A Phase 1/2a Single and Multiple Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Effects of ARO-HSD in Normal Healthy Volunteers as Well as in Patients With NASH or Suspected NASH
Phase: PHASE1
Conditions: Non-alcoholic Steatohepatitis
Sponsor: Arrowhead Pharmaceuticals



Arrowhead Pharmaceuticals, Inc.  
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Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
1. 
PROTOCOL SYNOPSIS 
 
Study Title:  A Phase 1/2a Single and Multiple Dose-Escalating Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamic Effects of ARO-HSD in Normal Healthy Volunteers as well as in Patients with 
NASH or Suspected NASH  
Study Number:  AROHSD1001 
Phase:  Phase 1/2a  
Number of Sites:  One or more sites in Australia, New Zealand, and Asia 
Study Treatments:   
There will be two study treatments; one active (Test Formulation) and one placebo (Reference Formulation).   
Test Formulation:   
The test formulation is active ARO-HSD Injection (also referred to as ARO-HSD).  The active pharmaceutical ingredient 
(API) contained in ARO-HSD is a synthetic, double-stranded, small interfering RNA (siRNA) duplex conjugated to an 
N-acetyl-galactosamine targeting ligand to facilitate hepatocyte delivery. 
Reference Formulation:   
The reference formulation is placebo (PBO): normal saline (0.9%) administered subcutaneously, volume matched to the 
corresponding ARO-HSD dose volume. 
Study Objective and Endpoints:   
• 
The objective of the study is to assess the safety and tolerability of ARO-HSD in normal healthy volunteers 
(NHVs) and patients with NASH or suspected NASH. 

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Protocol No.: AROHSD1001 
 
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Primary Endpoint:   
• 
The incidence and frequency of adverse events (AEs) possibly or probably related to treatment after single 
doses in healthy volunteers and after multiple doses in patients with NASH or suspected NASH 
Secondary Endpoints 
• 
Pharmacokinetics of ARO-HSD  
Exploratory Endpoints  
(All Cohorts) 
• 
Change in fasting LDL-C, Total Cholesterol, non-HDL-C, HDL-C, VLDL-C, and triglycerides compared to 
baseline 
 (Patient cohorts 1b, 3band 4b) 
• 
Change in ALT and in AST as a marker of ARO-HSD activity compared to baseline  
• 
Change in cytokeratin-18 compared to baseline 
• 
Change in IL-1β, IL-6, IL-10, INF-gamma, and TNF-α compared to baseline 
• 
Change in retinol and retinol binding protein compared to baseline 
• 
Change in liver fat using MRI-PDFF compared to baseline 
• 
Change in blood exosomal HSD17β13 mRNA levels (if feasible) compared to baseline 
• 
Change in blood exosomal PNPLA3 mRNA levels (if feasible) compared to baseline 
• 
Change in Enhanced Liver Fibrosis (ELF) Score at EOS compared to baseline 
• 
Change in Pro-C3 at EOS compared to baseline 
• 
Liver biopsy derived HSD17β13 mRNA expression compared to baseline  
• 
Liver biopsy derived HSD17β13 protein expression compared to baseline in response to multiple doses of 
ARO-HSD (if scientifically feasible) 
• 
Liver biopsy derived change in PNPLA3 mRNA expression compared to baseline 
• 
Liver biopsy derived change in PNPLA3 protein expression compared to baseline in response to multiple doses 
of ARO-HSD (if scientifically feasible) 
 

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Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
Study Population/Patient Number:  This study will be conducted in adult males and females, aged 18 through 65 
years (minimum of 19 years of age for NASH or suspected NASH patients) with BMI between 18.0 and 40.0 kg/m² 
enrolled and dosed as follows (see also Cohort Summary below): 
NHV Cohorts 1, 2, 3, and 4: Each double-blind cohort will enroll eight (8) subjects (4 active: 4 PBO) with all 
cohorts planned to receive single escalating doses of ARO-HSD or placebo at dose levels of 25 mg (Cohort 1), 
50 mg (Cohort 2), ≤ 100 mg (Cohort 3), and ≤ 200 mg (Cohort 4).  These dose levels represent the highest 
dose that may be used in the cohort but after Cohort 1, the Data Safety Committee (DSC) may adjust the dose 
lower if indicated. 
• 
Patient Cohorts 1b, 3band 4b: All patients will have suspected NASH and meet patient entry criteria.  Cohorts 
are open label with up to 6 patients per cohort.  All subjects will receive two doses of ARO-HSD at dose 
levels of 25 mg (Cohort 1b), ≤ 100 mg (Cohort 3b) and ≤ 200 mg (Cohort 4b).  These dose levels represent the 
highest dose that may be used in the cohort but after Cohort 1, the DSC may adjust the dose lower if indicated. 
 
*Any NASH/Suspected NASH patient already in Screening when a patient cohort has reached capacity 
(defined as up to six patients who have completed D1 in Cohort 3b and up to six patients who have completed 
D1 in Cohort 4b and up to six patients who have completed D1 in Cohort 1b), may participate in the study up 
to an additional two patients per cohort. 
 
Cohort Summary 
Cohort 
Population 
Blinding 
# Subjects 
Dosing Schedule 
1 
NHVs 
Double blind 
8 (4 active: 
4 placebo) 
25 mg Day 1 only 
1b 
Patients with suspected NASH 
(biopsies on screen and day 71) 
Open Label 
up to 6 
(all active) 
25 mg Days 1, 29 
2 
NHVs  
Double blind 
8 (4 active: 
4 placebo) 
50 mg Day 1 only 
3 
NHVs  
Double blind 
8 (4 active: 
4 placebo) 
≤ 100 mg Day 1 only 
4 
NHVs  
Double blind 
8 (4 active: 
4 placebo) 
≤ 200 mg Day 1 only 
3b 
Patients with suspected NASH 
(biopsies on screen and day 71) 
Open Label 
up to 6 
(all active) 
≤100 mg Days 1, 29 
4b 
Patients with suspected NASH 
(biopsies on screen and day 71) 
Open Label 
up to 6 
(all active) 
≤200 mg Days 1, 29 
Approximately 50 subjects may be enrolled in the study (not including replacements or optional expansion cohort).   
Number of Doses per Treatment:  Single dose (Cohorts 1, 2, 3, 4) or two doses (Cohorts 1b, 3b and 4b) dosed 28 days 
apart 
Study Duration:  For subjects in Cohorts 1 through 4, the duration of the study clinic visits is approximately 
158 days from screening to the End-of-Study visit.  For subjects in Cohorts 1b, 3b and 4b, the duration of the study 
clinic visits is approximately up to 173 days from screening to the End-of-Study visit.  Additionally, all subjects will 
have a 90-day post-end of study visit follow-up phone call assessing compliance with contraception.  
Study Confinement:  For all NHV cohorts (1-4), clinical facility confinement will be approximately 3 days for dose 
administration (Day -1 through 24-hour assessments) with discharge on Day 2.  Subjects will return to the clinical 
facility for outpatient visits per the Schedule of Assessments.  Patients in Cohorts 1b, 3b and 4b will be at the facility 
for approximately 4 hours (2 hours before dosing and 2 hours after dosing) on dosing days.  
 
 

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Study Design/Methods:   
Participants who have signed an EC/IRB-approved informed consent form and have met all the protocol eligibility criteria 
during screening may be enrolled into the study in a double-blind or open label fashion depending on the cohort.  Cohorts 
1 through 4 (NHVs) will begin with administration of ARO-HSD or PBO to two sentinel participants (one ARO-HSD, 
one PBO).  Following the Day 3 evaluation in these participants, if there are no significant safety concerns, the remaining 
participants in the cohort will be treated at the discretion of the Principal Investigator (PI).  Dosing of participants will be 
staggered by at least 30 minutes such that no two participants will be dosed simultaneously.  Sentinel dosing is not required 
in NASH/suspected NASH patient cohorts. 
Dose levels by cohort are outlined in the Cohort Summary above and Dose Escalation Schedule below.  NHV Cohorts 1 
through 4 will enroll sequentially with patient cohorts opening for enrollment in a step-wise manner.  Screening for all 
cohorts may begin once Cohort 1 has been opened for enrollment.  
Dose escalation will require approval by the DSC based on all cumulative available safety data for prior cohorts, and 
through at least Day 15 of the current cohort as shown in Figure 1.  Based on this cumulative safety data the DSC will 
vote to approve dose escalation to the next single dose NHV cohort as well as vote to open a NASH/suspected NASH 
patient cohort at the dose most recently tested in NHVs.  Escalation to the next dose level will proceed until the highest 
planned dose level is completed, or the trial is halted prematurely by the PI, DSC, or Sponsor due to safety or other 
reasons.  Where specified, dose levels represent the highest dose which may be used.  The DSC may adjust doses 
downward if indicated based on review of available safety data and pharmacodynamic data (if available).  All subjects 
who withdraw from the study prior to their End of Study (EOS) visit, for reasons other than an AE, may be replaced. 
Cohort 1b (25 mg on Days 1 and 29) will enroll sequentially after Cohorts 3b and 4b are enrolled and will not require 
DSC approval to initiate enrollment as the dose is lower than the 200 mg top dose used in cohorts 4 and 4b which have 
already been opened by the DSC.  
In double-blind cohorts, treatment un-blinding may occur, at the PI’s discretion, only where deemed necessary for 
treatment of an AE or for a decision to be made regarding trial continuation.  After all subjects in double-blinded 
cohorts have completed their EOS visit (not including the 90-day follow-up call), all blinded cohorts may be unblinded. 
Single and multiple doses of ARO-HSD will be evaluated in a sequential manner as shown in the Dose Escalation 
Schedule.   
 

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Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
Dose Escalation Schedule 
  
 
AE 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 a 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 AEs/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 

Arrowhead Pharmaceuticals, Inc.  
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Protocol No.: AROHSD1001 
 
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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 until the highest planned dose cohort is 
completed, unless the trial is stopped early by the DSC, PI or Sponsor.  A decision to stop the trial early or discontinue 
drug in an individual subject, group of subjects or to halt enrollment temporarily or permanently may be indicated 
based on any of the following:  
1. A serious adverse reaction (i.e., a serious AE [SAE] considered at least possibly related to the IMP 
administration) in ONE subject; or severe non-serious adverse reactions (i.e.  severe non-serious AEs 
considered as, at least, possibly related to the IMP administration) in TWO subjects in the same cohort, 
independent of whether or not the events occur within the same system-organ-class. 
 
2. One of the following abnormal results at least possibly related to ARO-HSD: 
• 
In NHV cohorts: 
o Treatment emergent AST and/or ALT > 8X ULN which must be confirmed by repeat blood draw within 
48 hours of initial results; OR 
o A treatment emergent AST or ALT >3X ULN (must be confirmed on repeat) with a total bilirubin >2X 
ULN (must be confirmed on repeat); OR  
o A treatment emergent ALT or AST >3X ULN (must be confirmed on repeat) with symptoms of RUQ pain, 
fever, rash or eosinophilia; OR 
o A treatment emergent AST or ALT >3X ULN (must be confirmed on repeat) with an INR > 1.5 (must be 
confirmed on repeat) and which must not be explained by another plausible cause  
• 
See Appendix 16.1 for treatment modification guidelines in subjects/patients (NASH/Suspected NASH 
patients) with baseline/pre-dose elevated ALT or AST. 
If such serious adverse reactions or severe non-serious adverse reactions occur, enrollment and dosing in healthy 
volunteers will be paused pending a review of safety data and a decision on how to proceed by the DSC. 
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 the Dose Escalation Schedule above  
• 
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, oxygen saturation 
and temperature  

Arrowhead Pharmaceuticals, Inc.  
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Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
• 
Clinical laboratory measurements (e.g., chemistry including lipase and lipids, hemoglobin A1C, hematology, 
coagulation, and urinalysis) 
• 
Resting ECG measurements (measured after participant is semi-supine for at least 3 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚) 
• 
At each visit, participants will be asked about concomitant medications/therapy and will be instructed to 
volunteer any information regarding AEs and SAEs that they may have experienced.  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.  
• 
90-day post-end of study visit pregnancy follow-up phone call assessing compliance with contraception. 
Pharmacodynamic assessments:  
Pharmacodynamic assessments will be performed at specified time points per the Schedule of Assessments and will 
include fasting (at least 8 hours) LDL-C, total cholesterol, non-HDL-C, HDL-C, VLDL-C, triglycerides, retinol, retinol 
binding protein, cytokines, cytokeratin-18, blood exosomal HSD17β13 and PNPLA3 mRNA (if feasible), liver biopsy 
tissue PNPLA3 mRNA, liver biopsy tissue HSD17β13 mRNA, liver biopsy tissue PNPLA3 and HSD17β13 protein levels 
(if feasible), hemoglobin A1C, serum glucose, PRO-C3, ELF, MRI-PDFF and Fibroscan.  All serum tests will be 
completed after an 8-hour fast unless as otherwise specified.  Results, percent change, and duration of response (when 
applicable) from baseline to 4 weeks (or longer as necessary) will be analyzed and summarized by dose cohort and 
treatment group.  For lipid related and serum pharmacodynamic assessments, baseline is defined as the pre-dose value 
obtained nearest to the first dose. 
Immunogenicity: 
Samples will be collected for anti-drug antibody testing for cohorts (NASH patients only) at pre-dose, day 57, and EOS, 
or at Early Termination as per Schedule of Assessments. 
Pharmacokinetics & Urine/Plasma Drug Metabolites: 
Blood and urine samples will be collected for pharmacokinetic and drug metabolite analysis per the Schedule of 
Assessments. 
 
 
 

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Table 1 Schedule of Assessments for Cohorts 1-4 Single Dose: NHV 
 
 
 
 
Assessment 
Screening 
(Day -45 
to  
Day -1) 
Pre-
dose 
Day 1  
24 hr 
post-
dose 48 hr Day 8 
Day 
15 
Day 
29 
 
Day 
57, 71 
 
End of 
Study (or 
Early Term) 
Day 113 
 90 days 
after EOS 
 0 
min 
15 
min 
30 
min 1 hr 2 hr 4 hr 8 hr 12 hr 18 hr 
Day 
43 
Day 
85, 99 
Visit Window 
 
-2hrs ±2 minutes PK only, ±10 minutes other procedures 
±1 hr 
±2d ±2d ±2d ±2d ±2d ±2d 
±2d 
±7d 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical Hx  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam (See Section 10.3.2) 
X 
X 
 
 
 
 
 
 
 
 
 
as 
needed 
 
as 
needed 
as 
needed 
as 
needed 
as 
needed 
as 
needed 
as 
needed 
X 
 
BMI 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant Meds/Therapies  
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram (See 
Section 10.3.3)   
X 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
 
Urine Pregnancy Test (WOCP) 
confirmed negative pre-dose  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
FSH (post-menopause)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals (BP, temp, HR, RR, O2)  
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV, Hep B, C   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Labs (heme, coag, lipase, chem, 
lipids) 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hemoglobin A1c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood PK including met ID 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Urine PK including met ID 
 
spot 
Day 1 0-4 hr, 4-12 hr, 12-24 hr urine collections 
spot spot spot spot 
 
 
 
 
 
Urinalysis   
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administration of ARO-HSD  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy phone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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Table 2 Schedule of Assessments for Cohorts 1b, 3b, 4b: Subjects with suspected NASH (biopsies on screen and day 71) 
 
1 Body weight only 
2 10-minute window allowed 
3 Liver biopsy can be done at D1, as long it is completed prior to any D1 procedures  
Assessment 
Screening 
(Day -60 
to  
Day -1) 
Pre-
dose 
Day 1  
24 hr 
post-
dose 
Day 15 Day 29 Day 57 Day 71 Day 85 
End of Study (or 
Early Term)  
Day 113 
90 days 
after EOS 
 
0 min 30 min 
1 hr 
2 hr 
Visit Window 
-2hrs 
±2min (PK only), ±10min 
±1hr 
±2d 
±2d 
±2d 
±5d 
±2d 
±5d 
±7d 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical Hx  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam (See Section 10.3.2) 
X 
X 
 
 
 
 
as 
needed 
as 
needed as needed 
as 
needed 
as 
needed 
as 
needed 
X 
 
BMI (Height and Body Weight) 
X 
X1 
 
 
 
 
 
 
X 1 
 
X1 
 
X1 
 
Concomitant Meds/Therapies  
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram (See Section 10.3.3)   
X 
X 
 
 
X 
X 
X 
 
(0, 1, 
2hr) 2
 
 
 
X 
 
Urine Pregnancy Test (WOCP) confirmed 
negative pre-dose/pre-bx 
X 
X 
 
 
 
 
 
 
pre-dose 
 
pre-bx 
 
X 
 
FSH (post-menopause)  
X 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Vitals (BP, temp, HR, RR, O2)  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV, Hep B, C   
X 
 
 
 
 
 
 
 
 
 
 
 
Labs (heme, coag, chem, lipase, lipids) 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Retinol, RBP, blood for exosomes, 
cytokine panel 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Hemoglobin A1c 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Pro-C3, ELF, Cytokeratin-18 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood PK  
 
X 
 
X 
X 
X 
X 
X 
pre-dose 
 
 
 
 
 
Genotyping (HSD17β13, PNPLA3) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Liver Biopsy, FibroScan, MRI-PDFF 
X 3 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Administration of ARO-HSD 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 

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Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
 
 
 
Anti-Drug Antibodies  
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Adverse Events Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy phone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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

Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 15 of 59 
Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
3. 
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 
ICH E6 Good Clinical Practice guidelines.  I have read and agree to comply with the Investigator 
obligations stated in this protocol, as well as with any and all applicable federal, state, or local 
laws and regulations.  Any changes in procedure will only be made if necessary, to protect the 
safety, rights or welfare of participants. 
I agree to conduct or to supervise the trial in person. 
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 
 
 
 
 
 

Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 16 of 59 
Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
4. 
LIST OF ABBREVIATIONS AND TERMS 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
API 
Active Pharmaceutical Ingredient 
AST 
Aspartate transaminase 
ARO 
Arrowhead Pharmaceuticals, Inc. 
AUC 
Area under the curve 
AUCinf 
Area under the curve from time 0 to infinity 
BP 
Blood pressure 
cGCP 
current Good Clinical Practice 
cGMP 
current Good Manufacturing Practice 
Cmax 
Concentration maximum (peak) 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically significant 
CTN 
Clinical Trial Notification 
CVA 
Cerebrovascular accident 
dL 
deciliter 
DSC  
Data Safety Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELF 
Enhanced Liver Fibrosis (Score) 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GTT 
Glucose Tolerance Test 
HBV 
Hepatitis B virus 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
HSD 
Hydroxysteroid dehydrogenase 
ICH 
International Council for Harmonisation  
IRB 
Institutional Review Board 
Kg 
Kilogram 
L 
Liter 
LISR 
Local injection site reactions 
LOF 
Loss of function 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 

Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 17 of 59 
Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
milligram 
mmHg 
millimeters of mercury 
MRI 
Magnetic resonance imaging 
NAFLD 
Non-alcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
Non-alcoholic steatohepatitis 
NHV 
Normal healthy volunteers 
NOAEL 
No observed adverse event level 
NYHA 
New York Heart Association 
OTC 
Over the Counter 
PBO 
Placebo 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PT 
Prothrombin Time or Preferred Term 
PTT 
Partial thromboplastin 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 
RBP 
Retinol Binding Protein 
RNA 
Ribonucleic acid 
RNAi 
RNA interference 
SAE 
Serious Adverse Event  
SD 
Standard Deviation  
siRNA 
Short interfering RNA oligonucleotides  
SOA 
Schedule of Assessments 
SOC 
System Organ Class 
SubI 
Subinvestigator 
T2DM 
Type 2 diabetes mellitus 
t1/2 
terminal elimination half-life 
TE 
Treatment Emergent 
TIA 
Transient Ischemic Attack 
ULN 
Upper Limit of Normal 
WOCP 
Women of Childbearing Potential 

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Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 23 of 59 
Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
of ARO-HSD or PBO to two sentinel participants (one ARO-HSD, one PBO).  Following the 
Day 3 evaluation in these participants, if there are no significant safety concerns, the remaining 
participants in the cohort will be treated at the discretion of the Principal Investigator (PI).  
Dosing of participants will be staggered by at least 30 minutes such that no two participants will 
be dosed simultaneously.  Sentinel dosing is not required in patient cohorts. 
Dose levels by cohort are outlined in Table 4 and Figure 1.  Cohorts 1 through 4 will enroll 
sequentially with patient cohorts opening for enrollment in a step-wise manner.  Screening for all 
Cohorts may begin once Cohort 1 has been opened for enrollment.  
Clinical facility confinement will be approximately 3 days for first dose administration in NHV 
cohorts (Cohorts 1, 2, 3, and 4) with discharge on Day 2.  Subjects will return to the clinical 
facility for outpatient visits per the Schedule of Assessments.  Subjects in cohorts 1b, 3b and 4b 
will be at the facility for approximately 4 hours (2 hours before dosing and 2 hours after dosing) 
on dosing days. 
Table 4  Cohort Summary 
Cohort 
Population 
Blinding 
# Subjects 
Dosing Schedule 
1 
NHVs 
Double blind 
8 (4 active: 
4 placebo) 
25 mg Day 1 only 
1b 
Patients with suspected NASH 
(biopsies on screen and day 71) 
Open Label 
up to 6 
(all active) 
25 mg Days 1, 29 
2 
NHVs  
Double blind 
8 (4 active: 
4 placebo) 
50 mg Day 1 only 
3 
NHVs  
Double blind 
8 (4 active: 
4 placebo) 
≤ 100 mg Day 1 only 
4 
NHVs  
Double blind 
8 (4 active: 
4 placebo) 
≤ 200 mg Day 1 only 
3b 
Patients with suspected NASH 
(biopsies on screen and day 71) 
Open Label 
up to 6 
(all active) 
≤ 100 mg Days 1, 29 
4b 
Patients with suspected NASH 
(biopsies on screen and day 71) 
Open Label 
up to 6 
(all active) 
≤ 200 mg Days 1, 29 
In the NHV and suspected NASH patient dose escalation part of the study, dose escalation will 
require approval by the DSC based on all cumulative available safety data for prior cohorts, and 
through at least Day 15 of the current cohort.  Based on available safety data through Day 15, the 
DSC will vote to approve dose escalation to the next single dose NHV cohort as well as vote to 
open a suspected NASH patient cohort at the dose most recently tested in NHVs.  DSC decisions 
will be based on all aggregate safety data available including all data available at least through 
Day 15 of the current cohort as shown in Figure 1.  Escalation to the next dose level will proceed 
until the highest planned dose level is completed, or the trial is halted prematurely by the PI, 
DSC, or Sponsor due to safety or other reasons.  All subjects who withdraw from the study prior 
to their EOS visit, for reasons other than an adverse event, may be replaced. 
Cohort 1b will enroll after completion of cohorts 3b and 4b and will not require DSC approval to 
initiate enrollment as they use doses lower than the 200 mg top dose used in cohorts 4 and 4b 
which have already been opened by the DSC. 

Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 24 of 59 
Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
In double-blind cohorts, treatment un-blinding may occur at the PI’s discretion only 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 the final planned study visit (not 
including the 90-day follow-up call), Sponsor may be unblinded at Sponsor’s request.  After all 
subjects in double blinded cohorts have completed their EOS visit (not including the 90-day 
follow-up call), all blinded cohorts may be unblinded. 
Single and multiple doses of ARO-HSD will be evaluated in in a sequential manner as shown in 
Figure 1.   
Figure 1: Dose Escalation Schedule 
 
 

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Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 29 of 59 
Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
6. 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 Screening 
7. History of malignancy 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 interval may be entered following approval by the Medical Monitor 
8. History of major surgery within 1 month prior to Screening 
9. Excessive use of alcohol within three months prior to the Screening visit (i.e., > 14 units 
per week or > 4 units on a given day for men and > 7 units per week or > 3 units on a 
given day for women [1 unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% 
alcohol])  
10. Use of illicit drugs (such as cocaine or phencyclidine [PCP]) within 1 year prior to the 
Screening visit or positive urine drug screen at Screening (a urine drug screen positive for 
benzodiazepines, amphetamines, opioids or cannabis is acceptable for enrollment if the 
positive test is due to a substance used for medical reasons)  
11. Use of an investigational agent or device within 30 days prior to dosing or current 
participation in an investigational study involving a therapeutic intervention  
12. Blood donation (≥ 500 mL) within 7 days prior to study treatment administration  
13. 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 
Additional Exclusion Criteria for patient Cohorts 1b, 3b and 4b 
14. Weight loss of more than 5% within 3 months prior to randomization 
15. Cirrhosis [based on screening biopsy or historical biopsy showing definitive cirrhosis or 
based on Screening FibroScan > 20 kPa (one retest allowed) or if using an alternate 
ultrasound elastography method a value indicative of cirrhosis]  
16. Other well documented causes of chronic liver disease based on medical history (e.g., 
Wilson’s disease, alpha-1 antitrypsin deficiency, hemochromatosis, autoimmune 
hepatitis) 
17. Homozygous HSD17βB13 rs72613567 or other loss of function variants at Screening 
18. Values at Screening representing any of ALT>250 U/L; INR > 1.5, creatinine 
> 2.0 mg/dL (176.84 umol/L); platelets < 100,000 

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Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 37 of 59 
Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
An abbreviated physical exam will be performed at pre-dose and EOS.  Areas examined include: 
• Constitutional 
• Heart 
• Lungs 
• Abdomen 
• Extremities 
• Brief Neuro 
• Additional examination may be performed at investigator discretion 
 
At all other time points outlined in the Schedule of Assessments, a symptom-directed physical 
exam will be performed as needed.  Height (during screening, in centimeters, without shoes) and 
weight (kilograms, without shoes) should be recorded to determine BMI where specified in 
SOA.   
10.3.3 Electrocardiogram 
A single 12-lead ECG measurement will be obtained at time points outlined in the Schedule of 
Assessments after the participant is semi-supine for at least 3 minutes.  On dosing days ECGs 
will be performed pre-dose and 1 and 2 hours post-dose and may be performed more frequently 
if indicated.  ECGs should be performed within a window of 10 minutes, prior to other invasive 
procedures such as blood draws.  Any abnormal ECGs will be repeated in triplicate, with each 
measurement approximately 1 minute apart. Only abnormal ECG readings that are considered 
clinically significant in the opinion of the investigator need to be repeated in triplicate. Triplicate 
ECGs are three tracings approximately 1 minute apart. If the originally scheduled ECG is 
considered clinically significant, both the first tracing and the triplicate tracings will be entered 
into the EDC. 
10.3.4 Vital Sign Assessments 
Systolic/diastolic blood pressure, temperature, heart rate, respiratory rate (breaths/min) and 
oxygen levels will be obtained at time points outlined in the Schedule of Assessments after the 
participant is semi-supine for at least 3 minutes.  Vitals signs will be obtained prior to 
venipuncture and other invasive procedures.  
10.3.5 Clinical Laboratory Tests 
Blood and urine samples will be collected to perform clinical laboratory tests.  Participants will 
be required to fast for the screening and other pharmacodynamic sample collections.  
Central labs will be utilized. However, local labs may be utilized as necessary if needed by the 
investigator or for emergent situations. 
Within the screen period, 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 baseline data 
and eligibility for enrolment.  One repeat Screening lab draw is allowed per assessment to 

Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 38 of 59 
Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
establish eligibility.  The results will be assessed by the PI, or medically qualified designee, 
before study enrollment.  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.  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, phosphate, total calcium, 
albumin, total protein, total bilirubin, lipase and amylase, conjugated bilirubin, alkaline 
phosphatase (ALP), alanine aminotransferase (ALT), and aspartate transaminase (AST), 
hemoglobin A1C 
• 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 
• Urine drug screen: urine will be analyzed for benzodiazepines, amphetamines, 
methamphetamines, methadone, phencyclidine, barbiturates, opiates, cocaine, ecstasy and 
cannabinoids 
• Microscopic urinalysis will be performed if indicated: white blood cells, red blood cells, 
epithelial cells, bacteria 
• Serology: Hepatitis B surface antigen, 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.   
• FSH:  Post-menopausal status will be confirmed by follicle-stimulating hormone (FSH) 
level consistent with post-menopausal state. 
• Pregnancy:  Females of childbearing potential will have a urine pregnancy test at 
Screening and pre-dose on dosing days and biopsy days.  If urine pregnancy test is 
positive, dosing or biopsy should not occur, and the patient will be referred to their 
primary care provider for follow up.  
• Lipid Parameters: LDL-C, total cholesterol, non-HDL-C, HDL-C, VLDL-C, and 
triglycerides 
• Retinoid pathway markers: retinol, retinol binding protein 

Arrowhead Pharmaceuticals, Inc.  
Confidential 
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Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
• NASH biomarkers: ELF [Hyaluronic acid (HA), Procollagen III amino terminal peptide 
(PIIINP), Tissue inhibitor of metalloproteinase 1 (TIMP-1)], cytokeratin-18, PRO-C3, 
IL-1β, IL-6, IL-10, INF-gamma, and TNF-α 
• Immunogenicity: Specified subjects will be assessed for anti-drug antibodies.  
• Genotype: All patient cohorts will be assessed for HSD17βB13 and PNPLA3 gene 
variants with the subject’s written consent. 
• Exosomal analysis: blood will be drawn for exosomal analysis of PNPLA3 and 
HSD17B13 if technically feasible.  
The Day 1 (pre-dose) value will be used as each participant’s baseline value for data analysis 
purposes or as otherwise specified.  If Day 1 or as otherwise specified values are erroneous or 
not available and repeat blood draw is not possible, the pre-dose value closest to Day 1 (e.g., 
Screening) may be used as baseline. 
10.3.6 Hepatic Imaging (only for patient Cohorts 1b, 3b and 4b) 
Patients must fast from food for at least 4 hours prior to MRI.  
Magnetic Resonance Imaging:  Liver fat content via MRI-PDFF will be evaluated and quantified 
per the Schedule of Assessments.  MRI reading for eligibility and post-dose will be completed 
centrally.  
FibroScan®: Per the Schedule of Assessments, pre-dose and post-dose liver stiffness will be 
evaluated using FibroScan® standard procedures.  No centralized reading is required for 
FibroScan.  An equivalent ultrasound elastography method may be used. 
Please see separate imaging manual for specific instructions related to hepatic MRI.   
10.3.7 Liver Biopsy (only for Cohorts 1b, 3b and 4b) 
With training and Sponsor approval, only those sites capable of processing biopsy tissue in 
accordance with the Laboratory and Biopsy Manuals will be required to obtain samples for 
protein expression analysis at the time points outlined in the Schedule of Assessments. 
Samples will be used to assess effect of treatment on: 
• HSD17B13 mRNA and PNPLA3 mRNA.  
• Protein expression for HSD17B13 and PNPLA3 (if scientifically feasible).   
The liver biopsy procedure and D1 dosing can be done on the same date. The only requirement is 
for the liver biopsy procedure to be completed before any other D1 procedures, especially 
dosing.   

Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 40 of 59 
Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
If the patient agrees to an additional biopsy core during Screening to confirm NASH diagnosis, 
the histopathology can be conducted as an option by the sites and histopathology costs will be 
covered by the Sponsor. This optional procedure should not be used to confirm patient eligibility.  
Please see separate laboratory and biopsy manuals for specific instructions related to biopsy 
performance.  
10.3.8 Pharmacokinetics 
Samples (blood and urine) for analysis of circulating ARO-HSD will be obtained at time points 
following study drug administration as outlined in the Schedule of Assessments.  ARO-HSD 
metabolites in blood and urine will be identified in samples taken at timepoints per the schedule 
of assessments in NHV cohorts. 
Please see separate laboratory manual for specific instructions related to PK and met ID 
processing. 
10.3.8.1 
Blood Sample Collection, Processing, and Analysis  
Blood samples from participants will be collected at time points outlined in the Schedule of 
Assessments 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.  
The actual sample times will be recorded 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. 
Whole blood will be collected and processed per the Laboratory Manual.  
10.3.8.2 
Urine Sample Collection, Processing and Analysis  
Urine samples from participants will be collected at time points outlined in the Schedule of 
Assessments.  For spot urine collection, the actual urine collection time and volume will be 
recorded.  For interval sample collections, the start and stop time of urine sample collection 
(along with volume) will be recorded with an attempt to void at the end of the collection interval.  
All times must be recorded in the 24-hour format.  An explanation must be given for any sample 
taken outside of the set sampling times. 
Urine will be collected and processed per the Laboratory Manual.  
10.3.9 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 CRF.  If 
necessary, paracetamol may be used during the study as necessary. 

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Arrowhead Pharmaceuticals, Inc.  
Confidential 
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Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
whether related to this product or not.  (Refer to 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 pre-existing 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) 
• 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. 

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Arrowhead Pharmaceuticals, Inc.  
Confidential 
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Protocol No.: AROHSD1001 
 
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designee’s) clinical judgment.  The intensity should be assigned to one of the following 
categories: 
• 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 an 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 predefined outcomes as described in 
Section 11.1.  
11.5.2 AEs at the Injection Site and Local Injection Site Reactions (LISRs) 
AEs at the injection site will be graded as either Mild, Moderate or Severe.  A local injection site 
reaction is defined as an adverse reaction (usually immunologic) developing at the site of 
injection and lasting at least 48 hours.  For the data reporting and analysis purposes, the 
definition of LISR based on duration of at least 48 hours and based on the specified MedDRA 
preferred times is provided in Appendix 16.2.  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 
 
11.5.3 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) 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. 

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Arrowhead Pharmaceuticals, Inc.  
Confidential 
Page 59 of 59 
Protocol No.: AROHSD1001 
 
Version 7.0, 12 March 2021 
17. 
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