A Phase 3 Study to Evaluate the Efficacy and Safety of ARO-APOC3 / VSA001 / SAR449124 Injection in Chinese Adults With Familial Chylomicronemia Syndrome
Phase: PHASE3
Conditions: Familial Chylomicronemia Syndrome
Sponsor: Visirna Therapeutics HK Limited

Protocol No.: VSA001-3001 
Version No.: 3.5 
Visirna Therapeutics 
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Title Page 
A Phase 3 Study to Evaluate the Efficacy and Safety of VSA001 
Injection in Chinese Adults with Familial Chylomicronemia 
Syndrome 
Study number: VSA001-3001 
Product ID: 
VSA001 
Sponsor: 
Visirna Therapeutics HK Limited 
Version No.: 
3.5 
Version Date: 
March 10, 2025 
NCT05902598

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History and Summary of Protocol Revision 
Document Revision History: 
Version No. 
Version date 
Description and Justification of Revision 
1.0 
December 9, 2022 
New document, not applicable 
2.0 
February 20, 2023 
The following revisions were made based on the review opinions at 
the academic conference of Shanghai Huashan Hospital: 
1. Given that there is currently no PK data for the Chinese 
population, the subgroup analysis results of the completed 
Phase 1/2a clinical study of VSA001 Injection are 
summarized in Section 3.2.3, which shows no significant 
differences in PK, PD, and safety between Asian and non-
Asian participants; 
2. In Section 5.1.2, “PI or designee” conducting informed 
consent was changed to “PI or designated study doctor” to 
comply with GCP; 
3. In Section 5.1.5, the time window for PK blood collection is 
changed from 15 minutes to 30 minutes to facilitate clinical 
implementation; 
4. In Section 7.2.5, “general practitioner” was replaced with 
“treating physician” to comply with clinical practice in China. 
In addition, the wordings in the initial version of the protocol 
(including completeness, consistency, typos, word order, language 
style, abbreviations, etc.) were corrected and revised; and the 
operational details were improved (e.g., the sampling time points 
for test items and the categories of laboratory tests were refined in 
the Schedule of Activities and Sections 10 and 11). 
3.0 
March 10, 2023 
The following revisions were made based on the review opinions 
from the Ethics Committee of Shanghai Huashan Hospital: 
1. In Section 3.2.3., the safety results from the latest interim 
analysis of the Phase 2b clinical study of VSA001 conducted 
in other indication population (patients with severe 
hypertriglyceridemia) abroad were added; 
2. Section 5.1.1. summarizes the overall design of this study as 
a randomized, double-blind, placebo-controlled, dose-
selection study and clarifies the dose finding objective by 
setting up two parallel dose groups; 
3. In Section 7.2.2., “recreational drug use” was replaced with 
“drug abuse” to comply with Chinese regulations and the 
understanding of clinicians; 
4. Appendix 4. Food Fatty Acid Content Table was added for the 
investigator to guide participants in low-fat diet treatment. 
In addition, errors in Protocol v2.0 were corrected by supplementing 
or revising the following operational details: 
1. It is described in Note “b” under the “Schedule of Activities: 
Randomized Period” that urine pregnancy tests on Day 1 and 
subsequent dosing visit days will be performed pre-dose at the 

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local laboratory and must be negative; 
2. Specific test items for lipid parameters at screening, baseline 
(Day 1), and follow-up visits are described in Note “j” under 
the “Schedule of Activities: Randomized Period” and in 
Section 10.1; 
3. In the “Schedule of Activities”, the time points and frequency 
of dietary assessments were adjusted, and the time window for 
ECG sampling was adjusted (extended to 30 min); 
4. In Section 5.4.1., the planned data safety reviews were 
changed from “evaluations for imbalances between active and 
placebo groups for AEs and SAEs” to “assessments for 
significant safety events such as AEs and SAEs between 50 
mg dose group and 25 mg dose group”. 
3.1 
June 8, 2023 
The following updates were made based on the latest data from the 
global clinical studies of VSA001: 
1. Elevation of glycated hemoglobin (HbA1c) was added as a 
possible reason for discontinuation of treatment in the 
“Synopsis”; 
2. HbA1c testing at Months 2, 13, and 14 and its purpose were 
added in the “Schedule of Activities”; 
3. Poor glycemic control was added as a potential risk of 
participation in the study in Section 3.3.4.; 
4. The benefit-risk assessment results of continuing the evaluation 
of 25 mg and 50 mg doses in patients with familial 
chylomicronemia syndrome (FCS) were added in Section 
3.3.5.; 
5. Elevation of HbA1c was added as a new situation that may 
warrant discontinuation of study treatment in Section 5.4.1.; 
6. The statement “Adjustment of diabetes treatment regimen is 
allowed during the study)” was added in Section 5.6.; 
7. The rationale for continuing the evaluation of 25 mg and 50 mg 
dose levels in FCS participants was added in Section 5.7.; 
8. Principles for discontinuation of treatment in participants with 
elevated HbA1c were added in Section 7.4.; 
9. Appendix 5 Glycemic Control-Related Guidelines in Diabetes 
was added. 
10. The estimated upper limit of enrollment was updated in 
“Synopsis” and Sections 12.3, 5.1.1, and 5.2. 
In addition, operational details in the body text and the “Schedule 
of Activities” were supplemented and corrected, and the typos in 
“Appendix 2 Liver-related Study Modification and Follow-up 
Guidelines” were corrected. 
3.2 
August 8, 2023 
The following revisions were made based on the updated safety 
information of the global studies, feedback on feasibility collected 
during the implementation of the protocol, and the review opinions 
from the Ethics Committee of Shanghai Huashan Hospital: 
1. Procedure for handling participants with acute pancreatitis who 

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are unblinded and directly transferred to the open-label 
treatment phase was added in “Methodology” of the Synopsis 
and in Section 5.1.1. “Overview of Study Design”; 
2. The number of screening tests for triglycerides was increased 
to a total of three in “Inclusion Criterion #3” of the Synopsis 
and in Section 6.1 “Participant Inclusion Criteria”; 
3. The screening period was extended to 56 days in the Synopsis, 
“Schedule of Activities: Randomized Period”, and Section 5.1. 
“Overall Study Design”, highlighting that the eligibility criteria 
will be judged based on the values of liver function, blood 
glucose, and CBC tests within 28 days prior to randomization; 
4. In the “Schedule of Activities: Randomized Period”, the “blood 
glucose” was moved from “Routine laboratory tests h” to 
“Liver function tests and CBC i”, and “liver function, blood 
glucose, and CBC” tests were added for Day 15 to enhance 
safety monitoring of liver enzymes and blood glucose (adding 
testing at Months 1, 2, 3, 5, 7, 8, 10, and 11); 
5. The alert value reporting range of >4000 mg/dL (45 mmol/L) 
for triglyceride (TG) was added in Section 7.2.4. “Central 
Laboratory Lipid Testing”; 
6. The note “(or carbon dioxide)” was added after the blood 
chemistry parameter “bicarbonate” in Section 11.1.5.2. to cover 
different names of this test item in study sites; the test item 
“anion gap” was deleted because most of the participating sites 
could not provide test reports containing this item; 
7. Guidelines for further monitoring and resumption of 
medication after treatment discontinuation in patients with poor 
glycemic control (elevated glycated hemoglobin) were added 
to Appendix 5; 
8. Appendix 6 was added, which provides a categorized summary 
of specific laboratories for laboratory test items; 
Others: In Section 11. “Assessment of Safety”, duplicate 
descriptions were deleted, and operational details were refined; and 
relevant sections were corrected accordingly to ensure consistency. 
3.3 
May 23, 2024 
Prefilled syringe (PFS) is the proposed market dosage form of 
VSA001 for subcutaneous administration, which can facilitate 
clinical use and reduce the risk of medication errors. In the extension 
period of this study, the Sponsor will provide PFS after relevant 
approvals are obtained and PFS is imported, by which time all 
participants would have received the active drug. Therefore, the 
following updates were made accordingly: 
1. PFS was added to the “Abbreviations” in the Synopsis; 
2. The description of sample size re-estimation in the “Synopsis” 
and Sections 12.3 was deleted based on the actual number of 
participants enrolled in the study; 
3. PFS-related content was added in Section 8. Study Drug 
Materials and Management; 
4. Relevant details on treatment discontinuation were added to 

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Appendix 5 Glycemic Control-Related Guidelines in Diabetes; 
Others: Operational details in the protocol were updated, and typos 
in the protocol content were corrected to maintain consistency. 
3.4 
September 2, 2024 
Based on the analysis results of the Phase 3 global FCS study 
(AROAPOC3-3001) of this product, the proposed market dose of 
VSA001 is 25 mg. In the extension period of this study, all 
participants will receive VSA001 25 mg Q3M after approval of this 
version, so the following updates were made accordingly: 
1. The doses of the extension phase were combined into 25 mg 
Q3M in the “Study Design Diagram” in the Synopsis and 
Section 5.1.1. Overview of Study Design; 
2. The time windows for visits at Months 7, 8, and 11 of the 
randomized period and all visits of the extension period in the 
“Schedule of Activities” of the Synopsis were updated to ± 10 
days; 
3. Relevant details on treatment discontinuation in Appendix 5 
Glycemic Control-Related Guidelines in Diabetes were 
optimized; 
4. In Appendix 6. Instructions on Clinical Laboratory Tests, ADA 
testing facility was changed to Chongqing Denali Medpharma 
Co., Ltd. 
3.5 
March 10, 2025 
It is planned to provide the participants with the opportunity to 
continue medication after the end of the study, and update the global 
clinical study data of VSA001 in the protocol. The specific updates 
are as follows: 
1. Section 7.6 Drug Therapy after the End of Study was added to 
provide the participants with the opportunity to continue the 
treatment after the end of the study, so that participants can 
obtain continuous benefits; 
2. In Section 3.2.3 Clinical Studies, Section 3.3.4 Poor Glycemic 
Control, Section 3.3.5 Benefit-Risk Assessment, and Section 
5.7 Rationale for Dose and Schedule of Administration, the 
global clinical study data of VSA001 were updated to provide 
the latest study progress and results. 
 
 

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Signature Page of Sponsor 
This study protocol (A Phase 3 Study to Evaluate the Efficacy and Safety of VSA001 Injection 
in Chinese Adults with Familial Chylomicronemia Syndrome) has been reviewed and approved 
by the following representative of Visirna Therapeutics HK Limited. 
 
 
<signed> 
Name (Print) 
 
Signature 
 
 
 
 
 
 
Title 
 
Date (DDMMMYYYY) 
 
 

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INVESTIGATOR’S AGREEMENT 
Protocol Title:  
A Phase 3 Study to Evaluate the Efficacy and Safety of VSA001 
Injection in Chinese Adults with Familial Chylomicronemia Syndrome 
Protocol Number: 
VSA001-3001 
Version:  
Protocol Amendment 3.5 
By my signature below, I attest to the following: 
● 
I have received and read the Investigator’s Brochure for VSA001 (ARO-APOC3).  
● 
I have carefully read this study protocol. 
● 
I agree to conduct the trial according to the protocol (subject to any amendments) and in 
accordance with the principles of International Council for Harmonisation (ICH) E6 Good 
Clinical Practice guidelines and all applicable regulations or requirements.  
● 
I understand that any changes to the protocol must be approved by the Sponsor, Visirna 
Therapeutics HK Limited, the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC), and in certain cases, the National Medical Products Administration 
(NMPA) or other applicable regulatory agencies, before they may be implemented.  
● 
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
Printed Name of Investigator: 
 
Signature of Investigator: 
 
Date: 
 
 
 

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PROCEDURES IN CASE OF EMERGENCY 
Medical Monitor Contact: 
● 
Medical Monitor Contact of CRO 
Name: 
Tel: 
Email:
● 
Visirna Medical Monitor Contact 
Name:
 
Email:
 
 
 

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SYNOPSIS 
Title of Study: 
A Phase 3 Study to Evaluate the Efficacy and Safety of VSA001 Injection in Chinese Adults with Familial 
Chylomicronemia Syndrome 
Name of Sponsor/Company: 
Visirna Therapeutics HK Limited 
Name of Investigational Product: 
VSA001 Injection (also referred to as ARO-APOC3 Injection, Plozasiran) 
Name of Active Ingredient: 
VSA001(ARO-APOC3) 
Registration classification: 
Chemical Drug Class 1 
Indication: 
Familial Chylomicronemia Syndrome (FCS) 
Protocol No.: 
VSA001-3001 
Phase: 
3 
Country: 
China 
Study Center(s): 
Multiple sites, China 
Background: 
Familial chylomicronemia syndrome (FCS) is a severe and ultrarare genetic disease, with a prevalence of 
approximately 1 in 1,000,000 based on incomplete statistics, often caused by various monogenic 
mutations. FCS leads to extremely high fasting triglyceride (TG) levels, typically over 900 mg/dL. Such 
severe elevations lead to various serious signs and symptoms including acute pancreatitis (which can be 
fatal), chronic daily abdominal pain, type 2 diabetes mellitus, hepatic steatosis, and cognitive issues (aka 
“brain fog”). Currently, the therapeutic options that can adequately treat FCS are very limited with only 
one antisense oligonucleotide inhibitor of apolipoprotein C3 (APOC3, APOC-III), approved in Europe. 
APOC3 is an 8.8 kilodalton (kDa) protein component of triglyceride-rich lipoproteins (TRLs) such as 
very-low-density lipoprotein cholesterol (VLDL-C), intermediate density lipoprotein cholesterol (IDL-
C), chylomicrons, high-density lipoprotein cholesterol (HDL-C), and remnant particle lipoproteins. 
APOC3 is synthesized predominantly in hepatocytes. It inhibits the hydrolysis of TG on TRLs at the 
muscle and adipose tissue capillary level through inhibition of lipoprotein lipase (LPL), and delays 
clearance of lipoprotein remnants by the liver by inhibiting hepatocyte receptor-mediated uptake. APOC3 
functions as a key regulator of fasting and postprandial plasma TG levels. 
VSA001 (ARO-APOC3) is a synthetic, double-stranded, hepatocyte-targeted RNA interference (RNAi) 
trigger (also referred to as a small interfering RNA [siRNA]) designed to specifically silence messenger 
RNA (mRNA) transcripts from the APOC3 gene using an RNAi mechanism. Given the important role of 
APOC3 in serum TG level modulation and its primary source of synthesis in hepatocytes, reduction of 
APOC3 through a hepatocyte-targeted RNAi strategy is likely to reduce circulating TG, benefiting several 
patient populations, including patients with FCS. 
Objectives: 
The primary objective of this study is to evaluate the efficacy and safety of VSA001 in Chinese adults 
with FCS. 
 
Endpoints: 
Primary and secondary endpoints are for the randomized period only, except as noted. 

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Primary endpoints: 
● 
Percent change from baseline at Month 10 in fasting serum TG 
 
Key secondary endpoints: 
● 
Percent change from baseline at Months 10 and 12 (averaged) in fasting serum TG 
● 
Percent change from baseline at Month 10 in fasting serum APOC3 
● 
Percent change from baseline at Month 12 in fasting serum APOC3 
 
Other secondary endpoints: 
● 
Percent change from baseline at Month 10 in fasting serum non-high density lipoprotein cholesterol 
(non-HDL-C) and HDL-C 
● 
Percent change from baseline at Month 12 in fasting serum TG, non-HDL-C, and HDL-C 
● 
Proportion of participants achieving fasting serum TG of <500 mg/dL at Month 10 
● 
Proportion of participants achieving fasting serum TG of <500 mg/dL at Month 12 
● 
Change and percent change from baseline at each scheduled assessment in fasting serum TG up to 
Month 12 
● 
Participant incidence of treatment emergent adverse events (TEAEs) (either period) 
● 
Incidence of positively adjudicated events of acute pancreatitis (either period) 
 
Exploratory study endpoints: 
Exploratory endpoints are for both the randomized period and the extension period, except as noted. 
● 
Change and percent change from baseline at each scheduled assessment in fasting serum lipid 
parameters (total cholesterol, low-density lipoprotein cholesterol [LDL-C], HDL-C, non-HDL-C, 
VLDL-C, total apolipoprotein B [APOB], APOB-48, lipoprotein(a) [LP(a)], APOB-100, APOC2, 
APOC3, apolipoprotein A-I [APOA1], and apolipoprotein A-V [APOA5]), with all values drawn 
after at least a 10-hour fast. 
● 
Changes from baseline at each scheduled assessment in fasting serum blood glucose, glycated 
hemoglobin (HbA1c), homeostatic model assessment for insulin resistance (HOMA-IR), and C-
peptide 
● 
Change and percent change from baseline at each scheduled assessment in fasting serum TG, 
APOC3, non-HDL-C, and HDL-C (extension period only) 
● 
Proportion of participants reaching fasting serum TG of <500 mg/dL at each scheduled assessment 
● 
Incidence of hospitalizations for abdominal pain 
● 
Participant incidence of emergent apheresis 
● 
Pharmacokinetic (PK) parameters of VSA001 
● 
Incidence of anti-drug antibodies to VSA001 
● 
Change from baseline at each scheduled assessment in European Organisation for the Research and 
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 score 
● 
Change from baseline at each scheduled assessment in EORTC QLQ-PAN26 score 
● 
Change from baseline at each scheduled assessment in EuroQol 5-dimension instrument (EQ-5D-
5L) score 
 
Estimand of primary endpoint: 

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The key clinical question of interest 
Difference in medians of percent change from baseline in fasting serum TG at Month 10 in the test group 
(VSA001 25 mg or VSA001 50 mg Q3M) relative to control group (placebo Q3M) in Chinese adults with 
FCS, regardless of discontinuation of treatment for any reason/concomitant therapy/rescue 
medication/background treatment changes/other intercurrent events. 
 
Definition of estimand 
● 
Treatment policy strategy: randomization to the test group (VSA001 25 mg Q3M /VSA001 50 
mg Q3M) or control group (placebo Q3M) for 10 months of treatment, regardless of 
discontinuation of treatment for any reason/concomitant therapy/rescue medication/background 
treatment changes/other intercurrent events 
● 
Target population: adult patients with FCS who meet the eligibility criteria 
● 
Variable: percent change from baseline in fasting serum TG at Month 10 
● 
Treatment policy strategy - intercurrent events: regardless of discontinuation of treatment for 
any reason/concomitant therapy/rescue medication/background treatment changes/other 
intercurrent events 
● 
Population-level summary: median percent change from baseline in fasting serum TG in 
treatment and control groups 
Study design: 
 
Q3M=every 3 months 
* Stabilization of diet, medications, and laboratory values will be reviewed during screening period 
** Participants in the 50 mg group who have entered the open-label period before dose combination will 
switch to 25 mg at the next treatment visit 
Methodology: 
This study will be conducted in adult patients with FCS. Participants with diagnosis of FCS will initiate 
a treatment stabilization period for at least 4 weeks, during which diet, lifestyle, and medication regimen 
will be stabilized. Enrolled participants will be counseled to remain on a diet comprising ≤20 g of fat per 
day and stable treatment regimen throughout the study, as per the Principal Investigator’s (PI’s) discretion 
and in accordance with the standard of care in China. 
Randomized period 
Extension period 
End of double-blind treatment** 
Rollover to open-label treatment 
Scree
ning* 
Rand
omiza
tion 
Baseline 
Placebo (volume-matched) Q3M (n=5) 
Placebo (volume-matched) Q3M (n=5) 
Month 12 
Month 24
Primary endpoint 
(Percent change from baseline at Month 10 in fasting serum TG level) 

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In the randomized period, approximately 30 participants who have met all protocol eligibility criteria 
during screening (including 10% dropout) will be randomized in a double-blinded fashion to receive 4 
total doses of VSA001 Injection or matching placebo, administered subcutaneously (SC) once every 3 
months (Q3M). Blinding will be preserved to the extent possible; however, treatment unblinding may 
occur, at the PI’s or medical monitor’s discretion, when deemed necessary for treatment of an adverse 
event (AE) or for a safety event-related decision or a decision to be made regarding trial continuation in 
an individual participant. 
Participants who complete the randomized period will continue in an open-label extension period, where 
all participants will receive VSA001. In the early stage of the extension period, participants will remain 
blinded to their original treatment assignment and will initially receive VSA001 at the dose corresponding 
to their study treatment dose in the randomized period. Thus, participants who received VSA001 25 mg 
Q3M or 50 mg Q3M will continue to receive the same dose. Participants who received placebo will switch 
to active treatment based on the initial dosing group to which they were assigned (i.e., VSA001 25 mg 
Q3M or 50 mg Q3M). 
Based on the analysis results of the Phase 3 global FCS study (AROAPOC3-3001) of this product, the 
proposed market dose of VSA001 is 25 mg. In the extension period of this study, all participants should 
receive VSA001 25mg Q3M after approval of  the protocol (V3.4). However, participants in the 50 mg 
group who entered the open-label period earlier will timely switch to 25 mg at the next treatment visit. 
For any participant experiencing acute pancreatitis, the participant may be unblinded and transitioned to 
the open-label treatment period of the study after assessment by the Investigator. This will be documented 
via the Interactive Web Response System (IWRS). 
● 
If the participant had been assigned to receive placebo, they will be re-assigned to receive open-label 
treatment with VSA001 if they are clinically stable based on the assessment of the Investigator in 
consultation with the Medical Monitor, and relevant procedures will start from Month 12 of the 
Schedule of Activities. 
● 
If the participant had been assigned to receive VSA001, they will restore open-label treatment with 
VSA001 if they are clinically stable based on the assessment of the Investigator in consultation with 
the Medical Monitor, and until at least 3 months have passed since the receiving the last dose of 
study drug, i.e., starting from Month 12 of the Schedule of Activities. Treatment adjustments to 
participants with alanine aminotransferase (ALT) increased or aspartate aminotransferase (AST) 
increased will be based on the Consensus: guidelines: best practices for detection, assessment and 
management of suspected acute drug-induced liver injury during clinical trials in patients with 
nonalcoholic steatohepatitis (Regev A, 2019). 
Study Duration: 
The duration of the study is expected to be 30 months; the enrollment will last 6 months, and follow-up 
will last 24 months. Statistical data of the trial supporting NDA will be cut off at Month 12 after the first 
dose in the randomized period. 
Main Inclusion and exclusion criteria: 
To be eligible for enrollment, participants must meet all the following inclusion criteria: 
1. 
Males or non-pregnant (who do not plan to become pregnant), non-lactating females ≥18 years 
of age; 
2. 
Able and willing to provide written informed consent prior to the performance of any study-
specific procedures; 
3. 
Fasting TG ≥10 mmol/L (~880 mg/dL) at screening, that is refractory to standard lipid lowering 
therapy (sample drawn after at least the minimum time on stable lipid-lowering regimen 
described in Table 2). Three repeat tests are allowed to qualify. 
4. 
A diagnosis of FCS based on a documented history of fasting TG levels in excess of 1000 

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mg/dL (for at least 1 prior occasion) in the absence of clear triggering factors (e.g., alcohol, 
binge eating, etc.), and at least one of the following: 
a. 
A supportive genetic test (from a source-verifiable medical record or based on screening 
genotype). Supportive genetic testing includes but is not limited to homozygous, 
compound heterozygous, or double heterozygote for loss-of-function or otherwise 
inactivating mutations in genes affecting lipoprotein lipase activity including LPL, 
APOC2, APOA5, GPIHBP1, GPD1, or LMF1; or evidence of low LPL activity (<20% of 
normal) based on source-verifiable documentation; or 
b. 
Documented history of recurrent episodes of acute pancreatitis, not caused by alcohol or 
cholelithiasis; or 
c. 
Documented history of recurrent hospitalizations for severe abdominal pain without other 
explainable cause; or 
d. 
Documented history of childhood or adolescent pancreatitis; or 
e. 
Family history of hypertriglyceridemia-induced pancreatitis. 
5. 
Willing to follow dietary counseling as per PI judgment based on local standard of care, 
consistent with the diet control regimen with an intake of ≤20 g of fat per day during the study. 
6. 
If on medications for management of type 2 diabetes, or other medications allowed in Table 2, 
the dosing regimen must be stable before collection of qualifying lipid parameter at screening. 
7. 
Participants with a medical history of clinical atherosclerotic cardiovascular disease (ASCVD) 
or those with elevated 10-year ASCVD risk (e.g., ≥7.5% per American Heart 
Association/American College of Cardiology risk calculator) must be on appropriate lipid-
lowering therapy as per local standard of care (i.e., including moderate to high intensity statin, 
as determined by PI according to participant’s condition) prior to collection of qualifying TG 
levels. 
8. 
Participants of childbearing potential must agree to use a highly effective form of contraception 
(see Appendix 1), during the study and for at least 24 weeks after the last dose of investigational 
product (IP). Women of childbearing potential on a hormonal contraceptive must be stable on 
the medication for ≥1 menstrual cycle prior to Day 1 of the study. Participants must not plan to 
donate sperm or eggs during the study and for at least 24 weeks after the last dose of IP. 
Note: All laboratory tests (except for coagulation) used as inclusion criteria will be assessed by a central 
laboratory and may be repeated once (except for TG), 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. 
A participant will be excluded from the study if any of the following criteria apply: 
1. 
Current use or use within the last 1 year (before screening) of any hepatocyte-targeted siRNA 
or antisense oligonucleotide molecule. 
2. 
Diabetes mellitus with any of the following: 
a. 
Newly diagnosed within 12 weeks of screening; 
b. 
HbA1c ≥ 9.0% at screening. 
3. 
Active pancreatitis within 12 weeks before Day 1. 
4. 
History of acute coronary syndrome events within 24 weeks of Day 1. 
5. 
History of major surgeries within 12 weeks of Day 1. 
6. 
Any of the following abnormal laboratory values at screening: 
a. 
ALT or AST ≥ 3 × ULN at screening; 
b. 
Total bilirubin ≥1.5×ULN (if the participant has a prior diagnosis and documentation of 
Gilbert’s syndrome, then total bilirubin must be ≤3 mg/dL at screening); 

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c. 
Estimated glomerular filtration rate <30 mL/min/1.73 m2 at screening, using the Chronic 
Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation; 
d. 
Spot urine protein/spot urine creatinine ratio greater than 3 g/day; 
e. 
Clinically significant abnormality in prothrombin time, partial thromboplastin time, or 
INR. 
7. 
Uncontrolled hypertension (blood pressure >160/100 mmHg at screening); if untreated, 
participant may be rescreened once hypertension is treated and controlled. 
8. 
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; 
b. 
Current use of glucagon-like peptide-1 (GLP-1) receptor agonists or planned use during 
the study; 
c. 
Plasma apheresis within 4 weeks prior to Day 1 or planned during the study; 
d. 
Blood donation of 50 to 499 mL within 4 weeks of collection of qualifying lipid parameter 
collection or of >499 mL within 8 weeks of qualifying lipid parameter collection. 
9. 
On treatment with human immunodeficiency virus (HIV) antiretroviral therapy (Note: 
determination of HIV status is not a required study procedure). 
10. Seropositive for hepatitis B virus (HBV) or hepatitis C virus (HCV) (hepatitis B surface antigen 
[HBsAg] and HBV DNA positive, or HCV RNA positive). 
11. New York Heart Association (NYHA) Class II, III, or IV heart failure or last known ejection 
fraction of <30%. 
12. Clinical evidence of primary hypothyroidism (screening TSH > ULN and free T4< LLN), 
primary subclinical hypothyroidism (screening TSH > ULN and free T4 WNL), or secondary 
hypothyroidism (screening TSH < LLN and free T4 < LLN). 
13. History of hemorrhagic stroke within 24 weeks of first dose. 
14. History of bleeding diathesis or coagulopathy. 
15. Current diagnosis of nephrotic syndrome. 
16. 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 approximately corresponds to 80 mL of 
wine, 200 mL of beer, or 25 mL of 40% alcohol). 
17. 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 cancer, 
superficial bladder tumors, or in situ cervical cancer. Currently receiving systemic cancer 
treatment(s) or, in the PI’s opinion, at risk of relapse for recent cancer. 
18. 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. 
19. Any concomitant medical or psychiatric condition or cognitive disorder caused by serious 
social situation or any other situation that, in the PI’s judgment, would make it difficult to 
comply with protocol requirements or put the participant at additional safety risk. 
Note: All laboratory tests used as exclusion criteria may be repeated once and the repeat value may be 
used for exclusion purposes. 
Participant Withdrawal Criteria: 
Withdrawal means that the participant is no longer receiving the study treatment (early termination of the 
study treatment). There are two conditions in which participants can withdraw study treatment: 
● 
Withdrawal decided by participants 

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Participants may discontinue study treatment or withdraw from the study at any time. Reasons for 
withdrawal from the study may include, but are not limited to: 
1. 
The participant withdraws his/her informed consent; 
2. 
The participant is lost to follow-up/dies. 
● 
The investigator may also terminate the participant’s participation in the study at any time at 
his or her discretion. Reasons for the investigator’s decision to withdraw a participant from the 
study may include: 
1. 
According to the judgment of the investigator, intolerable AEs have occurred; 
2. 
Unexpected medical conditions: the restrictions of this protocol are not conducive to the health 
of the participants, and the protocol treatment should be discontinued; 
3. 
According to the judgment of the investigator, there is a co-morbidity that is likely to 
significantly affect the assessment of clinical status or that is likely to affect the safety of the 
participant; 
4. 
Poor compliance and unable to receive treatment and attend visits as scheduled; 
5. 
For other reasons, the investigator judges that it is not appropriate for the participant to continue 
the study (such as pregnancy). 
Investigational drug, dosage and administration: 
The test formulation is active VSA001 administered SC. The active pharmaceutical ingredient contained 
in VSA001 is a synthetic, double-stranded siRNA duplex conjugated to a NAG-targeting ligand to 
facilitate hepatocyte delivery. 
Dosage: VSA001 (25 mg or 50 mg) administration on Day 1, then Q3M. 
Duration of treatment: 
The duration of the study is approximately 112 weeks from screening to the End-of-Study (EOS) 
examination. The screening period will last up to 8 weeks (Day -56 to Day -1). The treatment period will 
last up to 104 weeks (52 weeks in the randomized period and 52 weeks in the extension period). 
Reference therapy, dose and administration: 
The placebo is normal saline (0.9%) administered SC, volume-matched to the corresponding VSA001 
dose volume. 
Treatment compliance: 
All study treatments will be administered at the study site. The investigational product (IP) will be 
dispensed by clinical study site staff members on the day of dosing and recorded in the drug accountability 
records. The date and time of study treatment administration will be recorded on the electronic Case 
Report Form (eCRF) on dosing days. Any confirmed pregnancy in the study will lead to permanent 
discontinuation of IP dosing of that participant. 
A decision to pause/suspend dosing in an individual participant may be indicated based on any of the 
following: 
● 
A need for apheresis or other emergent interventions indicated to lower TG 
● 
Elevation of glycated hemoglobin meeting the criteria for treatment discontinuation 
● 
In participants with normal AST and ALT on Day 1, treatment emergent elevations ≥3× ULN 
at least possibly related to IP per study Investigator (must be confirmed by repeat blood draw 
within 72 hours of initial results) 
● 
In participants with elevated AST or ALT on Day 1, treatment emergent elevations >2× 
baseline at least possibly related to IP per study Investigator (must be confirmed by repeat 
blood draw within 72 hours of initial results) 
Refer to “Consensus: guidelines: best practices for detection, assessment and management of suspected 
acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis” (Regev 

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A, 2019) for adjustments of treatment for participants with elevated AST or ALT. 
Concomitant medications: 
Use of optimal statin therapy, nicotinic acid, niacin, omega-3 fatty acids (prescription or OTC), or fibrates 
or other lipid management regimens, is acceptable if the participant has been on a stable regimen for at 
least 4 weeks as confirmed at screening and if the participant is willing to maintain a constant dosing 
regimen during the treatment period. Adjustments to medication regimens during the study, including 
lipid-lowering and diabetes mellitus therapies, are only allowed if, at the discretion of the PI, they are 
needed to provide adequate supportive care. 
Statistical method: 
Sample Size Considerations 
Participants will be randomized in a 2:1:2:1 ratio into VSA001 25 mg dose group and volume-matched 
placebo group, VSA001 50 mg dose group and volume-matched placebo group. The two placebo groups 
will be pooled for statistical analysis, i.e. the randomization ratio of active groups to pooled placebo group 
is 1:1:1. 
The significance of the median difference in percent change from baseline in TG at Month 10 between 
each active treatment group and placebo group will be judged using the Wilcoxon (Mann-Whitney) rank-
sum test with correction for continuity. Type I errors will be controlled using Holm's method. 
These estimates assume an average of 
 reduction from baseline in fasting TG at Month 10 
in participants receiving VSA001 25 mg and VSA001 50 mg, respectively, and a 
 reduction in 
participants receiving placebo. The standard deviation is assumed to be 
 for all three groups, and the 
level of significance α is set to be two-sided 0.05. 
It is expected that 27 participants completing the 10-month follow-up will provide a power of greater than 
85% to detect at least one VSA001 group with statistically significant differences versus the pooled 
placebo group. Assuming a dropout rate of 10% at Month 10, a total of approximately 30 participants 
would need to be enrolled. Taking into account the effects of uncertainties such as competitive enrollment, 
block randomization, and COVID-19, approximately 36 participants will be enrolled. 
 
General rules for statistical analysis and data processing rules: 
SAS® system 9.4 or higher version will be used for analysis, and all tables, images, and listings will be 
generated as RTF/PDF files. 
The Statistic Analysis Plan (SAP) will be finalized before the database lock. 
Data will be analyzed by treatment group: VSA001 25 mg, VSA001 50 mg, or pooled placebo. In 
descriptive statistical analysis, the number (N) of participants in each treatment group or in the pooled 
group, the number and percentage (%) of participants and the number and percentage of missing 
participants under each classification level will be provided for categorical data, unless otherwise 
indicated. For continuous variables, data will be presented as number of participants in the treatment 
groups or total group (N), number of participants without missing results (n) and number of participants 
with missing results (nmiss), arithmetic mean, standard deviation, median, minimum, and maximum. 
 
Efficacy Analysis 
For endpoint analysis based on Month 10 data, the laboratory value will be the arithmetic mean of two 
values taken 2-7 days apart during Month 10. If only one value is available during Month 10, then this 
value will be used for endpoint analysis. For data analysis purposes, baseline for fasting serum TG will 
be defined as the arithmetic mean of Day 1 pre-dose assessment and the last fasting assessment prior to 
Day 1. If only one pre-dose value is available, the pre-dose value closest to the first dose will be used. 
 
Primary Efficacy Endpoint Analysis 

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The significance of the median difference between active treatment and placebo will be judged using the 
Wilcoxon (Mann-Whitney) rank-sum test with correction for continuity. 
The median difference between groups and its 95% confidence interval will be estimated using the 
Hodges-Lehmann method. 
 
Analysis of Key Secondary Efficacy Endpoints and Other Continuous Efficacy Endpoints 
Same as methods for primary analyses of the primary efficacy endpoint. 
 
Exploratory endpoint analysis 
Descriptive statistics will be provided for the secondary endpoints. For the analysis of exploratory 
endpoints, descriptive summaries will be provided, as applicable, and any inferential statistics (i.e., p-
values) will be considered only as exploratory. 
 
Safety Analysis 
Incidence and severity of treatment-emergent adverse events 
In general, safety analyses will be performed and the results summarized by cohort and treatment group. 
Adverse events (AEs) will be coded using the latest version of MedDRA by System Organ Class (SOC) 
and Preferred Term (PT). All treatment-emergent adverse events (TEAEs) will be summarized by 
seriousness, severity, and relationship to IP. The incidence and frequency of TEAEs, serious adverse 
events (SAEs), and serious TEAEs leading to discontinuation, will be summarized by cohort per SOC, 
PT, and severity. Treatment-related TEAEs (TRAEs) will also be summarized in a similar manner. AEs 
will also be summarized in participant listings. The duration of AEs will be determined and included in 
listings, along with the action taken and outcome. The incidence/change of biomarkers will be 
summarized using descriptive statistics (shift tables may be provided). 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 participant listings. 
 
Others 
Electrocardiogram (ECG) parameters, changes from baseline, and qualitative assessments will be 
summarized. 
For long-term safety endpoints, descriptive statistics will be provided by active dose received. 
 
Immunogenicity Analysis 
Anti-drug Antibody Test Positivity and Titer 
The number of participants to test positive for ADA at baseline and post-treatment will be summarized. 
Maximum ADA titer and range of titer values will be presented. VSA001 treatment-induced ADA 
formation, if any, will be analyzed to ascertain if the ADA response duration is transient or persistent 
using the definitions in the white paper published by Shankar et al (2014). The effect of ADA development 
on VSA001 PK, pharmacodynamics (PD), efficacy, and safety will be analyzed. 
 
Definitions of analysis sets 
Analysis dataset 
Definition/Criteria 
Full analysis set 
(FAS) 
• 
Intention-to-treat analysis set: Including all randomized participants. 
• 
For FAS-based analyses and outputs, participant grouping will be based 
on the treatment assigned at randomization. 

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Per protocol set 
(PPS) 
• 
PPS will include participants in the FAS without major protocol 
deviations that would affect efficacy assessments. 
• 
See the Protocol Deviation Management Plan/Medical Monitoring Plan 
for the definition of protocol deviations requiring removal of participants 
from the PPS. The rules for ultimate inclusion of participants in the PPS 
will be reviewed and determined at the data review meeting prior to 
database lock. 
• 
For PPS-based analyses and outputs, participant grouping will be based 
on the actual treatment received. 
Safety set (SS) 
• 
SS will include all randomized participants who have received at least 1 
dose of the study drugs. 
• 
For SS-based analyses and outputs, participant grouping will be based on 
the group of the actual treatment received. 
PK Analysis Set 
(PKS) 
• 
PKS will include all participants who have been randomized and received 
at least one dose of study drug and have at least one evaluable plasma 
concentration data after dosing. 
Planned Analyses 
Primary Analysis 
The primary analysis will include data from the randomized period. The primary analysis is planned when 
all randomized participants complete the randomized period or discontinue from study, whichever is 
earlier. 
 
Final Analysis 
The final analysis will include data from the randomized and extension periods. The final analysis is 
planned when all participants complete the extension period or discontinue from study, whichever is 
earlier. 
 
Multiplicity 
Placebo groups will be pooled for descriptive summary and statistical analysis. In this study, the primary 
efficacy endpoint and key secondary endpoints will be tested in sequence using the Fixed Sequence 
Design. When comparing the difference between each VSA001 treatment group and placebo group 
separately in the testing of each endpoint, type I error within each endpoint will be controlled using Holm's 
method. 
The testing sequence of the fixed sequence procedure is shown in the table below: 
Endpoints 
Test Sequence 
Percent change from baseline at Month 10 in fasting TG (primary 
endpoint) 
1 
Percent change from baseline at Months 10 and 12 in fasting TG (mean) 
2 
Percent change from baseline at Month 10 in fasting APOC3 
3 
Percent change from baseline at Month 12 in fasting APOC3 
4 
 

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Schedule of Activities: Randomized Period 
Visit 
Screening 
Randomized period 
Day 
1b 
Day 
2 
Day 
15 
Month 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12a 
Study Day 
Day -56 to 
Day -1 
Day (±5 days) 
Day (±10 
days) 
Day (±5 
days) 
±10 
days 
±5 
days 
30 
60 
90b 
120 
150 
180b 
210 
240 
270b 
300 
330 
360b 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dietary counseling/maintain 
dietc 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review 
with 
participant 
signs and symptoms of 
pancreatitis and when to 
seek medical care 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteriad 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and Weighte 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital 
signs 
(BP, 
temperature, 
respiratory 
rate, heart rate) 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including 
genotype) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinations 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Single 12-lead ECGf 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Triplicate 12-lead ECGg 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
HBV and HCV serology 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
(women 
not 
of 
childbearing potential to 
confirm 
postmenopausal 
status) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (for women 
of childbearing potential) 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid function test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Visit 
Screening 
Randomized period 
Day 
1b 
Day 
2 
Day 
15 
Month 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12a 
Study Day 
Day -56 to 
Day -1 
Day (±5 days) 
Day (±10 
days) 
Day (±5 
days) 
±10 
days 
±5 
days 
30 
60 
90b 
120 
150 
180b 
210 
240 
270b 
300 
330 
360b 
Routine laboratory testsh 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Liver function tests (ALP, 
ALT, AST, TBL), blood 
glucose, and CBCi 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
APOC3 
and 
lipid 
parametersj 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
X 
X 
Child-Pugh score 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-Drug Antibody 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Sparse-PK Samplingm 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
IP administrationn 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Follow-up 24 h post-dose 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dietary assessmento 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Quality of Life Assessment 
(EQ-5D-5L, EORTC QLQ-
C30, EORTC QLQPAN26) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant 
medications/therapies 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events (including 
documentation 
of 
pancreatitis, abdominal pain 
or 
events 
requiring 
apheresis) 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total cholesterol; BP = blood pressure; ECG 
= electrocardiogram; EORTC QLQ = European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire; EQ-5D-5L = EuroQol 5-
dimension instrument; FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; IP = investigational product; PK = pharmacokinetics. 
a. 
If a participant discontinues study participation early, then the Month 24 assessments (see Schedule of Activities: Extension period) should be completed at the 
time of early discontinuation, if possible. 
b. 
Assessments completed on dosing days are to be done pre-dose, and Day 1 assessments will be used as baseline, unless otherwise specified. Urine pregnancy tests 
on Day 1 and subsequent dosing visit days will be performed pre-dose and must be negative. 
c. 
It is recommended that all enrolled participants maintain on a diet of ≤ 20 g of fat per day from the start of screening and throughout the study. The special diet of 

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patients will be determined by the PI. 
d. 
Assessments of all eligibility criteria (including laboratory values) must be completed within 56 days prior to Day 1, and all laboratory tests at screening and Day 
1, except for coagulation, will be performed by the central laboratory. 
e. 
Height (cm) at screening visit only; weight (kg) at all indicated visits. 
f. 
Single 12-lead ECG will be performed in the supine position after the participant has rested comfortably for 5 min. ECGs will be collected prior to any blood 
draws. 
g. 
Triplicate 12-lead ECG will be performed using validated ECG services equipment approximately time-matched to whole blood PK collections for all participants: 
ECG assessments should be done within -30 min prior to the pre-dose PK blood collections, and within 30 min before the 2-hour and 4-hour post-dose PK blood 
collections. 
h. 
Blood and urine samples will be collected at screening after obtaining informed consent. Routine laboratory tests (blood chemistry, coagulation, urinalysis, and 
HbA1c) after Day 1 will be performed in the laboratory of the site. At study visits with blood draws for clinical laboratory tests or lipid parameter measurements, 
participants will have fasted for at least 10 hours prior to blood draw unless otherwise specified. HbA1c will be continuously assessed during the study, and the 
results will be used to determine whether treatment should be discontinued for the participants according to the criteria for treatment discontinuation (Appendix 
5); samples collected on Month 2 (Day 60) will be analyzed for HbA1c only. 
i. 
Liver function, blood glucose, and CBC tests after Day 1 will be performed in the laboratory of the study. Any elevation in ALP, ALT, AST, or TBL test results 
will be evaluated and followed by the laboratory of the site as described in the consensus guidelines for suspected drug-induced liver injury during clinical trials 
in patients with nonalcoholic steatohepatitis, and participants will have fasted for at least 10 hours prior to blood draw. The CBC will be used to monitor platelet 
counts. Only liver function, blood glucose, and CBC within 28 days prior to randomization will be accepted for the review of eligibility criteria. 
j. 
Whole blood for pharmacodynamic (PD) analysis will be drawn after the site has confirmed the participant has maintained a stable diet for ≥4 weeks and stable 
background medications. These samples will be transported to the Sponsor’s designated central laboratory for APOC3 and lipid parameter measurements. Only 
lipid parameters (TG, LDL-C, TC, non-HDL-C, HDL-C, VLDL-C, LP[a]) are required at screening, i.e., APOC3 testing is not required. At baseline (Day 1) and 
subsequent visits, lipid testing parameters will include TG, LDL-C, TC, non-HDL-C, HDL-C, VLDL-C, APOB-48, LP[a], APOB-100, total APOB, APOC-III, 
APOC-II, APOA-I, and APOA-V. Lipid parameter testing must be done after the participant has fasted for ≥10 hours before collection at each study visit. 
k. 
At Month 10, collect lipids twice, 2 to 7 days apart, for calculation of study endpoints. 
l. 
Child-Pugh score will be determined based upon clinical evaluations by the Investigator and pre-dose Day 1 baseline laboratory values. 
m. Sparse PK sampling plan: All participants who have signed the informed consent for PK sampling will have whole blood for plasma PK samples drawn within 30 
min pre-dose and at 4 hours (±30 min) post-dose at Day 1 and Month 3 after study treatment administration (VSA001 or placebo). 
n. 
Prior to each dosing, the Investigator must make assessments based on the participant’s most recent available laboratory test results (including but not limited to 
urine pregnancy, liver function, and HbA1c) and clinical condition to confirm eligibility for dosing. At Month 12, all participants will receive the first open-label 
dose of VSA001 at the dose corresponding to their study treatment dose in the randomized period (remain blinded to the initial treatment assigned in the randomized 
period until the last participant finishes the assessments in the randomized period. Thus, participants who received VSA001 25 mg Q3M or 50 mg Q3M will 
continue to receive the same dose. Participants who received placebo will switch to active treatment based on the initial dosing group to which they were assigned 
(i.e., VSA001 25 mg Q3M or 50 mg Q3M). All participants in the open-label period will receive VSA001 25 mg Q3M after approval of the new version of the 
protocol (V3.4). 
o. 
Diet will be recorded on at least 3 of the past 5 days before the study visit. 
 
 

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Schedule of Activities: Extension period 
Visit 
Extension period 
Month 
13 
14 
15 
18 
21 
24/EOSa 
Study Day 
Day (±10 days) 
390 
420 
450b 
540b 
630b 
720b 
Dietary counseling/maintain diet 
X 
X 
X 
X 
X 
X 
Review with participant signs and symptoms of pancreatitis and when to seek 
medical care 
X 
X 
X 
X 
X 
X 
Weight 
 
 
X 
X 
X 
X 
Vital signs (BP, temperature, respiratory rate, heart rate) 
 
 
X 
X 
X 
X 
Physical examination (symptom-directed) 
 
 
X 
X 
X 
X 
Single 12-lead ECGc 
 
 
X 
X 
X 
X 
Pregnancy test (for women of childbearing potential) 
X 
X 
X 
X 
X 
X 
Routine laboratory testsd 
X 
X 
X 
X 
X 
X 
Liver function tests (ALP, ALT, AST, TBL) and CBCe 
X 
X 
X 
X 
X 
X 
APOC3 and lipid parametersf 
X 
X 
X 
X 
X 
X 
Anti-Drug Antibody 
 
 
X 
X 
 
X 
IP administrationg 
 
 
X 
X 
X 
 
Dietary assessmenth 
 
 
X 
X 
X 
X 
Quality of Life Assessment (EQ-5D-5L, EORTC QLQ-C30, EORTC 
QLQPAN26) 
 
 
 
 
 
X 
Concomitant medications/therapies 
X 
X 
X 
X 
X 
X 
Adverse events (including documentation of pancreatitis, abdominal pain, or 
events requiring apheresis) 
X 
X 
X 
X 
X 
X 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; BP = blood pressure; ECG = 
electrocardiogram; EORTC QLQ = European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire; EOS = end of study; EQ-5D-5L 
= EuroQol 5-dimension instrument; IP = investigational product. 
a. 
If a participant discontinues study participation early, then the Month 24 assessments should be completed at the time of early discontinuation, if possible. 
b. 
Safety assessments completed on dosing days are to be done pre-dose, unless otherwise specified. 
c. 
Single 12-lead ECG will be performed in the supine position after the participant has rested comfortably for 5 min. ECGs will be collected prior to any blood 
draws. 
d. 
Routine laboratory tests (blood chemistry, coagulation, urinalysis, blood glucose, and HbA1c) will be performed in the laboratory of the site. At study visits with 
blood draws for clinical laboratory tests or lipid parameter measurements, participants will have fasted for at least 10 hours prior to blood draw unless otherwise 
specified. HbA1c will be continuously assessed during the study, and the results will be used to determine whether treatment should be discontinued for the 

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participants according to the criteria for treatment discontinuation (Appendix 5); samples collected at Months 13 and 14 will be analyzed for HbA1c only. 
e. 
Any elevation in ALP, ALT, AST, or TBL test results will be evaluated and followed by the laboratory of the site as described in the consensus guidelines for 
suspected drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis. The CBC will be used to monitor platelet counts. 
f. 
Samples for APOC3 and lipid parameter measurements will be transported to the Sponsor's designated central laboratory for testing. Lipid parameter testing must 
be done after the participant has fasted for ≥10 hours before collection at each study visit. 
g. 
Prior to each dosing, the Investigator must make assessments based on the participant’s most recent available laboratory test results (including but not limited to 
urine pregnancy, liver function, and HbA1c) and clinical condition to confirm eligibility for dosing. 
h. 
Diet will be recorded on at least 3 of the past 5 days before the study visit. 
 

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1. 
Table of Contents, List of Tables, and List of Figures 
Table of Contents 
Title Page 
 .............................................................................................................................. 1 
History and Summary of Protocol Revision .............................................................................. 2 
Signature Page of Sponsor ......................................................................................................... 6 
INVESTIGATOR’S AGREEMENT ......................................................................................... 7 
PROCEDURES IN CASE OF EMERGENCY ......................................................................... 8 
SYNOPSIS  .............................................................................................................................. 9 
1. 
Table of Contents, List of Tables, and List of Figures ....................................... 24 
2. 
List of Abbreviations and Definition of Terms .................................................. 29 
3. 
Introduction ........................................................................................................ 32 
3.1. 
Overview of Disease Background ...................................................................... 32 
3.1.1. 
Familial chylomicronemia syndrome ................................................................. 32 
3.1.2. 
Apolipoprotein C3 .............................................................................................. 33 
3.2. 
Overview of VSA001 Development .................................................................. 33 
3.2.1. 
Mechanisms of Action and Therapeutic Rationale ............................................ 34 
3.2.2. 
Preclinical Studies .............................................................................................. 34 
3.2.3. 
Clinical Studies .................................................................................................. 35 
3.3. 
Potential Risks for Study Participation .............................................................. 36 
3.3.1. 
Embryo-fetal....................................................................................................... 36 
3.3.2. 
Hepatic function ................................................................................................. 37 
3.3.3. 
Injection Site AEs............................................................................................... 37 
3.3.4. 
Poor glycemic control ........................................................................................ 37 
3.3.5. 
Benefit-risk Assessment ..................................................................................... 38 
4. 
Study Objectives and Endpoints ........................................................................ 39 
4.1. 
Objective ............................................................................................................ 39 
4.2. 
Endpoints ............................................................................................................ 39 
4.2.1. 
Primary endpoint ................................................................................................ 39 
4.2.2. 
Key secondary endpoints ................................................................................... 40 
4.2.3. 
Secondary endpoints .......................................................................................... 40 
4.2.4. 
Exploratory endpoints ........................................................................................ 40 
5. 
Investigational Plan ............................................................................................ 41 
5.1. 
Overall study design ........................................................................................... 41 
5.1.1. 
Overview of study design ................................................................................... 41 
5.1.2. 
Informed Consent ............................................................................................... 43 
5.1.3. 
Screening ............................................................................................................ 44 
5.1.4. 
Treatment Period ................................................................................................ 45 
5.1.5. 
PK sample collection .......................................................................................... 46 
5.1.6. 
Adverse Event Monitoring ................................................................................. 46 

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5.1.7. 
Early Termination .............................................................................................. 46 
5.2. 
Number of participants ....................................................................................... 47 
5.3. 
Treatment Assignment ....................................................................................... 47 
5.4. 
Dose Modification Criteria ................................................................................. 47 
5.4.1. 
Data Safety Committee and Safety Criteria for Dose Modification or 
Discontinuation .................................................................................................. 48 
5.5. 
Criteria for Study Termination ........................................................................... 49 
5.6. 
Discussion of Study Design (Including the Choice of Control Groups) ............ 49 
5.7. 
Rationale for Dose and Schedule of Administration .......................................... 50 
6. 
Selection and Withdrawal of Participants .......................................................... 51 
6.1. 
Participant Inclusion Criteria ............................................................................. 51 
6.2. 
Participant Exclusion Criteria ............................................................................ 53 
6.3. 
Participant Withdrawal Criteria ......................................................................... 54 
7. 
Treatment of Participants ................................................................................... 55 
7.1. 
Description of study drug ................................................................................... 55 
7.2. 
Restrictions and Concomitant Medications ........................................................ 55 
7.2.1. 
Fasting ................................................................................................................ 55 
7.2.2. 
Drug Abuse or Alcohol ...................................................................................... 55 
7.2.3. 
Concomitant medications ................................................................................... 55 
7.2.4. 
Central laboratory lipid examinations ................................................................ 56 
7.2.5. 
Notifying attending physician ............................................................................ 57 
7.3. 
Treatment compliance ........................................................................................ 57 
7.4. 
Principle of treatment discontinuation ............................................................... 57 
7.5. 
Randomization and Blinding .............................................................................. 58 
7.5.1. 
Randomization ................................................................................................... 58 
7.5.2. 
Blinding .............................................................................................................. 59 
7.6. 
Drug Therapy after the End of Study ................................................................. 59 
8. 
Study Drug Materials and Management ............................................................. 60 
8.1. 
Study Drugs ........................................................................................................ 60 
8.2. 
Study Drug Packaging and Labeling .................................................................. 60 
8.2.1. 
Vial ..................................................................................................................... 60 
8.2.2. 
Prefilled Syringe ................................................................................................. 60 
8.3. 
Storage of Study Drug ........................................................................................ 61 
8.4. 
Study Drug Preparation ...................................................................................... 61 
8.5. 
Administration .................................................................................................... 61 
8.6. 
Study Drug Accountability ................................................................................. 62 
8.7. 
Study Drug Handling and Disposal .................................................................... 63 
9. 
PK Assessments ................................................................................................. 63 
9.1. 
PK Assessments ................................................................................................. 63 
9.1.1. 
Sample Collection .............................................................................................. 63 

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9.1.2. 
Sample Analysis ................................................................................................. 63 
10.
Assessment of Efficacy ...................................................................................... 63 
10.1. 
Serum Triglycerides and Other Lipid Parameters .............................................. 64 
10.2. 
Glucose Metabolism ........................................................................................... 64 
10.3. 
Acute Pancreatitis Events ................................................................................... 64 
10.3.1. 
Detecting and Reporting Pancreatic Events ....................................................... 65 
10.4. 
Diet ..................................................................................................................... 65 
10.5. 
Patient-Reported Outcomes ................................................................................ 66 
10.5.1. 
EuroQoL 5-Dimension Questionnaire ............................................................... 66 
10.5.2. 
EORTC QLQ-C30 Questionnaire ...................................................................... 66 
10.5.3. 
EORTC QLQ-PAN26 Questionnaire ................................................................. 66 
11.
Assessment of Safety ......................................................................................... 66 
11.1. 
Safety Parameters ............................................................................................... 66 
11.1.1. 
Demographics/Medical History ......................................................................... 66 
11.1.2. 
Vital Signs .......................................................................................................... 67 
11.1.3. 
Physical Examination ......................................................................................... 67 
11.1.4. 
Electrocardiogram .............................................................................................. 67 
11.1.5. 
Laboratory Assessments ..................................................................................... 67 
11.1.5.1. 
Hematology ........................................................................................................ 68 
11.1.5.2. 
Blood Chemistry ................................................................................................ 68 
11.1.5.3. 
Coagulation ........................................................................................................ 68 
11.1.5.4. 
Urine Testing ...................................................................................................... 68 
11.1.5.5. 
Virus Serology.................................................................................................... 68 
11.1.5.6. 
Pregnancy Screen ............................................................................................... 69 
11.1.6. 
Anti-Drug Antibodies ......................................................................................... 69 
11.1.7. 
Early Termination Procedures ............................................................................ 69 
11.2. 
Adverse Events ................................................................................................... 69 
11.2.1. 
Definition of Adverse Events ............................................................................. 69 
11.2.1.1. 
Adverse Events ................................................................................................... 69 
11.2.1.2. 
Serious Adverse Event ....................................................................................... 70 
11.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events ................................................................................................... 70 
11.4. 
Timing, Frequency, and Method of Detecting Adverse Events ......................... 71 
11.5. 
Recording Adverse Events ................................................................................. 71 
11.5.1. 
Adverse Events of Special Interest..................................................................... 71 
11.6. 
Evaluating Adverse Events ................................................................................ 72 
11.6.1. 
Assessment of Severity ...................................................................................... 72 
11.6.2. 
Assessment of Causality..................................................................................... 73 
11.7. 
Follow-up of Adverse Events ............................................................................. 74 
11.8. 
Prompt Reporting of Serious Adverse Events .................................................... 74 

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11.8.1. 
Completion and Transmission of the Serious Adverse Event Reports .............. 74 
11.8.2. 
Pregnancy Reporting .......................................................................................... 75 
11.8.3. 
Serious Adverse Event Reports to the IRB ........................................................ 75 
11.8.4. 
Regulatory Requirements for Reporting of Serious Adverse Events ................. 75 
11.8.5. 
Post-study Adverse Events ................................................................................. 75 
11.8.6. 
Serious Adverse Events Related to Study Participation..................................... 76 
12. 
Statistics ............................................................................................................. 76 
12.1. 
General Considerations ...................................................................................... 76 
12.2. 
Analysis Populations .......................................................................................... 76 
12.3. 
Sample Size Considerations ............................................................................... 76 
12.4. 
Analysis Methods ............................................................................................... 77 
12.4.1. 
Baseline Data...................................................................................................... 77 
12.4.2. 
Efficacy .............................................................................................................. 77 
12.4.3. 
Safety .................................................................................................................. 79 
12.4.4. 
Pharmacokinetics and Pharmacodynamics ........................................................ 79 
12.4.5. 
Immunogenicity (Anti-Drug Antibodies) .......................................................... 79 
13. 
Direct Access to Source Data/Documents ......................................................... 79 
13.1. 
Study Monitoring ............................................................................................... 79 
13.2. 
Protocol Deviations ............................................................................................ 80 
13.3. 
Clinical Laboratory Certification and Reference Ranges .................................. 81 
13.4. 
Audits and Inspections ....................................................................................... 81 
13.5. 
Institutional Review Board/Independent Ethics Committee Approval .............. 81 
14. 
Quality Control and Quality Assurance ............................................................. 82 
15. 
Ethics .................................................................................................................. 82 
15.1. 
Ethics Review ..................................................................................................... 82 
15.2. 
Ethical Conduct of the Study ............................................................................. 82 
15.3. 
Written Informed Consent .................................................................................. 83 
16. 
Data Handling and Record Keeping ................................................................... 83 
16.1. 
Inspection of Records ......................................................................................... 83 
16.2. 
Retention of Records .......................................................................................... 83 
17. 
Publication Policy .............................................................................................. 84 
17.1. 
Ownership .......................................................................................................... 85 
17.2. 
Confidentiality .................................................................................................... 85 
18. 
References .......................................................................................................... 86 
Appendix 1. Contraception ..................................................................................................... 89 
Appendix 2. Liver-related Study Dose Modification and Follow-up Guidelines ................... 90 
Appendix 3. Adverse Events of Special Interest - List of MedDRA Preferred Terms or 
Search Strategy ................................................................................................... 92 
Appendix 4. Table of Fatty Acid Content of Food ................................................................. 94 
Appendix 5. Glycemic Control-related Guidelines ................................................................. 99 

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Appendix 6. Description of Clinical Laboratory Tests ......................................................... 101 
 
List of Tables 
Table 1: Abbreviations .......................................................................................................... 29 
Table 2: Restricted Concomitant Medications .................................................................... 56 
Table 3: Injection Number and Volume Per Dose Cohort ................................................. 62 
 
List of Figures 
Figure 1: Study Flow Chart...................................................................................................... 43 
 
 

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2. 
List of Abbreviations and Definition of Terms 
The following abbreviations and special terms are used in this study protocol. 
Table 1: Abbreviations 
Abbreviations 
Definition 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
API 
Active Pharmaceutical Ingredient 
APOA-I or APOA1 
Apolipoprotein A-I 
APOA-V or APOA5 
Apolipoprotein A-V 
APOB 
Apolipoprotein B 
APOB-100 
Apolipoprotein B-100 
APOB-48 
Apolipoprotein B-48 
APOC2 
Apolipoprotein C2 
APOC3 
Apolipoprotein C3 
ARO-APOC3 
Short name for ARO-APOC3 Injection 
ARO-APOC3 Injection 
Clinical drug product solution ready for SC injection 
ASCVD 
Arteriosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
CECT 
Contrast-enhanced computed tomography 
cGMP 
Current Good Manufacturing Practice 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COVID 
Coronavirus Disease 
CRA 
Clinical Research Associate 
CRO 
Contract research organization 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Event 
DNA 
Deoxyribonucleic acid 
DSC 
Data Safety Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EORTC QLQ 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire 
EOS 
End of study 
EQ-5D-5L 
European Quality of Life Five Dimension Five Level Scale 
ET 
Early Termination 

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Abbreviations 
Definition 
FAS 
Full analysis set 
FCS 
Familial chylomicronemia syndrome 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GPIHBP1 
Glycosylphosphatidylinositol-anchored 
high-density 
lipoprotein-binding 
protein 1 
HbA1c 
Glycated haemoglobin 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human Immunodeficiency Virus 
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
HR 
Heart rate 
HTG 
Hypertriglyceridaemia 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IDL-C 
Intermediate-density lipoprotein cholesterol 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
kDa 
Kilodalton 
LISR 
Local injection site reactions 
LDL-C 
Low-density lipoprotein cholesterol 
LMF1 
Lipase maturation factor 1 
LPL 
Lipoprotein lipase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
NAG 
N-Acetylgalactosamine 
NCA 
Noncompartmental Analysis 
NHV 
Normal healthy volunteers 
NLME 
Nonlinear mixed effects 
NOAEL 
No observed adverse effect level 
Non-HDL-C 
Non-high-density lipoprotein cholesterol 

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Abbreviations 
Definition 
NYHA 
New York Heart Association 
OTC 
Over-the-counter 
PD 
Pharmacodynamics 
PFS 
Prefilled Syringe 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PT 
Preferred term 
Q3M 
Once every 3 months 
QTcF 
QT interval corrected by Fridericia's formula 
RISC 
Ribonucleic acid-induced silencing complex 
RNA 
Ribonucleic acid 
RNAi 
Ribonucleic acid interference 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SHTG 
Severe hypertriglyceridaemia 
siRNA 
Small interfering ribonucleic acid 
SOA 
Schedule of activities 
SOC 
System Organ Class 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TRAE 
Treatment-related adverse event 
TRL 
Triglyceride-rich lipoprotein 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
VLDL-C 
Very low density lipoprotein cholesterol 
WNL 
Within normal range 
 
 

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3. 
Introduction 
3.1. 
Overview of Disease Background 
3.1.1. 
Familial chylomicronemia syndrome 
Familial chylomicronemia syndrome (FCS) is a severe and ultrarare genetic disease, with an 
estimated prevalence of approximately 1 in 1,000,000. FCS is often caused by various 
monogenic mutations (e.g., null mutations in the genes coding for lipoprotein lipase [LPL], 
glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 [GPIHBP1], 
apolipoprotein C2 [APOC2], apolipoprotein A5 [APOA5], or lipase maturation factor 1 
[LMF1]). FCS generally results in extremely high fasting TG levels (above 900 mg/dL), 
ranking the first 0.1% of the TG levels. Such severe elevations lead to various serious signs 
and symptoms including acute pancreatitis (which can be fatal), chronic daily abdominal pain, 
type 2 diabetes mellitus, hepatic steatosis, and cognitive issues (aka “brain fog”). In recent 
years, a stepwise calculation method- and scoring-based approach has been proposed for 
clinical diagnosis of FCS (Falko 2018; Stroes 2017; Moulin 2018). Genetic testing has 
gradually become a common test in the clinical care of patients with dyslipidaemia. FCS is one 
of the blood lipid abnormalities for which genetic testing may be clinically useful; however, 
no clinical practice guidelines have been available for genetic testing for patients who may 
have inherited dyslipidaemia (Brown 2020). Currently, there are very limited treatment choices 
that can adequately treat FCS. Only one antisense oligonucleotide inhibitor of apolipoprotein 
C3 (APOC3) was approved for marketing in Europe and Brazil. 
The only effective treatment is a diet extremely low in fat (about 20 g per day). This diet does 
not normalize TG levels but reduces the risk of pancreatitis. However, diet compliance is one 
of the major barriers to reducing the risk of pancreatitis. Generally, the available therapies 
lower TG levels through the LPL pathway which usually causes dysfunction in FCS patients, 
making these therapies mostly ineffective. FCS patients are also at a risk of significantly 
increased TG levels after meals (usually > 500 mg/dL), generally leading to severe abdominal 
pain and a risk of postprandial pancreatitis, which usually requires hospitalization. Pancreatitis 
is one of the major complications of FCS that can be life-threatening; it is induced by digestion 
of TG in a large number of chylomicrons by pancreatic lipase. Pancreatitis is estimated to have 
a mortality of 10% for each episode and can lead to other life-threatening conditions such as 
sepsis, acute respiratory distress syndrome, hypovolaemic shock, and renal failure. 
Acute pancreatitis is a condition known to be associated with severe hypertriglyceridaemia 
(SHTG, including FCS), and is characterized by severe, persistent upper abdominal pain and 
increased serum lipase and/or amylase. It can lead to organ failure, frequent emergency clinic 
visits, hospitalization, chronic abdominal pain, and even death. Recurrence of acute pancreatitis 
can cause chronic pancreatitis, resulting in pancreatic failure and chronic abdominal pain, as 
well as associated pancreatic endocrine dysfunction (e.g., diabetes mellitus). The mortality rate 
associated with acute pancreatitis attacks ranges from 3% (mild cases) to 30% (severe cases). 

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Hypertriglyceridaemia (HTG)-associated acute pancreatitis has higher morbidity and mortality 
than pancreatitis of other etiologies (FDA 2018). The risk of acute pancreatitis increases with 
increasing serum TG levels, and the incidence of acute pancreatitis increases by 3% to 4% for 
every 100 mg/dL (1.13 mmol/L) increase in TG levels (Gelrud 2017; Scherer 2014). 
3.1.2. 
Apolipoprotein C3 
APOC3 is an 8.8 kilodalton (kDa) protein component of triglyceride-rich lipoproteins (TRLs) 
such as very-low-density lipoprotein cholesterol (VLDL-C), intermediate density lipoprotein 
cholesterol (IDL-C), chylomicrons, high-density lipoprotein cholesterol (HDL-C), and 
remnant particle lipoproteins. APOC3 is mainly synthesized in hepatocytes (about 80% in 
hepatocytes and 20% in intestinal cells), and its key function is to inhibit LPL-mediated 
hydrolysis of TG on TRLs on the surface of capillary endothelial cells of muscle and adipose 
tissues. APOC3 also delays clearance of lipoprotein remnants by the liver by inhibiting 
hepatocyte receptor-mediated uptake. APOC3 functions as a key regulator of fasting and 
postprandial plasma TG levels (Crosby 2014). 
Studies in transgenic mice overexpressing APOC3 and APOC3-knockout mice suggest that 
APOC3 would delay in vivo VLDL-C hydrolysis and may delay the catabolism of TRL residues 
in liver and other tissues (Aalto-Setala 1992; Aalto-Setala 1996; Gerritsen 2005; Jong 2001; 
Khetarpal 2015). Plasma TG, VLDL-C, and IDL-C were significantly lower, and TG clearance 
was higher in the APOC3-knockout rabbit model than in wild-type animals. Both aortic and 
coronary atherosclerosis were significantly reduced in gene-knockout rabbits compared to 
wild-type controls (Yan 2020). 
Two reports concurrently published in 2014 used complementary genetic methods to 
demonstrate that APOC3 functional deletion mutations were closely associated with reduced 
TG and reduced incidence of coronary artery disease, while marked hepatic steatosis was not 
observed (Crosby 2014; Jorgensen 2014). Compared with non-carriers, patients with APOC3 
homozygous deficiencies had an 88% reduction in APOC3 and a 59% reduction in TG (Lek 
2016; Saleheen 2017). In addition, patients with APOC3 homozygous deficiencies (“human 
knockout”) did not appear to present adverse phenotypes (Lek 2016; Proctor 2003). Given the 
important role of APOC3 in serum TG level modulation and its hepatocyte primary source of 
synthesis, it is an ideal target for hepatocyte targeted ribonucleic acid interference (RNAi) 
mediated gene silencing. 
Reducing APOC3 through a hepatocyte-targeting RNAi strategy may reduce circulating TG, 
potentially benefiting multiple patient populations including FCS patients, who remain at a 
high risk of high TG-induced pancreatitis after receiving the current standard of care. 
3.2. 
Overview of VSA001 Development 
Below is a brief overview of the available information for VSA001 (ARO-APOC3); a 
comprehensive review of available data (i.e., a review prior to the start of the study) is included 

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in the Investigator's Brochure (IB). 
3.2.1. 
Mechanisms of Action and Therapeutic Rationale 
VSA001 (ARO-APOC3) acts through the mechanism of RNAi. RNAi-based therapeutics have 
the potential to silence the expression of any specific target gene. RNAi is a naturally- occurring 
phenomenon by which siRNAs trigger a sequence- specific down- modulation of gene 
expression. RNAi-triggering molecules are synthetic oligonucleotides intended to silence the 
expression of specific genes in a targeted manner (Fire 1998). The RNAi trigger is a short, 
double-stranded siRNA conjugated to an N-acetyl galactosamine (NAG ) targeting moiety, 
acting as a ligand for the highly expressed, hepatocyte-specific asialoglycoprotein receptor. 
Available nonclinical and clinical pharmacokinetic (PK) data show rapid absorption and 
clearance of all NAG conjugated triggers from the blood stream within 24 to 48 hours post-SC 
administration. 
VSA001 is a synthetic, hepatocyte-targeted, double-stranded RNAi trigger designed to 
specifically silence messenger RNA (mRNA) transcription of the APOC3 gene using the RNA 
interference (RNAi) mechanism. Preclinical distribution studies show that VSA001 is 
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, a single RNAi trigger into RISC can result in the 
degradation of many mRNA molecules. Prolonged reduction in the expression of the 
corresponding proteins can provide sustained pharmacological activity for a duration 
significantly exceeding that of plasma exposure.  
It is expected that silencing hepatic APOC3 and blocking APOC3-mediated lipoprotein lipase 
(LPL) inhibition with VSA001 can enhance peripheral LPL activity and reduce serum TG. In 
addition, APOC3 silencing eliminates steric hindrance of APOC3 on hepatocytes, leading to 
increased hepatic clearance of TRL. 
3.2.2. 
Preclinical Studies 
The sponsor is conducting a comprehensive preclinical program to support SC administration 
of VSA001 (ARO-APOC3). The studies of potential clinical significance and relevant to this 
protocol are summarized below. 
Proof-of-concept studies in animal models support the use of siRNA targeting APOC3 as a 
potential treatment option for SHTG and FCS. The results of potential clinical significance and 
relevant to this protocol are summarized below. Details regarding preclinical pharmacology, 
PK, and toxicology results are provided in the Investigator’s Brochure (IB). 
● 
Preclinical pharmacology of ADS-005, the active pharmaceutical ingredient (API) in 

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VSA001, showed that treatment with ADS-005 in transgenic mice (TgAPOC3) resulted 
in dose-dependent decreases in liver APOC3 mRNA level, which was associated with 
a >90% decrease in serum APOC3. The decreased serum APOC3 was associated with 
decreased serum lipids (91% maximum mean reduction in TG, 45% maximum mean 
reduction in total cholesterol, and 64% maximum mean reduction in low-density 
lipoprotein C [LDL-C]). 
● 
Similar reductions in serum APOC3 were also observed following treatment with ADS-
005 in rhesus monkey model of diet-induced dyslipidaemia. VSA001 treatment was well 
tolerated in toxicology studies in rats and non-human primates. 
● 
Results of the non-Good Laboratory Practice (GLP) in vitro toxicology studies suggest 
that at the ADS-005 concentrations up to 250 μg/mL (far exceeding the expected blood 
concentration with the clinically used dose). 
– 
The possibility of ADS-005 exposure inducing a congenital immune system is 
minimal. 
– 
There is no possibility of complement activation, mitochondrial toxicity/cytotoxicity, 
or platelet aggregation in whole blood. 
● 
A set of genotoxicity and safety pharmacology studies recommended by the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) showed that ADS-005 was not genotoxic and had no adverse effects on the 
central nervous, respiratory, or cardiovascular system. 
● 
GLP toxicity studies where rats and cynomolgus monkeys received multiple doses of 
ADS-005 SC showed that ADS-005 treatment was well tolerated, with a No Observed 
Adverse Effect Level (NOAEL) of 300 mg/kg for both species. 
● 
In rat and cynomolgus monkey studies, significant histopathologic adverse outcomes were 
consistent with those observed with other NAG-siRNA drugs for SC administration. 
3.2.3. 
Clinical Studies 
A Phase 1 single and multiple ascending dose study (AROAPOC31001) to evaluate the safety, 
tolerability, PK and pharmacodynamics (PD) of ARO-APOC3 (VSA001) in healthy adult 
subjects and patients with HTG and chylomicronemia syndrome (CS, including FCS) has been 
completed. Results of study AROAPOC31001 showed that in healthy participants, ARO-
APOC3 treatment reduced serum TG, LDL-C, and apolipoprotein B (APOB), and increased 
HDL-C by reducing production of APOC3 in liver through the action of RNAi. The 10, 25, 50 
and 100 mg doses all showed sustained PD activity, lasting for more than 3 months. Except for 
mild, transient local injection site reactions (LISRs) and transient, self-limiting alanine 
aminotransferase (ALT) increased, single and repeat doses of ARO-APOC3 were well 
tolerated in healthy participants; based on the safety profile of the Phase 1 data, it was 
considered acceptable to further perform later-phase clinical evaluation. Preliminary data from 
participants with FCS also suggested significant reductions in APOC3 and TG following repeat 
doses (at baseline and on Day 29) of AROAPOC3 25 mg and 50 mg. See the IB for more 

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information on the results of study AROAPOC31001. 
Results of the Phase 1 study support the design information for conducting randomized, double-
blind, placebo-controlled Phase 2 studies in patients with SHTG (AROAPOC3-2001) and 
mixed dyslipidaemia (AROAPOC3-2002), as well as an open-label extension study in patients 
from these studies (AROAPOC3-2003). PK and PD model analysis results of the Phase 1 study 
support selecting 25 and 50 mg once-every-3-month (Q3M) doses for the Phase 3 clinical study 
in FCS patients. In addition, the completed Phase 1 clinical study included a small proportion 
(12.5%) of Asian participants to compare for any differences in PK, PD, or safety of ARO-
APOC3 (VSA001) in Asian and non-Asian participant subgroups, showing that there were no 
significant differences between the two subgroups, as specified in the ARO-APOC3 Ethnic 
Sensitivity Assessment Report (version 1.0, dated September 21, 2022). 
The AROAPOC3-2001 study is a completed phase IIb, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of ARO-APOC3 (VSA001) in adult patients 
with SHTG. Participants were randomized in a 3:1 ratio to either ARO-APOC3 10 mg, 25 mg, 
or 50 mg dose group or placebo group to receive two subcutaneous doses on Day 1 and at Week 
12, respectively. A total of 229 participants were randomized in the study and a total of 226 
participants were included in the final analysis set at EOS. During the study period, a total of 
171 participants (75.7%) experienced at least one TEAE. Overall, the most commonly reported 
TEAEs were poor glycemic control, COVID-19, upper respiratory tract infection and headache. 
ARO-APOC3 was generally well tolerated and all doses demonstrated acceptable safety and 
tolerability profiles. The incidence of TEAEs was generally balanced between ARO-APOC3 
and placebo. The proportion of participants who experienced SAEs was higher in the placebo 
group (16.4%) than in the ARO-APOC3 groups (3.6% to 12.5%). No SAEs reported were 
considered by the investigator or sponsor to be related to ARO-APOC3 treatment. In contrast, 
the SAEs were considered related to the basic pathology and comorbidities of the participant 
population/study participants. There was a modest numerical increase in HbA1c levels in all 
ARO-APOC3 treatment groups compared with placebo, mostly driven by diabetics with poor 
glycemic control at baseline, predominantly those who received the 50 mg dose. Although all 
doses of ARO-APOC3 showed increased HbA1 levels compared with placebo, the ARO-
APOC3 25 mg dose was associated with a lower magnitude of effect on HbA1c levels as well 
as better glycemic control compared with the ARO-APOC3 10 and 50 mg doses. 
3.3. 
Potential Risks for Study Participation 
3.3.1. 
Embryo-fetal 
Limited GLP toxicology and clinical studies related to reproductive toxicity have been 
available. Therefore, eligible participants (men and women, including their partners) enrolled 
in this study must agree to use highly effective contraceptive methods or exercise abstinence 
(only acceptable if the method is in line with the participant’s normal lifestyle) during the study 
(Appendix 1). 

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3.3.2. 
Hepatic function 
The target organ of VSA001 (ARO-APOC3) is liver. Literature on siRNA describes ALT 
changes associated with the off-target effect of microRNA in hepatocytes induced by the 
siRNA seed region (Janas 2018). Screening was performed for the presence of potential 
messenger RNA (mRNA) and microRNA homologies in the siRNA sequences of VSA001 
sense and antisense strands, where sequences with homology were not considered. Therefore, 
such off-target effects are not expected to occur. 
However, transient mild to moderate ALT increased was occasionally observed in study 
AROAPOC31001 (see the IB for details), which was not accompanied by International 
Normalized Ratio (INR) or total bilirubin (TBL) increased. To reduce this risk, a fixed stop 
rule for ALT and aspartate aminotransferase (AST) increased is included in this study protocol 
(Appendix 2). Blood samples will be collected as specified in the Schedule of Activities (SOA), 
and liver function and any potential liver injury will be evaluated. The Data Safety Committee 
(DSC) will regularly review all available safety data, including laboratory data (Section 5.4.1). 
3.3.3. 
Injection Site AEs 
Other modified siRNA candidate drugs for SC administration evaluated in clinical studies were 
associated with mild to moderate LISRs (e.g., pain and erythema) (Appendix 3). Commonly 
reported in study AROAPOC31001 were mild injection site adverse events (AEs). In this study, 
measures such as rotating the injection site and allowing VSA001 solution to recover to room 
temperature before injection will be taken to minimize LISRs. 
3.3.4. 
Poor glycemic control 
Interim analyses for the two Phase 2 clinical trials in patients with SHTG (AROAPOC3-2001) 
and mixed dyslipidaemia (AROAPOC3-2002) noted unbalanced changes in glycosylated 
haemoglobin (HbA1c) over time, mainly presented as significantly increased HbA1c in 
participants in the ARO-APOC3 treatment group compared to the placebo group. These 
changes were mainly observed in participants who had diabetes at baseline and were observed 
to be the most significant in the subset of participants treated with the highest dose of ARO-
APOC3 (50 mg). Based on these observations, the rules for treatment discontinuation and 
safety precautions for all ongoing ARO-APOC3 clinical studies have been updated. In the 
extension period (AROAPOC3-2003) to the aforementioned two Phase 2 clinical trials, 
assessment at the 50 mg dose level has been stopped, and participants who have been enrolled 
to receive or have already received the 50 mg dose will switch to the 25 mg dose for the next 
scheduled dose according to the study Schedule of Activities. 
This study is a phase III clinical study to evaluate the efficacy and safety of VSA001 in FCS 
patients, which is consistent with the overseas phase III clinical study in FCS patients 
(AROAPOC3-3001 study). The data from the AROAPOC3-3001 randomized double-blind 
study are summarized as follows: ARO-APOC3 25 mg Q3M and 50 mg Q3M both resulted in 

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great reductions in triglycerides, and approximately 80% of participants in both dose groups 
achieved 50% reduction in triglycerides. Compared to placebo, 25 mg and 50 mg doses of 
VSA001 provided similar efficacy results. The incidence of TEAEs was generally balanced 
between the ARO-APOC3 groups and the placebo group. No death occurred during the study 
period; the incidences of SAEs and Grade ≥ 3 TEAEs were higher in the placebo group than in 
the VSA001 groups. The observed TEAEs generally showed no dose dependence. Based on 
the analysis results of the phase III global FCS study (AROAPOC3-3001) of this product, the 
proposed market dose is 25 mg. 
The study will continue to evaluate the dose of 50 mg in FCS participants in the randomized 
treatment period, but the evaluation frequency of HbA1c will be increased (Schedule of 
Activities: Randomized period; Schedule of Activities: Extension Period). In addition, 
relevant criteria for treatment discontinuation are established (Appendix 5). All participants 
in the open-label period will receive VSA001 25 mg Q3M in the extension period (after 
approval of protocol V3.4). 
3.3.5. 
Benefit-risk Assessment 
To date, VSA001 (ARO-APOC3) has demonstrated an acceptable benefit-risk profile, yet 
further clinical studies with longer exposure periods are warranted. Results of the Phase 1 study 
AROAPOC31001 showed that treatment with ARO-APOC3 10-100 mg resulted in significant 
and durable reductions in serum APOC3 compared to placebo in healthy participants and 
patients with HTG and chylomicronemia (including FCS). 
Silencing APOC3 resulted in reductions in serum TG and other lipid parameters. In normal 
healthy volunteers (NHVs) receiving a single dose of ARO-APOC3, serum APOC3 decreased 
in a dose-dependent manner by up to 94% from baseline. In addition, TG (by up to -66%) and 
non-HDL-C (by up to -31%) were also reduced, and HDL-C (by up to +74%) was increased, 
with the dose effect generally associated with the decreased serum APOC3 in participants in 
the active drug group. In NHVs receiving repeated doses of ARO-APOC3, APOC3 (by up to -
94%), TG (by up to -75%) and non-HDL-C (by up to -39%) continued to decrease, and HDL-
C (by up to +75%) increased. These responses continued until Week 16 (12 weeks after the last 
dose). 
In patients with HTG and/or chylomicronemia receiving repeated doses of ARO-APOC3, 
compared to single dose, ARO-APOC3 produced similar or even greater effects at similar doses. 
Decreases in APOC3 (by up to -98%), TG (by up to -87%), and non-HDL-C (by up to -55%) 
and increases in HDL-C (by up to +120%) were observed. The effects of ARO-APOC3 
treatment on these and other key lipid parameters continued until Week 16 (12 weeks after the 
last dose). 
ARO-APOC3 treatment was generally well tolerated. No deaths or discontinuations from study 
due to AE were reported during the studies. Three participants reported 3 serious adverse events 
(SAEs), all of which were considered to be unrelated to the investigational product, and all the 

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participants completed study. There is no clear evidence that the frequency or severity of AEs 
would increase with dose. The reporting rate of treatment-emergent adverse events (TEAEs) 
was similar in the pooled placebo group and ARO-APOC3 treatment group. Most TEAEs were 
unrelated to study treatment, and no participants withdrawn from study due to TEAE. Overall, 
the AEs observed in this Phase 1 study were typical AEs expected to be observed in follow-up 
for a group of normal participants over the same time period. The most commonly reported 
drug-related AE was LISRs, which were all mild. Injection site AEs are expected based on the 
similar results reported in other clinical studies of siRNA for SC administration. Overall, there 
were no clinically significant trends in adverse laboratory test results. No clinically significant 
adverse changes or outcomes of particular concern were observed in electrocardiography 
(ECG), vital signs, or physical examination, either. 
Unbalanced changes in HbA1c as treatment prolonged were observed in the interim analyses 
for the overseas Phase 2 clinical studies (AROAPOC3-2001 and AROAPOC3-2002) of ARO-
APOC3, with HbA1c observed to be significantly increased in participants with diabetes in the 
ARO-APOC3 treatment group compared to the placebo group, particularly in participants in 
the 50 mg dose group. The data from the AROAPOC3-3001 randomized double-blind study in 
FCS patients are summarized as follows: ARO-APOC3 25 mg Q3M and 50 mg Q3M both 
resulted in great reductions in triglycerides, and approximately 80% of participants in both dose 
groups achieved 50% reduction in triglycerides. Compared to placebo, 25 mg and 50 mg doses 
of ARO-APOC3 provided similar efficacy results. The incidence of TEAEs was generally 
balanced between the VSA001 groups and the placebo group. No death occurred during the 
study period; the incidences of SAEs and Grade ≥ 3 TEAEs were higher in the placebo group 
than in the ARO-APOC3 groups. The observed TEAEs generally showed no dose dependence. 
Based on the analysis results of the Phase III global FCS study (AROAPOC3-3001) of this 
product, the proposed market dose of VSA001 is 25 mg. In FCS participants of the study 
(VSA001-3001 study), on the premise of increasing the evaluating frequency of HbA1c and 
establishing relevant criteria for treatment discontinuation, the 25 mg and 50 mg dose groups 
will continue to be evaluated during the randomized treatment period. In addition, all 
participants in the open-label period will receive VSA001 25 mg Q3M in the extension period 
(after approval of protocol V3.4). 
4. 
Study Objectives and Endpoints 
4.1. 
Objective 
The primary objective of this study is to evaluate the efficacy and safety of VSA001 in adults 
with FCS. 
4.2. 
Endpoints 
4.2.1. 
Primary endpoint 
The primary endpoint for this study is as follows: 

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● 
Percent change from baseline at Month 10 in fasting serum TG 
4.2.2. 
Key secondary endpoints 
The key secondary endpoints for this study are as follows: 
● 
Percent change from baseline at Months 10 and 12 (averaged) in fasting serum TG 
● 
Percent change from baseline at Month 10 in fasting serum APOC3 
● 
Percent change from baseline at Month 12 in fasting serum APOC3 
4.2.3. 
Secondary endpoints 
The following secondary endpoints are for the randomized period only, except as noted. 
● 
Percent change from baseline at Month 10 in fasting serum non-high density lipoprotein 
cholesterol (non-HDL-C) and HDL-C 
● 
Percent change from baseline at Month 12 in fasting serum TG, non-HDL-C, and HDL-
C 
● 
Proportion of participants achieving fasting serum TG of <500 mg/dL at Month 10 
● 
Proportion of participants achieving fasting serum TG of <500 mg/dL at Month 12 
● 
Change and percent change from baseline at each scheduled assessment in fasting serum 
TG up to Month 12 
● 
Incidence of TEAEs in the participants (either period) 
● 
Incidence of positively adjudicated events of acute pancreatitis (either period) 
Note: Any AEs and SAEs reported by the investigator during the study that are consistent 
with acute pancreatitis events will be adjudicated by the blinded Data Safety Committee 
based on the Atlanta Classification for Acute Pancreatitis 2013 for fulfillment of any 2 of 
the following 3 criteria: 
1. 
Abdominal pain consistent with symptoms of acute pancreatitis (acute episodes of 
persistent, severe upper abdominal 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) or magnetic resonance imaging (MRI) or transabdominal 
ultrasonography 
4.2.4. 
Exploratory endpoints 
The following exploratory endpoints are for both the randomized period and the extension 
period A, except as noted. 
● 
Change and percent change from baseline at each scheduled assessment in fasting serum 
lipid parameters (total cholesterol, low-density lipoprotein cholesterol [LDL-C], HDL-C, 
non-HDL-C, VLDL-C, total apolipoprotein B [APOB], APOB-48, lipoprotein(a) [LP(a)], 
APOB-100, APOC2, APOC3, apolipoprotein A-I [APOA1], and apolipoprotein A-V 
[APOA5]), with all values drawn after at least a 10-hour fast. 

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● 
Changes from baseline at each scheduled assessment in fasting serum blood glucose, 
glycated hemoglobin (HbA1c), homeostatic model assessment for insulin resistance 
(HOMA-IR), and C-peptide 
● 
Change and percent change from baseline at each scheduled assessment in TG, APOC3, 
non-HDL-C, and HDL-C (extension period only) 
● 
Proportion of participants reaching TG of <500 mg/dL at each scheduled assessment 
● 
Incidence of hospitalizations for abdominal pain 
● 
Participant incidence of emergent apheresis 
● 
PK parameters of VSA001 
● 
Incidence of anti-drug antibodies (ADA) to VSA001 
● 
Change from baseline at each scheduled assessment in European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 
score 
● 
Change from baseline at each scheduled assessment in EORTC QLQ-PAN26 score 
● 
Change from baseline at each scheduled assessment in EuroQol 5-dimension instrument 
(EQ-5D-5L) score 
5. 
Investigational Plan 
5.1. 
Overall study design 
5.1.1. 
Overview of study design 
This is a randomized, double-blind, placebo-controlled, dose-finding clinical trial that will 
include 2 parallel dose groups: 25 mg and 50 mg. Following a once-every-3-month dosing 
regimen and using the percent change from baseline at Month 10 in fasting serum TG as the 
primary endpoint, the efficacy of VSA001 in patients with FCS will be evaluated. At the same 
time, the occurrence of safety events in the participants during the treatment period will be 
collected, and the optimal dose for Chinese patients with FCS will be explored based on the 
benefit-risk assessment. 
This study will be conducted in adult participants with FCS. participants who have signed the 
Informed Consent Form (ICF) previously approved by the Independent Ethics Committee (IEC) 
or Institutional Review Board (IRB) may enter screening, during which eligibility assessments 
will be completed. At the same time, a stable diet, lifestyle and medication scheme will be 
maintained at the Principal Investigator (PI)’s discretion and based on the local standard of care 
during this period. All other eligibility criteria assessments and review of laboratory test values 
must be completed within 8 weeks prior to Day 1. 
During the randomized period, approximately 30 participants (meeting all eligibility criteria 
during the screening period) will be randomized in a double-blinded manner to receive SC 
administration of either VSA001 or matching placebo once every 3 months (Q3M; Figure 1), 
for a total of 4 doses. Blinding will be preserved during randomized period; however, treatment 

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unblinding may occur, at the PI’s or medical monitor’s discretion, when deemed necessary for 
treatment of an adverse event (AE) or for a safety event-related decision or a decision to be 
made regarding trial continuation in an individual participant. 
Early in the extension period of the study, participants will remain blinded to the treatment 
assignment for the randomized period and will start to receive open-label VSA001 at the same 
dose as the study treatment dose that they received during the randomized period. Thus, 
participants who received VSA001 25 mg Q3M or 50 mg Q3M will continue to receive the 
same dose. Participants who received placebo will switch to active treatment based on the 
initial dosing group to which they were assigned (i.e., VSA001 25 mg Q3M or 50 mg Q3M). 
Based on the analysis results of the Phase 3 global FCS study (AROAPOC3-3001) of this 
product, the proposed market dose of VSA001 is 25 mg. In the extension period of the study, 
after the approval of the protocol (V3.4), all participants should receive treatment with VSA001 
25 mg Q3M; participants in the 50 mg group who earlier entered the open-label period will 
also be switched to the 25 mg treatment group for the next dose. 
At the PI’s discretion and based on the local standard of care, it is recommended that all 
enrolled participants maintain a diet containing ≤20 g fat per day from starting screening and 
throughout the study and maintain a stable treatment regimen throughout the study. The 
specific diet for a patient will be determined by the PI. Dietary counseling will start during the 
treatment stabilization period and be performed at each subsequent study visit to promote 
compliance, and dietary assessments will be performed in accordance with the SOAs (Schedule 
of Activities: Randomized Period and schedule of activities: extension period) and Section 10.4. 

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Figure 1: Study Flow Chart 
 
Q3M=once every 3 months 
* Stabilization of diet, medications, and laboratory values will be reviewed during screening period 
** Participants in the 50 mg group who have entered the open-label period before dose combination will 
switch to 25 mg at the next treatment visit 
For any participant experiencing acute pancreatitis, the participant may be unblinded and 
transitioned to the open-label treatment period of the study after assessment by the Investigator. 
This will be documented via the Interactive Web Response System (IWRS). 
• If the participant had been assigned to receive placebo, they will be re-assigned to receive 
open-label treatment with VSA001 if they are clinically stable based on the assessment of 
the Investigator in consultation with the Medical Monitor, and relevant procedures will start 
from Month 12 of the Schedule of Activities. 
• If the participant had been assigned to receive VSA001, they will restore open-label 
treatment with VSA001 if they are clinically stable based on the assessment of the 
Investigator in consultation with the Medical Monitor, and until at least 3 months have 
passed since the receiving the last dose of study drug, i.e., starting from Month 12 of the 
Schedule of Activities. 
5.1.2. 
Informed Consent 
Before starting any screening procedure, the PI or designated study doctor will inform the 
participant of the nature and purpose of the study, including the risks and benefits involved, 
possible AEs, and the fact that participation in the study is voluntary, and provide a copy of the 
IRB/IEC-approved ICF for review. Each participant will provide a written Informed Consent 
Form to participate in the study in the presence of the PI or designated study doctor and confirm 
receipt of the above information, and the ICF will also be signed and dated by the PI or 
Screen
ing* 
Rando
mizati
on 
Extension period 
End of double-blind treatment** 
Rollover to open-label treatment 
24 Months 
Baseline 
Primary endpoint 
(Percent change from baseline at Month 10 in fasting serum TG level) 
Placebo (volume-matched) Q3M (n=5) 
Placebo (volume-matched) Q3M (n=5) 
12 Months 
Randomized period 

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designated study doctor. The time that each participant gives informed consent will be recorded 
in the site source documentation. The PI will retain a signed original of the Informed Consent 
Form and provide a copy to the participant. 
Informed Consent Form will be signed in accordance with the principles of the ICH Good 
Clinical Practice (GCP) procedures. For all participants considering to participate in the study 
and be subsequently enrolled or excluded, the PI or medically qualified designee completes 
recording of whether the participant meets the inclusion criteria. Detail information of 
screening failures can be recorded using the Study Eligibility Screening Form or Participant 
Screening Failure Log. The procedures outlined in the SOA (Schedule of Activities: 
Randomized Period) will be followed. The time restriction for fasting outlined in Section 7.2.1 
will be followed. 
No study assessment or procedure will be performed until the participant has signed the ICF. 
5.1.3. 
Screening 
See Schedule of Activities: Randomized Period for the SOA for screening. Before laboratory 
assessment of fasting blood lipid parameters judged to be acceptable, it should be confirmed 
that the diet has remained stable for at least 4 weeks. Enrolled participants will be counseled to 
remain on a diet comprising ≤20 g of fat per day throughout the study, as per the Principal 
Investigator’s (PI’s) discretion and in accordance with the local standard of care The specific 
diet will be determined by the PI based on each individual's specific diagnosis and medical 
needs. Dietary assessment and counseling will be initiated during Screening, and dietary 
counseling will be provided throughout the study to promote compliance. The PI may make 
dietary changes as appropriate. 
Only liver function, blood glucose, and hematology tests within 28 days prior to randomization 
will be acceptable for assessment of in/exclusion criteria; other eligibility criteria assessments 
and review of laboratory test values (Section 6) must be completed within 8 weeks prior to Day 
1. During Screening and throughout the study, participants' blood lipid parameters will be 
collected in a fasted state (no food or beverages other than water and essential oral medications 
allowed for at least 10 hours) to assess the eligibility. 
A screening failure refers to where a participant did not enter study despite having given 
consent to participate in the clinical study. It is required to provide essential information of 
screening failures and ensure that screening failures are reported in a transparent manner and 
that questions from regulatory authorities are responded to. At a minimum, demographics, 
screen failure details, eligibility criteria, and any serious adverse events (SAEs) should be 
included. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. For each screening/re-screening, a re-screened participant will be assigned a new 
participant screening number. 

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5.1.4. 
Treatment Period 
Participants meeting the eligibility requirements at Screening will be enrolled in the study. All 
dose cohorts will enroll in parallel, and participants will be randomized in a 2:1:2:1 ratio into 
each dose cohort (VSA001 25 mg dose group, volume-matched placebo group, VSA001 50 
mg dose group and volume-matched placebo group). 
During the 12-month randomized period (Schedule of Activities: Randomized Period), each 
participant will receive in a double-blinded manner either the active treatment or placebo by 
SC injection Q3M, as specified below: 
● 
VSA001 25 mg (n=10) or volume-matched placebo (n=5) Q3M; or 
● 
VSA001 50 mg (n=10) or volume-matched placebo (n=5) Q3M 
During the 12-month extension period (Schedule of Activities: Extension Period), each 
participant will be treated with the active drug (VSA001 25 mg or 50 mg) in an open-label 
manner Q3M. A discussion of dosing in these study parts is provided in Section 5.3. 
Each participant will visit the clinical institution on Day 1 (baseline). Study treatment will be 
administered on Day 1, which must be within 8 weeks following the start of screening 
assessments. Upon a participant’s arrival at the clinical institution, the PI or designated study 
staff will meet with the participant to reiterate all the study procedures and encourage the 
participant to ask any questions, and the participant will be asked questions about protocol 
compliance and safety monitoring. participants will then return to the clinical trial institution 
for a visit following the SOA, and each visit typically will last approximately 4 hours, unless 
additional monitoring is deemed necessary by the PI for safety reasons. 
All visits will be conducted at the clinical study site. At the PI’s discretion and with prior 
approval of the sponsor, study assessments may be allowed to be performed at a qualified 
medical institution in the patient's location during non-treatment visits. Use of a qualified 
medical institution in the patient's location will depend on the qualifications of the local 
medical institution (such as a tertiary hospital) and the ability of the PI to adequately monitor 
the participant’s safety. The method and any specific risks associated with it must be clearly 
outlined in an IEC/IRB-approved ICF when using the service of a local medical institution. 
Some participants enrolled in this study may have hepatic enzyme increased at baseline. 
Instructions for adjusting the treatment for participants with ALT/AST increased are provided 
in Appendix 2. 
The parameters to be assessed and the assessment schedule is presented in the SOA. During 
the study, participants will receive the following assessments regularly: medical history review, 
physical examination, vital signs measurement (blood pressure, body temperature, heart rate, 
respiratory rate), weight measurement, AE monitoring, ECG, pregnancy test (for women of 
childbearing potential), laboratory assessments, and review of concomitant medications. Blood 
samples will be collected for plasma concentration analysis of HDL-C, LDL-C, VLDL-C, TG 

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and other specified lipid or metabolic parameters, hematology, serum lipase and insulin, 
HbA1c, C-peptide, coagulation, serum biochemistry, and VSA001. Urinalysis will include 
random urine creatinine and random urine protein. Before blood sampling, the participant will 
be required to fast overnight for at least 10 hours. 
Clinically significant changes (including AEs) will be followed up until the event resolves or 
is considered to have been medically stable. 
5.1.5. 
PK sample collection 
Pre-dose and post-dose PK samples will be collected at Day 1 and Month 3 for all participants. 
The PK sampling points are within 30 min pre-dose and 4 h±30 min post-dose. If the 
recommended time window is missed, every attempt will 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. 
5.1.6. 
Adverse Event Monitoring 
Safety assessments include AEs and serious adverse events (SAEs), physical examinations, 
vital sign measurements (blood pressure, heart rate, body temperature, and respiratory rate), 
ECG, clinical laboratory tests, concomitant medications/therapy, and reasons for treatment 
discontinuation. Safety assessments will be performed at the time points specified in the SOA 
(from signing Informed Consent Form to the Month 24/End-of-Study [EOS] visit) (Schedule 
of Activities: Randomized Period and Schedule of Activities: Extension Period). The sponsor 
will regularly review/monitor the safety data (including safety laboratory results) at least 
monthly. 
A TEAE is defined as an AE or worsening of a pre-existing condition that occurs after treatment 
with the IP. Reporting and follow-up of TEAEs may continue until the EOS and for up to 6 
months following the last dose. All SAEs occurring during the reporting period must be 
reported to the sponsor using the SAE Report Form immediately upon receipt of the notification, 
in addition to reporting using the electronic Case Report Form (eCRF). All AEs/SAEs will be 
followed until resolution, until the condition stabilizes, until the event is otherwise explained, 
or until the participant is lost to follow-up. However, the sponsor must be notified immediately 
if the PI becomes aware of any SAE (including death) at any time after the participant has 
ended study treatment and considers that there is a reasonable relatedness of the event to the 
IP. Abnormalities in laboratory or ancillary examinations/tests (e.g., ECG) may be reported as 
an AE if deemed clinically significant by the PI. Laboratory or ancillary examinations/tests 
abnormalities not reported as clinically significant are not to be reported as AEs in the study 
database. 
5.1.7. 
Early Termination 
If a participant is discontinued from study prematurely, every reasonable effort should be made 
for the participant to attend the Month 24/EOS visit within 30 days of making the decision to 

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discontinue the participant's participation in the study. The reason for early termination from 
the study will be documented in source documents and eCRF(s). Participants who have 
discontinued VSA001 treatment due to SAE are encouraged to continue receiving medical 
monitoring follow-up until the event resolves. 
5.2. 
Number of participants 
Thirty participants are expected to be enrolled in this study. Taking into account the effects of 
uncertainties such as competitive enrollment, block randomization, and COVID-19, 
approximately 36 participants will be enrolled. 
5.3. 
Treatment Assignment 
All dose cohorts will enroll in parallel, and participants will be randomized in a 2:1:2:1 ratio 
into each dose cohort (VSA001 25 mg dose group, volume-matched placebo group, VSA001 
50 mg dose group and volume-matched placebo group). 
During the randomized period, each participant will receive in a double-blinded manner either 
the active treatment or placebo by SC injection Q3M, as specified below: 
● 
VSA001 25 mg (n=10) or volume-matched placebo (n=5) Q3M; or 
● 
VSA001 50 mg (n=10) or volume-matched placebo (n=5) Q3M 
During the extension period, each participant will receive active treatment in an open-label 
manner Q3M, as specified below: 
● 
Early in the extension period of the study, participants will remain blinded to the treatment 
assignment for the randomized period and will start to receive active drug treatment at the 
same dose as the study treatment dose that they received during the randomized period. 
Thus, participants who received VSA001 25 mg Q3M or 50 mg Q3M will continue to 
receive the same dose. Participants who received placebo will switch to active treatment 
based on the initial dosing group to which they were assigned (i.e., VSA001 25 mg Q3M 
or 50 mg Q3M). 
● 
Later in the extension period, after the last participant has completed observations for the 
randomized period, all participants will be switched to open-label VSA001 treatment 
Q3M. 
● 
Based on the analysis results of the Phase 3 global FCS study (AROAPOC3-3001) of this 
product, the proposed market dose of VSA001 is 25 mg. In the extension period of the 
study, after the approval of this version of protocol (V3.4), all participants will receive 
treatment with VSA001 25 mg Q3M; participants in the 50 mg group who earlier entered 
the open-label period will also be switched to the 25 mg treatment group for the next dose. 
5.4. 
Dose Modification Criteria 
No such dose modifications as dose escalation or dose reduction will be made. 

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5.4.1. 
Data Safety Committee and Safety Criteria for Dose Modification or 
Discontinuation 
A Data Safety Committee (DSC), consisting of the CRO and sponsor medical monitors and 
investigators, etc., will be formed. The DSC will review the safety data after approximately 10 
participants have received at least 1 dose of the IP and half of the total number of participants 
planned to be enrolled have received at least 1 dose of the IP. The study sponsor may also 
require the DSC to convene an interim meeting to review the safety data and make suggestions 
related to the study. The planned safety review will include assessment of important safety 
events such as AEs and SAEs in the 50 mg versus 25 mg dose groups. Where any potential 
safety signal is detected, the DSC may be required to review the safety data at other 
unscheduled meetings. The DSC may also make suggestions to the sponsor regarding any 
follow-up actions and modifying, terminating, or continuing the study as planned. The DSC 
will review blinded data at public meetings in the presence of the sponsor. The sponsor will 
provide up-to-date information on study enrollment and conduct, and will inform the DSC of 
any study-related information, including safety concerns based on blinded data, that may be 
relevant to DSC review. 
The DSC may advise the sponsor to suspend further treatment to allow time for evaluating the 
safety data and recommending actions to be taken, which may include but are not limited to 
one of the following: 
● 
Continue without protocol amendment 
● 
Continue after protocol amendment 
● 
Termination of the study 
● 
Suspension of the study 
● 
Other changes 
The sponsor or PI may discontinue any participant’s participation in the study at any time. 
A decision to modify the study or to suspend or permanently discontinue treatment for an 
individual participant or dose group, or to suspend/permanently stop enrollment, may be made 
in case of any of the following: 
● 
Any confirmed pregnancy in the study will lead to permanent discontinuation of IP dosing 
of that participant. 
● 
ALT/AST increased may require interruption of study treatment (Appendix 2). 
● 
For participants requiring extracorporeal blood purification or other emergency 
interventions to reduce TG, the next dose should be delayed until the PI assesses that the 
condition has been clinically stable in consultation with the medical monitor. 
● 
For participants who have experienced acute pancreatitis, the next dose should be delayed 
until the PI assesses that the condition has been clinically stable in consultation with the 
medical monitor. The PI will assess the patient based on the local diagnostic and treatment 
criteria and develop the treatment scheme for episodes of acute pancreatitis; this may 

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include referral to the participant's attending physician or other specialists when necessary. 
For any participant experiencing acute pancreatitis, the participant may be unblinded and 
transitioned to the open-label treatment period of the study after assessment by the 
Investigator. This will be documented via the Interactive Web Response System (IWRS). 
o 
If the participant had been assigned to receive placebo, they will be re-assigned to 
receive open-label treatment with VSA001 if they are clinically stable based on the 
assessment of the Investigator in consultation with the Medical Monitor, and 
relevant procedures will start from Month 12 of the Schedule of Activities. 
o 
If the participant had been assigned to receive VSA001, they will restore open-label 
treatment with VSA001 if they are clinically stable based on the assessment of the 
Investigator in consultation with the Medical Monitor, and until at least 3 months 
have passed since the receiving the last dose of study drug, i.e., starting from Month 
12 of the Schedule of Activities. 
● 
HbA1c increased meeting the criteria for discontinuation of study treatment (Appendix 
5). 
5.5. 
Criteria for Study Termination 
The sponsor reserves the right to terminate the study at any time. The circumstances under 
which the study may be terminated include: 
● 
It is in the best interest of participants’ wellbeing to terminate the study. 
● 
Further conducting the clinical trial will no longer be for scientific purposes. 
Reasons will be provided in the event of this happening. The PI reserves the right to terminate 
the study for safety reasons at any time during collaboration with the sponsor. 
5.6. 
Discussion of Study Design (Including the Choice of Control Groups) 
The primary objective of this study is to evaluate the efficacy and safety of VSA001 in adults 
with FCS. 
For participants diagnosed with FCS based on the study inclusion criteria and confirmed to be 
receiving a stable diet and stable lipid-lowering and antidiabetic treatment regimens (if 
applicable, it is allowed to modify the antidiabetic treatment regimen during the study) (Section 
5.1.3), all remaining eligibility assessments will be completed within 8 weeks prior to 
randomization on Day 1. The Treatment Period will begin on Day 1 and last for 24 weeks. 
Dietary education will start at the beginning of the screening period and be repeated at intervals 
throughout the treatment period. This approach is expected to minimize the potential impact of 
dietary changes that may alter TG levels and/or confound the interpretation of study results. 
A placebo-controlled design is selected for the randomized period as it is impractical to remain 
blinded to the active control (no clinical standard of care has been available for the disease). 
The protocol requires that all participants in the active drug group and placebo group receiving 
lipid-lowering therapy should keep the treatment regimen stable during the study, despite that 

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other lipid-lowering therapies would have a limited effect on TG compared to the potent TG-
lowering effect of VSA001. For example, SHTG patients treated with ω-3 fatty acids had a 
placebo-adjusted TG reduction of only 33% (Bays 2011) and patients with mild TG increased 
treated with gemfibrozil had a TG reduction of 31% (Rubins 1999). Therefore, when VSA001 
is used in combination with a best lipid-lowering therapy, additional TG-lowering and lipid-
lowering effects are expected. In this Phase 3 study, concomitant use of best statins therapy, 
niacin, ω-3 fatty acids (prescription or non-prescription) or fibrates or other lipid management 
regimens is allowed as long as the participant has received a stable regimen for at least 4 weeks 
prior to screening laboratory assessments and agrees to continue receiving this baseline 
regimen during study treatment. At randomization, subjects will be stratified by TG level at 
screening (≥2,000 mg/dL vs. <2,000 mg/dL). 
An open-label design without a control group is chosen for the extension period to allow all 
participants to receive active treatment. The durations of treatment and assessments are 
intended to ensure adequate exposure to VSA001 to evaluate its efficacy and safety in long-
term use. 
5.7. 
Rationale for Dose and Schedule of Administration 
In the Phase 1 study evaluating ARO-APOC3 (VSA001) in healthy participants, serum APOC3 
and TG following 10, 25, or 50 mg dose continued to decrease until Week 16. Beyond Week 
16, these PD parameters gradually increased in some healthy participants, and increased 
compared to the lowest level after about Week 8 in the 50 mg cohort. A relatively marked dose 
effect was observed with the HDL-C level, which increased with dose, and HDL-C increased 
in a dose-dependent manner. While a limited number of participants were enrolled in the Phase 
1 study, available data from patients with HTG and chylomicronemia showed that treatment 
with ARO-APOC3 50 mg on Days 1 and 29 maintained reductions in APOC3 and TG 
following the second dose until Week 12. Additional analysis of Phase 1 study 
AROAPOC31001 suggested similar percent reductions from baseline in APOC3 and TG in 
participants with chylomicronemia without genetically documented FCS and participants with 
genetically documented FCS. 
Dose simulation of serum APOC3 and TG responses using a population PD model developed 
based on data collected in the Phase 1 study AROAPOC31001 suggested that 100 mg dosing 
may have provided only a small incremental improvement in reducing TG compared to the 50 
mg Q3M dosing regimen. Therefore, limiting the dose below 50 mg Q3M in this Phase 3 study 
is expected to be favorable for optimizing the benefit-risk ratio for participants with FCS. 
Direct clinical observations and modeling results also suggested that the duration of ARO-
APOC3’s effects may be short in participants with chylomicronemia, including FCS, and that 
patients with FCS may require a higher dose compared to the general population with SHTG. 
Therefore, a dose lower than 25 mg Q3M is not recommended for patients with FCS. 
Examination of the limited data from study AROAPOC31001 did not reveal any significant 

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difference in the safety profile between the 25 mg and 50 mg doses, suggesting that the benefit-
risk ratios for the two dose levels could be further studied in more FCS patients. Therefore, the 
recommended doses to be studied in the randomized double-blind period of this Phase 3 trial 
are 25 mg Q3M and 50 mg Q3M. 
Assuming a weight conversion and an average participant weight of 70 kg, the higher dose 50 
mg is about 1/420 of the NOAEL (300 mg/kg) in the 4-week/3-dose GLP toxicology studies in 
rats and monkeys. In chronic GLP toxicity studies, the NOAEL was 15 mg/kg in rats and 180 
mg/kg in monkeys. Assuming a participant weigh of 70 kg, in this study, the safety factor for 
the proposed 50 mg dose is about 20 when calculated based on the NOAEL for rat and 250 
when calculated based on the NOAEL for monkey. Additionally, it should be noted that the 
dose frequency in this study is Q3M, whereas the dose frequency in chronic toxicology studies 
(6-month rat and 9-month monkey) was every 4 weeks. Therefore, there was a wide margin of 
safety between clinical doses and animal toxicology study NOAELs. 
It was noted in interim analyses for overseas Phase 2 clinical studies of ARO-APOC3 
(AROAPOC3-2001 and AROAPOC3-2002) that among patients with SHTG and mixed 
dyslipidaemia, HbA1c was significantly increased in participants in the ARO-APOC3 
treatment group compared to participants in the placebo group, and these changes were mainly 
observed in participants who had diabetes at baseline and were observed to be the most 
significant in the subset of participants treated with the highest dose of ARO-APOC3 (50 mg); 
corresponding risk control measures have been developed for overseas clinical studies. This 
study is a Phase III clinical study to evaluate the efficacy and safety of VSA001 in FCS patients, 
which is consistent with the overseas Phase 3 clinical study in FCS patients (AROAPOC3-
3001 study). The data from the AROAPOC3-3001 randomized double-blind study are 
summarized as follows: VSA001 25 mg Q3M and 50 mg Q3M both resulted in great reductions 
in triglycerides, and approximately 80% of participants in both dose groups achieved 50% 
reduction in triglycerides. Compared to placebo, 25 mg and 50 mg doses of VSA001 provided 
similar efficacy results. The incidence of TEAEs was generally balanced between the VSA001 
groups and the placebo group. No death occurred during the study period; the incidences of 
SAEs and Grade ≥ 3 TEAEs were higher in the placebo group than in the VSA001 groups. The 
observed TEAEs generally showed no dose dependence. Based on the analysis results of the 
phase III global FCS study (AROAPOC3-3001) of this product, the proposed market dose is 
25 mg. (Appendix 5). All participants in the open-label period will receive VSA001 25 mg 
Q3M in the extension period (after approval of protocol V3.4). 
6. 
Selection and Withdrawal of Participants 
6.1. 
Participant Inclusion Criteria 
To be eligible for enrollment, participants must meet all the following inclusion criteria: 
1. 
Males or non-pregnant (who do not plan to become pregnant), non-lactating females ≥18 

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years of age. 
2. 
Able and willing to provide written informed consent prior to the performance of any 
study-specific procedures. 
3. 
Fasting TG ≥10 mmol/L (~880 mg/dL) at screening, that is refractory to standard lipid 
lowering therapy (sample drawn after at least the minimum time on stable lipid-lowering 
regimen described in the protocol). Three repeat tests are allowed to qualify. 
4. 
A diagnosis of FCS based on a documented history of fasting TG levels in excess of 1000 
mg/dL (for at least 1 prior occasion) in the absence of clear triggering factors (e.g., alcohol, 
binge eating, etc.), and at least one of the following: 
a. 
A supportive genetic test (from a source-verifiable medical record or based on 
screening genotype). Supportive genetic testing includes but is not limited to 
homozygous, compound heterozygous, or double heterozygote for loss-of-
function or otherwise inactivating mutations in genes affecting lipoprotein lipase 
activity including LPL, APOC2, APOA5, GPIHBP1, GPD1, or LMF1; or 
evidence of low LPL activity (<20% of normal) based on source-verifiable 
documentation; or 
b. 
Documented history of recurrent episodes of acute pancreatitis, not caused by 
alcohol or cholelithiasis; or 
c. 
Documented history of repeated hospitalization for severe abdominal pain with no 
other explainable causes; or 
d. 
Documented history of childhood or adolescent pancreatitis; or 
e. 
Family history of hypertriglyceridemia-induced pancreatitis. 
5. 
Willing to follow dietary counseling as per PI judgment based on local standard of care, 
consistent with the diet control regimen with an intake of ≤20 g of fat per day during the 
study. 
6. 
If type 2 diabetes management drugs or other medications specified in the Table 2 (see 
Section 7.2.3) are being used, the dosing regimen must remain stable until qualified lipid 
parameters are collected at screening. 
7. 
Participants with a medical history of clinical atherosclerotic cardiovascular disease 
(ASCVD) or those with elevated 10-year ASCVD risk (e.g., ≥7.5% per American Heart 
Association/American College of Cardiology risk calculator) must be on appropriate 
lipid-lowering therapy as per local standard of care (i.e., including moderate to high 
intensity statin, as indicated) prior to collection of qualifying TG levels. 
8. 
Participants of childbearing potential must agree to use a highly effective form of 
contraception (Appendix 1)during the study and for at least 24 weeks after the last dose 
of investigational product. Women of childbearing potential on a hormonal contraceptive 
must be stable on the medication for ≥ 1 menstrual cycle prior to Day 1 of the study. Males 
must have agreed to not donate sperms during the study and for at least 24 weeks 
following the last dose of IP. Note: All laboratory tests (except for coagulation) used as 
inclusion criteria will be assessed by a central laboratory and may be repeated once 

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(except for TG), 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. 
6.2. 
Participant Exclusion Criteria 
A participant will be excluded from the study if any of the following criteria apply: 
1. 
Current use or use within the last 1 year (before screening) of any hepatocyte-targeted 
siRNA or antisense oligonucleotide molecule. 
2. 
Diabetes mellitus with any of the following: 
a. 
Newly diagnosed within 12 weeks of screening; 
b. 
HbA1c ≥ 9.0% at screening. 
3. 
Active pancreatitis within 12 weeks prior to Day 1. 
4. 
History of acute coronary syndrome events within 24 weeks of Day 1. 
5. 
History of major surgeries within 12 weeks of Day 1. 
6. 
Any of the following abnormal laboratory values at screening: 
a. 
ALT or AST ≥ 3 × ULN at screening; 
b. 
Total bilirubin ≥1.5×ULN (if the participant has a prior diagnosis and 
documentation of Gilbert’s syndrome, then total bilirubin must be ≤3 mg/dL at 
screening); 
c. 
Estimated glomerular filtration rate <30 mL/min/1.73 m2 at screening, using the 
Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation; 
d. 
Spot urine protein/spot urine creatinine ratio greater than 3 g/day; 
e. 
Clinically significant abnormality in prothrombin time, partial thromboplastin 
time, or INR. 
7. 
Uncontrolled hypertension (blood pressure >160/100 mmHg at screening); if untreated, 
participant may be rescreened once hypertension is treated and controlled. 
8. 
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; 
b. 
Current use of glucagon-like peptide-1 (GLP-1) receptor agonists or planned use 
during the study; 
c. 
Plasma apheresis within 4 weeks prior to Day 1 or planned during the study; 
d. 
Blood donation of 50 to 499 mL within 4 weeks of collection of qualifying lipid 
parameter collection or of >499 mL within 8 weeks of qualifying lipid parameter 
collection. 
9. 
On treatment with human immunodeficiency virus (HIV) antiretroviral therapy (Note: 
determination of HIV status is not a required study procedure). 
10. Seropositive for hepatitis B virus (HBV) or hepatitis C virus (HCV) (hepatitis B surface 
antigen [HBsAg] and HBV DNA positive, or HCV RNA positive). 
11. New York Heart Association (NYHA) Class III or IV heart failure or last known ejection 
fraction of <30%. 

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12. Clinical evidence of primary hypothyroidism (screening TSH > ULN and free T4< LLN), 
primary subclinical hypothyroidism (screening TSH > ULN and free T4 WNL), or 
secondary hypothyroidism (screening TSH < LLN and free T4 < LLN). 
13. History of hemorrhagic stroke within 24 weeks of first dose. 
14. History of bleeding diathesis or coagulopathy. 
15. Current diagnosis of nephrotic syndrome. 
16. 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 approximately corresponds to 
80 mL of wine, 200 mL of beer, or 25 mL of 40% alcohol) for both females and males. 
17. 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 
cancer, superficial bladder tumors, or in situ cervical cancer. Currently receiving systemic 
cancer treatment(s) or, in the PI’s opinion, at risk of relapse for recent cancer. 
18. 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. 
19. Any concomitant medical or psychiatric condition or cognitive disorder caused by serious 
social situation or any other situation that, in the PI’s judgment, would make it difficult to 
comply with protocol requirements or put the participant at additional safety risk. 
Note: All laboratory tests used as exclusion criteria can be repeated once, and the re-test value can be used 
for exclusion. 
6.3. 
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 PI, medically qualified designee, or sponsor will withdraw a 
participant from the study, per the following criteria, to protect the participant’s health: 
● 
The need to take medication which could interfere with study measurements 
● 
Intolerable/Unacceptable adverse events 
● 
Major violation of or deviation from study protocol procedures 
● 
Noncompliance of participant with the protocol 
● 
Participant is unwilling to proceed or consent is withdrawn 
● 
If in the investigator’s judgment withdrawal from study would be in the participant’s best 
interest 
Reasons for withdrawal will be documented in the eCRF along with all AEs and necessary 
treatments and be included in the final Clinical Study Report (CSR). 
If a participant has withdrawn from study due to an AE/SAE, the PI or a medically qualified 
designee will evaluate the emergency nature of the event. If needed for the situation, the PI or 
medically qualified designee will take appropriate diagnostic and therapeutic measures. If the 
situation is not an immediate emergency, the PI, or medically qualified designee, at the clinical 

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study facility will attempt to contact the Medical Monitor or medically qualified designee for 
consultation. Provision of medical assistance, diagnosis, or advice to participants will not be 
stopped due to failure 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. 
7. 
Treatment of Participants 
7.1. 
Description of study drug 
There will be 2 study treatments, i.e., 1 active drug and 1 placebo (control), both to be 
administered by SC injection. 
Investigational product: VSA001 Injection, to be administered SC. The active pharmaceutical 
ingredient contained in VSA001 is a synthetic, double-stranded siRNA duplex conjugated to a 
NAG-targeting ligand to facilitate hepatocyte delivery. 
Control drug: The control drug is placebo: normal saline (0.9%) administered SC, volume-
matched to the corresponding VSA001 dose volume. 
See Section 8 for more information on study drug materials and management. 
7.2. 
Restrictions and Concomitant Medications 
7.2.1. 
Fasting 
Participants will fast for at least 10 hours prior to blood draw on the day of dosing or any other 
date on which blood is drawn for measurement of lipid parameters, unless otherwise specified. 
7.2.2. 
Drug Abuse or 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 avoid frequent alcohol intake during the study (not more than 14 units per week 
[1 unit approximately corresponds to 80 mL of wine, 200 mL of beer, or 25 mL of 40% 
alcohol]). 
Participants 
must 
avoid 
drug 
abuse 
(e.g. 
MDMA 
[methylenedioxymethamphetamine], cocaine, cannabis, ketamine) throughout the study. 
7.2.3. 
Concomitant medications 
Use of best statins therapy, niacin, ω-3 fatty acids (prescription or non-prescription) or fibrates 
or other lipid management regimens is allowed if the participant has received treatment with a 
stable regimen for a duration specified in Table 2 prior to eligibility screening laboratory 
assessments and agrees to maintain the stable regimen during study treatment. Adjustments to 
medication regimens during the study, including lipid-lowering and diabetes mellitus therapies, 
are only allowed if, at the discretion of the PI, they are needed to provide adequate supportive 
care. These changes must be recorded in the eCRF no later than the next study visit. Participants 

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will be instructed to provide the PI with the specific information (indication, dose and date of 
administration) if they have used any medications, and this information will be recorded in the 
eCRF. The medical monitor or designee should be notified before any change is made to a 
participant's prescribed lipid-lowering therapy. Information of any extracorporeal blood 
purification during the study will be recorded in the eCRF. 
Table 2: Restricted Concomitant Medications 
Restricted background medications 
Duration of receiving a stable regimen prior to 
eligibility screening laboratory assessments 
Lipid-lowering therapies (including statins) 
>4 weeks 
• 
Fibrates 
>6 weeks 
• 
PCSK9 Inhibitors 
>8 weeks 
Beta-blockers, thiazide diuretics 
>4 weeks 
Tretinoin 
>8 weeks 
Atypical antipsychotics 
>12 weeks 
Diabetes mellitus medications 
>12 weeks 
Oral estrogens, tamoxifen, raloxifene 
>16 weeks 
Immunosuppressants 
>24 weeks 
7.2.4. 
Central laboratory lipid examinations 
Central lab results may unblind the treatment assignment for VSA001. Central lab results for 
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 PI, and will remain blinded from Day 1. After Day 1, PI 
should not have local non-protocol tests of these lipid parameters performed for the participant 
from the first dose of IP to the Month 13 visit for the participant. 
Between the Month 10 and Month 13 visits, if a baseline LDL-C ≥130 mg/dL (≥3.37 mmol/L) 
in a participant has increased by ≥25% from baseline at 2 consecutive visits, the participant's 
LDL-C values will be unblinded for the remainder of the study, and the central lab will notify 
the PI to perform medical follow-up. Between the Month 10 and Month 13 visits, if a baseline 
LDL-C <130 mg/dL (<3.37 mmol/L) in a participant has increased later to ≥130 mg/dL (≥3.37 
mmol/L) at 2 consecutive visits, the central lab will notify the PI to perform medical follow-
up. For all such cases, the PI will contact the participant to provide appropriate medical follow-
up, which includes dietary and medication compliance counseling, and may also include 
adjusting the participant's lipid-lowering regimen based on the country-specific guidelines (e.g., 
starting statins therapy or increasing the dose of statins therapy for a previously treated 
participant). 
If any participant has been noted with TG increased by >40% from baseline or absolute 
TG >4,000 mg/L (45 mmol/L) during treatment, the central lab will immediately notify the PI, 
who will determine appropriate monitoring and follow-up. 

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After completing the Month 13 visit until the Month 24/EOS visit, the central lab will provide 
the PI with available results of the lipid parameters for each participant. 
7.2.5. 
Notifying attending physician 
The PI or designee is responsible for notifying the participant's local attending physician, with 
the participant’s consent, that the participant has been participated in the trial, sending 
correspondence describing the trial nature, treatments, expected benefits or AEs, as well as the 
concomitant medications that should not be used. 
7.3. 
Treatment compliance 
All study treatments will be administered at the study site. The (IP will be dispensed by clinical 
study site staff members on the day of dosing and recorded in the drug accountability records. 
The date and time of study treatment administration will be recorded on the eCRF on dosing 
days. 
7.4. 
Principle of treatment discontinuation 
Any confirmed pregnancy in the study will lead to permanent discontinuation of IP dosing of 
that participant. 
A decision to suspend dosing in an individual participant may be indicated based on any of the 
following: 
● 
A need for apheresis or other emergent interventions indicated to lower TG 
● 
In participants with normal AST and ALT on Day 1, treatment emergent elevations ≥3× 
ULN at least possibly related to IP per Investigator must be confirmed by repeat blood 
draw within 72 hours of initial results. For participants with any of the following results, 
refer to Appendix 2 for the specific instructions on treatment discontinuation or 
interruption: 
– 
ALT or AST ≥5×ULN (according to Appendix 2: permanently discontinue IP dosing 
for the participant; according to the SOA: allow the participant to continue attending 
study follow-up visits until EOS visit) 
– 
ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN 
– 
ALT or AST ≥3 × ULN with new-onset fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
– 
ALT or AST ≥3×ULN with INR >1.5 emerging during treatment (must be confirmed 
repeatedly) that cannot be explained by any other reasonable reasons* 
* For example, presence of Gilbert's syndrome or hemolytic disease: re-test in case of 
baseline direct bilirubin >0.5 mg/dL. 
● 
Some participants enrolled in this study may have transaminases increased at baseline. In 
participants with elevated AST or ALT on Day 1, treatment emergent elevations >2× 
baseline at least possibly related to IP per Investigator must be confirmed by repeat blood 
draw within 72 hours of initial results, as follows. For participants with any of the 

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following results, refer to Appendix 2 for the specific instructions on treatment 
discontinuation or interruption: 
– 
ALT or AST ≥300 U/L (according to Appendix 2: permanently discontinue IP 
dosing for the participant; according to the SOA: allow the participant to continue 
attending study follow-up visits until EOS visit) 
– 
ALT or AST ≥2 × ULN with new-onset fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, or eosinophilia (>5%) 
– 
ALT or AST ≥ 2 × ULN and total bilirubin ≥ 2 × ULN 
– 
ALT or AST ≥2×baseline value with INR >1.5 emerging during treatment (must be 
confirmed repeatedly) that cannot be explained by any other reasonable reasons* 
* For example, presence of Gilbert's syndrome or hemolytic disease: re-test in case of 
baseline direct bilirubin >0.5 mg/dL. 
Instructions for adjusting the treatment for participants with ALT/AST increased are provided 
in Appendix 2. 
● 
At the investigator’s discretion, any participant with poorly controlled diabetes may return 
to the study site or go to a medical institution recognized by the sponsor and investigators 
before the next scheduled dose for an unscheduled visit to evaluate the changes in HbA1c, 
so as to determine whether treatment can be continued. IP treatment should be 
discontinued if the participant meets the following criteria: 
– 
HbA1c measurement >10% at the last visit before the next dose, or 
– 
HbA1c increased by >2% from baseline at the last visit before the next dose, or 
– 
Baseline HbA1c >7.5% and increased by >1% from baseline at both two study visits 
(the last visit being the one before the next dose) 
Instructions for adjusting the treatment for participants with HbA1c increased are provided in 
Appendix 5. 
7.5. 
Randomization and Blinding 
7.5.1. 
Randomization 
All potential participants who sign an informed consent at screening will receive a number (i.e., 
a screening number). For participants who are deemed eligible, this 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. Participants will be randomized in a 2:1:2:1 ratio into each dose cohort 
(VSA001 25 mg dose group, volume-matched placebo group, VSA001 50 mg dose group and 
volume-matched placebo group) Treatments will be administered per the randomized sequence 
generated by an Interactive Web Response System (IWRS). Active drug treatment or placebo 
will be assigned using a block randomization method. At randomization, subjects will be 
stratified by TG level at screening (≥2,000 mg/dL vs. <2,000 mg/dL). 

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7.5.2. 
Blinding 
The treatment assignment (active drug vs. placebo) will be blinded for this clinical study. 
Assignment of dose groups will not be blinded as different required injection volumes are 
prescribed for different dose groups. Thus, participants will receive treatment with the active 
drug or placebo injection matching the dose group they are assigned to (Section 8.5). To mask 
the slight color difference between the active drug and placebo, the syringes will be blinded at 
the pharmacy as described in the Investigational Product Management Manual, so that the 
blinded staff and participants will remain blinded to the treatment assignment. During the 
extension period, participants will receive open-label treatment, yet will at the early stage 
remain blinded to the treatment they were initially assigned to in the randomized period. 
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 requiring unblinding. However, in 
the event of any medical emergency, if knowledge of the treatment assignment for an individual 
participant is deemed critical to the wellbeing and management of the participant, the PI or 
documented designated treating physician may unblind the treatment assignment. For non-
emergencies, the investigator should contact the responsible medical monitor to discuss the 
participant’s situation and the requirement for unblinding. Unblinding will be performed only 
for the specific participant being discussed on. Information of unblinding will be recorded in 
the electronic data capture system. The medical monitor should be notified immediately. 
The randomization scheme will exercise strict access permission. Staff involved in IP 
dispensing will be responsible for ensuring compliance with the randomization scheme. Non-
blinded clinical study monitors (CRAs) will verify whether the randomization was correct. 
If the PI considers, based on the severity of an AE, it necessary to immediately know the 
identify and dose of the product concerned, unblinding will be completed in the IWRS system. 
Only designated non-blinded pharmacists, PI, and co-investigators may have access to 
unblinding for medical emergencies in the IWRS. The medical monitor should be notified in a 
timely manner. 
Where a participant requires emergency unblinding (the PI and medical monitor have/have not 
had discussion before unblinding), the PI may also need to complete the Study Site Unblinding 
Report Form to document the medical rationale for the need for unblinding and then forward 
the form to the medical monitor. 
A discussion on blinding the central lab test results of TG and blood lipid parameters is 
provided in Section 10.1. 
7.6. 
Drug Therapy after the End of Study 
This clinical study ends when the participants have completed the End of Study visit (EOS) at 
Months 24. Participants in the open-label treatment period can discuss with the investigator to 
choose to continue treatment with the study drugs VSA001 or other treatments. If the 

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participant chooses to continue the study drug, after assessment by the sponsor, he/she may 
continue to receive the study drug until the study drug is available or another treatment is 
recommended by the clinician. This period is drug therapy after the end of study, and diagnosis 
and treatment will be performed according to clinical routines, and the sponsor will not collect 
relevant data. If the participant experiences an AE in the period of continuing administration, 
he/she should actively report it to the investigator. The study team will document and process 
all unsolicited AEs to ensure participant safety is properly managed. 
8. 
Study Drug Materials and Management 
8.1. 
Study Drugs 
The sponsor is responsible for supplying VSA001 and a detailed instruction on the preparation 
of VSA001 before injection, as specified in the Investigational Product Management Manual. 
Therefore, VSA001 will be supplied in a single sterile 2 mL vial or prefilled syringe containing 
VSA001. The correct dose of VSA001 will be prepared by the pharmacy before dosing for a 
participant. The placebo (0.9% normal saline) will be provided by the sponsor. 
8.2. 
Study Drug Packaging and Labeling 
8.2.1. 
Vial 
VSA001 will be supplied in Type 1 2.0 mL sterile glass vials (0.7 mL nominal volume, 0.5 mL 
extractable volume). 
Strength 
200 mg/mL 
Appearance 
Clear, colorless to yellow solution 
Inactive ingredients 
0.5 mM sodium dihydrogen phosphate, 0.5 mM 
disodium hydrogen phosphate, and water for injection 
Transportation and storage Cold storage (2-8 ℃) 
8.2.2. 
Prefilled Syringe 
The 50 mg dose will be provided in a single-dose PFS. Each PFS contains 50 mg of ADS-
005/1 mM aqueous phosphate buffer. The packaging system for VSA001 Injection PFS is a 1 
mL long Type I clear glass syringe with a 29 Gauge staked needle and rigid needle shield and 
a bromobutyl FluoroTec coated plunger. The final assembly of the syringe includes a standard 
plunger rod and finger flange. Each PFS will be individually packaged in a carton. 
Strength 
200 mg/mL 
Syringe volume 
0.25 mL 
Appearance 
Clear, colorless to yellow solution 
Inactive ingredients 
0.5 mM sodium dihydrogen phosphate, 0.5 mM 
disodium hydrogen phosphate, and water for injection 
Transportation and storage Cold storage (2-8 ℃) 
The 25 mg dose will be provided in a single-dose PFS. Each PFS contains isotonic saline for 
25 mg of ADS-005. The packaging system for VSA001 Injection PFS is a 1 mL long Type I 

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clear glass syringe with a 29 Gauge staked needle and rigid needle shield and a bromobutyl 
FluoroTec coated plunger. The final assembly of the syringe includes a standard plunger rod 
and finger flange. Each PFS will be individually packaged in a carton. 
Strength 
50 mg/mL 
Syringe volume 
0.50 mL 
Appearance 
Clear, colorless to yellow solution 
Inactive ingredients 
0.9% sodium chloride and water for injection 
Transportation and storage Cold storage (2-8 ℃) 
8.3. 
Storage of Study Drug 
VSA001 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 labeled in accordance 
with the current Good Manufacturing Practice (cGMP)/GCP. 
IP supplies will be securely stored at the clinical study site under appropriate conditions. The 
IP must be stored under physical conditions meeting the IP-specific requirements in a secure 
area accessible only by PI-authorized personnel. 
8.4. 
Study Drug Preparation 
VSA001 will be prepared by the pharmacist or qualified staff at the clinical study site according 
to the Investigational Product Management Manual. Sterile techniques will be used to ensure 
sterility of the solution to be injected. The preparation time of the active drug must be recorded 
and tracked to demonstrate stability of the drug prepared. See the Investigational Product 
Management Manual for more specific information. 
The sponsor will provide the PI with an adequate quantity of clinical drugs. The PI must ensure 
that the IP provided by the sponsor is correctly received by the non-blinded responsible person, 
recording all the drug shipping receipts in an appropriate drug accountability form prepared by 
the clinical study site pharmacy, and that the drugs are stored under the recommended storage 
conditions in a secure area. The PI is also responsible for ensuring that the non-blinded 
responsible person would not compromise the integrity of the packaged study drugs prior to 
dispensing. 
Only participants enrolled in the study may receive IP, in accordance with all applicable 
regulatory requirements. An authorized and trained staff member at each clinical study site will 
dispense the IP per predefined drug dispensing requirements. Drug dispensing will be 
rechecked by a second site staff. 
8.5. 
Administration 
IP will be administered by appropriately trained clinical study site staff. 
Vials will be administered as single SC doses (Table 3). The injection site will be marked and 
photographed for subsequent observation. The abdomen is the preferred place for the injection. 

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Optional additional sites are the upper arms and thighs (inner). 
Table 3: Injection Number and Volume Per Dose Cohort 
VSA001 dose a 
Concentrat
ion 
Total injection 
volume 
Injection number 
per dose 
Total number of 
study injections 
25 mg 
200 mg/mL 
0.13 mL 
Single 
8 
50 mg 
200 mg/mL 
0.25 mL 
Single 
8 
a The injection volume of the placebo (normal saline) is matched to VSA001 for the first 4 study injections. 
Each dose of active drug (VSA001) or placebo (0.9% normal saline) will be administered SC 
by appropriately trained and qualified clinical staff designated by the PI. Injections will be 
made into the SC tissue at an appropriate site (e.g., abdomen, thigh, upper arm). The abdomen 
is the preferred place for the injection. There should be different injection sites (multiple 
injections at the same accurate site are not allowed, yet alternative injections at different sites 
in the abdomen are allowed). The injection site location is to be recorded in the eCRF. Before 
dosing, the IP vial must be allowed sufficient time to recover to room temperature. Do not 
inject into areas of active skin diseases or lesions such as sunburn, rash, inflammation, or skin 
infection. The injection volume for each site should not exceed about 0.25 mL. 
PFS is a ready-to-use injection that will be injected SC by an investigator or appropriately 
trained and qualified clinical staff designated by the investigator. Injections will be made into 
the SC tissue at an appropriate site (e.g., abdomen, thigh, upper arm). The abdomen is the 
preferred place for the injection. There should be different injection sites (multiple injections 
at the same accurate site are not allowed, yet alternative injections at different sites in the 
abdomen are allowed). The injection site location is to be recorded in the eCRF. Before dosing, 
the PFS must be allowed sufficient time to recover to room temperature. Do not inject into 
areas of active skin diseases or lesions such as sunburn, rash, inflammation, or skin infection. 
See the Investigational Product Management Manual for more information. In the open-label 
period, the sponsor will provide PFSs to the patients after obtaining the relevant approval and 
completing the import. 
8.6. 
Study Drug Accountability 
All material supplied is for use only in this clinical study and should not be used for any other 
purpose. In accordance with all applicable regulatory requirements, designated site staff will 
be responsible for IP accountability and reconciliation and maintenance of related 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. Non-blinded CRAs will perform 
initial and ongoing IP container and placebo accountability. Non-blinded CRAs will protect 
the integrity of blinded assignment and not participate in data review for study participants. 
Used VSA001/placebo containers will be stored isolated by participant and be provided to non-
blinded CRAs during IP and placebo reconciliation. 
The Drug Dispensing Record must be kept up to date and will contain the following 

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information: 
● 
Participant identification information of dispensed drug 
● 
The date(s), quantity, batch number(s) and expiration dates of the IP dispensed to the 
participant. 
The date and time of dispensing and preparation will be retained to support IP dosing. 
Authorized pharmacists or qualified staff, who are non-blinded personnel, will be informed of 
participants’ treatment assignment (i.e., active drug or placebo). The pharmacy will dispense 
the IP, and the study site will provide the study drug only to participants enrolled in this study 
in accordance with the study protocol and procedures specified in the Investigational Product 
Management Manual. Each participant will be given only the IP as assigned by the IWRS. 
Study drug dosing will be recorded in the eCRF. During the study, the inventory must be 
available for inspection by the CRA. At the end of the study, the medications supplied will be 
collected by the study monitor or be returned to the sponsor or the sponsor-designated 
warehouse by the PI or designee. 
8.7. 
Study Drug Handling and Disposal 
For this study, used and partially used drug containers will be retained for a period sufficient 
for accountability, and will be retained, collected or destroyed by the sponsor as per the relevant 
regulations. 
9. 
PK Assessments 
9.1. 
PK Assessments 
9.1.1. 
Sample Collection 
Plasma PK samples for VSA001 analysis will be collected by venipuncture before IP dosing 
and 4 hours after IP dosing at Day 1 and Month 3 for all participants (20 in the active drug 
group and 10 in the placebo group). 
9.1.2. 
Sample Analysis 
Whole blood will be collected and handled in accordance with the Central Lab Manual. Plasma 
samples will be analyzed using cross-validated methods. The criteria for repeated analysis 
defined in the corresponding internal procedures will be followed. Validation studies (designed 
to determine the validity, including the accuracy, precision, reproducibility, specificity, 
recovery, and freezing stability of the analytical method) conducted by the designated 
bioanalysis laboratory will be provided in the final report as an appendix. 
10. Assessment of Efficacy 
Efficacy assessments will be performed at post-IP dosing time points outlined in the SOA 
(Schedule of Activities: Randomized Period and Schedule of Activities: Extension Period). 

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Efficacy assessments are required to be performed at the study site at the treatment visits, 
Month 10 visit, and Month 24/EOS visit. 
10.1. Serum Triglycerides and Other Lipid Parameters 
Blood samples for lipid parameters will be collected from participants by venipuncture. The 
actual blood collection time will be recorded in the source documents. All deviations outside 
the range allowed above will be documented as protocol deviations. In all such cases, 
appropriate time corrections for the actual time of sample collection will be incorporated at the 
time of data analysis. Blood samples will be collected at time points outlined in the SOA. The 
actual sample times (time samples are 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 samples taken outside of the set sampling 
times. 
Fasting serum TG and other lipid parameters will be collected at the screening visit and on Day 
1 prior to dosing after at least a 10-hour fast (only 7 items will be detected during the screening 
period: TG, LDL-C, total cholesterol, non-HDL-C, HDL-C, VLDL-C, and LP[a]; on Day 1 
and at subsequent visits, 14 items will be detected: TG, LDL-C, total cholesterol, non-HDL-C, 
HDL-C, VLDL-C, APOB-48, LP[a], APOB-100, total APOB, APOC3, APOC2, APOA1 and 
APOA5). The Day 1 values will be used as each participant’s baseline value for data analysis 
purposes (except fasting serum TG). 
After completion of the Month 13 visit, the central laboratory will provide available lipid 
parameter results to the PI through the Month 24/EOS Visit. 
10.2. Glucose Metabolism 
Serum samples will be collected at screening and 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. After Day 1, fasting serum blood glucose, HbA1c, insulin and C-peptide 
will be measured as per the SOA and assessed by a local laboratory. 
10.3. Acute Pancreatitis Events 
All treatment-emergent AEs and SAEs reported by the Investigator through Month 24/EOS 
that are consistent or possibly represent an event of acute pancreatitis will be adjudicated 
according to the 2013 Revision of the Atlanta Classification Criteria for Acute Pancreatitis, and 
should meet 2 of the following 3 criteria: 
1. 
Abdominal pain consistent with symptoms of acute pancreatitis (acute episodes of 
persistent, severe, upper abdominal pain often radiating to the back); 
2. 
Serum lipase activity (or amylase activity) ≥3 × ULN; 
3. 
Characteristic findings of acute pancreatitis on upper abdominal computed tomography 
(CT), magnetic resonance imaging (MRI), or transabdominal ultrasonography. Note: 

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Consult a specialist if necessary. 
10.3.1. Detecting and Reporting Pancreatic Events 
During each study visit, the PI 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 PI or medically qualified designee will also be responsible for detecting, recording, 
and reporting pancreatic events that meet the criteria and definition of acute pancreatitis 
(according to the 2013 Revision of the Atlanta Classification Criteria for Acute Pancreatitis) 
and events that possibly represent pancreatitis. 
Adverse event 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 include 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 PI will follow each 
participant and provide further information on the participant’s condition as deemed 
appropriate. 
The PI will follow all pancreatic or possible pancreatic AEs until resolution, until the condition 
stabilizes, or until the event is otherwise explained. Once resolved, the PI or medically qualified 
designee will update the appropriate AE page and SAE report form of the eCRF (if the event 
is serious). The PI, or medically qualified designee, will ensure that follow-up includes any 
supplemental investigations that 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 PI. 
10.4. Diet 
Participant diet will be recorded as per the SOA. At these study visits, the participant will be 

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asked to report their dietary management of FCS for at least 3 of the past 5 days. 
10.5. Patient-Reported Outcomes 
Participants will complete the EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-PAN26 
questionnaires as per the SOA. 
10.5.1. EuroQoL 5-Dimension Questionnaire 
The EQ-5D-5L comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression (Herdman 2011). Each dimension has 5 levels: no problems, slight 
problems, moderate problems, sever problems, and extreme problems. The EQ-5D-5L also 
includes a visual analog scale (VAS) to record the participant’s self-rated health, where the 
endpoints are labeled “The best health you can imagine” and “The worst health you can 
imagine”. The VAS can be used as a quantitative measure of health outcome that reflects the 
participant’s own judgment. 
10.5.2. EORTC QLQ-C30 Questionnaire 
The EORTC QLQ-C30 instrument consists of 30 questions: 28 questions about specific aspects 
of quality of life, and 2 questions about overall health and overall quality of life. It has been 
translated into 100 languages and validated. The EORTC QLQ-C30 was initially developed 
and validated in patients with lung cancer (Aaronson 1993), and subsequently shown to be 
useful for the assessment of quality of life in patients with chronic pancreatitis (Fitzsimmons 
2005) and in patients with LPL deficiency (Johnson 2015). 
10.5.3. EORTC QLQ-PAN26 Questionnaire 
The EORTC QLQ-PAN26 instrument consists of 26 items related to disease symptoms, 
treatment side effects, and specific emotional issues such as abdominal pain, gastrointestinal 
symptoms, or anxiety. It focuses on patient-reported outcomes among patients with pancreatic 
cancer (Fitzsimmons 1999) and was subsequently shown to be useful for the assessment of 
quality of life in patients with chronic pancreatitis (Fitzsimmons 2005) and in patients with 
LPL deficiency (Johnson 2015). 
11. Assessment of Safety 
11.1. Safety Parameters 
Safety assessments will be performed at the time points outlined in the SOA (Schedule of 
Activities: Randomized Period and Schedule of Activities: Extension Period). 
A comprehensive safety assessment, including blood and urine tests, is required at the study 
site at dosing visits, the Month 10 visit, and the Month 24/EOS visit. 
11.1.1. Demographics/Medical History 
Participant demographics (e.g., date of birth, race and ethnicity, sex) and medical history will 

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be collected during the screening period. Medical history will include medication use over the 
previous 30 days, including vitamins, OTC medications, prescription drugs, drug abuse or 
supplements, and alcohol and tobacco use. 
11.1.2. Vital Signs 
Systolic/diastolic blood pressure (mmHg), body temperature (degrees Celsius [℃]), heart rate 
(beats/minute), and respiratory rate (breaths/minute) will be obtained after the participant is 
semi-supine or sitting for at least 3 minutes. Vital signs will be obtained prior to venipuncture 
and other invasive procedures. 
11.1.3. Physical Examination 
A complete physical examination will be performed at screening, including 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 as indicated. 
11.1.4. Electrocardiogram 
Standard single 12-lead ECG, which will be recorded at Screening and the time points outlined 
in the SOA, can be performed on local ECG equipment. 
Triplicate 12-lead ECG measurements approximately time-matched to PK blood collections 
will be obtained using validated ECG services equipment from a study site at Day 1 and Month 
3 (before dosing, 2 hours after dosing, and 4 hours after dosing). Any abnormal and clinically 
significant ECGs, as per the PI’s medical judgment, will be repeated in triplicate, with each 
measurement approximately 1 minute apart. For all triplicate ECGs, the ECGs must be acquired 
using the same ECG services equipment and results should be interpreted at a central laboratory. 
The participant should be supine or semi-supine for at least 5 minutes before each ECG is 
obtained. ECGs will be performed prior to venipuncture and any other invasive procedures. 
More details of ECG collections are available in SOA. 
The electrophysiological parameters assessed will be heart rate (HR), PR interval, QRS 
duration, QT interval, and Fridericia-corrected QT interval (QTcF) among other ECG 
parameters. 
11.1.5. Laboratory Assessments 
Blood and urine samples will be collected at the study site and shipped to the central laboratory 
for laboratory tests, PK, PD (APOC3), ADA and lipid parameter analysis during the screening 
period and on Day 1. 
Blood and urine samples will be collected for the laboratory tests detailed below, to establish 
baseline data and eligibility for enrollment, and subsequent safety laboratory assessments will 
be conducted in the laboratory of each study site. Each participant is allowed to undergo a 
second blood draw for laboratory tests during the screening period to establish eligibility. The 

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results will be assessed by the PI or medically qualified designee before study enrollment. Any 
abnormality in laboratory values deemed clinically significant by the PI or a medically 
qualified designee (i.e., those that would jeopardize the safety of the participant or impact on 
the validity of the study results), will result in exclusion of that participant. 
At all non-dosing post-Day 1 visits, in the event of logistical disruptions (e.g., COVID-related 
reasons) where a participant does not have direct access to the site, follow-up tests for relevant 
safety measures may be performed at an alternative location accepted by the sponsor, 
investigator/study site (e.g., local medical institution, or local laboratory). Samples will be 
collected with the central laboratory’s collection kit through home healthcare service and 
shipped to the central laboratory for testing of APOC3, blood lipids, and anti-drug antibody. 
Any abnormal and clinically significant laboratory result, as per the PI’s medical judgment, 
should be documented as an AE or SAE, if applicable. 
Refer to the Laboratory Manual for additional details on clinical laboratory tests. 
11.1.5.1. Hematology 
The following parameters will be assessed: hemoglobin, red blood cell count, hematocrit, mean 
cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, platelets, white cell 
count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. 
11.1.5.2. Blood Chemistry 
The following parameters will be assessed: sodium, potassium, chloride, bicarbonate (or 
carbon dioxide), glucose, urea/urea nitrogen, creatinine, creatine kinase, uric acid, phosphate, 
total calcium, albumin, globulins, total protein, total bilirubin, amylase, lipase, HbA1c, serum 
insulin, C-peptide, conjugated bilirubin, gamma-glutamyltransferase, alkaline phosphatase 
(ALP), ALT, AST, lactate dehydrogenase, and C-reactive protein. 
11.1.5.3. Coagulation 
The following parameters will be assessed: partial thromboplastin time, prothrombin time with 
INR, and fibrinogen. 
11.1.5.4. Urine Testing 
The following parameters will be assessed: leukocytes, nitrites, urobilinogen, protein, pH, 
blood, specific gravity, ketones, bilirubin, and glucose. Urine sediment microscopy will be 
performed if indicated, including white blood cells, red blood cells, epithelial cells, and bacteria. 
Random urine creatinine and random urine protein tests will also be performed. 
11.1.5.5. Virus Serology 
The following parameters will be assessed: HBsAg, HBV DNA and HCV antibody, and HCV 
RNA screening. If necessary, counseling services concerning HBsAg, hepatitis C and their 
subsequent results will be provided to participants by the PI or medically trained designee. 

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11.1.5.6. Pregnancy Screen 
Postmenopausal status will be confirmed by follicle-stimulating hormone (FSH) level 
consistent with postmenopausal state. Blood (screening period) and subsequent urine 
qualitative pregnancy tests will be conducted for women of childbearing potential (for those 
with negative blood pregnancy tests). 
11.1.6. Anti-Drug Antibodies 
Serum samples will be used to assess anti-drug antibody, blood samples will be collected at the 
study site and shipped to the central laboratory for testing. 
11.1.7. 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 the 
participant’s study participation. The reason for early termination from the study will be 
documented in source documents and eCRF(s). Procedures as outlined for Month 24/EOS in 
the SOA (Schedule of Activities: Extension Period) will be completed. Participants who 
discontinue the study due to SAE will be encouraged to continue to remain available for 
follow‑up for medical monitoring until resolution. 
11.2. Adverse Events 
The PI and clinical facility staff are responsible for detection, recording, and reporting of events 
that meet the criteria and definition of various AEs as listed below. Adverse events will be 
recorded from time of signed consent through to the EOS visit; only AEs that occur post-dose 
will be considered treatment-emergent. The PI and clinical facility staff are responsible for 
detection, recording, and reporting of pregnancy and appropriate follow-up. Any known 
pregnancy that occurs within 24 weeks after the last dose of IP should be reported by the 
participant to the PI. Information regarding any reported pregnancy should be collected up to 
1 year after birth or until the end of the pregnancy. 
11.2.1. Definition of Adverse Events 
11.2.1.1. Adverse Events 
An 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 ICH E2a: Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, 27 October 1994). 
Treatment-emergent AEs will be defined as AEs with onset after administration of the study 

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drug, or when a preexisting medical condition increases in severity or frequency after study 
drug administration. 
Adverse events will not include: 
● 
A medical 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 and does not worsen 
during the study 
● 
Any situation where an untoward medical occurrence has not occurred (for example, 
hospitalizations for cosmetic elective surgery or “social” admissions) 
● 
An overdose of either the IP or a concurrent medication without any resulting signs or 
symptoms. 
11.2.1.2. Serious Adverse Event 
An SAE is an AE occurring during any study phase (i.e., screening, treatment, or follow- up), 
and at any dose of the IP or placebo, that fulfills one or more of the following: 
● 
Results in death 
● 
Is immediately 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 in-patient hospitalization or prolongation of existing hospitalization 
● 
Results in persistent or significant disability or incapacity 
● 
Results in a congenital abnormality or birth defect 
● 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
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 outcomes listed in the 
above definition. These events should also be considered serious. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
11.3. Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events 
Abnormal assessments (e.g., ECGs and vital signs) that are judged by the PI as clinically 
significant or result in clinical sequelae will be recorded as AEs. Laboratory abnormalities will 
be reported by the PI as AEs if the abnormality is considered clinically significant or results in 
clinical sequelae. Laboratory abnormalities or other abnormal assessments not reported as 

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clinically significant (CS) are not reported as AEs in the study database. 
Clinically significant abnormal laboratory findings or other clinically significant 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 PI (or medically qualified designee) will exercise his or her medical and scientific 
judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. 
11.4. Timing, Frequency, and Method of Detecting Adverse Events 
Any preexisting conditions or signs and/or symptoms present in a participant prior to the start 
of the study (i.e., before informed consent) should be recorded as Medical/Surgical history. 
All AEs occurring after informed consent and on or before the final visit must be reported as 
AEs; only AEs that occur post-dose will be considered treatment-emergent. All AEs must be 
recorded irrespective of whether they are considered drug-related. Reporting and follow-up of 
TEAEs may continue until the EOS and for up to 6 months following the last dose. 
At each visit/assessment in the period defined above, AEs will be evaluated by the PI (or 
medically qualified designee) and recorded. 
11.5. Recording Adverse Events 
When an AE occurs, it is the responsibility of the PI (or medically qualified designee) to review 
all documentation (e.g., hospital disease course records, laboratory and diagnostic reports) 
relative to the event. The PI or a medically qualified designee will record the AE on the AE 
page of the eCRF. Additional reporting requirements for an AE meeting serious criteria are 
discussed in Section 11.8. 
The PI or medically qualified designee will establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In all cases, the diagnosis should be reported as 
an event rather than an individual sign/symptom. It is not acceptable for the PI to send 
photocopies of the participant’s medical records to the Sponsor in lieu of completion of the AE 
page of the eCRF. 
11.5.1. Adverse Events of Special Interest 
Adverse events of special interest (AESI) include hypersensitivity/anaphylaxis, injection site 
reactions, and potential hepatotoxicity events. The PI and designated clinical staff are 
responsible for detecting, recording, and reporting these events. AESIs that occur after the first 
dose of IP will be considered treatment-emergent. AESIs should be recorded on a specially 
designated eCRF. A list of Medical Dictionary for Regulatory Activities (MedDRA) Preferred 
Terms or search strategies for the AESI categories is provided in Appendix 3. 
The criteria used for the assessment or grading of the AESIs are provided below. 

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A. 
Hypersensitivity/Anaphylaxis: The assessment of hypersensitivity and anaphylaxis 
will be based on the Sampson criteria (refer to Appendix 3). 
B. 
Injection site reactions: LISRs are graded based on the latest version of the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
(Version 5.0): 
● 
Mild: Tenderness with or without associated symptoms (e.g., warmth, erythema, 
itching), mild pain, and mild erythema 
● 
Moderate: Pain with associated phlebitis or lipodystrophy and edema 
● 
Severe: Tissue ulceration or necrosis with associated severe tissue damage or if 
operative intervention is indicated. 
C. 
Potential hepatotoxicity events: abnormal liver function tests that may indicate 
potential hepatotoxicity events are graded based on the latest version of CTCAE Version 
5.0. Specifically, laboratory test results that indicate an increase in the level of ALT and 
AST in a blood specimen are graded as follows: 
● 
Grade 1: If normal at baseline, >ULN-3.0 × ULN; if abnormal at baseline, 1.5-3.0 
× the baseline value 
● 
Grade 2: If normal at baseline, >3.0-5.0 × ULN; if abnormal at baseline, >3.0-5.0 
× the baseline value 
● 
Grade 3: If normal at baseline, >5.0-20 × ULN; if abnormal at baseline, >5.0-20 × 
the baseline value 
● 
Grade 4: If normal at baseline, >20 × ULN; if abnormal at baseline, >20.0 × the 
baseline value 
11.6. Evaluating Adverse Events 
11.6.1. Assessment of Severity 
The PI or medically qualified designee will assess severity for each AE reported during the 
study. The assessment will be based on the PI’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 CTCAE (Version 5.0) and assigned to one of the following categories: 
● 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. Medical intervention not indicated. 
● 
Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities. Symptomatic; 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 
disabling. 
● 
Death: An event that results in death. 
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utilized for rating the severity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” if it meets one of the predefined outcomes described in Section 
11.2.1.2. 
11.6.2. Assessment of Causality 
The PI (or medically qualified designee) is obligated to assess the relationship between IP and 
the occurrence of each AE/SAE. The PI (or medically qualified designee) will use clinical 
judgment to determine the causal relationship. Other plausible causes will be considered and 
investigated, such as natural history of the underlying diseases, concomitant therapy, other risk 
factors, and the temporal relationship of the event to the IP. The PI (or a medically qualified 
designee) will also consult the IB in the determination of his/her assessment. 
There may be situations where an SAE has occurred and the PI has minimal information to 
include in the initial SAE report. However, the PI (or medically qualified designee) must assess 
causality for every event prior to transmitting the SAE report form. The PI (or medically 
qualified designee) may change his/her opinion of causality considering follow-up information, 
amending the SAE report form accordingly. The result of causality assessment is one of the 
criteria used when determining whether to report to the regulatory authorities as required. 
The PI (or a medically qualified designee) will provide the assessment of causality using 3 
possible categories: Not Related, Possibly Related, or Probably Related. 
An AE will be considered “not related” to use of the product if any of the following tests are 
met: 
● 
An unreasonable temporal relationship between the administration of the product and the 
onset of the AE (e.g., the event occurred either before, or too long after the administration 
of the product, but is considered product-related) 
● 
A causal relationship between the product and the AE is biologically implausible (e.g., 
death from a traffic accident) 
● 
A clearly more likely alternative explanation for the AE is present (e.g., typical adverse 
reaction to a concomitant drug and/or typical disease-related event) 
An AE will be considered “possibly related” when an event follows a reasonable temporal 
sequence from administration of the study drug, but which could also be explained by 
concurrent disease 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. Other examples include 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. 

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11.7. Follow-up of Adverse Events 
After the initial AE, the PI is required to proactively follow each participant and provide further 
information on the participant’s condition as deemed appropriate. 
All AEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up. Once resolved, the appropriate 
AE page and SAE report form of the eCRF will be updated (if the event is serious). The PI, or 
medically qualified designee, will ensure that follow-up includes any supplemental 
investigations that 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 PI, or medically qualified designee, will attempt to obtain postmortem findings, including 
histopathology, and provide all additional information in a follow-up SAE report. 
New or updated information regarding an SAE will be recorded on a new SAE report form 
marked as follow-up with the appropriate follow-up number added to the report. The follow-
up report will be signed and dated by the PI (or a medically qualified designee). 
11.8. Prompt Reporting of Serious Adverse Events 
Any AE meeting serious criteria (i.e., SAE) must be reported promptly to the Sponsor’s 
designated Pharmacovigilance Contract Research Organization (CRO), and IRB/IEC in 
accordance with applicable local/institutional requirements. 
11.8.1. Completion and Transmission of the Serious Adverse Event Reports 
Once a PI becomes aware that an SAE has occurred in a study participant, she/he will report 
the information on an SAE report form to the designated Pharmacovigilance CRO immediately. 
The SAE report form will always be completed as thoroughly as possible with all available 
details of the event and signed by the PI (or medically qualified designee). If the PI does not 
have all information regarding an SAE, he/she will not wait to receive additional information 
before reporting the event. The SAE report form will be updated when additional information 
is received. 
The PI (or medically qualified designee) will always provide an assessment of causality at the 
time of the initial report as described in Section 11.6.2. However, as new information becomes 
available, causality may be modified. 
Email transmission of the SAE report form is the preferred method to transmit this information 
to the designated Pharmacovigilance CRO. Facsimile is acceptable if email is unavailable. In 
rare circumstances, notification by telephone is acceptable, with a copy of the SAE report sent 
by overnight mail. Notification by telephone does not replace the need for the PI, or medically 
qualified designee, to complete and sign the SAE report form within the outlined specified time 
frames. 

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The Sponsor will provide a list of project contacts for SAE receipt, fax numbers, telephone 
numbers and mailing addresses. Any event that in the opinion of the PI may be of immediate 
or potential concern for the participant’s health or well-being will be reported to the Sponsor 
emergency contact listed in the Protocol. 
11.8.2. 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 immediately and not later than 24 hours of initially becoming aware 
of the pregnancy by the PI. 
Any known pregnancy that occurs within 24 weeks after the last dose of IP should be reported 
by the participant to the PI. 
Pregnancies are not SAEs. However, pregnancy data will be collected at the initial notification, 
birth/termination of pregnancy, and for at least 1 year after birth or until the end of the 
pregnancy. 
Any SAE that occurs during pregnancy (e.g., serious maternal complications, therapeutic or 
spontaneous miscarriage, ectopic pregnancy, stillbirth, etc.) must be reported in accordance 
with the procedure for reporting SAEs. 
11.8.3. Serious Adverse Event Reports to the IRB 
The PI, or responsible person per local requirements, will comply with the applicable local 
regulatory requirements related to the reporting of SAEs to regulatory authorities and the 
appropriate IEC/IRB. 
11.8.4. Regulatory Requirements for Reporting of Serious Adverse Events 
The PI (or medically qualified designee) will promptly report all SAEs in accordance with the 
procedures detailed in Section 11.8.1. Prompt notification of SAEs by the PI is essential so that 
the Sponsor may comply with its regulatory obligations. 
Any SAEs requiring expedited reporting will be reported by the Sponsor to relevant regulatory 
authorities, PIs, and IRBs/IECs in accordance with the Sponsor’s procedures and local 
regulatory requirements. 
11.8.5. Post-study Adverse Events 
A post-study AE is defined as any event that occurs outside of the AE detection period defined 
in Section 11.4. Investigators are not obligated to actively seek AEs in former study participants. 
However, if the PI learns of any SAE at any time after a participant has been discharged from 
the study, and he/she considers the event reasonably related to the investigational product, the 
PI will promptly notify the Sponsor. 

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11.8.6. Serious Adverse Events Related to Study Participation 
An SAE considered related to study participation (e.g., procedures, invasive tests, a change in 
existing therapy), even if it occurs during the pre- or post-treatment period, will be reported 
promptly (refer to Section 11.6). 
12. Statistics 
12.1. General 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 (SAP) will only occur prior to database lock. Descriptive statistics will be 
presented for all analyses unless otherwise specified. For continuous variables, data will be 
summarized as number (n), mean, median, standard deviation, minimum, and maximum. 
Discrete variables will be presented as frequencies and proportions or percents. Data will be 
analyzed by treatment group (VSA001 25 mg, VSA001 50 mg, or pooled placebo). 
Additional details of all planned analyses for this study will be provided in the SAP. 
12.2. Analysis Populations 
The analysis sets for this study are defined as follows: 
● 
Full Analysis Set (FAS): All randomized participants will be included in FAS. All 
efficacy analyses will be performed using the FAS. Participants will be analyzed 
according to the study treatment assigned at randomization. 
● 
Safety Analysis Set: All participants who received 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 received. 
● 
Per-Protocol set: All randomized participants who completed the study without any major 
protocol deviations. 
● 
PK Analysis Set: All participants who have been randomized and received at least one 
dose of study drug and have at least one evaluable plasma concentration data after dosing. 
12.3. Sample Size Considerations 
Participants will be randomized in a 2:1:2:1 ratio into VSA001 25 mg dose group and volume-
matched placebo group, VSA001 50 mg dose group and volume-matched placebo group. The 
two placebo groups will be pooled for statistical analysis, i.e., the randomization ratio of 
treatment groups to pooled placebo group is 1:1:1. 
The significance of the median difference in percent change from baseline in TG at Month 10 
between each active treatment group and placebo group will be judged using the Wilcoxon 
(Mann-Whitney) rank-sum test with correction for continuity. Type I errors will be controlled 
using Holm's method. 

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These estimates assume an average of
reduction from baseline in fasting TG at 
Month 10 in participants receiving VSA001 25 mg and VSA001 50 mg, respectively, and 
reduction in participants receiving placebo. The standard deviation is assumed to be
for 
all three groups (Witztum 2019), and the level of significance α is set to be two-sided 0.05. 
It is expected that 27 participants completing the 10-month follow-up will provide a power of 
greater than 85% to detect at least one VSA001 group with statistically significant differences 
versus the pooled placebo group. Assuming a dropout rate of 10% at Month 10, a total of 
approximately 30 participants would need to be enrolled. Taking into account the effects of 
uncertainties such as competitive enrollment, block randomization, and COVID-19, 
approximately 36 participants will be enrolled. 
Randomization will be stratified by level of TG at screening (≥ 2000 vs. < 2000 mg/dL). 
12.4. Analysis Methods 
The primary analysis will include data from the randomized period. The final analysis will 
include data from the randomized and extension periods. The primary analysis is planned when 
all randomized participants complete the randomized period or discontinue from study, 
whichever is earlier. The final analysis is planned when all participants complete the extension 
period or discontinue from study, whichever is earlier. 
12.4.1. Baseline Data 
Demographics will be tabulated by participant and summarized by cohort and treatment group. 
Eligibility assessments at baseline, including medical/surgical history data, physical 
examination data (including height and weight) will be listed for each participant. 
Medical history will be listed by participant. Medical history will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Prior and Concomitant Medications will be 
coded using the World Health Organization Drug Dictionary (WHO-DD), and summarized by 
Anatomic Therapeutic Classification and WHO-DD active ingredients.  
12.4.2. Efficacy 
To control the family-wise Type I error at a 0.05 level, a fixed sequential testing procedure will 
be implemented in a hierarchical step-down manner. The hypothesis testing procedure from 
primary efficacy endpoint to key secondary endpoints will use a fixed-sequence stepping-down 
procedure. Only if the primary efficacy analysis of primary endpoint proves significantly in 
favor of active treatment groups will the key secondary endpoints be tested. 
To strictly control the family-wise Type I error, inferential conclusions about these efficacy 
endpoints will require statistical significance from both dose levels of the previous one. Within 
each endpoint, there are two tests, VSA001 25 mg vs. placebo and VSA001 50 mg vs. placebo. 
When performing the efficacy analysis for an endpoint, the adjustment for multiplicity of 
testing 2 VSA001 treatment groups vs placebo group will be carried out using Holm's step-

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down procedure. The sequence of hypothesis testing is as follows: 
Endpoints 
Test Sequence 
Percent change in fasting TG at Month 10 (primary endpoint) 
1 
Percent change in fasting TG at Month 10 and Month 12 (averaged) 
2 
Percent change in fasting APOC3 at Month 10 
3 
Percent change in fasting APOC3 at Month 12 
4 
The primary objective of this study is to evaluate the effect of VSA001 on fasting serum TG 
levels in adults with FCS. The primary endpoint is percent change from baseline at Month 10 
in fasting serum TG levels. The primary analysis of the primary endpoint will evaluate the 
difference in means between each VSA001 dose cohort and the pooled placebo cohort and will 
be conducted in all randomized participants (FAS). The estimand of interest is the difference 
in means of percent change from baseline in fasting TG at Month 10 in adults with FCS (as 
defined by the inclusion/exclusion criteria), regardless of treatment compliance or other 
intercurrent events post-baseline. 
For endpoint analysis based on Month 10 data, the laboratory value will be the arithmetic mean 
of two values during Month 10. If only one value is available during Month 10, then this value 
will be used for endpoint analysis. For data analysis purposes, baseline for fasting serum TG 
will be defined as the arithmetic mean of Day 1 pre-dose assessment and the last fasting 
assessment prior to Day 1. If only one pre-dose value is available, the pre-dose value closest to 
the first dose will be used. 
The primary efficacy analysis will use the Wilcoxon (Mann-Whitney) rank-sum test with 
correction for continuity to determine the significance of the median difference between the 
active treatment and placebo groups. The median difference between groups and its 95% 
confidence interval will be estimated using the Hodges-Lehmann method. 
Similar to the primary analysis of Month 10 fasting TG (primary endpoint), the Wilcoxon rank-
sum test with the Hodges-Lehmann method will be used to test and evaluate the key secondary 
endpoints listed above, with testing order 2 to 4. Wilcoxon rank-sum test with Hodges-
Lehmann method will also be used to test other continuous secondary endpoints but will only 
be considered exploratory. The same sensitivity analyses of the primary endpoint will be 
applied to these 3 key secondary endpoints and other secondary endpoints as well. 
For the analysis of exploratory endpoints, descriptive summaries will be provided, as 
appropriate, and any inferential statistics (i.e., p-values) will be considered only as exploratory. 
Descriptive statistics will be provided for the secondary endpoints. 
For long-term efficacy endpoints such as change and percent change from baseline in TG, 
APOC3, non-HDL-C, and HDL-C and other lipid parameters in the extension period, 
descriptive statistics will be provided by active dose received. For participants who receive 
placebo in the randomized period, baseline of long-term endpoints will be re-derived using the 
value of the last assessment prior to receiving the first dose of active IP in the extension period. 

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For participants who receive active drug in the randomized period, baseline is the value of last 
assessment prior to first dose of active IP in the randomized period. 
12.4.3. Safety 
In general, safety analyses will be performed and the results summarized by cohort and 
treatment group. Adverse events will be coded using the latest version of MedDRA and 
summarized by System Organ Class (SOC) and Preferred Term (PT). Overall Summaries of 
TEAEs will be tabulated by seriousness, severity, and relationship to IP. The incidence and 
frequency of TEAEs, LISR-related TEAEs, serious TEAEs, and serious TEAEs leading to 
discontinuation, will be summarized by cohort per SOC, PT, and severity. Drug-related TEAEs 
will be listed in a similar manner. AEs will also be summarized in listings. The duration of AEs 
will be determined and included in listings, along with the action taken and outcome. The 
incidence/change of biomarkers will be summarized using descriptive statistics. Shift tables 
may be provided. 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 participant listings. ECG parameters, changes from baseline, and 
qualitative assessments will be summarized. Pregnancy and FSH test results will be listed. 
For long-term safety endpoints, descriptive statistics will be provided by active dose received 
similar to long-term efficacy endpoints. 
12.4.4. Pharmacokinetics and Pharmacodynamics 
For all participants undergoing sparse PK sampling, plasma concentrations of VSA001 will be 
tested and exposure (Cmax and AUC [if data permit]) assessed. Detailed analysis plans and 
results will be reported separately. 
Derivative change and percent change from Day will be summarized for fasting APOC3, 
APOC2, and APOA5. 
12.4.5. Immunogenicity (Anti-Drug Antibodies) 
The number of participants to test positive for ADA at baseline and post-treatment will be 
summarized. Maximum ADA titer and range of titer values will be presented. ARO-APOC3 
treatment-induced ADA formation, if any, will be analyzed to ascertain if the ADA response 
duration is transient or persistent using the definitions in the white paper published by Shankar 
et al. (2014) The effect of ADA formation on VSA001 PK, PD, efficacy, and safety will be 
analyzed. 
13. Direct Access to Source Data/Documents 
13.1. Study Monitoring 
Visirna is responsible for ensuring that the study is properly conducted in accordance with the 
protocol and that the data recorded on the eCRFs are valid. Participant confidentiality will be 

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maintained. 
In accordance with applicable regulations, GCP and Visirna procedures, Visirna will be 
responsible for assigning a clinical research associate (CRA) who will contact the study site to 
organize a visit prior to participant enrollment to review the protocol and data collection 
procedures with the study site staff. In addition, the assigned CRA will periodically contact the 
site, including conducting on-site visits. The extent, nature and frequency of on-site visits will 
be based on such considerations as the study objective or endpoints, the purpose of the study, 
study design complexity, and enrollment rate. 
During these site visits, the CRA will perform the following: 
● 
Check the progress of the study 
● 
Review study data collected 
● 
Conduct source document verification 
● 
Identify any issues and address their resolution 
● 
Check IP accountability 
● 
Review blood and urine samples and ensure they are labeled and stored correctly. 
This will be done to verify the following: 
● 
Data are authentic, accurate and complete 
● 
The rights of participants are being protected 
● 
The study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The PI allows the CRA direct access to all relevant documents and arranges a time for 
him/herself or his/her staff to discuss findings and any relevant issues with the CRA. 
At the end of the study, the CRA will conduct the following activities in conjunction with the 
PI or study site staff as appropriate: 
● 
Return of all study data to Visirna 
● 
Data queries 
● 
Accountability, reconciliation, and arrangement for unused IP 
● 
Inventory and final disposition (e.g., destruction, and shipping to repository). 
● 
Review of site study records for completeness 
13.2. Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. The PI will conduct the study in 
accordance with the approved protocol and will not arbitrarily implement any deviation from 
or changes to the study protocol, except where necessary to eliminate an immediate hazard to 
study participants. 

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Deviations may result from the action or inaction of the participant, PI, or site staff. Examples 
of deviations include, but are not limited to: 
● 
Failure to adhere to study exclusion and inclusion criteria 
● 
Failure to comply with dispensing or dosing requirements 
● 
Use of medications, food, drink, herbal remedies, or supplements that are specifically 
prohibited in the protocol 
● 
Missed or out-of-window visits 
● 
Drug dosing not administered within the time frame specified in the protocol 
● 
Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc. - either tests not done, incorrect tests 
done, or not done within the time frame specified in the protocol 
● 
Procedural deviations such as incorrect storage of study drugs, failure to update the ICF 
when new risks become known, failure to obtain IRB/IEC approvals for the protocol, and 
ICF revisions 
Protocol deviations impacting participant safety or eligibility will be reported to the Sponsor 
or contract research organization within 2 business days of occurrence and to the 
IRB/IEC/regulatory authorities as per local regulatory requirements. 
The PI is responsible for ensuring that any known protocol deviations are recorded and reported 
in accordance with the protocol. The nature and reasons for protocol deviations will be recorded. 
13.3. Clinical Laboratory Certification and Reference Ranges 
Before the initiation of this study, the PI or designee will obtain a copy of the certification form 
for all clinical laboratories (except the central laboratory) used in the study, with the 
certification number and expiration date. Reference ranges for each clinical laboratory test used 
in this study will be obtained from the laboratory, which will perform the test for the study. In 
the event of COVID-related restrictions prohibiting participant site visits, local laboratories 
with associated local lab reference ranges may be utilized with prior Sponsor approval. 
13.4. Audits and Inspections 
To ensure compliance with GCP and all applicable regulatory requirements, Visirna may 
conduct a quality assurance audit of the study site. Regulatory agencies may also conduct a 
regulatory inspection of this study. Such audits/inspections can occur at any time during or 
after completion of the study. If an audit or inspection occurs, the PI and clinical site agree to 
notify the Sponsor as soon as possible following awareness of an impending regulatory 
inspection. The PI and the clinical site agree to allow the auditor/inspector direct access to all 
relevant documents and allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues. 
13.5. Institutional Review Board/Independent Ethics Committee Approval 

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Prior to initiation of the study, written IRB/IEC approval of the protocol and ICFs, based on 
the principles of ICH GCP procedures, will be received. A copy of the signed and dated 
approval letter will be provided to the clinical study site and Visirna prior to study 
commencement. Any written information or advertisements to be used for patient recruitment 
will be approved by the IRB/IEC prior to use. A list of the IRB/IEC voting members, their titles 
or occupations, Federal Wide Assurance number (where applicable) and their institutional 
affiliations will be requested before study initiation. 
Protocol amendments that may impact participant safety or the validity of the study will be 
approved by the IRB/IEC, following written consent of the Sponsor. 
14. Quality Control and Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit. For more details on the audit assessment, refer to Section 
13.4. 
15. Ethics 
15.1. Ethics Review 
The final study protocol (including the final version of the ICF) must be approved or given a 
favorable opinion in writing by the IRB/IEC (as appropriate). The PI must submit written 
approval to the Sponsor before enrolling any patient/participant into the study. 
The PI is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB/IEC should approve all advertising 
used to recruit of patients for the study. As required by the regulations, the IRB/IEC must re-
approve the protocol upon receipt of the amendment. 
The PI is also responsible for providing the IRB/IEC with records of serious adverse drug 
reactions reported in any other studies conducted with the IP. The Sponsor will provide this 
information to the PI. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC according to regulations and guidelines. 
15.2. Ethical Conduct of the Study 
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/IEC, and written 
approval obtained before patients are enrolled. The composition of the IRB/IEC will also be 
provided to the Sponsor. If approval is suspended or terminated by the IRB/IEC, the PI will 
notify the Sponsor immediately. 
Where applicable, the clinical study site and Visirna agree to abide by the guidelines for 

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compensation for injuries resulting from participating in a company-sponsored research project. 
15.3. Written Informed Consent 
Informed consent should be obtained before the participant participates in the study. The 
contents and process of obtaining informed consent should be in accordance with all applicable 
regulatory requirements. Study participation includes all screening procedures, as well as any 
wash-out of prohibited drugs. 
It is the responsibility of the PI or medically qualified designee to obtain a signed informed 
consent form (ICF) from every patient participating in this study after adequate explanation of 
the objectives, methods and potential risks of the study. The PI or a 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 (i.e., ICF template) will be provided by the PI or by Visirna. 
For this study, each eligible participant will be required to sign an ICF before participation in 
the study. 
All eligible participants will have the study explained by the PI or designee. They will receive 
a full explanation, in lay terms, of the objectives 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 this study is for research purposes only and is not expected to provide 
any therapeutic benefit to individuals. During the informed consent process, the PI or designee 
will also review and discuss with each participant all currently approved therapies for the 
treatment of FCS that are commercially available in the respective region (if any). It should be 
pointed out that participants can withdraw from the study at any time without any 
discrimination. 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 ICF to retain. 
16. Data Handling and Record Keeping 
16.1. Inspection of Records 
The Sponsor will be allowed to conduct site visits to the investigation facilities for the purpose 
of monitoring any aspect of the study. The PI agrees to allow the monitor to inspect the drug 
storage area, study drug stocks, drug accountability records, participant medical records and 
study source documents, and other records relative to study conduct. 
16.2. Retention of Records 
Following closure of the study, the PI must maintain site study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., 
audit or inspection) and whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems and staff. When permitted by 

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laws/regulations or institutional policy, some of these records can be stored in a format other 
than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised 
before such action is taken. The PI must assure that all reproductions are legible, are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
regenerating a hard copy, if required. Furthermore, the PI must ensure that there is an 
acceptable back-up of reproductions and that an acceptable quality control process exists for 
making these reproductions. 
Visirna will inform the PI of the time period for retaining these records to comply with all 
applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by any institutional requirements or 
laws or regulations, or Visirna 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 IRB/IEC approval letter, letter of constitution of the IRB/IEC, and 
copies of any other correspondence relevant to the study with the IRB/IEC or regulatory 
authorities 
● 
The IRB/IEC-approved ICF 
● 
Current curriculum vitae (signed and dated) of the PI and coworkers with major 
responsibilities in the trial 
● 
Site Signature and Delegation of Responsibility Log 
● 
Financial Disclosure Form(s) (where applicable) 
● 
Blank Case Report Form (CRF)/eCRF 
● 
Signed participant ICFs 
● 
Laboratory reference ranges (signed and dated) 
● 
The completed Clinical Trial Notification Application Form (where applicable) 
● 
Clinical raw data including the source data forms, all clinical laboratory report forms, 
participant CRFs, drug accountability forms, and dispensing records, etc. 
17. Publication Policy 
No publication of the results shall take place without the written consent of Visirna. Prior to 
submitting for any publication, presentation, use for instructional purposes, or otherwise 
disclosing the study results generated by the site (collectively, a “Publication”), the PI shall 
provide Visirna with a copy of the proposed Publication and allow Visirna a period of at least 
thirty (30) days [or for abstracts, at least five (5) working days] to review the proposed 
Publication. Proposed publications shall not include any confidential information of Visirna. 
At Visirna’s request, the submission or other disclosure of a proposed Publication will be 
delayed for a sufficient length of time to allow Visirna to seek patent or similar protection of 

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any inventions, know-how, or other intellectual or industrial property rights disclosed in the 
proposed Publication. 
If a written study contract for the conduct of the study, which includes publication provisions 
inconsistent with the statement is executed, that contract’s publication provisions shall apply 
rather than this statement. 
17.1. Ownership 
All information provided by Visirna, as well as all data and information generated by the study 
site as part of the study (other than a participant’s medical records), are the sole property of 
Visirna. 
All rights, ownership and interests in any inventions, know-how or other intellectual or 
industrial property rights that are conceived or reduced to practice by the study site staff during 
or as because of the study are the sole property of Visirna and are hereby assigned to Visirna. 
If a written contract for the conduct of the study that includes ownership provisions inconsistent 
with this statement is executed between Visirna and study site, the contract’s ownership 
provisions shall apply rather than this statement. 
17.2. Confidentiality 
All information provided by Visirna and all data and information generated by the site as part 
of the study (other than a participant’s medical records), will be kept confidential by the PI and 
other site staff. The PI or other study site staff may not use such information and data for any 
purpose other than conducting the study. These restrictions do not apply to: (1) information 
that becomes publicly available through no fault of the PI or the study site staff; (2) information 
that must be disclosed to the IRB/IEC in confidence for study evaluation purposes only; (3) 
information that must be disclosed to provide appropriate medical care to a study participant; 
or (4) study results that may be published as described in the next paragraph. If a written 
contract for the conduct of the study that includes confidentiality provisions inconsistent with 
this statement is executed, that contract’s confidentiality provisions shall apply rather than this 
statement. 
The Sponsor complies with data minimization principles in order to collect and process the 
minimum amount of personal data necessary for 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 will conduct 
periodic risk assessments/reviews and, as appropriate, update its information security policies 
and procedures. 

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18. References 
Aalto-Setala K, Fisher EA, Chen X, Chajek-Shaul T, Hayek T, Zechner R, et al. Mechanism 
of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very 
low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced 
apo E on the particles. J Clin Invest. 1992;90:1889-1900. 
Aalto-Setala K, Weinstock PH, Bisgaier CL, Wu L, Smith JD, Breslow JL. Further 
characterization of the metabolic properties of triglyceride-rich lipoproteins from human and 
mouse apoC-III transgenic mice. J Lipid Res. 1996;37:1802-1811. 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365-376. 
Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification 
of acute pancreatitis--2012: revision of the Atlanta classification and definitions by 
international consensus. Gut. 2013;62:102-111. 
Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. 
Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride 
levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study 
with an open-label Extension [MARINE] trial). Am J Cardiol. 2011;108:682-690. 
Brown EE, Sturm AC, Cuchel M, Braun LT, Duell PB, Underberg JA, et al. Genetic testing in 
dyslipidemia: A scientific statement from the National Lipid Association. J Clin Lipidol. 2020 
Jul-Aug;14(4):398-413. doi: 10.1016/j.jacl.2020.04.011. Epub 2020 May 7. PMID: 32507592. 
Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, et al. Loss-of-function 
mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371:22-31. 
Falko JM. Familial chylomicronemia syndrome: a clinical guide for endocrinologists. Endocr 
Pract. 2018 Aug;24(8):756-763. doi: 10.4158/EP-2018-0157. PMID: 30183397. 
FDA Meeting Transcript Endocrinologic and Metabolic Drugs Advisory Committee Meeting. 
May 10, 2018. Available from: https://www.fda.gov/media/116320/download. 
Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic 
interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806-811. 
Fitzsimmons D, Johnson CD, George S, Payne S, Sandberg AA, Bassi C, et al. Development 
of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core 
cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study 
Group on Quality of Life. Eur J Cancer. 1999;35(6):939-41. 

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Fitzsimmons D, Kahl S, Butturini G, van Wyk M, Bornman P, Bassi C, et al. Symptoms and 
quality of life in chronic pancreatitis assessed by structured interview and the EORTC QLQ- 
C30 and QLQ-PAN26. Am J Gastroenterol. 2005;100:918-926. 
Gelrud A, Williams KR, Hsieh A, Gwosdow AR, Gilstrap A, Brown A. The burden of familial 
chylomicronemia syndrome from the patients' perspective. Expert Rev Cardiovasc Ther. 
2017;15:879-887. 
Gerritsen G, Rensen PC, Kypreos KE, Zannis VI, Havekes LM, Willems van Dijk K. ApoC- 
III deficiency prevents hyperlipidemia induced by apoE overexpression. J Lipid Res. 
2005;46:1466-1473. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, et al. Development 
and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20:1727-1736. 
Janas MM, Harbison CE, Perry VK, Carito B, Sutherland JE, Vaishnaw AK, et al. The 
Nonclinical Safety Profile of GalNAc-conjugated RNAi Therapeutics in Subacute Studies. 
Toxicol Pathol. 2018;46:735-745. 
Johnson C, Stroes ES, Soran H, Wierzbicki A, Moulin P, Bruckert E, et al. Issues Affecting 
Quality of Life and Disease Burden in Lipoprotein Lipase Deficiency (LPLD) - First Step 
Towards a PRO Measure in LPLD (abstract). Value Health. 2015;18:A707 
Jong MC, Rensen PC, Dahlmans VE, van der Boom H, van Berkel TJ, Havekes LM. 
Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in 
wild-type and apoE knockout mice. J Lipid Res. 2001;42:1578-1585. 
Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Loss-of-function 
mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32-41. 
Khetarpal SA, Rader DJ. Triglyceride-rich lipoproteins and coronary artery disease risk: new 
insights from human genetics. Arterioscler Thromb Vasc Biol. 2015;35:e3-9. 
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of 
protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285-291. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al; CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009;150:604-612. 
Mogg R, Mehrotra DV. Analysis of antiretroviral immunotherapy trials with potentially non- 
normal and incomplete longitudinal data. Stat Med. 2007;26:484-497. 
Moulin P, Dufour R, Averna M, Arca M, Cefalù AB, Noto D, et al. Identification and diagnosis 
of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations 
and proposal of an "FCS score". Atherosclerosis. 2018 Aug;275:265-272. doi: 

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10.1016/j.atherosclerosis.2018.06.814. Epub 2018 Jun 18. PMID: 29980054. 
Proctor SD, Mamo JC. Intimal retention of cholesterol derived from apolipoprotein B100- and 
apolipoprotein B48-containing lipoproteins in carotid arteries of Watanabe heritable 
hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol. 2003;23:1595-1600. 
Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the 
secondary prevention of coronary heart disease in men with low levels of high-density 
lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention 
Trial Study Group. N Engl J Med. 1999;341:410-418. 
Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, et al. Human 
knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 
2017;544:235-239. 
Scherer J, Singh VP, Pitchumoni CS, Yadav D. Issues in hypertriglyceridemic pancreatitis: an 
update. J Clin Gastroenterol. 2014;48:195-203. 
Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga A, et al; American 
Association of Pharmaceutical Scientists. Assessment and reporting of the clinical 
immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical 
recommendations. AAPS J. 2014;16:658-673. 
Stroes E, Moulin P, Parhofer KG, Rebours V, Löhr JM, Averna M. Diagnostic algorithm for 
familial 
chylomicronemia 
syndrome. 
Atheroscler 
Suppl. 
2017 
Jan;23:1-7. 
doi: 
10.1016/j.atherosclerosissup.2016.10.002. Epub 2016 Dec 18. PMID: 27998715. 
Van Horn L, Carson JA, Appel LJ, Burke LE, Economos C, Karmally W, et al. Recommended 
Dietary Pattern to Achieve Adherence to the American Heart Association/American College 
of Cardiology (AHA/ACC) Guidelines: A Scientific Statement from the American Heart 
Association. Circulation. 2016;134:e505-e29. 
Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, Williams KR, et al. 
Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med. 
2019;381:531-542. 
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:ATVBAHA120314368. 
 
 

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Appendix 1. 
Contraception 
Females not of childbearing potential must be surgically sterilized or postmenopausal (defined 
as cessation of regular menstrual periods for at least 12 months without an alternative medical 
cause) with supportive follicle-stimulating hormone (FSH) levels consistent with 
postmenopausal state based on laboratory reference ranges. 
If a participant’s urine pregnancy test result is positive, the participant will be referred to her 
attending physician for follow-up. Female participants with a positive pregnancy test at 
screening or on Day 1 pre-dose will not be enrolled in the study. Female participants who 
become pregnant during the study period will no longer receive investigational product (IP) 
but may continue to participate in study follow-up. 
All participants (female participants of childbearing potential with male partners and male 
participants with female partners of childbearing potential) must consent to use a highly 
effective form of contraception during the study and for at least 24 weeks after the last dose of 
study treatment. 
The followings are acceptable methods of highly effective contraception: 
● 
Using twice the normal protection of birth control (condom + one other form of highly 
effective contraception); birth control pills, injectable birth control, birth control patches, 
vaginal contraceptive ring or contraceptive implant associated with inhibition of ovulation, 
or intrauterine device; or 
● 
Surgical sterilization as a single form of birth control: i.e., tubal ligation, hysterectomy, 
bilateral oophorectomy, vasectomy, or equivalent effective surgical form of birth control; 
or 
● 
True sexual abstinence for the duration of the study and for at least 24 weeks after the last 
dose of IP is acceptable only when in line with the preferred and usual lifestyle of the 
participant. 
The following methods are not considered “true” abstinence and are not acceptable methods of 
contraception: periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational ammenorrhea methods. 
 
 

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Appendix 2. 
Liver-related Study Dose Modification and Follow-up Guidelines 
Treatment-
Emergent ALT/AST 
Treatment-
Emergent Total 
Bilirubin (TBL) 
Liver 
Symptoms 
Action 
If normal at baseline: 
ALT/AST ≥ 5 × ULN 
If increased at 
baselinea: ALT/AST 
≥ 300 U/L 
Normal or increased 
Participants with 
Gilbert’s syndrome or 
hemolysis - no 
change in baseline 
TBL 
None 
Discontinue IP. Confirm ALT, 
AST, ALP, and TBL within 72 
hours. 
Initiate close observation and 
workup for competing etiologies. b 
Follow-up for symptoms. 
If normal at baseline: 
ALT/AST ≥ 3 × ULN 
If increased at 
baselinea: ALT/AST 
≥ 2 × baseline 
Normal 
Participants with 
Gilbert’s syndrome or 
hemolysis - no 
change in baseline 
TBL 
None 
Confirm ALT, AST, ALP, TBL 
within 72 hours. 
Initiate close observation and 
workup for competing etiologies. b 
Follow-up for symptoms. 
If normal at baseline: 
ALT/AST ≥ 3 × ULN 
If increased at 
baselinea: ALT/AST 
≥ 2 × baseline 
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 (e.g., 
rash, > 5% 
eosinophilia) 
Interrupt IP. Confirm ALT, AST, 
ALP, and TBL within 72 hours. 
Initiate close observation and 
workup for competing etiologies. 
b IP therapy can be restarted only if 
an alternative etiology is identified 
and liver enzymes return to 
baseline. IP cannot be restarted if 
hepatic decompensation occurred. 
Follow-up for symptoms. 
If normal at baseline: 
ALT/AST ≥ 3 × ULN 
If increased at 
baselinea: ALT/AST 
≥ 2 × baseline 
TBL ≥ 2 × ULN or 
INR increased to > 
1.5 (for participants 
with Gilbert's 
syndrome or 
hemolysis - doubling 
of direct bilirubin if 
baseline TBL > 0.5 
mg/dL) 
None 
Interrupt IP. Confirm ALT, AST, 
ALP, and TBL within 72 hours. 
Initiate close observation and 
workup for competing etiologies. 
b IP therapy 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. 
a Increased at baseline is defined as ALT ≥ 1.5 × ULN. 
b Acute and chronic viral hepatitis (hepatitis A-E), cholelithiasis, alcoholism or other drugs (both prescribed 
and over-the-counter herbs and supplements). If needed, consider consultation with hepatologist for 
identification of alternative etiologies and follow-up. 
Source: Adapted from Regev A, Palmer M, Avigan MI, Dimick-Santos L, Treem WR, Marcinak JF, 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;49:702-713. 

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Guidelines for Close Observation for Potential Drug-Induced Liver Injury 
Within 72 hours, perform a complete medical history, physical examination, 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, over-the-counter (OTC) medications, drug abuse, and special diets 
● 
Alcohol consumption 
● 
Exposure to environmental chemical agents 
● 
Past medical history 
● 
Complete review of physical systems 
● 
Liver 
biochemistries 
including 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase, total bilirubin (TBL), and international 
normalized ratio (INR). 
Evaluate participants 2 or 3 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 medical history, physical 
examination, and laboratories, if the results can be transmitted promptly to the Principal 
Investigator. 
 
 

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Appendix 3. 
Adverse Events of Special Interest - List of MedDRA Preferred Terms or 
Search Strategy 
Injection Site Reactions: 
As determined by the Sponsor’s pharmacovigilance personnel, the following Medical 
Dictionary for Regulatory Activities (MedDRA) preferred terms will represent injection site 
reactions: 
Injection site discomfort 
Injection site calcification 
Injection site discoloration 
Injection site cellulitis 
Injection site erythema 
Injection site dermatitis 
Injection site irritation 
Injection site erosion 
Injection site inflammation 
Injection site fibrosis 
Injection site induration 
Injection site indentation 
Injection site pain 
Injection site necrosis 
Injection site edema 
Injection site nodule 
Injection site pruritus 
Injection site ulcer 
Injection site rash 
Injection site bruising 
Injection site urticaria 
Injection site haematoma 
Injection site reaction 
Injection site hypersensitivity 
Injection site swelling 
Injection site infection 
Injection site abscess 
Injection site pallor 
Injection site abscess sterile 
Injection site paraesthesia 
Injection site atrophy 
Injection site warmth 
Hypersensitivity/Anaphylaxis Events: 
A participant is said to have an episode fulfilling Sampson criteria if at least one of the 
following criteria is met: 
Criterion 1: The participant experienced an onset of both Condition 1 and Condition 2 within 
24 hours post dosing with study drug: 
● 
Condition 1 - a skin or mucous membrane AE 
● 
Condition 2 - a respiratory compromise AE or an end-organ dysfunction/reduced blood 
pressure AE, or reduced systolic blood pressure under 90 mmHg or greater than 30% 
decrease from baseline based on the vital signs data 
Criterion 2: The participant experienced an onset of any 2 or more conditions within 24 hours 
post dosing with study drug: 
● 
Condition 1 - a skin or mucous membrane AE 
● 
Condition 2 - a respiratory compromise AE 
● 
Condition 3 - an end-organ dysfunction/reduced blood pressure AE, or reduced systolic 
blood pressure 
● 
Condition 4 - a gastrointestinal AE 

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Criterion 3: The participant experienced reduced systolic blood pressure within 24 hours post 
dosing with study drug, and at least 1 qualifying event. * 
*A qualifying event is defined as any of the following occurring during the study, after the first 
administration of the study drug associated with the current reduced systolic blood pressure 
event. 
● 
Condition 1 - an event meeting Criterion 1 
● 
Condition 2 - an injection site reaction 
● 
Condition 3 - AE under Anaphylactic reaction Standardized MedDRA Query (SMQ) or 
the Angioedema SMQ or the Hypersensitivity SMQ considered to be related to the study 
drug. 
Potential Hepatotoxicity Events: 
The following Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms may 
represent hepatic events: 
Drug-induced liver injury 
Liver injury 
Hepatotoxicity 
Hepatic enzyme increased 
Acute hepatic failure 
Alanine aminotransferase abnormal 
Ascites 
Alanine aminotransferase increased 
Hepatic failure 
Aspartate aminotransferase abnormal 
Hepatic fibrosis 
Aspartate aminotransferase increased 
Hepatic necrosis 
Bilirubin conjugated abnormal 
Hepatic steatosis 
Bilirubin conjugated increased 
Hepatobiliary disease 
Hepatic enzyme abnormal 
Hepatocellular injury 
Hepatic enzyme increased 
Hyperbilirubinaemia 
Liver function test increased 
Jaundice 
Transaminases increased 
Liver disorder 
Hypertransaminasaemia 
 
 

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Appendix 4. 
Table of Fatty Acid Content of Food 
Sr. 
No. 
Food Name 
Fatty Acid 
(g/100 g edible 
portion) 
Sr. 
No. 
Food Name 
Fatty Acid 
(g/100 g edible 
portion) 
1 
Wheat flour (standard 
flour) 
1.7 
24 
Dried bean curd 
32.7 
2 
Wheat flour (strong 
flour) 
1.0 
25 
Agrocybe aegerita 
(dried) 
1.5 
3 
Hanging noodles 
(strong flour) 
1.0 
26 
T. gambasum (dried) 3.6 
4 
Dragon whiskers 
noodles 
(vegetarian/egg) 
1.2 
27 
Pholiota adiposa 
(dried) 
1.8 
5 
Noodles (cut/cooked) 
0.3 
28 
Collybia albuminosa 
(dried) 
2.1 
6 
Steamed twisted roll 
(with milk) 
2.1 
29 
Boletus edulis (dried) 0.9 
7 
Steamed bun (strong 
flour) 
0.9 
30 
Suillus bovinus 
(dried) 
1.6 
8 
Gluten 
Unknown 
31 
Tricholoma 
matsutake (dried) 
1.7 
9 
Long-shaped rice 
0.9 
32 
Russula sanguinea 
(dried) 
3.8 
10 
Rice flour 
0.7 
33 
Hohenbuehelia 
serotina (dried) 
0.8 
11 
Corn kernels (yellow, 
dry) 
0.7 
34 
Hazel mushroom 
(dried) 
6.1 
12 
Corn flour (yellow) 
1.3 
35 
Undaria pinnatifida 
(dried) 
1.4 
13 
Corn grits (yellow) 
1.0 
36 
Kelp 
6.0 
14 
Millet (yellow) 
2.6 
37 
Ficus carica (dried) 
3.4 
15 
Fagopyrum 
esculentum flour 
1.9 
38 
Pecan (cooked) 
61.7 
16 
Naked oats flour 
5.8 
39 
Chestnuts (cooked) 
1.4 
17 
Soy milk powder 
(Duoli brand) 
4.3 
40 
Pine nuts (cooked) 
38.6 
18 
Soybean milk powder 
(Damo brand) 
8.6 
41 
Almonds (cooked, 
shelled) 
52.0 
19 
Firm tofu 
7.5 
42 
Cashew nuts (cooked, 
shelled) 
48.7 
20 
Soft tofu 
5.4 
43 
Hazelnut kernel 
(cooked) 
50.6 
21 
Soybean milk 
1.5 
44 
Pistachio (cooked) 
50.7 
22 
Beancurd skin 
21.4 
45 
Torreya grandis 
(cooked) 
54.5 
23 
Yuba 
25.3 
46 
Peanuts (roasted, 
Qinjian brand) 
44.0 
47 
Sunflower seeds 
(creamy) 
51.7 
67 
Ham core 
44.4 
48 
Sunflower seed 
(cooked) 
46.8 
68 
Barbecued pork 
8.7 

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Sr. 
No. 
Food Name 
Fatty Acid 
(g/100 g edible 
portion) 
Sr. 
No. 
Food Name 
Fatty Acid 
(g/100 g edible 
portion) 
49 
Pumpkin seeds (white, 
cooked) 
50.5 
69 
Spareribs in soy 
sauce 
25.2 
50 
Watermelon seeds 
(black, cooked) 
44.0 
70 
Fragrant leached meat 50.4 
51 
Pork (front rump, 
Duroc × Landrace × 
Yorkshire pigs) 
23.0 
71 
Beef (back, top) 
11.4 
52 
Pork (front rump, 
excellent hybrid pigs) 
27.7 
72 
Beef (fillet, beef 
fillet) 
4.6 
53 
Pork (hind rump, 
Duroc × Landrace × 
Yorkshire pigs) 
8.3 
73 
Beef (rump) 
2.4 
54 
Pork (hind rump, 
excellent hybrid pigs) 
9.6 
74 
Beef (shoulder) 
29.0 
55 
Pork (hard rib, Duroc 
× Landrace × 
Yorkshire pigs) 
52.0 
75 
Beef (brisket) 
26.4 
56 
Pork (hard rib, 
excellent hybrid pigs) 
49.5 
76 
Beef (belly, tender 
loin) 
27.9 
57 
Pork (faux-filet, Duroc 
× Landrace × 
Yorkshire pigs) 
7.1 
77 
Beef (eye round, 
sirloin tip) 
1.6 
58 
Pork (faux-filet, 
excellent hybrid pigs) 
5.8 
78 
Beef (groin beef) 
2.7 
59 
Porcine skin 
26.8 
79 
Beef (shank) 
3.0 
60 
Pork chop (Duroc × 
Landrace × Yorkshire 
pigs) 
23.0 
80 
Omasum (black) 
1.5 
61 
Pork chop (excellent 
hybrid pigs) 
29.8 
81 
Beef in spiced sauce 
9.5 
62 
Pork stomach 
2.8 
82 
Beef (fragrant) 
9.5 
63 
Pork liver 
3.5 
83 
Beef shank (bay leaf) 5.0 
64 
Pork tongue (pig’s 
tongue as food) 
11.3 
84 
Sliced dried beef 
(Changfu brand) 
4.9 
65 
Pork kidney (kidney) 
1.3 
85 
Ham 
3.0 
66 
Ham core with whole 
lean meat 
17.6 
86 
Sandwich ham 
4.0 
87 
Crispy sausage 
21.4 
111 
Young pigeon 
(braised in brown 
sauce) 
19.7 
88 
Hot dog 
22.4 
112 
Milk (Guangming 
brand) 
3.0 
89 
Ham sausage 
13.0 
113 
Milk (Robust brand) 
3.6 
90 
Luncheon meat 
28.4 
114 
Milk (Sanyuan brand) 3.7 
91 
Pork floss 
9.0 
115 
Milk (Mengniu/Yili) 
3.5 
92 
Braised pork face 
28.0 
116 
Milk (partially 
defatted) 
1.2 
93 
Smoked tenderloin 
3.5 
117 
Milk (degreased) 
0.2 

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Sr. 
No. 
Food Name 
Fatty Acid 
(g/100 g edible 
portion) 
Sr. 
No. 
Food Name 
Fatty Acid 
(g/100 g edible 
portion) 
94 
Dried pork slices 
7.8 
118 
Milk (fortified with 
zinc and calcium) 
2.9 
95 
Meat crisp 
24.0 
119 
School milk 
2.5 
96 
Roast mutton (spiced) 4.8 
120 
Whole milk powder 
(Sanlu) 
28.0 
97 
Mutton shashlik (raw) 4.3 
121 
Whole milk powder 
(Yili) 
24.6 
98 
Donkey meat (spiced) 5.3 
122 
Low-fat milk powder 
(Yili) 
10.4 
99 
Venison (sika deer) 
1.2 
123 
Milk powder for 
middle-aged and 
elderly 
5.5 
100 
Chicken breast 
1.8 
124 
Yogurt (flavored) 
3.0 
101 
Chicken leg 
6.8 
125 
Yogurt (with fruit 
tablets) 
2.7 
102 
Chicken wings 
10.9 
126 
Cheese (Guangming 
brand) 
26.8 
103 
Chicken nuggets (with 
starch) 
8.6 
127 
Low-fat cheese 
11.0 
104 
Pheasant 
1.9 
128 
Cream 
81.3 
105 
Braised chicken 
(spiced and boneless) 
10.2 
129 
Full-fat sweetened 
condensed milk 
9.5 
106 
Roast chicken 
16.0 
130 
Egg (red skin) 
8.7 
107 
Spring chicken 
(cooked) 
17.1 
131 
Silkie egg (green 
skin) 
8.8 
108 
Roast duck 
23.9 
132 
Sea duck egg 
11.5 
109 
Preserved goose 
20.3 
133 
Salted duck egg 
(boiled) 
11.2 
110 
Young pigeon 
32.2 
134 
Grass carp 
1.8 
135 
Silver carp 
1.5 
158 
Black sesame 
dumplings 
Unknown 
136 
Crucian carp 
1.1 
159 
Fermented glutinous 
rice 
Unknown 
137 
Hairtail 
2.9 
160 
Pancake 
Unknown 
138 
Yellow croaker (small 
croaker) 
3.6 
161 
Mooncake 
Unknown 
139 
Mackerel 
27.6 
162 
Spring rolls 
(vegetarian) 
Unknown 
140 
Double-fin shark 
0.1 
163 
Pizza (cheese) 
4.8 
141 
Fish steak 
2.2 
164 
Sandwich (chicken) 
14.9 
142 
Fish ball 
1.2 
165 
Hot dog (original 
flavor) 
13.7 
143 
Caviar 
6.4 
166 
Sachima egg crisp 
28.8 
144 
Grass carp (black) 
15.3 
167 
Hamburger (regular, 
cheese, single patty) 
10.9 
145 
Clove fish (spicy) 
25.4 
168 
Hamburger (double 
patty) 
13.6 

Protocol No.: VSA001-3001 
Version No.: 3.5 
Visirna Therapeutics 
Confidential 
 
97 
Sr. 
No. 
Food Name 
Fatty Acid 
(g/100 g edible 
portion) 
Sr. 
No. 
Food Name 
Fatty Acid 
(g/100 g edible 
portion) 
146 
Swordfish (fried) 
11.3 
169 
Fried rice with 
shrimps 
Unknown 
147 
Fried dace with salted 
black beans 
29.8 
170 
Breakfast milk 
2.9 
148 
Eel (braised in brown 
sauce) 
6.9 
171 
Eight treasures 
congee 
Unknown 
149 
Shrimp paste 
5.3 
172 
Black sesame paste 
Unknown 
150 
Sea crab (small) 
0.6 
173 
Cornmeal 
9.1 
151 
Crab stick 
0.3 
174 
Oatmeal 
9.1 
152 
Clam ball 
8.3 
175 
Braised beef instant 
noodles 
15.8 
153 
Turtle egg 
6.1 
176 
Fried noodles with 
sizzling beef 
16.6 
154 
Cuttlefish ring 
2.0 
177 
Fried Chinese leek 
dumpling 
Unknown 
155 
Cuttlefish ball 
4.2 
178 
Shrimp ravioli 
Unknown 
156 
Chicken liver and 
vegetable puree 
(Heinz) 
1.6 
179 
Glutinous rice ball 
Unknown 
157 
Rice flour (high 
protein, Heinz) 
1.7 
180 
Fried rice with 
assorted meats 
Unknown 
181 
Biscuit (sandwich) 
28.8 
205 
Stuffed rice nuts 
39.6 
182 
Biscuit (stuffed) 
15.0 
206 
Mini puff 
42.6 
183 
Biscuit (stuffed with 
sweet crisp) 
33.2 
207 
Popcorn 
11.4 
184 
Biscuit (stuffed with 
soda) 
18.3 
208 
Fish granules 
2.3 
185 
Biscuit (salty) 
24.2 
209 
Pineapple juice 
(Taihu brand) 
0.2 
186 
Dumplings 
Unknown 
210 
Grapefruit juice drink 0.3 
187 
Steamed stuffed bun 
Unknown 
211 
Coconut water drink 
1.9 
188 
Rice cake (egg-milk 
flavor) 
28.3 
212 
Sour milk drink 
1.2 
189 
Snow rice cake 
16.6 
213 
TANG 
1.8 
190 
Egg roll 
33.4 
214 
Lemon tea 
1.4 
191 
Chocolate pie 
13.0 
215 
Coffee bean 
8.3 
192 
French burritos 
32.2 
216 
Ground coffee 
0.4 
193 
Doritos 
23.4 
217 
Ice cream 
(strawberry) 
3.0 
194 
Corn crisp 
32.8 
218 
Ice cream (with 
cream) 
12.1 
195 
Crisps 
28.0 
219 
Popsicle 
0.9 
196 
Onion ring 
20.1 
220 
Milk candy 
Unknown 
197 
Rice crust (bean 
flavor) 
28.9 
221 
Peanut nougat 
Unknown 
198 
Rice crust (millet) 
34.9 
222 
Green plum with 
snow-like powder 
0.8 

Protocol No.: VSA001-3001 
Version No.: 3.5 
Visirna Therapeutics 
Confidential 
 
98 
Sr. 
No. 
Food Name 
Fatty Acid 
(g/100 g edible 
portion) 
Sr. 
No. 
Food Name 
Fatty Acid 
(g/100 g edible 
portion) 
199 
Instant seaweed 
2.7 
223 
Preserved fruit 
0.4 
200 
Mushroom slices 
7.0 
224 
Walnut oil 
94.7 
201 
Potato chips (barbecue 
flavor) 
35.4 
225 
Peanut oil 
95.5 
202 
Potato chips (spicy) 
37.7 
226 
Sunflower seed oil 
95.5 
203 
Potato rings 
40.1 
227 
Corn germ oil 
95.6 
204 
Strange-flavored 
chickpeas 
9.4 
228 
Rice bran oil 
94.4 
229 
Camellia oleifera seed 
oil 
95.4 
239 
Salad dressing 
74.7 
230 
Sesame oil 
95.3 
240 
Strawberry jam 
0.8 
231 
Soybean salad oil 
95.5 
241 
Tomato sauce 
0.1 
232 
Salad oil 
95.3 
242 
Fermented bean curd 
(white) 
7.2 
233 
Dark soy sauce 
0.3 
243 
Chopped chili pepper 0.4 
234 
Hoisin sauce 
未知 
244 
Pickled cabbage 
1.3 
235 
Beef paste 
未知 
245 
Chicken powder 
4.8 
236 
Peanut butter 
50.5 
246 
Chicken extract 
2.6 
237 
Peanut butter (with 
chocolate) 
52.7 
247 
Thousand Island 
salad dressing 
41.1 
238 
Sesame paste 
63.9 
 
 
 
Source: Chinese Food Ingredient List (Standard Version) 
 
 

Protocol No.: VSA001-3001 
Version No.: 3.5 
Visirna Therapeutics 
Confidential 
 
99 
Appendix 5. 
Glycemic Control-related Guidelines 
Discontinuation principles related to increased HbA1c: 
Participants should discontinue investigational product (IP) if they meet the following criteria: 
● 
Glycosylated hemoglobin (HbA1c) measurement > 10% at the last visit prior to the next 
dose; or 
● 
HbA1c increased by >2% from baseline at the last visit before the next dose, or 
● 
In participants with a baseline HbA1c > 7.5% who had an increase from baseline by >1% 
at two study visits (the last visit being the visit prior to the next dose). 
 
Relevant monitoring guidelines for increased HbA1c: 
● 
Investigators are encouraged to evaluate diabetes mellitus status and adjust diabetes 
mellitus management according to clinical practice and diabetes mellitus care guidance. 
● 
At the Investigator’s discretion, any participants with inadequately controlled diabetes 
mellitus may return to the study site or a study facility recognized by the Sponsor and the 
Investigator for an unscheduled visit prior to the next planned dose to evaluate changes in 
HbA1c to confirm continued treatment eligibility: 
o 
If the participant’s HbA1c test value is increased by > 2% from baseline, it is 
necessary to conduct an unscheduled visit within 14 days and optimize 
hypoglycemic therapy according to clinical practice guidelines 
o 
After optimized hypoglycemic therapy, HbA1c will be retested within 14 days 
before the next dose 
o 
If the HbA1c retest results after optimized hypoglycemic therapy show: 
Measure HbA1c 
Do HbA1c levels 
rise to the 
discontinuation 
criteria? 
Yes 
No 
The drug will be 
discontinued and 
the participant will 
be followed up and 
monitored 
according to the 
guidelines for 
monitoring 
increased HbA1c 
Continue 
treatment 
•
HbA1c 
measurement > 10% at
the last visit prior to 
the next dose; or 
•
HbA1c 
increased
by >2% from baseline 
at the last visit before 
the next dose, or 
•
In participants with a
baseline 
HbA1c 
>
7.5% who had an
increase from baseline
by > 1% at two study 
visits (the last visit 
being the visit prior to 
the next dose). 

Protocol No.: VSA001-3001 
Version No.: 3.5 
Visirna Therapeutics 
Confidential 
 
100 
 
If the test value is decreased by ≥ 1% from the last time and HbA1c is ≤ 9.5%, 
the dosing can be continued according to the Schedule of Activities 
 
If the test value is decreased by ≥ 1% from the last time and HbA1c is still > 
9.5%, or if the test value is decreased by < 1% from the last time and HbA1c is 
≤ 9.5%, the investigator may discuss subsequent treatment with the medical 
monitor 
 
If the test value is decreased by < 1% from the last time and HbA1c is > 9.5%, 
the dosing should be interrupted once 
● 
If the dosing is interrupted twice, the participant will withdraw from the trial. 
 
 

Protocol No.: VSA001-3001 
Version No.: 3.5 
Visirna Therapeutics 
Confidential 
 
101 
Appendix 6. 
Description of Clinical Laboratory Tests 
Blood and urine samples of participants will be collected at the study site and shipped to the 
designated 
central 
laboratory 
for 
all 
laboratory 
tests, 
pharmacokinetics 
(PK), 
pharmacodynamics (PD, specifically APOC3 protein), anti-drug antibody (ADA) and lipid 
testing during the screening period and on Day 1 (except coagulation). Safety laboratory testing 
after Day 1 will be conducted in the laboratory of the study site, and the investigator may add 
unscheduled visits and laboratory testing during the study according to the specific situation of 
the participant. 
Laboratory 
Visits 
Testing Item 
Data 
Analysis 
Institution 
Remaining 
Sample 
Disposal 
Institution 
Chongqing 
Denali 
Medpharma 
Co., Ltd. 
Day 1, 
Month 3 
Sparse PK: Pharmacokinetics samples will be 
collected pre-dose and post-dose to test blood 
concentrations of the investigational product 
R&G 
PharmaStudi
es Co., Ltd. 
Chongqing 
Suxin 
Medical 
Waste 
Treatment 
Co., Ltd. 
Day 1, 
Months 1, 
3, 6, 9, 12, 
15, 18, and 
24/or early 
termination 
ADA: Used to observe the immunogenicity of 
investigational products 
Teddy 
Clinical 
Research 
Laboratory 
(Shanghai) 
Limited* 
Screening 
period 
• Virology (HBsAg, HBV DNA and HCV 
antibody, HCV RNA) 
• Pregnancy screening: FSH (for 
postmenopausal women), and serum beta-
HCG (for women of childbearing age) 
• C-peptide, insulin, TSH, FT4, blood 
chemistry, HbA1c, and hematology 
• Urinalysis, urine sediment microscopy, 
random urine creatinine, and random urine 
protein 
• 7-item lipid test (TG, LDL-C, TC, non-HDL-
C, HDL-C, VLDL-C, and LP[a]) 
R&G 
PharmaStudi
es Co., Ltd. 
Shanghai 
Solid 
Waste 
Disposal 
Co., Ltd.* 
Day 1 
(baseline) 
• C-peptide, insulin, blood chemistry, HbA1c, 
and hematology 
• Urinalysis, urine sediment microscopy, 
random urine creatinine, and random urine 
protein 
• APOC3 and lipid parameters (TG, LDL-C, 
TC, non-HDL-C, HDL-C, VLDL-C, APOB-
48, LP[a], APOB-100, total APOB, APOC-III, 
APOC-II, APOA-I, and APOA-V) 
At Months 
1, 2, 3, 4, 5, 
6, 7, 8, 9, 
• APOC3 and lipid parameters (TG, LDL-C, 
TC, non-HDL-C, HDL-C, VLDL-C, APOB-
48, LP[a], APOB-100, total APOB, APOC-III, 

Protocol No.: VSA001-3001 
Version No.: 3.5 
Visirna Therapeutics 
Confidential 
 
102 
10*, 11, 12, 
13, 14, 15, 
18, 21, and 
24/or early 
termination 
APOC-II, APOA-I, and APOA-V) 
• Lipid parameter testing must be done after the 
participant has fasted for ≥ 10 hours before 
collection at each study visit 
• At Month 10, blood lipid data will be collected 
2 times, 2-7 days apart, for efficacy 
assessment 
Laboratory 
of study site 
Screening 
period 
Coagulation only 
R&G 
PharmaStudi
es Co., Ltd. 
Medical 
institutions 
Day 1 
Urine pregnancy (for women of childbearing age), 
coagulation 
All 
visits 
after Day 1 
• Routine laboratory tests (kidney function, 
electrolytes, coagulation, urine tests, blood 
glucose, HbA1c, insulin, C-peptide, etc.) 
• Liver function tests (ALP, ALT, AST, TBL), 
hematology 
• Urine pregnancy (for women of childbearing 
age) 
• Note: For specific details, see the Schedule of 
Activities (SOC) 
*Among them, samples for APOA-V/APOB-48/APOB-100 will be undertaken by Wuxi Teddy Medical 
Testing Co., Ltd., a subsidiary of Shanghai Teddylab, while the remaining samples will be disposed of by 
Wuxi Industrial Waste Safety Disposal Co., Ltd. 
All laboratory tests (except for coagulation) used as inclusion criteria will be assessed by a 
central laboratory and may be repeated once (except for TG), and the repeat value may be used 
for inclusion purposes. Three repeat TG tests are allowed during screening period to confirm 
the results. Local laboratory testing may be permitted in limited circumstances and only with 
prior Sponsor approval. 
At all non-dosing post-Day 1 visits, in the event of logistical disruptions (e.g., COVID-related 
reasons) where a participant does not have direct access to the site, follow-up tests for relevant 
safety measures may be performed at an alternative location accepted by the sponsor, 
investigator/study site (e.g., local medical institution, or local laboratory). Samples will be 
collected with the central laboratory’s collection kit through home healthcare service and 
shipped to the central laboratory for testing of APOC3, blood lipids, and anti-drug antibody (if 
necessary).