A Double-Blind, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and Safety of ARO-APOC3 in Adults With Severe Hypertriglyceridemia
Phase: PHASE2
Conditions: Severe Hypertriglyceridemia
Sponsor: Arrowhead Pharmaceuticals

 
 
A Double-Blind, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and 
Safety of ARO-APOC3 in Adults with Severe Hypertriglyceridemia 
Protocol Number: AROAPOC3-2001 
Original Protocol: 24 NOV 2020 
Amendment 1, Version Date 19 JAN 2021 
Amendment 2, Version Date 19 April 2021 
Amendment 3, Version Date 01 November 2021 
Amendment 4, Version Date 22 November 2022 
Amendment 5, Version Date 26 January 2023 
 
Product number: 
ARO-APOC3 
Indication: 
Severe Hypertriglyceridemia (SHTG) 
IND Number:  
144947 
EudraCT Number: 
2021-000687-30 
Sponsor:  
Arrowhead Pharmaceuticals, Inc. 
177 East Colorado Boulevard, Suite 700 
Pasadena, CA 91105 
USA 
Sponsor’s Responsible Medical 
Monitor: 
  
 
 
Arrowhead Pharmaceuticals, Inc. 
177 East Colorado Boulevard, Suite 700 
Pasadena, CA 91105 
+1 (626) 304 3400 
 
 
This study will be performed in compliance with the protocol, the principles of Good Clinical 
Practices (GCP), and all applicable regulatory requirements and guidelines. 
 
 
 
Confidentiality Statement: Information contained in this protocol 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 participant to obtain consent. 

 
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1. 
PROTOCOL SYNOPSIS 
TITLE OF STUDY:  
A Double-Blind, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and Safety of 
ARO-APOC3 in Adults with Severe Hypertriglyceridemia  
PROTOCOL NUMBER:  
AROAPOC3-2001 
PHASE OF DEVELOPMENT: 
Phase 2b 
STUDY SITES:  
Approximately 80 centers globally 
STUDY TREATMENTS:  
There will be 2 study treatments; 1 active (Test Formulation) and 1 placebo (Reference 
Formulation).  
Test Formulation:  
The test formulation is active ARO-APOC3 Injection (also referred to as ARO-APOC3) 
administered subcutaneously (SC). The active pharmaceutical ingredient (API) contained in 
ARO-APOC3 is a synthetic, double-stranded, short interfering RNA (siRNA) duplex conjugated to 
an N-acetyl-galactosamine targeting ligand to facilitate hepatocyte delivery. 
Reference Formulation: 
The reference formulation is placebo: normal saline (0.9%) administered SC, volume matched to 
the corresponding ARO-APOC3 dose volume. 
Doses and Number of Doses per Treatment:  
Three dose levels of ARO-APOC3 will be compared to placebo in participants with severely high 
triglycerides (TG), or SHTG, who had mean fasting TG of ≥500 mg/dL (5.65 mmol/L) and 
≤4000 mg/dL (45.2 mmol/L) at Screening. A total of approximately 216 participants will be 
enrolled in the study. All dose cohorts will enroll in parallel with 72 participants per dose cohort 
randomly assigned in a 3:1 ratio to receive AROAPOC3 or placebo. Each participant will receive 
SC injections on Day 1 and Week 12 for a total of 2 injections as follows:  
• 
ARO-APOC3 10 mg (n=54) or volume-matched placebo (n=18) at Day 1 and 
Week 12; 
• 
ARO-APOC3 25 mg (n=54) or volume-matched placebo (n=18) at Day 1 and 
Week 12; or 
• 
ARO-APOC3 50 mg (n=54) or volume-matched placebo (n=18) at Day 1 and 
Week 12.  
The duration of the study is approximately 54 weeks from Screening to the Week 48 End-of-Study 
(EOS) examination. 
STUDY OBJECTIVE:  
The primary objective of the study is to evaluate the safety and efficacy of ARO-APOC3 in adults 
with SHTG and to select a dosing regimen for later stage clinical studies in this patient population. 

 
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STUDY DESIGN: 
This is a randomized, double-blind, placebo-controlled, Phase 2b clinical study. After informed 
consent participants will be assessed for eligibility. Participants who have met all the protocol 
eligibility criteria during Screening may be enrolled and randomly assigned to treatment in a 
double-blind fashion. Participants will be randomly assigned 3:1 to receive 1 of 3 ARO-APOC3 
dosing regimens or matched placebo (see Study Schema). All dose cohorts will enroll in parallel. 
Enrolled participants will be counseled to remain on stable background medications and on the 
specified diet throughout the study, as recommended by the Investigator in accordance with local 
standard of care. The specifics of the diet will be at the discretion of the Investigator based on each 
individual’s diagnosis and medical needs.  
Study Schema 
 
Abbreviations: EOS = end of study; W = week. 
 
Blinding will be preserved to the extent possible; however, treatment unblinding may occur, at the 
Investigator’s or Medical Monitor’s discretion, where deemed necessary for treatment of an 
adverse event (AE) or for a safety-related decision or a decision to be made regarding study 
continuation in an individual participant.  
Adverse Event Monitoring 
Safety assessments will include:  
AEs and serious AEs (SAEs), physical examinations, vital sign measurements (blood pressure, 
heart rate, temperature, and respiratory rate), electrocardiograms (ECGs), clinical laboratory tests, 
concomitant medications/therapy, and reasons for treatment discontinuation. Safety assessments 
will be performed at specified time points and up to study completion.  
The AE/SAE reporting period for an enrolled participant will begin when the participant provides 
informed consent. Treatment-emergent AEs (TEAEs) and SAEs are defined as those that occur 
following investigational product (IP) administration or are a pre-existing condition exacerbated by 
IP. The TEAE reporting period begins after the first dose and extends until the EOS visit is 
complete. All SAEs that occur during the reporting period, in addition to reporting via electronic 
case report forms (eCRFs), must also be reported to the Sponsor via the SAE report form 
immediately upon becoming aware of the event. All AEs/SAEs will be followed until resolution, 
until the condition stabilizes, until the event causality is otherwise explained, or until the 
participant is lost to follow-up. If the Investigator 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 reasonably 

 
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related to the IP, the Investigator will promptly notify the Sponsor. Laboratory or diagnostic 
assessment (eg, ECG) abnormalities will be reported as AEs if considered clinically significant 
(CS) by the Investigator. Laboratory or diagnostic assessment abnormalities not reported as AEs 
are not to be reported as CS in the study database. 
TREATMENT STOPPING RULES:  
A decision to pause/suspend dosing in an individual participant may be indicated based on any of 
the following:  
• 
Any confirmed pregnancy in the study will lead to permanent discontinuation of IP 
dosing of that participant; or 
• 
A need for apheresis or other emergent interventions indicated to lower TG; or 
• 
Acute pancreatitis; or 
• 
In participants with normal (per central laboratory reference range) aspartate 
aminotransaminase (AST) or alanine aminotransferase (ALT) on Day 1, treatment-
emergent elevations >3× upper limit of normal (ULN) at least possibly related to IP 
per study Investigator, must be confirmed by repeat blood draw within 72 hours of 
initial results. Refer to Appendix 1 for specific guidelines regarding treatment 
discontinuation or interruption for participants with any of the below findings:  
− AST or ALT >5× ULN will lead to permanent discontinuation of IP dosing of that 
participant per Appendix 1. The participant will remain on study follow-up visits 
until EOS as per the Schedule of Assessments (SOA) (refer to Table 1). 
− 
AST or ALT >3× ULN with a total bilirubin >2× ULN 
− 
AST or ALT >3× ULN with the new appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
− 
AST or ALT >3× ULN with a treatment-emergent international normalized ratio 
(INR) >1.5 (must be confirmed on repeat) and which is not explained by another 
plausible cause. 
* if Gilbert's syndrome or hemolysis: doubling of direct bilirubin if baseline 
>0.5 mg/dL. 
• 
Some participants enrolling into this study may have baseline elevations in 
transaminases.  In participants with elevated (per central laboratory reference range) 
AST or ALT on Day 1, treatment-emergent elevations >2× baseline or ≥300 U/L 
(whichever occurs first) at least possibly related to IP per study Investigator, as 
specified below, must be confirmed by repeat blood draw within 72 hours of initial 
results.  Refer to Appendix 1 for specific guidelines regarding treatment 
discontinuation or interruption for participants with any of the below findings: 
− 
AST or ALT >3× baseline or ≥300 U/L (whichever occurs first)  

 
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− 
AST or ALT >2× baseline or ≥300 U/L (whichever occurs first) with the new 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, or eosinophilia (>5%) 
− 
AST or ALT >2×baseline or ≥300 U/L with a total bilirubin >2× ULN 
− 
AST or ALT >2× baseline or ≥300 U/L or with a treatment-emergent INR >1.5 
(must be confirmed on repeat) and which is not explained by another plausible 
cause. 
* if Gilbert's syndrome or hemolysis: doubling of direct bilirubin if baseline 
>0.5 mg/dL. 
Treatment modification guidelines for participants with elevated AST or ALT are provided in 
Appendix 1. 
Study Drug Discontinuation Criteria for Increased HbA1c 
Regarding glycated hemoglobin (HbA1c) drug discontinuation criteria, participants should 
discontinue IP if they meet the following criteria (refer to Appendix 3): 
• 
HbA1c measurement >10% (or >86 mmol/mol International Federation of Clinical 
Chemistry [IFCC] units) at the last visit prior to the next dose; or  
• 
An increase from baseline HbA1c >2% (or > 17 mmol/mol IFCC units) at the last visit 
prior to the next dose; or  
• 
In participants with a baseline HbA1c >7.5% (or >58 mmol/mol IFCC units), an 
increase in HbA1c from baseline >1% (or >8.6 mmol/mol IFCC units) at repeat study 
visits with the last one being the visit prior to the next dose. 
Participants who discontinue IP due to HbA1c determinations will be followed for 6 months after 
their last dose per the Schedule of Assessments. 
For any participant experiencing an acute pancreatitis, all TG levels will be provided by the central 
laboratory to the Investigator and Medical Monitor, and the participant will be unblinded to their 
assigned treatment allocation.  If the participant was assigned to receive ARO-APOC3, their next 
dose should be postponed until they are clinically stable based on the assessment of the 
Investigator in consultation with the Medical Monitor. If the participant was assigned to placebo, 
further dosing will be discontinued; however, the participant may continue to be followed for the 
remainder of the 48-week Treatment Period, after which, the subject may opt to receive ARO-
APOC3 in the planned open-label extension study.  
Sponsor or Investigator can discontinue any participant at any time.  
DATA SAFETY COMMITTEE: 
An independent Data Safety Committee (DSC) will review safety data after half of the total 
number of participants planned for enrollment have received at least 1 dose of IP. The DSC 
meetings may also occur on an ad hoc basis to review safety data and to make decisions related to 
the study if needed. Details of DSC structure, processes, and possible actions are provided in the 
DSC charter. 

 
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The DSC may recommend to the Sponsor to pause additional dosing in the study to allow time to 
evaluate safety data and recommend the action to be taken, which may include, but is not limited 
to, one of the following: 
• 
The study may continue without modifications  
• 
The study may continue with modifications  
• 
The study should be terminated  
• 
The study should be temporarily suspended  
• 
Other changes  
STUDY DURATION (PLANNED):  
The duration of the study is approximately 54 weeks from Screening to the Week 48 EOS 
examination.  
The Screening period will last up to approximately 6 weeks (Day -42 to Day -1). TG values 
assessed during the Screening period for eligibility and lipid parameters evaluated throughout the 
study will be collected from participants in a fasted state. 
After Week 48, participants will be eligible and invited to consent and continue in an open-label 
extension study. All placebo participants who opt to continue will switch to active drug during the 
extension study.  
STUDY POPULATION/NUMBER OF PARTICIPANTS PLANNED:  
This study will be conducted in adults with SHTG (fasting TG ≥500 mg/dL, [5.65 mmol/L]). A 
total of approximately 216 participants will be enrolled in the study.  
STUDY ELIGIBILITY: 
Inclusion Criteria:  
To be eligible for enrollment, participants must meet all the following inclusion criteria: 
1. Males or nonpregnant (who do not plan to become pregnant), nonlactating females 
≥18 years of age; 
2. Based on medical history, prior evidence of fasting TG ≥500 mg/dL (5.65 mmol/L);  
3. A mean fasting TG ≥500 mg/dL (5.65 mmol/L) and ≤4000 mg/dL (45.2 mmol/L) collected 
at two separate and consecutive visits at least 7 days apart and no more than 17 days apart 
during the Screening period; 
4. If the participant has a medical history of clinical ASCVD or elevated 10-year ASCVD 
risk (eg, ≥7.5% per American Heart Association/American College of Cardiology 
[ACC/AHA] risk calculator for subjects >40 years of age or Framingham risk score 
calculator for subjects under the age of 40) then the participant must be on appropriate 
lipid-lowering therapy as per local standard of care (ie, including moderate-to-high 
intensity statin, as indicated) prior to collection of qualifying TG levels; 
5. Able and willing to provide written informed consent prior to the performance of any 
study-specific procedures; 

 
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6. Willing to follow diet counseling and maintain a stable diet as per Investigator judgment 
based on local standard of care; 
7. Participants of childbearing potential must agree to use highly-effective contraception, 
during the study and for at least 24 weeks following the last dose of IP. Males must not 
donate sperm during the study and for at least 24 weeks following the or last dose of IP; 
8. Women of childbearing potential on hormonal contraceptives must be stable on the 
medication for >2 menstrual cycles prior to Day 1; and 
9. Participants on any of the following medications must be on a stable regimen for the 
specified duration prior to collection of Screening Visit (S2) laboratory tests and for the 
duration of study participation: 
Medication 
 
Time on stable regimen prior to collection 
of Screening Visit (S2) laboratory tests  
Lipid-lowering therapies (including statins) 
>4 weeks 
Beta-blockers, thiazide diuretics 
>4 weeks 
Fibrates 
>6 weeks 
PCSK9 inhibitors 
>8 weeks 
Retinoids 
>8 weeks 
Atypical antipsychotics  
>12 weeks 
Diabetes mellitus medications 
>12 weeks 
Anticoagulation therapy 
>12 weeks 
Thyroid hormone replacement therapy 
>12 weeks 
Testosterone replacement therapy 
>16 weeks 
Oral estrogens, tamoxifen, raloxifene 
>16 weeks 
Immunosuppressants 
>24 weeks 
NOTE: All laboratory tests used as inclusion criteria will be assessed by a central laboratory 
and may be repeated once and the repeat value may be used for inclusion purposes. Local 
laboratory testing may be permitted in limited circumstances and only with prior Sponsor 
approval. 
 
Exclusion Criteria:  
1. Current use or use within the last 365 days from Day 1 of any hepatocyte-targeted siRNA 
or antisense oligonucleotide molecule; 
2. Active pancreatitis within 12 weeks prior to Day 1; 
3. Known genetically confirmed diagnosis of Familial Chylomicronemia Syndrome (FCS) 

 
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4. Any planned bariatric surgery or similar procedures to induce weight loss during the period 
starting at consent through end of the study; 
5. History of major surgery within 12 weeks of Day 1 or planned major surgery during the 
study;  
6. Planned coronary intervention (such as stent placement or heart bypass) during the study; 
7. History of acute coronary syndrome event within 24 weeks of Day 1; 
8. New York Heart Association (NYHA) Class II, III, or IV heart failure or last known 
ejection fraction of <30%; 
9. Uncontrolled hypertension (sitting blood pressure >160/100 mmHg at Screening); 
participant may be re-screened once hypertension is controlled;  
10. History of hemorrhagic stroke within 24 weeks of Day 1; 
11. History of bleeding diathesis or coagulopathy; 
12. Current diagnosis of nephrotic syndrome; 
13. Any of the following laboratory values at Screening: 
a. Hepatic: ALT or AST >2× ULN at Screening; 
b. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (using the 
Modification of Diet in Renal Disease [MDRD] equation) at Screening; 
c. HbA1c >9.0% (or >75 mmol/mol IFCC units) at Screening; 
d. Spot urine protein/spot urine creatinine ratio >3 grams per day; 
e. Clinically significant abnormality in PT, aPTT, or INR 
14. Use of any of the following:  
a. Systemic use of corticosteroids or anabolic steroids within 4 weeks prior to Day 1 or 
planned use during the study (stable doses of testosterone replacement therapy 
>16 weeks prior to Screening (visit S2) is permitted for a documented history of 
hypogonadism [low testosterone] as verified in subject health records)  
b. Plasma apheresis within 4 weeks prior to Day 1 or planned during the study; 
15. Blood donation of 50 to 499 mL within 4 weeks of Screening (visit S2) laboratory 
collection or of >499 mL within 8 weeks of Screening (visit S2) laboratory collection;  
16. Known history of human immunodeficiency virus infection; 
17. Seropositive (hepatitis B surface antigen [HBsAg] +) for hepatitis B virus (HBV) or 
hepatitis C virus (HCV) (HCV seropositivity requires positive test for antibodies 
confirmed with positive test for HCV RNA); 
18. Clinical evidence of uncontrolled hypothyroidism or hyperthyroidism as per Investigator’s 
judgment;  
19. History of malignancy within the last 2 years prior to the date of consent requiring 
systemic treatment except for adequately treated basal cell carcinoma, squamous cell skin 

 
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cancer, superficial bladder tumors, or in situ cervical cancer. Currently receiving systemic 
cancer treatment(s) or, in the Investigator's opinion, at risk of relapse for recent cancer; 
20. Use of an investigational agent or device within 30 days or within 5 half-lives, based on 
plasma pharmacokinetics (PK) (whichever is longer) prior to Day 1 or current participation 
in an interventional investigational study. Participants previously exposed to 
ARO-APOC3, or ARO-ANG3 will require a washout period of at least 1 year from last 
dose; 
21. Unwilling to limit alcohol consumption to within moderate limits for the duration of the 
study, as follows: not more than 14 units per week (1 unit = 80 mL of wine, 200 mL of 
beer, or 25 mL of 40% alcohol); or 
22. Any concomitant medical or psychiatric condition or social situation or any other situation 
that, in the Investigator’s judgment, would make it difficult to comply with protocol 
requirements or put the participant at additional safety risk. 
All laboratory tests used as exclusion criteria may be repeated once and the repeat value may be 
used for exclusion purposes. 
ENDPOINTS:  
Primary Endpoint:  
The primary endpoint of the study is: 
• 
Percent change from baseline at Week 24 in fasting TG.  
Secondary Endpoints:  
The following are the secondary endpoints to be evaluated in this study: 
• 
Percent change over time through Week 48 in fasting TG; 
• 
Percent change from baseline at Week 24 and over time through Week 48 in 
apolipoprotein (Apo)C-III; 
• 
Percent change from baseline at Week 24 and over time through Week 48 in fasting 
non-high-density lipoprotein-cholesterol (non-HDL-C); 
• 
Percent change from baseline at Week 24 and over time through Week 48 in fasting 
HDL-C; 
• 
Percent change from baseline at Week 24 and over time through Week 48 in fasting 
total apolipoprotein B (ApoB); 
• 
Percent change from baseline at Week 24 and over time through Week 48 in fasting 
low-density lipoprotein-cholesterol (LDL-C) using ultracentrifugation; 
• 
Change from baseline in plasma concentrations of ARO-APOC3 over time through 
Week 12; and 
• 
The frequency and severity of AEs and SAEs over time through Week 48. 
Exploratory Endpoints:  

 
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The following are the exploratory endpoints defined in this study: 
• 
Change and/or percent change from baseline over time through Week 48 in TG and 
other fasting lipid parameters (total cholesterol, LDL-C measured using Martin-
Hopkins methodology, LDL/HDL ratio, very-low-density lipoprotein-cholesterol 
[VLDL-C], ApoB-48, lipoprotein [LP][a], ApoB-100, ApoC-II, ApoA-I and ApoA-V 
[all values drawn after at least a 10-hour fast]); 
• 
Change from baseline at Week 24 and overtime through Week 48 in fasting serum 
blood glucose, HbA1c, homeostatic model assessment for insulin resistance (HOMA-
IR) and C-peptide; 
• 
Change from baseline over time through Week 48 in high sensitivity C-reactive protein 
(hsCRP); 
• 
Cumulative number of on-study occurrences of acute pancreatitis events over time 
through Week 48; 
• 
Cumulative number of on-study hospitalizations for abdominal pain over time through 
Week 48; 
Note: All AEs and SAEs reported by the Investigator during the study that are 
consistent with an event of acute pancreatitis as per the 2013 Atlanta definition 
meeting 2 of the following 3 criteria: (1) abdominal pain consistent with acute 
pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the 
back); (2) serum lipase activity (or amylase activity) ≥3× ULN; and (3) characteristic 
findings of acute pancreatitis on contrast-enhanced computed tomography (CECT), 
magnetic resonance imaging (MRI), or transabdominal ultrasonography.  
• 
Proportion of participants requiring emergent apheresis over time through Week 48; 
• 
Change and percent change from baseline to Week 24 in liver fat content using MRI-
proton density fat fraction (PDFF); only in participants with a liver fat fraction of ≥8% 
at Screening; and 
• 
Emergence of and levels of anti-drug antibodies to ARO-APOC3 in those receiving 
ARO-APOC3 over time through Week 48. 
DATA ANALYSIS / STATISTICAL METHODS: 
Statistical Considerations:  
The primary analysis of the primary endpoint will evaluate the difference in means between each 
ARO-APOC3 dose group and pooled placebo groups and will be conducted in all randomized 
participants who receive at least 1 dose of IP (Full Analysis Set [FAS]). Primary and all secondary 
efficacy endpoints, along with aggregate safety and tolerability data summaries, tabulated by 
treatment group, will be evaluated and reported after all randomized participants complete the 
Week 48 study visit.  
Based on the previous Phase 1 study it is assumed that ARO-APOC3 dose groups will have 50% to 
70% more reduction than placebo, with a standard deviation of 10% for ARO-APOC3 dose groups 
and 40% for placebo. With these assumptions, the study will have greater than 99% power to detect 
any active treatment dose cohort which is significantly different from placebo with 18 complete 

 
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participants per treatment group, using a two-sided test and 1.67% level of significance, adjusted 
for multiplicity. With the considerations of dropout and to observe more participants for clinical 
safety, a total of 216 participants will be randomly assigned to treatment in a 3:1 (active to placebo) 
ratio within each dose cohort (72 participants per dose cohort). 
Randomization to placebo and active dose cohorts will be stratified based on: 
• 
Mean level of TG at Screening (≥1000 mg/dL versus <1000 mg/dL). 
Prespecified subgroup analyses will be conducted for: 
• 
Participants with a genotype consistent with FCS (including but not limited to 
homozygous, compound heterozygous, or double heterozygous loss-of-function or 
otherwise inactivating mutations in genes affecting lipoprotein lipase (LPL) activity 
including LPL, APOC2, APOA5, GPIHBP1, LIPG, GPD1, or LMF1); 
• 
Participants with TG at baseline of 500 to 2000 mg/dL (5.65 to 22.6 mmol/L); and 
• 
Participants with TG at baseline of >2000 mg/dL (22.5 mmol/L). 
Efficacy and Pharmacodynamic Analyses:  
The primary analysis will be performed using a mixed model repeated measures (MMRM) 
approach and will evaluate the difference in means between each ARO-APOC3 dose group and 
pooled placebo groups in all randomized subjects who receive at least 1 dose of IP (FAS). The 
estimand of interest is the difference in means of percent change from baseline in fasting TG at 
Week 24 in adult SHTG population (as defined by the inclusion/exclusion criteria), regardless of 
treatment compliance or other intercurrent events post-baseline. When performing the primary 
analysis, the adjustment for multiplicity of testing several arms versus placebo will be carried out 
using Holm’s step-down procedure. 
All continuous secondary endpoints will be analyzed in a similar manner to the primary endpoint, 
unless otherwise noted. For the analysis of exploratory endpoints, descriptive summaries will be 
provided, as applicable, and any inferential statistics (ie, p-values) will be considered only as 
exploratory.  
The final study report will be created following the completion of the study (Week 48). 
Tolerability and Safety Data:  
In general, safety analyses will be performed and the results summarized by dose 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 dose cohort per SOC, PT, and severity. All AEs 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 listings. Electrocardiogram parameters, changes 
from baseline, and qualitative assessments will be summarized. Pregnancy and follicle-stimulating 
hormone (FSH) test results will be listed separately by time point.  

 
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All safety and tolerability analyses will be performed using the Safety Analysis Population, defined 
as all enrolled participants who received at least 1 dose of IP.  
Pharmacokinetics:  
Plasma concentrations of ARO-APOC3 will be measured in all participants to evaluate trough and 
postdose levels throughout the study per the Schedule of Assessments (SOA). Serial PK sampling 
will be conducted in a subgroup of participants at specifically designated PK sites.  
Full PK group: In each of the dose cohorts, 16 PK participants (12 active, 4 placebo, for 48 total 
participants for PK) will be enrolled at the designated PK sites. Plasma concentrations will be 
measured predose and serially postdose as per the SOA. Only samples collected from participants 
receiving active treatment will be included in the PK analysis.  
Sparse Sample PK group: At the Day 1 and Week 12 visits, all other participants at all sites will 
provide a predose PK sample and PK sample postdose as per the SOA.  
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, standard 
deviation, minimum, and maximum. 
 

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Recommended time window for PK samples at the 24-hour time point: ±60 minutes (Section 10.5). If the recommended time window is missed, every attempt should be 
made to collect this PK sample as soon as possible within the same study visit. Only samples collected from participants receiving active treatment will be included in the 
PK analysis. For postdose samples that require next-day collection, participants may return to the clinical facility to have their blood drawn or they may opt to have their 
PK samples collected through home health. 
13. All other participants (Sparse PK participants) will have PK samples drawn predose and at least 15 minutes postdose on dosing days. 

 
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2. 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS .............................................................................................2 
2. 
TABLE OF CONTENTS ...........................................................................................17 
3. 
STUDY INFORMATION AND SIGNATURE .........................................................22 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................23 
5. 
BACKGROUND ........................................................................................................27 
5.1. 
Overview of Severe Hypertriglyceridemia (SHTG) ...................................................27 
5.2. 
Overview of ARO-APOC3 Development ..................................................................29 
5.2.1. 
Mechanism of Action of ARO-APOC3 and Therapeutic Rationale ..........................29 
5.2.1.1. 
siRNA Mechanism of Action .....................................................................................29 
5.2.2. 
Preclinical Studies ......................................................................................................31 
5.2.3. 
Clinical Studies ...........................................................................................................31 
5.3. 
Risk Assessment for Participants ................................................................................32 
5.4. 
Study Rationale ...........................................................................................................33 
5.5. 
Rationale for Dose and Schedule of Administration ..................................................33 
5.6. 
Benefit-Risk Assessment ............................................................................................34 
6. 
STUDY OBJECTIVES ..............................................................................................36 
7. 
STUDY PLAN............................................................................................................36 
7.1. 
Overall Study Design and Plan ...................................................................................36 
7.1.1. 
Number of Study Sites ................................................................................................37 
7.1.2. 
Number of Participants ...............................................................................................37 
7.1.3. 
Estimated Study Duration ...........................................................................................37 
7.2. 
Discussion of Study Design, Including Choice of Control Group .............................38 
8. 
SUBJECT SELECTION .............................................................................................39 
8.1. 
Inclusion Criteria ........................................................................................................39 
8.2. 
Exclusion Criteria .......................................................................................................40 
8.3. 
Participant Withdrawal Criteria ..................................................................................42 
8.3.1. 
Data Safety Committee and Treatment Stopping Rules .............................................42 
8.3.2. 
Study Drug Discontinuation Criteria for Increased HbA1c .......................................44 
8.4. 
Restrictions and Concomitant Medications ................................................................45 
8.5. 
Lipid Monitoring ........................................................................................................46 

 
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9. 
INVESTIGATION PRODUCT ..................................................................................47 
9.1. 
Description, Identification, and Dosage .....................................................................47 
9.2. 
Supply, Preparation, Storage, and Labeling of ARO-APOC3 ....................................47 
9.3. 
Study Drug Handling ..................................................................................................48 
9.4. 
Allocation to Treatment ..............................................................................................48 
9.5. 
Study Formulation Administration .............................................................................49 
9.6. 
Accountability of Study Supplies ...............................................................................49 
9.7. 
Retention of Investigational Product Vials .................................................................50 
9.8. 
Blinding and Code-Break ...........................................................................................50 
10. 
STUDY METHODS AND PROCEDURES ..............................................................51 
10.1. 
Overview of Procedures .............................................................................................51 
10.2. 
Screening Diet Stabilization Period ............................................................................52 
10.3. 
Selection and Screening ..............................................................................................52 
10.4. 
On-Study Procedures/Assessments ............................................................................53 
10.4.1. 
Efficacy Assessments .................................................................................................53 
10.4.1.1. 
Serum Triglycerides ....................................................................................................53 
10.4.1.2. 
Other Lipid Parameters ...............................................................................................53 
10.4.1.3. 
Glucose Metabolism ...................................................................................................53 
10.4.1.4. 
Magnetic Resonance Imaging .....................................................................................53 
10.4.1.5. 
Blood Sampling for Pharmacodynamic Analysis .......................................................54 
10.4.2. 
Pharmacokinetic Assessments ....................................................................................54 
10.4.2.1. 
Sample Processing and Analysis for Pharmacokinetic Samples ................................54 
10.4.3. 
General and Safety Assessments ................................................................................54 
10.4.3.1. 
Demographics and Medical History ...........................................................................55 
10.4.3.2. 
Physical Examination .................................................................................................55 
10.4.3.3. 
Vital Signs ..................................................................................................................55 
10.4.3.4. 
Electrocardiogram .......................................................................................................56 
10.4.3.5. 
Clinical Laboratory Tests for Safety ...........................................................................56 
10.4.3.6. 
Early Termination Procedures ....................................................................................57 
10.4.3.7. 
Follow-Up Procedures ................................................................................................57 
10.4.4. 
Acute Pancreatitis Events ...........................................................................................57 

 
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10.4.4.1. 
Detecting and Reporting Pancreatic Events ...............................................................57 
10.4.4.2. 
Hospitalization for Abdominal Pain ...........................................................................58 
10.5. 
Timing of Treatments and Procedures ........................................................................59 
10.6. 
Pregnancy Testing and Contraception Requirements .................................................59 
11. 
ADVERSE EVENTS..................................................................................................60 
11.1. 
Definitions ..................................................................................................................60 
11.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events ...........................................................................................................61 
11.3. 
Timing, Frequency, and Method of Detecting Adverse Events .................................61 
11.4. 
Recording of Adverse Events .....................................................................................62 
11.5. 
Evaluating Adverse Events .........................................................................................62 
11.5.1. 
Severity of Adverse Events ........................................................................................62 
11.5.2. 
Injection Site Reactions ..............................................................................................62 
11.5.3. 
Assessment of Causality .............................................................................................63 
11.5.4. 
Follow-up of Adverse Events .....................................................................................64 
11.6. 
Prompt Reporting of Serious Adverse Events ............................................................64 
11.6.1. 
Completion and Transmission of the Serious Adverse Event Reports .......................64 
11.6.2. 
Pregnancy Reporting ..................................................................................................65 
11.6.3. 
SAE Reports to the IRB/EC .......................................................................................65 
11.7. 
Regulatory Requirements for Reporting of SAEs ......................................................65 
11.8. 
Poststudy Adverse Events...........................................................................................66 
11.9. 
Serious Adverse Events Related to Study Participation .............................................66 
12. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .............................66 
12.1. 
Endpoints ....................................................................................................................66 
12.1.1. 
Primary Endpoint ........................................................................................................66 
12.1.2. 
Secondary Endpoints ..................................................................................................66 
12.1.3. 
Exploratory Endpoints ................................................................................................67 
12.2. 
Analysis Populations ..................................................................................................68 
12.3. 
Sample Size Considerations .......................................................................................68 
12.4. 
Interim Analysis ..........................................................................................................68 
12.5. 
Stratification ...............................................................................................................68 
12.6. 
Analysis Methods .......................................................................................................69 

 
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12.6.1. 
Screening Data ............................................................................................................69 
12.6.2. 
Efficacy and Pharmacodynamics Analysis .................................................................69 
12.6.3. 
Pharmacokinetics Analysis .........................................................................................70 
12.6.4. 
Safety/Tolerability Analysis .......................................................................................70 
12.6.5. 
Analysis of Immunogenicity (Anti-drug Antibodies) Data ........................................70 
12.7. 
Data Recording and Quality Control ..........................................................................71 
13. 
STUDY APPROVAL AND CONDUCT ...................................................................71 
13.1. 
Regulatory Approval ..................................................................................................71 
13.2. 
Institutional Review Board (IRB)/Ethics Committee (EC) Approval ........................71 
13.3. 
Ethical Considerations ................................................................................................71 
13.4. 
Written Informed Consent ..........................................................................................72 
13.5. 
Emergency Contact with Principal Investigator .........................................................72 
13.6. 
Notification of General Practitioner ...........................................................................72 
13.7. 
Clinical Laboratory Certification and Reference Ranges ...........................................72 
13.8. 
Protocol Deviations ....................................................................................................73 
13.9. 
Termination of the Study ............................................................................................73 
14. 
STUDY ADMINISTRATION ...................................................................................74 
14.1. 
Study Monitoring ........................................................................................................74 
14.2. 
Quality Assurance .......................................................................................................75 
14.3. 
Records Retention .......................................................................................................75 
15. 
INFORMATION DISCLOSURE AND INVENTIONS ............................................76 
15.1. 
Ownership ...................................................................................................................76 
15.2. 
Confidentiality ............................................................................................................76 
15.3. 
Data Protection ...........................................................................................................77 
15.4. 
Publication ..................................................................................................................77 
16. 
REFERENCES ...........................................................................................................78 
APPENDIX 1. LIVER-RELATED STUDY MODIFICATION AND FOLLOWUP 
GUIDELINES .............................................................................................................82 
APPENDIX 2. LOCAL INJECTION SITE REACTIONS ........................................................84 
APPENDIX 3. GLYCEMIC CONTROL-RELATED GUIDELINES .......................................85 
 
 

 
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List of Tables 
Table 1: 
Schedule of Assessments ............................................................................................13 
Table 2  
Restricted Concomitant Medications ..........................................................................46 
Table 3 
Injection Number and Volume Per Dose Cohort ........................................................49 
Table 4 
Liver Related Study Modification and Follow-Up Guidelines for Participants .........82 
Table 5 
Local Injection Site Reactions (LISRS) .....................................................................84 
 
List of Figures 
Figure 1 
siRNA Mechanism of Action .....................................................................................30 
Figure 2 
Study Schema .............................................................................................................36 
 

 
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3. 
STUDY INFORMATION AND SIGNATURE 
Protocol Title: A Double-Blind, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy 
and Safety of ARO-APOC3 in Adults with Severe Hypertriglyceridemia 
Protocol Number: AROAPOC3-2001 
Version: Amendment 5, Version Date 26 January 2023 
INVESTIGATOR SIGNATURE: 
I have read and understand the information in this protocol and agree to conduct the study 
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 study. I agree to 
ensure that all who assist me in the conduct of the study are aware of their obligations. 
 
 
 
 
Signature 
Date 
 
 
Printed Name 
 
 
 
 

 
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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ASCVD 
Atherosclerotic cardiovascular disease 
AE 
Adverse event 
AHA/ACC 
American Heart Association/American College of Cardiology 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
API 
Active pharmaceutical ingredient 
ApoB 
Apolipoprotein B 
ApoB-48 
Apolipoprotein B 48  
ApoB-100 
Apolipoprotein B 100  
ApoA-I 
Apolipoprotein A-I 
ApoA-V or APOA5 
Apolipoprotein A-V 
ApoC-II or APOC2 
Apolipoprotein C-II 
ApoC-III or APOC3 
Apolipoprotein C-III 
AST 
Aspartate aminotransferase 
ARO 
Arrowhead Pharmaceuticals, Inc 
ARO-APOC3 Injection Clinical drug product solution ready for SC injection 
ARO-APOC3 
Short name for ARO-APOC3 Injection 
CECT 
Contrast-enhanced computed tomography 
COVID 
Coronavirus disease 
CTCAE 
Common Terminology Criteria for Adverse Events 
GalNAc 
N-acetyl galactosamine 
GCP 
Good Clinical Practice 
cGMP 
Current Good Manufacturing Practice 
CM 
Chylomicronemia 
CRA 
Clinical Research Associate 
CRF 
Case report form 
CRO 
Contract Research Organization 
CS 
Clinically significant 
DSC  
Data Safety Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 

 
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eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
ET 
Early Termination 
FAS 
Full Analysis Set 
FCS 
Familial Chylomicronemia Syndrome 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GPIHBP1 
Glycosylphosphatidylinositol anchored high-density lipoprotein binding 
protein 1 
HbA1c 
Glycated hemoglobin  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein-cholesterol 
HOMA-IR 
Homeostatic model assessment for insulin resistance 
hsCRP 
high sensitivity C-reactive protein 
HTG 
Hypertriglyceridemia 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation  
IDL 
Intermediate-density lipoprotein 
IFCC 
International Federation of Clinical Chemistry 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
IWRS 
Interactive Web Response System 
LD 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein-cholesterol 
LIPG 
Endothelial lipase 
LISR 
Local injection site reaction 
LMF1 
Lipase maturation factor 1 

 
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Lp(a) 
Lipoprotein (a) 
LPL 
Lipoprotein lipase 
MCH 
Mean cell hemoglobin 
MCHC 
Mean cell hemoglobin concentration 
MCM 
Multifactorial chylomicronemia 
MCV 
Mean cell volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRI-PDFF 
Magnetic resonance imaging-proton density fat fraction 
mRNA 
Messenger ribonucleic acid 
NCEP 
National Cholesterol Education Program 
NHV 
normal healthy volunteer 
NOAEL 
No adverse effect level 
non-HDL-C 
non-high-density lipoprotein-cholesterol 
NYHA 
New York Heart Association 
OTC 
Over-the-counter 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Preferred Term 
Q12W 
Once every 12 weeks 
RISC 
RNA-induced silencing complex 
RNA 
Ribonucleic acid 
RNAi 
RNA interference 
SAE 
Serious adverse event  
SC 
Subcutaneous 
SD 
Standard deviation 
SHTG 
Severely high hypertriglyceridemia 
siRNA 
Short interfering RNA oligonucleotides  
SOA 
Schedule of Assessments 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride(s) 

 
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TRL 
TSH 
Triglyceride-rich lipoprotein 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
VLDL-C 
Very low-density lipoprotein-cholesterol 
 
Definition of Terms  
Investigational Product (IP) is defined as, “A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use” (from International Council for Harmonisation [ICH] 
of Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonised 
Tripartite Guideline E6: Guideline for Good Clinical Practice). 

 
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5. 
BACKGROUND 
Severely high hypertriglyceridemia (SHTG) is a disorder characterized by marked elevations in 
triglyceride (TG) levels which can lead to acute pancreatitis, as well as an increased risk of 
cardiovascular disease and atherosclerosis (Hegele 2014, Scherer 2014). Acute pancreatitis 
typically causes severe upper abdominal pain and may result in emergency room visits, 
hospitalizations, and even deaths (Chatila 2019, Scherer, 2014). The National Cholesterol 
Education Program (NCEP) Adult Treatment Panel III recommends TG-lowering therapy when 
TG are ≥500 mg/dL (≥5.65 mmol/L) to prevent acute pancreatitis (NCEP 2002, Pedersen 2016). 
This threshold was also used to define adult patients with SHTG indicated for TG-lowering 
medications such as VASCEPA® (icosapent ethyl), and EPANOVA® (omega-3-carboxylic acid) 
in the United States (US) and is the threshold used in the 2018 American Heart 
Association/American College of Cardiology (AHA/ACC) Guideline on the Management of 
Blood Cholesterol (Grundy 2019). Lowering TG below 500 mg/dL (5.65 mmol/L) has been 
shown to be associated with significant clinical benefits (Christian 2012, Chen 2017, 
Murphy 2013). Compared with TG ≥500 mg/dL (≥5.65 mmol/L), TG <500 mg/dL 
(<5.65 mmol/L) was associated with a lower incidence of acute pancreatitis (0.47 versus 
1.09 event per 100 person-years), cardiovascular events (4.93 versus 6.30 event per 
100 person-years), and overall healthcare utilization and costs (Christian, 2012).  
5.1. 
Overview of Severe Hypertriglyceridemia (SHTG) 
The prevalence of SHTG in adults in the US is approximately 1.7%, based on the NHANEs 
database (2001-2006) of individuals with TG levels between 500 and 2000 mg/dL (5.65 to 
22.6 mmol/L) (Christian 2011, Laufs 2020). The prevalence of adults with TG levels 
>885 mg/dL (>10 mmol/L) or >1000 mg/dL (>11.3 mmol/L) are even lower (range 1:600 to 
1:1000, or between 0.1% to 0.2%) (Laufs 2020, Brown 2018). SHTG can be caused by many 
factors, including a combination of genetics, diet, lifestyle choices (eg, excessive alcohol intake), 
and comorbid conditions, such as obesity, metabolic syndrome, hypothyroidism, and Type 2 
diabetes mellitus (Laufs 2020, Yuan 2007). Genetic causes of SHTG are typically associated 
with high TG levels in excess of 885 mg/dL (10 mmol/L) and can have both monogenic 
(Familial Chylomicronemia Syndrome [FCS or hypertriglyceridemia Type 1]) and polygenic 
(Multifactorial Chylomicronemia [MCM or Type 5 hyperlipoproteinemia]) determinants 
(Paquette 2019). FCS is an autosomal recessive and rare condition with an estimated prevalence 
of 1 to 2 in a million that is caused by loss-of-function mutations in the gene encoding 
lipoprotein lipase (LPL) or, less frequently, by mutations in genes encoding other proteins 
necessary for LPL function (De La Torre 2000, Laufs 2020, Warden 2020). LPL activity is the 
primary mechanism by which plasma TG are hydrolyzed, with subsequent efficient removal of 
TG-rich lipoprotein (TRL) remnants by the hepatocyte. Patients with FCS routinely have TG 
levels >2000 mg/dL (>22.6 mmol/L), with some as high as 15000 mg/dL (169.5 mmol/L) 
(Gaudet 2014, Warden 2020). The other form of chylomicronemia, MCM, may include 
heterozygous variants in the 5 genes associated with FCS, as well as variants in other genes 
associated with regulating TG levels (Laufs 2020). MCM commonly involves increased 
polygenic risk on top of exacerbating factors such as a diet rich in fats and simple sugars, 

 
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obesity, and diabetes (Paquette 2019). The prevalence of MCM is estimated to be 1 in 600 to 1 in 
1000 adults (Warden 2020, Brown 2018).  
Acute pancreatitis, a known condition associated with SHTG, is characterized by severe and 
persistent upper abdominal pain and elevated serum lipase and/or amylase levels that may result 
in organ failure, frequent emergency room visits, hospitalizations, chronic abdominal pain, and 
even deaths. The recurrence of acute pancreatitis can lead to chronic pancreatitis and associated 
pancreatic endocrine dysfunction such as diabetes mellitus. Mortality associated with an attack 
of acute pancreatitis can range from 3% in mild cases to 30% in severe cases (FDA 2018). 
Morbidity and mortality of acute pancreatitis associated with hypertriglyceridemia (HTG) is 
greater than for other etiologies (FDA 2018). The risk of acute pancreatitis increases relative to 
the elevation in serum TG levels with the incidence of acute pancreatitis increasing 3% to 4% for 
every 100 mg/dL (1.13 mmol/L) increase in TG level (Scherer 2014, Gelrud 2017). For example, 
the lifetime risk of acute pancreatitis is approximately 5% in patients with TG levels 
>1000 mg/dL (>11.3 mmol/L), which increases to approximately 10% to 20% in patients with 
TG levels >2000 mg/dL (22.6 mmol/L) (Scherer 2014; Sanchez 2021; Esparza 2019). Even 
within a lower threshold, the risk for acute pancreatitis was more than 5-fold higher for adults 
with TG levels ≥443 mg/dL (≥5.01 mmol/L) compared with individuals with TG levels in the 
normal range (<89 mg/dL or 1.01 mmol/L) (Pedersen 2016). 
Conventional management of SHTG includes dietary restrictions of fat, lipid-lowering 
medications (eg, statins, omega-3-fatty acids), and other lifestyle changes (eg, smoking 
cessation, exercise, and weight reduction). In cases of acute pancreatitis due to SHTG, insulin 
infusions and apheresis may be used to rapidly reduced TG levels. Reduction and maintenance of 
TG levels to below 500 mg/dL (5.65 mmol/L) can effectively prevent recurrences of pancreatitis 
(NCEP 2002). However, this threshold level is difficult to achieve for many patients, despite 
dietary restrictions and the availability of lipid-lowering medications, including omega-3-fatty 
acids used to lower TG. Many available medications, including fibrates and omega-3-fatty acids, 
work through a LPL pathway. These treatments are not effective in patients with SHTG 
secondary to defective LPL pathways. 
Apolipoprotein C3 (APOC3, ApoC-III), a component of TRLs, has been identified as a key 
regulator of serum TG levels and plays an important role in the pathogenesis of SHTG 
(Gaudet 2014, Khetarpal 2015, Saleheen 2017, Jorgensen 2014). Predominantly produced in 
hepatocytes, APOC3 inhibits hydrolysis of TG through inhibition of LPL (LPL dependent 
pathway) and delays clearance of lipoprotein remnants by hepatocyte receptor-mediated uptake 
(LPL-independent pathway), resulting in hypertriglyceridemia (TG and HDL Working Group 
2014). Insights gained from studies in transgenic mice overexpressing APOC3 and in Apoc3 
knockout mice have shown that APOC3 delays very low-density lipoprotein (VLDL) hydrolysis 
in vivo and may delay the catabolism of TRL remnants by the liver and other tissues 
(Aalto-Setala 1992, Aalto-Setala 1996, Gerritsen 2005, Jong 2001, Khetarpal 2015). APOC3 
knockout models in rabbits also exhibited significantly lower plasma levels of TG, VLDL, and 
intermediate-density lipoproteins (IDL) as well as greater TG clearance compared with wild-type 
animals. Both aortic and coronary atherosclerosis were significantly reduced in knockout rabbits 
compared with wild-type controls (Yan 2020). Loss-of-function mutations in APOC3 in humans 
are associated with lower TG levels and decreased incidence of coronary artery disease. 

 
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Heterozygosity of “loss-of-function” mutations in APOC3 caused a 46% reduction in circulating 
APOC3 levels with associated reductions in TG of 39% (TG and HDL Working Group 2014). 
APOC3 homozygous-deficient individuals demonstrate APOC3 reductions of 88% and TG 
reductions of 59% compared to non-carriers (Saleheen 2017, Lek 2016). Individuals with 
APOC3 deficiency do not demonstrate significant hepatic steatosis and appear phenotypically 
normal other than lower TG and higher high-density lipoprotein-cholesterol (HDL-C) 
(Jorgensen 2014). 
5.2. 
Overview of ARO-APOC3 Development 
A brief overview of existing information on ARO-APOC3 is provided below; a comprehensive 
review of available data is contained in the Investigator’s Brochure (IB) provided by the 
Sponsor, which should be reviewed prior to initiating the study. 
5.2.1. 
Mechanism of Action of ARO-APOC3 and Therapeutic Rationale 
5.2.1.1. 
siRNA Mechanism of Action 
ARO-APOC3 works through a mechanism of RNA interference (RNAi). RNAi-based 
therapeutics have the potential to silence the expression of any specific target gene. RNAi is a 
naturally occurring phenomenon by which short interfering RNA oligonucleotides (siRNAs) 
trigger a sequence-specific down-regulation of gene expression. RNAi triggers refer to synthetic 
oligonucleotides designed to target for silencing specific gene expression (Fire 1998). The RNAi 
trigger is a short, double-stranded siRNA conjugated to a hepatocyte-targeted N-acetyl 
galactosamine (GalNAc) targeting moiety, acting as a ligand for the highly expressed, 
hepatocyte-specific asialoglycoprotein receptor. Available non-clinical and clinical 
pharmacokinetics (PK) data show rapid absorption and clearance of all GalNac conjugated 
triggers from the blood stream within 24 to 48 hours post-subcutaneous (SC) administration.  
ARO-APOC3 is a synthetic, double-stranded, hepatocyte-targeted RNAi trigger designed to 
specifically silence messenger RNA (mRNA) transcripts from the APOC3 gene using an RNAi 
mechanism. Preclinical distribution studies show that ARO-APOC3 is primarily distributed to 
the liver where the trigger molecule is taken up by hepatocytes via receptor-mediated 
endocytosis. Introduction of the double-stranded RNAi trigger into the cytoplasm of hepatocytes 
results in its association with the protein components of the RNA-induced silencing complex 
(RISC), resulting in “on-target” highly sequence-specific degradation of mRNA complementary 
to the antisense strand of the RNAi trigger. Active RISC is a multiple turnover enzyme complex; 
therefore, incorporation of a single RNAi trigger into RISC can result in the degradation of many 
mRNA molecules, and subsequently, prolonged reduction of the expression of the corresponding 
protein. The persistence of pharmacologic activity significantly beyond the period of plasma 
exposure is due in part to this unique RNAi mechanism in which a small amount of guide strand 
can persist and be active within RISC in the cytoplasm of target cells for extended periods of 
time. 

 
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Figure 1 
siRNA Mechanism of Action 
 
Abbreviations: mRNA = messenger ribonucleic acid; RISC = RNA-induced silencing complex; siRNA = short 
interfering RNA oligonucleotides. 
Silencing of hepatic APOC3 using ARO-APOC3 is expected to lower serum TG by preventing 
APOC3-mediated inhibition of LPL, thus allowing enhanced peripheral LPL activity. 
Additionally, APOC3 silencing will remove the steric blockade of APOC3 at the hepatocyte, 
leading to enhanced clearance of TRLs from circulation by the liver. 

 
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5.2.2. 
Preclinical Studies 
The Sponsor is conducting a comprehensive preclinical program to support the SC 
administration of ARO-APOC3. Studies of potential clinical significance and relevance to this 
protocol are summarized below. 
Proof-of-concept studies in animal models support the use of siRNA against APOC3 as a 
potential treatment of SHTG. Findings of potential clinical significance and relevance to this 
protocol are summarized below. Additional details regarding preclinical pharmacology, PK, and 
toxicology results are provided in the IB. 
• Preclinical pharmacology of ADS-005, the active pharmaceutical ingredient (API) in 
ARO-APOC3, shows that ADS-005 treatment in transgenic mice (TgAPOC3) 
resulted in dose-dependent reduction of hepatic APOC3 mRNA levels, which 
correlated with reduced serum APOC3 of >90%. Reductions in serum APOC3 were 
associated with reductions in serum lipids (maximum mean reduction of 91% in TG, 
45% in total cholesterol, and 64% in low-density lipoprotein-cholesterol [LDL-C]).  
• Similar reductions in serum APOC3 were also observed after ADS-005 doses in a 
diet-induced dyslipidemic rhesus monkey model. ARO-APOC3 has been well 
tolerated in rats and in non-human primate toxicology studies.  
• Results of non-Good Laboratory Practice (GLP) in vitro toxicology studies indicate 
there is minimal potential for induction of the innate immune system, no potential for 
complement activation, mitochondrial toxicity/cytotoxicity, or platelet aggregation in 
whole blood associated with ADS-005 exposure at concentrations up to 250 μg/mL, 
which far exceeds the blood concentrations anticipated at the doses to be used 
clinically.  
• ADS-005 was shown to be non-genotoxic and had no adverse effects on the central 
nervous, respiratory, or cardiovascular systems as demonstrated by the results of the 
International Council for Harmonisation (ICH)-recommended battery of genetic 
toxicity and safety pharmacology studies.  
• Multiple-dose GLP toxicity studies with SC administration of ADS-005 in rats and 
cynomolgus monkeys indicate ADS-005 was well tolerated and the no adverse effect 
level (NOAEL) was 300 mg/kg in both species.  
• In both rat and cynomolgus monkey studies, the prominent histopathologic findings 
were consistent with those described for other SC administered GalNAc-siRNA 
drugs. 
5.2.3. 
Clinical Studies 
The Sponsor is investigating ARO-APOC3, which contains the API ADS-005, as a potential 
therapeutic candidate for the treatment of SHTG. The Sponsor has completed a Phase 1, single 
and multiple dose-escalating study (AROAPOC31001) to evaluate the safety, tolerability, PK, 
and pharmacodynamic (PD) effects of ARO-APOC3 in adult healthy volunteers as well as in 
patients with HTG. Interim results from Study AROAPOC31001 show that, in healthy 

 
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volunteers, treatment with ARO-APOC3 reduces hepatic production of ApoC3 via RNAi, 
leading to reductions in serum TG, LDL-C, and ApoB, and increases in high-density lipoprotein-
cholesterol (HDL-C). Results from the Phase 1 study provided information for the design of the 
current Phase 2 study, AROAPOC3-2001. Detailed Phase 1 results are provided in the IB.  
5.3. 
 Risk Assessment for Participants 
• Embryo-Fetal: Limited GLP toxicology and clinical studies have been conducted. 
Accordingly, eligible participants enrolled in this study, both male and female 
(including partners), must agree to use 2 highly-effective forms of contraception 
during the study or agree to abstinence (acceptable only if this method is in alignment 
with the normal lifestyle of the participant).  
• Liver Function: ARO-APOC3 targets the liver. siRNA literature has described 
alanine aminotransferase (ALT) changes associated with off-target effects of the 
siRNA seed region on microRNAs in the hepatocyte (Janas 2018). The siRNA 
sequence of the ARO-APOC3 sense and antisense molecules have been screened for 
potential mRNA and microRNA homology and sequences with homology were 
excluded from consideration. Thus, no such off-target effects are anticipated. In the 
AROAPOC31001 study, transient mild to moderate elevations in ALT were 
occasionally seen (See IB for details) without accompanying elevation in 
international normalized ratio (INR) or total bilirubin. To mitigate this risk, the 
proposed study protocol has built in stopping rules for ALT and aspartate 
aminotransferase (AST) elevation. Blood samples will be drawn as specified in the 
Schedule of Assessments (SOA) (Table 1) to evaluate liver injury and liver function. 
The Data Safety Committee (DSC) will review all available safety data including 
laboratory data periodically.  
• Injection Site Adverse Events (AEs): Other SC-administered, modified siRNA drug 
candidates evaluated in clinical studies have been associated with mild to moderate 
injection site reactions (ISRs) (eg pain, erythema). Generally mild injection site AEs 
have been reported in the AROAPOC1001 study. In this study, steps will be taken to 
minimize ISRs such as rotating injection sites and allowing the ARO-APOC3 
solution to come to room temperature prior to injection. 
• Glycemic Control: An administrative analysis of the 2 ongoing Phase 2 studies has 
indicated increases in serum glycated hemoglobin (HbA1c) in the ARO-APOC3 
treatment group versus the placebo group. The increased HbA1c values were 
observed in a small group of subjects who had preexisting diabetes at baseline and 
particularly in a subset of subjects in the highest (50 mg) ARO-APOC3 dose group.  
To mitigate the risk of worsening glycemic control investigators are encouraged to 
evaluate the diabetes status and adjust diabetes treatment according to clinical 
practice and diabetes care guidance.  

 
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In addition, any subject with worsening diabetic control may return for an 
unscheduled visit for evaluation of HbA1c prior to the next planned dose to confirm 
continued treatment eligibility  
For those subjects who, despite diabetes treatment adjustments, remain with elevated 
HbA1c above protocol pre-established level a number of study drug discontinuation 
criteria have been established (Appendix 3).  
Routine monitoring of HbA1c and fasting glucose concentrations will be assessed as 
part of the clinical laboratory panels to monitor glycemic control, as specified in the 
SOA (Table 1).  
5.4. 
Study Rationale 
Interim results from the Phase 1, first in human study AROAPOC31001 show that, in healthy 
volunteers, treatment with ARO-APOC3 reduces hepatic production of APOC3 via RNAi, 
leading to reductions in serum TG, LDL-C, and apolipoprotein B (ApoB), and increases in 
HDL-C. Doses of 10, 25, 50, and 100 mg all demonstrated durable PD activity lasting beyond 
Week 12. Aside from mild and transient ISRs and transient, self-limited ALT elevations, single 
and repeat doses of ARO-APOC3 were well tolerated in healthy volunteers and the safety profile 
based on Phase 1 warrants additional later stage clinical evaluation. 
Based on these results, this current study will be conducted in adults with SHTG, defined as 
patients whose mean fasting triglyceride level is ≥500 mg/dL (5.65 mmol/L) and ≤4000 mg/dL 
(45.2 mmol/L) at Screening. The design is intended to evaluate the effects of 3 different dosing 
levels of ARO-APOC3 (10, 25, or 50 mg) with 2 doses administered per dose level on Day 1 and 
Week 12, against volume-matched placebo in lowering TG levels on top of lipid-lowering 
medications and dietary modifications. Plasma concentrations of ARO-APOC3 will also be 
measured over time to evaluate the PK profile. Administration of doses on Day 1 and Week 12 
with extended follow-up through Week 48 will allow complete assessment of effect duration. 
This study is expected to inform on dose level and dose interval selection for later stage clinical 
development.  
5.5. 
Rationale for Dose and Schedule of Administration 
In the Phase 1 study evaluating ARO-APOC3 in healthy volunteers, single doses of 10, 25, or 
50 mg consistently reduced serum APOC3 and TG levels through Week 16 with a gradual rise in 
these PD parameters occurring in several healthy volunteers after Week 16 and an increase from 
nadir levels occurring after approximately Week 8 in the 50 mg cohorts. A clearer dose response 
is seen with HDL-C with dose-dependent HDL-C increases demonstrated with increasing doses. 
While limited data are available for patients with HTG, ARO-APOC3 50 mg administered on 
Days 1 and 29 maintains APOC3 reduction through Week 12.  
The 10, 25, 50, and 100 mg dose levels were assessed in the Phase 1 study (AROAPOC31001), 
and based on safety and efficacy analyses from that study the dose levels of 10, 25, and 50 mg 
were selected for use in this Phase 2 study based on their durable PD activity and overall 
safety/tolerability profile. The 10, 25, and 50 mg single doses of ARO-APOC3 demonstrate PD 

 
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activity lasting beyond Week 12. The proposed study design is intended to evaluate the duration 
of effect after doses of 10, 25, or 50 mg administered on Day 1 and Week 12 with follow-up 
through Week 48. This design will inform on optimal dose and duration based on time for TG, 
APOC3 levels, and other lipid parameters to return to baseline after the second dose. The results 
of this study will inform on dose level and intervals to be used in later stage clinical studies. 
The planned dose levels of 10, 25, and 50 mg are approximately 1/2100th, 1/840th, and 1/420th, 
respectively, of the NOAEL (300 mg/kg) from 4 week/3 dose GLP toxicology studies in both 
rats and monkeys, assuming weight-based conversion and an average 70 kg participant. In 
chronic GLP toxicity studies, the NOAEL was 15 mg/kg in the rat and 180 mg/kg in monkeys. 
Assuming a 70 kg participant, this translates into a safety margin for the top proposed dose of 
50 mg in this study of approximately 20-fold based on the rat NOAEL and 250-fold based on the 
monkey NOAEL. It should be additionally noted that the dose frequency in this proposed study 
is only once every 12 weeks (Q12W), whereas the dose frequency in chronic toxicology studies 
(6-month rat and 9-month monkey) was every 4 weeks. Therefore, there is a wide margin of 
safety between planned clinical doses and animal toxicology study NOAELs.  
5.6. 
Benefit-Risk Assessment 
ARO-APOC3 has been shown to have a favorable benefit-risk profile to date that warrants 
further clinical investigation and longer exposure periods. As of the October 08, 2020 (for 
non-safety) and October 15, 2020 (for safety) cutoff dates, interim PD data from the Phase 1 
study AROAPOC31001 showed that administration of ARO-APOC3 at doses ranging from 10 to 
100 mg resulted in significant and durable reduction of serum APOC3 when compared with 
placebo in healthy volunteers as well as in patients with HTG and CM. 
Silencing of APOC3 led to reductions in the levels of serum TG and other lipid parameters. 
Results using single doses of ARO-APOC3 in normal healthy volunteers (NHVs) demonstrate 
dose-dependent reductions in serum APOC3 of up to -94%when compared to baseline. As would 
be predicted, knockdown of APOC3 resulted in decreased fasting serum TG (up to -66%) and 
non-HDL-C (up to -31%) as well as increased serum HDL-C levels (up to +74%) with a dose 
response generally correlating with APOC3 serum level reductions in participants receiving the 
active drug. Results for repeat doses of AROAPOC3 in NHVs demonstrated consistent 
reductions of APOC3 (up to -94%), TGs (up to -75%), and non-HDL-C (up to -34%), and 
increases in HDL-C levels (up to +75%). These responses were overall sustained through Week 
16, which is 12 weeks after the last dose. 
Results for repeat doses of ARO-APOC3 in patients with HTG and/or CM demonstrated similar 
or even larger effects of ARO-APOC3 at similar doses studied in NHVs. Reductions of serum 
APOC3 (up to -98%), TGs (up to -88%), non-HDL-C (up to -58%), and increases in HDL-C 
levels (up to +122%) were observed. The effects of ARO-APOC3 treatment on these and other 
key lipid parameters were sustained over the 16 weeks of study duration. 
ARO-APOC3 has been generally well tolerated and has demonstrated favorable safety and 
tolerability. There have been no deaths in the study or study discontinuation due to AEs. Three 
(3) serious AEs (SAEs) involving 3 subjects have been reported, all of which were deemed not 
related to study drug, and the subjects completed the study. There is no clear pattern of an 

 
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increased frequency or intensity of AEs with increasing dose level. The combined placebo 
treatment-emergent AEs (TEAEs) reported were comparable to those seen in the ARO-APOC3 
treatment group. The majority of the reported TEAEs were not related to study treatment, and 
there were no subjects that discontinued from the study due to TEAEs. The most frequently 
reported AEs that were drug-related were the ISRs, which were all mild in intensity. The AEs at 
the injection site are anticipated based on similar findings reported in other clinical studies of 
SC-administered siRNA therapeutics. Overall, there were no clinically significant (CS) adverse 
laboratory trends observed. There were no CS adverse electrocardiogram (ECG), vital sign, or 
physical examination findings during the mentioned study period. 
The Sponsor conducted an administrative analysis of the ongoing Phase 2 studies 
(AROAPOC3-2001 and AROAPOC3-2002). This analysis identified substantially decreased 
mean serum APOC3 levels and median triglyceride levels in subjects receiving ARO-APOC3.  
In the course of the review an apparent increase in the level of HbA1c was observed when 
comparing subjects in the placebo group and those receiving ARO-APOC3. The increase in 
HbA1c was observed mostly in subjects with pre-existing diabetes and was most notable in the 
ARO-APOC3 50 mg dose cohort. A meaningful improvement in lipids and lipoprotein 
metabolism, particularly a decrease in triglycerides, may minimize the risk of pancreatitis and 
coronary artery disease, which is the goal of therapy in these patient populations.  
This observation does not impose an immediate health risk because worsening of diabetes 
control can be managed with diet, treatment adjustments, and compliance to treatment.  
Therefore, in light of the risk mitigation strategies put in place to address the increased HbA1c 
(see Appendix 3) and the clinically meaningful decreases in triglycerides, likely reducing the risk 
for pancreatitis, the benefit risk assessment remains acceptable in this patient population. 
 

 
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6. 
STUDY OBJECTIVES  
The primary objective of the study is to evaluate the safety and efficacy of ARO-APOC3 in 
adults with SHTG and to select a dosing regimen for later stage clinical studies in this patient 
population. 
7. 
STUDY PLAN 
7.1. 
Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, Phase 2b clinical study. Participants who 
have signed an Ethics Committee (EC)/Institutional Review Board (IRB) approved informed 
consent form may initiate screening during which eligibility assessments will be completed. 
Participants must maintain a stable diet and stable lipid-lowering therapy, diabetes mellitus 
therapies, and other background medications, as applicable (see Sections 8.1, 8.4, and 10.2), 
throughout the Screening period and for the duration of the 48-week Treatment Period. Enrolled 
participants will remain on a specified diet throughout the study, as recommended by the 
Investigator, in accordance with local standard of care. Dietary counseling will continue to be 
performed throughout the study as per the SOA (Table 1). Participants who have met all the 
protocol eligibility criteria during screening may be randomized into the study in a double-blind 
fashion. All dose cohorts will enroll in parallel with participants randomly assigned to treatment 
in a 3:1 ratio to receive ARO-APOC3 (10, 25, or 50 mg) or placebo. Each participant will 
receive a total of 2 SC injections on Day 1 and Week 12. 
Figure 2 
Study Schema 
 
 
Abbreviations: EOS = end of study; W = week. 
 
Blinding will be preserved to the extent possible (or unless otherwise specified); however, 
treatment unblinding may occur at the Investigator’s or Medical Monitor’s discretion where 
deemed necessary for treatment of an AE or for a decision to be made regarding study 
continuation in an individual participant. 

 
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Adverse Event Monitoring 
Safety assessments will include: AEs and 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 up to study completion.  
The AE/SAE reporting period for an enrolled participant will begin when the participant 
provides informed consent. Treatment-emergent AEs (TEAEs) and SAEs are defined as AEs that 
occur following investigational product (IP) administration or a pre-existing condition 
exacerbated following IP administration. The TEAE-reporting period begins after the first dose 
and extends until the End-of-Study (EOS) visit is complete. All SAEs that occur during the 
reporting period, in addition to reporting via electronic case report forms (eCRFs), must also be 
reported to the Sponsor via the SAE report form within 24 hours of being notified. All 
AEs/SAEs will be followed until resolution, until the condition stabilizes, until the event 
causality is otherwise explained, or until the participant is lost to follow-up. If the Investigator 
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 reasonably related to the IP, the Investigator will promptly 
notify the Sponsor. Laboratory or diagnostic assessment (eg, ECG) abnormalities will be 
reported as AEs if considered CS by the Investigator. Laboratory or diagnostic assessment 
abnormalities not reported as AEs are not to be reported as CS in the study database. 
7.1.1. 
Number of Study Sites 
Approximately 80 centers globally. 
7.1.2. 
Number of Participants 
Approximately 216 participants.  
7.1.3. 
Estimated Study Duration 
The duration of the study is approximately 54 weeks from Screening to the Week 48 EOS 
examination. The treatment duration of the study will be approximately 48 weeks from Day 1 to 
the Week 48 EOS examination. The overall study duration from first participant enrolled to last 
participant last visit is expected to be approximately 2 years.  
The Screening period will last up to approximately 6 weeks (Day -42 through Day -1) consisting 
of dietary stabilization and other required eligibility assessments. Laboratory values assessed to 
determine TG eligibility during the Screening period and all other lipid parameters throughout 
the study will be collected from participants in a fasted state.  
At Week 48, participants will be eligible and invited to consent and continue in an open-label 
extension study. All placebo participants will switch to active drug during the extension study.  

 
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7.2. 
Discussion of Study Design, Including Choice of Control Group 
The primary objective of the study is to select 1 dose and dose interval for later stage clinical 
studies based on evaluation of the safety and efficacy of 3 doses of ARO-APOC3 in participants 
with SHTG.  
Participants confirmed to be on a stable diet and on stable background medications, as applicable 
(see Sections 8.1, 8.4, and 10.2), will complete all eligibility assessments within 6 weeks (Day -
42 to Day -1) prior randomization on Day 1 in accordance with the SOA (Table 1). The 
Treatment Period will begin on Day 1 and will continue for 48 weeks. Dietary counseling will 
commence at the start of the Screening Period and will be reinforced at intervals throughout the 
Treatment Period. This approach is necessary to minimize the potential effects of dietary changes 
that can alter TG levels and confound interpretation of study results. 
A placebo-controlled design was chosen because it would have been impractical to maintain 
blinding with an active control. All participants in active and placebo groups on lipid-lowering 
therapies will be required to remain on a stable regimen during the study. In response to diabetes 
evaluations, adjustments to treatment medication are allowed at the discretion of the Principal 
Investigator (refer to see Section 8.1 and Section 8.4). Compared with the potent effect of ARO-
APOC3 in lowering TG levels, other first-line therapies have modest effects on TGs. For 
example, patients with SHTG receiving omega-3 fatty acid only had a 33% placebo-adjusted 
reduction in TG (Bays 2011), and patients with mild TG elevations receiving gemfibrozil had a 
31% reduction in TG (Rubins 1999). Thus, additional TG and lipid-lowering effect is expected 
when ARO-APOC3 is used on top of optimal lipid-lowering therapy. In this Phase 2 study, 
concomitant use of optimal statin therapy, nicotinic acid/niacin, omega-3 fatty acids (prescription 
or over-the-counter [OTC]), or fibrates or other lipid management regimens will be permitted as 
long as the participants have had a stable regimen (see Sections 8.1 and 8.4 [Table 2]) prior the 
Screening laboratory assessments and will agree to stay on this baseline regimen during the 
Treatment Period. Randomization will be stratified by mean level of TG at Screening 
(≥1000 mg/dL versus <1000 mg/dL). 
The duration of the treatment is intended to ensure adequate exposure to ARO-APOC3 to 
evaluate the safety and efficacy for its long-term use and to facilitate selection of a lowest 
effective dose to maximally lower TG. The primary analysis will be at Week 24. Additional 
analysis at various timepoints from Week 24 over time through Week 48 will assess the 
durability of the treatment effect, additional efficacy outcomes, and long-term safety. 

 
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8. 
SUBJECT SELECTION 
The proposed participant population is adults with SHTG, defined as mean fasting TG level 
≥500 mg/dL (≥5.65 mmol/L) and ≤4000 ml/dL (45.2 mmol/L) at Screening (Esparza 2019). The 
NCEP Adult Treatment Panel III recommends TG-lowering therapy when TG are ≥500 mg/dL 
(≥5.65 mmol/L) to prevent acute pancreatitis (NCEP 2002, Pedersen 2016). This threshold was 
also used to define adult patients with SHTG indicated for TG-lowering medications such as 
VASCEPA® (icosapent ethyl), and EPANOVA® (omega-3-carboxylic acid) in the US, and is the 
threshold used in the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol 
(Grundy 2019). Lowering TG below 500 mg/dL (5.65 mmol/L) has been shown to be associated 
with significant clinical benefits (Christian 2012, Chen 2017, Murphy 2013). Compared with TG 
≥500 mg/dL (≥5.65 mmol/L), TG <500 mg/dL (<5.65 mmol/L) was associated with a lower 
incidence of acute pancreatitis (0.47 versus 1.09 events per 100 person-years), cardiovascular 
events (4.93 versus 6.30 events per 100 person-years), and overall healthcare utilization and 
costs (Christian 2012). To ensure that appropriate participants are selected, the inclusion and 
exclusion criteria are provided in Section 8.1 and Section 8.2. 
Information about the study population size is provided in Section 7.1.2. 
8.1. 
Inclusion Criteria 
To be eligible for enrollment, participants must meet all the following inclusion criteria: 
1. Males or nonpregnant (who do not plan to become pregnant), nonlactating females 
≥18 years of age; 
2. Based on medical history, prior evidence of fasting TG ≥500 mg/dL (5.65 mmol/L);  
3. A mean fasting TG ≥500 mg/dL (5.65 mmol/L) and ≤4000 ml/dL (45.2 mmol/L) 
collected at two separate and consecutive visits at least 7 days apart and no more than 17 
days apart during the Screening period; 
4. If the participant has a medical history of clinical ASCVD or elevated 10-year ASCVD 
risk (eg, ≥7.5% per American Heart Association/American College of Cardiology 
[ACC/AHA] risk calculator for subjects >40 years of age or Framingham risk score 
calculator for subjects under the age of 40) then participant must be on appropriate lipid-
lowering therapy as per local standard of care (ie, including moderate-to-high intensity 
statin, as indicated) prior to collection of qualifying TG levels;  
5. Able and willing to provide written informed consent prior to the performance of any 
study-specific procedures;  
6. Willing to follow diet counseling and maintain a stable diet as per Investigator judgment 
based local standard of care;  
7. Participants of childbearing potential must agree to use highly effective contraception as 
described in Section 10.6, during the study and for at least 24 weeks following the last 
dose of IP. Males must agree to not donate sperm during the study and for at least 
24 weeks following the last dose of IP.  

 
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8. Women of childbearing potential on hormonal contraceptives must be stable on the 
medication for >2 menstrual cycles prior to Day 1; and 
9. Participants on any of the following medications must be on a stable regimen for the 
specified duration prior to collection of Screening Visit (S2) laboratory tests and for the 
duration of study participation. 
Medication 
Time on stable regimen prior to collection of 
Screening Visit (S2) laboratory tests  
Lipid-lowering therapies (including statins) 
>4 weeks 
Beta-blockers, thiazide diuretics 
>4 weeks 
Fibrates 
>6 weeks 
PCSK9 inhibitors 
>8 weeks 
Retinoids 
>8 weeks 
Atypical antipsychotics  
>12 weeks 
Diabetes mellitus medications 
>12 weeks 
Anticoagulation therapy 
>12 weeks 
Thyroid hormone replacement therapy 
>12 weeks 
Testosterone replacement therapy 
>16 weeks 
Oral estrogens, tamoxifen, raloxifene 
>16 weeks 
Immunosuppressants 
>24 weeks 
NOTE: All laboratory tests used as inclusion criteria will be assessed by a central laboratory and may be 
repeated once and the repeat value may be used for inclusion purposes. Local laboratory testing may be 
permitted in limited circumstances and only with prior Sponsor approval (see Table 1). 
8.2. 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1. Current use, or use within the last 365 days from Day 1, of any hepatocyte-targeted 
siRNA or antisense oligonucleotide molecule;  
2. Active pancreatitis within 12 weeks prior to Day 1; 
3. Known genetically-confirmed diagnosis of FCS 
4. Any planned bariatric surgery or similar procedures to induce weight loss during the 
period starting at consent through EOS; 
5. History of major surgery within 12 weeks of Day 1 or planned major surgery during the 
study; 
6. Planned coronary intervention (such as stent placement or heart bypass) during the study; 

 
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7. History of acute coronary syndrome event within 24 weeks of Day 1;  
8. New York Heart Association (NYHA) Class II, III, or IV heart failure or last known 
ejection fraction of <30%; 
9. Uncontrolled hypertension (sitting blood pressure >160/100 mmHg at Screening), 
participant may be rescreened once hypertension is controlled; 
10. History of hemorrhagic stroke within 24 weeks of Day 1; 
11. History of bleeding diathesis or coagulopathy; 
12. Current diagnosis of nephrotic syndrome; 
13. Any of the following laboratory values at Screening: 
a. Hepatic: ALT or AST >2× upper limit of normal (ULN) at Screening  
b. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (using the 
Modification of Diet in Renal Disease [MDRD equation]) at Screening  
c. HbA1c >9.0% (or >75 mmol/mol International Federation of Clinical Chemistry 
[IFCC] units) at Screening; 
d. Spot urine protein/spot urine creatinine ratio >3 grams per day; 
e. Clinically significant abnormality in PT, aPTT, or INR; 
14. Use of any of the following:  
a. Systemic corticosteroids or anabolic steroids within 4 weeks prior to Day 1 or 
planned use during the study (stable doses of testosterone replacement therapy 
>16 weeks prior to Screening [visit S2] is permitted for a documented history of 
hypogonadism [low testosterone] as verified in subject health records) 
b. Plasma apheresis within 4 weeks prior to Day 1 or planned during the study;  
15. Blood donation of 50 to 499 mL within 4 weeks of Screening (visit S2) laboratory 
collection or of >499 mL within 8 weeks of Screening (visit S2) laboratory collection;  
16. Known history of human immunodeficiency virus infection; 
17. Seropositive (hepatitis B surface antigen [HBsAg] +) for hepatitis B virus (HBV) or 
hepatitis C virus (HCV) (HCV seropositivity requires positive test for antibodies 
confirmed with positive test for HCV RNA);  
18. Clinical evidence of uncontrolled hypothyroidism or hyperthyroidism as per 
Investigator’s judgment; 
19. History of malignancy within the last 2 years prior to the date of consent except for 
adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder 
tumors, or in situ cervical cancer. Currently receiving systemic cancer treatment(s) or, in 
the Investigator's opinion, at risk of relapse for recent cancer;  
20. Use of an investigational agent or device within 30 days or within 5 half-lives, based on 
plasma PK (whichever is longer) prior to Day 1 or current participation in an 
interventional investigational study. Participants previously exposed to ARO-APOC3 or 
ARO-ANG3 will require a washout period of at least 1 year from last dose; 

 
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21. Unwilling to limit alcohol consumption to within moderate limits for the duration of the 
study, as follows: not more than 14 units per week (1 unit = 80 mL of wine, 200 mL of 
beer, or 25 mL of 40% alcohol); 
22. Any concomitant medical or psychiatric condition or social situation or any other 
situation that, in the Investigator’s judgment, would make it difficult to comply with 
protocol requirements or put the participant at additional safety risk. 
All laboratory tests used as exclusion criteria may be repeated once and the repeat value may be 
used for exclusion purposes. 
8.3. 
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 Investigator, medically trained designee, or Sponsor 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; 
• noncompliance of participant with protocol; 
• participant unwilling to proceed and/or consent is withdrawn; or 
• withdrawal from the study if, in the Investigator’s judgment, it is in the participant’s 
best interest. 
The reasons for withdrawal will be recorded on the eCRF and included in the final clinical study 
report, along with any AEs and any necessary medical treatment.  
If a participant is withdrawn from the study due to significant AE or SAE, the Investigator, or 
medically trained designee, will evaluate the urgency of the event. If the situation warrants, the 
Investigator, or medically trained designee, will take appropriate diagnostic and therapeutic 
measures. If the situation is not an immediate emergency, the Investigator, or medically trained 
designee, at the clinical study facility will attempt to contact the 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. 
8.3.1. 
Data Safety Committee and Treatment Stopping Rules 
An independent DSC will be assembled to review safety data after half of the total number of 
participants planned for enrollment have received at least 1 dose of IP. This group may also be 
asked by the study Sponsor to meet on an ad hoc basis to review safety data and make 
recommendations related to the study. Planned safety reviews will include evaluations for 
imbalances between active and placebo groups for AEs and SAEs. The DSC may be asked to 
review safety data at additional unscheduled meetings should a potential safety signal be 

 
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detected. The DSC may also make recommendations to the Sponsor for modifying, stopping, or 
continuing the study as planned. Blinded data will be reviewed initially and if there are any 
concerns or unblinded review is warranted based on blinded review, the DSC may review 
unblinded data in a closed session. 
The DSC may recommend to the Sponsor to pause additional dosing to allow for time to 
evaluate safety data and recommend the action to be taken, which may include, but is not limited 
to, one of the following: 
• The study may continue without modifications  
• The study may continue with modifications 
• The study should be terminated 
• The study should be temporarily suspended 
• Other changes 
Sponsor or Investigator can discontinue any participant at any time.  
A decision to modify the study or pause/suspend dosing in an individual participant, group of 
participants, or to halt enrollment temporarily or permanently may be indicated based on any of 
the following:  
• Any confirmed pregnancy in the study will lead to permanent discontinuation of IP 
dosing of that participant; or 
• A need for apheresis or other emergent interventions indicated to lower TG; or 
• Acute pancreatitis; or 
• In participants with normal (per central laboratory reference range) aspartate 
aminotransaminase (AST) or alanine aminotransferase (ALT) on Day 1, treatment-
emergent elevations >3× upper limit of normal (ULN) at least possibly related to IP 
per study Investigator, must be confirmed by repeat blood draw within 72 hours of 
initial results. Refer to Appendix 1 for specific guidelines regarding treatment 
discontinuation or interruption for participants with any of the below findings:  
− AST or ALT >5× ULN will lead to permanent discontinuation of IP dosing of that 
participant per Appendix 1. The participant will remain on study follow-up visits 
until EOS as per the Schedule of Assessments (SOA) (refer to Table 1). 
− AST or ALT >3× ULN with a total bilirubin >2× ULN 
− AST or ALT >3× ULN with the new appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
− AST or ALT >3× ULN with a treatment-emergent international normalized ratio 
(INR) >1.5 (must be confirmed on repeat) and which is not explained by another 
plausible cause. 

 
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* if Gilbert's syndrome or hemolysis: doubling of direct bilirubin if baseline 
>0.5 mg/dL. 
Some participants enrolling into this study may have baseline elevations in 
transaminases.  In participants with elevated (per central laboratory reference range) AST 
or ALT on Day 1, treatment-emergent elevations >2× baseline or ≥300 U/L (whichever 
occurs first) at least possibly related to IP per study Investigator, as specified below, must 
be confirmed by repeat blood draw within 72 hours of initial results.  Refer to Appendix 
1 for specific guidelines regarding treatment discontinuation or interruption for 
participants with any of the below findings: 
− AST or ALT >3× baseline or ≥300 U/L (whichever occurs first)  
− AST or ALT >2× baseline or ≥300 U/L (whichever occurs first) with the new 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, or eosinophilia (>5%) 
− AST or ALT >2×baseline or ≥300 U/L with a total bilirubin >2× ULN 
− AST or ALT >2× baseline or ≥300 U/L or with a treatment-emergent INR >1.5 
(must be confirmed on repeat) and which is not explained by another plausible 
cause 
* if Gilbert's syndrome or hemolysis: doubling of direct bilirubin if baseline >0.5 mg/dL. 
Treatment modification guidelines for participants with elevated AST or ALT are 
provided in Appendix 1. 
For any participant experiencing an acute pancreatitis, all TG levels will be provided by 
the central laboratory to the Investigator and Medical Monitor, and the participant will be 
unblinded to their assigned treatment allocation.  If the participant was assigned to 
receive ARO-APOC3, their next dose should be postponed until they are clinically stable 
based on the assessment of the Investigator in consultation with the Medical Monitor.  If 
the participant was assigned to placebo, further dosing will be discontinued; however the 
participant may continue to be followed for the remainder of the 48-week Treatment 
Period, after which, the subject may opt to receive ARO-APOC3 in the planned open-
label extension study.  
8.3.2. 
Study Drug Discontinuation Criteria for Increased HbA1c 
Regarding HbA1c drug discontinuation criteria participants should discontinue IP if they 
meet the following criteria (refer to Appendix 3): 
• HbA1c measurement >10% (or 86 mmol/mol IFCC units) at the last visit prior to 
the next dose; or  
• An increase from baseline HbA1c >2% (or >17 mmol/mol IFCC units) at the last 
visit prior to the next dose; or  

 
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• In participants with a baseline HbA1c >7.5% (or >58 mmol/mol IFCC units), an 
increase in HbA1c from baseline >1% (or >8.6 mmol/mol IFCC units) at repeat 
study visits with the last one being the visit prior to the next dose. 
Participants who discontinue IP due to HbA1c elevations will be followed for 6 months after 
their last dose per the Schedule of Assessments. 
8.4. 
Restrictions and Concomitant Medications 
1. Fasting: On the day of dosing or on other days with blood draws for lipid parameter 
measurement, participants will have fasted for at least 10 hours prior to IP administration 
or blood draw unless otherwise specified.  
2. Recreational Drugs & Alcohol: Participants will be instructed to abstain from consuming 
alcohol for at least 48 hours prior to their clinic visit on dosing days and during the clinic 
visit. In addition, participants will be instructed to refrain from regular use of alcohol (ie, 
more than 14 units per week [1 unit = 80 mL of wine, 200 mL of beer, or 25 mL of 
40% alcohol]) for the study duration. Participants must abstain from use of recreational 
drugs throughout the study. 
3. Concomitant Medications: Use of optimal statin therapy, nicotinic acid/niacin, omega-3 
fatty acids (prescription or OTC), fibrates, or other lipid management regimens, is 
acceptable if the participant has been on a stable regimen for the minimum period 
specified in Table 2 (below) prior to the S2 Screening Visit and if the participant is 
willing to maintain a constant dosing regimen during the Treatment Period. Adjustments 
to medications regimens during the study, including lipid-lowering and diabetes mellitus 
therapies, are only allowed if, at the discretion of the Investigator, this is needed to 
provide adequate supportive care. These changes must be documented in the eCRF no 
later than at the next study visit. Participants will be instructed to inform the Investigator 
of the details (indication, dose, and dates of administration) if they do take any 
medication, and these details will be recorded in the eCRF. Before making any changes 
to a participant’s prescription lipid-lowering therapy, the Medical Monitor or designee 
should be notified. Use of apheresis during the study will also be recorded in the eCRF.  
4. Local Laboratory Lipid Testing: Some laboratory results may potentially unblind 
treatment assignment to ARO-APOC3. Central laboratory results of fasting serum TG 
and other lipid parameters (LDL-C, total cholesterol, non-HDL-C, HDL-C, VLDL-C, 
ApoB-48, LP[a], ApoB-100, total ApoB, ApoC-III, ApoC-II, ApoA-I, and ApoA-V) will 
not be reported to the Investigator and will be blinded after Day 1. After Day 1, 
Investigators should not perform local non-protocol testing of these analytes during a 
participant’s study participation from first dose administration of IP until after the 
participant’s EOS visit.  

 
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Table 2  
Restricted Concomitant Medications 
Restricted Background Medications 
Time on stable regimen prior to collection of 
Screening Visit (S2) laboratory tests and 
throughout study duration 
Lipid-lowering therapies (including statins) 
>4 weeks 
Fibrates 
>6 weeks 
PCSK9 inhibitors 
>8 weeks 
Beta-blockers, Thiazide diuretics 
>4 weeks 
Retinoids 
>8 weeks 
Atypical antipsychotics 
>12 weeks 
Diabetes Mellitus medications 
>12 weeks 
Anticoagulation therapy 
>12 weeks 
Thyroid hormone replacement therapy 
>12 weeks 
Testosterone replacement therapy 
>16 weeks 
Oral estrogens, tamoxifen, raloxifene 
>16 weeks 
Immunosuppressants  
>24 weeks 
 
8.5. 
Lipid Monitoring 
Following the Week 24 visit, in cases where a participant with a baseline LDL-C >130 mg/dL 
(>3.37 mmol/L) experiences an increase from baseline >25% on two consecutive visits, LDL-C 
values for this subject will be unblinded for the remainder of the study, and the central laboratory 
will notify the Investigator and Medical Monitor for medical follow-up. Appropriate medical 
follow-up will include dietary and medication compliance counseling, which may also include 
modification to the participant’s lipid-lowering regimen to lower LDL-C according to 
country-specific guidelines (eg, initiate statin therapy or increase the statin dose for patients who 
are already on treatment). 
Following the Week 24 visit, in cases where a participant with a baseline LDL-C <130 mg/dL 
(<3.37 mmol/L) subsequently experiences an increase to >130 mg/dL (>3.37 mmol/L) on two 
consecutive visits, LDL-C values for this subject will be unblinded for the remainder of the 
study, and the central laboratory will notify the Investigator and Medical Monitor for appropriate 
medical follow-up. Appropriate medical follow-up will include dietary and medication 
compliance counseling, which may also include modification to the participant’s lipid-lowering 
regimen to lower LDL-C according to country-specific guidelines (eg, initiate statin therapy or 
increase the statin dose for patients who are already on treatment).  
In cases where any participant with a history of acute pancreatitis in the 24 months prior to Study 
Day 1 has a TG>2000 mg/dL (22.6 mmol/L) at any post-baseline visit, the central laboratory will 

 
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notify the Investigator and Medical Monitor. A fasting TG repeat test will be requested. If the 
retest confirms TG >2000 mg/dL (>22.6 mmol/L), the Investigator and Medical Monitor will be 
informed so that appropriate medical follow-up can be initiated. Appropriate medical follow-up 
will include dietary and medication compliance counseling, which may also include modification 
to the participant’s lipid lowering regimen. 
9. 
INVESTIGATION PRODUCT 
9.1. 
Description, Identification, and Dosage 
The Sponsor is responsible for the supply of ARO-APOC3 together with detailed instructions (in 
the Pharmacy Manual) describing preparation of ARO-APOC3. The placebo (normal saline 
0.9%) will be supplied by the clinical site or may be provided by the Sponsor upon request.  
Accordingly, ARO-APOC3 will be supplied as single sterile 2-mL vials containing 
ARO-APOC3 with the correct dose of ARO-APOC3 prepared by the Pharmacy prior to dosing 
participants. 
Placebo will be 0.9% normal saline administered SC.  
Doses administered per Dose Level:  
Each dose of either active drug (ARO-APOC3) or placebo (normal saline 0.9%), will be 
administered by SC injection by the Investigator or appropriately trained and qualified clinical 
staff designated by the Investigator. Injections will be made into the SC tissue at an appropriate 
site (eg, abdomen, thigh, upper arm, etc) using a 25 to 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 are acceptable). Injection site location is to be 
recorded in the eCRF. Prior to dose administration, the IP vial must be allowed sufficient time to 
come to room temperature. Do not inject into areas of active skin disease or injury such as 
sunburns, skin rashes, inflammation, or skin infections. Injection volume per site should not 
exceed approximately 0.25 mL. 
There will be no dose escalation or dose reduction (ie, the same IP dose will be administered to 
each participant within dose cohort).  
9.2. 
Supply, Preparation, Storage, and Labeling of ARO-APOC3 
ARO-APOC3 will be supplied as a sterile Type-1 glass 2.0-mL vial (0.7 mL nominal volume, 
0.5 mL withdrawable volume).  
Strength  
200 mg/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, 2ºC to 8ºC 

 
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ARO-APOC3 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 to demonstrate 
administration within prepared drug stability boundaries. Please refer to the Pharmacy Manual 
for more detailed instructions. 
The IP vials will be labeled per current Good Manufacturing Practice (cGMP)/Good Clinical 
Practice (GCP).  
Investigational product supplies will be stored at clinical sites securely under the appropriate 
conditions. 
9.3. 
Study Drug Handling 
The Sponsor will provide the Investigator with a sufficient quantity of clinical drug supplies. The 
Investigator must ensure that deliveries of IP 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 
Investigator to ensure that the integrity of packaged study product not be jeopardized prior to 
dispensing.  
Only participants enrolled in the study may receive IP in accordance with all applicable 
regulatory requirements. Only authorized site staff may supply or administer IP. The IP must be 
stored in a secure area with access limited to the Investigator and authorized staff and under the 
physical conditions that are consistent with the IP-specific requirements.  
An authorized and trained staff member at each clinical study site will dispense the IP per 
predefined drug dispensing requirements. The dispensing will be verified by a second member of 
site staff.  
ARO-APOC3 will be supplied by the Sponsor and labeled with the drug name, batch number, 
expiration date (as applicable), and storage conditions. The IP will be dispensed by clinical study 
site staff members on the day of dosing and recorded in the drug accountability records. A 
Pharmacy Manual will be prepared to define the procedures for dispensing. 
9.4. 
Allocation to Treatment 
All potential participants who sign an informed consent at Screening will receive a unique 
identifier (ie, a Screening Number). For participants who are deemed eligible, this unique 
screening number will become the participant’s permanent study ID number. 
Eligible participants will be allocated a unique randomization number in accordance with the 
randomization schedule. Each participant will be randomly assigned 3:1 to either active 
(ARO-APOC3) treatment in 1 of 3 dose groups (10, 25, or 50 mg) or to placebo treatment. 
Treatments will be administered per the randomized sequence generated by an Interactive Web 

 
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Response System (IWRS). The allocation of active treatment or placebo will be performed using 
a block randomization algorithm. 
9.5. 
Study Formulation Administration 
Appropriately trained employees of the clinical site will administer the IP. Each dose will be 
administered as a single SC injection. The site of injection will be marked and mapped for later 
observation. The preferred site of injection is the abdomen. Optional additional sites are the 
upper arms and thighs. 
Table 3 
Injection Number and Volume Per Dose Cohort 
ARO-APOC3 
Dose1 
Concentration 
Total Injection 
Volume 
Number of 
Injections per 
Planned Dose 
Total Number of 
Study Injections 
10 mg 
200 mg/mL 
0.05 mL 
Single 
2 
25 mg 
200 mg/mL 
0.13 mL 
Single 
2 
50 mg 
200 mg/mL 
0.25 mL 
Single 
2 
1 Placebo injections of normal saline will be volume matched.  
9.6. 
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 Investigator is responsible for the IP accountability, reconciliation, and record 
maintenance at the investigational site. In accordance with all applicable regulatory 
requirements, the Investigator or designated site staff must maintain IP accountability records 
throughout the course of the study. This person will document the amount of IP received from 
the Sponsor and the amount administered to participants. A non-blinded Clinical Research 
Associate (CRA) will perform initial and ongoing IP 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-APOC3/placebo will be retained 
sequestered per participant (where allowable by local policy) and made available to the 
non-blinded CRA during IP and placebo 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 dose preparation and dispensation will be maintained to support 
administration of IP. The authorized pharmacist or qualified staff will be unblinded to treatment 
assignment (ie, active or placebo). 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 and the Pharmacy Manual. Each 
participant will be given only the IP as assigned by the IWRS. Investigational product 
administration will be documented and recorded on the eCRFs. The inventory must be available 

 
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for inspection by the non-blinded monitor during the study. Drug supplies will either be collected 
at the end of the study by the study monitor or returned by the Investigator or designee to the 
Sponsor, or the designated Sponsor-approved depot.  
9.7. 
Retention of Investigational Product Vials 
For this study, used and partially used drug vials will be retained for an adequate period to allow 
accountability. No additional IP samples will be retained. 
9.8. 
Blinding and Code-Break 
Treatment assignment (active versus placebo) is blinded in this clinical study. Dose group 
assignment is not blinded due to required injection volume differences dictated by the respective 
dose group. Therefore, participants will receive an injection of either active or placebo volume 
matched to the assigned dose group (refer to Table 3). In order to mask for slight color 
differences between active and placebo, syringes will be blinded in the Pharmacy with 
translucent wrapping to mask the blinded staff and participants to the treatment assignment in 
accordance with instructions provided in the Pharmacy Manual. 
Blinding of IP/placebo assignment is critical to the integrity of this clinical study. 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 Investigator or 
documented designated treating physician, or the Medical Monitor can unblind the treatment 
assignment. If the situation is not an immediate emergency, the Investigator 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. The 
unblinding will be documented in the electronic data capture system. The study monitor should 
be informed promptly. 
The randomization schedules will be maintained under controlled access. The personnel involved 
in the dispensing of IP will be accountable for ensuring compliance to randomization schedules. 
The non-blinded CRA will verify correct randomization.  
If the Investigator considers an AE to be of such severity as to require immediate specific 
knowledge of the identity and dose of the relevant product, unblinding will be completed via 
IWRS system. Medical emergency unblinding in IWRS is only accessible to the designated, 
unblinded Pharmacist, Investigator, and Sub-Investigator. The Medical Monitor should be 
informed promptly. 
If a participant requires emergency unblinding (with or without a discussion between the 
Investigator and the Medical Monitor preceding the unblinding), the Investigator may also be 
required to complete a ‘Drug Safety Unblinding Request/Notification Form’ to document the 
medical rationale necessitating the unblinding. This form is then forwarded to the Medical 
Monitor. 

 
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10. 
STUDY METHODS AND PROCEDURES  
10.1. 
Overview of Procedures 
The SOA is provided in Table 1. Potential participants will visit the site to provide informed 
consent prior to the start of any screening assessments. Initial eligibility assessments will begin 
up to 6 weeks prior to randomization, beginning with the first Screening Visit (S1).  
At the Investigator’s discretion and if permitted by local requirements, the first and second 
Screening visit (S1 and S2) assessments may be conducted concurrently within the S2 visit 
window (Day -35 to Day -21) as long as the participant meets stable diet, stable background 
medications, and fasting requirements as outlined in Sections 8.1, 8.4, and 10.2. 
The total duration between the initial Screening Visit (S1) and randomization on Day 1 may take 
up to 6 weeks. Dietary counseling will be reinforced at intervals throughout the study (for 
details, see Section 10.2).  
Participants who successfully pass the Screening requirements will be enrolled into the study. All 
dose cohorts will enroll in parallel with participants randomized 3:1 to receive ARO-APOC3 or 
placebo. Each participant will receive SC injection on Day 1 and Week 12, for a total of 2 
injections as follows:  
• ARO-APOC3 10 mg (n=54) or volume-matched placebo (n=18) at Day 1 and 
Week 12; 
• ARO-APOC3 25 mg (n=54) or volume-matched placebo (n=18) at Day 1 and 
Week 12; or 
• ARO-APOC3 50 mg (n=54) or volume-matched placebo (n=18) at Day 1 and 
Week 12. 
Each participant will present to the clinical facility on Day 1 (baseline). On arrival at the clinical 
facility, the Investigator or designee will meet with the participants to reiterate all study 
procedures and encourage participants to ask any questions. All participants will undergo a 
check-in procedure during which questions will be asked regarding protocol compliance and 
safety monitoring. Participants will return to the clinical facility for visits as per the SOA, with 
each visit generally lasting approximately 2 hours, unless additional monitoring is needed at 
Investigator’s discretion for safety reasons. 
All Screening Visits, Day 1, and Week 12 study visits must be conducted at the clinical study 
site. At the discretion of the Investigator and with prior Sponsor approval, utilization of home 
health care services to conduct other study assessment visits is permissible when COVID 
pandemic restrictions or other logistical disruptions occur in order to avoid missed study visits. 
Utilization of home health services to conduct study assessments is contingent upon compliance 
with local laws and regulations and the capability of the Investigator to adequately monitor 
participant safety. In cases where home health care services are to be utilized, this approach, and 
any specific risks associated with it, must be clearly outlined in the EC/IRB approved informed 
consent form.  

 
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All participants will have a predose and postdose PK sample collected at Day 1 and Week 12 as 
specified in the SOA (Table 1). In a subset of participants undergoing full PK (12 active, 
4 placebo in each dose cohort), PK will be measured predose and serially postdose on Day 1 and 
Week 12 as per the SOA (Table 1). Pharmacokinetic time points on Day 1 and Week 12 are at 
predose, 0.25, 1, 3, 6, and 24 hours postdose. Time window for PK sample through the 6-hour 
timepoint is ±5 minutes. Time window for PK sample at the 24-hour time point is ±60 minutes. 
If the recommended time window is missed, every attempt should be made to collect this PK 
sample as soon as possible within the same study visit. Only samples collected from participants 
receiving active treatment will be included in the PK analysis. For postdose samples that require 
next-day collection, participants may return to the clinical facility to have their blood drawn or 
they may opt to have their PK samples collected through home health.  
Parameters to be assessed and the timing of assessments are provided in the SOA in Table 1. At 
regular intervals during the study, participants will undergo the following evaluations: medical 
history review, physical examinations, vital sign measurements (blood pressure, temperature, 
heart rate, respiratory rate), weight measurement, AE monitoring, ECGs, pregnancy test (females 
of childbearing potential), laboratory assessments, and concomitant medication review. Blood 
samples will be collected for HDL-C, LDL-C, VLDL-C, TG, and other specified lipid or 
metabolic parameters, hematology, serum lipase and insulin, HbA1c, C-peptide, coagulation, 
chemistry analysis, and urinalysis. Blood samples will also be collected for PK and 
immunogenicity analysis. Participants will have fasted for at least 10 hours predose. 
Clinically significant changes including AEs will be followed until resolution is achieved or 
considered medically stable.  
10.2. 
Screening Diet Stabilization Period 
Confirmation of >2 weeks diet stabilization will precede qualifying TG laboratory assessments at 
Screening. Enrolled participants will be counseled to remain on the specified diet throughout the 
study, as recommended by the Investigator in accordance with local standard of care. For 
example, in the US, Investigators may refer to the guidelines established by the AHA/ACC 
(Van Horn 2016). The specifics of the diet will be at the discretion of the Investigator based on 
each individual’s specific diagnosis and medical needs. Dietary assessment and counseling will 
begin during the Screening Period with dietary counseling performed throughout the study to 
facilitate compliance as per the SOA (Table 1). 
This diet may vary at the Investigator’s discretion and certain populations may require more 
strict dietary regimens. 
10.3. 
Selection and Screening 
Prior to commencement of any screening procedures, the Investigator or designee will inform the 
participant about the nature and purpose of the study, including the risks and benefits involved, 
possible AEs, the fact that their participation is voluntary and provide a copy of the 
IRB/EC-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 Investigator or designee, who will also sign and date the informed consent form. 

 
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Time of consent will be recorded in the site’s source document for each participant. The original 
signed consent form will be retained by the Investigator, and a copy of the original will be given 
to the participant.  
Informed consent will be performed per the Principles of the ICH GCP procedures. 
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 Investigator 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 SOA 
(Table 1) will be performed. Timing will abide by fasting restrictions outlined in Section 8.4. 
No study assessment or procedure will occur before the participant has signed the informed 
consent.  
10.4. 
On-Study Procedures/Assessments 
10.4.1. 
Efficacy Assessments 
10.4.1.1. Serum Triglycerides  
In order to determine the average (arithmetic mean) TG level during Screening, two fasting 
serum TG levels will be collected separately and consecutively at least 7 days but no more than 
17 days apart in accordance with the SOA (Table 1).  
Fasting TG levels will be assessed by a central laboratory using a standard method. Beginning on 
Day 1, predose fasting TG will be collected as part of the lipid parameter panel in accordance 
with the SOA (Table 1).  
10.4.1.2. Other Lipid Parameters 
Lipid parameters (TG, LDL-C, total cholesterol, non-HDL-C, HDL-C, VLDL-C, ApoB-48, 
Lp(a), ApoB-100, total ApoB, ApoC-III, ApoC-II, ApoA-I, and ApoA-V,) will be collected on 
Day 1 prior to dosing, after at least a 10-hour fast, and measured by a central laboratory. LDL-C 
will be measured using an ultracentrifugation methodology preferentially as well as 
Martin-Hopkins methodology (which will be used as back-up).  
10.4.1.3. Glucose Metabolism 
Serum samples will be collected on Day 1 after at least 10 hours of fasting and prior to dosing. 
The Day 1 values will be used as each participant’s baseline value for data analysis purposes. 
Fasting serum blood glucose, HbA1c, homeostatic model assessment for insulin resistance 
(HOMA-IR), and C-peptide will be measured as per the SOA and assessed by a central 
laboratory. 
10.4.1.4. Magnetic Resonance Imaging 
Magnetic resonance imaging (MRI) using magnetic resonance imaging-proton density fat 
fraction (MRI-PDFF) for the evaluation of percentage liver fat will be conducted at Screening, 
after completion of the S2 visit, and at Week 24, as outlined in the SOA (Table 1) and in 

 
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accordance with procedural standards detailed in the Imaging Acquisition Manual. Selected sites 
(where MRI-PDFF is available) will perform MRI-PDFF assessments at screening until up to 
35 participants with baseline liver fat fraction ≥8% have been enrolled in each of the 3 dosing 
cohorts, after which MRI-PDFF will no longer be included as an evaluation. The MRI protocol 
used should be consistent across all individual participant visits (same MRI imaging 
technique/protocol will be used predose and at Week 24 on a participant-by-participant basis). 
Please refer to the Imaging Acquisition Manual for further instructions. 
10.4.1.5. Blood Sampling for Pharmacodynamic Analysis 
Fasting 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. During Weeks 24 and 48, two fasting 
PD blood samples will be collected, each separated by at least 2 days and no more than 7 days. 
Blood samples will be collected at time points outlined in the SOA (Table 1).  
The actual sample times (times samples taken) 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. 
10.4.2. 
Pharmacokinetic Assessments 
Plasma samples for analysis of circulating ARO-APOC3 will be obtained in a subset of 
participants at time points following IP administration as outlined in the SOA (Table 1). Blood 
samples will be collected from participants through an indwelling cannula or through repeated 
venipuncture. For postdose samples that require next-day collection (nonfasting permitted), 
participants may return to the clinical facility to have their blood drawn, or they may opt to have 
their PK samples collected through home health. Sparse sampling PK blood draws and analysis 
will also be conducted on all participants not included in the specified PK group as per the SOA. 
10.4.2.1. Sample Processing and Analysis for Pharmacokinetic Samples 
Whole blood 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. 
10.4.3. 
General and Safety Assessments 
General assessments include optional genotype, medical history, and demographics. Safety will 
be evaluated by the incidence, frequency, and severity of AEs and SAEs, including ISRs. 

 
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The safety of ARO-APOC3 will also be evaluated by the collection of the following 
measurements performed at time points specified in the SOA (Table 1) as well as CS changes 
from baseline to scheduled time points:  
• Monitoring of AEs/SAEs 
• Physical examinations 
• Vital signs 
• ECG measurements 
• Clinical laboratory assessments (hematology, chemistry, HbA1c, coagulation, 
amylase, lipase, urinalysis) 
• Concomitant medications/therapy 
• 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 IP 
administration. All AEs/SAEs that occur during the AE reporting period specified in the protocol 
must be reported to the Sponsor, regardless of the relationship of the AE to IP. Any known 
untoward event that occurs beyond the AE reporting period that the Investigator considers an 
SAE and possibly related to IP will be reported to the Sponsor. 
10.4.3.1. Demographics and Medical History 
Participant demographics (eg, date of birth, race and ethnicity, sex) and medical history will be 
collected during the Screening period. Medical History will include medication use over the 
previous 30 days, including vitamins, OTC medications, prescription drugs, recreational drugs or 
supplements, and alcohol and tobacco use. 
Optionally, participants will be invited to consent for pharmacogenetic analyses. Participants 
who consent will have blood sample drawn for these analyses.  
10.4.3.2. Physical Examination 
A complete physical examination will be performed at Screening and as per SOA (Table 1). At 
Screening, height (centimeters, without shoes) and weight (kilograms, without shoes). At all 
other time points outlined in the SOA, a symptom-directed physical examination will be 
performed if indicated.  
10.4.3.3. Vital Signs 
Systolic/diastolic blood pressure (mm Hg), temperature (degrees Celsius [°C]), heart rate 
(beats/minute), and respiratory rate (breaths/minute) will be obtained at time points outlined in 
the SOA (Table 1) after the participant is sitting for at least 3 minutes. Vital signs will be 
obtained prior to venipuncture and other invasive procedures.  

 
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10.4.3.4. Electrocardiogram 
A single 12-lead ECG measurement will be obtained at time points outlined in the SOA 
(Table 1) after the participant is semisupine for at least 3 minutes. Any abnormal and CS ECGs, 
as per the Investigator’s medical judgment, will be repeated in triplicate, with each measurement 
approximately 1 minute apart. ECGs will be performed prior to venipuncture and any other 
invasive procedures.  
10.4.3.5. Clinical Laboratory Tests for Safety 
Blood and urine clinical laboratory samples for safety will be collected at the site and shipped to 
the central laboratory for analysis. In the event of major logistical disruptions (eg, 
COVID-related) where a participant does not have direct access to the site, lab samples may be 
collected at alternative location (eg, home health, local laboratory) using the central laboratory 
kit and shipped to the central laboratory for analysis. If central laboratory kit collection is not 
available, local laboratory safety testing may only be permitted in limited circumstances and only 
with prior Sponsor approval. In accordance with the SOA (Table 1), blood and urine samples 
will be collected for the laboratory tests detailed below, to establish baseline data and eligibility 
for enrollment. One repeat Screening laboratory draw is allowed per assessment to establish 
eligibility. The results will be assessed by the Investigator or medically qualified designee before 
study enrollment. Any abnormality in laboratory values (that are confirmed on repeat) deemed 
CS by the Investigator or medically qualified designee (ie, 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.  
Refer to the Laboratory Manual for additional details on clinical laboratory tests. 
Biochemistry: Sodium, potassium, chloride, bicarbonate, glucose, urea, creatinine, creatine 
kinase, uric acid, phosphate, total calcium, anion gap, albumin, globulins, protein, total bilirubin, 
amylase, lipase, HbA1c, serum insulin, C-peptide, conjugated bilirubin, gamma-glutamyl 
transferase (GGT), alkaline phosphatase (ALP), ALT, AST, lactate dehydrogenase (LD), 
C-reactive protein, thyroid-stimulating hormone (TSH) and free T4.  
Hematology: Hemoglobin, red blood cell (RBC) count, 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 with INR and fibrinogen. 
Urinalysis: Leukocytes, nitrites, urobilinogen, protein, pH, blood, specific gravity, ketones, 
bilirubin, and glucose.  
Microscopic urinalysis will be performed if indicated: white blood cells, red blood cells, 
epithelial cells, bacteria. 
Spot urine protein and spot urine creatinine: will be performed at screening only in order to 
determine the spot urine protein/spot urine creatinine ratio. 

 
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Serology: HBsAg, and hepatitis C antibody screen. If necessary, participants will be counseled 
by the Investigator, or medically trained designee, concerning the blood tests for HBsAg, and 
hepatitis C antibody, and their subsequent results.  
Follicle-stimulating hormone (FSH): Postmenopausal status at screening will be supported 
based on FSH level consistent with postmenopausal state.  
Immunogenicity: Participants will be assessed for anti-drug antibodies.  
The Day 1 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 Screening value may be used as baseline. 
10.4.3.6. Early Termination Procedures 
If a participant discontinues from the study prematurely, every reasonable effort will be made to 
perform the Early Termination Visit within 30 days of the decision to terminate a subject’s study 
participation. The reason for Early Termination will be documented in source documents and 
eCRF. Procedures as outlined in the SOA (Table 1) will be completed. Participants who 
discontinue ARO-APOC3 due to SAE will be encouraged to remain available for follow-up for 
medical monitoring until resolution. 
10.4.3.7. Follow-Up Procedures 
Contact will be made with each participant and documented to verify the following: 
• AEs occurring over the 24 hours following doses at Day 1 and at Week 12 
10.4.4. 
Acute Pancreatitis Events 
All treatment-emergent AEs and SAEs reported by the Investigator through Week 48/EOS that 
are consistent or possibly represent an event of acute pancreatitis will be adjudicated by a 
blinded, independent committee according to the 2013 Atlanta definition meeting 2 of the 
following 3 criteria:  
1. Abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, 
epigastric pain often radiating to the back) 
2. Serum lipase activity (or amylase activity) ≥3 ×ULN 
3. Characteristic findings of acute pancreatitis on contrast-enhanced computed tomography 
(CECT), MRI, or transabdominal ultrasonography 
This committee will meet to review and assess the blinded data as described in the independent 
adjudication committee charter. 
10.4.4.1. Detecting and Reporting Pancreatic Events 
During each study visit, the Investigator and clinical staff will be responsible for educating 
and/or reminding study participants on the signs and symptoms of acute pancreatitis and when to 
seek care. The Investigator or medically qualified designee will also be responsible for detecting, 

 
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recording, and reporting pancreatic events that meet the criteria and definition of acute 
pancreatitis (according to the 2013 Atlanta definition) and events that possibly represent 
pancreatitis.  
Adverse events terms that could signal a potential case of pancreatitis are listed below according 
to the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PT). These PTs 
represent possible pancreatitis events but are not limited to the following: 
Any PTs that includes pancreatitis 
Abdominal rigidity 
Amylase increased 
Acute abdomen 
Blood bilirubin increased 
Ascites 
Lipase increased 
Gastrointestinal pain  
Hyperamylasaemia 
Intra-abdominal pressure increased 
Hyperbilirubinaemia 
Jaundice  
Hyperlipasaemia 
Nausea 
Pancreatic enzymes increased 
Pancreatic duct rupture 
Ultrasound pancreas abnormal 
Peripancreatic fluid collection 
Abdominal distension 
Vomiting 
Abdominal pain 
Vomiting projectile 
Abdominal rebound tenderness 
 
 
After the initial AE of pancreatitis or possible pancreatitis events, the Investigator will follow 
each subject and provide further information on the participant’s condition as deemed 
appropriate. 
The Investigator will follow all pancreatitis or possible pancreatic AEs until resolution until the 
condition stabilizes, or until the event is otherwise explained. Once resolved, the Investigator or 
medically qualified designee will update the appropriate AE eCRF page and SAE report form (if 
the event is serious). The Investigator or medically qualified designee will ensure that follow-up 
includes any supplemental investigations as may be indicated to elucidate the possible pancreatic 
AE or SAE.  
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 Investigator. 
10.4.4.2. Hospitalization for Abdominal Pain 
All SAEs resulting in hospitalizations for abdominal pain will also be recorded as described in 
Section 10.4.4.  

 
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10.5. 
Timing of Treatments and Procedures  
Actual times of procedures for each participant will vary depending on scheduling and will be 
recorded in the eCRF. 
In the event of multiple procedures scheduled at the same time, non-invasive procedures (ie, vital 
signs, ECGs, AE assessment) will be conducted prior to invasive procedures (ie, blood sample 
collection). Timing of activities may be adjusted slightly to accommodate all procedures. 
The following windows are allowed for study assessments/visits: 
Predose 
Any time during the study visit, and before first dose  
Plasma PK1 up to 6-hour sampling timepoint 
±5 minutes 
Plasma PK1 24-hour sampling timepoint  
±60 minutes 
Day 1 
Not Applicable 
Post-baseline visits 
±5 days 
Abbreviation: PK = pharmacokinetic. 
1 Only for Full PK Group assessments. 
10.6. 
Pregnancy Testing and Contraception Requirements 
Female participants of childbearing potential will have urine pregnancy tests at Screening 
(visits S1 and S3), Day 1 (baseline), and at subsequent study visits prior to dosing throughout the 
study, as indicated in Table 1. Females not of childbearing potential must be either surgically 
sterile or postmenopausal (defined as cessation of regular menstrual periods for at least 
12 months without an alternative medical cause) with supportive FSH consistent with 
postmenopausal state based on laboratory reference ranges. 
If a subject’s urine pregnancy test is positive, the participant will be referred to their primary care 
provider for follow-up. Female participants with a positive pregnancy test at Screening or on 
Day 1 predose will not be enrolled in the study. Female participants who become pregnant 
between Day 1 and Week 12 will not receive the second administration of IP but may otherwise 
continue in the study.  
All participants (female participants of childbearing potential with male partners and male 
participants with female partners of childbearing potential) must consent to use one of the 
following highly effective contraception methods during the study and for at least 24 weeks 
following the last dose of IP:  
• Using twice the normal protection of birth control by using a condom AND one other 
form of contraception; either birth control pills (The Pill), injectable birth control, 
birth control patch, vaginal contraceptive ring, or contraceptive implant associated 
with inhibition of ovulation, or intrauterine device; 
• Surgical sterilization as a single form of birth control: ie, tubal ligation, hysterectomy, 
bilateral oophorectomy, vasectomy, or equivalently effective surgical form of birth 
control; 

 
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• True sexual abstinence for the duration of the study and for at least 24 weeks 
following the last dose of IP is acceptable only when in line with the preferred and 
usual lifestyle of the participant. Periodic abstinence (calendar, symptothermal, 
postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea methods are not considered “true” abstinence and are not 
acceptable methods of contraception. 
11. 
ADVERSE EVENTS 
The Investigator and clinical facility staff are responsible for detection, recording, and reporting 
of events that meet the criteria and definition of various AEs as listed below. AEs will be 
recorded from time of signed consent through to EOS; only AEs that occur postdose will be 
considered treatment-emergent. The Investigator and clinical facility staff are responsible for 
detection, recording, and reporting of pregnancy and appropriate follow-up. Information 
regarding any reported pregnancy should be collected for at least 1 year after birth or longer if it 
is decided that addition follow-up is required, or until the end of the pregnancy. 
11.1. 
Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical 
investigation participant 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 Council for 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 IP, or 
when a pre-existing medical condition increases in severity or frequency after IP 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); or 
• An overdose of either the IP or a concurrent medication without any resulting signs or 
symptoms. 
A Serious Adverse Event (SAE) is an AE that: 
• Results in death; 

 
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• 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; or 
• 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. 
11.2. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events 
Abnormal assessments (eg, ECGs and vital signs) that are judged by the Investigator as CS or 
result in clinical sequelae should be recorded as AEs. Laboratory abnormalities should be 
reported by the Investigator as AEs if the abnormality is considered CS or result in clinical 
sequelae. Laboratory abnormalities not reported as AEs are not to be reported as CS in the study 
database. 
Clinically significant abnormal laboratory findings or other CS 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.  
The Investigator 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 
CS. 
11.3. 
Timing, Frequency, and Method of Detecting Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a participant prior to the start of 
the study (ie, 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 postdose 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 Investigator, 
or medically qualified designee, and recorded in the medical notes and eCRF. 

 
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11.4. 
Recording of Adverse Events 
When an AE occurs, it is the responsibility of the Investigator or medically qualified designee to 
review all documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
relative to the event. The Investigator or medically qualified designee will then record the AE on 
the AE case report form (CRF). Additional reporting requirements for an AE meeting serious 
criteria are discussed in Section 11.5. 
The Investigator 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 Investigator to send photocopies of the subject’s medical records to the 
Sponsor in lieu of completion of the appropriate AE eCRF pages. 
11.5. 
Evaluating Adverse Events 
11.5.1. 
Severity of Adverse Events 
The Investigator or medically qualified designee will assess the severity for each AE reported 
during the study. The assessment will be based on the Investigator’s, or medically qualified 
designee’s, clinical judgment. The severity of all AEs will be graded using the latest version of 
the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. 
If an AE cannot be graded using the CTCAE criteria, it should be graded as mild, moderate, 
severe, life-threatening, or death using the following definitions: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities. Medical intervention not indicated.  
• Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities. Noninvasive medical intervention indicated. 
• Severe: An event that prevents normal everyday activities but not immediately 
life-threatening. 
• Life-threatening: An event that places the participant at immediate risk of death or is 
disabling. 
• Death: An event that results in death. 
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 predefined outcomes as described in 
Section 11.1. 
11.5.2. 
Injection Site Reactions 
For purposes of data analysis, a local injection site reaction (LISR) is defined as an adverse 
reaction (usually immunologic) developing at the site of injection and lasting at least 48 hours 

 
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which must be based on the specified Medical Dictionary for Regulatory Activities (MedDRA) 
PT as provided in Appendix 2. For data analysis purposes, AEs at the injection site with reported 
terms of bruising or hematoma will not be considered LISRs. Injection site reactions are graded 
based on CTCAE.  
Grade 1: Tenderness with or without associated symptoms (eg, warmth, erythema, 
itching). 
Grade 2: Pain; lipodystrophy; edema; phlebitis. 
Grade 3: Ulceration or necrosis; severe tissue damage; operative intervention indicated. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Results in death. 
11.5.3. 
Assessment of Causality 
The Investigator or medically qualified designee is obligated to assess the relationship between 
IP and the occurrence of each AE. The Investigator 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 IP will be considered and investigated. The Investigator or medically qualified 
designee will also consult the IB in the determination of his/her assessment. 
There may be situations when an SAE has occurred and the Investigator has minimal information 
to include in the initial SAE report. However, it is very important that the Investigator or 
medically qualified designee always assess causality for every event prior to transmission of the 
SAE report form. The Investigator 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 Investigator or medically qualified designee will provide the assessment of causality 
utilizing 3 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 (eg, 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 (eg, 
death as a passenger in an automobile accident); 
• A clearly more likely alternative explanation for the AE is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event). 
An AE will be considered “Possibly related” when an event follows a reasonable temporal 
sequence from administration of the IP, but which could also be explained by concurrent disease 

 
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or other drugs or chemicals. Or an event that follows a known or expected response pattern to the 
drug but that could have been produced by a number of other factors.  
An AE will be considered “Probably related” when an event follows a reasonable temporal 
sequence from administration of the IP, unlikely to be attributed to concurrent disease or other 
drugs or chemicals. Also, an event that follows a known or expected response pattern to the IP, 
or that is confirmed by stopping or reducing the dosage of the IP and that could not reasonably 
be explained by known characteristics of the participant’s clinical state. 
11.5.4. 
Follow-up of Adverse Events 
After the initial AE, the Investigator 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 eCRF page and SAE report form (if event is serious) will be updated. The Investigator 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 the event of a fatal outcome in an SAE, the Investigator 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 Investigator. 
11.6. 
Prompt Reporting of Serious Adverse Events 
Any AE meeting serious criteria MUST be reported promptly to the designated 
Pharmacovigilance Contract Research Organization (CRO), and the IRB/EC in accordance with 
applicable local/institutional requirements.  
11.6.1. 
Completion and Transmission of the Serious Adverse Event Reports 
Once an Investigator 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 
immediately. The SAE report form will always be completed as thoroughly as possible with all 
available details of the event and signed by the Investigator or medically qualified designee. If 
the Investigator 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 Investigator or medically qualified designee will always provide an assessment of causality 
at the time of the initial report as described in Section 11.5.3. However, as new information 
becomes available, causality may be modified. 

 
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Electronic transmission of the SAE report form is 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 report sent by overnight mail. Initial notification 
via the telephone does not replace the need for the Investigator 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 Investigator 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.  
Sponsor Emergency Contact 
 
* 
*Regional contact information will be provided in the site 
manual. 
 
Sponsor Medical Monitor Contact 
  
Telephone: 
 
 
11.6.2. 
Pregnancy Reporting  
Pregnancy occurring in a participant or in the female partner of a male participant during the 
study must be reported on a pregnancy reporting form or on an SAE form to the designated 
Pharmacovigilance CRO within 24 hours of initially becoming aware of the pregnancy by the 
Investigator. 
Pregnancies are not SAEs. However, pregnancy data will be collected at the initial notification, 
birth/termination of pregnancy, and for up to 1 year after birth.  
Any SAE that occurs during pregnancy (serious maternal complications, therapeutic abortion, 
ectopic pregnancy, stillbirth etc) must be reported in accordance with the procedure for reporting 
SAEs. 
11.6.3. 
SAE Reports to the IRB/EC 
The Investigator, 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 
EC.  
11.7. 
Regulatory Requirements for Reporting of SAEs 
The Investigator or medically qualified designee will promptly report all SAEs in accordance 
with the procedures detailed in Section 11.6.1. Prompt notification of SAEs by the Investigator is 
essential so that the Sponsor may comply with its regulatory obligations. 

 
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Any SAEs requiring expedited reporting will be reported by the Sponsor to relevant regulatory 
authorities, Investigators, and IRBs/ECs in accordance with the Sponsor’s procedures and local 
regulatory requirements. 
11.8. 
Poststudy Adverse Events 
A poststudy AE is defined as any event that occurs outside of the AE detection period defined in 
Section 11.3. 
Investigators are not obligated to actively seek AEs in former study participants. However, if the 
Investigator 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 reasonably related to the IP, the 
Investigator will promptly notify the Sponsor.  
11.9. 
Serious Adverse Events Related to Study Participation 
An SAE considered related to study participation (eg, procedures, invasive tests, a change in 
existing therapy), even if it occurs during the pre- or post-treatment period, will be reported 
promptly (see Section 11.7). 
12. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
Statistical analyses and descriptive summaries will be presented for primary, secondary, and 
exploratory endpoints using appropriate methods. Any proposed amendments to the Statistical 
Analysis Plan will only occur prior to database lock. Descriptive statistics will be presented for 
all analyses unless otherwise specified. For continuous variables, data will be presented as 
number (n), mean, median, standard deviation (SD), minimum, and maximum. Discrete variables 
will be presented as frequencies and proportions or percent. Data will be analyzed by treatment 
groups of ARO-APOC3 10, 25, and 50 mg, and placebo. 
Additional details of all planned analyses for this study will be provided in the Statistical 
Analysis Plan. 
12.1. 
Endpoints 
12.1.1. 
Primary Endpoint 
The primary endpoint in this study is: 
• Percent change from baseline at Week 24 in fasting TG.  
12.1.2. 
Secondary Endpoints 
The following secondary endpoints will be evaluated: 
• Percent change over time through Week 48 in fasting TG;  
• Percent change from baseline at Week 24 and over time through Week 48 in 
ApoC-III;  

 
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• Percent change from baseline at Week 24 and over time through Week 48 in fasting 
non-HDL-C; 
• Percent change from baseline at Week 24 and over time through Week 48 in fasting 
HDL-C; 
• Percent change from baseline at Week 24 and over time through Week 48 in fasting 
total ApoB; 
• Percent change from baseline at Week 24 and over time through Week 48 in fasting 
LDL-C using ultracentrifugation;  
• Change in plasma concentrations of ARO-APOC3 over time through Week 12; and 
• The frequency and severity of AEs and SAEs over time through Week 48. 
12.1.3. 
Exploratory Endpoints 
The following exploratory endpoints are defined in this study: 
• Change and/or percent change from baseline over time through Week 48 in TG and 
other fasting lipid parameters (total cholesterol, LDL-C measured using Martin-
Hopkins methodology, LDL/HDL ratio, VLDL-C, ApoB-48, Lp(a), ApoB-100, 
ApoC-II, ApoA-I and ApoA-V [all values drawn after at least 10-hour fast]);  
• Change from baseline to Week 24 and overtime through Week 48 in fasting serum 
blood glucose, HbA1c, HOMA-IR and C-peptide; 
• Change from baseline over time through Week 48 in high sensitivity C-reactive 
protein (hsCRP); 
• Cumulative number of on-study occurrences of acute pancreatitis events over time 
through Week 48; 
• Cumulative number of on-study hospitalizations for abdominal pain over time 
through Week 48; 
• Note: All AEs and SAEs reported by the Investigator during the study that are 
consistent with an event of acute pancreatitis, as per the 2013 Atlanta definition, 
meeting 2 of the following 3 criteria: (1) abdominal pain consistent with acute 
pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the 
back); (2) serum lipase activity (or amylase activity) ≥3× ULN; and (3) characteristic 
findings of acute pancreatitis on CECT, MRI, or transabdominal ultrasonography.  
• Proportion of participants requiring emergent apheresis over time through Week 48; 
• Change and percent change from baseline to Week 24 in liver fat content using MRI-
PDFF (only in participants with a liver fat fraction of ≥8% at Screening); and 
• Emergence of and levels of anti-drug antibodies to ARO-APOC3 in those receiving 
ARO-APOC3 over time through Week 48. 

 
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12.2. 
Analysis Populations 
The following study populations are defined in this study: 
• Full Analysis Set (FAS): All randomized participants who receive at least 1 dose of 
IP. All efficacy analyses will be performed using FAS. Participants will be analyzed 
according to the treatment assigned at randomization. 
• Safety Analysis Set: All participants who receive at least 1 dose of IP. All safety and 
tolerability analyses will be performed using this set. Participants will be analyzed 
according to the treatment they actually received. 
• PK Analysis Set: All FAS participants who have sufficient plasma concentration data 
to facilitate determination of PK parameters. 
12.3. 
Sample Size Considerations 
From previous Phase 1 study, the PD data of patients with SHTG showed fasting TG reduction 
of 57.7% (SD=18.2%) for ARO-APOC3 10 mg dose group, 73.6% (SD=9.6%) for 25 mg dose 
group, and 80.1% (SD=7.0%) for 50 mg dose group, while 0.4% reduction in placebo group with 
SD as 41.7%. Therefore, it’s reasonable to assume ARO-APOC3 dose groups will have 50% to 
70% more reduction than placebo, with SD of 10% for ARO-APOC3 dose groups and 40% for 
placebo. 
With these assumptions, the study will have greater than 99% power to detect any active 
treatment dose cohort which is significantly different from placebo with 18 complete participants 
per treatment group, using a two-sided test and 1.67% level of significance, adjusted for 
multiplicity. With the considerations of dropout and to observe more participants for clinical 
safety, 72 participants per active treatment group or placebo is designed. A total of 
216 participants will be randomly assigned to treatment in a 3:1 (active to placebo) ratio within 
each dose cohort (72 participants per dose cohort). 
12.4. 
Interim Analysis 
An interim analysis is planned for this study after all participants have completed the Week 24 
visit. The interim analysis will be conducted by an unblinded independent biostatistician and 
reviewed by the unblinded individual(s) from sponsor or their designee. Safety data and select 
PD data, will be reviewed in aggregate, comparing the treatment groups: ARO-APOC3 (10, 25, 
or 50 mg) to pooled placebo. Following receipt of the interim analysis data, recipients will not be 
involved in further planning or conduct of the study so as to maintain the study blind. The 
primary endpoint will be evaluated and, therefore, no adjustment to the alpha level for the final 
analysis is necessary. 
12.5. 
Stratification 
Randomization to placebo and active groups will be stratified based on: 
• Mean level of TG at Screening (≥1000 mg/dL versus <1000 mg/dL). 

 
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Prespecified subgroup analyses will be conducted for: 
• Participants with a genotype consistent with FCS (including but not limited to 
homozygous, compound heterozygous, or double heterozygous loss-of-function or 
otherwise inactivating mutations in genes affecting lipoprotein lipase activity 
including LPL, APOC2, APOA5, GPIHBP1, LIPG, GPD1, or LMF1); 
• Participants with TG at baseline of 500 to 2000 mg/dL (5.65 to 22.6 mmol/L); and 
• Participants with TG at baseline of >2000 mg/dL (>22.6 mmol/L). 
12.6. 
Analysis Methods 
12.6.1. 
Screening Data 
Demographics will be tabulated by participant and summarized by for each dose level and for 
pooled placebo. Eligibility assessments at baseline, including medical/surgical history data and 
physical examination data (including height and weight), will be listed for each participant. 
Medical history will be summarized and listed by participant. Medical history will be coded 
using MedDRA. Prior and concomitant medications will be coded using the World Health 
Organization Drug Dictionary into drug class (Anatomical Therapeutic Chemical Level 4) and 
PT. Preferred terms will be summarized and listed, and verbatim terms will be listed by 
participant. 
12.6.2. 
Efficacy and Pharmacodynamics Analysis 
The primary objective of this study is to evaluate the effect of ARO-APOC3 on fasting TG levels 
in adults with SHTG. The primary endpoint is the percent change from baseline at Week 24 in 
fasting TG levels. The primary analysis of the primary endpoint will evaluate the difference in 
means between each ARO-APOC3 dose cohort and pooled placebo cohort and will be conducted 
in all randomized participants who receive at least 1 dose of IP (FAS). The estimand of interest is 
the difference in means of percent change from baseline in fasting TG at Week 24 in adult SHTG 
population (as defined by the inclusion/exclusion criteria), regardless of treatment compliance or 
other intercurrent events post-baseline.  
For endpoint analysis based on Week 24 data, the laboratory value will be the arithmetic mean of 
two fasting TG values, separated by at least 2 days and no more than 7 days, taken during 
Week 24. If only one value is available during Week 24, then this value will be used for endpoint 
analysis. For data analysis purposes, baseline will be defined as the arithmetic mean of Day 1 
predose assessment and two fasting TG values collected during the Screening period. 
The primary analysis will be performed using a mixed model repeated measures (MMRM) 
approach with treatment, study visit, stratification factor, and baseline TG level included as 
model terms. The model will also include treatment by visit and treatment by baseline interaction 
terms. The primary estimate of interest will be the difference in means between each active 
treatment dose group and pooled placebo group, evaluated at Week 24. When performing the 
primary analysis, the adjustment for multiplicity of testing several arms versus placebo will be 

 
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carried out using Holm’s step-down procedure. Normality and other statistical assumptions will 
be assessed. 
All continuous secondary endpoints will be analyzed in a similar manner to the primary 
endpoint, unless otherwise noted. The frequency and severity of AEs and SAEs over time 
through Week 48 will be summarized with descriptive statistics.  
For the analysis of exploratory endpoints, descriptive summaries will be provided, as applicable, 
and any inferential statistics (ie, p-values) will be considered only as exploratory. For lipid 
related, lipoprotein and serum pharmacodynamic assessments, baseline is defined as the predose 
value on Day 1. 
The final study report will be created following the completion of the study (Week 48). 
12.6.3. 
Pharmacokinetics Analysis 
Plasma concentrations of ARO-APOC3 will be measured in all participants to evaluate trough 
and postdose levels through the study (see the SOA in Table 1). Serial PK sampling will be 
conducted in a subset of participants at specifically designated PK sites. 
Full PK group: In each of the dose cohorts, 16 PK participants (12 active, 4 placebo for a total 
of 48 participants for PK) will be enrolled at the designated PK sites. Plasma concentrations will 
be measured predose and serially postdose as per the SOA. Only samples collected from 
participants receiving active treatment will be included in the PK analysis. 
Sparse Sample PK group: All other participants at all sites will provide a predose PK sample 
and one additional sample at >15 minutes postdose at Day 1 and Week 12 as per the SOA.  
12.6.4. 
Safety/Tolerability Analysis 
In general, safety analyses will be performed and the results summarized by treatment groups. 
Post-treatment safety assessments will be compared with measurements recorded at baseline. 
Treatment-emergent AEs will be summarized using the latest version of MedDRA by System 
Organ Class (SOC) and PT. The incidence of AEs, SAEs, related AEs, related SAEs, and AEs 
leading to discontinuation, will be summarized by treatment group and by dose level per SOC, 
PT, and severity. All AEs 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 listings. ECG parameters, changes from baseline, and qualitative assessments will 
be summarized. Pregnancy and FSH test results will be listed separately by time point.  
12.6.5. 
Analysis of Immunogenicity (Anti-drug Antibodies) Data 
The number of participants to test positive for anti-drug antibody (ADA) at baseline and 
post-treatment will be summarized. Maximum ADA titer and range of titer values will be 
presented. If any, ARO-APOC3 treatment-induced ADA formation will be analyzed to ascertain 
if the ADA response duration is transient or persistent using the definitions in the white paper by 

 
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Shankar et al (Shankar 2014). The effect of ADA formation status on ARO-APOC3 PK, PD, and 
safety (AE) will be analyzed. 
12.7. 
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 eCRFs 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.  
13. 
STUDY APPROVAL AND CONDUCT 
The following conditions will be met: 
13.1. 
Regulatory Approval 
The requirements for the conduct of clinical studies in accordance with local applicable 
regulations will be met before commencement of this study. 
13.2. 
Institutional Review Board (IRB)/Ethics Committee (EC) Approval 
Prior to initiation of the study, written IRB/EC approval of the Protocol and Informed Consent 
Forms, based on the principles of ICH GCP, will be received. A copy of the signed and dated 
letter of approval will be provided to the clinical site and the Sponsor prior to study 
commencement. Any written information and/or advertisements to be used for participant 
recruitment will be approved by the IRB/EC prior to use. A list of the IRB/EC 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 participant safety or the validity of the study will be 
approved by the IRB/EC, following written agreement from the Sponsor. 
13.3. 
Ethical Considerations 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory 
requirement(s). The protocol will be submitted for approval to the IRB/EC, and written approval 
obtained before participants are enrolled. The composition of the IRB/EC will also be provided 
to the Sponsor. If approval is suspended or terminated by the IRB/EC, the Investigator will 
notify the Sponsor immediately. 
Where applicable, the clinical site and the Sponsor 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. 

 
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13.4. 
Written Informed Consent 
Informed consent will be obtained before the participant 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 
washout of excluded medications. 
It is the responsibility of the Investigator 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 Investigator or medically 
qualified designee must also explain to the participants 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 Investigator or by the Sponsor. 
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 Investigator 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 participant 
will be given a copy of the signed informed consent form to retain. 
13.5. 
Emergency Contact with Principal Investigator 
Suitable arrangements will be made for participants to contact the Investigator or medically 
trained designee in the event of an emergency. 
13.6. 
Notification of General Practitioner 
It is the responsibility of the Investigator or designee, to notify, where applicable, with the 
consent of the participant, the general practitioner of the subject’s participation in the study, by 
sending a letter stating the nature of the study, treatments, expected benefits or AEs and 
concomitant drugs to be avoided. 
13.7. 
Clinical Laboratory Certification and Reference Ranges 
Before the initiation of this study, the Investigator 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 central laboratory, which will 
perform the test for the study. In the event of major logistical disruptions (eg, COVID-related) 
where a participant does not have direct access to the site and central laboratory kit collection is 
not available, local laboratory safety testing with associated local lab reference ranges may only 
be permitted in limited circumstances and only with prior Sponsor approval.  

 
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13.8. 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. The Investigator will conduct the study 
in compliance with the approved protocol and will not implement any deviation from or changes 
to the protocol, except where necessary to eliminate an immediate hazard to study participants. 
Deviations may result from the action or inaction of the participant, Investigator, 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; and 
• Procedural deviations such as incorrect storage of IP, failure to update the informed 
consent form when new risks become known, failure to obtain IRB/EC approvals for 
the protocol, and informed consent form revisions. 
Protocol deviations impacting participant safety or eligibility will be reported to the Sponsor or 
CRO within 2 business days of occurrence and to the IRB/EC/competent regulatory authority per 
local regulatory requirements.  
The Investigator 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. 
13.9. 
Termination of the Study 
The Sponsor reserves the right to discontinue the study at any time. The circumstances under 
which the study may be terminated include:  
• Discontinuation of the study is in the interest of the health of trial participants;  
• Continuation of the clinical trial no longer serves a scientific purpose  
Reasons will be provided in the event of this happening. The Investigator reserves the right to 
discontinue the study for safety reasons at any time in collaboration with the Sponsor. 

 
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14. 
STUDY ADMINISTRATION 
14.1. 
Study Monitoring 
The Sponsor is responsible for assuring the proper conduct of the study about protocol adherence 
and validity of the data recorded on the eCRFs. Participant confidentiality will be maintained. 
In accordance with applicable regulations, GCP, and the Sponsor’s procedures, the Sponsor will 
be responsible for assigning a study monitor (CRA) who will contact the site to organize a visit 
prior to participant enrollment 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 and remote monitoring visits. The extent, nature and frequency of monitoring 
visits will be based on such considerations as the study objective and/or endpoints, the purpose 
of the study, study design complexity and enrollment rate. 
During special circumstances (eg, COVID-19 restrictions) the specific guidance from local 
public health and other competent authorities regarding the protection of individuals’ welfare 
must be applied. For the duration of such special circumstances, remote monitoring may be 
implemented to adhere to study specifications. 
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 IP accountability; and 
• 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; and 
• Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The Investigator 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 
Investigator or site staff as appropriate: 
• Return of all study data to the Sponsor; 
• Data queries; 

 
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• Accountability, reconciliation and arrangements for unused IP(s); 
• Inventory and final disposition (eg, destruction, shipping to repository, etc); and 
• Review of site study records for completeness. 
14.2. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor 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 Investigator and clinical site agree 
to notify Sponsor as soon as possible following awareness of an impending regulatory 
inspection. The Investigator 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. 
14.3. 
Records Retention 
Following closure of the study, the Investigator 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 
(eg, 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 of these records can be maintained in a format 
other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The Investigator 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 Investigator must 
ensure there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
The Sponsor will inform the Investigator 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 the Sponsor’s 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 IRB/EC and 
copies of any other correspondence relevant to the study with the IRB/EC or 
regulatory authorities; 
• The IRB/EC-approved informed consent form; 
• Current curriculum vitae (signed and dated) of the Principal Investigator and co-
workers with major responsibilities in the study; 

 
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• Site Signature and Delegation of Responsibility Log; 
• Food and Drug Administration (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 Clinical Trial Notification Application Form (where applicable); and 
• Clinical raw data including the Source Data Forms, all clinical laboratory report 
forms, participant CRFs, drug accountability forms, and dispensing records, etc. 
15. 
INFORMATION DISCLOSURE AND INVENTIONS 
15.1. 
Ownership 
 
 
 
 
 
 
 
 
 
15.2. 
Confidentiality 
 
 
 
 
 
 
 
 
 
 
 

 
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15.3. 
Data Protection 
The sponsor complies with data minimization principles and will collect and process the 
minimum amount of personal data necessary for purposes of the study. The sponsor has 
implemented information security policies and procedures designed to prevent unauthorized 
persons from gaining access to personal data collected and processed in the context of the study 
(“Clinical Data”) and to ensure that persons authorized to access Clinical Data gain access only 
in accordance with their access rights. The sponsor also maintains policies and procedures for 
detecting, monitoring, and responding to data security incidents and, as appropriate, for reporting 
data security incidents to regulators and/or individuals. The sponsor carries out periodic risk 
assessments/reviews and, as appropriate, updates its information security policies and 
procedures.  
Clinical Data received by the sponsor is pseudonymized/key-coded and the key is retained by the 
study site. Where third party processors are engaged to process Clinical Data, due diligence is 
carried out to ensure such third parties are capable of maintaining appropriate security measures 
to protect Clinical Data. For transfers of Clinical Data to countries outside of the European 
Economic Area and United Kingdom, consistent with the requirements of the General Data 
Protection Regulation (“GDPR”), the sponsor will ensure that appropriate safeguards are in place 
such as “standard contractual clauses” or such transfers will be made in reliance on an Article 49 
GDPR derogation. 
15.4. 
Publication 
 
 
 
 
 
 
  
 
 
 
 
 
 
 

 
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Cardiology (AHA/ACC) Guidelines: A Scientific Statement from the American Heart 
Association. Circulation. 2016;134:e505-e29. 
Warden BA, Minnier J, Duell PB, Fazio S, and Shapiro MD. Chylomicronemia Syndrome: 
Familial or Not? J Clin Lipidol. 2020;2:201-6. 
Yan H, Niimi M, Matsuhisa F, Zhou H, Kitajima S, Chen Y, et al. Apolipoprotein CIII 
Deficiency Protects against Atherosclerosis in Knockout Rabbits. Arterioscler Thromb Vasc 
Biol. 2020;40(9):2095-2107. 
Yuan G, Al-Shali KZ, and Hegele RA. Hypertriglyceridemia: Its Etiology, Effects and 
Treatment. CMAJ. 2007;176:1113-20. 
 
 

 
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APPENDIX 1. LIVER-RELATED STUDY MODIFICATION AND 
FOLLOWUP GUIDELINES  
Table 4 
Liver Related Study Modification and Follow-Up Guidelines for Participants 
Treatment-Emergent 
AST or ALT 
Treatment-
Emergent Total 
Bilirubin (TBL)  
Liver Symptoms  
Action  
Normal baseline: AST   
or ALT >3× ULN  
Elevated baseline: AST 
or ALT >2× baseline or 
>300 U/L (whichever 
occurs first) 
Normal 
Participants with 
Gilbert’s 
syndrome or 
hemolysis- no 
change in baseline 
TBL 
None 
Confirm AST, ALT, ALP, TBL 
within 72 hours. Initiate close 
observation and workup for 
competing etiologies1 
Follow-up for symptoms. 
Normal baseline: AST 
or ALT >5× ULN 
Elevated baseline: AST 
or ALT >3× baseline or 
≥300 U/L (whichever 
occurs first) 
Normal  
Participants with 
Gilbert’s 
syndrome or 
hemolysis- no 
change in baseline 
TBL 
None  
Discontinue IP.  
Confirm AST, ALT, ALP, TBL 
within 72 hours. Initiate close 
observation and workup for 
competing etiologies1 
Refer to guidelines for close 
observation below.  Follow-up 
for symptoms. 
Normal baseline: AST   
or ALT >3× ULN  
Elevated baseline: AST 
or ALT >2× baseline or 
>300 U/L  
(whichever occurs first)  
Normal  
Participants with 
Gilbert’s 
syndrome or 
hemolysis- no 
change in baseline 
TBL 
 Symptoms of 
clinical hepatitis – 
severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain or; 
immunologic 
reactions (eg rash, 
>5% eosinophilia) 
Interrupt IP.  Confirm AST, 
ALT, ALP, TBL within 72 
hours. Initiate close observation 
and workup for competing 
etiologies.1  
IP can be restarted only if an 
alternative etiology is identified 
and liver enzymes return to 
baseline. IP cannot be restarted 
if hepatic decompensation 
occurred. 
Refer to guidelines for close 
observation below. Follow-up 
for symptoms. 
Normal baseline: AST 
or ALT >3× ULN  
Elevated baseline: AST 
or ALT >2× baseline or 
≥300 U/L (whichever 
occurs first)  
TBL >2× ULN  
or increased INR 
to >1.5 
In participants 
with Gilbert’s 
syndrome or 
hemolysis- 
None  
Interrupt IP.  
Confirm AST, ALT, ALP, TBL 
within 72 hours. Initiate close 
observation and workup for 
competing etiologies.1  

 
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doubling of direct 
bilirubin if 
baseline 
>0.5 mg/dL  
Initiate close observation and 
workup for competing 
etiologies.1 
IP can be restarted only if an 
alternative etiology is identified 
and liver enzymes return to 
baseline. IP cannot be restarted 
if hepatic decompensation 
occurred. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; IP = investigational product; TBL = total bilirubin; ULN = upper limit of 
normal.  
Source: Regev A, Palmer M, Avigan MI, et al. Consensus: guidelines: best practices for detection, assessment and 
management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic 
steatohepatitis. Aliment Pharmacol Ther. 2019;49:702-13. 
1Acute and chronic viral hepatitis (hepatitis A - E), cholelithiasis, alcohol, other drugs both prescribed and over-the-
counter herbs and supplements. 
 
Guidelines for Close Observation for Potential Drug-Induced Liver Injury:  
Within 72 hours, perform a complete history, physical, and liver biochemistries, including 
evaluation of: 
• New or worsening signs and symptoms of clinical hepatitis such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia  
• Concomitant medications, including acetaminophen, dietary supplements, herbal 
remedies, OTC medications, recreational drug use, and special diets  
• Alcohol consumption  
• Exposure to environmental chemical agents  
• Past medical history  
• Complete review of systems  
• Liver biochemistries including ALT, AST, alkaline phosphatase, total bilirubin, and 
INR.  
Evaluate participants two or three times a week for signs and symptoms of clinical hepatitis and 
obtain liver biochemistries until biochemistries stabilize. 
If biochemistries stabilize and the participant is asymptomatic, monitor liver biochemistries once 
a week until they return to baseline. 
Participants who live far from study sites may be evaluated locally for history, physical exam, 
and laboratories, if the results are communicated promptly to the site Investigator. 
 

 
Protocol Number: AROAPOC3-2001 
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APPENDIX 2. LOCAL INJECTION SITE REACTIONS 
 
Table 5 
Local Injection Site Reactions (LISRS) 
The following MedDRA Preferred Terms determined by the Sponsor’s pharmacovigilance 
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 paint 
Injection site erosion 
Injection site edema 
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 
 
 
LISRs will only include events that start on the day of injection and persist for at least 48 hours 
post injection (ie, event onset date on the day of injection and 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 following calculation will be utilized to determine the percentage of injections leading to 
local injection site reactions: 
(A/B)*, where A = number of injections with a local injection site reactions, and B = total 
number of injections.