished within 14 days of the fourth patient being dosed. 
 
From:  
In Cohorts 2b, 3b, 4b, 5b, 6, 7, 8 and 9, 4 eligible CHB patients who have signed an HDEC (or local 
equivalent) approved informed consent form will receive three doses of ARO-HBV at dose intervals 
ranging from once every week to once every 4 weeks in an open label fashion. Screening for the CHB 
cohorts can begin once Cohort 1 dosing has commenced. These cohorts will be opened for accrual 
once the corresponding NHV cohort receiving the same dose level has reached Day 8, based on 
agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8 and 9 can be opened for enrollment 
concurrently with or any time after Cohort 5 has reached Day 8 and there is sufficient viral antigen 
response data from CHB patients to determine a dose level for these cohorts. The planned dose level 
for Cohorts 6 through 9 is ≤ 400 mg.   Cohorts 2b through Cohort 7 will be enrolled in sequence (as 
shown in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the 
DSC has voted post Cohort 5 to open the remaining CHB patient cohorts and once a specified dose (≤ 
400 mg) has been identified. 
To: 
In Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, 4 eligible CHB patients who have signed an HDEC 
(or local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose 
intervals ranging from once every week to once every 4 weeks in an open label fashion. Screening for 
the CHB cohorts can begin once Cohort 1 dosing has commenced. These cohorts will be opened for 
accrual once the corresponding NHV cohort receiving the same dose level has reached Day 8, based 
on agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8, 9, 10 and 11 can be opened for 
enrollment any time after Cohort 5 has reached Day 8 (and DSC has approved opening of such 
cohorts) and there is sufficient viral antigen response data from CHB patients to determine a dose 
level for these cohorts. The planned dose level for Cohorts 6 through 11 is between 100 and  400 mg.   
Cohorts 2b through Cohort 7 and Cohorts 10 and 11 will be enrolled in sequence (as shown in Figure 
1). Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the DSC has voted post 
Cohort 5 to open the remaining CHB patient cohorts and once a specified dose (≤ 400 mg) has been 
identified. 
 


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Protocol No.: AROHBV1001 
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Added: 
 
For clarity, after Cohort 5 is through Day 8, the DSC will review all available safety data and vote 
to open Cohorts 5b, 6, 7, 8, 9, 10 and 11. Cohorts 5b, 8 and 9 may enroll and dose patients in parallel. 
Cohorts 5b through 7 and Cohorts 10 and 11 must enroll sequentially, meaning that Cohort 5b must 
be fully enrolled with each subject receiving at least a first dose before Cohort 6 can enroll. Cohort 
6 must be fully enrolled with each subject receiving at least a first dose before Cohort 7 can enroll. 
Cohort 7 must be fully enrolled with each subject receiving at least a first dose before Cohort 10 can 
enroll and Cohort 10 must be fully enrolled with each subject receiving at least a first dose before 
Cohort 11 can enroll. It is the intent that Cohorts 7, 10 and 11 will be treated at increasing dose 
levels starting with a dose equal to Cohort 6. 
  
18. Section/page:  7.1, Number of Subjects, p. 38 
From: 
A total of approximately 30 NHV and 32 CHB participants (not including potential replacements) 
may be enrolled in the study. 
To: 
A total of approximately 30 NHV and 40 CHB participants (not including potential replacements) may 
be enrolled in the study.   
 
19. Section/page:  9.1, Overview of Procedures, p. 51 
From: 
For CHB patients in Cohorts 2b, 3b, 4b, 5b, 6, 7, 8 and 9, 4 eligible CHB patients who have signed an 
HDEC (or local equivalent) approved informed consent form will receive three doses of ARO-HBV at 
dose intervals ranging from once every week to once every 4 weeks in an open label fashion. Screening 
for the CHB cohorts can begin once Cohort 1 dosing has commenced. These cohorts will be opened for 
accrual once the corresponding NHV cohort receiving the same dose level has reached Day 8, based 
on agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8 and 9 can be opened for enrollment 
concurrently with or any time after Cohort 5 has reached Day 8 and there is sufficient viral antigen 
response data from CHB patients to determine a dose level for these cohorts. The planned dose level 
for Cohorts 6-9 is ≤ 400 mg.   Cohorts 2b through Cohort 7 will be enrolled in sequence (as shown in 
Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the DSC has voted 


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Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
post Cohort 5 to open the remaining CHB patient cohorts and once a specified dose (≤ 400 mg) has 
been identified. 
To: 
For CHB patients in Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, 4 eligible CHB patients who have 
signed an HDEC (or local equivalent) approved informed consent form will receive three doses of 
ARO-HBV at dose intervals ranging from once every week to once every 4 weeks in an open label 
fashion. Screening for the CHB cohorts can begin once Cohort 1 dosing has commenced. These 
cohorts will be opened for accrual once the corresponding NHV cohort receiving the same dose level 
has reached Day 8, based on agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8, 9, 10 
and 11 can be opened for enrollment any time after Cohort 5 has reached Day 8 (and DSC has 
approved opening of such cohorts) and there is sufficient safety and viral antigen response data from 
CHB patients to determine a dose level for these cohorts. It is the intent that Cohorts 7, 10 and 11 
will be treated at increasing dose levels starting with a dose equal to Cohort 6.  The planned dose 
level for Cohorts 6-11 is ≤ 400 mg (expected to be between 100 mg and 400 mg).   Cohorts 2b 
through Cohort 7 and Cohorts 10 and 11 will be enrolled in sequence (as shown in Figure 1). 
Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the DSC has voted post 
Cohort 5 to open the remaining CHB patient cohorts and once a specified dose (≤ 400 mg) has been 
identified. 
 
20. Section/page:  9.3.6, Clinical Laboratory Tests and Pharmacodynamic Values, p. 54 
Added: 
Cellular Immunology Studies: For all CHB patient cohorts, blood samples to evaluate changes 
in anti-viral host immunologist profile will be collected on Day 1 (pre-dose), 43 and 113. This 
will include T cell subsets (activation and exhaustion state), NK cell subsets (activation and 
exhaustion state), B cell subset, monocyte subsets and HBV antigen specific T cell response 
(including HBcAg, HBsAg). Cellular immunology studies will be conducted if scientifically 
feasible. 
 
 
 
 


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Protocol No.: AROHBV1001 
Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
21. Section/page:  9.5, Study Formulation Administration, p. 56 
From: 
Table 2: Injection number and volume per cohort 
Cohort Dose 
Concentration
Total Injection 
Volume 
# Injections per planned 
dose 
1 
35 mg 
200 mg/mL 
0.175 mL 
Single 
2 
100 mg 200 mg/mL 
0.5 mL 
Single 
3 
200 mg 200 mg/mL 
1.0 mL 
Single 
4 
300 mg 200 mg/mL 
1.5 mL 
Single 
5 
400 mg 200 mg/mL 
2.0 mL 
Two (at separate sites) 
 
To: 
Table 2: Injection number and volume per cohort 
Cohort* Dose 
Concentration 
Total Injection 
Volume 
# Injections per planned 
dose 
1 
35 mg 
200 mg/mL 
0.175 mL 
Single 
2, 2b 
100 mg 
200 mg/mL 
0.5 mL 
Single 
3, 3b 
200 mg 
200 mg/mL 
1.0 mL 
Single 
4, 4b 
300 mg 
200 mg/mL 
1.5 mL 
Single 
5, 5b 
400 mg 
200 mg/mL 
2.0 mL 
Two (at separate sites) 
*Dose for Cohorts 6, 7, 8, 9, 10 and 11 to be determined based on safety and viral antigen 
response seen in Cohorts 2b, 3b, 4b, and 5b. The planned dose level for Cohorts 6 through 11 is 
between 100 and ≤ 400 mg.  
 


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Version 2.0, 13 June 2018                                                                  Protocol Amendment Summary of Changes 
 
22. Section/page:  11.5, Pharmacodynamic Data, pp. 67-68 
From: 
The whole blood collected for pharmacodynamic analysis following multiple doses of ARO-HBV at 
different dose levels will undergo analysis for changes in HBV-DNA, HBV-RNA (if scientifically 
feasible) and viral antigens based on reference laboratory (VIDRL) generated values. 
To: 
The whole blood collected for pharmacodynamic analysis following multiple doses of ARO-HBV at 
different dose levels will undergo analysis for changes in HBV-DNA, HBV-RNA (if scientifically 
feasible) and viral antigens based on reference laboratory (VIDRL) generated values. Cellular 
immunologic assessments will also be conducted (if scientifically feasible) at University of Auckland.  
Immunology assessments (CHB patients only) 
 
Changes in profile from pre-dose to post-dose time points for: T cell subsets (activation 
and exhaustion state), NK cell subsets (activation and exhaustion state), B cell subset, 
monocyte subsets. To be conducted if scientifically feasible. 
 
Changes from pre-dose to post-dose time points for: HBV antigen specific T cell response 
(including HBcAg, HBsAg). To be conducted if scientifically feasible. 
 


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
PROTOCOL 
NUMBER: 
AROHBV1001 
STUDY TITLE: 
A Phase 1/2a Single Dose-Escalating Study to Evaluate the Safety, 
Tolerability and Pharmacokinetic Effects of ARO-HBV in Normal 
Adult Volunteers and Multiple Escalating Doses Evaluating Safety, 
Tolerability and Pharmacodynamic Effects in HBV Patients 
VERSION/DATE: 
Version 3.0, 26 July 2018  
 
 
OVERVIEW/RATIONALE:   
This amendment: 
 
1. Based on previous experience with siRNA compounds targeting HBV (including ARC-520) 
subjects continued to experience anti-viral effects and in some cases HBsAg becoming 
undetectable even six months or more after the last dose received. For these reasons, infrequent 
follow up to measure further changes in viral antigens every 2 months for approximately 1 year 
after the last planned dose will allow optimal monitoring of patient benefit.  
 
2. Language is clarified to allow a limited number of CHB patients who are eligible to be enrolled 
into cohorts 2b through 5b (previously filled) so as not to turn down eligible patients from the 
study. This is done by expanding the maximum number of patients to be enrolled into cohorts 2b 
through 5b from 4 up to 8 patients. Additionally, this increased cohort size in the dose escalation 
part of the study should help sponsor to better understand dose response allowing for selection of 
an optimal dose for later stage clinical trials.  
 
3. Language is added to define the term “HBsAg loss” which is traditionally a reduction in HBsAg 
below the level of quantitation (< 0.05 IU/mL).  
 
4. Language is added that if feasible, final HBsAg pharmacodynamic analysis will be done on 
batched samples run at the end of the study to limit inter-test variability. 
 
5. Corrects any administrative, grammatical, formatting errors and inconsistencies; rewording for 
clarity 
 
 
 
SUMMARY OF CHANGES: 
1. Section/page:  Title Page, page 1 
  
Added:  
This amendment provides for additional follow up to track safety and HBV antiviral effect after 
the last dose in CHB patients and expands the size of select cohorts.  
 


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
 
2. Section/page:  1 Protocol Synopsis, Study Population/Patient Number, pp. 3-4 
 
From: 
CHB cohorts will each enroll 4 subjects in an open label fashion to receive escalating multiple doses 
of ARO-HBV. In addition, any patient volunteering for inclusion in Cohort 5b, 8 or 9 that has signed 
an informed consent at the time that the fourth patient in that cohort is enrolled, may also be enrolled 
if enrolment can be accomplished within 14 days of the fourth patient being dosed. 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially into 
a total of 8 open label cohorts (Cohorts 2b through 7 and Cohorts 10 and 11, 4 patients per cohort) at 
planned dose levels of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) and 400 mg 
(Cohort 5b) to receive three doses (Q28 days) of active treatment in an open label fashion. Cohort 6 
will enroll 4 CHB subjects (after Cohort 5b has completed enrollment) to receive three doses two 
weeks apart. Cohorts 7, 10 and 11 will enroll 4 CHB patients sequentially (after Cohort 6 has 
completed enrollment) to receive three doses a week apart at increasing dose levels starting with a 
dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially (after 
being opened at the final planned DSC meeting) with enrollment and dosing in a later cohort not 
initiating until all subjects in the earlier cohort have received at least their first scheduled dose. Cohort 
8 will enroll 4 HBeAg positive treatment naïve CHB patients to receive three monthly doses of ARO-
HBV. Cohort 9 will enroll 4 HBeAg positive entecavir or tenofovir experienced CHB patients to 
receive three monthly doses of ARO-HBV. 
 
To: 
CHB cohorts 2b, 3b, 4b and 5b will each enroll a minimum of 4 and a maximum of 8 subjects in 
an open label fashion to receive escalating multiple doses of ARO-HBV. Cohorts 6, 7, 8, 9, 10 and 
11 will each enroll a maximum of 4 subjects.  
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially into 
a total of 8 open label cohorts (Cohorts 2b through 7 and Cohorts 10 and 11). Cohorts 2b through 5b 
will enroll at planned dose levels of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) 
and 400 mg (Cohort 5b) to receive three doses (Q28 days) of active treatment in an open label 
fashion. Cohort 6 will enroll CHB subjects (after Cohort 5b has completed enrollment) to receive 
three doses two weeks apart. Cohorts 7, 10 and 11 will enroll CHB patients sequentially (after Cohort 
6 has completed enrollment) to receive three doses a week apart at increasing dose levels starting with 
a dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially (after 


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
being opened at the final planned DSC meeting) with enrollment and dosing in a later cohort not 
initiating until all subjects in the earlier cohort have received at least their first scheduled dose. Cohort 
8 will enroll HBeAg positive treatment naïve CHB patients to receive three monthly doses of ARO-
HBV. Cohort 9 will enroll HBeAg positive entecavir or tenofovir experienced CHB patients to 
receive three monthly doses of ARO-HBV.  
 
From: 
A total of approximately 30 NHV and 40 CHB participants (not including potential replacements) 
may be enrolled in the study.   
To: 
A total of approximately 30 NHV and a minimum of 40 or a maximum of 56 CHB participants (not 
including potential replacements) may be enrolled in the study.   
 
3. Section/page:  1 Protocol Synopsis, Study Duration , p. 4 
 
From: 
 
For each CHB patient in the multi-dose Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11 the duration of 
the study clinic visits is approximately 25 weeks from screening to the Day 113 EOS examination. 
To: 
For each CHB patient in the multi-dose Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11 the duration of 
the study clinic visits is approximately 25 weeks from screening to the Day 113 EOS examination.  
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up 
Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after the last 
dose. Subjects consenting to additional follow up will continue on NUCs. Subjects not consenting 
to additional follow up will be followed per protocol based on Schedule of Assessment Tables 1.2, 
1.3 and 1.4. 


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
4. Section/page:  1 Protocol Synopsis, Study Design/Methods, p. 5 
From: 
 
CHB patients: 
In Cohorts 2b, 3b, 4b, 5b, 6, 7, 8 and 9, 4 eligible CHB patients per cohort who have signed an HDEC 
(or local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose 
intervals ranging from once every week to once every 4 weeks in an open label fashion.  
To: 
 
CHB patients: 
In Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, eligible CHB patients who have signed an HDEC (or 
local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose 
intervals ranging from once every week to once every 4 weeks in an open label fashion. 
Added: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up 
Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after the 
last dose. Subjects consenting to additional follow up will continue on NUCs. Subjects not 
consenting to additional follow up will be followed per protocol based on Schedule of 
Assessment Tables 1.2, 1.3 and 1.4.  
5. Section/page:  1 Protocol Synopsis, Data Analysis, p. 9 
  
Added:  
Two separate data analyses will be performed, one for all subjects through EOS (Day 29 for NHVs 
and Day 113 for CHB patients), and one additional and separate analysis for CHB patients who 
consent to the additional follow up. 
 
6. Section/page:  1 Protocol Synopsis, Data Analysis, pp. 9-10 
From: 
 
Virology assessments (CHB patients only) 
Virologic parameters will be summarized by cohort for the following: 
• 
Percent of patients with loss of HBsAg at EOS and time to occurrence (Kaplan Meier) 


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
To: 
 
Virology assessments (CHB patients only) 
Virologic parameters will be summarized by cohort for the following: 
• 
Percent of patients with loss of HBsAg (defined as HBsAg < 0.05 IU/mL) at EOS and time to 
occurrence (Kaplan Meier) 
 
7. Section/page:  Schedule of Assessments, p. 16 
 
 Added:  
Table 1.5: Additional Follow-Up Schedule of Assessments (All CHB Cohorts) 
 
Assessment 
Day  
169 (±5) 
Day  
225 (±5) 
Day  
281 (±5) 
Day  
337 (±5) 
Day  
393 (±5) 
Early 
Termination 
 
Physical Exam1 
X1 
X1 
X1 
X1 
X1 
X1 
Vital Signs (BP, temp, RR, 
heart rate) 
X 
X 
X 
X 
X 
X 
Clinical Labs (heme, coag, 
chem, UA) 
X 
X 
X 
X 
X 
X 
Quantitative HBsAg, 
HBcrAg, HBeAg (e+ only) 
HBV DNA, HBV RNA 
X 
X 
X 
X 
X 
X 
Quantitative anti-HBs, 
qualitative anti-HBe (e+ 
only) 
X 
X 
X 
X 
X 
X 
HBV genotyping (if 
technically feasible) 
X 
X 
X 
X 
X 
X 
HBV sequencing (if 
technically feasible) 
X 
X 
X 
X 
X 
X 
Concomitant 
Meds/Therapies 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
 
1. Symptom-directed PEs to be performed by visit as necessary. 
 
 


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
 
8. Section/page: 6.1, Study Design, pp. 31-32 
From: 
Summary of Participant Profile by Cohort: 
• 
Cohorts 1-5: NHVs, adult males and females, aged 18-55 years 
• 
Cohorts 2b, 3b, 4b, 5b, 6, 7, 10 and 11: Any CHB patient regardless of HBeAg or prior 
therapy status (as long as other Inclusion and Exclusion criteria are met).  
• 
Cohort 8: HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or 
Interferon) 
• 
Cohort 9: HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 
12 months). 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially in 
Cohorts 2b through 7 and Cohorts 10 and 11) into a total of 8 open label cohorts (4 patients per 
cohort) at planned dose levels of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) and 
400 mg (Cohort 5b) to receive three doses (Q28 days) of active treatment in an open label fashion. 
Cohort 6 will enroll 4 CHB subjects (after Cohort 5b has completed enrollment) to receive three 
doses two weeks apart. Cohorts 7, 10 and 11 will enroll 4 CHB patients sequentially (after Cohort 6 
has completed enrollment) to receive three doses a week apart at increasing dose levels starting with a 
dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially (after 
being opened at the final planned DSC meeting) with enrollment and dosing in a later cohort not 
initiating until all subjects in the earlier cohort have received at least their first scheduled dose. Cohort 
8 will enroll 4 HBeAg positive treatment naïve CHB patients to receive three monthly doses of ARO-
HBV. Cohort 9 will enroll 4 HBeAg positive entecavir or tenofovir experienced CHB patients to 
receive three monthly doses of ARO-HBV. 
To: 
Summary of Participant Profile by Cohort and Cohort Size: 
• 
Cohorts 1-5: NHVs, adult males and females, aged 18-55 years 
o 6 NHV subjects per cohort 
• 
Cohorts 2b, 3b, 4b, 5b, 6, 7, 10 and 11: Any CHB patient regardless of HBeAg or prior 
therapy status (as long as other Inclusion and Exclusion criteria are met).  


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
o Cohorts 2b, 3b, 4b and 5b will enroll a minimum of 4 and a maximum of 8 
patients per cohort. 
o Cohorts 6, 7, 10 and 11 will enroll a maximum of 4 patients per cohort. 
• 
Cohort 8: HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or 
Interferon) 
o Cohort 8: Maximum of 4 patients per cohort 
• 
Cohort 9: HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 
12 months). 
o Cohort 9: Maximum of 4 patients per cohort 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially in 
Cohorts 2b through 7 and Cohorts 10 and 11) into a total of 8 open label cohorts. Cohorts 2b 
through 5b will enroll at planned dose levels of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg 
(Cohort 4b) and 400 mg (Cohort 5b) to receive three doses (Q28 days) of active treatment in an 
open label fashion. Cohort 6 will enroll CHB subjects (after Cohort 5b has completed enrollment) to 
receive three doses two weeks apart. Cohorts 7, 10 and 11 will enroll CHB patients sequentially (after 
Cohort 6 has completed enrollment) to receive three doses a week apart at increasing dose levels 
starting with a dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll 
sequentially (after being opened at the final planned DSC meeting) with enrollment and dosing in a 
later cohort not initiating until all subjects in the earlier cohort have received at least their first 
scheduled dose. Cohort 8 will enroll HBeAg positive treatment naïve CHB patients to receive three 
monthly doses of ARO-HBV. Cohort 9 will enroll HBeAg positive entecavir or tenofovir experienced 
CHB patients to receive three monthly doses of ARO-HBV. 
Deleted: 
Any patient volunteering for inclusion in Cohort 5b, 8 or 9 that has signed an informed consent at 
the time that the fourth patient in that cohort is enrolled, may also be enrolled if enrolment can be 
accomplished within 14 days of the fourth patient being dosed. 
Added (p. 33): 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up 
Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after the last 
dose. Subjects consenting to additional follow up will continue on NUCs. Subjects not consenting 


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
to additional follow up will be followed per protocol based on Schedule of Assessment Tables 1.2, 
1.3 and 1.4. 
 
9. Section/page: 6.4, Duration of the Study, pp. 37-38 
From: 
For each CHB patient in the multi-dose cohorts the duration of the study clinic visits is approximately 
25 weeks from screening to the Day 113 EOS examination.   
To:  
For each CHB patient in the multi-dose cohorts the duration of the study clinic visits is approximately 
25 weeks from screening to the Day 113 EOS examination.  CHB patients consenting to additional 
follow up will be followed as per Additional Follow-Up Schedule of Assessments (Table 1.5), every 
56 days (± 5 days) for 5 additional visits after the last dose. Subjects consenting to additional follow 
up will continue on NUCs. Subjects not consenting to additional follow up will be followed per 
protocol based on Schedule of Assessment Tables 1.2, 1.3 and 1.4. 
  
10. Section/page:  7.1, Number of Subjects, p. 38 
From: 
A total of approximately 30 NHV and 40 CHB participants (not including potential replacements) may 
be enrolled in the study.   
To: 
A total of approximately 30 NHV and a minimum of 40 or a maximum of 56  CHB participants (not 
including potential replacements) may be enrolled in the study. 
 
11. Section/page:  9.1, Overview of Procedures, pp. 51-52 
Added: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up 
Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after the last 
dose. Subjects consenting to additional follow up will continue on NUCs. Subjects not consenting 
to additional follow up will be followed per protocol based on Schedule of Assessment Tables 1.2, 
1.3 and 1.4. 
 


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
12. Section/page:  9.3.9, Follow-Up Procedures, p. 55 
From: 
Follow-Up Procedures: Day 90 (± 5 days) Telephone Call   
Documented telephone contact with each participant to verify compliance with contraceptive 
measures and absence of any known pregnancy. 
 
To: 
Follow-Up Procedures  
Day 90 (± 5 days) Telephone Call   
Documented telephone contact with each participant to verify compliance with contraceptive 
measures and absence of any known pregnancy at 90 days post EOS (Day 29 for NHVs and Day 
113 for CHB patients). 
Additional CHB Follow-up 
CHB patients consenting to additional follow up will be followed as per Additional Follow-
Up Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after 
the last dose. Subjects consenting to additional follow up will continue on NUCs. Subjects 
not consenting to additional follow up will be followed per protocol based on Schedule of 
Assessment Tables 1.2, 1.3 and 1.4.  
 
13. Section/page:  11, , Data Analysis and Statistical Considerations, p. 66 
Added: 
11.1 
Data analysis through EOS and Additional follow-up 
Two separate data analyses will be performed,  one for all subjects through EOS (Day 29 
for NHVs and Day 113 for CHB patients), and one additional and separate analysis for 
CHB patients who consent to the additional follow up.   
 
14. Section/page:  11.6, Pharmacodynamic Data, pp. 68-69 
From: 
Virology assessments (CHB patients only) 
• 
Virologic parameters will be summarized by cohort for the following: 


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
• 
Quantitative HBsAg (qHBsAg): Log change from baseline to nadir and duration of 
response from nadir back to approximately 20% of baseline or EOS (HBsAg will not be 
followed beyond EOS) 
• 
Percent of patients with loss of HBsAg at EOS and time to occurrence (Kaplan Meier) 
• 
Percent of patients with anti-HBS seroconversion at EOS and time to occurrence (Kaplan 
Meier). 
• 
Change in Anti-HBs (quantitative) over time  
• 
Quantitative HBV DNA (when quantifiable at baseline): Log change from baseline to EOS 
• 
Quantitative HBV RNA: Log change from baseline to nadir and duration of response from 
baseline to EOS (if scientifically feasible) 
• 
Quantitative HBcrAg: Log change from baseline to nadir and duration of response from 
baseline to EOS 
• 
Quantitative HBeAg (HBeAg positive only):  Log change from baseline to nadir and 
duration of response from baseline to EOS 
• 
Emergence of HBV mutations (sequencing of ARO-HBV target site, Core/pre-core, 
HBsAg epitope, any other mutations by deep sequencing) 
Descriptive statistics of virologic parameters will include mean, median, count, SD, minimum, and 
maximum. Additional details will be provided in the statistical analysis plan. Separate analysis will 
be completed for all CHB patients receiving at least one dose, all HBeAg negative patients and all 
HBeAg positive patients, all treatment naïve and all entecavir or tenofovir experienced patients.   
To: 
Virology assessments (CHB patients only) 
• 
Virologic parameters will be summarized by cohort for the following: 
• 
Quantitative HBsAg (qHBsAg): Log change from baseline to nadir and duration of 
response from nadir back to approximately 20% of baseline or EOS. In CHB patients who 
consent to additional follow up, HBsAg will be followed until the end of the additional 
follow-up period or early termination and summarized separately.   
• 
Percent of patients with loss of HBsAg (defined as quantitative HBsAg < 0.05 IU/mL) at 
EOS and time to occurrence (Kaplan Meier). In CHB patients who consent to additional 


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Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
follow up, HBsAg loss will be monitored until the end of the additional follow-up period 
or early termination and summarized separately.   
• 
Percent of patients with anti-HBS seroconversion at EOS and time to occurrence (Kaplan 
Meier). In CHB patients who consent to additional follow up, anti-HBS seroconversion 
will be monitored until the end of the additional follow-up period or early termination 
and summarized separately.   
• 
Change in Anti-HBs (quantitative) to EOS. In CHB patients who consent to additional 
follow up, change in Anti-HBs (quantitative) will be monitored until the end of the 
additional follow-up period or early termination and summarized separately.   
• 
Quantitative HBV DNA (when quantifiable at baseline): Log change from baseline to EOS. 
In CHB patients who consent to additional follow up, HBV DNA will be monitored until 
the end of the additional follow-up period or early termination and summarized 
separately.   
• 
Quantitative HBV RNA: Log change from baseline to nadir and duration of response from 
baseline to EOS (if scientifically feasible). In CHB patients who consent to additional 
follow up, HBV RNA will be monitored until the end of the additional follow-up period 
or early termination and summarized separately. 
• 
Quantitative HBcrAg: Log change from baseline to nadir and duration of response from 
baseline to EOS. In CHB patients who consent to additional follow up, HBcrAg will be 
monitored until the end of the additional follow-up period or early termination and 
summarized separately. 
• 
Quantitative HBeAg (HBeAg positive only):  Log change from baseline to nadir and 
duration of response from baseline to EOS. In CHB patients who consent to additional 
follow up, HBeAg will be monitored until the end of the additional follow-up period or 
early termination and summarized separately. 
• 
Emergence of HBV mutations (sequencing of ARO-HBV target site, Core/pre-core, 
HBsAg epitope, any other mutations by deep sequencing) to EOS. In CHB patients who 
consent to additional follow up, HBV mutations will be monitored until the end of the 
additional follow-up period or early termination and summarized separately. 
Descriptive statistics of virologic parameters will include mean, median, count, SD, minimum, and 
maximum. Additional details will be provided in the statistical analysis plan. If feasible, Clinical 


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Page 12 of 12 
Protocol No.: AROHBV1001 
Version 3.0, 26 July 2018                                                                  Protocol Amendment Summary of Changes 
 
Study Report analysis of, quantitative HBsAg through EOS will be based on a final batched 
analysis of samples.  
Separate analysis will be completed for all CHB patients receiving at least one dose, all HBeAg 
negative patients and all HBeAg positive patients, all treatment naïve and all entecavir or tenofovir 
experienced patients.   
 


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Page 1 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
PROTOCOL 
NUMBER: 
AROHBV1001 
STUDY TITLE: 
A Phase 1/2a Single Dose-Escalating Study to Evaluate the Safety, 
Tolerability and Pharmacokinetic Effects of ARO-HBV in Normal 
Adult Volunteers and Multiple Escalating Doses Evaluating Safety, 
Tolerability and Pharmacodynamic Effects in HBV Patients 
VERSION/DATE: 
Version 4.0, 01 October 2018  
 
 
OVERVIEW/RATIONALE:   
This amendment: 
 
1. Adds two CHB open-label Cohorts 1b and 1c with 8 subjects each receiving ARO-HBV at 25 and 
50 mg respectively every 28 days. Total number of CHB participants increases to minimum of 48 
or a maximum of 72 subjects (not including potential subject replacements). These cohorts are 
being added to better understand HBV viral antigen dose response after already completing 100 
mg through 400 mg dose levels.  
 
2. Adds a whole blood sample collection for SNP analysis for IFN response genes for all CHB 
subjects if actively participating in the study, after consent for genetic testing is obtained. 
 
3. Clarifies dose levels for Cohorts 6-11 (which are all already fully enrolled) decided from previous 
Data Safety Committee Meetings. 
 
4. Defines study completion for CHB subjects at Day 113 EOS regardless of whether subject re-
consents to continue Additional Follow-Up visits until Day 393.  
 
5. Corrects protocol language stating Additional Follow Up visits for CHB subjects will be 
conducted every 56 days (± 5 days) for 5 additional visits after Day 113 to agree with Table 1.5 
Schedule of Assessments. 
 
6. Corrects any administrative, grammatical, formatting errors and inconsistencies; rewording for 
clarity 
 
SUMMARY OF CHANGES: 
1. Section/page:  Title Page, page 1 
  
From: 
This amendment provides for additional follow up to track safety and HBV antiviral effect after the 
last dose in CHB patients and expands the size of select cohorts.   
 
To:  
This amendment adds two CHB open-label Cohorts 1b and 1c with 8 subjects each receiving ARO-
HBV at 25 and 50 mg respectively every 28 days, whole blood sample collection for SNP analysis 
for IFN response genes for all CHB subjects, and clarifies dose levels for Cohorts 6-11.  


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Page 2 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
2. Section/page:  1 Protocol Synopsis, Study Objectives, p. 3 
 
Added: 
 
Exploratory Objectives 
• 
To evaluate the effect of interferon response gene single nucleotide polymorphisms (SNPs) 
including IL28B on response to ARO-HBV 
 
3. Section/page:  1 Protocol Synopsis, Study Population/Patient Number, pp. 3-4 
 
From: 
This study will be conducted in NHVs, adult males and females, aged 18-55 years with BMI between 
19.0 and 35.0 kg/m² (Cohorts 1 – 5) and in HBeAg negative or HBeAg positive CHB patients, aged 
18-65 years with BMI between 19.0 and 38.0 kg/m² (Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11). 
Cohort 8 will enroll HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or 
Interferon) and Cohort 9 will enroll HBeAg positive NUC experienced patients (on entecavir or 
tenofovir for at least 12 months). Cohorts 2b, 3b, 4b, 5b, 6, 7, 10 and 11 will enroll either HBeAg 
positive or negative patients regardless of previous NUC or PEG IFN treatment experience. All 
patients will be started on entecavir or tenofovir on Day 1. Patients currently on PEG IFN will not be 
allowed.   
 
To: 
This study will be conducted in NHVs, adult males and females, aged 18-55 years with BMI between 
19.0 and 35.0 kg/m² (Cohorts 1 – 5) and in HBeAg negative or HBeAg positive CHB patients, aged 
18-65 years with BMI between 19.0 and 38.0 kg/m² (Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 
11). Cohort 8 will enroll HBeAg positive treatment naïve patients (no prior chronic exposure to 
NUCs or Interferon) and Cohort 9 will enroll HBeAg positive NUC experienced patients (on 
entecavir or tenofovir for at least 12 months). Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10 and 11 will 
enroll either HBeAg positive or negative patients regardless of previous NUC or PEG IFN treatment 
experience. All patients will be started on entecavir or tenofovir on Day 1. Patients currently on PEG 
IFN will not be allowed.   
 
From: 
Summary of Participant Profile by Cohort: 
• 
Cohorts 2b, 3b, 4b, 5b, 6, 7, 10 and 11: Any CHB patient regardless of HBeAg or prior therapy 
status (as long as other Inclusion and Exclusion criteria are met). 
 
To: 
Summary of Participant Profile by Cohort: 
• 
Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10 and 11: Any CHB patient regardless of HBeAg or prior 
therapy status (as long as other Inclusion and Exclusion criteria are met). 
 
Deleted: 
Additional intermediate dose cohorts may be added if approved by Sponsor, HDEC (or local 
equivalent) and the Data Safety Committee (DSC). 
 
From: 
CHB cohorts 2b, 3b, 4b and 5b will each enroll a minimum of 4 and a maximum of 8 subjects in an 
open label fashion to receive escalating multiple doses of ARO-HBV. Cohorts 6, 7, 8, 9, 10 and 11 
will each enroll a maximum of 4 subjects. 
 


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Page 3 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
To: 
CHB cohorts 1b, 1c, 2b, 3b, 4b and 5b will each enroll a minimum of 4 and a maximum of 8 subjects 
in an open label fashion to receive escalating multiple doses of ARO-HBV. Cohorts 6, 7, 8, 9, 10 and 
11 will each enroll a maximum of 4 subjects. 
 
From: 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially into 
a total of 8 open label cohorts (Cohorts 2b through 7 and Cohorts 10 and 11). Cohorts 2b through 5b 
will enroll at planned dose levels of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) 
and 400 mg (Cohort 5b) to receive three doses (Q28 days) of active treatment in an open label 
fashion. Cohort 6 will enroll CHB subjects (after Cohort 5b has completed enrollment) to receive 
three doses two weeks apart. Cohorts 7, 10 and 11 will enroll CHB patients sequentially (after Cohort 
6 has completed enrollment) to receive three doses a week apart at increasing dose levels starting with 
a dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially (after 
being opened at the final planned DSC meeting) with enrollment and dosing in a later cohort not 
initiating until all subjects in the earlier cohort have received at least their first scheduled dose. Cohort 
8 will enroll HBeAg positive treatment naïve CHB patients to receive three monthly doses of ARO-
HBV. Cohort 9 will enroll HBeAg positive entecavir or tenofovir experienced CHB patients to 
receive three monthly doses of ARO-HBV. Cohorts 8 and 9 may enroll in parallel with Cohort 5b 
once opened by the DSC. The dose used for Cohorts 6, 7, 8, 9, 10 and 11 will be ≤ 400 mg with an 
expected dose level of between 100 mg to 400 mg. An additional cohort using an intermediate dose 
level and dose frequency may be added with approval of the HDEC (or local equivalent) and DSC. 
CHB patient Screening for all CHB cohorts may start when Cohort 1 opens for enrollment. However, 
no CHB patients may be dosed until their respective cohort is approved for dosing by the DSC. CHB 
dosing may begin and NHV dose escalation may occur based on DSC approval which can occur by 
vote after cumulative data through Day 8 from the current NHV cohort is available. See Figure 1 for 
dose escalation schedule). CHB patients on current NUC therapy (entecavir or tenofovir) will stay on 
NUC therapy for the study duration. CHB patients not on NUC therapy (NUC naïve) will be started 
on either entecavir or tenofovir (selection between entecavir and tenofovir based on site Principal 
Investigator (PI) discretion) on Day 1.  Either tenofovir disoproxil fumarate (including generic) or 
tenofovir alafenamide are acceptable. 
 
To: 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially into 
a total of 10 open label cohorts (Cohorts 2b through 7, and Cohorts 10 and 11, and Cohort 1b and 
1c). Cohorts 1b, and 1c through 5b will enroll at planned dose levels of 25 mg (Cohort 1b), 50 mg 
(Cohort 1c), 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) and 400 mg (Cohort 5b) 
to receive three doses (Q28 days) of active treatment in an open label fashion. Cohort 6 will enroll 
CHB subjects (after Cohort 5b has completed enrollment) to receive three doses two weeks apart. 
Cohorts 7, 10 and 11 will enroll CHB patients sequentially (after Cohort 6 has completed enrollment) 
to receive three doses a week apart at increasing dose levels starting with a dose equal to Cohort 6. 
Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially (after being opened at the final 
planned DSC meeting) with enrollment and dosing in a later cohort not initiating until all subjects in 
the earlier cohort have received at least their first scheduled dose. Cohort 8 will enroll HBeAg 
positive treatment naïve CHB patients to receive three monthly doses of ARO-HBV. Cohort 9 will 
enroll HBeAg positive entecavir or tenofovir experienced CHB patients to receive three monthly 
doses of ARO-HBV. Cohorts 8 and 9 may enroll in parallel with Cohort 5b once opened by the DSC. 
Cohorts 6 through 11 will enroll at planned dose levels of 100 mg (Cohorts 6 and 7), 200 mg 
(Cohort 10), and 300 mg (Cohorts 8, 9, and 11). CHB patient screening for all CHB cohorts may 


Arrowhead Pharmaceuticals  
Confidential 
Page 4 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
start when Cohort 1 opens for enrollment. However, no CHB patients may be dosed until their 
respective cohort is approved for dosing by the DSC (not including Cohorts 1b and 1c). CHB dosing 
may begin and NHV dose escalation may occur based on DSC approval which can occur by vote after 
cumulative data through Day 8 from the current NHV cohort is available. See Figure 1 for dose 
escalation schedule). CHB patients on current NUC therapy (entecavir or tenofovir) will stay on NUC 
therapy for the study duration. CHB patients not on NUC therapy (NUC naïve) will be started on 
either entecavir or tenofovir (selection between entecavir and tenofovir based on site Principal 
Investigator (PI) discretion) on Day 1.  Either tenofovir disoproxil fumarate (including generic) or 
tenofovir alafenamide are acceptable. 
 
From: 
A total of approximately 30 NHV and a minimum of 40 or a maximum of 56 CHB participants (not 
including potential replacements) may be enrolled in the study.   
 
To: 
A total of approximately 30 NHV and a minimum of 48 or a maximum of 72 CHB participants (not 
including potential replacements) may be enrolled in the study.   
4. Section/page:  1 Protocol Synopsis, Study Duration, p. 4 
 
From: 
For each CHB patient in the multi-dose Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11 the duration of 
the study clinic visits is approximately 25 weeks from screening to the Day 113 EOS examination. 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up 
Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after the last 
dose. 
 
To: 
For each CHB patient in the multi-dose Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11 the 
duration of the study clinic visits is approximately 25 weeks from screening to the Day 113 EOS 
examination. CHB patients consenting to additional follow up will be followed as per Additional 
Follow-Up Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after 
Day 113.  
 
5. Section/page:  1 Protocol Synopsis, Study Design/Methods, pp. 5-6 
 
From: 
CHB patients: 
In Cohorts 2b, 3b, 4b, 5b, 6, 7, 8 and 9, eligible CHB patients per cohort who have signed an HDEC 
(or local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose 
intervals ranging from once every week to once every 4 weeks in an open label fashion.  
 
To: 
CHB patients: 
In Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, eligible CHB patients who have signed an 
HDEC (or local equivalent) approved informed consent form will receive three doses of ARO-HBV 
at dose intervals ranging from once every week to once every 4 weeks in an open label fashion. 
 


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Page 5 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
From: 
These cohorts will be opened for accrual once the corresponding NHV cohort receiving the same single 
dose level has reached Day 8, based on agreement of the DSC that it is safe to proceed. 
 
 
To: 
These cohorts (not including Cohorts 1b and 1c) will be opened for accrual once the corresponding 
NHV cohort receiving the same single dose level has reached Day 8, based on agreement of the DSC that 
it is safe to proceed.  
 
From: 
The planned dose level for Cohorts 6-11 is between 100 and 400 mg.    
 
To: 
Dose levels for Cohorts 6-11 is between 100 and 300 mg. 
 
From: 
Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the DSC has voted post Cohort 
5 to open the remaining CHB patient cohorts and once a specified dose (≤ 400 mg) has been identified. 
 
To: 
Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the DSC has voted post Cohort 
5 to open the remaining CHB patient cohorts and the specified dose (≤ 300 mg) has been identified. 
Cohorts 1b and 1c are open for enrollment with the addition of this protocol amendment and may 
enroll in parallel. 
 
From: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule 
of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after the last dose. 
 
To: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule 
of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. 
 
From: 
                   Figure 1: Dose Escalation Schedule 
Healthy Volunteers (double blind) * 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose 
Regimen 
Cohort 1 
 
35 mg 
 
N/A 
N/A 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 29, 
57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 29, 
57 


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Page 6 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
Cohort 4 
300 mg 
 
Cohort 4b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 29, 
57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
400 mg dosed 
on Day 1, 29, 
57 
 
 
  
 
Cohort 6 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 15, 29 
 
 
 
Cohort 7 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 8, 15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
Dose TBD** 
Day 1, 29, 57  
 
 
 
Cohort 9 HBeAg+, 
entecavir or tenofovir 
experienced  
Dose TBD** 
Day 1, 29, 57  
 
 
 
Cohort 10 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 8, 15 
 
 
 
Cohort 11 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 8, 15  
* All Cohorts use 2 sentinel subjects 
To: 
                   Figure 1: Dose Escalation Schedule 
Healthy Volunteers (double blind) * 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose 
Regimen 
Cohort 1 
 
35 mg 
 
Cohort 1b (all eligible 
CHB patients regardless 
of NUC or HBeAg 
status) 
25 mg dosed 
on Day 1, 29, 
57 
 
 
 
Cohort 1c (all eligible 
CHB patients regardless 
of NUC or HBeAg 
status) 
50 mg dosed 
on Day 1, 29, 
57 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 29, 
57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 29, 
57 


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Page 7 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
Cohort 4 
300 mg 
 
Cohort 4b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 29, 
57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
400 mg dosed 
on Day 1, 29, 
57 
 
 
  
 
Cohort 6 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 15, 
29 
 
 
 
Cohort 7 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 8, 
15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
300 mg dosed 
on Day 1, 29, 
57  
 
 
 
Cohort 9 HBeAg+, 
entecavir or tenofovir 
experienced  
300 mg dosed 
on Day 1, 29, 
57  
 
 
 
Cohort 10 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 8, 
15 
 
 
 
Cohort 11 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 8, 
15  
* All Cohorts use 2 sentinel subjects 
 
Deleted: 
** Dose for Cohort 6, 7, 8, 9, 10 and 11 to be determined based on safety and viral antigen response 
seen in Cohorts 2b, 3b, 4b, and 5b. The planned dose level for Cohorts 6-11 is ≤ 400 mg.  Cohorts 6-
11 may be opened for enrollment any time after Cohort 5 Day 8 safety evaluation with a vote from 
the DSC. Cohorts 2b through Cohort 7 and Cohorts 10 and 11 will be enrolled in sequence (as shown 
in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the DSC has 
voted post Cohort 5 to open the remaining CHB patient cohorts and once a specified dose (≤ 400 mg) 
has been identified. 
 
Deleted: 
Additional intermediate dose cohorts may be added if approved by Sponsor, HDEC (or local 
equivalent) and the Data Safety Committee (DSC). 


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Page 8 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
6. Section/page:  1 Protocol Synopsis, Study Assessments, p. 8 
 
From:  
Immunogenicity: 
For Cohorts 2b, 3b, 4b, 5b, and 6-11 blood samples for the anti-drug antibodies test will be collected 
at screening, Day 57 and Day 113 or at the end of study visit. 
 
To:  
Immunogenicity: 
For Cohorts 1b, 1c, 2b, 3b, 4b, 5b, and 6-11 blood samples for the anti-drug antibodies test will be 
collected at screening, Day 57 and Day 113 or at the end of study visit. 
 
Added: 
Genetic Testing (CHBs only): 
If subject consents to genetic testing while actively participating in the study, one whole blood 
sample will be collected on Day 1 or any time thereafter for SNP analysis for IFN response genes. 
 
7. Section/page:  1 Protocol Synopsis, Data Analysis, p. 10 
 
Deleted: 
(HBsAg will not be followed beyond EOS) 
 
Added: 
Genetic Testing (CHBs only): 
Evaluate mean and maximum nadir HBsAg decline in relationship to patient variants in interferon 
response genes (e.g. IL28B). 
 
8. Section/page:  1 Protocol Synopsis, Table 1.2, p. 12-13 
 
From: 
Table 1.2: Cohorts 2b, 3b, 4b, 5b, 8 and 9 (CHB patients, three Q28 day doses) 
 
To: 
Table 1.2: Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 8 and 9 (CHB patients, three Q28 day doses) 
 
Added: 
 
Assessment 
Screen 
(Days  
-60 to -
1) 
 
Day 
1 
Day  
2 
Day  
8  
 
Day 
15 
(± 2) 
 
Day  
29, 57 
(± 2)  
Day 
43, 
71 
(± 2) 
Day 
85 (± 
2) 
Day  
113 
(± 2) 
EOS 
Early 
Termination 
 
SNP Analysis 
 
 
X11 
 
 
 
 
 
 
 
 
11. If genetic testing consent is obtained, one-time whole blood sample collection will be on Day 1 or any time thereafter for 
SNP analysis for IFN response genes. 
 
9. Section/page:  1 Protocol Synopsis, Table 1.3, p. 14 
 
Added: 
 
Assessment 
Screen 
(Days  
-60 to -
1) 
 
Day 
1 
Day  
2 
Day  
8  
 
Day 
15 
(± 2) 
 
Day  
29, 57 
(± 2)  
Day 
43, 
71 
(± 2) 
Day 
85 (± 
2) 
Day  
113 
(± 2) 
EOS 
Early 
Termination 
 


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Page 9 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
SNP Analysis 
 
 
X12 
 
 
 
 
 
 
 
 
12. If genetic testing consent is obtained, one-time whole blood sample collection will be on Day 1 or any time thereafter 
for SNP analysis for IFN response genes. 
 
10. Section/page:  1 Protocol Synopsis, Table 1.4, p. 16 
 
Added: 
 
Assessment 
Screen 
(Days  
-60 to -
1) 
 
Day 
1 
Day  
2 
Day  
8  
 
Day 
15 
(± 2) 
 
Day  
29, 57 
(± 2)  
Day 
43, 
71 
(± 2) 
Day 
85 (± 
2) 
Day  
113 
(± 2) 
EOS 
Early 
Termination 
 
SNP Analysis 
 
 
X11 
 
 
 
 
 
 
 
 
11. If genetic testing consent is obtained, one-time whole blood sample collection will be on Day 1 or any time thereafter 
for SNP analysis for IFN response genes. 
 
11. Section/page: 3 List of Abbreviations and Terms, pp. 21-22 
 
Added: 
IFN 
Interferon 
SNP 
Single Nucleotide Polymorphism 
 
12. Section/page: 4.5 Rationale for the Study, p. 26 
 
Added: 
The 25 and 50 mg dose levels (Cohorts 1b and 1c) are being added after enrollment and dosing of 
Cohorts 2b through 5b (dose levels of 100 mg through 400 mg) have been completed to better 
understand dose response at lower doses. 
 
13. Section/page: 4.7 Justification for Starting Dose in Humans, p. 29 
 
Added: 
After dose escalation through 400 mg, to better understand dose response at low doses, protocol 
amendment 4.0 added a 25 and 50 mg X3 Q28 days cohort (Cohorts 1b and 1c). 
 
14. Section/page:  5.3 Exploratory Objectives, p. 30 
 
Added: 
 
Exploratory Objectives 
• 
To evaluate the effect of interferon response gene single nucleotide polymorphisms (SNPs) 
including IL28B on response to ARO-HBV 
 
15. Section/page: 6.1 Study Design, pp. 31-35 
 
From: 
CHB patients: 
HBeAg negative or HBeAg positive CHB patients, aged 18-65 years with BMI between 19.0 and 
38.0 kg/m² (Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11) will be enrolled. Cohort 8 will enroll HBeAg 
positive treatment naïve patients (no prior chronic exposure to NUCs or Interferon) and Cohort 9 will 
enroll HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 months). 


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Page 10 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
Cohorts 2b, 3b, 4b, 5b, 6, 7, 10 and 11 will enroll either HBeAg positive or negative patients 
regardless of previous NUC or PEG IFN treatment experience. 
 
To: 
CHB patients: 
HBeAg negative or HBeAg positive CHB patients, aged 18-65 years with BMI between 19.0 and 
38.0 kg/m² (Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11) will be enrolled. Cohort 8 will enroll 
HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or Interferon) and 
Cohort 9 will enroll HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 
12 months). Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10 and 11 will enroll either HBeAg positive or 
negative patients regardless of previous NUC or PEG IFN treatment experience. 
 
From: 
Summary of Participant Profile by Cohort and Cohort Size: 
 
• 
Cohorts 2b, 3b, 4b, 5b, 6, 7, 10 and 11: Any CHB patient regardless of HBeAg or prior 
therapy status (as long as other Inclusion and Exclusion criteria are met).  
o Cohorts 2b, 3b, 4b and 5b will enroll a minimum of 4 and a maximum of 8 patients 
per cohort. 
 
To: 
Summary of Participant Profile by Cohort and Cohort Size: 
• 
Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10 and 11: Any CHB patient regardless of HBeAg or 
prior therapy status (as long as other Inclusion and Exclusion criteria are met).  
o Cohorts 1b, 1c, 2b, 3b, 4b and 5b will enroll a minimum of 4 and a maximum of 8 
patients per cohort. 
 
From: 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially in 
Cohorts 2b through 7 and Cohorts 10 and 11) into a total of 8 open label cohorts. Cohorts 2b through 
5b will enroll at planned dose levels of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) 
and 400 mg (Cohort 5b) to receive three doses (Q28 days) of active treatment in an open label 
fashion. Cohort 6 will enroll CHB subjects (after Cohort 5b has completed enrollment) to receive 
three doses two weeks apart. Cohorts 7, 10 and 11 will enroll CHB patients sequentially (after Cohort 
6 has completed enrollment) to receive three doses a week apart at increasing dose levels starting with 
a dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially (after 
being opened at the final planned DSC meeting) with enrollment and dosing in a later cohort not 
initiating until all subjects in the earlier cohort have received at least their first scheduled dose. Cohort 
8 will enroll HBeAg positive treatment naïve CHB patients to receive three monthly doses of ARO-
HBV. Cohort 9 will enroll HBeAg positive entecavir or tenofovir experienced CHB patients to 
receive three monthly doses of ARO-HBV. The dose used for Cohorts 6, 7, 8, 9, 10 and 11 will be ≤ 
400 mg with an expected dose level of between 100 mg to 400 mg. An additional cohort using an 
intermediate dose level and dose frequency may be added with approval of the HDEC (or local 
equivalent) and DSC. CHB patient Screening for all CHB cohorts may start when Cohort 1 opens for 
enrollment. However, no CHB patients may be dosed until their respective cohort is approved for 
dosing by the DSC. CHB dosing may begin and NHV dose escalation may occur based on DSC 
approval which can occur by vote after cumulative data through Day 8 from the current NHV cohort 
is available. (See Figure 1 for dose escalation schedule). 
 
To: 


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Page 11 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially in 
Cohorts 2b through 7, Cohorts 10 and 11, and Cohorts 1b and 1c into a total of 10 open label 
cohorts. Cohorts 1b, and 1c through 5b will enroll at planned dose levels of 25 mg (Cohort 1b), 50 
mg (Cohort 1c), 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) and 400 mg (Cohort 
5b) to receive three doses (Q28 days) of active treatment in an open label fashion. Cohorts 6 through 
11 will enroll at planned dose levels of 100 mg (Cohorts 6 and 7), 200 mg (Cohort 10), and 300 mg 
(Cohorts 8, 9, and 11). Cohort 6 will enroll CHB subjects (after Cohort 5b has completed enrollment) 
to receive three doses two weeks apart. Cohorts 7, 10 and 11 will enroll CHB patients sequentially 
(after Cohort 6 has completed enrollment) to receive three doses a week apart at increasing dose 
levels starting with a dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll 
sequentially (after being opened at the final planned DSC meeting) with enrollment and dosing in a 
later cohort not initiating until all subjects in the earlier cohort have received at least their first 
scheduled dose. Cohort 8 will enroll HBeAg positive treatment naïve CHB patients to receive three 
monthly doses of ARO-HBV. Cohort 9 will enroll HBeAg positive entecavir or tenofovir experienced 
CHB patients to receive three monthly doses of ARO-HBV. CHB patient screening for all CHB 
cohorts may start when Cohort 1 opens for enrollment. However, no CHB patients may be dosed until 
their respective cohort is approved for dosing by the DSC (not including Cohorts 1b and 1c). CHB 
dosing may begin and NHV dose escalation may occur based on DSC approval which can occur by 
vote after cumulative data through Day 8 from the current NHV cohort is available. (See Figure 1 for 
dose escalation schedule). 
 
From: 
In Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, eligible CHB patients who have signed an HDEC (or 
local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose 
intervals ranging from once every week to once every 4 weeks in an open label fashion. Screening for 
the CHB cohorts can begin once Cohort 1 dosing has commenced. These cohorts will be opened for 
accrual once the corresponding NHV cohort receiving the same dose level has reached Day 8, based 
on agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8, 9, 10 and 11 can be opened for 
enrollment any time after Cohort 5 has reached Day 8 (and DSC has approved opening of such 
cohorts) and there is sufficient viral antigen response data from CHB patients to determine a dose 
level for these cohorts. The planned dose level for Cohorts 6 through 11 is between 100 and 400 mg.   
Cohorts 2b through Cohort 7 and Cohorts 10 and 11 will be enrolled in sequence (as shown in Figure 
1). Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the DSC has voted post 
Cohort 5 to open the remaining CHB patient cohorts and once a specified dose (≤ 400 mg) has been 
identified. 
 
To: 
In Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, eligible CHB patients who have signed an 
HDEC (or local equivalent) approved informed consent form will receive three doses of ARO-HBV 
at dose intervals ranging from once every week to once every 4 weeks in an open label fashion. 
Screening for the CHB cohorts can begin once Cohort 1 dosing has commenced. These cohorts (not 
including Cohort 1b and 1c) will be opened for accrual once the corresponding NHV cohort 
receiving the same dose level has reached Day 8, based on agreement of the DSC that it is safe to 
proceed. Cohorts 6, 7, 8, 9, 10 and 11 can be opened for enrollment any time after Cohort 5 has 
reached Day 8 (and DSC has approved opening of such cohorts) and there is sufficient viral antigen 
response data from CHB patients to determine a dose level for these cohorts. Dose levels for Cohorts 
6 through 11 is between 100 and 300 mg.   Cohorts 2b through Cohort 7 and Cohorts 10 and 11 will 
be enrolled in sequence (as shown in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other 
CHB cohorts after the DSC has voted post Cohort 5 to open the remaining CHB patient cohorts and 
once a specified dose (≤ 400 mg) has been identified. Cohorts 1b and 1c are open for enrollment 
with the addition of this protocol amendment and may enroll in parallel. 


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Page 12 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
 
From: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule 
of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after the last dose. 
 
To: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule 
of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. 
 
From: 
                   Figure 1: Dose Escalation Schedule 
Healthy Volunteers (double blind) * 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose 
Regimen 
Cohort 1 
 
35 mg 
 
N/A 
N/A 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 29, 
57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 29, 
57 
Cohort 4 
300 mg 
 
Cohort 4b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 29, 
57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
400 mg dosed 
on Day 1, 29, 
57 
 
 
  
 
Cohort 6 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 15, 29 
 
 
 
Cohort 7 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 8, 15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
Dose TBD** 
Day 1, 29, 57  
 
 
 
Cohort 9 HBeAg+, 
entecavir or tenofovir 
experienced  
Dose TBD** 
Day 1, 29, 57  
 
 
 
Cohort 10 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 8, 15 
 
 
 
Cohort 11 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
Dose TBD** 
Day 1, 8, 15  
* All Cohorts use 2 sentinel subjects 


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Page 13 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
To: 
                   Figure 1: Dose Escalation Schedule 
Healthy Volunteers (double blind) * 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose 
Regimen 
Cohort 1 
 
35 mg 
 
Cohort 1b (all eligible 
CHB patients regardless 
of NUC or HBeAg 
status) 
25 mg dosed 
on Day 1, 29, 
57 
 
 
 
Cohort 1c (all eligible 
CHB patients regardless 
of NUC or HBeAg 
status) 
50 mg dosed 
on Day 1, 29, 
57 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 29, 
57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 29, 
57 
Cohort 4 
300 mg 
 
Cohort 4b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 29, 
57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
400 mg dosed 
on Day 1, 29, 
57 
 
 
  
 
Cohort 6 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 15, 
29 
 
 
 
Cohort 7 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 8, 
15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
300 mg dosed 
on Day 1, 29, 
57  
 
 
 
Cohort 9 HBeAg+, 
entecavir or tenofovir 
experienced  
300 mg dosed 
on Day 1, 29, 
57  
 
 
 
Cohort 10 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 8, 
15 
 
 
 
Cohort 11 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 8, 
15  
* All Cohorts use 2 sentinel subjects 
Deleted: 


Arrowhead Pharmaceuticals  
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Page 14 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
** Dose for Cohort 6, 7, 8, 9, 10 and 11 to be determined based on safety and viral antigen response 
seen in Cohorts 2b, 3b, 4b, and 5b. The planned dose level for Cohorts 6-11 is ≤ 400 mg.  Cohorts 6-
11 may be opened for enrollment any time after Cohort 5 Day 8 safety evaluation with a vote from 
the DSC. Cohorts 2b through Cohort 7 and Cohorts 10 and 11 will be enrolled in sequence (as shown 
in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the DSC has 
voted post Cohort 5 to open the remaining CHB patient cohorts and once a specified dose (≤ 400 mg) 
has been identified. 
 
Deleted: 
Additional intermediate dose cohorts may be added if approved by Sponsor, HDEC (or local 
equivalent) and the Data Safety Committee (DSC). 
 
16. Section/page: 6.4 Duration of the Study, p. 38 
From: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule 
of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after the last dose. 
 
To: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule 
of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. 
 
Added: 
All CHB subjects who complete the study until Day 113 EOS examination are considered to 
complete the study and may continue to attend the Additional Follow-Up visits per the Schedule of 
Assessments (Table 1.5) if re-consent is obtained. If a subject withdraws from the Additional 
Follow-Up visits before the Day 393 visit, he or she will still be considered as a completed subject 
and reason for not continuing with the Additional Follow-Up visits per protocol will be recorded.   
 
17. Section/page:  7.1 Number of Subjects, p. 38 
From: 
A total of approximately 30 NHV and a minimum of 40 or a maximum of 56  CHB participants (not 
including potential replacements) may be enrolled in the study. 
 
To: 
A total of approximately 30 NHV and a minimum of 48 or a maximum of 72 CHB participants (not 
including potential replacements) may be enrolled in the study.   
18. Section/page:  9.1 Overview of Procedures, pp. 51-52 
From: 
Based on observations for all NHV subjects in a cohort through Day 8, dosing will begin for the next 
NHV cohort and as applicable the next CHB cohort at the discretion of the DSC.   
 
To: 
Based on observations for all NHV subjects in a cohort through Day 8, dosing will begin for the next 
NHV cohort and as applicable the next CHB cohort at the discretion of the DSC (not including 
Cohorts 1b and 1c).   
 
From: 


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Page 15 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
For CHB patients in Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, eligible CHB patients who have 
signed an HDEC (or local equivalent) approved informed consent form will receive three doses of 
ARO-HBV at dose intervals ranging from once every week to once every 4 weeks in an open label 
fashion. Screening for the CHB cohorts can begin once Cohort 1 dosing has commenced. These 
cohorts will be opened for accrual once the corresponding NHV cohort receiving the same dose level 
has reached Day 8, based on agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8, 9, 10 
and 11 can be opened for enrollment any time after Cohort 5 has reached Day 8 (and DSC has 
approved opening of such cohorts) and there is sufficient safety and viral antigen response data from 
CHB patients to determine a dose level for these cohorts. It is the intent that Cohorts 7, 10 and 11 will 
be treated at increasing dose levels starting with a dose equal to Cohort 6.  The planned dose level for 
Cohorts 6-11 is ≤ 400 mg (expected to be between 100 mg and 400 mg).   Cohorts 2b through Cohort 
7 and Cohorts 10 and 11 will be enrolled in sequence (as shown in Figure 1). Cohorts 8 and 9 may be 
enrolled in parallel with other CHB cohorts after the DSC has voted post Cohort 5 to open the 
remaining CHB patient cohorts and once a specified dose (≤ 400 mg) has been identified. 
 
To: 
For CHB patients in Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, eligible CHB patients who 
have signed an HDEC (or local equivalent) approved informed consent form will receive three doses 
of ARO-HBV at dose intervals ranging from once every week to once every 4 weeks in an open label 
fashion. Screening for the CHB cohorts can begin once Cohort 1 dosing has commenced. These 
cohorts (not including Cohorts 1b and 1c) will be opened for accrual once the corresponding NHV 
cohort receiving the same dose level has reached Day 8, based on agreement of the DSC that it is safe 
to proceed. Cohorts 6, 7, 8, 9, 10 and 11 can be opened for enrollment any time after Cohort 5 has 
reached Day 8 (and DSC has approved opening of such cohorts) and there is sufficient safety and 
viral antigen response data from CHB patients to determine a dose level for these cohorts. It is the 
intent that Cohorts 7, 10 and 11 will be treated at increasing dose levels starting with a dose equal to 
Cohort 6.  Dose levels for Cohorts 6-11 is ≤ 300 mg.   Cohorts 2b through Cohort 7 and Cohorts 10 
and 11 will be enrolled in sequence (as shown in Figure 1). Cohorts 8 and 9 may be enrolled in 
parallel with other CHB cohorts after the DSC has voted post Cohort 5 to open the remaining CHB 
patient cohorts and once a specified dose (≤ 400 mg) has been identified. Cohorts 1b and 1c are open 
for enrollment with the addition of this protocol amendment and may enroll in parallel. 
 
From: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule 
of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after the last dose. 
 
To: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule 
of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. 
 
19. Section/page:  9.3.6 Clinical Laboratory Tests & Pharmacodynamic Values, p. 55 
Added: 
Interferon Response Gene SNP testing: Patient’s interferon response gene SNPs will be evaluated 
(if patient consents to limited genetic testing). A blood sample for pharmacogenomics (DNA) 
research is optional and will only be collected from subjects who consent separately to this 
component of the study. Subjects who are enrolled in the study at the time of this amendment will 
be contacted to ask for their consent for this component of the study. Sample can be collected any 
time after the consent has been signed. This sample can be used to assess impact of IL28B 
polymorphism on efficacy of ARO-HBV treatment. In addition, samples can be used to investigate 
the potential association of genetic factors with efficacy, safety, or pharmacokinetics of ARO-HBV, 


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Page 16 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
CHB infection, or HBV-related disease or may be used to develop tests/assays related to ARO-HBV 
or HBV. These analyses will be performed at the sponsor’s discretion, will always be under the 
sponsor's supervision, and may be reported separately. 
 
20. Section/page:  9.3.9 Follow-Up Procedures, p. 56 
From: 
Additional CHB Follow-Up 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule 
of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after the last dose. 
 
To: 
Additional CHB Follow-Up 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule 
of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. 
 
21. Section/page:  9.5 Study Formulation Administration, p. 57 
From: 
 
Table 2: Injection number and volume per cohort 
Cohort* 
Dose 
Concentration Total Injection 
Volume 
# Injections per planned 
dose 
1 
35 mg 
200 mg/mL 
0.175 mL 
Single 
2, 2b 
100 mg 
200 mg/mL 
0.5 mL 
Single 
3, 3b 
200 mg 
200 mg/mL 
1.0 mL 
Single 
4, 4b 
300 mg 
200 mg/mL 
1.5 mL 
Single 
5, 5b 
400 mg 
200 mg/mL 
2.0 mL 
Two (at separate sites) 


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Page 17 of 17 
Protocol No.: AROHBV1001 
Version 4.0, 01 Oct 2018                                                                  Protocol Amendment Summary of Changes 
 
To: 
Table 2: Injection number and volume per cohort 
Cohort 
Dose 
Concentration Total Injection 
Volume 
# Injections per planned 
dose 
1 
35 mg 
200 mg/mL 
0.175 mL 
Single 
1b 
25 mg 
200 mg/mL 
0.125 mL 
Single 
1c 
50 mg 
200 mg/mL 
0.25 mL 
Single 
2, 2b, 6, 7 
100 mg 
200 mg/mL 
0.5 mL 
Single 
3, 3b, 10 
200 mg 
200 mg/mL 
1.0 mL 
Single 
4, 4b, 8, 9, 11 
300 mg 
200 mg/mL 
1.5 mL 
Single 
5, 5b 
400 mg 
200 mg/mL 
2.0 mL 
Two (at separate sites) 
 
Deleted: 
*Dose for Cohorts 6, 7, 8, 9, 10 and 11 to be determined based on safety and viral antigen 
response seen in Cohorts 2b, 3b, 4b, and 5b. The planned dose level for Cohorts 6 through 11 is 
between 100 and ≤ 400 mg.  
22. Section/page:  11.6 Pharmacodynamic Data, Virology Assessments (CHB patients only) p. 70 
Added: 
• 
Virologic response parameters may be summarized based on presence of interferon response 
gene SNPs (e.g. IL28B). 
 


Arrowhead Pharmaceuticals  
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Page 1 of 41 
Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
PROTOCOL 
NUMBER: 
AROHBV1001 
STUDY TITLE: 
A Phase 1/2a Single Dose-Escalating Study to Evaluate the Safety, 
Tolerability and Pharmacokinetic Effects of ARO-HBV in Normal 
Adult Volunteers and Multiple Escalating Doses Evaluating Safety, 
Tolerability and Pharmacodynamic Effects in HBV Patients 
VERSION/DATE: 
Version 5.0, 04 January 2019  
 
 
OVERVIEW/RATIONALE:   
This amendment which is specific to Hong Kong only: 
 
1.  Adds a single open-label CHB cohort (Cohort 12) with 12 subjects each receiving ARO-HBV at 
200 mg every 28 days starting on Day 1, and the investigational capsid assembly modulator 
(CAM), JNJ-56136379 at 250 mg QD starting on Day 1 through Day 84.  All subjects will 
continue on, or be started on entecavir or tenofovir (NUC) for the duration of the study.  
 
2. Corrects any administrative, grammatical, formatting errors and inconsistencies; rewording for 
clarity 
 
SUMMARY OF CHANGES: 
1. Section/page:  Title Page, page 1 
  
From: 
This amendment adds two CHB open-label Cohorts 1b and 1c with 8 subjects each receiving ARO-HBV at 25 
and 50 mg respectively every 28 days, whole blood sample collection for SNP analysis for IFN response genes 
for all CHB subjects, and clarifies the dose levels for Cohorts 6-11.   
 
To:  
This amendment, specific to Hong Kong only, adds a single open-label CHB cohort (Cohort 12) with 12 
subjects each receiving ARO-HBV at 200 mg every 28 days starting on Day 1, and the investigational capsid 
assembly modulator (CAM), JNJ-56136379 at 250 mg QD starting on Day 1 through Day 84. All subjects 
will continue on, or be started on entecavir or tenofovir (NUC) for the duration of the study. 
  
2. Section/page:  1 Protocol Synopsis, Study Treatments, p. 2 
 
From: 
There will be two study treatments; one active (Test Formulation) and one placebo (Reference Formulation). 
 
To:  
There will be up to three study treatments (depending on the cohort); two active (Test Formulation) ARO-
HBV and JNJ-56136379 (JNJ-6379) and one placebo (Reference Formulation). 
 
 
 
 


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Page 2 of 41 
Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
3. Section/page:  1 Protocol Synopsis, Study Treatments, Test Formulations, p2 
 
Added: 
Cohort 12 only will add JNJ-56136379 (JNJ-6379) as a study treatment to be evaluated in CHB patients in 
combination with ARO-HBV. JNJ-6379 is a capsid assembly modulator (CAM) being developed for the 
treatment of hepatitis B infection. JNJ-6379 binds to the HBV core protein and interferes with the viral 
capsid assembly process and resulting in the formation of empty viral capsids devoid of HBV-DNA. JNJ-
6379 also acts at an early stage of the viral life cycle by inhibiting the de novo formation of cccDNA. 
 
4. Section/page:  1 Protocol Synopsis, Exploratory Objectives, pp. 2-3 
 
From: 
• 
To determine the reduction from Day 1 pre-dose baseline to post-dose nadir of HBcrAg, HBV RNA (if 
scientifically feasible) and HBeAg (e+ patients only), in response to ARO-HBV in CHB patients as a 
measure of activity. 
• 
To evaluate the effect of single doses of ARO-HBV on cytokines (Cytokine panel A: interleukin-6 [IL-6], 
monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-alpha [TNF-alpha], interleukin-8 [IL-
8], interleukin-1beta [IL-1beta], interferon alpha [IFN alpha], IL-10, IL-12 [p40], IL-12 [p70], macrophage 
inflammatory protein-1alpha [Mip-1alpha]) in NHVs. 
• 
To evaluate the effect of single escalating doses of ARO-HBV on complement factors Bb, CH50, C5a, 
C4a, and C3a in NHVs. 
• 
To collect plasma samples in NHVs for subsequent metabolite identification (reported in a separate report 
outside of this study) 
• 
To collect urine samples in NHVs for subsequent determination of urinary excretion and metabolite 
identification (reported in a separate report outside of this study).  
• 
To evaluate the effect of multiple doses of ARO-HBV on cytokines (Cytokine panel B: TNF alpha, IFN 
gamma, CXCL-9, and CXCL-10) in CHB patients 
• 
To evaluate the effect of multiple doses of ARO-HBV on HBV patient immune cell profile including T-
cells, NK cells, B cells and monocytes (if scientifically feasible). 
• 
To evaluate the effect of multiple doses of ARO-HBV on HBV antigen specific T-cell response (if 
scientifically feasible).  
• 
To evaluate the effect of interferon response gene single nucleotide polymorphisms (SNPs) including 
IL28B on response to ARO-HBV 
 
To: 
• 
To determine the reduction from Day 1 pre-dose baseline to post-dose nadir of HBcrAg, HBsAg, HBV 
RNA (if scientifically feasible) and HBeAg (e+ patients only), in response to ARO-HBV (alone or in 
combination with JNJ-6379) in CHB patients as a measure of activity. 
 
• 
To evaluate the effect of single doses of ARO-HBV on cytokines (Cytokine panel A: interleukin-6 [IL-6], 
monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-alpha [TNF-alpha], interleukin-8 [IL-
8], interleukin-1beta [IL-1beta], interferon alpha [IFN alpha], IL-10, IL-12 [p40], IL-12 [p70], macrophage 
inflammatory protein-1alpha [Mip-1alpha]) in NHVs. 
 
• 
To evaluate the effect of single escdalating doses of ARO-HBV on complement factors Bb, CH50, C5a, 
C4a, and C3a in NHVs. 


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Page 3 of 41 
Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
• 
To collect plasma samples in NHVs for subsequent metabolite identification (reported in a separate report 
outside of this study) 
• 
To collect urine samples in NHVs for subsequent determination of urinary excretion and metabolite 
identification (reported in a separate report outside of this study).  
• 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with JNJ-6379) on 
cytokines (Cytokine panel B: TNF alpha, IFN gamma, CXCL-9, and CXCL-10) in CHB patients 
• 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with JNJ-6379) on HBV 
patient immune cell profile including T-cells, NK cells, B cells and monocytes (if scientifically feasible). 
• 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with JNJ-6379) on HBV 
antigen specific T-cell response (if scientifically feasible).  
• 
To evaluate the effect of interferon response gene single nucleotide polymorphisms (SNPs) including 
IL28B on response to ARO-HBV (alone or in combination with JNJ-6379). 
• 
To determine the incidence and frequency of adverse events possibly or probably related to treatment as 
a measure of the safety and tolerability of ARO-HBV in combination with JNJ-6379 in patients 
chronically infected with hepatitis B virus (CHB) (Cohort 12 only). 
   
5. Section/page:  1 Protocol Synopsis, Study Population/Patient Number, pp. 3-4 
 
From: 
This study will be conducted in NHVs, adult males and females, aged 18-55 years with BMI between 19.0 and 
35.0 kg/m² (Cohorts 1 – 5) and in HBeAg negative or HBeAg positive CHB patients, aged 18-65 years with 
BMI between 19.0 and 38.0 kg/m² (Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11). Cohort 8 will enroll 
HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or Interferon) and Cohort 9 will 
enroll HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 months). Cohorts 1b, 
1c, 2b, 3b, 4b, 5b, 6, 7, 10 and 11 will enroll either HBeAg positive or negative patients regardless of previous 
NUC or PEG IFN treatment experience. All patients will be started on entecavir or tenofovir on Day 1. Patients 
currently on PEG IFN will not be allowed. 
 
To: 
This study will be conducted in NHVs, adult males and females, aged 18-55 years with BMI between 19.0 and 
35.0 kg/m² (Cohorts 1 – 5) and in HBeAg negative or HBeAg positive CHB patients, aged 18-65 years with 
BMI between 19.0 and 38.0 kg/m² (Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12). Cohort 8 will 
enroll HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or Interferon) and Cohort 9 
will enroll HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 months). 
Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10, 11 and 12 will enroll either HBeAg positive or negative patients 
regardless of previous NUC or PEG IFN treatment experience. Only Cohort 12 patients will start JNJ-6379 on 
Day 1 and continue until Day 84. All patients will be started on entecavir or tenofovir on Day 1. Patients 
currently on PEG IFN will not be allowed. 
 
From: 
Summary of Participant Profile by Cohort: 
• 
Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10 and 11: Any CHB patient regardless of HBeAg or prior therapy 
status (as long as other Inclusion and Exclusion criteria are met) 
 
To: 
Summary of Participant Profile by Cohort: 
• 
Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10, 11 and 12: Any CHB patient regardless of HBeAg or prior therapy 
status (as long as other Inclusion and Exclusion criteria are met). 
 
 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
From: 
CHB cohorts 1b, 1c, 2b, 3b, 4b and 5b will each enroll a minimum of 4 and a maximum of 8 subjects in an open 
label fashion to receive escalating multiple doses of ARO-HBV. Cohorts 6, 7, 8, 9, 10 and 11 will each enroll a 
maximum of 4 subjects. 
 
To: 
CHB cohorts 1b, 1c, 2b, 3b, 4b and 5b will each enroll a minimum of 4 and a maximum of 8 subjects in an open 
label fashion to receive escalating multiple doses of ARO-HBV. Cohorts 6, 7, 8, 9, 10 and 11 will each enroll a 
maximum of 4 subjects. Cohort 12 will enroll 12 CHB patients to each receive 250 mg daily oral JNJ-
6379+NUCs+200mg ARO-HBV Q28 days X3 doses. 
 
From: 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially into a total of 8 
open label cohorts (Cohorts 2b through 7 and Cohorts 10 and 11). Cohorts 2b through 5b will enroll at planned 
dose levels of 100 mg (Cohort 2b), 200 mg (Cohort 3b), 300 mg (Cohort 4b) and 400 mg (Cohort 5b) to receive 
three doses (Q28 days) of active treatment in an open label fashion. Cohort 6 will enroll CHB subjects (after 
Cohort 5b has completed enrollment) to receive three doses two weeks apart. Cohorts 7, 10 and 11 will enroll 
CHB patients sequentially (after Cohort 6 has completed enrollment) to receive three doses a week apart at 
increasing dose levels starting with a dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will 
enroll sequentially (after being opened at the final planned DSC meeting) with enrollment and dosing in a later 
cohort not initiating until all subjects in the earlier cohort have received at least their first scheduled dose. 
Cohort 8 will enroll HBeAg positive treatment naïve CHB patients to receive three monthly doses of ARO-
HBV. Cohort 9 will enroll HBeAg positive entecavir or tenofovir experienced CHB patients to receive three 
monthly doses of ARO-HBV. Cohorts 8 and 9 may enroll in parallel with Cohort 5b once opened by the DSC. 
The dose used for Cohorts 6, 7, 8, 9, 10 and 11 will be ≤ 400 mg with an expected dose level of between 100 
mg to 400 mg. An additional cohort using an intermediate dose level and dose frequency may be added with 
approval of the HDEC (or local equivalent) and DSC. CHB patient Screening for all CHB cohorts may start 
when Cohort 1 opens for enrollment. However, no CHB patients may be dosed until their respective cohort is 
approved for dosing by the DSC. CHB dosing may begin and NHV dose escalation may occur based on DSC 
approval which can occur by vote after cumulative data through Day 8 from the current NHV cohort is 
available. See Figure 1 for dose escalation schedule). CHB patients on current NUC therapy (entecavir or 
tenofovir) will stay on NUC therapy for the study duration. CHB patients not on NUC therapy (NUC naïve) will 
be started on either entecavir or tenofovir (selection between entecavir and tenofovir based on site Principal 
Investigator (PI) discretion) on Day 1.  Either tenofovir disoproxil fumarate (including generic) or tenofovir 
alafenamide are acceptable. 
 
To: 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially into a total of 
10 open label cohorts (Cohorts 2b through 7, and Cohorts 10 and 11, and Cohort 1b and 1c). Cohorts 1b, and 
1c through 5b will enroll at planned dose levels of 25 mg (Cohort 1b), 50 mg (Cohort 1c), 100 mg (Cohort 2b), 
200 mg (Cohort 3b), 300 mg (Cohort 4b) and 400 mg (Cohort 5b) to receive three doses (Q28 days) of active 
treatment in an open label fashion. Cohort 6 will enroll CHB subjects (after Cohort 5b has completed 
enrollment) to receive three doses two weeks apart. Cohorts 7, 10 and 11 will enroll CHB patients sequentially 
(after Cohort 6 has completed enrollment) to receive three doses a week apart at increasing dose levels starting 
with a dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially (after being 
opened at the final planned DSC meeting) with enrollment and dosing in a later cohort not initiating until all 
subjects in the earlier cohort have received at least their first scheduled dose. Cohort 8 will enroll HBeAg 
positive treatment naïve CHB patients to receive three monthly doses of ARO-HBV. Cohort 9 will enroll 
HBeAg positive entecavir or tenofovir experienced CHB patients to receive three monthly doses of ARO-HBV. 
Cohorts 8 and 9 may enroll in parallel with Cohort 5b once opened by the DSC. Cohorts 6 through 11 will 
enroll at planned dose levels of 100 mg (Cohorts 6 and 7), 200 mg (Cohort 10), and 300 mg (Cohorts 8, 9, 
and 11). CHB patient screening for all CHB cohorts may start when Cohort 1 opens for enrollment. However, 
no CHB patients may be dosed until their respective cohort is approved for dosing by the DSC (not including 
Cohorts 1b and 1c). CHB dosing may begin and NHV dose escalation may occur based on DSC approval 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
which can occur by vote after cumulative data through Day 8 from the current NHV cohort is available. See 
Figure 1 for dose escalation schedule). CHB patients on current NUC therapy (entecavir or tenofovir) will stay 
on NUC therapy for the study duration. CHB patients not on NUC therapy (NUC naïve) will be started on either 
entecavir or tenofovir (selection between entecavir and tenofovir based on site Principal Investigator (PI) 
discretion) on Day 1.  Either tenofovir disoproxil fumarate (including generic) or tenofovir alafenamide are 
acceptable. 
 
Added: 
Cohort 12 will enroll 12 CHB patients to receive ARO-HBV 200 mg on Days 1, 29 and 57. Like all other 
CHB cohorts, patients enrolling in Cohort 12 will either enter the study on NUCs or start NUCs on Day 1. 
Cohort 12 patients will also initiate daily JNJ-6379 250 mg on Day 1 and continue through Day 84. 
 
From: 
A total of approximately 30 NHV and a minimum of 48 or a maximum of 72 CHB participants (not 
including potential replacements) may be enrolled in the study 
 
To: 
A total of approximately 30 NHV and a minimum of 60 or a maximum of 84 CHB participants (not 
including potential replacements) may be enrolled in the study.   
6. Section/page:  1 Protocol Synopsis, Number of Doses per Treatment, p. 4 
From: 
Single dose (Healthy Volunteer Cohorts 1 through 5) or three doses ranging in frequency from once weekly to 
once every 4 weeks (CHB patients). 
To: 
Single dose (Healthy Volunteer Cohorts 1 through 5) or three doses of ARO-HBV ranging in frequency from 
once weekly to once every 4 weeks (CHB patients).  
Daily dose of JNJ-6379 250 mg from Day 1 through Day 84 (Cohort 12 CHB patients only). 
7. Section/page:  1 Protocol Synopsis, Study Duration, p. 4 
 
From: 
For each CHB patient in the multi-dose Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11 the duration of the 
study clinic visits is approximately 25 weeks from screening to the Day 113 EOS examination. CHB patients 
consenting to additional follow up will be followed as per Additional Follow-Up Schedule of Assessments 
(Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. 
 
To: 
For each CHB patient in the multi-dose Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12 the duration of 
the study clinic visits is approximately 25 weeks from screening to the Day 113 EOS examination.  CHB 
patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule of 
Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. 
 
 
 
 
 
 
 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
8. Section/page:  1 Protocol Synopsis, Study Design/Methods, pp. 5-7 
 
From: 
CHB patients: 
In Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, eligible CHB patients who have signed an HDEC (or 
local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose intervals 
ranging from once every week to once every 4 weeks in an open label fashion. Screening for the CHB cohorts 
can begin once Cohort 1 dosing has commenced. These cohorts (not including Cohorts 1b and 1c) will be 
opened for accrual once the corresponding NHV cohort receiving the same single dose level has reached Day 8, 
based on agreement of the DSC that it is safe to proceed.   
 
To: 
CHB patients: 
In Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12, eligible CHB patients who have signed an HDEC (or 
local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose intervals 
ranging from once every week to once every 4 weeks in an open label fashion. In addition, Cohort 12 patients 
will also initiate daily JNJ-6379 250 mg on Day 1 and continue through Day 84. Screening for the CHB 
cohorts can begin once Cohort 1 dosing has commenced. These cohorts (not including Cohorts 1b, 1c and 12) 
will be opened for accrual once the corresponding NHV cohort receiving the same single dose level has reached 
Day 8, based on agreement of the DSC that it is safe to proceed. 
 
From: 
Cohorts 6, 7, 8, 9, 10 and 11 can be opened for enrollment any time after Cohort 5 has reached Day 8 (and DSC 
has approved opening of such cohorts) and there is sufficient viral antigen response data from CHB patients to 
determine a dose level for these cohorts (at the discretion of the DSC). Dose levels for Cohorts 6-11 is between 
100 and 300 mg.   Cohorts 2b through Cohort 7 and Cohorts 10 and 11, will be enrolled in sequence (as shown 
in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the DSC has voted post 
Cohort 5 to open the remaining CHB patient cohorts and the specified dose (≤ 300 mg) has been identified. 
Cohorts 1b and 1c are open for enrollment with the addition of this protocol amendment and may enroll in 
parallel. 
 
To: 
Cohorts 6, 7, 8, 9, 10 and 11 can be opened for enrollment any time after Cohort 5 has reached Day 8 (and DSC 
has approved opening of such cohorts) and there is sufficient viral antigen response data from CHB patients to 
determine a dose level for these cohorts (at the discretion of the DSC). Dose levels for Cohorts 6-12 is between 
100 and 300 mg.   Cohorts 2b through Cohort 7 and Cohorts 10 and 11, will be enrolled in sequence (as shown 
in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other CHB cohorts after the DSC has voted post 
Cohort 5 to open the remaining CHB patient cohorts and the specified dose (≤ 300 mg) has been identified. 
Cohort 12 is open for enrollment in Hong Kong only. Cohorts 1b and 1c are open for enrollment with the 
addition of a protocol amendment and may enroll in parallel.  
 
 
Added: 
Enrollment in Cohort 12 can begin once enrollment is full in Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11. The 
ARO-HBV dose level for Cohort 12 is 200 mg Q28 days (Days 1, 29, 57). Cohort 12 patients will also initiate 
daily JNJ-6379 250 mg on Day 1 and continue through Day 84. 
   
 
 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
 From: 
                   Figure 1: Dose Escalation Schedule 
Healthy Volunteers (double blind) * 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose 
Regimen 
Cohort 1 
 
35 mg 
 
Cohort 1b (all eligible 
CHB patients regardless 
of NUC or HBeAg 
status) 
25 mg dosed 
on Day 1, 29, 
57 
 
 
 
Cohort 1c (all eligible 
CHB patients regardless 
of NUC or HBeAg 
status) 
50 mg dosed 
on Day 1, 29, 
57 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 29, 
57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 29, 
57 
Cohort 4 
300 mg 
 
Cohort 4b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 29, 
57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
400 mg dosed 
on Day 1, 29, 
57 
 
 
  
 
Cohort 6 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 15, 
29 
 
 
 
Cohort 7 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 8, 
15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
300 mg dosed 
on Day 1, 29, 
57  
 
 
 
Cohort 9 HBeAg+, 
entecavir or tenofovir 
experienced  
300 mg dosed 
on Day 1, 29, 
57  
 
 
 
Cohort 10 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 8, 
15 
 
 
 
Cohort 11 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 8, 
15  
* All Cohorts use 2 sentinel subjects 
 


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Page 8 of 41 
Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
To: 
Figure 1: Dose Escalation Schedule 
Healthy Volunteers (double blind) * 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose Regimen 
Cohort 1 
 
35 mg 
 
Cohort 1b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 25 mg 
dosed on Day 1, 29, 
57 
 
 
 
Cohort 1c (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 50 mg 
dosed on Day 1, 29, 
57 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 100 mg 
dosed on Day 1, 29, 
57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 200 mg 
dosed on Day 1, 29, 
57 
Cohort 4 
300 mg 
 
Cohort 4b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 300 mg 
dosed on Day 1, 29, 
57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 400 mg 
dosed on Day 1, 29, 
57 
 
 
  
 
Cohort 6 (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 100 mg 
dosed on Day 1, 15, 
29 
 
 
 
Cohort 7 (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 100 mg 
dosed on Day 1, 8, 
15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
ARO-HBV 300 mg 
dosed on Day 1, 29, 
57  
 
 
 
Cohort 9 HBeAg+, entecavir 
or tenofovir experienced  
ARO-HBV 300 mg 
dosed on Day 1, 29, 
57  
 
 
 
Cohort 10 (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 200 mg 
dosed on Day 1, 8, 
15 
 
 
 
Cohort 11 (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 300 mg 
dosed on Day 1, 8, 
15  
 
 
 
Cohort 12 (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
JNJ-6379 daily 
250mg + ARO-
HBV 200 mg dosed 
on Day 1, 29, 57 
* All NHV Cohorts use 2 sentinel subjects 
 
 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
9. Section/page:  1 Protocol Synopsis, Treatment Stopping Rules, p. 8 
 
From: 
Escalation to the next cohort will proceed according to the study design through the 400 mg dose level and until 
all subsequent cohorts are completed unless the trial is stopped early by the DSC or Sponsor. A decision to stop 
the trial early or discontinue drug in an individual subject or group of subjects may be indicated based on any of 
the following:  
 
1. A single Serious Adverse Event (SAE, defined in Section 9.1) considered at least possibly related to 
ARO-HBV  
2. One of the following abnormal results at least possibly related to ARO-HBV: 
• 
In NHVs, treatment emergent ALT or AST > 3X ULN, which must be confirmed by repeat blood 
draw within 48 hours of initial results.  
• 
In CHB patients, treatment emergent ALT or AST > 3X Day 1 pre-dose baseline, confirmed by 
repeat blood draw within 48 hours of initial results AND ALT > 10X ULN AND any one of the 
following: 
o 
Total Bilirubin newly elevated to 2X ULN AND 2X Day 1 pre-dose baseline (confirmed on 
repeat lab draw within 48 hours) or 
o 
Decrease in serum albumin of 0.5 g/dL or greater confirmed on repeat lab draw within 48 
hours 
 
• 
Treatment emergent platelet count < 70,000 per microliter in NHVs or < 50,000 in CHB patients, 
confirmed on repeat measure within 48 hours of initial results 
• 
Treatment emergent serum creatinine > 180 μmol/L confirmed by repeat blood draw within 48 
hours of initial results 
 
 
To: 
Escalation to the next cohort will proceed according to the study design through the 400 mg dose level and until 
all subsequent cohorts are completed unless the trial is stopped early by the DSC or Sponsor. A decision to stop 
the trial early or discontinue drug in an individual subject or group of subjects may (following a case-by-case 
decision based on consultation between the sponsor, DSC and the PI) be indicated based on any of the 
following:  
 
1. A single Serious Adverse Event (SAE, defined in Section 9.1) considered at least possibly related to 
ARO-HBV or JNJ-6379 
2. One of the following abnormal results at least possibly related to ARO-HBV or JNJ-6379: 
• 
In NHVs, treatment emergent ALT or AST > 3X ULN, which must be confirmed by repeat blood 
draw within 48 hours of initial results.  
• 
In CHB patients, treatment emergent ALT or AST > 3X Day 1 pre-dose baseline, confirmed by 
repeat blood draw within 48 hours of initial results AND ALT > 10X ULN AND any one of the 
following: 
o 
Total Bilirubin newly elevated to 2X ULN AND 2X Day 1 pre-dose baseline (confirmed on 
repeat lab draw within 48 hours) or 
o 
Decrease in serum albumin of 0.5 g/dL or greater confirmed on repeat lab draw within 48 
hours 
 
• 
Treatment emergent platelet count < 70,000 per microliter in NHVs or < 50,000 in CHB patients, 
confirmed on repeat measure within 48 hours of initial results 
• 
Treatment emergent serum creatinine > 180 μmol/L confirmed by repeat blood draw within 48 
hours of initial results 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
 
10. Section/page:  1 Protocol Synopsis, Study Assessments, p. 9 
 
From:  
Immunogenicity: 
For Cohorts 1b, 1c, 2b, 3b, 4b, 5b, and 6-11 blood samples for the anti-drug antibodies test will be collected at 
screening, Day 57 and Day 113 or at the end of study visit. 
 
To:  
Immunogenicity: 
For Cohorts 1b, 1c, 2b, 3b, 4b, 5b, and 6-12 blood samples for the anti-drug antibodies test will be collected at 
screening, Day 57 and Day 113 or at the end of study visit. 
 
From: 
Pharmacokinetics (NHVs only): 
Blood samples will be collected from each subject for pharmacokinetic analysis after dose 1 (Cohorts 1-5) 
per the Schedule of Assessments 
 
To: 
Pharmacokinetics (NHVs only and limited PK in Cohort 12): 
Blood samples will be collected from each subject for pharmacokinetic analysis after dose 1 (Cohorts 1-5) 
per the Schedule of Assessments and for Cohort 12 patients per the Schedule of Assessments. 
 
11. Section/page:  1 Protocol Synopsis, Data Analysis, pp. 10-11 
 
From: 
Two separate data analyses will be performed, one for all subjects through EOS (Day 29 for NHVs and Day 113 
for CHB patients), and one additional and separate analysis for CHB patients who consent to the additional 
follow up. 
 
To: 
Two separate data analyses will be performed, one for all subjects through EOS (Day 29 for NHVs and Day 113 
for CHB patients), and one additional and separate analysis for CHB patients who consent to the additional 
follow up through Day 393. Separate analyses including and excluding Cohort 12 may also be completed. 
 
From: 
Safety population:  All participants (NHV and CHB patients) that received at least one dose of study treatment. 
 
To: 
Safety population:  All participants (NHV and CHB patients) that received at least one dose of ARO-HBV or 
JNJ-6379. 
 
From: 
Pharmacokinetics (NHV subjects only): 
Plasma concentrations of ARO-HBV product constituents will be used to calculate the following PK parameters: 
maximum observed plasma concentration (Cmax), area under the plasma concentration time curve (AUC) from 
time 0 to 24 hours (AUC0-24), AUC from time 0 extrapolated to infinity (AUCinf), and terminal elimination half-
life (t½). Pharmacokinetic parameters will be determined using non-compartmental methods. Descriptive statistics 
of PK parameters will include mean, standard deviation (SD), coefficient of variation, median, minimum, and 
maximum. PK results will be analyzed for dose proportionality, and sex differences.  
 
PK population:  All NHV subjects that received at least one dose of active study treatment (ARO-HBV). 
To: 
Pharmacokinetics (NHV subjects and limited PK in Cohort 12): 






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Page 13 of 41 
Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
13. Section/page: 3 List of Abbreviations and Terms, pp. 24-25 
 
Added: 
CAM 
Capsid Assembly Modulator 
cccDNA 
Covalently Closed Circular DNA 
JNJ-6379 
JNJ-56136379, a capsid assembly modulator (CAM) 
 
 
14. Section/page: 4.1 Background Information, p. 27 
 
Added: 
JNJ-6379 is a capsid assembly modulator (CAM) being developed for the treatment of hepatitis B infection. 
JNJ-6379 binds to the HBV core protein and interferes with the viral capsid assembly process and resulting 
in the formation of empty viral capsids devoid of HBV-DNA. JNJ-6379 also acts at an early stage of the viral 
life cycle by inhibiting the de novo formation of cccDNA. It is thought that by using an siRNA approach to 
silence production of viral antigen in combination with NUCs to inhibit viral replication and JNJ-6379 
which inhibits capsid assembly and cccDNA formation the response to treatment and potentially the rate of 
functional cure could be enhanced. 
 
 
15. Section/page: 4.2 AROHBV and JNJ-6379 Pre-Clinical Pharmacology and Toxicology Studies, pp. 
27-28 
 
From: 
4.2   ARO-HBV Pre-clinical Pharmacology and Toxicology Studies 
ARO-HBV has been studied in rats and in monkeys in single and multi-dose toxicity studies up to doses of 300 
mg/kg. Further details regarding the nonclinical safety results are provided in the Investigator’s Brochure. 
 
To: 
4.2   ARO-HBV and JNJ-6379 Pre-clinical Pharmacology and Toxicology Studies 
ARO-HBV has been studied in rats and in monkeys in single and multi-dose toxicity studies up to doses of 300 
mg/kg. Further details regarding the nonclinical safety results are provided in the Investigator’s Brochure.  The 
human JNJ-6379 exposure at 28 days of 250 mg oral dose and the observed NOAEL in 6 month rat and 9 
month dog exposure studies are described in Table 1.  Details regarding nonclinical safety results using JNJ-
6379 are provided in the JNJ-56136379 Investigator’s Brochure. 
 
 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
 
Added: 
 
Table 1. 
 
Sex 
NOAEL 
(mg 
eq./kg/day) 
Cmax 
(ng/mL) 
AUC0-24h 
(ng.h/mL) 
Ratio Total 
Concentration 
Ratio 
Concentration 
Corrected for 
Plasma Protein 
Bindingb 
Cmax 
A/H 
Ratio 
AUC0-24h 
A/H 
Ratio 
Cmax 
A/H 
Ratio 
AUC0-24h 
A/H 
Ratio 
Human exposurea 
13,798 
265,384 
- 
- 
 
 
6M rat 
M 
30 
7,540 
93,100 
0.6 
0.4 
0.9 
0.6 
M 
100c 
13,600d 
180,000d 
1.0 
0.7 
1.7 
1.1 
F 
100 
19,900 
233,000  
1.4 
0.9 
2.4 
1.5 
9M dog 
M 
25 
30,000 
606,000 
2.2 
2.3 
3.3 
3.5 
F 
12.5 
22,500 
383,000 
1.6 
1.4 
2.5 
2.2 
250 mg JNJ-56136379 once daily for 28 days (Study 56136379HPB1001). 
b Ratio of the total Cmax or AUC corrected for species difference in plasma unbound fraction. Calculation: [animal 
Cmax or AUC0-24h x animal free fraction] / [human Cmax or AUC0-24h x human free fraction]. 
c A dose of 100 mg eq./kg/day in male rats is considered to be above the NOAEL due to kidney findings in male 
rats, which are likely not relevant for human.  
d The plasma Cmax of 13,600 ng/mL and AUC0-24h of 180,000 ng.h/mL in male rats at 100 mg eq./kg/day corresponds 
to an unbound Cmax of 1,754 ng/mL and AUC0-24h of 23,220 ng.h/mL (fraction unbound rat plasma=12.9%). This 
unbound plasma exposure will be achieved in humans at a total plasma Cmax of 22,784 ng/ml and AUC0-24h of 
301,558 ng h/mL (fraction unbound in human plasma=7.7%). 
 
 
16. Section/page: 4.3 ARO-HBV Clinical Studies, pp. 29-30 
 
Deleted: There have been no previous studies in humans with ARO-HBV. 
 
From: 
The potent reductions in viral antigens seen using ARC-520/521 and as described in the Investigator Brochure 
provides strong proof of concept for testing of next generation siRNA compounds like ARO-HBV in HBV 
patients. Additionally, the human safety profile seen with ARC-520/521 across several multi-dose clinical 
studies in HBV patients and two SAD healthy volunteer studies is encouraging. Further details on ARC-521 and 
ARC-520 clinical experience are presented in the Investigator’s Brochure. 
 
To: 
The potent reductions in viral antigens seen using ARC-520/521 and as described in the Investigator Brochure 
provides strong proof of concept for testing of next generation siRNA compounds like ARO-HBV in HBV 
patients. Additionally, the human safety profile seen with ARC-520/521 across several multi-dose clinical 
studies in HBV patients and two SAD healthy volunteer studies is encouraging. Updated interim clinical safety 
and pharmacologic activity data for ARO-HBV from the  ongoing AROHBV1001 study are presented in the 
Investigator’s Brochure 2nd Edition. These data indicate that ARO-HBV has been well tolerated and has 
demonstrated promising pharmacologic activity against the HBV virus based on reductions of viral antigens 
and HBV DNA. Pharmacodynamic data to date justify the further clinical development of ARO-HBV with 
the goal of developing finite regimens aimed at HBsAg clearance in patients with chronic HBV. 
 
 


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17. Section/page: 4.4 JNJ-6379 Clinical Studies, p. 30-32 
 
Added: 
4.4    JNJ-6379 Clinical Studies 
Antiviral Activity 
Interim data of the ongoing clinical study 56136379HPB1001 (Sessions 8 to 11), in CHB-infected subjects 
show that JNJ-6379 administration at doses of 25- to 250-mg leads to reduction in HBV DNA. A mean (±SD) 
reduction in plasma HBV DNA levels of 2.16 (0.49) log10 IU/mL (25 mg), 2.89 (0.48) log10 IU/mL (75 
mg), 2.70 (0.53) log10 IU/mL (150 mg), and 2.70 (0.33) log10 IU/mL (250 mg) from baseline was observed 
at Day 29. In the 250-mg dosing group, 5 out of 12 subjects achieved HBV DNA levels below the LLOQ of 
the HBV DNA assay, while 3 out of 12 subjects in both the 75-mg and 150-mg dosing groups and none (out 
of 12) of the subjects in the 25-mg dosing group achieved this. A more pronounced and consistent decline in 
HBV DNA levels was observed across subjects in the 75-mg, 150-mg, and 250-mg group compared with the 
25-mg group. 
In line with HBV DNA levels, reductions in HBV RNA levels were observed with JNJ‑56136379 treatment. 
Baseline levels of HBV RNA were generally low and sometimes undetectable, especially in the higher dose 
groups, limiting the HBV RNA decline observable in this study. No notable changes in HBsAg or HBeAg 
were observed. 
Safety 
Healthy Subjects 
In a pooled analysis of 123 adult healthy subjects, 98 subjects received at least one dose of JNJ-6379. Eleven 
subjects did not complete their treatment: due to withdrawal by subject (such as withdrawal of consent or 
withdrawal due to personal reasons) (4 [3.3%] subjects), lost to follow-up (1 [0.8%] subject), other reasons 
(2 [1.6%] subjects) or due to adverse events (AEs) (4 [3.3%] subjects, see below). 
There were no deaths and 2 subjects experienced a serious adverse event (SAE), both considered not related 
to JNJ-6379: one during the screening phase (spontaneous abortion; moderate) in study 5636379HPB1004, 
and the other (wrist fracture right; severe) in study 563679HPB1002, 24 days after the last single dose of 
JNJ-56136379. Apart from the severe wrist fracture, no severe AEs were reported. In most cases AEs were 
mild and not considered related to JNJ-56136379.  
Two subjects in study 56136379HPB1001 Part 1, single dose escalation phase, discontinued from further 
dosing with JNJ-56136379 in subsequent sessions due to an AE. One subject in study 56136379HPB1001 
Part 2, multiple dose phase, discontinued JNJ-6379 treatment after administration of JNJ-6379 150 mg bid 
for 2 days, followed by JNJ-6379 100 mg for 9 days due to the AEs abdominal pain lower and dizziness 
postural. These AEs were considered by the investigator of mild severity and possibly related to JNJ-6379 
and resolved after discontinuation. 


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Overall, the most common treatment-emergent AEs, experienced by >10% of all subjects treated with JNJ-
6379 was headache (27 [27.6%] subjects on JNJ-56136379 versus 3 [12.0%] subjects on placebo). 
Most graded laboratory abnormalities were grade 1 or 2, except for a grade 3 amylase and grade 4 lipase 
elevation in 1 subject in study 56136379HPB1002 (both observed during follow-up), a grade 3 lipase 
elevation in another subject in study 56136379HPB1002 (observed when subject on treatment), and 2 grade 
3 LDL cholesterol elevations in one subject each from study 56136379HPB1002 and study 
56136379HPB1003 (both observed when subjects on treatment). Based on these cases, lipase and amylase 
have been identified as laboratory abnormalities of interest. The pooled data show that 5 (5.1%) and 6 (6.1%) 
subjects on JNJ-6379 had lipase and amylase elevations, respectively versus none on placebo.  
CHB Infected Subjects 
In the unblinded 25-250 mg sessions of Part 2 of study 56136379HPB1001 in CHB-infected subjects, no 
deaths were reported. No other SAEs, AEs leading to discontinuation or grade 4 AEs were observed in the 
25, 75 and 250 mg treatment groups. 
One subject in the JNJ-6379 150 mg treatment group experienced several grade 3 SAEs (idiopathic 
intracranial hypertension, headache, epilepsy, gliosis, brain edema, brain neoplasm, brain compression) 2 
days after completing treatment with JNJ-6379. The subject was withdrawn from the study. All SAEs were 
considered not related to study drug with outcome unknown. Despite several attempts to reach the patient, 
the patient was lost to follow-up. 
One subject experienced the grade 3 AE AST increased and grade 4 AE ALT increased during JNJ-6379 150 
mg treatment. Both AEs were considered probably related to study drug, which was withdrawn, due to the 
protocol defined stopping criteria. The AEs were considered resolved after end of treatment. The subject also 
had the AEs liver tenderness (grade 1, possibly related, resolved before end of treatment) and abdominal 
distension (grade 1, not related, resolved after end of treatment) for which study drug was withdrawn. 
Other grade 3 AEs were reported for 1 subject during JNJ-56136379 25 mg treatment (amylase increased, 
possibly related, resolved before end of treatment), for 1 subject during JNJ-6379 75 mg treatment (ALT 
increased, possibly related, resolved after end of treatment) and 1 subject after JNJ-6379 150 mg treatment 
(AST increased, probably related, resolved). 
The most frequently reported treatment-emergent AEs across all doses (>1 subject) on JNJ-6379 were 
headache (4 [11.8%] subjects on JNJ-6379 versus 6 [42.9%] subjects on placebo), nausea (2 [5.9%] subjects 
versus 0 subjects, respectively), dyspepsia (2 [5.9%] subjects versus 0 subjects, respectively), ALT increased 
(2 [5.9%] subjects versus 1 [7.1%] subject, respectively), amylase increased (2 [5.9%] subjects versus 0 
subjects, respectively), and hypophosphatemia (2 [5.9%] subjects versus 0 subjects, respectively). All other 
AEs were reported in 1 subject at most. No dose-related trend in AEs was observed. The majority of AEs 
were grade 1. 


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The majority of laboratory abnormalities were grade 1 or 2. No grade 3 or 4 laboratory abnormalities were 
observed in the 250 mg treatment group. Grade 4 ALT elevations were observed in 1 subject each in the 75 
and 150 mg treatment groups and were related to the AEs discussed above (for the subject in the 75 mg 
treatment group, this was observed during follow-up). Grade 3 pancreatic amylase (discussed above as AE) 
and grade 3 triglycerides (observed during follow-up) were observed in 1 subject each in the 25 mg treatment 
group. Grade 3 AST elevation was observed in 1 subject in the 75 mg treatment group (observed during 
follow-up) and in 2 subjects in the 150 mg group (for 1 subject observed during follow-up) (discussed as AE 
above). Grade 3 hyperkalemia was observed in 1 subject in the 150 mg treatment group. 
No ECG-related or vital sign-related AEs were reported. No clinically relevant changes from baseline in ECG 
or vital signs values were observed. 
Further details regarding clinical safety results using JNJ-6379 are provided in the JNJ-56136379 
Investigator’s Brochure. 
 
18. Section/page: 4.5 ARO-HBV and JNJ-6379 Pre-Clinical Pharmacokinetic and Product Metabolism 
Studies, pp. 32-33 
 
From: 
4.4   ARO-HBV Pre-Clinical Pharmacokinetic and Product Metabolism Studies 
PK parameters for ARO-HBV have been evaluated in both rats and monkeys. Results of these studies can be 
found in the Investigator’s Brochure.  In general, ARO-HBV will be unmeasurable in the circulation within 1-2 
days following a single dose. 
 
To: 
4.5    ARO-HBV and JNJ-6379 Pre-Clinical Pharmacokinetic and Product Metabolism Studies 
PK parameters for ARO-HBV have been evaluated in both rats and monkeys. Results of these studies can be 
found in the Investigator’s Brochure.  In general, ARO-HBV will be unmeasurable in the circulation within 1-2 
days following a single dose. In healthy subjects, JNJ-6379 is rapidly absorbed from the oral tablets, with a 
median tmax ranging between 1.26 and 3 hours in fasting conditions, and around 4 hours in fed conditions. 
Mean terminal half-life (t1/2term) was comparable between studies 56136379HPB1001 and 56136379HPB1003, 
ranging between 93.3 and 116 hours across the dose levels in both studies, suggesting no significant difference 
in clearance between Asian and non-Asian subjects. In study 56136379HPB1003, approximately 18% of the 
administered dose was excreted via the kidney, resulting in a mean renal clearance of 0.161 L/h. No significant 
difference was observed in healthy volunteers when compared to patients with CHB. Details regarding 
pharmacokinetics and metabolism of JNJ-6379 are provided in the latest ARO-HBV and JNJ-56136379 
Investigator’s Brochure. 
 
 


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19. Section/page: 4.6 Rationale for the Study, p. 34 
 
Added: 
Cohort 12 uses a combination of NUCs + ARO-HBV + JNJ-6379. Throughout the study all patients have 
been treated with the combination of NUCs + ARO-HBV in all other cohorts (Cohorts 1b through 11). It is 
thought that by using an siRNA approach to silence production of viral antigens in combination with NUCs 
to inhibit viral replication and JNJ-6379 which inhibits capsid assembly and cccDNA formation the response 
to treatment and potentially the rate of functional cure could be enhanced. ARO-HBV + NUCs has been well 
tolerated throughout the AROHBV1001 study. JNJ-6379 in combination with NUCs has also been well 
tolerated in CHB clinical studies. In vitro, JNJ-6379 does not inhibit phosphorylation of tenofovir or 
entecavir. Based on results from GLP toxicology studies and in vitro assessments of drug metabolism and 
transport for both JNJ-6379 and ARO-HBV, as well as safety and tolerability results from prior human 
studies in healthy volunteers and CHB, there is no indication that JNJ-6379 and ARO-HBV will have 
overlapping or additive toxicity. As such, the benefit of this combination “triple” therapy is expected to 
outweigh risk of toxicity. 
 
 
20. Section/page: 4.7 Risk Assessment for Participants, pp. 34-36 
 
From: 
4.6     Risk Assessment for Participants 
• 
Embryo-fetal toxicity: Limited GLP toxicology as well as preliminary non-GLP embryo-fetal studies 
have been conducted. Accordingly, eligible participants enrolled in this study, both male and female 
(including partners), must agree to use two effective methods of contraception (double barrier 
contraception or hormonal contraception along with a barrier contraceptive) during the study and 
for 3 months post-dose, or agree to abstinence (acceptable only if this method is in alignment with 
the normal life style of the patient).  
• 
Injection Site Reaction Risk: Other subcutaneously administered modified siRNA drug candidates 
evaluated in clinical studies have been associated with mild to moderate injection site reactions (e.g. 
pain, erythema). This study includes a protocol for evaluation and grading of injection site reactions 
based on pre-defined criteria for mild, moderate and severe reactions. Injection site reactions will 
be photographed for tracking resolution and/or progression. Additionally, steps will be taken to 
minimize injection site reactions such as rotating injection sites and allowing the ARO-HBV 
solution to come to room temperature prior to injecting. 
• 
Hepatic Toxicity (theoretical risk): ARO-HBV targets the liver. Arrowhead has not seen meaningful 
drug induced transaminase changes with a previously studied liver targeted RNAi-based therapeutic 
(ARC-520/521) targeting HBV. However, another company (Alnylam Therapeutics) developing an 
siRNA for AATD has seen evidence of mild to moderate elevations in transaminases using 
hepatocyte targeted siRNA conjugates similar to those used by Arrowhead. Alnylam has described 
that these ALT changes were due to off- target effects of the siRNA seed region on microRNAs in 
the hepatocyte (Vaishnaw et al, 2017; Schlegel et al, 2017). The siRNA sequence of the ARO-HBV 


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sense and antisense molecules have been screened for potential mRNA and microRNA off-target 
effects. No such off-target effects are anticipated. Multi-dose (3 weekly doses) GLP toxicity studies 
with ARO-HBV in rats and monkeys demonstrate no evidence of hepatic toxicity up to doses of 300 
mg/kg. To mitigate this risk, the proposed study has built in stopping rules for ALT and AST 
elevation. Labs to evaluate liver injury and liver function will be drawn frequently.  The Drug Safety 
Committee will include a hepatologist member with extensive clinical trial experience and 
significant experience in evaluation of liver targeted therapeutics, including siRNAs. Additionally, 
the planned starting dose of 35 mg is approximately 1/50th (assuming weight based conversion and 
a 60-kg subject) of the lowest dose of 30 mg/kg used in both the multi-dose rat and monkey GLP 
toxicity studies. This starting dose provides a safety margin of over 500-fold from the monkey 
NOAEL.     
• 
Host or viral induced ALT flares (theoretical risk): Fluctuations in ALT are part of the natural 
history of CHB infection. In fact, many experts believe that ALT increase represents innate 
immune responses against infected hepatocytes and is required for HBsAg seroclearance. ALT 
elevation can also be seen in the setting of rebounding (such as with NUC discontinuation) HBV 
DNA levels or fluctuations of HBV DNA such as with NUC non-compliance.  It is likely that host 
induced ALT flares will be seen in ARO-HBV studies as part of the normal sequelae associated 
with HBV. This risk will be mitigated by starting all patients NUCs (entecavir or tenofovir) upon 
entering the study, or kept on NUCs if NUC experienced. Measures of liver injury (ALT, AST) 
and of liver function (bilirubin, albumin and coagulation factors) will be measured frequently. 
Stopping rules for adverse changes in liver function are included. Additionally, “ALT Flare 
Guidelines” are specified in Appendix 1 to help investigators evaluate ALT elevations during the 
study 
 
To: 
4.7     Risk Assessment for Participants 
4.7.1 ARO-HBV: 
• 
Embryo-fetal toxicity: Limited GLP toxicology as well as preliminary non-GLP embryo-fetal studies 
have been conducted. Accordingly, eligible participants enrolled in this study, both male and female 
(including partners), must agree to use two effective methods of contraception (double barrier 
contraception or hormonal contraception along with a barrier contraceptive) during the study and 
for 3 months post-dose, or agree to abstinence (acceptable only if this method is in alignment with 
the normal life style of the patient).  
• 
Injection Site Reaction Risk: Other subcutaneously administered modified siRNA drug candidates 
evaluated in clinical studies have been associated with mild to moderate injection site reactions (e.g. 


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pain, erythema). This study includes a protocol for evaluation and grading of injection site reactions 
based on pre-defined criteria for mild, moderate and severe reactions. Injection site reactions will 
be photographed for tracking resolution and/or progression. Additionally, steps will be taken to 
minimize injection site reactions such as rotating injection sites and allowing the ARO-HBV 
solution to come to room temperature prior to injecting. 
• 
Hepatic Toxicity (theoretical risk): ARO-HBV targets the liver. Arrowhead has not seen meaningful 
drug induced transaminase changes with a previously studied liver targeted RNAi-based therapeutic 
(ARC-520/521) targeting HBV. However, another company (Alnylam Therapeutics) developing an 
siRNA for AATD has seen evidence of mild to moderate elevations in transaminases using 
hepatocyte targeted siRNA conjugates similar to those used by Arrowhead. Alnylam has described 
that these ALT changes were due to off- target effects of the siRNA seed region on microRNAs in 
the hepatocyte (Vaishnaw et al, 2017; Schlegel et al, 2017). The siRNA sequence of the ARO-HBV 
sense and antisense molecules have been screened for potential mRNA and microRNA off-target 
effects. No such off-target effects are anticipated. Multi-dose (3 weekly doses) GLP toxicity studies 
with ARO-HBV in rats and monkeys demonstrate no evidence of hepatic toxicity up to doses of 300 
mg/kg. To mitigate this risk, the proposed study has built in stopping rules for ALT and AST 
elevation. Labs to evaluate liver injury and liver function will be drawn frequently.  The Drug Safety 
Committee will include a hepatologist member with extensive clinical trial experience and 
significant experience in evaluation of liver targeted therapeutics, including siRNAs. Additionally, 
the planned starting dose of 35 mg is approximately 1/50th (assuming weight based conversion and 
a 60-kg subject) of the lowest dose of 30 mg/kg used in both the multi-dose rat and monkey GLP 
toxicity studies. This starting dose provides a safety margin of over 500-fold from the monkey 
NOAEL.     
• 
Host or viral induced ALT flares (theoretical risk): Fluctuations in ALT are part of the natural 
history of CHB infection. In fact, many experts believe that ALT increase represents innate immune 
responses against infected hepatocytes and is required for HBsAg seroclearance. ALT elevation can 
also be seen in the setting of rebounding (such as with NUC discontinuation) HBV DNA levels or 
fluctuations of HBV DNA such as with NUC non-compliance.  It is likely that host induced ALT 
flares will be seen in ARO-HBV studies as part of the normal sequelae associated with HBV. This 
risk will be mitigated by starting all patients NUCs (entecavir or tenofovir) upon entering the study, 
or kept on NUCs if NUC experienced. Measures of liver injury (ALT, AST) and of liver function 
(bilirubin, albumin and coagulation factors) will be measured frequently. Stopping rules for adverse 
changes in liver function are included. Additionally, “ALT Flare Guidelines” are specified in 
Appendix 1 to help investigators evaluate ALT elevations during the study. 
 
 


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4.7.2. JNJ-6379: 
• 
Changes in amylase, lipase, cholesterol: Based on data from Study 56136379HPB1002, lipase 
and amylase elevations were identified as laboratory abnormalities of interest. In addition, based 
on preclinical findings in rats and dogs, increased cholesterol was identified as laboratory 
abnormality of interest. Serum lipase, amylase and cholesterol will be monitored in patients.  
• 
Emergence of Resistance: Treatment with JNJ-56136379 may lead to emergence of viral variants 
with reduced susceptibility or resistance to JNJ-56136379. Based on pre-clinical data, these 
variants remain susceptible to TDF and ETV but might affect treatment options with CAMs in 
the future. 
4.7.3. ARO-HBV and JNJ-6379 combined 
• 
Overlapping drug toxicity (theoretical risk): Cohort 12 proposes the addition of JNJ-6379 to the 
treatment regimen of ARO-HBV+NUC which has been used throughout the study. Based on 
available clinical and pre-clinical experience with each compound as well as combination clinical 
studies of ARO-HBV with NUCs and JNJ-6379 with NUCs, clinically significant overlapping 
toxicity is not expected in Cohort 12. 
21. Section/page: 4.8 Justification for Dose of ARO-HBV and JNJ-6379, p. 36-37 
 
From:  
4.6     Justification for Starting Dose in Humans  
 
To: 
4.8     Justification for Dose of ARO-HBV and JNJ-6379  
 
Added: 
For cohort 12, the dose of ARO-HBV administered will be 200mg on Days 1, 29, and 57. ARO-HBV has been 
shown to be well tolerated and and effective at reducing viral antigens at doses up to 400mg dosed on Days 1, 
29 and 57 (see Investigator’s Brochure 2nd Edition). Since there was no obvious dose response observed 
between 100mg and 400mg ARO-HBV dosed on Days 1, 29, and 57, the second lowest dose level of 200 mg 
was chosen for cohort 12. The JNJ-6379 dose to be administered will be 250 mg given once daily. This dose is 
currently tested for up to 48 weeks in the ongoing Phase 2a study 56136379HPB2001 and has been selected 
based on all safety, PK, and antiviral activity data available following completion of the highest JNJ-6379 dose 
group (who received 250 mg once daily) in the Phase 1 study 56136379HPB1001 in treatment-naïve CHB-
infected subjects treated for 28 days. No SAEs or AEs leading to treatment discontinuation were reported for 
CHB-infected subjects who received 250 mg JNJ-6379 once daily for 28 days, and all AEs were grade 1. In 
addition, no treatment-emergent laboratory abnormalities of >grade 2, ECG or vital signs abnormalities of 
≥grade 2 were reported for these subjects, and no abnormalities were reported as AEs. The dose of 250 mg 
once daily has been selected to efficiently inhibit HBV DNA replication across a broad spectrum of patients 


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and viral variants. In addition, 250 mg is expected to increase the potential to trigger the secondary mode of 
action (MoA) (i.e., inhibition of de novo cccDNA formation) which requires about 10-fold higher 
concentrations of JNJ-6379 than the primary MoA of inhibition, ie, interfering with capsid assembly (EC90 
primary MoA=376 nM and EC90 secondary MoA=4019 nM).  
22. Section/page:  5.3 Exploratory Objectives, pp. 38-39 
 
From: 
• 
To determine the reduction of HBcrAg, HBV RNA (if scientifically feasible) and HBeAg (e+ only), in 
response to ARO-HBV in CHB patients as a measure of activity 
• 
To evaluate the effect of single doses of ARO-HBV on cytokines (Cytokine panel A: interleukin-6 [IL-6], 
monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-alpha [TNF-alpha], interleukin-8 [IL-
8], interleukin-1beta [IL-1beta], interferon alpha [IFN alpha], IL-10, IL-12 [p40], IL-12 [p70], macrophage 
inflammatory protein-1alpha [Mip-1alpha]) in healthy volunteers. 
• 
To evaluate the effect of single escalating doses of ARO-HBV on complement factors Bb, CH50, C5a, C4a, 
and C3a in healthy volunteers. 
• 
To collect plasma samples in healthy volunteers for subsequent metabolite identification (reported in a 
separate report outside of this study) 
• 
To collect urine samples in healthy volunteers for subsequent determination of urinary excretion and 
metabolite identification (reported in a separate report outside of this study).  
• 
To evaluate the effect of multiple doses of ARO-HBV on cytokines (Cytokine panel B: TNF alpha, IFN 
gamma, CXCL-9, and CXCL-10) in CHB patients 
• 
To evaluate the effect of multiple doses of ARO-HBV on HBV patient immune cell profile including T-cells, 
NK cells, B cells and monocytes in a limited number of HBV patients in New Zealand only (if scientifically 
feasible). 
• 
To evaluate the effect of multiple doses of ARO-HBV on HBV antigen specific T-cell response in a limited 
number of HBV patients in New Zealand only (if scientifically feasible).  
• 
To evaluate the effect of interferon response gene single nucleotide polymorphisms (SNPs) including 
IL28B on response to ARO-HBV 
 
To: 
• 
To determine the reduction of HBcrAg, , HBsAg, HBV RNA (if scientifically feasible) and HBeAg (e+ only), 
in response to ARO-HBV (alone or in combination with JNJ-6379) in CHB patients as a measure of activity 
• 
To evaluate the effect of single doses of ARO-HBV on cytokines (Cytokine panel A: interleukin-6 [IL-6], 
monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-alpha [TNF-alpha], interleukin-8 [IL-


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8], interleukin-1beta [IL-1beta], interferon alpha [IFN alpha], IL-10, IL-12 [p40], IL-12 [p70], macrophage 
inflammatory protein-1alpha [Mip-1alpha]) in healthy volunteers. 
• 
To evaluate the effect of single escalating doses of ARO-HBV on complement factors Bb, CH50, C5a, C4a, 
and C3a in healthy volunteers. 
• 
To collect plasma samples in healthy volunteers for subsequent metabolite identification (reported in a 
separate report outside of this study) 
• 
To collect urine samples in healthy volunteers for subsequent determination of urinary excretion and 
metabolite identification (reported in a separate report outside of this study).  
• 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with JNJ-6379)  on 
cytokines (Cytokine panel B: TNF alpha, IFN gamma, CXCL-9, and CXCL-10) in CHB patients 
• 
To evaluate the effect of multiple doses of ARO-HBV (alone or in combination with JNJ-6379)  on HBV 
patient immune cell profile including T-cells, NK cells, B cells and monocytes in a limited number of HBV 
patients in New Zealand only (if scientifically feasible). 
• 
To evaluate the effect of multiple doses of ARO-HBV on HBV antigen specific T-cell response in a limited 
number of HBV patients in New Zealand only (if scientifically feasible).  
• 
To evaluate the effect of interferon response gene single nucleotide polymorphisms (SNPs) including IL28B 
on response to ARO-HBV (alone or in combination with JNJ-6379). 
• 
To determine the incidence and frequency of adverse events possibly or probably related to treatment as a 
measure of the safety and tolerability of ARO-HBV in combination with JNJ-6379 in patients chronically 
infected with hepatitis B virus (CHB) (Cohort 12 only). 
 
23. Section/page: 6.1 Study Design, pp. 40-44 
 
From: 
CHB patients: 
HBeAg negative or HBeAg positive CHB patients, aged 18-65 years with BMI between 19.0 and 38.0 kg/m² 
(Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11) will be enrolled. Cohort 8 will enroll HBeAg positive 
treatment naïve patients (no prior chronic exposure to NUCs or Interferon) and Cohort 9 will enroll HBeAg 
positive NUC experienced patients (on entecavir or tenofovir for at least 12 months). Cohorts 1b, 1c, 2b, 3b, 4b, 
5b, 6, 7, 10 and 11 will enroll either HBeAg positive or negative patients regardless of previous NUC or PEG 
IFN treatment experience. All patients will be started on entecavir or tenofovir on Day 1. Patients currently on 
PEG IFN will not be allowed. 
 
To: 
CHB patients: 


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HBeAg negative or HBeAg positive CHB patients, aged 18-65 years with BMI between 19.0 and 38.0 kg/m² 
(Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12) will be enrolled. Cohort 8 will enroll HBeAg positive 
treatment naïve patients (no prior chronic exposure to NUCs or Interferon) and Cohort 9 will enroll HBeAg 
positive NUC experienced patients (on entecavir or tenofovir for at least 12 months). Cohorts 1b, 1c, 2b, 3b, 4b, 
5b, 6, 7, 10, 11 and 12 will enroll either HBeAg positive or negative patients regardless of previous NUC or PEG 
IFN treatment experience. All patients will be started on entecavir or tenofovir on Day 1. Cohort 12 will start on 
JNJ-6379 on Day 1 and continue oral 250 mg QD through Day 84. Patients currently on PEG IFN will not be 
allowed.   
 
From: 
• 
Cohorts 1-5: NHVs, adult males and females, aged 18-55 years 
o 
6 NHV subjects per cohort 
• 
Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10 and 11: Any CHB patient regardless of HBeAg or prior therapy status 
(as long as other Inclusion and Exclusion criteria are met).  
o 
Cohorts 1b, 1c, 2b, 3b, 4b and 5b will enroll a minimum of 4 and a maximum of 8 patients per 
cohort. 
o 
Cohorts 6, 7, 10 and 11 will enroll a maximum of 4 patients per cohort. 
• 
Cohort 8: HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or Interferon) 
o 
Cohort 8: Maximum of 4 patients per cohort 
• 
Cohort 9: HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 months). 
o 
Cohort 9: Maximum of 4 patients per cohort 
 
To: 
Summary of Participant Profile by Cohort and Cohort Size: 
• 
Cohorts 1-5: NHVs, adult males and females, aged 18-55 years 
o 
6 NHV subjects per cohort 
• 
Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 10, 11 and 12: Any CHB patient regardless of HBeAg or prior therapy 
status (as long as other Inclusion and Exclusion criteria are met).  
o 
Cohorts 1b, 1c, 2b, 3b, 4b and 5b will enroll a minimum of 4 and a maximum of 8 patients per 
cohort. 
o 
Cohorts 6, 7, 10 and 11 will enroll a maximum of 4 patients per cohort. 
o 
Cohort 12 will enroll 12 patients. 


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• 
Cohort 8: HBeAg positive treatment naïve patients (no prior chronic exposure to NUCs or Interferon) 
o 
Cohort 8: Maximum of 4 patients per cohort 
• 
Cohort 9: HBeAg positive NUC experienced patients (on entecavir or tenofovir for at least 12 months). 
o 
Cohort 9: Maximum of 4 patients per cohort 
 
From: 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially in Cohorts 2b 
through 7, Cohorts 10 and 11, and Cohorts 1b and 1c into a total of 10 open label cohorts. Cohorts 1b, and 1c 
through 5b will enroll at planned dose levels of 25 mg (Cohort 1b), 50 mg (Cohort 1c), 100 mg (Cohort 2b), 200 
mg (Cohort 3b), 300 mg (Cohort 4b) and 400 mg (Cohort 5b) to receive three doses (Q28 days) of active treatment 
in an open label fashion. Cohorts 6 through 11 will enroll at planned dose levels of 100 mg (Cohorts 6 and 7), 
200 mg (Cohort 10), and 300 mg (Cohorts 8, 9, and 11). Cohort 6 will enroll CHB subjects (after Cohort 5b has 
completed enrollment) to receive three doses two weeks apart. Cohorts 7, 10 and 11 will enroll CHB patients 
sequentially (after Cohort 6 has completed enrollment) to receive three doses a week apart at increasing dose 
levels starting with a dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially 
(after being opened at the final planned DSC meeting) with enrollment and dosing in a later cohort not initiating 
until all subjects in the earlier cohort have received at least their first scheduled dose. Cohort 8 will enroll HBeAg 
positive treatment naïve CHB patients to receive three monthly doses of ARO-HBV. Cohort 9 will enroll HBeAg 
positive entecavir or tenofovir experienced CHB patients to receive three monthly doses of ARO-HBV.  CHB 
patient screening for all CHB cohorts may start when Cohort 1 opens for enrollment. However, no CHB patients 
may be dosed until their respective cohort is approved for dosing by the DSC (not including Cohorts 1b and 1c). 
CHB dosing may begin and NHV dose escalation may occur based on DSC approval which can occur by vote 
after cumulative data through Day 8 from the current NHV cohort is available. (See Figure 1 for dose escalation 
schedule).  
CHB patients on current NUC therapy (entecavir or tenofovir) will stay on NUC therapy for the study duration. 
CHB patients not on NUC therapy (NUC naïve) will be started on either entecavir or tenofovir (selection between 
entecavir and tenofovir based on site Principal Investigator (PI) discretion) on Day 1.  Either tenofovir disoproxil 
fumarate (including generic) or tenofovir alafenamide are acceptable. 
To: 
CHB patients regardless of HBeAg status or NUC/Interferon use history will enroll sequentially in Cohorts 2b 
through 7, Cohorts 10 and 11, and Cohorts 1b and 1c into a total of 10 open label cohorts. Cohorts 1b, and 1c 
through 5b will enroll at planned dose levels of 25 mg (Cohort 1b), 50 mg (Cohort 1c), 100 mg (Cohort 2b), 200 
mg (Cohort 3b), 300 mg (Cohort 4b) and 400 mg (Cohort 5b) to receive three doses (Q28 days) of active treatment 
in an open label fashion. Cohorts 6 through 12 will enroll at planned dose levels of 100 mg (Cohorts 6 and 7), 
200 mg (Cohort 10, 12), and 300 mg (Cohorts 8, 9, and 11). Cohort 6 will enroll CHB subjects (after Cohort 5b 


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has completed enrollment) to receive three doses two weeks apart. Cohorts 7, 10 and 11 will enroll CHB patients 
sequentially (after Cohort 6 has completed enrollment) to receive three doses a week apart at increasing dose 
levels starting with a dose equal to Cohort 6. Cohorts 5b through 7 and Cohorts 10 and 11 will enroll sequentially 
(after being opened at the final planned DSC meeting) with enrollment and dosing in a later cohort not initiating 
until all subjects in the earlier cohort have received at least their first scheduled dose. Cohort 8 will enroll HBeAg 
positive treatment naïve CHB patients to receive three monthly doses of ARO-HBV. Cohort 9 will enroll HBeAg 
positive entecavir or tenofovir experienced CHB patients to receive three monthly doses of ARO-HBV.  CHB 
patient screening for all CHB cohorts may start when Cohort 1 opens for enrollment. However, no CHB patients 
may be dosed until their respective cohort is approved for dosing by the DSC (not including Cohorts 1b,1c and 
12). CHB dosing may begin and NHV dose escalation may occur based on DSC approval which can occur by 
vote after cumulative data through Day 8 from the current NHV cohort is available. (See Figure 1 for dose 
escalation schedule).  
CHB patients on current NUC therapy (entecavir or tenofovir) will stay on NUC therapy for the study duration. 
CHB patients not on NUC therapy (NUC naïve) will be started on either entecavir or tenofovir (selection 
between entecavir and tenofovir based on site Principal Investigator (PI) discretion) on Day 1.  Either tenofovir 
disoproxil fumarate (including generic) or tenofovir alafenamide are acceptable. During the extended follow up 
period after Day 113, NUCs may be discontinued at investigator discretion if subject becomes HBsAg 
undetectable (< 0.05 IU/mL). 
 
Added: 
Cohort 12 will enroll 12 CHB patients in an open label fashion to receive 200 mg ARO-HBV on Days 1, 29 
and 57 as well as JNJ-6379 250 mg oral once daily starting on Day 1 and continuing through Day 84. Like 
all other cohorts, patients enrolling in Cohort 12 will either enter the study on NUCs or start NUCs on Day 1. 
Enrollment in Cohort 12 can begin once enrollment is full in Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11. The 
ARO-HBV dose level for Cohort 12 is 200 mg Q28 days (Days 1, 29, 57). Cohort 12 is open for enrollment in 
Hong Kong only. 
 
From: 
In Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, eligible CHB patients who have signed an HDEC (or 
local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose intervals 
ranging from once every week to once every 4 weeks in an open label fashion. Screening for the CHB cohorts 
can begin once Cohort 1 dosing has commenced. These cohorts (not including Cohorts 1b and 1c) will be 
opened for accrual once the corresponding NHV cohort receiving the same dose level has reached Day 8, based 
on agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8, 9, 10 and 11 can be opened for enrollment 
any time after Cohort 5 has reached Day 8 (and DSC has approved opening of such cohorts) and there is 
sufficient viral antigen response data from CHB patients to determine a dose level for these cohorts. Dose levels 
for Cohorts 6 through 11 is between 100 and 300 mg.   Cohorts 2b through Cohort 7 and Cohorts 10 and 11 will 
be enrolled in sequence (as shown in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other CHB 


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cohorts after the DSC has voted post Cohort 5 to open the remaining CHB patient cohorts and once a specified 
dose (≤ 400 mg) has been identified. Cohorts 1b and 1c are open for enrollment with the addition of this 
protocol amendment and may enroll in parallel. 
 
To: 
In Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12, eligible CHB patients who have signed an HDEC (or 
local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose intervals 
ranging from once every week to once every 4 weeks in an open label fashion. Screening for the CHB cohorts 
can begin once Cohort 1 dosing has commenced. These cohorts (not including Cohorts 1b and 1c) will be 
opened for accrual once the corresponding NHV cohort receiving the same dose level has reached Day 8, based 
on agreement of the DSC that it is safe to proceed. Cohorts 6, 7, 8, 9, 10 and 11 can be opened for enrollment 
any time after Cohort 5 has reached Day 8 (and DSC has approved opening of such cohorts) and there is 
sufficient viral antigen response data from CHB patients to determine a dose level for these cohorts. Dose levels 
for Cohorts 6 through 11 is between 100 and 300 mg.   Cohorts 2b through Cohort 7 and Cohorts 10 and 11 will 
be enrolled in sequence (as shown in Figure 1). Cohorts 8 and 9 may be enrolled in parallel with other CHB 
cohorts after the DSC has voted post Cohort 5 to open the remaining CHB patient cohorts and once a specified 
dose (≤ 400 mg) has been identified. Cohorts 1b,1c and Cohort 12 are open for enrollment with the addition of 
applicable protocol amendments and may enroll in parallel. 
 
From: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule of 
Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. Subjects consenting to 
additional follow up will continue on NUCs. Subjects not consenting to additional follow up will be followed per 
protocol based on Schedule of Assessment Tables 1.2, 1.3 and 1.4.  
 
To: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up Schedule of 
Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. Subjects consenting to 
additional follow up will continue on NUCs and may have NUCs discontinued at the investigator’s discretion 
if patients become HBsAg undetectable (< 0.05 IU/mL). Subjects not consenting to additional follow up will 
be followed per protocol based on Schedule of Assessment Tables 1.2, 1.3 and 1.4. 
 
 


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From: 
                     Figure 1. Dose Escalation Schedule 
Healthy Volunteers (double blind)* 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose 
Regimen 
Cohort 1 
 
35 mg 
 
Cohort 1b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
25 mg dosed 
on Day 1, 29, 
57 
 
 
 
Cohort 1c (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
50 mg dosed 
on Day 1, 29, 
57 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 29, 
57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
200 mg dosed 
on Day 1, 29, 
57 
Cohort 4 
300 mg 
 
Cohort 4b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
300 mg dosed 
on Day 1, 29, 
57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
400 mg dosed 
on Day 1, 29, 
57 
 
 
  
 
Cohort 6 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 15, 
29 
 
 
 
Cohort 7 (all eligible 
CHB patients regardless 
of NUC or HBeAg status) 
100 mg dosed 
on Day 1, 8, 
15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
300 mg dosed 
on Day 1, 29, 
57  
 
 
 
Cohort 9 HBeAg+, 
entecavir or tenofovir 
experienced  
300 mg dosed 
on Day 1, 29, 
57  
 
 
 
Cohort 10 (all eligible 
CHB patients regardless 
of NUC or HBeAg status)  
200 mg dosed 
on Day 1, 8, 
15 
 
 
 
Cohort 11 (all eligible 
CHB patients regardless 
of NUC or HBeAg status)  
 
300 mg dosed 
on Day 1, 8, 
15  
*All cohorts will start with two sentinel subjects  
 


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To: 
Figure 1. Dose Escalation Schedule 
Healthy Volunteers (double blind)* 
CHB Patients (open label) 
Cohort 
 Dose 
(Day 1) 
Day 8 safety 
evaluation 
Cohort 
Dose Regimen 
Cohort 1 
 
35 mg 
 
Cohort 1b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 25 mg dosed 
on Day 1, 29, 57 
 
 
 
Cohort 1c (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 50 mg dosed 
on Day 1, 29, 57 
Cohort 2 
 
100 mg 
 
Cohort 2b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 100 mg 
dosed on Day 1, 29, 57 
Cohort 3 
 
200 mg  
 
Cohort 3b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 200 mg 
dosed on Day 1, 29, 57 
Cohort 4 
300 mg 
 
Cohort 4b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 300 mg 
dosed on Day 1, 29, 57 
Cohort 5 
 
400 mg  
 
Cohort 5b (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 400 mg 
dosed on Day 1, 29, 57 
 
 
  
 
Cohort 6 (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 100 mg 
dosed on Day 1, 15, 29 
 
 
 
Cohort 7 (all eligible CHB 
patients regardless of NUC 
or HBeAg status) 
ARO-HBV 100 mg 
dosed on Day 1, 8, 15 
 
 
 
Cohort 8 HBeAg+, 
treatment naïve  
ARO-HBV 300 mg 
dosed on Day 1, 29, 57  
 
 
 
Cohort 9 HBeAg+, entecavir 
or tenofovir experienced  
ARO-HBV 300 mg 
dosed on Day 1, 29, 57  
 
 
 
Cohort 10 (all eligible CHB 
patients regardless of NUC 
or HBeAg status)  
ARO-HBV 200 mg 
dosed on Day 1, 8, 15 
 
 
 
Cohort 11 (all eligible CHB 
patients regardless of NUC 
or HBeAg status)  
 
ARO-HBV 300 mg 
dosed on Day 1, 8, 15  
 
 
 
Cohort 12 (all eligible CHB 
patients regardless of NUC 
or HBeAg status)  
JNJ-6379 250mg QD + 
ARO-HBV 200 mg 
dosed on Day 1, 29, 57 
*All NHV cohorts will start with two sentinel subjects 
 
 
 
 


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24. Section/page: 6.2 Rationale for Study Design, p. 45 
Added: 
Cohort 12 uses a combination of NUCs + ARO-HBV + JNJ-6379. Throughout the study all patients have 
been treated with the combination of NUCs + ARO-HBV. It is thought that by using an siRNA approach to 
silence production of viral antigen in combination with NUCs to inhibit viral replication and JNJ-6379 
which inhibits capsid assembly and cccDNA formation the response to treatment and potentially the rate of 
functional cure could be enhanced. ARO-HBV + NUCs has been well tolerated throughout the 
AROHBV1001 study. JNJ-6379 in combination with NUCs has also been well tolerated in CHB clinical 
studies. In vitro, JNJ-6379 does not inhibit phosphorylation of tenofovir or entecavir. It is not expected that 
JNJ-6379 and ARO-HBV will have overlapping or additive toxicity. As such, the benefit of this combination 
“triple” therapy is expected to outweigh risk of toxicity. 
 
25. Section/page: 6.3 Criteria for Dose-escalation and Stopping Rules, p. 46 
From: 
A decision to stop the trial early or discontinue drug in an individual subject or group of subjects may be indicated 
based on any of the following:  
1. A single Serious Adverse Event(SAE) (defined in Section 9.1) considered at least possibly related to 
ARO-HBV  
2. One of the following abnormal results at least possibly related to ARO-HBV: 
o 
In NHVs, treatment emergent ALT or AST > 3X ULN which must be confirmed by repeat 
blood draw within 48 hours of initial results. 
o 
In CHB patients, treatment emergent ALT or AST > 3X Day 1 pre-dose baseline confirmed by 
repeat blood draw within 48 hours of initial results AND ALT > 10X ULN AND any one of 
the following: 
 
Total Bilirubin newly elevated to 2X ULN AND 2X Day-1 pre-dose baseline 
(confirmed on repeat lab draw within 48 hours) or 
 
Decrease in serum albumin of 0.5 g/dL or greater (confirmed on repeat lab draw within 
48 hours) 
o 
Treatment emergent platelet count < 70,000 per microliter in NHVs or < 50,000 in CHB 
patients, confirmed on repeat measure within 48 hours of initial results 
o 
Treatment emergent serum creatinine > 180 μmol/L confirmed by repeat blood draw within 48 
hours of initial results 


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To: 
A decision to stop the trial early or discontinue drug in an individual subject or group of subjects may (following 
a case-by-case decision based on consultation between the sponsor, DSC and the PI) be indicated based on any 
of the following:  
1. A single Serious Adverse Event(SAE) (defined in Section 9.1) considered at least possibly related to 
ARO-HBV and/or JNJ-6379 
2. One of the following abnormal results at least possibly related to ARO-HBV and/or JNJ-6379: 
o 
In NHVs, treatment emergent ALT or AST > 3X ULN which must be confirmed by repeat 
blood draw within 48 hours of initial results. 
o 
In CHB patients, treatment emergent ALT or AST > 3X Day 1 pre-dose baseline confirmed by 
repeat blood draw within 48 hours of initial results AND ALT > 10X ULN AND any one of 
the following: 
 
Total Bilirubin newly elevated to 2X ULN AND 2X Day-1 pre-dose baseline 
(confirmed on repeat lab draw within 48 hours) or 
 
Decrease in serum albumin of 0.5 g/dL or greater (confirmed on repeat lab draw within 
48 hours) 
o 
Treatment emergent platelet count < 70,000 per microliter in NHVs or < 50,000 in CHB 
patients, confirmed on repeat measure within 48 hours of initial results 
o 
Treatment emergent serum creatinine > 180 μmol/L confirmed by repeat blood draw within 48 
hours of initial results 
26. Section/page:  7.1 Number of Subjects, p. 48 
From: 
A total of approximately 30 NHV and a minimum of 48 or a maximum of 72  CHB participants (not including 
potential replacements) may be enrolled in the study. 
 
To: 
A total of approximately 30 NHV and a minimum of 50 or a maximum of 84 CHB participants (not including 
potential replacements) may be enrolled in the study.   
 
27. Section/page:  7.2 Inclusion Criteria for CHB Patient Cohorts, pp. 49-50 
From: 
5. Participants using two effective methods of contraception (double barrier contraception or hormonal 
contraception along with a barrier contraceptive, both male and female partners) during the study and for 3 
months following the dose of ARO-HBV.  Males must not donate sperm for at least 3 months after the last 
study treatment. Male partners of female subjects and female partners of male subjects must also use 


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contraception, if they are of childbearing potential. Females of childbearing potential must have a negative 
urine pregnancy test at Screening and on Day 1, pre-dose. Females not of childbearing potential must be 
post-menopausal (defined as cessation of regular menstrual periods for at least 12 months), confirmed by 
follicle-stimulating hormone (FSH) level in the post-menopausal range.  
a. 
Using twice the normal protection of birth control by using a condom AND one other form of 
the following (abstinence is acceptable at PI’s discretion): 
• 
Birth control pills (The Pill) 
• 
Depot or injectable birth control 
• 
IUD (Intrauterine Device) 
• 
Birth Control Patch (e.g., Ortho Evra) 
• 
NuvaRing® 
• 
Surgical sterilization, i.e., tubal ligation or hysterectomy for women or vasectomy for men 
or other forms of surgical sterilization 
To: 
5. Participants using two effective methods of contraception (double barrier contraception or hormonal 
contraception along with a barrier contraceptive, both male and female partners) during the study and for 3 
months following the dose of ARO-HBV.  Males must not donate sperm for at least 3 months after the last 
study treatment. Male partners of female patients and female partners of male patients must also use 
contraception, if they are of childbearing potential. Females of childbearing potential must have a negative 
urine pregnancy test at Screening and on Day 1, predose. Females not of childbearing potential must be 
post-menopausal (defined as cessation of regular menstrual periods for at least 12 months), confirmed by 
follicle-stimulating hormone (FSH) level in the post-menopausal range.  
• 
Using twice the normal protection of birth control by using a condom AND one other form of 
the following (abstinence is acceptable at PI’s discretion): 
• 
Birth control pills (The Pill) 
o 
Cohort 12 Only: Female subjects of childbearing potential who are on a stable 
treatment regimen with hormonal contraceptives (i.e., same dose and not starting 
or stopping hormonal contraceptive use) for ≥3 months prior to screening should 
continue the same dose regimen until 12 weeks after EOT. Ethinylestradiol-
containing contraceptives are only allowed if the ethinylestradiol content is ≤20 
µg. For female subjects of childbearing potential who will start a hormonal 
contraceptive 
treatment 
during 
the 
study, 
ethinylestradiol-containing 
contraceptives are not allowed. 
• 
Depot or injectable birth control 
• 
IUD (Intrauterine Device) 
• 
Birth Control Patch (e.g., Ortho Evra) 
• 
NuvaRing® 
• 
Surgical sterilization. i.e, tubal ligation or hysterectomy for women or vasectomy for ment 
or other forms of surgical sterilization 
From: 
12.  Patients with liver Elastography (i.e. FibroScan®) score ≤ 10.5 at or within 3 months of Screening 
To: 
12.  Patients with liver Elastography (i.e. FibroScan®) score ≤ 10.5 at or within 3 months of Screening (for 
Cohort 12 patients must have FibroScan < 9.0 kPa) 
 
Added: 
13.  No prior use of capsid assembly modulators 


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28. Section/page:  7.5 Restrictions and Concomitant Medications, Concomitant Medications CHB 
Patients, pp. 55-56 
Added: 
Based on results from drug-drug interaction study 56136379HPB1004 investigating the potential effect of 
co-administration of JNJ-6379 with oral contraceptives, it is not anticipated that the efficacy of oral 
contraceptives will be impacted during co-administration with JNJ-6379 since the exposure of a progestin 
sensitive to CYP3A4 induction was not significantly affected by co-administration of JNJ-56136379. In 
contrast, it is anticipated that co-administration with ethinyl-estradiol-containing contraceptives will result in 
an increased exposure to ethinyl-estradiol. In the current study, female subjects of childbearing potential 
who are on a stable treatment regimen with hormonal contraceptives (ie, same dose and not starting or 
stopping hormonal contraceptive use) for ≥3 months prior to screening, should continue the same dose 
regimen until 12 weeks after EOT. Ethinyl-estradiol-containing contraceptives are only allowed if the 
ethinyl-estradiol content is ≤20 µg. For female subjects of childbearing potential who will start a hormonal 
contraceptive treatment during the study, ethinyl-estradiol-containing contraceptives are not allowed, given 
the observed increase in ethinyl-estradiol in study 56136379HPB1004. Co-administration of JNJ-6379 170 
mg qd with oral midazolam as a CYP3A4 probe showed a reduction of 41.7% in Cmax and 53.9% in AUC 
(study 56136379HPB1004), implying that JNJ-6379 may induce the metabolism of CYP3A4 sensitive 
substrates. Questions regarding use of ARO-HBV or JNJ-6379 concomitantly with other medications should 
be discussed with Sponsor medical monitor. 
 
29. Section/page:  8 Investigational Product, p. 56 
Added: 
Arrowhead Pharmaceuticals, Inc. is responsible for the supply to the clinical site of active drug supplies 
together with detailed instructions (in a pharmacy manual) describing preparation and administration of 
ARO-HBV and of JNJ-6379.  The PBO (normal saline 0.9%) will be supplied by the clinical site. 
 
30. Section/page:  8.1 ARO-HBV Description, Identification and Dosage, p. 56 
From: 
Arrowhead Pharmaceuticals, Inc. is responsible for the supply of active drug supplies together with detailed 
instructions (in a pharmacy manual) describing preparation and administration of ARO-HBV.  The PBO (normal 
saline 0.9%) will be supplied by the clinical site. 
Accordingly, ARO-HBV will be supplied as single sterile 2-mL vials containing ARO-HBV, with the correct 
dose of ARO-HBV prepared by the Pharmacy prior to dosing participants. 
The placebo (PBO) will be 0.9% normal saline administered subcutaneously.  
To: 
ARO-HBV will be supplied as single sterile 2-mL vials containing ARO-HBV, with the correct dose of ARO-
HBV prepared by the Pharmacy prior to dosing participants. 
The placebo (PBO) will be 0.9% normal saline administered subcutaneously.  
 
 


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31. Section/page:  8.3 JNJ-6379 Physical Description of Study Drug(s), p. 57 
Added: 
8.3   JNJ-6379 Physical Description of Study Drug(s) 
JNJ-56136379 supplied for this study is formulated as oral tablets containing 25 mg and 100 mg JNJ-
56136379-AAA. Refer to the IB for a list of excipients. 
32. Section/page:  8.4 Packaging and Storage, p. 57-58 
Added: 
8.4   Packaging and Storage 
JNJ-56136379 will be packaged in bottles. All study drugs will be dispensed in child-resistant packaging. No 
study drugs can be repacked without prior approval from the sponsor. 
JNJ-56136379 must be stored on site in the original package at controlled temperatures ranging from 15°C to 
30°C. The NUCs ETV (Baraclude®) and TDF (Viread®) must be stored on site in the original package at 
controlled temperatures ranging from 15°C to 25°C. Refer to the pharmacy manual/study site investigational 
product and procedures manual for additional guidance on study drug preparation, handling, and storage. 
33. Section/page:  8.5 Study Drug Handling, p. 58 
From: 
ARO-HBV will be supplied by Arrowhead Pharmaceuticals, Inc. and labeled with the drug name, batch 
number, expiration date (as applicable) and storage conditions. Individual doses will be dispensed by clinical 
trial site staff members at the time of dosing and recorded in the drug accountability records. A Pharmacy 
Manual will be prepared to define the procedures for dispensing. 
 
To: 
ARO-HBV and JNJ-6379 will be supplied by Arrowhead Pharmaceuticals, Inc. and labeled with the drug 
name, batch number, expiration date (as applicable) and storage conditions. Individual doses will be dispensed 
by clinical trial site staff members at the time of dosing and recorded in the drug accountability records. A 
Pharmacy Manual will be prepared to define the procedures for dispensing. 
34. Section/page:  8.6 Accountability of Study Supplies, pp. 59-60 
From: 
Used vials of ARO-HBV will be retained sequestered per participant and cohort and made available to the non-
blinded CRA during study drug and placebo reconciliation, where allowable by local policy. 
 
To: 
Used vials of ARO-HBV will be retained sequestered per participant and cohort and made available to the non-
blinded CRA during study drug and placebo reconciliation, where allowable by local policy. Used bottles of JNJ-
6379 will be retained sequestered per participant and made available to the CRA for study drug reconciliation. 


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From: 
A Drug Dispensing Log must be kept current and will contain the following information: 
• the identification of the participant to whom the drug was dispensed; and 
• the date(s) and quantity of the drug dispensed to the participant. 
The date and time of dose preparation and release will be maintained to support administration of study drug/PBO. 
The authorized pharmacist or qualified staff will be un-blinded to the doses. The pharmacy will dispense the study 
medication and the study center will administer the study medication only to participants included in this study 
following the procedures set out in the study protocol. Each participant will be given only the study medication 
carrying his/her study number.  Study drug administration will be documented on the CRFs and/or other study 
drug record. The inventory must be available for inspection by the non-blinded monitor during the study. Drug 
supplies, excluding partially used or empty containers, will either be collected at the end of the study by the study 
monitor or returned by the PI or designee to Arrowhead Pharmaceuticals Inc. or its designee. When requested in 
writing by the Sponsor, following drug accountability and reconciliation, unused drug supplies may be destroyed 
by the PI or designee provided such disposition does not expose humans to risks from the drug and is permitted 
per the site’s Standard Operating Procedures. Records shall be maintained by the PI of any such alternate 
disposition of the test drug. These records must show the identification and quantity of each unit disposed of, the 
method of destruction (considering the requirements of local law), and the person who disposed of the test 
substance. Such records must be submitted to the Sponsor. 
 
To: 
A Drug Dispensing Log must be kept current and will contain the following information: 
• the identification of the participant to whom the drug was dispensed; and 
• the date(s) and quantity of the drug dispensed to the participant. 
The date and time of ARO-HBV/placebo dose preparation and release will be maintained to support 
administration of study drug/PBO. The authorized pharmacist or qualified staff will be un-blinded to the doses. 
The pharmacy will dispense ARO-HBV/placebo and the study center will administer ARO-HBV only to 
participants included in this study following the procedures set out in the study protocol.  The pharmacy will 
dispense JNJ-6379 to the site staff who will provide it to the patients who will take their daily dose of 250 mg 
(oral) at home.  Patients will record taking their daily dose of JNJ-6379 on a diary provided to the clinical site.  
Patients will bring their used bottles of JNJ-6379 and diaries with them to each subsequent visit so that the 
study staff may count the remaining tablets, compare the count to the patient’s recorded diary and ascertain 
the level of patient compliance with study treatment.  Patients will be provided with additional JNJ-6379 at 
each visit to cover the period of time until their next clinic visit.  The pharmacy/clinical site will dispense JNJ-
6379 only to participants included in this study following the procedures set out in the study protocol. 
Each participant will be given only the study medication carrying his/her study number.  Study drug 
administration will be documented on the CRFs and/or other study drug record.  


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
The study drug inventory must be available for inspection by the non-blinded monitor during the study. Drug 
supplies, excluding partially used or empty containers, will either be collected at the end of the study by the 
study monitor or returned by the PI or designee to Arrowhead Pharmaceuticals Inc. or its designee. When 
requested in writing by the Sponsor, following drug accountability and reconciliation, unused drug supplies may 
be destroyed by the PI or designee provided such disposition does not expose humans to risks from the drug and 
is permitted per the site’s Standard Operating Procedures. Records shall be maintained by the PI of any such 
alternate disposition of the test drug. These records must show the identification and quantity of each unit 
disposed of, the method of destruction (considering the requirements of local law), and the person who disposed 
of the test substance. Such records must be submitted to the Sponsor. 
35. Section/page:  8.7 Retention of Investigational Product Vials, p. 60 
From: 
For this study, used and partially used drug vials will be retained for an adequate period to allow accountability 
by the non-blinded CRA. No additional study drug samples will be retained. 
 
To: 
For this study, used and partially used drug vials and bottles will be retained for an adequate period to allow 
accountability by the non-blinded CRA. No additional study drug samples will be retained. 
36. Section/page:  8.8 Allocation to Treatment, p. 60 
 Added: 
Only patients enrolled into Cohort 12 will received JNJ-6379. 
37. Section/page:  8.9 Blinding and Code Break, p. 60 
From: 
Blinding of study drug/PBO assignment is critical to the integrity of this clinical trial. 
 
To: 
Blinding of study drug (ARO-HBV)/PBO assignment is critical to the integrity of this clinical trial. 
38. Section/page:  9.1 Overview of Procedures, pp. 62-63 
From: 
For CHB patients in Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10 and 11, eligible CHB patients who have signed 
an HDEC (or local equivalent) approved informed consent form will receive three doses of ARO-HBV at dose 
intervals ranging from once every week to once every 4 weeks in an open label fashion.   
 
To: 
For CHB patients in Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12, eligible CHB patients who have 
signed an HDEC (or local equivalent) approved informed consent form will receive three doses of ARO-HBV 
at dose intervals ranging from once every week to once every 4 weeks in an open label fashion. 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
Added: 
Cohort 12 will enroll 12 CHB patients in an open label fashion to receive 200 mg ARO-HBV on Days 1, 29 
and 57 as well as JNJ-6379 250 mg oral once daily starting on Day 1 and continuing through Day 84. Like all 
other cohorts, patients enrolling in Cohort 12 will either enter the study on NUCs or start NUCs on Day 1.   
Enrollment in Cohort 12 can begin once enrollment is full in Cohorts 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11.  
 
39. Section/page:  9.3.6 Clinical Laboratory Tests & Pharmacodynamic Values, p. 65 
From: 
Biochemistry: Sodium, potassium, chloride, bicarbonate, glucose, urea, creatinine (including calculated 
creatinine clearance), creatine kinase, uric acid, phosphate, total calcium, anion gap, cholesterol, albumin, 
globulins, protein, total bilirubin, conjugated bilirubin, gamma glutamyltransferase (GGT), alkaline phosphatase 
(ALP), alanine aminotransferase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LD), 
triglycerides, C-reactive protein and Troponin l. 
 
To: 
Biochemistry: Sodium, potassium, chloride, bicarbonate, glucose, urea, creatinine (including calculated 
creatinine clearance), creatine kinase, uric acid, phosphate, total calcium, anion gap, cholesterol, albumin, 
globulins, protein, total bilirubin, conjugated bilirubin, gamma glutamyltransferase (GGT), alkaline phosphatase 
(ALP), alanine aminotransferase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LD), 
triglycerides, amylase, lipase, C-reactive protein and Troponin l. 
 
 
40. Section/page:  9.3.7 Pharmacokinetics, pp. 66-67 
From: 
Samples for analysis of circulating AD04872 and AD05070 will be obtained at time points following the end of 
infusion outlined in the Schedule of Assessments. 
To: 
Samples for analysis of circulating AD04872 and AD05070 will be obtained at time points following the end of 
injection outlined in the Schedule of Assessments. 
Plasma concentrations of ARO-HBV, NUC and JNJ-6379 will be measured at a single post-dose time point in 
Cohort 12 only. 
 
41. Section/page:  9-4 Allocation of Formulations, p. 67 
From: 
Four NHV participants will receive active treatment and 2 participants will receive PBO in each dose level.  
Treatments will be administered per the randomized sequence kept by the pharmacy or in a secure place at the 
clinical site, under control of the un-blinded staff member.  All CHB patients will receive active treatment. 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
To: 
Four NHV participants will receive active treatment and 2 participants will receive PBO in each dose level.  
Treatments will be administered per the randomized sequence kept by the pharmacy or in a secure place at the 
clinical site, under control of the un-blinded staff member.  All CHB patients will receive active treatment.  
CHB patients in Cohort 12 will receive daily oral JNJ-6379 + ARO-HBV. 
 
42. Section/page:  9.5 Study Formulation Administration, p. 68 
From: 
Appropriately trained employees of the clinical site will administer the study treatment. 
 
To: 
Appropriately trained employees of the clinical site will administer ARO-HBV/PBO. 
 
From: 
Table 2.  Injection number and volume per cohort 
Cohort 
Dose 
Concentration 
Total Injection Volume 
# Injections per planned dose 
1 
35 mg 
200 mg/mL 
0.175 mL 
Single 
1b 
25 mg 
200 mg/mL 
0.125 mL 
Single 
1c 
50 mg 
200 mg/mL 
0.25 mL 
Single 
2, 2b, 6, 7 
100 mg 
200 mg/mL 
0.5 mL 
Single 
3, 3b, 10 
200 mg 
200 mg/mL 
1.0 mL 
Single 
4, 4b, 8, 9, 11 
300 mg 
200 mg/mL 
1.5 mL 
Single 
5, 5b 
400 mg 
200 mg/mL 
2.0 mL 
Two (at separate sites) 
 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
To: 
Table 2: Injection number and volume per cohort 
Cohort 
Dose 
Concentration 
Total Injection Volume 
# Injections per planned dose 
1 
35 mg 
200 mg/mL 
0.175 mL 
Single 
1b 
25 mg 
200 mg/mL 
0.125 mL 
Single 
1c 
50 mg 
200 mg/mL 
0.25 mL 
Single 
2, 2b, 6, 7 
100 mg 
200 mg/mL 
0.5 mL 
Single 
3, 3b, 10, 12 
200 mg 
200 mg/mL 
1.0 mL 
Single 
4, 4b, 8, 9, 11 
300 mg 
200 mg/mL 
1.5 mL 
Single 
5, 5b 
400 mg 
200 mg/mL 
2.0 mL 
Two (at separate sites) 
 
Added: 
JNJ-6379 will be dispensed to patients in Cohort 12 only who will take their daily dose (250 mg oral) at 
home.  Patients will bring all remaining tablets to their subsequent visits for compliance assessment, and 
receive additional tablets to cover their daily doses until the next subsequent visit. 
 
43. Section/page:  9.7 Safety Endpoints, p. 69 
From: 
The safety of ARO-HBV will be evaluated by collection of the following measurements performed at specified 
time points: 
 
To: 
The safety of ARO-HBV (alone or in combination with JNJ-6379) will be evaluated by collection of the 
following measurements performed at specified time points: 
 
 
 
 
 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
44. Section/page:  11.4 Safety/Tolerability Data,  p. 79 
From: 
The whole blood collected for analysis following a single dose of ARO-HBV at different dose levels will 
undergo analysis for cytokines and complement changes. Results, percent change, and duration of response 
from baseline to 24 hours (or 48 hours, as necessary) will be analyzed where indicated by initial testing at pre-
dose and at 2-hours post-administration. If cytokine or complement levels are elevated from pre-dose to 2-hours 
post-dose then all other specified timepoints (See Schedule of Assessments) will also be analyzed. Results for 
cytokines and complement will be summarized by dose cohort and treatment group. 
 
To: 
The whole blood collected for analysis following a single dose of ARO-HBV at different dose levels will 
undergo analysis for cytokines (Panel A) and complement changes. Results, percent change, and duration of 
response from baseline to 24 hours (or 48 hours, as necessary) will be analyzed where indicated by initial 
testing at pre-dose and at 2-hours post-administration. If cytokine or complement levels are elevated from pre-
dose to 2-hours post-dose then all other specified timepoints (See Schedule of Assessments) will also be 
analyzed. Whole blood collected following multiple doses of ARO-HBV for cytokine Panel B samples will 
only be analyzed at discretion of and with notification by Sponsor. Results, percent change, and duration of 
response from baseline will be analyzed where indicated. Results for cytokines and complement will be 
summarized by dose cohort and treatment group. 
45. Section/page:  11.5 Pharmacokinetic Data,  p. 79 
Added: 
Plasma concentrations of ARO-HBV, NUC and JNJ-6379 will be measured at a single 2 hour post-dose time 
point in Cohort 12 only. 
 
From: 
Pharmacokinetic parameters will be tabulated and summarized by dose level. The concentration-time 
profiles for each participant and the mean concentration-time profiles by dose level will be plotted with 
concentration presented on both linear and logarithmic scales. 
To: 
Pharmacokinetic parameters will be tabulated and summarized by dose level where applicable. The 
concentration-time profiles for each participant and the mean concentration-time profiles by dose level will be 
plotted with concentration presented on both linear and logarithmic scales. Cohort 12 CHB patient limited PK 
data will be evaluated separately from NHV PK data. 
46. Section/page:  14.1 Ownership,  pp. 88-89 


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Protocol No.: AROHBV1001 
Version 5.0, 04 Jan 2019                                                                  Protocol Amendment Summary of Changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
47. Section/page:  14.3 Publication,  p. 89 
 
 
 
 
 
 
 
 
 
 
 


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Protocol No.: AROHBV1001 
Version 6.0, 28 Feb 2020                                                                  Protocol Amendment Summary of Changes 
 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
PROTOCOL 
NUMBER: 
AROHBV1001 
STUDY TITLE: 
A Phase 1/2a Single Dose-Escalating Study to Evaluate the Safety, 
Tolerability and Pharmacokinetic Effects of ARO-HBV in Normal 
Adult Volunteers and Multiple Escalating Doses Evaluating Safety, 
Tolerability and Pharmacodynamic Effects in HBV Patients 
VERSION/DATE: 
Version 6.0, 28 February 2020  
 
 
OVERVIEW/RATIONALE:   
This amendment which is specific to Hong Kong only: 
 
1. Reduces the protocol required follow-up period to Day 337 (±5 days) for the open-label CHB 
Cohort 12 patients only. All previously enrolled CHB cohorts will continue with follow-up visits 
until Day 393 (±5 days).  
 
2. Corrects any administrative, grammatical, formatting errors and inconsistencies; rewording for 
clarity 
 
SUMMARY OF CHANGES: 
1. Section/page:  Title Page, page 1 
  
From: 
225 South Lake Ave., Suite 1050, 
Pasadena, CA 91101 
 
To:  
177 E. Colorado Blvd., Suite 700 
Pasadena, CA 91105 
2. Section/page:  Title Page, page 1 
  
From: 
This amendment, specific to Hong Kong only, adds a single open-label CHB cohort (Cohort 12) with 
12 subjects each receiving ARO-HBV at 200 mg every 28 days starting on Day 1, and the 
investigational capsid assembly modulator (CAM), JNJ-56136379 at 250 mg QD starting on Day 1 
through Day 84. All subjects will continue on, or be started on entecavir or tenofovir (NUC) for the 
duration of the study. 
 
To:  
This amendment, specific to Hong Kong only, reduces the protocol required follow-up period to Day 
337 (±5 days) for the open-label CHB Cohort 12 patients only. All previously enrolled CHB cohorts 
will continue with follow-up visits until Day 393 (±5 days). 
  


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Protocol No.: AROHBV1001 
Version 6.0, 28 Feb 2020                                                                  Protocol Amendment Summary of Changes 
 
3. Section/page:  1 Protocol Synopsis, Study Duration, p. 4 
                         6.4 Duration of the Study, p. 47 
From: 
For each CHB patient in the multi-dose Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12 the 
duration of the study clinic visits is approximately 25 weeks from screening to the Day 113 EOS 
examination. CHB patients consenting to additional follow up will be followed as per Additional 
Follow-Up Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after 
Day 113. Subjects consenting to additional follow up will continue on NUCs. Subjects not consenting 
to additional follow up will be followed per protocol based on Schedule of Assessment Tables 1.2, 
1.3 and 1.4. 
To: 
For each CHB patient in the multi-dose Cohorts 1b, 1c, 2b, 3b, 4b, 5b, 6, 7, 8, 9, 10, 11 and 12 the 
duration of the study clinic visits is approximately 25 weeks from screening to the Day 113 EOS 
examination. With the exception of Cohort 12 patients, all other CHB patients consenting to 
additional follow up will be followed as per Additional Follow-Up Schedule of Assessments (Table 
1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. Only Cohort 12 patients will 
require follow-up until the Day 337 (±5 days) visit. Subjects consenting to additional follow up will 
continue on NUCs. Subjects not consenting to additional follow up will be followed per protocol 
based on Schedule of Assessment Tables 1.2, 1.3 and 1.4. 
4. Section/page:  1 Protocol Synopsis, Study Design/Methods CHB patients, p. 6 
                         6.1 Study Design, CHB Patients, p. 43 
                         9.1 Study Methods and Schedules, Overview of Procedures, p. 63 
                         9.3.9 Follow-up Procedures, Additional CHB Follow-up, p. 67 
 
From: 
CHB patients consenting to additional follow up will be followed as per Additional Follow-Up 
Schedule of Assessments (Table 1.5), every 56 days (± 5 days) for 5 additional visits after Day 113. 
Subjects consenting to additional follow up will continue on NUCs. Subjects not consenting to 
additional follow up will be followed per protocol based on Schedule of Assessment Tables 1.2, 1.3 
and 1.4. 
 
To: 
With the exception of Cohort 12 patients, all other CHB patients consenting to additional follow up 
will be followed as per Additional Follow-Up Schedule of Assessments (Table 1.5), every 56 days (± 
5 days) for 5 additional visits after Day 113. Only Cohort 12 patients will require follow-up until the 
Day 337 (±5 days) visit. Subjects consenting to additional follow up will continue on NUCs. Subjects 
not consenting to additional follow up will be followed per protocol based on Schedule of 
Assessment Tables 1.2, 1.3 and 1.4. 
 
5. Section/page:  1 Protocol Synopsis, Data Analysis, p. 10 
 
From: 
Two separate data analyses will be performed, one for all subjects through EOS (Day 29 for NHVs 
and Day 113 for CHB patients), and one additional and separate analysis for CHB patients who 
consent to the additional follow up through Day 393. Separate analyses including and excluding 
Cohort 12 may also be completed. 
 
To: 


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Protocol No.: AROHBV1001 
Version 6.0, 28 Feb 2020                                                                  Protocol Amendment Summary of Changes 
 
Two separate data analyses will be performed, one for all subjects throgh EOS (Day 29 for NHVs and 
Day 113 for CHB patients), and one additional and separate analysis for CHB patients who consent to 
the additional follow up through Day 337 (Cohort 12 only) or Day 393. Separate analyses including 
and excluding Cohort 12 may also be completed. 
 
6. Section/page:  1 Protocol Synopsis, Table 1.5 Additional Follow-Up Schedule of Assessments (All 
CHB Cohorts), p. 17 
 
Add: 
Footnote 2 to the Day 337 (±5 days) visit column: 
2. Only Cohort 12 patients will require follow-up until the Day 337 (±5 days) visit. 
 
7. Section/page:  1 Protocol Synopsis, Data Analysis, p. 10 
 
From: 
Two separate data analyses will be performed, one for all subjects through EOS (Day 29 for NHVs 
and Day 113 for CHB patients), and one additional and separate analysis for CHB patients who 
consent to the additional follow up through Day 393. Separate analyses including and excluding 
Cohort 12 may also be completed. 
 
To: 
Two separate data analyses will be performed, one for all subjects throgh EOS (Day 29 for NHVs and 
Day 113 for CHB patients), and one additional and separate analysis for CHB patients who consent to 
the additional follow up through Day 337 (Cohort 12 only) or Day 393. Separate analyses including 
and excluding Cohort 12 may also be completed. 
8. Section/page:  6.4 Duration of the Study, p. 48 
 
From: 
All CHB subjects who complete the study until Day 113 EOS examination are considered to complete 
the study and may continue to attend the Additional Follow-Up visits per the Schedule of 
Assessments (Table 1.5) if re-consent is obtained. If a subject withdraws from the Additional Follow-
Up visits before the Day 393 visit, he or she will still be considered as a completed subject and reason 
for not continuing with the Additional Follow-Up visits per protocol will be recorded. 
To: 
All CHB subjects who complete the study until Day 113 EOS examination are considered to complete 
the study and may continue to attend the Additional Follow-Up visits per the Schedule of 
Assessments (Table 1.5) if re-consent is obtained. If a subject withdraws from the Additional Follow-
Up visits before the Day 337 (Cohort 12 only) or 393 visit, he or she will still be considered as a 
completed subject and reason for not continuing with the Additional Follow-Up visits per protocol 
will be recorded.