Clinical trial NCT03360747
Conditions: Familial Chylomicronemia Syndrome Lipoprotein Lipase Deficiency Hyperlipoproteinemia Type 1
Keywords: Familial Lipoprotein Lipase Deficiency Hyperlipoproteinemias Familial Hyperlipoproteinemia Type 1 Hyperlipoproteinemia Type I Hyperchylomicronemia, Familial Lipoprotein Lipase Deficiency, Familial Hyperlipidemias Dyslipidemias Lipid Metabolism Disorders Lipid Metabolism, Inborn Errors Metabolic Diseases Metabolism, Inborn Errors Genetic Diseases, Inborn
Sponsor: Akcea Therapeutics
Start date: 2017-12-21; Completion date: 2018-09-04
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single center, open-label study to evaluate the efficacy of AKCEA-ANGPTL3-LRx for reduction of triglyceride (TG) levels in participants with FCS.

Detailed description:

Arms: arm 1: Participants received a subcutaneous (SC) injection of AKCEA-ANGPTL3-LRx, 20 milligrams (mg), weekly (QW) for 13-weeks of treatment period. Participants were followed up to Week 26.
Interventions: intervention 1: AKCEA-ANGPTL3-LRx
Intervention descriptions: intervention 1: AKCEA-ANGPTL3-LRx at dose 20 mg, administered via SC injection QW.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase 2 Open-Label Study to Assess the Pharmacodynamics, 
Pharmacokinetics, Safety and Tolerability of AKCEA-ANGPTL3-LRX 
(ISIS 703802) Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS) 
NCT Number: 
NCT03360747 
Document Date(s): 
Protocol Version 1: 20-July-2017 
Protocol Amendment Version 1: 26-October-2017 
 
 
 




ISIS 703802 CS3 
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Protocol 
 
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Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
IONIS PHARMACEUTICALS, INC. 
 
 
ISIS 703802-CS3 
 
A Phase 2 Open-Label Study to Assess the Pharmacodynamics, 
Pharmacokinetics, Safety and Tolerability of AKCEA-ANGPTL3-
LRX (ISIS 703802) Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS) 
 
Original Protocol – 20 JULY 2017 
 






ISIS 703802 CS3 
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Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. and Akcea 
Therapeutics that must not be disclosed to anyone other than the recipient study staff and 
members of the independent ethics committee, institutional review board, or authorized 
regulatory agencies.  This information cannot be used for any purpose other than the evaluation 
or conduct of the clinical investigation without the prior written consent of Ionis 
Pharmaceuticals, Inc. and Akcea Therapeutics.




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TABLE OF CONTENTS 
 
Page 
ISIS 703802-CS3............................................................................................................................ 1 
A PHASE 2 OPEN-LABEL STUDY TO ASSESS THE PHARMACODYNAMICS, 
PHARMACOKINETICS, SAFETY AND TOLERABILITY OF AKCEA-
ANGPTL3-LRX (ISIS 703802) ADMINISTERED SUBCUTANEOUSLY TO 
PATIENTS WITH FAMILIAL CHYLOMICRONEMIA SYNDROME (FCS) ....... 1 
PROTOCOL SYNOPSIS ........................................................................................................... 10 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 15 
STUDY GLOSSARY .................................................................................................................. 16 
1. 
OBJECTIVES ................................................................................................................. 20 
1.1 
Primary Objective(s) ......................................................................................................20 
1.2 
Secondary Objective(s) ..................................................................................................20 
2. 
BACKGROUND AND RATIONALE .......................................................................... 20 
2.1 
Overview of Disease ......................................................................................................20 
2.2 
Therapeutic Rationale ....................................................................................................21 
2.3 
AKCEA-ANGPTL3-LRX (ISIS 703802) .......................................................................21 
2.3.1 
Mechanism of Action .............................................................................................21 
2.3.2 
Chemistry ...............................................................................................................22 
2.3.3 
Preclinical Experience ............................................................................................23 
2.3.3.1 
Preclinical Pharmacology ................................................................................23 
2.3.3.2 
Preclinical Toxicology .....................................................................................24 
2.3.4 
Clinical Experience ................................................................................................25 
2.3.4.1 
ISIS 563580-CS1 Phase 1 SAD/MAD ............................................................26 
2.4 
Rationale for Dose and Schedule of Administration .....................................................26 
2.5 
Benefit-Risk Assessment ...............................................................................................27 
2.5.1 
Benefit Assessment ................................................................................................27 
2.5.2 
Risk Assessment .....................................................................................................27 
2.5.3 
Overall Assessment of Benefit:Risk .......................................................................28 
3. 
EXPERIMENTAL PLAN .............................................................................................. 28 
3.1 
Study Design ..................................................................................................................28 
3.2 
Number of Study Centers ..............................................................................................28 
3.3 
Number of Subjects .......................................................................................................28 
3.4 
Overall Study Duration and Follow-up .........................................................................29 
3.4.1 
Screening ................................................................................................................29 
3.4.2 
Treatment ................................................................................................................29 
3.4.3 
Post-Treatment .......................................................................................................29 
3.5 
End-of-Study ..................................................................................................................29 
4. 
SUBJECT ENROLLMENT ........................................................................................... 29 


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4.1 
Screening .......................................................................................................................29 
4.2 
Registration ....................................................................................................................30 
4.3 
Replacement of Subjects ................................................................................................30 
5. 
SUBJECT ELIGIBILITY .............................................................................................. 30 
5.1 
Inclusion Criteria ...........................................................................................................30 
5.2 
Exclusion Criteria ..........................................................................................................31 
6. 
STUDY PROCEDURES ................................................................................................ 33 
6.1 
Study Schedule ..............................................................................................................33 
6.1.1 
Screening ................................................................................................................33 
6.1.2 
Treatment Period ....................................................................................................33 
6.1.4 
Post-Treatment Period ............................................................................................34 
6.2 
Study/Laboratory Assessments ......................................................................................34 
6.3 
Restriction on the Lifestyle of Subjects .........................................................................34 
6.3.1 
Contraception Requirements ..................................................................................34 
6.3.2 
Other Requirements ................................................................................................35 
7. 
STUDY DRUG ................................................................................................................ 35 
7.1 
Study Drug Description .................................................................................................35 
7.1.1 
AKCEA-ANGPTL3-LRX (ISIS 703802) ................................................................35 
7.2 
Packaging and Labeling .................................................................................................35 
7.3 
Study Drug Accountability ............................................................................................36 
8. 
TREATMENT OF SUBJECTS ..................................................................................... 36 
8.1 
Study Drug Administration ............................................................................................36 
8.2 
Other Protocol-Required Drugs .....................................................................................36 
8.3 
Other Protocol-Required Treatment Procedures ............................................................36 
8.4 
Treatment Precautions ...................................................................................................36 
8.5 
Safety Monitoring Rules ................................................................................................36 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ..............................................37 
8.5.2 
Safety Monitoring for Renal Function ...................................................................38 
8.5.3 
Safety Monitoring Rules for Platelet Count Results ..............................................39 
8.5.4 
Safety Monitoring for Minor Bleeding Events .......................................................41 
8.6 
Stopping Rules ...............................................................................................................41 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................41 
8.6.2 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules for 
Renal Function Test Results ...................................................................................42 
8.6.3 
Stopping Rule for Platelet Count Results ...............................................................42 
8.7 
Adjustment of Dose and/or Treatment Schedule ...........................................................43 
8.8 
Discontinuation of Study Drug/Treatment ....................................................................44 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from 
Post-Treatment Follow-up Period ..........................................................................44 
8.9 
Withdrawal of Subjects from the Study .........................................................................44 


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8.10 
Concomitant Therapy and Procedures ...........................................................................45 
8.10.1 
Concomitant Therapy .............................................................................................45 
8.10.2 
Concomitant Procedures .........................................................................................46 
8.11 
Treatment Compliance ...................................................................................................47 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 47 
9.1 
Sponsor Review of Safety Information .........................................................................47 
9.2 
Regulatory Requirements ..............................................................................................47 
9.3 
Definitions .....................................................................................................................47 
9.3.1 
Adverse Event ........................................................................................................47 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................47 
9.3.3 
Serious Adverse Event (SAE) ................................................................................48 
9.3.3.1 
Adverse Events of Special Interest ..................................................................48 
9.4 
Monitoring and Recording Adverse Events ...................................................................48 
9.4.1 
Serious Adverse Events ..........................................................................................48 
9.4.2 
Non-Serious Adverse Events ..................................................................................49 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................49 
9.4.3.1 
Relationship to the Study Drug ........................................................................49 
9.4.3.2 
Severity ............................................................................................................50 
9.4.3.3 
Action Taken with Study Drug ........................................................................50 
9.4.3.4 
Treatment Given for Adverse Event ................................................................50 
9.4.3.5 
Outcome of the Adverse Event ........................................................................50 
9.5 
Procedures for Handling Special Situations ..................................................................51 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................51 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............52 
9.5.3 
Dosing Errors .........................................................................................................52 
9.5.4 
Contraception and Pregnancy .................................................................................52 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 53 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................53 
10.1.1 
Efficacy Endpoints .................................................................................................53 
10.1.2 
Safety Endpoints .....................................................................................................53 
10.2 
Sample Size Considerations ...........................................................................................54 
10.3 
Populations .....................................................................................................................54 
10.4 
Definition of Baseline ....................................................................................................54 
10.5 
Interim Analysis and Early Stopping Guidelines ..........................................................54 
10.6 
Planned Methods of Analysis ........................................................................................54 
10.6.1 
Demographic and Baseline Characteristics ............................................................54 
10.6.2 
Safety Analysis .......................................................................................................54 
10.6.2.1 
Adverse Events ................................................................................................55 
10.6.2.2 
Clinical Laboratory Data..................................................................................55 
10.6.2.3 
Vital Signs and Examinations ..........................................................................55 


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10.6.3  
Efficacy Analysis ...................................................................................................55 
10.6.4 
Pharmacokinetic Analysis ......................................................................................55 
10.6.5 
Pharmacodynamic Analysis ...................................................................................55 
10.6.6 
Immunogenicity Analysis ................................................................................56 
10.6.7 
Additional Analyses ...............................................................................................56 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 56 
11.1 
Informed Consent ..........................................................................................................56 
11.2 
Ethical Conduct of the Study .........................................................................................57 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................57 
11.4 
Subject Confidentiality ..................................................................................................57 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 58 
12.1 
Protocol Amendments ....................................................................................................58 
12.2 
Study Termination .........................................................................................................58 
12.3 
Study Documentation and Storage ................................................................................58 
12.4 
Study Monitoring ...........................................................................................................59 
12.5 
Language ........................................................................................................................59 
12.6 
Compensation for Injury ................................................................................................60 
13. 
REFERENCES ................................................................................................................ 61 
14. 
APPENDICES ................................................................................................................. 65 
Appendix A 
Schedule of Procedures ....................................................................................66 
Appendix B 
List of Laboratory Analytes .............................................................................70 
Appendix C 
PK Sampling Schedule ....................................................................................73 
Appendix D  
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......75 
Appendix E 
Post-prandial Meal, Sampling Schedule, and Assessment ..............................79 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ....................................................................................35 
Table 2 
Study Drug Dosing Information ............................................................................36 
Table 3 
Actions in Patients with Low Platelet Count .........................................................40 
 
TABLE OF FIGURES 
Page 
Figure 1 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  (MOE-
Gapmer).  The sequence of AKCEA-ANGPTL3-LRX is shown. ...........................23 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2 Open-Label Study to Assess the Pharmacodynamics, 
Pharmacokinetics, Safety and Tolerability of AKCEA-ANGPTL3-LRX (ISIS 
703802) Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS) 
Study Phase 
2 
Indication 
Familial Chylomicronemia Syndrome 
Objectives 
 
The primary objective is to evaluate the efficacy of AKCEA-ANGPTL3-LRX for 
reduction of triglyceride (TG) levels in patients with FCS  
Secondary objectives are: 
To evaluate the effect of AKCEA-ANGPTL3-LRX on plasma angiopoietin-like 3 
(ANGPTL3) and other lipid parameters. 
To evaluate the effect AKCEA-ANGPTL3-LRX  on postprandial TG 
To evaluate the pharmacokinetics of AKCEA-ANGPTL3-LRX 
To evaluate safety and tolerability of AKCEA-ANGPTL3-LRX  
Study Design 
This is an, open-label study in 3 FCS patients. After confirming eligibility for 
the study during the screening period, patients will enter a 13-week treatment 
period.  Study drug (AKCEA-ANGPTL3-LRX) will be administered every week 
for 13 weeks during the treatment period.  The patients will then enter a 13 
week post-treatment evaluation follow-up period. 
Number of Subjects 
3 
Study Population 
Inclusion: 
1. 
Must have given written informed consent (signed and dated) and any 
authorizations required by local law and be able to comply with all 
study requirements. 
2. 
Males or females aged > 18 years old at the time of informed consent 
3. 
Genetically confirmed homozygote or compound heterozygote for 
known null loss-of-function mutations in the LPL gene. 
4. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening. If the fasting TG 
< 750 mg/dL up to 2 additional tests may be performed in order to 
qualify. 
5. 
Willing to follow a diet comprising ≤ 20g fat per day during the study 
6.  Females:  must be non-pregnant and non-lactating and either;  
i. 
Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy); 
ii. 
Post-menopausal (defined as 12 months of spontaneous 
amenorrhea in females > 55 years of age or, in females ≤ 55 
years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved); 
iii. Abstinent* or, 
iv. If engaged in sexual relations of child-bearing potential, agree to 
use 2 highly effective contraceptive methods (refer to Section 
6.3.1) from the time of signing the informed consent form until at 
least 13 weeks after the last dose of Study Drug (AKCEA-
ANGPTL3-LRX) 


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7. 
Males:  Surgically sterile or if engaged in sexual relations with a 
female of child-bearing potential, subject is utilizing an acceptable 
contraceptive method (refer to Section 6.3.1) from the time of 
signing the informed consent form until at least at least 13 weeks 
after the last dose of Study Drug (AKCEA-ANGPTL3-LRX) 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line 
with the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a trial and withdrawal are not acceptable 
methods of contraception 
Exclusion: 
1. 
Diabetes mellitus with any of the following:  
a. 
Newly diagnosed within 12 weeks of screening  
b. 
HbA1c ≥ 9.0% at Screening  
c. 
Recent change in anti-diabetic pharmacotherapy (change in 
dosage or addition of new medication within 12 weeks of 
screening [with the exception of ± 10 units of insulin])  
d. 
Current use of GLP-1 agonists 
2.  Active pancreatitis within 2 weeks prior to screening 
3. 
History within 6 months of screening of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina, stroke, transient ischemic attack or unstable congestive 
cardiac failure requiring a change in medication) or major surgery 
within 3 months of screening 
4. 
Any of the following laboratory values at Screening  
a. 
Hepatic:  
• 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL  
• 
ALT > 2.0 x ULN  
• 
AST > 2.0 x ULN  
b. 
Renal:  
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) for 
protein on urine dipstick. In the event of a positive test 
eligibility may be confirmed by a quantitative total urine 
protein measurement of < 500 mg/24 hrs  
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick. In the event of a positive 
test eligibility may be confirmed with urine microscopy 
showing ≤ 5 red blood cells per high power field  
• 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 60 mL/min (MDRD or CKD-
EPI formulas can be used instead of Cockcroft-Gault for 
estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor)  
c. 
Platelet count < 140,000 mm3    
d. 
Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable 
for inclusion 


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5. 
Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg) 
6. 
History of bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening 
7. 
History of heart failure with NYHA greater than Class II 
8. 
Active infection requiring systemic antiviral or antimicrobial therapy 
that will not be completed prior to Study Day 1 
9. 
Known history of or positive test for human immunodeficiency virus 
(HIV), hepatitis C or chronic hepatitis B 
10. Malignancy within 5 years, except for basal or squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix that has been 
successfully treated 
11. Treatment with another investigational drug, biological agent, or 
device within 1-month of screening, or 5 half-lives of investigational 
agent, whichever is longer 
12. Unwilling to comply with lifestyle requirements 
13. Use of any of the following:  
a. 
Statins, omega-3 fatty acids (prescription or OTC), or fibrates 
unless on a stable dose for at least 3 months prior to screening 
and dose and regimen expected to remain constant during the 
treatment period. Patients taking OTC omega-3 fatty acids should 
make every effort to remain on the same brand throughout the 
study.  
b. 
Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior 
to screening  
c. 
Systemic corticosteroids or anabolic steroids within 6 weeks prior 
to screening unless approved by the Sponsor Medical Monitor  
d. 
Atypical antipsychotic medications (e.g., olanzapine and 
clozapine) unless on a stable dose for at least 3 months prior to 
screening and dose and regimen expected to remain stable 
throughout the study  
e. 
Antihypertensive medication unless on a stable dose for at least 4 
weeks prior to screening and dose and regimen expected to 
remain constant during the treatment period  
f. 
Glybera gene therapy within 2 years prior to screening  
g. 
Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban,  
apixaban) unless on a stable dose for at least 4 weeks prior to 
screening and regular clinical monitoring is performed  
h. 
Tamoxifen, estrogens or progestins unless on a stable dose for at 
least 4 months prior to screening and dose and regimen expected 
to remain constant during the treatment period i. Plasma 
apheresis within 4 weeks prior to screening or planned during the 
study  
i. 
Prior exposure to AKCEA-ANGPTL3-LRX  
j. 
Any other medication unless stable at least 4 weeks prior to 
screening (Occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion)  
14. Blood donation of 50 to 499 mL within 30 days of screening or of > 
499 mL within 60 days of screening  
15.  Known hypersensitivity to any of the excipients of the Study Drug  


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16. Have any other conditions, which, in the opinion of the Investigator or 
the Sponsor would make the patient unsuitable for inclusion, or could 
interfere with the patient participating in or completing the study  
Treatment Groups 
Single group, open-label treatment with AKCEA-ANGPTL3-LRX by 
subcutaneous injection at 20 mg weekly 
Study Drug Dosage and 
Administration 
The Sponsor will provide AKCEA-ANGPTL3-LRX in a single use vial with a 
concentration of 100 mg/mL.  
The study dose of 20 mg (0.2 mL) of AKCEA-ANGPTL3-LRX will be 
administered every week during the treatment period. All doses will be given 
by SC injection.  Self-administration will be allowed after appropriate training 
of patient and/or caregiver. 
Rationale for Dose and Schedule 
Selection 
A 20 mg weekly dose was selected as being the lowest dose that provided 
maximum TG lowering of approximately 60%, based on the TG lowering 
effect of AKCEA-ANGPTL3-LRX observed in healthy volunteers with elevated 
TGs.  
Study Visit Schedule and 
Procedures 
Detailed information regarding the study procedures are outlined in Section 6, 
Appendices A and C. 
The study for an individual subject will consist of the following periods:  
An up to 8-week screening period, including a diet stabilization period of at 
least 6 weeks 
A 13 week treatment period during which Study Drug will be administered 
open label by SC injection 
A 13-week post-treatment follow-up period 
Patients will receive up to 13 SC doses of AKCEA-ANGPTL3-LRXweekly.  
Patients will return regularly for outpatient visits throughout the treatment and 
post-treatment follow-up periods according to the Schedule of Procedures 
(Appendix A).  
Blood and urine samples will be collected regularly throughout the study for 
safety, efficacy, and PK analysis.  Appendix B shows a list of analytes 
required for the study and Appendix C details the PK sample schedules. 
Pharmacodynamic Evaluations 
Fasting TGs, plasma angiopoietin-like 3 (ANGPTL3), ANGPTL4, ANGPTL8, 
total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high 
density lipoprotein cholesterol (HDL-C), non-high density lipoprotein 
cholesterol (non-HDL-C), very low density lipoprotein cholesterol (VLDL-C). 
total apoC-III, apolipoprotein B-100 (apoB-100), apolipoprotein B-48 (apoB-
48), apolipoprotein A-1 (apoA-1), apolipoprotein A-2 (apoA-2), apolipoprotein 
E (apoE), very-low-density lipoprotein-triglyceride (VLDL-TG), chylomicron-
cholesterol (CM-C), chylomicron triglyceride (CM-TG), free fatty acids (FFA), 
and free glycerol levels 
Pharmacokinetic Evaluations 
The plasma PK of AKCEA-ANGPTL3-LRX (as total full length 
oligonucleotides, including, fully conjugated, partially conjugated, and 
unconjugated AKCEA-ANGPTL3-LRX) will be assessed following multiple-
dose SC administration.  The plasma trough levels of AKCEA-ANGPTL3-LRX 
during treatment period and those during post-treatment follow up period will 
be descriptively summarized with stratification by subject immunogenicity 
status if applicable. 
Safety and Tolerability 
Evaluations 
Safety and tolerability assessments include: adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, ECGs and use of 
concomitant medications.   


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Statistical Considerations 
There is no statistical rationale for the selected sample size.  The sample size 
is based on prior experience with second generation and N-acetyl 
galactosamine (GalNAc)-modified antisense oligonucleotides (ASOs) in 
healthy volunteers and to ensure that the safety, tolerability, 
pharmacokinetics, and preliminary pharmacodynamics of AKCEA-ANGPTL3-
LRX will be adequately assessed while minimizing unnecessary subject 
exposure. 
Sponsor / Collaborator 
Ionis Pharmaceuticals/Akcea Therapeutics 
 
 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
 
TREATMENT PERIOD 
Weeks 1 to 13 
 
All Subjects will be receive 20 mg of 
AKCEA-ANGPTL3-LRX administered 
weekly by SC injection 
 
Routine safety assessments:  PK and 
PD assessments at specified time 
points per the Schedule of Procedures 
in Appendix A. 
 
POST-TREATMENT 
EVALUATIONS    
  Weeks 13 to 26 
4 clinical visits for safety,  
PK and PD assessments 
 
END-OF-STUDY 
PROCEDURES 
Early termination or Day 
Week 26 / Day 182 
 
EARLY 
TREATMENT 
TERMINATION 
Follow Week 14 
Schedule of 
Procedures at ET;  
 
Patient strongly 
encouraged to visit 
clinic for post-
treatment 
assessments 
 
SCREENING / DIET RUN-IN 
 
Weeks –-8 to -1 (period may be reduced if the 
patient is following a stable low fat diet for a 
minimum of 6 weeks) 
 


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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
apoA-I 
Apolipoprotein A-I 
apoB 
Apolipoprotein B 
apoC-III 
Apolipoprotein C-III 
aPTT 
Activated partial thromboplastin time 
ASO 
Antisense oligonucleotide 
AST 
Aspartate aminotransferase 
AUCt 
Area under the plasma concentration-time curve from zero time 
(pre-dose) to selected time (t) after Study Drug administration 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CHD 
Coronary heart disease 
CK 
Creatine kinase 
Cmax 
Maximum observed drug concentration 
Day 1 
Defined as the first day Study Drug product is administered to 
the subject 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FCS 
Familial Chylomicronemia Syndrome 


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Abbreviation/Acronym 
Definition 
FH 
Familial hypercholesterolemia 
FHBL 
Familial hypobetalipoproteinemia  
FHBL2 
Familial combined hypolipidemia 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Glycated hemoglobin 
HDL-C 
High density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia 
HIV 
Human immunodeficiency virus 
HoFH 
Homozygous familial hypercholesterolemia 
HR 
Heart rate 
ICH 
International Conference on Harmonization 
INR 
International normalized ratio 
IRB 
Institutional review board 
LDL-C 
Low density lipoprotein cholesterol 
LDLR 
LDL receptor 
LLN 
Lower limit of normal 
Lp(a) 
Lipoprotein (a) 
LPL 
Lipoprotein lipase 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
Magnetic resonance imaging 


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Abbreviation/Acronym 
Definition 
mRNA 
messenger ribonucleic acid (RNA) 
MTP 
Microsomal triglyceride transfer protein 
NCS 
Not clinically-significant 
NEFA 
Non-esterified fatty acids 
Non-HDL-C 
Non-high density lipoprotein cholesterol 
OTC 
Over-the-counter 
P/C 
Urine protein/creatinine 
PCSK9 
Proprotein convertase subtilisin kexin type 9 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SC 
Subcutaneous 
siRNA 
Small interfering RNA 
Study Drug 
AKCEA-ANGPTL3-LRX (ISIS 703802) 
SUSAR 
Suspected unexpected serious adverse reactions 
t 
Times 
t1/2λz 
Plasma terminal elimination half-life  
TC 
Total cholesterol 


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Abbreviation/Acronym 
Definition 
TG 
Triglyceride 
Tmax 
Time to reach Cmax 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VLDL-C 
Very low density lipoprotein cholesterol 
 
 
 
 
 


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1. 
OBJECTIVES 
1.1 
Primary Objective(s) 
• The primary objective is to evaluate the efficacy of AKCEA-ANGPTL3-LRX (also known 
as ISIS 703802 in this document) for reduction of triglyceride (TG) levels in patients with 
FCS  
1.2 
Secondary Objective(s) 
• To evaluate the effect of AKCEA-ANGPTL3-LRX on plasma angiopoietin-like 3 
(ANGPTL3) and other lipid parameters. 
• To evaluate the effect of AKCEA-ANGPTL3-LRX on postprandial TG  
• To evaluate the pharmacokinetics of AKCEA-ANGPTL3-LRX  
• To evaluate safety and tolerance of AKCEA-ANGPTL3-LRX  
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia. It is a rare autosomal recessive disease that can be 
diagnosed either in childhood or adulthood.  
FCS is characterized by frequent and severe abdominal pain, repetitive colicky pain, repeated 
episodes of potentially fatal acute pancreatitis, and in children, can result in a failure to thrive 
(Brunzell 1999-2011; Tremblay et al. 2011).  Physical examination frequently reveals eruptive 
xanthomas, lipemia retinalis and hepatosplenomegaly, and plasma from patients appears 
lactescent, interfering with determination of other laboratory parameters (Tremblay et al. 2011).  
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  
Patients with FCS often present in infancy or childhood with recurrent episodes of abdominal 
pain or pancreatitis, eruptive xanthomas or hepatomegaly.  The diagnosis of FCS is then 
established by genotyping or confirmation of very low or absent lipoprotein lipase (LPL) enzyme 
activity in post heparin plasma (Brunzell 1999-2011).  
Patients with FCS carry a heavy burden of medical complications, the most serious being an 
extreme risk of recurrent and potentially fatal pancreatitis.  Due to the recurrent episodes of acute 
pancreatitis, these patients may also develop chronic pancreatitis and signs of exocrine or 
endocrine pancreatic insufficiency, including diabetes mellitus (Gaudet et al. 2013).  While the 
pathophysiology underlying chylomicron-related pancreatitis has not been completely 
elucidated, one hypothesis is that large chylomicrons lodged in pancreatic capillaries are exposed 
to pancreatic lipase, with the subsequent release of free fatty acids through the hydrolysis of 
chylomicron-associated TGs.  High concentrations of free fatty acids are thought to damage 
pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; Berglund et al. 2012).  


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The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 
triglycerides in chylomicrons along the luminal surface of capillaries, mainly in heart, skeletal 
muscle, and adipose tissue, promoting triglyceride clearance from the circulation.  LPL is 
regulated by a number of key genes, and loss-of-function mutations in one of these genes, or the 
LPL gene itself, results in FCS (Surendran et al. 2012).  In addition to loss of function mutations, 
null mutations, and nonsense mutations in the LPL gene, other genes currently identified in FCS 
patients, and known to directly influence LPL activity include: apolipoprotein C-II (APOC2) a 
cofactor for LPL (Schuster et al. 2011); apolipoprotein A-V (APOA5) (Schaap et al. 2004); 
lipase maturation Factor 1 (LMF1), a transmembrane protein involved in LPL maturation 
(Doolittle et al. 2009); glycosylphosphatidylinositol-anchored HDL-binding protein 1 
(GPIHBP1), a capillary endothelial cell protein that provides a platform for LPL-mediated 
processing of chylomicrons (Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
The preclinical and human genetic studies strongly support a potential role for an ASO approach 
to lower plasma ANGPTL3 in humans to decrease elevated TG and LDL-C levels in patients that 
cannot be adequately managed by existing therapies.  
Numerous genome-wide association studies have been published in recent years confirming the 
association of mutations in human ANGPTL3 with reductions in serum lipids in human subjects 
(Minicocci et al. 2013).  The mechanism(s) by which ANGPTL3 affects lipoprotein metabolism 
appears to be complex, as loss of ANGPTL3 leads to a decrease in multiple atherogenic 
lipoprotein levels that is hard to ascribe to any 1 single mode of action.  ANGPTL3 deficiency in 
animals accelerates the clearance of VLDL particles from plasma because of increase in 
lipoprotein lipase (LPL) activity, whereas overexpression or intravenous injection of 
recombinant ANGPTL3 has opposite effects.  These and other observations support a possible 
role of the LPL enzyme.  However, a direct demonstration of this mechanism has not been 
provided.  Understanding the mechanism of action of ANGPTL3 is a present area of active 
research (Gusarova et al. 2015; Haridas et al 2015; Wang X et al. 2015; Wang Y et al. 2015a; 
Wang Y et al. 2015b). 
The goal of the present protocol is to explore the effects of lowering ANGPTL3 in FCS patients 
using AKCEA-ANGPTL3-LRX (also known ISIS 703802, using a dose selected on the basis of 
results in healthy volunteers, to evaluate the safety, tolerability, pharmacokinetics, and 
pharmacodynamic effects of AKCEA-ANGPTL3-LRX in these patients. 
The known potential risks to study participants associated with AKCEA-ANGPTL3-LRX are 
further discussed in the Guidance to Investigator section of the Investigator’s Brochure. 
 
2.3 
AKCEA-ANGPTL3-LRX (ISIS 703802) 
2.3.1 
Mechanism of Action 
AKCEA-ANGPTL3-LRX is a second-generation ASO drug targeted to ANGPTL3 that has been 
covalently bonded to triantennary N-acetyl galactosamine (GalNAc), a high-affinity ligand for 


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the hepatocyte-specific asialoglycoprotein receptor (ASGPR) to form an ASO-GalNAc 
conjugate.  This GalNAc-conjugate approach results in enhanced ASO delivery to hepatocytes 
versus non-parenchymal cells and has increased ASO potency by approximately 10-fold in mice 
(Prakash et al. 2014).  The ASO portion of AKCEA-ANGPTL3-LRX is complementary to a 
region within the ANGPTL3 messenger ribonucleic acid (RNA) (mRNA) coding sequence, and 
binds to the mRNA via Watson and Crick base pairing.  The hybridization (binding) of AKCEA-
ANGPTL3-LRX to the cognate mRNA results in the Ribonuclease H1 (RNase H1)-mediated 
degradation of the ANGPTL3 mRNA, thus preventing production of the ANGPTL3 protein.  
Maximal antisense-mediated reduction of target mRNA levels is typically greater than 90% of 
control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  Furthermore, 
reduction in target mRNA levels using this approach correlates directly with a subsequent 
reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, AKCEA-ANGPTL3-LRX is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) 
that are connected sequentially by phosphorothioate and phosphodiester linkages (mixed 
backbone design).  The mixed backbone design reduces the total number of phosphorothioate 
linkages in the MOE-modified regions, which reduces non-specific interactions with proteins and 
further enhances potency of GalNAc conjugated ASOs.  The nucleotide sequence of AKCEA-
ANGPTL3-LRX (Figure 1) is complementary to a 20-nucleotide stretch within Exon 6 of the 
ANGPTL3 mRNA coding sequence at position 1169-1188 bp. 
Structurally, the oligonucleotide has 4 regions.  Two (2) of them, the 5 nucleotides at the 5′ end 
and the 5 nucleotides at the 3′ end, are composed of 2′-O-(2-methoxyethyl) (2′-MOE)-modified 
ribonucleotides.  These MOE-modified nucleotides confer (1) increased affinity for the target 
mRNA (Altmann et al. 1996; McKay et al. 1999), (2) increased resistance to exonucleases and 
endonucleases (thereby increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of 
some of the high dose toxicities thereby resulting in an improved safety profile compared to first 
generation antisense drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) 
(Henry et al. 2000).  The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and AKCEA-
ANGPTL3-LRX employs this chimeric structure to enable use of the RNase H1 mechanism for 
antisense activity.  This is because while the 2′-MOE modification confers increased stability and 
affinity, it does not support RNase H1 catalyzed cleavage of RNA hybridized to 2′-MOE-
modified nucleotides (McKay et al. 1999).  This is caused by conformational changes induced in 
the heteroduplex by 2′-alkoxy:RNA hybrids that are not recognized by RNase H enzymes (Inoue 
et al. 1987; Monia et al. 1993).  By limiting the 2′-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2′-MOE chemistry 
are preserved while also retaining RNase H1 recognition.  The fourth region is comprised of a 
triantennary cluster of N-acetyl galactosamine (GalNAc) sugars which is linked to the 5ʹ end of 
AKCEA-ANGPTL3-LRX via a phosphodiester linkage.  The GalNAc cluster is a high affinity 
ligand for the asialoglycoprotein receptor (ASGPR), a receptor expressed primarily on the 
surface of liver hepatocytes (Stockert 1995).  The GalNAc cluster enhances delivery of AKCEA-
ANGPTL3-LRX to liver hepatocytes over other cell types and enhances potency.  After 
internalization into cells, the GalNAc cluster is metabolized to release ‘free ASO’ inside the cell 
(Prakash et al. 2014). 




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modified ASO targeting ANGPTL3, led to dose-dependent reductions in both hepatic ANGPTL3 
mRNA and plasma ANGPTL3 with concomitant reductions in plasma TG and cholesterol.  
Importantly, the potency and the lipid-lowering effects of the ANGPTL3 ASO were independent 
of diet. 
Finally, administration of a mouse-specific ANGPTL3 ASO to western diet fed Ldlr-/-, a mouse 
model of FH, also led to significant reductions in hepatic ANGPTL3 mRNA and plasma 
ANGPTL3 protein with concomitant reductions in plasma TG and LDL-C that were similar to 
what was observed in wild type western diet fed mice, indicating that the absence of Ldlr does 
not affect the ASOs potency or lipid-lowering effects.  This suggests that administration of 
ANGPTL3 ASO administration is a promising target for clinical study in familial 
hypercholesterolemia patients. 
While formal pharmacology studies have not been conducted in the monkey with the human 
ANGPTL3 ASO, hepatic mRNA expression has been shown to be reduced by more than 60% in 
cynomolgus monkeys, the same model used to conduct the toxicology evaluation. 
2.3.3.2 
Preclinical Toxicology 
General toxicology studies for AKCEA-ANGPTL3-LRX consisted of sub-chronic (16-week) and 
chronic (26- or 39-week) toxicity studies CD-1 in mice and cynomolgus monkeys.  Since 
AKCEA-ANGPTL3-LRX is not fully complementary to the mouse ANGPTL3 transcript, 
treatment group receiving a mouse-specific inhibitor (ISIS 731875) was also included in the 
mouse study.  Please refer to the Investigator Brochure for a detailed description of the 
preclinical toxicology and pharmacokinetics with AKCEA-ANGPTL3-LRX. 
Pharmacokinetic data confirmed continuous and dose-dependent exposure to AKCEA-
ANGPTL3-LRX.  An estimated liver and plasma elimination half-life values of approximately 1 
week and 3-4 weeks for 2 mg/kg and 35 mg/kg, respectively, were observed in monkeys.  The 
most noteworthy findings observed in mice and monkeys following AKCEA-ANGPTL3-LRX 
treatment were, in general, non-specific class effects related to the uptake and accumulation of 
ASO and no toxicologically relevant findings were considered related to the pharmacologic 
inhibition of hepatic ANGPTL3 expression, either with the present series of studies or with the 
former development candidate targeting ANGPTL3. There were no test-article related changes in 
PLT count in either mouse or monkey in both sub-chronic and chronic studies. 
The most noteworthy finding in the monkey was the kidney alteration (hypoalbuminemia and 
proteinuria) seen in one early-sacrifice animal from the 16-week study at 35 mg/kg/week, a dose 
equivalent to at least ~190-fold of the 40 mg weekly clinical doses by plasma AUC.  Non-dose 
dependent increases in renal protein excretion (up to 2.2-fold in quantitative urine protein, 
protein/creatinine ratio or urine albumin) were also observed at 8 and/or 35 mg/kg/week 
(> ~ 30 to 190-fold of the 40 mg weekly clinical doses by plasma AUC) at the 16-week 
scheduled terminal necropsy. However, Similar kidney alterations were not seen at the 6-week 
interim at any doses or in the 39-week chronic monkey study up to 12 mg/kg/week (> ~200-fold 
of the 20 mg weekly clinical dose by plasma AUC). 
Additional findings related to ASO liver accumulation included increased alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) at 


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≥ 8 mg/kg/week in the 16- and 26-week mouse studies, and were correlated with individual 
hepatocyte necrosis (minimal to mild) in mouse liver.  Those changes were most prominent in 
the high dose groups (50 and 24 mg/kg/week for the 16- and 26-week studies, respectively). 
Conversely, no changes in liver enzymes were observed in monkeys from the 39-week toxicity 
study up to 12 mg/kg/week. In the 16-week monkeys study, increase in ALT was only evident in 
one early-sacrifice animal at 35 mg/kg/week, and non-statistically significant increases in ALT 
(<2-fold of the prestudy baseline) were also observed in the interim- and terminal-sacrifice 
animals at ≥ 8 mg/kg/week but showed no microscopic correlates or dose-dependency. 
Given the spectrum and severity of the test article-related clinicopathologic alterations present in 
monkeys at doses ≤ 12mg/kg/week (> ~100-fold of the 40 mg weekly clinical dose by plasma 
AUC) during the 39-week treatment phase, none would be regarded to represent an adverse 
effect (Dorato and Engelhardt 2005; Everds et al. 2013).  Considering the monkey to be the most 
relevant species, these data have characterized the safety profile and established appropriate 
therapeutic margins for the clinical evaluation of AKCEA-ANGPTL3-LRX in humans. 
2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with AKCEA-ANGPTL3-LRX 
can be found in the Investigator’s Brochure.  A summary is included below. 
The study drug, AKCEA-ANGPTL3-LRX, is being evaluated in Phase 1 in the clinical setting 
with single doses up to 120 mg and multiple doses up to 60 mg (once per week for 6 weeks). The 
parent drug ISIS 563580, an unconjugated 2′-MOE modified ASO that has the same base 
sequence as AKCEA-ANGPTL3-LRX, was also evaluated in a blinded, placebo-controlled Phase 
1 study. 
AKCEA-ANGPTL3-LRX Phase 1 SAD/MAD interim analysis of Study ISIS 703802-CS1 was 
performed in 44 subjects administered single ascending (20, 40 and 80 mg) or multiple 
ascending doses (10, 20, 40 and 60 mg/week for 6 weeks). Twelve participants were randomly 
assigned to single-dose groups (9 to active-agent dose groups and 3 to the placebo group) and 32 
were randomly assigned to multiple-dose groups (24 to active-agent dose groups and 8 to the 
placebo group). The main endpoints of the study were safety, tolerability, pharmacokinetics, 
pharmacodynamics and changes in lipids and lipoproteins. After 6 weeks of treatment, persons in 
the multiple dose groups treated with AKCEA-ANGPTL3-LRX had dose-dependent reductions in 
levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. 
placebo 1.6%) and in levels of triglycerides (reductions of 33.2 to 63.1% vs placebo 11.4%), 
LDL cholesterol (1.3 to 32.9% vs placebo 13.6%), very-low-density lipoprotein cholesterol (27.9 
to 60.0% vs placebo 4.0%), non–high-density lipoprotein cholesterol (10.0 to 36.6% vs placebo 
9.1%), apolipoprotein B (3.4 to 25.7% vs placebo 11.0%), and apolipoprotein C-III (18.9 to 
58.8% vs placebo 3.1%).  There were no serious adverse events documented during the trial. No 
protocol-defined injection-site reactions were reported. Of those participants who received the 
multiple-dose regimen, three reported headache (one who received placebo and two who 
received ANGPTL3-LRx) and three reported dizziness (two who received placebo and one who 
received ANGPTL3-LRx). There was no clinical evidence of prothrombotic effects, bleeding 
episodes, significant decreases in platelet count or thrombocytopenia, or significant changes in 


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liver or renal function. One subject in the 20 mg MAD group was lost to follow-up after 5 doses. 
There were no other discontinuations during the treatment period (Graham et al. 2017).  
The pharmacokinetics of AKCEA-ANGPTL3-LRX evaluated in Study ISIS 703802-CS1 showed 
rapid absorption following SC administration, with median time to maximum plasma 
concentrations (Tmax) ranging from 1 to 6 hours.  Similar Tmax values were observed at all dose 
levels.  After reaching Cmax, plasma concentrations of AKCEA-ANGPTL3-LRX declined in a 
multi-phasic fashion with a rapid disposition phase, followed by a slower elimination phase with 
terminal elimination half-life of 3 to 5 weeks.  The peak (Cmax) and total exposure (AUC) after a 
single SC dose increased approximately dose proportionally from 20 to 40 mg, and greater than 
dose proportionally from 40 to 80 mg, suggesting more efficient tissue uptake at lower doses.  
After single and multiple SC doses in the range of 10 to 60 mg, the Cmax and AUC increased 
approximately dose proportionally.  No accumulation based on Cmax or AUC was observed after 
6 weekly doses. 
2.3.4.1 
ISIS 563580-CS1 Phase 1 SAD/MAD  
In a Phase 1 study, ISIS 563580-CS1, healthy volunteers received subcutaneous administration 
of ISIS 563580 from 50 to 400 mg as a single dose, or 100 to 400 mg as multiple doses (8 doses 
in 36 days).  Overall, the safety findings from this study suggest that ISIS 563580 was not 
associated with any safety concerns.  There were 383 adverse events (AE) reported in the 
ISIS 563580-treated subjects of which 363 (95%) were mild in severity.  For the multiple-dose 
subjects, the most common treatment-emergent adverse events were AEs at the injection site.  
There was 1 serious adverse event (SAE) in the study of periorbital cellulitis which was 
considered a medically important event by the Investigator and was also considered unlikely 
related to Study Drug by the Investigator.  Together, the above suggest that ISIS 563580 was 
well-tolerated at the doses and regimen given, which exceed the dose levels and cumulative 
exposures to be tested in the current study.  There were no clinically-relevant changes in 
laboratory assessments and the heparin dose of 80 U/kg was well-tolerated in support of the 
post-heparin procedures.  ISIS 563580 produced dose-dependent reductions in plasma 
ANGPTL3 (up to 93%; group means up to 84%), TG (up to 63%; group means up to 49%) and 
TC (up to 46%; group means up to 28%) at Day 36 (Brandt et al. 2015). 
2.4 
Rationale for Dose and Schedule of Administration 
Safety data from the available chronic mouse (26-week) and monkey (39-week) studies support 
once-weekly dosing for chronic administration.  The No Adverse Effect Level (NOAEL) for 
AKCEA-ANGPTL3-LRX in chronic monkey study was determined to be 12 mg/kg/wk.    
Preclinical pharmacology experiments in Tg-mice and in non-human primates demonstrated that 
AKCEA-ANGPTL3-LRX achieved an equivalent reduction in ANGPTL3 plasma concentration 
to that of the unconjugated form, at 1/10th of the unconjugated ASO (ISIS 563580) dose.  The 
dose level planned for this study for AKCEA-ANGPTL3-LRX is 20 mg, which is the lowest dose 
that provided maximum TG lowering of approximately 60% in Study ISIS 703802-CS1 and is 
approximately 200-fold lower than NOAEL dose in monkey at 12 mg/kg/wk in the 39-week 
chronic monkey study up to terminal necropsy.  


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An interim analysis of the phase 1 study completed for all but the 120 mg single dose cohort 
showed approximately 60% reduction of TG at 20 mg dose.  However, at 40 mg and 60 mg dose 
the TG reduction did not differ significantly from 20 mg dose.  Thus, the lower dose was 
selected for this study for optimal risk to benefit.  
2.5 
Benefit-Risk Assessment 
2.5.1 
Benefit Assessment 
The current study is designed to evaluate the safety and tolerance of AKCEA-ANGPTL3-LRX in 
FCS subjects.  The dose selected is expected to reduce ANGPTL3 and result in a reduction of the 
severe hypertriglyceridemia and chylomicronemia that afflicts FCS subjects.  Importantly, 
although we do not know if subjects participating in this study would necessarily benefit from 
the treatment, the increased understanding of AKCEA-ANGPTL3-LRX in this population is 
expected to result in improved treatment options that would ultimately benefit all FCS patients, 
including participants in the study.  Due to the short duration of this trial any benefit observed is 
not expected to persist beyond the end of the study.  
2.5.2 
Risk Assessment 
The known potential risks to study participants associated with AKCEA-ANGPTL3-LRX are 
elaborated on in the Guidance to Investigator section of the Investigator’s Brochure.  
• In preclinical mouse studies, there were increases in ALT and AST and were correlated 
with increased incidence and/or severity of necrosis of individual hepatocytes (minimal 
to mild in severity).  Those changes were most prominent in the high dose groups and 
showed no clear progression over time. No increases in liver enzymes were observed in 
monkeys from the 39-week toxicity study up to 12 mg/kg/week (~200-fold of the 20 mg 
clinical dose by plasma AUC).  In the 16-week monkey study, increase in ALT was only 
evident in 1 early-sacrifice animal at 35 mg/kg/week, no meaningful increase in ALT was 
observed in the schedule sacrificed animals. 
• There were no observed significant changes in ALT and liver function in an ongoing 
Phase 1 human study (Graham et al. 2017).  The risk of observing significant ALT/AST 
changes in this clinical human study is expected to be relatively low with the proposed 20 
mg dose.  However, to evaluate and mitigate the potential for liver enzyme abnormalities, 
regular liver chemistry monitoring and stopping rules are included in the study as 
specified in Sections 8.5 and 8.6.  
• Injection site adverse events, while not considered safety issues, may affect the ability of 
the patient to tolerate dosing.  Injection site adverse events are the most common side 
effects observed following SC administration of 2′-MOE ASOs and are dose and 
concentration dependent.  Erythema is the most prevalent characteristic.  Generally, these 
events are mild and reversible, resolve spontaneously and do not worsen with time.  The 
histologic findings are consistent with a local inflammatory response.  While planned 
doses of AKCEA-ANGPTL3-LRX for clinical evaluation are generally below the doses 
that are historically associated with these effects, patients should be informed of the 
possibility of occurrence of injection site adverse events.  Symptomatic interventions 


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such as icing of the injection site or administration of NSAIDs prior to and/or after the 
SC dosing have been utilized. 
While the long term consequences of reducing ANGPTL3 as a target with the study drug are not 
known at this time, there is evidence in literature in humans in whom ANGPTL3 is absent from 
plasma, due to homozygous or compound heterozygous ANGPTL3 mutations, present a pan-
hypobetalipoproteinemia phenotype, with generalized and marked decreases (~50% to 70%) in 
all apoB-100 containing lipoproteins, including VLDL and LDL, as well as HDL.  This clinical 
phenotype has been termed familial combined hypolipidemia or FHBL2 (Romeo et al. 2009; 
Musunuru et al. 2010; Martin-Campos et al. 2012; Minicocci et al. 2012; Noto et al. 2012; 
Pisciotta et al. 2012; Wang et al. 2015).  Clinical studies in FHBL2 suggest a trend toward lower 
glucose and insulin levels and despite a reported decrease in VLDL production, there is no 
apparent difference in hepatic fat content compared to controls.  Remarkably, diabetes and 
cardiovascular disease are reportedly absent from those with homozygous FHBL2 and no 
adverse clinical phenotype has been reported to date. 
2.5.3 
Overall Assessment of Benefit:Risk 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above 
normal (1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 
15-20% of daily calorie intake) (Brunzell 1999-2011).  Given the unmet medical need for FCS 
patients, AKCEA-ANGPTL3-LRX has demonstrated the ability to reduce TGs by 60% in the 
Phase 1/2 study in healthy volunteers.  The objective of this study is to assess the effect of TG 
lowering in FCS patients.  Although the FCS patients enrolled in this study will not derive long 
term benefits due to the short duration of the study, the information obtained in the course of this 
study is critical to further development of AKCEA-ANGPTL3-LRX for this disease with an 
extremely high unmet need.  Taking into account the measures taken to minimize risk to subjects 
participating in this study, the fact that potential risks identified in association with AKCEA-
ANGPTL3-LRX are minimal and are manageable by routine monitoring exposure of FCS patients 
in this study is justified by the anticipated benefits that may be afforded to the wider population 
of FCS subjects by continued development of AKCEA-ANGPTL3-LRX.  
 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This will be a Phase 2 open-label multiple-dose study of approximately 3 subjects with FCS and 
will be treated with AKCEA-ANGPTL3-LRX. 
Subject will receive 20 mg of AKCEA-ANGPTL3-LRX SC weekly. 
3.2 
Number of Study Centers 
This study will be conducted at a single center but could be expanded to more than one center. 
3.3 
Number of Subjects 
Approximately 3 subjects will be treated in this study.  


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3.4 
Overall Study Duration and Follow-up 
The study will consist of a screen/ run-in period, study treatment, post-treatment and long term 
follow-up.  Please refer to the Schedule of Procedures in Appendix A.  
Subjects may be required to attend additional visits for monitoring of adverse events or abnormal 
investigation results.  The frequency of additional monitoring will be determined by the Study 
Medical Monitor in consultation with the Investigator. 
The length of subjects’ participation in the study may be up to 34 weeks, including an up to 8-
week screening period, that includes a 6-week diet stabilization / run-in period, a 13-week 
treatment period, and a 13-week post-treatment evaluation period.  Subjects will perform the first 
dosing at the site, with subsequent dosing occurring at home following training on how to dose.  
The diet stabilization period may be reduced if the patient is following a stable low fat diet for 
optimal disease control and disease management prior to screening. 
 3.4.1 
Screening 
Subject eligibility for the study will be determined within 56 days/8 weeks prior to study entry. 
3.4.2 
Treatment 
Eligible subjects will receive the first dose of study drug at the Study Center, at which time they 
will also be trained on self-administration of Study drug.  Subsequent administrations of study 
drug may occur at home or in the study center.  Eligible subjects will report to the Study Center 
for assessments at specified intervals throughout the 13-week treatment period as detailed in the 
Schedule of Procedures in Appendix A.    
3.4.3 
Post-Treatment 
Subjects are to return to the Study Center for follow-up visits every four weeks (refer to the 
Schedule of Procedures in Appendix A).  The final study visit will be Study Week 26. 
3.5 
End-of-Study 
The End-of-Study is defined as the last subject’s last visit. 
4. 
SUBJECT ENROLLMENT 
4.1 
Screening 
Before subjects may be enrolled into the Study, the Sponsor or designee requires a copy of the 
Study Center’s written independent ethics committee/institutional review board (IEC/IRB) 
approval of the protocol, informed consent form, and all other subject information and/or 
recruitment material. 
Subjects must sign the informed consent form before any screening tests or assessments are 
performed.  At the time of consent, the subject will be considered enrolled into the Study and 
will be assigned a unique screening number before any Study procedures, including screening 
procedures, are performed.  At the time of randomization or registration, subjects will be 
assigned a unique subject identification number.  This number will be used to identify the subject 
throughout the trial and must be used on all study documentation related to that subject.  The 


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screening number and subject identification number must remain constant throughout the entire 
trial.  Screening numbers and subject identification numbers, once assigned, will not be reused. 
4.2 
Registration 
Patients will be registered after all screening assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2.  No subject 
may begin treatment prior to assignment of a unique subject identification number. 
4.3 
Replacement of Subjects 
Due to the small number of subjects participating in the study, subjects who withdraw from the 
study may be replaced by allowing a new subject to be screened and enrolled.  The subjects who 
withdrew for safety reasons will not be replaced.  
5. 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 56 days of treatment day 1 or at the time point specified in the individual eligibility 
criterion listed. 
5.1 
Inclusion Criteria 
1. Must have given written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements. 
2. Males or females aged > 18 years old at the time of informed consent. 
3. Genetically confirmed homozygote or compound heterozygote for known null loss-of-
function mutations in the LPL gene. 
4. Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening. If the fasting TG < 750 mg/dL up to 
2 additional tests may be performed in order to qualify. 
5. Willing to follow a diet comprising ≤ 20g fat per day during the study. 
6. Females:  must be non-pregnant and non-lactating and either;  
i. 
Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy); 
ii. 
Post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 
years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without 
an alternative medical cause and FSH levels in the postmenopausal range for the 
laboratory involved); 
iii. 
Abstinent* or, 
iv. 
If engaged in sexual relations of child-bearing potential, agree to use 2 highly 
effective contraceptive methods (refer to Section 6.3.1) from the time of signing the 
informed consent form until at least 13 weeks after the last dose of Study Drug 
(AKCEA-ANGPTL3-LRX). 
7. Males:  Surgically sterile or if engaged in sexual relations with a female of child-bearing 
potential, subject is utilizing an acceptable contraceptive method (refer to Section 6.3.1) 


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from the time of signing the informed consent form until at least at least 13 weeks after 
the last dose of Study Drug (AKCEA-ANGPTL3-LRX). 
*  Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred 
and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial 
and withdrawal are not acceptable methods of contraception. 
5.2 
Exclusion Criteria 
1. Diabetes mellitus with any of the following:  
a. 
Newly diagnosed within 12 weeks of screening  
b. HbA1c ≥ 9.0% at Screening  
c. 
Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of 
new medication within 12 weeks of screening [with the exception of ± 10 units of 
insulin])  
d. Current use of GLP-1 agonists 
2. Active pancreatitis within 2 weeks prior to screening 
3. History within 6 months of screening of acute or unstable cardiac ischemia (myocardial 
infarction, acute coronary syndrome, new onset angina, stroke, transient ischemic attack 
or unstable congestive cardiac failure requiring a change in medication) or major surgery 
within 3 months of screening 
4. Any of the following laboratory values at Screening  
a. 
Hepatic:  
• Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and 
documentation of Gilbert’s syndrome in which case total bilirubin must be ≤ 3 
mg/dL  
• ALT > 2.0 x ULN  
• AST > 2.0 x ULN  
b. Renal:  
• Persistently positive (2 out of 3 consecutive tests ≥ 1+) for protein on urine 
dipstick. In the event of a positive test eligibility may be confirmed by a 
quantitative total urine protein measurement of < 500 mg/24 hrs  
• Persistently positive (2 out of 3 consecutive tests ≥ trace positive) for blood on 
urine dipstick. In the event of a positive test eligibility may be confirmed with 
urine microscopy showing ≤ 5 red blood cells per high power field  
• Estimated creatinine clearance calculated according to the formula of Cockcroft 
and Gault < 60 mL/min (MDRD or CKD-EPI formulas can be used instead of 
Cockcroft-Gault for estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor)  
c. 
Platelet count < 140,000 mm3    


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d. Any other laboratory abnormalities which, in the opinion of the Investigator or the 
Sponsor, would make the patient unsuitable for inclusion 
5. Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg)  
6. History of bleeding diathesis or coagulopathy or clinically-significant abnormality in 
coagulation parameters at Screening 
7. History of heart failure with NYHA greater than Class II 
8. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
9. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
10. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated 
11. Treatment with another investigational drug, biological agent, or device within 1-month 
of screening, or 5 half-lives of investigational agent, whichever is longer 
12. Unwilling to comply with lifestyle requirements (Section 6.3) 
13. Use of any of the following:  
a. Statins, omega-3 fatty acids (prescription or OTC), or fibrates unless on a stable dose 
for at least 3 months prior to screening and dose and regimen expected to remain 
constant during the treatment period. Patients taking OTC omega-3 fatty acids should 
make every effort to remain on the same brand throughout the study.  
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to screening  
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to screening unless 
approved by the Sponsor Medical Monitor  
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable 
dose for at least 3 months prior to screening and dose and regimen expected to remain 
stable throughout the study  
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to 
screening and dose and regimen expected to remain constant during the treatment 
period  
f. Glybera gene therapy within 2 years prior to screening  
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on 
a stable dose for at least 4 weeks prior to screening and regular clinical monitoring is 
performed  
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior 
to screening and dose and regimen expected to remain constant during the treatment 
period i. Plasma apheresis within 4 weeks prior to screening or planned during the 
study  
i. Prior exposure to AKCEA-ANGPTL3-LRX 


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j. Any other medication unless stable at least 4 weeks prior to screening (Occasional or 
intermittent use of over-the-counter medications will be allowed at Investigator’s 
discretion)  
14. Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 60 
days of screening  
15. Known hypersensitivity to any of the excipients of the Study Drug  
16. Have any other conditions, which, in the opinion of the Investigator or the Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the patient participating 
in or completing the study  
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
The study will consist of a Screening period, a Treatment period and a Post-treatment period. 
These periods are described below. 
All required study procedures are outlined in Appendix A. 
6.1.1 Screening 
Written informed consent for the study will be obtained prior to the performance of any 
study-related procedures including screening procedures.  A 4-week period is provided for 
completing screening assessments and determining subject eligibility for the study.  Safety labs 
may be re-tested for determination of subject eligibility after consultation with the Sponsor 
Medical Monitor. 
During the screening period, subjects will undergo a medical history and physical examination 
including vital signs, 12-lead ECG, and have blood and urine samples taken for clinical 
laboratory testing.  Subjects will be screened for HIV, hepatitis B, and hepatitis C. 
Eligible subjects will be on a stable low-fat diet (according to local clinical guidelines) beginning 
at least 6 weeks prior to the first dose of Study Drug.  The diet stabilization period may be 
reduced if the patient is following a stable low fat diet for optimal disease control and disease 
management prior to screening. 
6.1.2 Treatment Period 
Subjects will be managed on an outpatient basis.  Safety and clinical laboratory evaluations as 
well as blood sampling for PK analysis will be performed periodically throughout the treatment 
period.  Any AEs and concomitant medications will be recorded. 
Postprandial Assessment (Appendix E):  Subjects will consume standardized pre-cooked meals 
(lunches and dinners (provided) and instructions for breakfasts and snacks) for the 2 days prior to 
the post-prandial evaluations.  Patients will remain fasted after consuming the standardized pre-
cooked meal for the dinner on the evening prior to their visit.  Alcohol consumption is not 
allowed for the 2 days prior to the post-prandial evaluations.  On each of the post-prandial 
evaluation days, following the blood draws, patients will consume a standardized liquid meal 


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(which represents about a third of the daily caloric requirements) with a stable radioisotope 
tracer, followed by an 8 hour radioisotope infusion and serial blood sampling.  Patients will 
receive a standardized pre-cooked meal 9 hrs after consuming the liquid meal, after which they 
will fast until the 24 hour blood draw the following day. 
6.1.4 Post-Treatment Period 
Each subject will be followed for safety assessments for up to 13 weeks after the last dose of 
Study Drug.  During the post-treatment evaluation period, subjects will return to the 
Study Center for outpatient visits on Days 119, 147 and 182 for safety and clinical laboratory 
evaluations.  A ± 1-day excursion from the scheduled visit date is permitted for this time period.  
6.2 
Study/Laboratory Assessments  
Laboratory analyte samples will be collected throughout the Study.  A list of these analytes is 
contained in Appendix B.  Blood chemistry and urine samples (excluding 24-hour urine 
collection) should be taken be taken after fasting for approximately 10 hours.  During this time 
subjects can drink water and should ensure that they consume sufficient water to not become 
dehydrated. 
6.3 
Restriction on the Lifestyle of Subjects 
6.3.1 
Contraception Requirements 
All male subjects and women of childbearing potential must refrain from sperm/egg donation 
and either be abstinent† or practice effective contraception from the time of signing the informed 
consent form until at least a period of 13 weeks after their last dose of study treatment.  
Male subjects engaged in sexual relations with a female of child-bearing potential must also 
encourage their female partner to use effective contraception from the time of signing the 
informed consent until a period of 13 weeks after the subject’s last dose of study treatment. 
For the purposes of this study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet one of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause  and FSH levels in the postmenopausal range for the laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, effective contraception is defined as follows: 
For male subjects: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal 
foam/gel/film/cream/suppository 


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• Male subjects with partners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the Study Drug 
For female subjects and female partners of male subjects: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository 
†Note: Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a trial and withdrawal are not acceptable methods of contraception. 
*Note: A female condom and a male condom should not be used together as friction 
between the two can result in either or both products failing. 
6.3.2 
Other Requirements 
All subjects will be required to fast for approximately 10 hours before visits requiring fasted 
blood sampling.   
7. 
STUDY DRUG 
7.1 
Study Drug Description 
7.1.1 
AKCEA-ANGPTL3-LRX (ISIS 703802)  
Study Drug characteristics are listed in Table 1. 
A solution of Study Drug contained in stoppered glass vials will be provided.  The Study Drug 
and its storage and preparation instructions will be provided by the Sponsor or designee.  The 
Study Drug must be stored securely at 2° to 8° Celsius and be protected from light. 
Table 1 
Study Drug Characteristics 
Study Drug 
AKCEA-ANGPTL3-LRX 
(ISIS 703802) 
Strength 
100 mg/ mL  
Volume/Formulation 
0.8 mL/vial 
Route of Administration 
SC* 
* 
SC = subcutaneous 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug labeled in accordance with 
specific country regulatory requirements. 


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7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug 
supplies provided by the Sponsor.  The Study Center must return all used and unused Study Drug 
to the Sponsor or designee. 
8. 
TREATMENT OF SUBJECTS 
8.1 
Study Drug Administration 
Vials are for single use only.  Study staff will administer the first dose of Study Drug.  Doses 
will be administered by SC injection, patients or their caregivers may self-administer the study 
drug following the training given by the study center staff.   
 
Volumes to be administered are shown in Table 2.  Please refer to the Study Drug Manual 
provided by the Sponsor or designee for more detailed instructions for Study Drug preparation 
and/or administration. 
Table 2 
Study Drug Dosing Information 
Volume to Administer 
Total Dose 
0.20 mL  
20 mg (open label) 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs. 
Subjects will continue their stable lipid-lowering therapy through the end of the post-treatment 
evaluation period. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol-required treatment procedures other than those outlined in the 
schedule of procedures. 
8.4 
Treatment Precautions 
No specific treatment precautions are required. 
8.5 
Safety Monitoring Rules 
Please refer also to the Guidance for Investigator section of the Investigator’s Brochure. 
For the purposes of safety monitoring Baseline is defined as the average of the pre-dose test 
closest to Day 1 and Day 1. 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
In case of discrepancy between the test results from 2 sources, safety-mandated action must be 
initiated based on the more critical (lower or higher, as relevant) of the 2 values. 


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Confirmation Guidance:  At any time during the Study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring criteria presented below must 
be confirmed by performing measurements (ideally in the same laboratory that performed the 
initial measurement) on new specimens prior to administering the next dose of Study Drug.  All 
new specimen collections should take place as soon as possible (ideally within 3 days of the 
initial collection).   
Stopping Rule Guidance:  The Investigator may interrupt or permanently discontinue study 
treatment for any safety reason including clinically meaningful changes in clinical laboratory 
results.  The medical monitor should be informed. 
Re-dosing Guidance:  Subjects with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, subjects who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the subject is appropriate.  If any of the stopping criteria described 
in Section 8.6 are met, the subject will be permanently discontinued from further treatment with 
Study Drug, evaluated fully as outlined below and in consultation with the Sponsor Medical 
Monitor or appropriately qualified designee, and will be entered into the post-treatment 
evaluation portion of the study. 
Additional Guidance:  If possible, a PK sample should be collected as soon as possible after an 
SAE has occurred (preferably within 2 weeks).  In addition, if a patient is asked to return to the 
clinic for additional evaluations due to an AE, then a PK sample should be taken at the time of 
the unscheduled visit.  
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the FDA guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S. Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline, please refer to 
guidance in Section 8.5 above. 
All patients will have liver chemistry tests monitored every 2 weeks during and treatment and 
follow-up Period. 
• In the event of appearance of symptoms or signs of hepatic injury (jaundice, fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, abnormal bleeding 
or bruising, or eosinophilia > ULN) liver enzymes and bilirubin should be tested as soon 
as possible.  Testing at a lab that is local to the patient is permissible for this purpose. 
• In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x 
baseline value or 3 x ULN if the baseline value was > ULN) at any time during the study 
(treatment or post-treatment period), the initial measurement(s) should be confirmed as 
described in Section 8.5. 
• Patients with confirmed ALT or AST levels > 3 x ULN should have their liver chemistry 
tests (ALT, AST, ALP, international normalized ratio [INR] and total bilirubin) retested 
at least once weekly until ALT and AST levels become ≤ 1.2 x ULN. 


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• All results of liver function tests must be reviewed promptly (within 48 hours of receipt) 
by the Investigator or the designee to ensure that the result has not met the stopping rules 
per Section 8.6.1.  Further Investigation into Liver Chemistry Elevations: For patients 
with confirmed ALT or AST levels > 3 x ULN, the following evaluations should be 
performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational 
drug use, and special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (hepatitis A virus [HAV] immunoglobulin M [IgM], 
hepatitis B surface antigen [HBsAg], hepatitis C virus [HCV] antibody, 
Cytomegalovirus [CMV] IgM, and EBV antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor. Repetition of the above evaluations should be considered if a patient’s 
ALT and/or AST levels reach 5 x ULN. 
All routine liver function test results will be reviewed on an ongoing basis at the weekly safety 
review by the Medical Monitor. 
All lab alerts for abnormal liver function tests must be promptly (within 48 hours of receipt) 
reviewed by the Investigator and Medical Monitors. 
Lab alerts for abnormal liver chemistry tests will be issued for:  
1. ALT or AST > 3 x ULN;  
2. ALT or AST > 2 x baseline;  
3. total bilirubin > ULN;  
4. ALP > ULN.  
These alert levels are set to anticipate the risk of a combined elevation of aminotransferases and 
bilirubin as per the FDA Guidance referenced in Section 8.5.1.  A more frequent liver function 
test monitoring may be recommended by the Investigator if warranted.  The Investigator should 
inform the Medical Monitor. 
All clinically significant lab alerts for monitoring/ stopping rules as described above are 
reviewed promptly by the Medical Monitor and communicated with the Investigator and/or the 
study personnel within 24 hours of receiving an actionable lab alert. 
8.5.2 
Safety Monitoring for Renal Function 
All patients will have renal function tests monitored every 4 weeks throughout the study. 


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In the event of appearance of symptoms or signs consistent with renal dysfunction such as 
hematuria, polyuria, anuria, flank pain, new-onset hypertension, nausea and/or anorexia, renal 
function should be tested as soon as possible.  
During the course of the study, urinary surveillance will include urinalysis to include urine 
albumin/creatinine ratio (UACR), urine protein/creatinine ratio (UPCR) and urinary red blood 
cells (RBCs), as well as serum creatinine and cystatin-C to estimate glomerular filtration rate 
(eGFR), which will be monitored every 4 weeks.  
All renal function test results will be reviewed on an ongoing basis at the safety review by the 
Medical Monitor. 
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per Section 
8.6.2. 
Lab alerts for abnormal renal tests will be issued for:  
• Creatinine clearance (by CKD-EPI formula) decrease from baseline > 25%,  
• Urine albumin/creatinine ratio (UACR) > 250 mg/g, urine protein/creatinine ratio 
(UPCR) > 0.5 mg/mg, or  
• An increase in serum creatinine from baseline > 0.3 mg/dL). 
These alert levels are set to anticipate and prevent the risk of a medically significant change in 
renal function while receiving Study Drug. 
In the event of a confirmed (as described in Section 8.5) laboratory result meeting one or more of 
the above criteria, dosing with the Study Drug should be interrupted and the Study Medical 
Monitor informed.  
In addition, the following supplemental renal tests should be immediately obtained: 
• Serum creatinine,  
• Urine culture,  
• 24-hour urine sample for creatinine clearance, 
• Urine albumin and urine protein, 
• Urine microscopy sample with inspection of sediment. 
The Investigator should also review the patient’s concomitant medications for potentially 
nephrotoxic agents, and, with the results of these evaluations, review any decision to continue or 
discontinue the patient in consultation with the Study Medical Monitor. 
8.5.3 
Safety Monitoring Rules for Platelet Count Results 
All patients will have platelet counts monitored every 2 weeks for the duration of the study and 
must not receive Study Drug without an interpretable platelet count result in the prior 2 weeks. 


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In addition, platelet function may be evaluated by aggregometry, using an approved point-of-care 
diagnostic device, in all patients at each study site visit. 
All platelet count results must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rule and to 
determine whether the rate of decline is suggestive that the patient could be approaching the dose 
interruption rule of 75,000/mm3 as specified in Section 8.6.3. 
Any case of a platelet count reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is 
considered an adverse event of special interest and should be reported in an expedited fashion to 
the Sponsor. 
Lab alerts related to platelet monitoring/stopping rules are issued when:  
1. Platelet counts are < 140,000 mm3;  
2. When platelet count is ≥ 30% decreased from baseline, or  
3. When the hematology sample is unreportable.  
Actions to be taken in the event of reduced platelet count are shown in Table 3 below.  In the 
event of a platelet count ˂ 100,000/mm3 the laboratory tests outlined should be performed as 
soon as possible.  Additional lab tests will be determined by the Sponsor Medical Monitor or 
designee in consultation with the Investigator. 
Table 3 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation: 
Monitor every week* 
75K-100K/mm3 
Permanently reduce as follows: 
Reduce to 10 mg every week 
Closer observation: 
Monitor every week* 
50K-75K/mm3 
Pause dosing 
When platelet count returns to > 100K/mm3 restart 
dosing as follows only if approved by Sponsor 
Medical Monitor: 
Reduce to 10 mg every week 
or 
Permanently discontinue Study Drug if it occurs 
while on already reduced dose  
Closer observation: 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/non-
steroidal anti-inflammatory 
drug (NSAIDS)/ anticoagulant 
medication 
25K-50K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 
2 successive values show 
improvement then monitor 
every 2-3 days until platelet 
count stable 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 


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Platelet Count on Rx 
Drug Dose 
Monitoring 
˂ 25K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 
2 successive values show 
improvement then monitor 
every 2-3 days until platelet 
count stable 
Steroids recommended** 
Consider need for 
hospitalization and referral to 
hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 
* 
Once a patient commences weekly monitoring this frequency of monitoring should continue irrespective of 
whether the platelet count rises into the normal range. 
** 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after methylprednisolone). 
All clinically significant lab alerts for monitoring/stopping rules as described above are reviewed 
promptly by the Medical Monitor and communicated with the Investigator and/or the study 
personnel within 24 hours of receiving an actionable lab alert as described in Section 6.2. 
8.5.4 
Safety Monitoring for Minor Bleeding Events 
Patients will be instructed to promptly report any signs or symptoms of bleeding.  Minor 
bleeding events are those that do not fulfill the criteria for major bleeding or clinically-relevant, 
non-major bleeding events (which are defined in Section 8.6.3), for example excess bruising, 
petechiae, or gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR, hepatic 
enzymes, bilirubin and platelet count should be performed. 
8.6 
Stopping Rules  
For the purposes of the stopping rules, Baseline is defined as the average of the pre-dose test 
closest to Day 1 and Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of confirmed laboratory results meeting any of the following criteria, dosing of a 
patient with Study Drug will be stopped permanently: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x Baseline value or 3 x ULN if the Baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 


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4. ALT or AST > 3 x ULN (or the greater of 2 x Baseline value or 3 x ULN if the Baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation. 
8.6.2 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules for 
Renal Function Test Results 
In the event of an estimated creatinine clearance (by CKD-EPI formula) meeting any of the 
following criteria, or any change in renal biomarkers deemed by the nephrologist to require 
further evaluation, a serum creatinine and 24-hour urine sample for creatinine clearance and 
protein should be obtained: 
1. CKD-EPI decrease of > 40% from Baseline 
2. CKD-EPI value < 45 mL/min/1.73 m2 
Dosing of a patient with Study Drug (AKCEA-ANGPTL3-LRX) will be stopped permanently if 
24-hour urine testing confirms any of the following values in the absence of an alternative 
explanation: 
1. Urine protein is > 1.0 g 
2. Creatinine clearance decrease of > 40% from baseline 
3. Creatinine clearance < 45 mL/min/1.73 m2 
Irrespective of whether the stopping rule is confirmed or not, the follow-up schedule and 
frequency of renal function monitoring after the initial event will be determined by the Study 
Medical Monitor in consultation with the Investigator.  The Investigator should consider 
consulting a local nephrologist for any change of renal function that presents a concern.  If a 
renal biopsy is performed, a sample specimen should be made available for examination by an 
independent renal pathologist who has been engaged by the Sponsor to review such specimens.  
8.6.3 
Stopping Rule for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3. 
In the event of any platelet count less than 50,000/mm3, or a platelet count less than 75,000/mm3 
that occurs while the patient is already on reduced dose, dosing of the patient with Study Drug 
will be stopped permanently (Table 3).  
Platelet count will be monitored daily until 2 successive values show improvement then 
monitored every 2-3 days until platelet count is stable. 
Administration of steroids is recommended for patients whose platelet count is less than 
25,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
steroids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend 
Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 


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mg/kg/d for 2-4 weeks then taper; or methylprednisolone 30 mg/kg/day for 7 days (note: may 
require continuation with oral steroids after methylprednisolone). 
In the event of a platelet count ˂ 75,000/mm3 and > 50,000/mm3, and in the absence of major 
bleeding or clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing 
of a patient with Study Drug should be suspended temporarily until the platelet count has 
recovered to > 100,000/mm3.  If dosing is continued it must be at a reduced dose as shown in 
Table 3.  The suitability of the patient for continued dosing will be determined by the 
Investigator in consultation with the Study Medical Monitor and will be based on factors such as 
the original rate of decline in the patient’s platelet count, whether any bleeding events were 
experienced by the patient, and the speed of recovery of platelet count after interruption of 
dosing.  This will be documented in the patient by the investigator and filed in the TMF.rec. 
If, after reintroduction of Study Drug, the platelet count again falls below 75,000/mm3, then 
dosing of the patient with Study Drug will be stopped permanently. 
Once a patient commences weekly monitoring this frequency of monitoring should continue 
irrespective of whether the platelet count rises into the normal range. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
• 24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
8.7 
Adjustment of Dose and/or Treatment Schedule 
Dose frequency adjustments for platelet count reduction must be made in accordance with 
Section 8.6.3 and Table 3 (above). 


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Other dose adjustments, including dose interruptions, and/or decreasing the dose will be allowed 
for safety or tolerability in consultation with the Sponsor Medical Monitor.   
Patients may have their dose interrupted in response to AEs in consultation with Study Medical 
Monitor. 
8.8 
Discontinuation of Study Drug/Treatment 
A subject must permanently discontinue study treatment for any of the following: 
• The subject becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The subject withdraws consent 
• The subject experiences an adverse event (AE) that necessitates permanent 
discontinuation of Study Drug 
• The subject develops laboratory test abnormalities that meet any of the stopping rules 
listed in Sections 8.6.1 to 8.6.3 
The reason for discontinuation of Study Drug Treatment must be recorded in the electronic Case 
Report Form (eCRF) and source documentation. 
Subjects who discontinue treatment early should be entered into the post-treatment evaluation 
period.  Every effort should be made to complete the early termination study procedures and 
observations at the time of withdrawal (see Appendix A). 
If a subject discontinues treatment after only 1 dose, then the post-treatment evaluation 
procedures cohorts should be followed.   
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from 
Post-Treatment Follow-up Period 
Any patient who discontinues early from the treatment period or from post-treatment follow-up 
period should be followed as per the platelet monitoring rules shown in Table 3, Section 8.6.3 for 
the first 6 weeks after discontinuing Study Drug.  Following this period, if the platelet count is 
stable (at least 3 consecutive values that are stable as determined by the Sponsor Medical 
Monitor and > 100,000/mm3), the next platelet count should be taken within at least 6 weeks so 
that patients are monitored for at least 12 weeks after discontinuing Study Drug. 
If the patient declines or is unable to participate in the above, the early termination visit 
procedures should be performed at the time of withdrawal, at a minimum, and ideally within 
2 weeks from the last dose of Study Drug.  
8.9 
Withdrawal of Subjects from the Study 
Subjects must be withdrawn from the Study for any of the following: 
• Withdrawal of consent 
• The subject is unwilling or unable to comply with the protocol 


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Other reasons for withdrawal of subjects from the Study might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from Study, must 
be recorded in the eCRF.  
Any subject who withdraws consent to participate in the Study will be removed from further 
treatment and study observation immediately upon the date of request.  These subjects should be 
encouraged to complete the early termination study procedures and observations at the time of 
withdrawal (Appendix A).   
For subjects withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Appendix A).  
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the subject’s 
eCRF.  Adverse events related to administration of these therapies or procedures must also be 
documented on the appropriate eCRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including 
over-the-counter medications, herbal medications and vitamin supplements) administered 
between screening and the end of the post-treatment evaluation period.  All concomitant 
medications/treatments and significant non-drug therapies (including supplements and assistive 
devices) received by a subject, including changes in the subject’s current medications, must be 
recorded in the subject’s source documents and CRF.  Subjects taking over the counter (OTC) 
omega-3 fatty acids should make every effort to remain on the same brand throughout the study. 
Allowed Concomitant Therapy 
Ibuprofen may be used for symptomatic relief.  Any other therapy (including OTC medications) 
should be approved by the Sponsor Medical Monitor or designee. 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
The use of prescription and OTC medications including nonsteroidal anti-inflammatory drugs 
(with the exception of occasional ibuprofen) is prohibited during this study unless the occurrence 
of an AE requires a drug therapy.  In such cases, the Investigator must consult the Sponsor 
Medical Monitor to decide on subject continuation or withdrawal from the study. 


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Disallowed concomitant therapy are identified in exclusion criteria, Section 5.2, and include the 
following as specified*: 
• Anti-obesity medications (e.g., orlistat, sibutramine), or has discontinued treatment 
< 12 weeks prior to screening 
• Fibrates within 8 weeks of screening 
• Systemic corticosteroids or anabolic agents within 6 weeks of screening* 
• Treatment with another investigational drug, biological agent, or device within 4 weeks 
of screening or 5 half-lives of study agent, whichever is longer 
• Prior treatment with gene therapy 
• No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing 
omega-3 fatty acids [including OTC preparations]), glucagon-like peptide-1 (GLP-1) 
agonists, Glybera, or systemic corticosteroids may be started or adjusted after baseline 
qualification.   
• Doses of existing oral anti-diabetic medication, oral contraceptives, hormone replacement 
therapy, anticoagulants, or drugs or dietary supplements with potential lipid-altering 
effects should not be adjusted.   
• Study patients are prohibited from receiving other experimental agents during the study.  
This includes marketed agents at experimental dosages that are being tested for the 
treatment of hypertriglyceridemia. 
• Other experimental agents during the study including investigational drug, biological 
agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, 
whichever is longer.  This includes marketed agents at experimental dosages 
• Treatment with any non-Ionis oligonucleotide (including siRNA) at any time or prior 
treatment with an Ionis oligonucleotide or siRNA within 9 months of screening.  Patients 
that have previously received only 1 dose of an Ionis oligonucleotide as part of a clinical 
study may be included as long as ≥ 4 months has elapsed since dosing 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
 
*Note:  Concomitant therapy with oral corticosteroids used as replacement therapy for 
pituitary/adrenal disease as well as inhaled steroid therapy (e.g., Pulmicort®), or 
intra-articular, or topical may be acceptable; however, the subject must be on a stable 
regimen for at least 4 weeks prior to screening.  All exceptions should be discussed with 
the Sponsor Medical Monitor.  
8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
screening and the end of the post-treatment evaluation period. 


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8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The 
Study Center staff is required to document the receipt, dispensing, and return/destruction of 
study medication.  Subjects that are self-administering study medication at home must record 
treatment in a dosing diary that will be reviewed periodically by Study Center staff and the 
Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING  
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee in 
accordance with the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of serious adverse events (SAEs) including suspected unexpected serious adverse 
reactions (SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A 
and ICH E6.  Country-specific regulatory requirements will be followed in accordance with local 
country regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
For the purpose of regulatory reporting of SUSARs, there are no “expected” AEs in this study 
population. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
Study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any AE caused by the Study Drug. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the adverse event.  A suspected adverse reaction implies a lesser degree of certainty about 
causality than an adverse reaction. 


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9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or 
Sponsor, meets any of the following criteria: 
• Results in death 
• Is life threatening: that is, poses an immediate risk of death at the time of the event 
• An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death.  It does not include an AE or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE (See Section 9.5.2) 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Results in a congenital anomaly or birth defect in the offspring of the subject (whether 
the subject is male or female) 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may also be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
9.3.3.1 
Adverse Events of Special Interest 
For the purpose of this study severe reductions in platelet count < 50,000 mm3 are considered as 
an AE of special interest and should be subject to expediting reporting to the Sponsor following 
the same requirements as for SAE reporting (Section 9.4.1). 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of the 
Study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of subject safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to Study Drug) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the subject signs the informed consent form and stop at the end of the subject’s 
follow-up period.  When the Investigator is reporting by telephone, it is important to speak to 


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someone in person versus leaving a message.  An Initial Serious Adverse Event Form should be 
completed and a copy should be faxed to the Sponsor or designee.   
The contact information for reporting SAEs is as follows: 
Attention:  
 
Email: 
 
 
Fax: 
 
 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the subject’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
subject’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the informed consent form 
and will stop at the end of the subject’s follow-up period.  The Investigator will monitor each 
subject closely and record all observed or volunteered AEs on the Adverse Event Case Report 
Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (AKCEA-ANGPTL3-LRX or placebo) is characterized 
by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of Study Drug 
(e.g., confirmation by positive re-challenge test) 
• Possible:  The event cannot be explained by the subject’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and Study Drug (AKCEA-ANGPTL3-LRX or placebo) administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely 
(e.g., concomitant medications or ongoing medical conditions) or the temporal 
relationship to Study Drug (AKCEA-ANGPTL3-LRX or placebo) administration and/or 
exposure suggests that a causal relationship is unlikely (For reporting purposes, 
Unlikely/Remote will be grouped together with Not Related) 
• Not Related:  The event can be readily explained by the subject’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and Study Drug 


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9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D). 
Any AE not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the subject and does not affect the subject’s usual 
daily activities 
• Moderate:  The event causes the subject more discomfort and interrupts the subject’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
subject’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Study Drug 
Action taken with Study Drug (AKCEA-ANGPTL3-LRX or placebo) due to the event is 
characterized by 1 of the following. 
• None:  No changes were made to Study Drug (AKCEA-ANGPTL3-LRX or placebo) 
administration and dose 
• Permanently Discontinued:  Study drug was discontinued and not restarted 
• Temporarily Interrupted, Restarted – Same Dose:  Dosing was temporarily 
interrupted or delayed due to the AE and restarted at the same dose 
• Temporarily Interrupted, Restarted Reduced Dose:  Dosing was temporarily 
interrupted or delayed due to the AE and restarted at the next lower dose 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form.  Treatment should also be recorded on the concomitant 
treatment or ancillary procedures eCRF, as appropriate. 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE, then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 


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If the event is an SAE, then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment (e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia).  Whenever possible, 
the underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically-significant (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
All platelet count results must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the count has not met the stopping rule and to 
determine whether the rate of decline is suggestive that the patient could be approaching the dose 
interruption rule of 75,000/mm3 as specified in Section 8.6.3. 
Any case of a platelet count reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is 
considered an adverse event of special interest and should be reported in an expedited fashion to 
the Sponsor as per Sections 9.3.3.1 and 9.4.1). 
All results of liver function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per 
Section 8.6.1. 
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per 
Section 8.6.2. 


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9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the subject’s consent to 
participate in the Study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the Study and the timing of 
the procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3 
Dosing Errors 
Study Drug (AKCEA-ANGPTL3-LRX) errors should be documented as Protocol Deviations.  A 
brief description should be provided in the deviation, including whether the subject was 
symptomatic (list symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing eCRF.  If the subject takes a dose of 
Study Drug that exceeds protocol specifications and the subject is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4 
Contraception and Pregnancy 
Subjects must continue to use appropriate contraception with their partners, or refrain from 
sexual activity, as described in Section 6.3.1. 
If a subject becomes pregnant or a pregnancy is suspected, or if a male subject makes or believes 
that he has made someone pregnant during the Study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported by designating as ‘Follow-up’ on the 
Pregnancy Forms and reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the subject’s 
responsibility. 
Female subjects:  If a suspected pregnancy occurs while on the Study (including follow-up), a 
pregnancy test will be performed.  The subject with a confirmed pregnancy will be immediately 
withdrawn from treatment with Study Drug.  However, the subject will be encouraged to 
complete the post-treatment follow-up portion of the Study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 


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physician will assist the subject in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth.  Follow-up will be performed to the extent permitted by the applicable regulations 
and privacy considerations. 
Male subjects:  The progress of the pregnancy of a male subject’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by the applicable regulations and 
privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Subsets, and Covariates 
For fasting lipid measurements, the values for the Month 3 analysis time point are defined as the 
average of Week 13 (Day 85) and Week 14 (Day 92) fasting assessments. 
10.1.1 
Efficacy Endpoints 
• Percent change and absolute change from baseline in fasting TG 
• Percent change and absolute change from baseline in fasting ANGPTL3 
• Fasting lipid measurements, including:  non-HDL-C, apoB,  HDL-C, apoA-1, VLDL-C, 
and LDL-C 
• Percent change and change from baseline in other fasting lipid measurements including 
total cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, 
and LDL-C 
• Postprandial TG change from baseline 
• Frequency and severity of patient reported abdominal pain during the treatment period 
10.1.2 
Safety Endpoints  
• Adverse events 
• Vital signs and weight 
• Physical examinations  
• Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 


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10.2 
Sample Size Considerations 
There is no formal statistical justification for the selected sample size.  The sample size is 
selected based upon prior experience with AKCEA-ANGPTL3-LRX to ensure that the safety, 
tolerability and efficacy of AKCEA-ANGPTL3-LRX can be explored while minimizing 
unnecessary subject exposure.  In 6 healthy volunteers, AKCEA-ANGPTL3-LRX reported a 63% 
TG reduction after 6 weeks of administration. 
10.3 
Populations 
Safety Set:  All subjects who are enrolled and receive at least 1 dose of Study Drug. 
 
PK Set:  All subjects who receive at least 1 dose of Study Drug and have at least 1 evaluable PK 
sample. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, the baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
For other measurements, baseline will be the last non-missing assessment prior to the first dose 
of Study Drug. 
10.5 
Interim Analysis and Early Stopping Guidelines 
Since the study is open labeled no interim analysis will be performed to inform early stopping 
guidelines.  
10.6 
Planned Methods of Analysis 
Summary tabulations will be provided for disposition, demographic, baseline, efficacy, and 
safety data as noted in the following sections. 
All eCRF data, lab data, and any outcomes derived from the data will be provided in the patient 
data listings.  Patient data listings will be presented for all patients enrolled into the study.  
Descriptive summary statistics including n, mean, median, standard deviation, standard error, 
interquartile range (25th percentile, 75th percentile), and range (minimum, maximum) for 
continuous variables, and counts and percentages for categorical variables will be used to 
summarize most data.   
10.6.1 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
treatment group.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group 
and overall. 


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Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term 
and severity. 
10.6.2.1 
Adverse Events 
Treatment duration and amount of Study Drug received will be summarized.  Patient incidence 
rates of all AEs will be tabulated by MedDRA system organ class, and by MedDRA preferred 
term.  Narratives of treatment-emergent deaths, serious and significant AEs, including early 
withdrawals due to AEs, will also be provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug will be summarized. 
10.6.2.2 
Clinical Laboratory Data 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, complement, etc., will be summarized by study visit.  These 
safety variables will also be presented as change and percent change from baseline over time 
after Study Drug administration, as appropriate.  In addition, the number of patients who 
experience abnormalities in clinical laboratory evaluations will be listed. 
10.6.2.3 
Vital Signs and Examinations 
Vital signs, weight, and ECG measures will be tabulated by treatment group. 
10.6.3  
Efficacy Analysis 
Percent change and change from baseline to Month 3 in fasting TG will be summarized.  
Response rate of patients with fasting plasma TG < 750 mg/dL or achieving fasting TG ≥ 40% 
reduction from baseline at Month 3 will be summarized.  Response analysis will also be 
conducted using a range of fasting plasma TG thresholds for determination of responder status. 
Percent change and change from baseline to Month 3 will also be summarized by treatment 
group for other fasting lipid measures including ANGPTL3, non-HDL-C, apoB, HDL-C, apoA-
1, VLDL-C, and LDL-C, total cholesterol, and fasting total apoC-III. 
10.6.4 
Pharmacokinetic Analysis 
The plasma PK of AKCEA-ANGPTL3-LRX (as total full length oligonucleotides, including, fully 
conjugated, partially conjugated, and unconjugated AKCEA-ANGPTL3-LRX) will be assessed 
following multiple-dose SC administration.  The plasma trough levels of AKCEA-ANGPTL3-
LRX during treatment period and those during post-treatment follow up period will be 
descriptively summarized with stratification by subject immunogenicity status if applicable. 
10.6.5 
Pharmacodynamic Analysis 
The following parameters will be measured throughout the trial:  Fasting TGs, plasma 
angiopoietin-like 3 (ANGPTL3), ANGPTL4, ANGPTL8, total cholesterol (TC), low density 
lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), non-high density 
lipoprotein cholesterol (non-HDL-C), very low density lipoprotein cholesterol (VLDL-C), total 
apoC-III, apolipoprotein B-100 (apoB-100), apolipoprotein B-48 (apoB-48), apolipoprotein A-1 


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(apoA-1), apolipoprotein A-2 (apoA-2), apolipoprotein E (apoE), very-low-density 
lipoprotein-triglyceride (VLDL-TG), chylomicron-cholesterol (CM-C), chylomicron triglyceride 
(CM-TG), free fatty acids (FFA), and free glycerol levels. 
10.6.6 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not 
evaluable, and when applicable, titer of anti-AKCEA-ANGPTL3-LRX antibodies) before, during, 
and after treatment with AKCEA-ANGPTL3-LRX will be listed.  Subject ADA status 
(positive/negative or not evaluable) for all evaluable patients, along with the study day associated 
with the first positive IM status emerged (Tfirst, i.e., onset of ADA development), the last positive 
IM status observed (Tlast), the last ADA sample collection day, and subject - peak titer if 
applicable, will be listed and study day. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, 
positive, and unknown status by treatment group.  Furthermore, onset and titer of the ADA 
response, if applicable, will be summarized as median, quartiles (25% and 75%), and range. 
10.6.7 
Additional Analyses 
Additional analyses may be performed not specified in this open label study protocol from the 
data available. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor or designee. 
Before a subject’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the subject or legally acceptable representative after adequate explanation 
of the aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any Study Drug AKCEA-ANGPTL3-LRX are 
administered.  The subject or legally acceptable representative must be given sufficient time to 
consider whether to participate in the study.   
The acquisition of informed consent and the subject’s agreement or refusal to notify his/her 
primary care physician should be documented in the subject’s medical records and the informed 
consent form should be signed and personally dated by the subject or a legally acceptable 
representative and by the person who conducted the informed consent discussion (not necessarily 
an Investigator).  The original signed informed consent form should be retained in the Study 
Master File and in any other locations required by institutional policy, and a copy of the signed 
consent form should be provided to the subject or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally acceptable 
representative, the Investigator must provide an impartial witness to read the informed consent 
form to the subject and must allow for questions.  Thereafter, both the subject or legally 


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acceptable representative and the witness must sign the informed consent form to attest that 
informed consent was freely given and understood. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated October 
2002, the applicable regulations and guidelines of current Good Clinical Practice (GCP), as well 
as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed.  The more recent Declaration of Helsinki version from 
2013 is not being followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written subject information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor or designee before recruitment of subjects into the study and shipment of Study Drug.  
A copy of the written approval of any other items/materials that must be approved by the Study 
Center or IEC/IRB must also be received by the Sponsor or designee before recruitment of 
subjects into the study and shipment of Study Drug.  The Investigator’s Brochure must be 
submitted to the IEC/IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of SAEs occurring at the 
Study Center and other AE reports received from the Sponsor or designee, in accordance with 
local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor or designee. 
11.4 
Subject Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained.  On the case report 
forms or other documents submitted to the Sponsor or designee, subjects should be identified by 
initials (if permitted by local law) and a subject identification number only.  Documents that are 
not for submission to the Sponsor or designee (e.g., signed informed consent forms) should be 
kept in strict confidence by the Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the subject to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the subject. 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  
Agreement from the Investigator must be obtained for all protocol amendments and amendments 
to the informed consent document.  The regulatory authority and IEC/IRB must be informed of 
all amendments and give approval for any amendments likely to affect the safety of the subjects 
or the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor or designee. 
12.2 
Study Termination 
The Sponsor or designee reserves the right to terminate the study.  The Investigator reserves the 
right to terminate their participation in the study, according to the terms of the site contract.  The 
Investigator/Sponsor or designee should notify the IEC/IRB in writing of the trial’s completion 
or early termination and send a copy of the notification to the Sponsor or designee. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the subject’s case report 
form data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, imaging, and correspondence.  Case report 
form entries may be considered source data if the case report form is the site of the original 
recording (i.e., there is no other written or electronic record of data).   
The Investigator and Study Center staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor or designee and/or applicable regulatory authorities.  Elements should include: 
• 
Subject files containing completed case report forms, informed consents, and supporting 
copies of source documentation 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor or designee 
• 
If drug supplies are maintained at the Study Center, proof of receipt, Study Drug Product 
Accountability Record, Return of Study Drug Product for Destruction, final Study Drug 
product reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the case report forms must be 
maintained and be readily available. 


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No study document should be destroyed without prior written agreement between the Sponsor or 
designee and the Investigator.  Should the Investigator wish to assign the study records to 
another party or move them to another location, he/she must notify the Sponsor or designee. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., case report forms and other pertinent data) provided that 
subject confidentiality is respected. 
The Sponsor monitor or designee is responsible for inspecting the case report forms at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research.  
The monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the case report forms. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing case report forms, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department (or designees).  
Inspection of Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review 
of study-related records will occur to evaluate the trial conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
subject data received by the Sponsor or designee.  During this review, subject data will be 
checked for consistency, omissions, and any apparent discrepancies.  In addition, the data will be 
reviewed for adherence to the protocol and GCP.  To resolve any questions arising from the 
clinical data management review process, data queries and/or Study Center notifications will be 
sent to the Study Center for completion and return to Sponsor or designee. 
The Principal Investigator will sign and date the indicated places on the case report form.  These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case 
report form, the data queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Whenever possible, the trade name rather than 
the generic name for concomitant medications should be recorded and if possible, in English.  
Generic names are acceptable if the trade name is unknown.  Combination medications should be 
recorded using their trade name in English if possible. 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 


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12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Subjects will be treated and/or compensated for any study-
related illness/injury in accordance with the information provided in the Compensation for Injury 
section of the Informed Consent document. 
 
 


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14.
APPENDICES


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Appendix A 
Schedule of Procedures 
 
 


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Appendix A Schedule of Procedures  
Study Period 
Screen
/ Run-
in a 
Treatment Period 
Post-treatment 
Follow-up 
Study Week 
-8 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14/E
T 
18 
22 
26 
Study Day 
-56 To -
1 
1 
b 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
120 
148 
176 
Visit and Testing Window +/- Days 
0 
0 
 
2 
 
2 
 
2 
 
2 
 
2 
 
 
 
3 
3 
3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height & Weight c 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Vital Signs 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Physical Examination d 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
12- lead ECG (triplicate) 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Urinalysism 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Blood Draw e 
 
Chemistry Panel (+ CPK) ,f 
X 
X 
 
X g 
 
X 
 
X g 
 
X 
 
X g 
 
X g 
 
X 
 
X 
CBC with Differential f 
X 
X 
 
X g 
 
X 
 
X g 
 
X  
 
X g 
 
X g 
X  
X h 
X 
X 
Serum Lipid Panel  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
PD Panel 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
Coagulation (aPTT, PT, INR) 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Complement Markers C5A, Bb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
hsCRP,  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Hepatitis B, C. HIV.  TSH.  Free 
T4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK i 
 
X1 
 
 
 
X 1 
 
X 1 
 
X 1 
 
X 1 
 
 
X 
X 
X 
X 
Genetic Testing j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-ANGPTL3-LRX Antibodies 
 
X1 
 
 
 
X1 
 
 
 
X1 
 
 
 
 
X 
X 
 
X 
FSH (women only, if applicable) 
k 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test k 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 


ISIS 703802-CS3 
CONFIDENTIAL 
Original  
Protocol 
 
20 July 2017 
 
68 
Study Period 
Screen
/ Run-
in a 
Treatment Period 
Post-treatment 
Follow-up 
Study Week 
-8 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14/E
T 
18 
22 
26 
Study Day 
-56 To -
1 
1 
b 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
120 
148 
176 
Visit and Testing Window +/- Days 
0 
0 
 
2 
 
2 
 
2 
 
2 
 
2 
 
 
 
3 
3 
3 
HbA1C, FPG, and delipidated 
free glycerol  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet aggregation  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Archived Serum & Plasma m 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Blood viscosity  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Post-Prandial Assessment 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
Study Drug Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
All procedures and study samples are to be performed pre-dose at respective visits, unless specified 
a 
Screening procedures performed on the same day and the subject starts the tightly controlled diet, if needed. 
b 
After 56 days on the controlled diet, patients will have baseline measurements and be assessed for qualification of enrollment.  
c 
Height is only required on Day 1. 
 
d 
Full physical exam to be given at Screening and abbreviated physical exam to be given during treatment and follow-up period as indicated to assess changes 
from screening. 
 
e 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours, unless tests are repeated for safety reasons. 
f 
If the platelet value , serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) a repeat blood 
specimen should be re-drawn as soon as possible (ideally within 7 days).  All platelet count results will be reviewed promptly (within 48 hours of receipt) by the 
Investigator.  Any case of a platelet count ≤ 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
g 
Assessments and procedures to be conducted by either a home healthcare service or the Study Center.  Subject Study Center visits must be no more than 
4 weeks apart during the treatment period. 
h 
During follow-up period, hematology sampling for platelet values are taken every 14 days for 6 weeks after last dose of Study Drug, then at Week 22 and 
Week 26 Follow-up visits. 
i 
Refer to Appendix C for PK Sampling schedule. 
j 
Genetic testing will only be performed for eligibility if no documented genetic testing in medical history.  
k 
Women who are not surgically sterile or post-menopausal.  


ISIS 703802-CS3 
CONFIDENTIAL 
Original  
Protocol 
 
20 July 2017 
 
69 
l 
Subjects will be provided standardized meal at Screening visit and will return to the site 2 days later for pre-dose postprandial assessments.  Subjects will be 
provided standardized meal at the Week 14 visit and will return to the site 2 days later for post-dose postprandial assessments. 
m 
Urine, serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) and will be retained until completion of the 
final study report. 
 
Time (time is in reference to Study Drug administration): 
1 
Pre-dose 
 


ISIS 703802 CS3 
CONFIDENTIAL 
Original 
Protocol 
 
20 July 2017 
 
70 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 703802 CS3 
CONFIDENTIAL 
Original 
Protocol 
 
20 July 2017 
 
71 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of AKCEA-ANGPTL3-LRX or 
other similar oligonucleotides. 
Clinical Chemistry 
Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
Insulin 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect 
(unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline 
phosphatase 
• 
Creatinine kinase 
 
Fasting Lipid Panel 
• 
Total cholesterol 
• 
Total ApoB 
• 
ApoB-100 
• 
ApoB-48 
• 
LDL cholesterol 
• 
HDL cholesterol 
• 
Total Triglycerides 
• 
CM triglycerides 
• 
VLDL cholesterol 
• 
VLDL triglycerides 
• 
Non-HDL 
cholesterol 
 
Screening Tests 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis C antibody 
• 
HIV antibody 
• 
FSH (women only) 
• 
Serum βhCG 
• 
Drug screen 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Complement 
• 
C5a 
• 
Bb 
 
PD Panel  
• 
ANGPTL3 
• 
ANGPTL4 
• 
ANGPTL8 
• 
ApoA-I 
• 
ApoB 
• 
ApoC-III 
 
Specialized Lipoprotein 
and post-prandial 
Analyses1 
• 
Lipoprotein particle 
analysis 
• 
Oxidized 
chylomicrons and 
VLDLs 
• 
Isoprostanes 
• 
HDL function 
• 
Lipoprotein 
subclass analysis 
• 
Newly formed CM 
kinetics 
• 
Post-prandial lipid 
panel 
• 
Post-prandial 
platelet count 
• 
Post-prandial 
glucose 
Hematology 
• 
Blood viscosity 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets count 
• 
Platelets function 
• 
White blood cells 
• 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Thyroid Panel 
• 
TSH 
• 
Free T4 
• 
Free T3 
 
Pharmacokinetics and 
Immunogenicity2 
• AKCEA-ANGPTL3-
LRX levels in plasma 
• Anti- AKCEA-
ANGPTL3-LRX 
antibodies in plasma 
 
Genetic Testing 
• 
Molecular 
confirmation of FCS 
• 
Genetic sequencing 
of FCS causing 
genes3 
 
Post-Heparin Panel4 
• 
Post-heparin 
lipoprotein lipase 
mass 
• 
Post-heparin 
lipoprotein lipase 
activity 
• 
Post-heparin 
triglycerides 
Inflammatory 
• 
Hs-CRP  
• 
IL-1b, IL-6, IL-8 
• 
Cytokines panel 
 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination5 
• 
P/C Ratio6 
1 
Scope of specialized lipoprotein analyses will be determined based on results from fasting lipid panel 
2 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation, 
stability assessments, metabolite assessments, testing of additional exploratory pharmacodynamics markers, 
immunogenicity testing (or possibly for immunogenicity assay development and/or validation), or to assess other 
actions of AKCEA-ANGPTL3-LRX with plasma constituents 
3 
If the genotype is not already available, blood will be collected to assess genetic evidence of null loss-of-function 
for LPL.  May not be collected if adequate genetic data are available in medical history or if patient does not 
consent to genetic testing 


ISIS 703802 CS3 
CONFIDENTIAL 
Original 
Protocol 
 
20 July 2017 
 
72 
 
4 
Will be performed on samples per schedule in Appendix D.  Samples may be used to assay other analytes 
5 
Will be performed on abnormal findings unless otherwise specified 
6 
Will be performed at Screening only 


ISIS 703802 CS3 
CONFIDENTIAL 
Original 
Protocol 
 
20 July 2017 
 
73 
 
 
 
 
 
 
 
Appendix C 
PK Sampling Schedule  
 
 


ISIS 703802-CS3 
CONFIDENTIAL 
 Original 
Protocol 
 
 20 July 2017 
 
74 
Appendix C PK Sampling Schedule  
D1 
D29 
D43 
D57 
D71 
D92 
D120 
D148 
D176 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
Anytime 
Anytime 
Anytime 
Note:  D, Day 


ISIS 703802-CS3 
CONFIDENTIAL 
 Original 
Protocol 
 
20 July 2017 
 
75 
 
 
 
 
 
 
 
Appendix D  
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 
 
 


ISIS 703802-CS3 
CONFIDENTIAL 
 Original 
Protocol 
 
20 July 2017 
 
76 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities  
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010. 
 
 
 


ISIS 703802-CS3 
CONFIDENTIAL 
 Original 
Protocol 
 
20 July 2017 
 
77 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 


ISIS 703802-CS3 
CONFIDENTIAL 
 Original 
Protocol 
 
20 July 2017 
 
78 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities  
Continued 
 
 
 


ISIS 703802-CS3 
CONFIDENTIAL 
 Original 
Protocol 
 
20 July 2017 
 
79 
 
 
 
 
 
 
 
Appendix E 
Post-prandial Meal, Sampling Schedule, and 
Assessment 
 


ISIS 703802-CS3 
CONFIDENTIAL 
Original  
Protocol 
 
20 July 2017 
 
80 
Appendix E Post-prandial Meal, Sampling Schedule, and Assessment 
Post-prandial assessment for lipoproteins metabolism will be performed using a radiolabelled 
meal supplemented with a labeled tracer, 3H-palmitate (300µCi, 
 
 Canada), sonicated into the liquid meal.  Palmitate is a fatty acid that is a common 
constituent of any diet.  The 3H-palmitate tracer emits weak radioactivity, equivalent to an X-ray.  
Since dietary palmitate is incorporated into chylomicrons as they are formed in the enterocytes of 
the gut, this enables monitoring the appearance and clearance of newly-formed chylomicrons 
from circulation.  The methodology to be applied for studying post-prandial kinetics of 
chylomicrons appearance and clearance is well-established (Mittendorfer et al. 2003; 
Bickerton et al. 2007; Normand-Lauziere et al. 2010). 
A liquid meal (similar to a milkshake) containing a small amount (300µCi) of radiolabelled fatty 
acids (3H-palmitate) will be provided.  The liquid meal will provide about a third of the daily 
caloric requirements.  From 1 hr prior to 9 hrs after the ingestion of the meal, a constant infusion 
of [U-13C]-K palmitate (0.01µmol/kg/min in 100 ml 25% human serum albumin; 
 
) and a primed (1.6 µmol/kg) continuous 
(0.05 µmol/kg/min) infusion of [1,1,2,3,3-2H]-glycerol 
 
will be administered as previously described (Normand-Lauziere et al. 2010).  Plasma palmitate 
and glycerol appearance rates will be calculated using Steele’s non-steady state equation 
assuming a volume of distribution of 90ml/kg and 230ml/kg, respectively 
(Gastaldelli et al. 1999). 
Blood samples will be drawn at intervals before and after the ingestion of the radiolabelled meal 
on days prior to and after the Treatment phase as noted in the table below.  A standardized meal 
will be given to the participants after the 9 hr blood draw.  Blood will be collected in tubes 
containing Na2EDTA and Orlistat (30 µg/ml, 
 Canada) to prevent in vitro 
triacylglycerol lipolysis and separate samples will be collected in NaF tubes for plasma glucose 
determination. 
Post-prandial Sampling (Blood) Schedule 
Study Day 
D -1 
D1 
D103 
D104 
Visit Window 
+/- Days 
0 
0 
2 
0 
-1 hr pre-prandial, and 
0, 1, 2, 3, 4, 5, 6, 7, 8, 
and 9 hrs post prandial 
24 hrs post-prandial 
/pre SC injection 
-1 hr pre-prandial, and 
0, 1, 2, 3, 4, 5, 6, 7, 8, 
and 9 hrs post-prandial 
24 hrs post-prandial 
 
The following will be measured: 
• Plasma and CM fraction levels for 3H-tracer 
• Plasma [U-13C]-K palmitate and [1,1,2,3,3-2H]-glycerol appearance rates 


ISIS 703802-CS3 
CONFIDENTIAL 
Original  
Protocol 
 
20 July 2017 
 
81 
• Plasma and CM fraction levels for TG, TC, and apoB 
• Plasma, CM, and VLDL fraction levels for apo CIII, apo CII, and apo E 
• Plasma levels for glucose and insulin 
Plasma samples may also be used for profiling of drug binding proteins, bioanalytical method 
validation purposes, stability and metabolite assessments, or to assess other actions of AKCEA-
ANGPTL3-LRX with plasma constituents.  


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
1 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
IONIS PHARMACEUTICALS, INC. 
 
 
ISIS 703802-CS3 
 
A Phase 2 Open-Label Study to Assess the Pharmacodynamics, 
Pharmacokinetics, Safety and Tolerability of AKCEA-ANGPTL3-
LRX (ISIS 703802) Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS) 
 
Protocol Amendment 1 – 26 OCTOBER 2017 
 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
2 
 
ISIS 703802-CS3 
 
A Phase 2 Open-Label Study to Assess the Pharmacodynamics, 
Pharmacokinetics, Safety and Tolerability of AKCEA-ANGPTL3-
LRX (ISIS 703802) Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS) 
  
Protocol Amendment 1– 26 OCTOBER 2017 
 
Protocol History  
Original Protocol: 
 
20 JULY 2017 
Protocol Amendment 1:  
26 OCTOBER 2017 
 
Approved by: 
 
_
____________ 
 MD, FACP  
  
 
 
Akcea Therapeutics, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
Telephone: (617) 207-0202 
 
 
 
ISIS 703802-CS3 
Ionis Protocol Number ISIS 703802-CS3 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
3 
Protocol Amendment 1  
Clinical Phase:  2 
A Phase 2 Open-Label Study to Assess the Pharmacodynamics, 
Pharmacokinetics, Safety and Tolerability of AKCEA-ANGPTL3-
LRX (ISIS 703802) Administered Subcutaneously to Patients with 
Familial Chylomicronemia Syndrome (FCS)  
 
 Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Key sponsor contact:  
 
 - Akcea Therapeutics 
A Subsidiary of Ionis Pharmaceuticals, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA 02142 
Phone: 
 
E-mail: 
 
 
 Sponsor Medical Monitor: 
, MD 
 - Akcea Therapeutics 
A Subsidiary of Ionis Pharmaceuticals, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
Phone: 
 
Mobile: 
 
E-mail: 
 
Date: 
26 OCTOBER 2017 
 
 
 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. and Akcea Therapeutics 
that must not be disclosed to anyone other than the recipient study staff and members of the independent 
ethics committee, institutional review board, or authorized regulatory agencies.  This information cannot 
be used for any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc. and Akcea Therapeutics.




ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
5 
TABLE OF CONTENTS 
 
Page 
PROTOCOL SYNOPSIS ......................................................................................................................... 15 
STUDY DESIGN AND TREATMENT SCHEMA ................................................................................ 20 
STUDY GLOSSARY ................................................................................................................................ 21 
1. 
OBJECTIVES .............................................................................................................................. 24 
1.1 
Primary Objective(s) ................................................................................................................. 24 
1.2 
Secondary Objective(s) ............................................................................................................. 24 
2. 
BACKGROUND AND RATIONALE ....................................................................................... 24 
2.1 
Overview of Disease.................................................................................................................. 24 
2.2 
Therapeutic Rationale ................................................................................................................ 25 
2.3 
AKCEA-ANGPTL3-LRX (ISIS 703802) ................................................................................... 25 
2.3.1 
Mechanism of Action ........................................................................................................ 25 
2.3.2 
Chemistry .......................................................................................................................... 26 
2.3.3 
Preclinical Experience ....................................................................................................... 27 
2.3.3.1 
Preclinical Pharmacology ........................................................................................... 27 
2.3.3.2 
Preclinical Toxicology ............................................................................................... 28 
2.3.4 
Clinical Experience ........................................................................................................... 29 
2.3.4.1 
ISIS 563580-CS1 Phase 1 SAD/MAD ....................................................................... 30 
2.4 
Rationale for Dose and Schedule of Administration ................................................................. 30 
2.5 
Benefit-Risk Assessment ........................................................................................................... 30 
2.5.1 
Benefit Assessment ........................................................................................................... 30 
2.5.2 
Risk Assessment ................................................................................................................ 31 
2.5.3 
Overall Assessment of Benefit:Risk .................................................................................. 31 
3. 
EXPERIMENTAL PLAN ........................................................................................................... 32 
3.1 
Study Design ............................................................................................................................. 32 
3.2 
Number of Study Centers .......................................................................................................... 32 
3.3 
Number of Subjects ................................................................................................................... 32 
3.4 
Overall Study Duration and Follow-up ..................................................................................... 32 
3.4.1 
Screening ........................................................................................................................... 32 
3.4.2 
Treatment .......................................................................................................................... 32 
3.4.3 
Post-Treatment .................................................................................................................. 33 
3.5 
End-of-Study ............................................................................................................................. 33 
4. 
SUBJECT ENROLLMENT ........................................................................................................ 33 
4.1 
Screening ................................................................................................................................... 33 
4.2 
Registration ............................................................................................................................... 33 
4.3 
Replacement of Subjects ........................................................................................................... 33 
5. 
SUBJECT ELIGIBILITY ........................................................................................................... 33 
5.1 
Inclusion Criteria ....................................................................................................................... 33 
5.2 
Exclusion Criteria ...................................................................................................................... 34 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
6 
6. 
STUDY PROCEDURES ............................................................................................................. 36 
6.1 
Study Schedule .......................................................................................................................... 36 
6.1.1 
Screening ........................................................................................................................... 36 
6.1.2 
Treatment Period ............................................................................................................... 37 
6.1.4 
Post-Treatment Period ....................................................................................................... 37 
6.2 
Study/Laboratory Assessments ................................................................................................. 37 
6.3 
Restriction on the Lifestyle of Subjects ..................................................................................... 37 
6.3.1 
Contraception Requirements ............................................................................................. 37 
6.3.2 
Other Requirements ........................................................................................................... 38 
7. 
STUDY DRUG ............................................................................................................................. 38 
7.1 
Study Drug Description ............................................................................................................. 38 
7.1.1 
AKCEA-ANGPTL3-LRX (ISIS 703802) ........................................................................... 38 
7.2 
Packaging and Labeling ............................................................................................................ 39 
7.3 
Study Drug Accountability ........................................................................................................ 39 
8. 
TREATMENT OF SUBJECTS .................................................................................................. 39 
8.1 
Study Drug Administration ....................................................................................................... 39 
8.2 
Other Protocol-Required Drugs ................................................................................................. 39 
8.3 
Other Protocol-Required Treatment Procedures ....................................................................... 39 
8.4 
Treatment Precautions ............................................................................................................... 39 
8.5 
Safety Monitoring Rules ............................................................................................................ 39 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ......................................................... 40 
8.5.2 
Safety Monitoring for Renal Function .............................................................................. 41 
8.5.3 
Safety Monitoring Rules for Platelet Count Results ......................................................... 42 
8.5.4 
Safety Monitoring for Minor Bleeding Events .................................................................. 45 
8.6 
Stopping Rules .......................................................................................................................... 45 
8.6.1 
Stopping Rules for Liver Chemistry Elevations ................................................................ 45 
8.6.2 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules for Renal 
Function Test Results ........................................................................................................ 45 
8.6.3 
Stopping Rule for Platelet Count Results .......................................................................... 46 
8.7 
Adjustment of Dose and/or Treatment Schedule ....................................................................... 47 
8.8 
Discontinuation of Study Drug/Treatment ................................................................................ 47 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from Post-Treatment 
Follow-up Period ............................................................................................................... 47 
8.9 
Withdrawal of Subjects from the Study .................................................................................... 48 
8.10 
Concomitant Therapy and Procedures ....................................................................................... 48 
8.10.1 
Concomitant Therapy ........................................................................................................ 48 
8.10.2 
Concomitant Procedures .................................................................................................... 50 
8.11 
Treatment Compliance .............................................................................................................. 50 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .................................... 50 
9.1 
Sponsor Review of Safety Information ..................................................................................... 50 
9.2 
Regulatory Requirements .......................................................................................................... 50 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
7 
9.3 
Definitions ................................................................................................................................. 50 
9.3.1 
Adverse Event ................................................................................................................... 50 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ......................................................... 50 
9.3.3 
Serious Adverse Event (SAE) ........................................................................................... 51 
9.3.3.1 
Adverse Events of Special Interest ............................................................................. 51 
9.4 
Monitoring and Recording Adverse Events .............................................................................. 51 
9.4.1 
Serious Adverse Events ..................................................................................................... 51 
9.4.2 
Non-Serious Adverse Events ............................................................................................. 52 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ................................................ 52 
9.4.3.1 
Relationship to the Study Drug .................................................................................. 52 
9.4.3.2 
Severity....................................................................................................................... 52 
9.4.3.3 
Action Taken with Study Drug .................................................................................. 53 
9.4.3.4 
Treatment Given for Adverse Event........................................................................... 53 
9.4.3.5 
Outcome of the Adverse Event .................................................................................. 53 
9.5 
Procedures for Handling Special Situations .............................................................................. 54 
9.5.1 
Abnormalities of Laboratory Tests .................................................................................... 54 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ....................... 54 
9.5.3 
Dosing Errors .................................................................................................................... 55 
9.5.4 
Contraception and Pregnancy ............................................................................................ 55 
10. 
STATISTICAL CONSIDERATIONS ....................................................................................... 55 
10.1 
Study Endpoints, Subsets, and Covariates................................................................................. 55 
10.1.1 
Efficacy Endpoints ............................................................................................................ 56 
10.1.2 
Safety Endpoints................................................................................................................ 56 
10.2 
Sample Size Considerations ...................................................................................................... 56 
10.3 
Populations ................................................................................................................................ 56 
10.4 
Definition of Baseline................................................................................................................ 56 
10.5 
Interim Analysis and Early Stopping Guidelines ...................................................................... 56 
10.6 
Planned Methods of Analysis .................................................................................................... 57 
10.6.1 
Demographic and Baseline Characteristics ....................................................................... 57 
10.6.2 
Safety Analysis .................................................................................................................. 57 
10.6.2.1 
Adverse Events ........................................................................................................... 57 
10.6.2.2 
Clinical Laboratory Data ............................................................................................ 57 
10.6.2.3 
Vital Signs and Examinations .................................................................................... 57 
10.6.3  
Efficacy Analysis .............................................................................................................. 57 
10.6.4 
Pharmacokinetic Analysis ................................................................................................. 58 
10.6.5 
Pharmacodynamic Analysis .............................................................................................. 58 
10.6.6 
Immunogenicity Analysis........................................................................................... 58 
10.6.7 
Additional Analyses .......................................................................................................... 58 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS .......................................................... 58 
11.1 
Informed Consent ...................................................................................................................... 58 
11.2 
Ethical Conduct of the Study ..................................................................................................... 59 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
8 
11.3 
Independent Ethics Committee/Institutional Review Board ..................................................... 59 
11.4 
Subject Confidentiality .............................................................................................................. 59 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .............................................................. 60 
12.1 
Protocol Amendments ............................................................................................................... 60 
12.2 
Study Termination ..................................................................................................................... 60 
12.3 
Study Documentation and Storage ............................................................................................ 60 
12.4 
Study Monitoring ...................................................................................................................... 61 
12.5 
Language ................................................................................................................................... 61 
12.6 
Compensation for Injury ............................................................................................................ 62 
13. 
REFERENCES ............................................................................................................................. 63 
14. 
APPENDICES .............................................................................................................................. 67 
Appendix A 
Schedule of Procedures .............................................................................................. 68 
Appendix B 
List of Laboratory Analytes ....................................................................................... 72 
Appendix C 
PK Sampling Schedule ............................................................................................... 75 
Appendix D  
Grading Scale for Adverse Events Relating to Laboratory Abnormalities ................ 77 
Appendix E 
Post-prandial Meal, Sampling Schedule, and Assessment ......................................... 81 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ............................................................................................... 38 
Table 2 
Study Drug Dosing Information ....................................................................................... 39 
Table 3 
Actions in Patients with Low Platelet Count .................................................................... 44 
 
TABLE OF FIGURES 
Page 
Figure 1 
Design of Chimeric 2ʹ-MOE Phosphorothioate Oligonucleotides  (MOE-
Gapmer).  The sequence of AKCEA-ANGPTL3-LRX is shown. ...................................... 27 
 
 
 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
9 
 
PROTOCOL AMENDMENT 
Protocol Number: 
ISIS 703802-CS3 
Protocol Title: 
A Phase 2 Open-Label Study to Assess the Pharmacodynamics, 
Pharmacokinetics, Safety and Tolerability of AKCEA-ANGPTL3-LRX (ISIS 
703802) Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS)  
Amendment Number: Protocol Amendment 1 
Amendment Date: 
26 OCTOBER 2017 
 
The purpose of this protocol amendment is to implement the following modifications to Protocol ISIS 
703802-CS3 Original Protocol dated 20 July 2017: 
• 
Change in language for Exclusion Criteria on how to confirm urine laboratory tests  
• 
Further clarify in the Synopsis that subjects who are on a stable diet do not need to have a six 
week diet stabilization period during screening period 
• 
Include language requested by Health Authority 
• 
Include a measure of abdominal pain assessment (this change is not included in the table below, it 
has resulted in one additional line in the Schedule of Procedures, Appendix A). 
• 
Appendix E was modified to remove the stable isotope tracer [U-13C]-K palmitate and replace it 
by L-[5,5,5-D3] leucine, allowing to document kinetics of all apolipoprotein B containing 
lipoproteins. Section 6.1.2 has also been updated to align with these changes. 
• 
An objective has been added in order to align with the update to the post-prandial assessment: To 
evaluate postprandial lipoprotein kinetics: of CM, VLDL, IDL, LDL and HDL 
• 
Clarify various inconsistencies: 
o Screening period duration 
o Fibrates have been deleted from disallowed concomitant therapy 
o Change to contact for SAE reporting  
o Plasma TG is being updated to serum TG for efficacy analysis 
o Urine samples will not be archived  
o Appendix A has updates, including deletion of FSH at week 1, deletion of FPG since this 
parameter is being measured with the chemistry panel, platelet aggregation has been deleted 
from screening visit, footnote (a, g, l and m) in SOP have changed.  
o Appendix B has updates, including deletion of Post Heparin Panel, as that assessment will not 
be done, deletion of Free T3 under the Thyroid Panel, deletion of drug screen under 
Screening Tests, inclusion of cystatin-C under Clinical Chemistry Panel, inclusion of the 
category Cytokine Panel under Inflammatory and A/C Ratio (UACR) under Urinalysis, 
Specialized Lipoprotein and post-prandial Analyses section has been updated and 24 Hour 
Urine Test has been added (these changes do not appear in the table below, they appear 
updated in Appendix B). 
o Appendix E has been updated to have the pre-dose post-prandial assessment done over a 
period prior to first dose and the post-dose post-prandial assessment is now aligned with 


ISIS 703802-CS3 
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10 
week 14 in Appendix A (this change does not appear in the table below, it only appears 
updated in Appendix E). 
o Two new references have been included as a result to the changes to Appendix E. 
Protocol 
Section 
Description of Change 
Rationale 
Synopsis 
Section 5.2 
Subject 
Eligibility 
Exclusion 
Criteria 
WAS: 
• 
Persistently positive (2 out of 3 consecutive tests ≥ 1+) 
for protein on urine dipstick. In the event of a positive 
test eligibility may be confirmed by a quantitative total 
urine protein measurement of < 500 mg/24 hrs  
• 
Persistently positive (2 out of 3 consecutive tests ≥ trace 
positive) for blood on urine dipstick. In the event of a 
positive test eligibility may be confirmed with urine 
microscopy showing ≤ 5 red blood cells per high power 
field  
• 
Estimated creatinine clearance calculated according to 
the formula of Cockcroft and Gault < 60 mL/min (MDRD 
or CKD-EPI formulas can be used instead of Cockcroft-
Gault for estimation of GFR in patients with low body 
weight after discussion with Sponsor Medical Monitor) 
IS: 
• 
Positive test (including trace) for blood on 
urinalysis.  In the event of a positive test, eligibility 
may be confirmed with urine microscopy showing ≤ 
5 red blood cells per high power field 
• 
Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg. 
In the event of a UPCR above this threshold, 
eligibility may be confirmed by a quantitative total 
urine protein measurement of ˂ 300 mg/24-hr 
• 
Estimated creatinine clearance calculated according to 
the formula of Cockcroft and Gault < 60 mL/min (CKD-
EPI formulas can be used instead of Cockcroft-Gault for 
estimation of GFR in patients with low body weight after 
discussion with Sponsor Medical Monitor) 
Central laboratory will be 
used for this trial.  
Language revised to align 
with safety monitoring 
process at central laboratory.  
Synopsis Study 
Visit Schedule 
and 
Procedures 
WAS: 
• 
An up to 8-week screening period, including a diet 
stabilization period of at least 6 weeks 
IS: 
• 
An up to 8-week screening period, including a diet 
stabilization period of at least 6 weeks for subjects who 
are not already on a stable diet 
The additional language 
further clarifies that subjects 
already on a stable diet can 
forgo the diet stabilization 
period and aligns with other 
sections of the protocol. 
Synopsis and 
Section 1.2 
WAS: 
To evaluate the effect of AKCEA-ANGPTL3-LRX on postprandial 
TG  
 
IS: 
To evaluate the effect of AKCEA-ANGPTL3-LRX on postprandial 
TG and lipoprotein kinetics: of CM, VLDL, IDL, LDL and HDL 
An objective was added in 
order to align with the change 
made to the post-prandial 
assessment. 
Section 6.1.1 
WAS: 
A 4 week period… 
The inconsistency of this 
section was corrected to align 


ISIS 703802-CS3 
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Amendment 1 
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26 October 2017 
 
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IS: 
An up to 8 week period… Subjects on stable diet known to 
the investigator and followed at the site may skip the 4-week 
diet run-in. 
with all other sections and 
further instruction is provided 
for subject on a stable diet. 
Section 6.1.2 
WAS: 
… On each of the post-prandial evaluation days, following the 
blood draws, patients will consume a standardized liquid meal 
(which represents about a third of the daily caloric requirements) 
with a stable radioisotope tracer, followed by an 8 hour 
radioisotope infusion and serial 
 
IS: 
On each of the post-prandial evaluation days, following the first 
blood draw, patients will consume a standardized liquid meal 
(which represents about a third of the daily caloric requirements) 
containing a radioisotope tracer, followed by an 9 hour infusion 
of two stable isotope tracers and serial 
 
Section 6.1.4 
WAS: 
A ± 1-day excursion from the scheduled visit date is permitted for 
this time period.  
 
IS: 
A ± 3-day excursion from the scheduled visit date is permitted for 
this time period.  
Correction made to align with 
Appendix A. 
Section 6.2 
WAS: 
Blood chemistry and urine samples (excluding 24-hour urine 
collection) should be taken be taken after fasting… 
 
IS: 
Blood chemistry and urine samples (excluding 24-hour urine 
collection) should be taken after fasting… 
Error corrected 
Section 8.5.1 
WAS: 
All patients will have liver chemistry tests monitored every 2 
weeks during and treatment and follow-up Period. 
 
IS: 
All patients will have liver chemistry tests monitored every 2 
weeks during the treatment and follow-up Period. 
Error corrected. 
Section 8.10.1 
WAS: 
Fibrates within 8 weeks of screening 
 
IS: 
Not applicable 
The inconsistency of this 
section was corrected to align 
with all other sections. 
Section 9.4.1 
WAS: 
Attention: 
 
Email: 
 
Fax: 
 
 
 
The safety reporting vendor 
was changed. 


ISIS 703802-CS3 
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Amendment 1 
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26 October 2017 
 
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IS: 
 
 – USA: 
Telephone: 
 or 
 
Facsimile: 
 or 
 
e-mail: 
 
Section 10.6.3 
WAS: 
Response rate of patients with fasting plasma TG < 750 mg/dL or 
achieving fasting TG ≥ 40% reduction from baseline at Month 3 
will be summarized.  Response analysis will also be conducted 
using a range of fasting plasma TG thresholds for determination 
of responder status. 
 
IS: 
Response rate of patients with fasting serum TG < 750 mg/dL or 
achieving fasting TG ≥ 40% reduction from baseline at Month 3 
will be summarized.  Response analysis will also be conducted 
using a range of fasting serum TG thresholds for determination of 
responder status. 
The matrix in which TG are 
measured in serum. 
Section 11.1  
WAS: 
Not applicable 
 
IS: 
The sponsor shall maintain all records referred to in the 
applicable Regulations for a period of 25 years. 
Requested by Health 
Authority 
Appendix A 
footnote 
WAS: 
Urine, serum and plasma samples will be collected and stored for 
follow-up exploration of laboratory findings and/or AEs (e.g., 
measurement of cytokine and/or chemokine levels, measurement 
of additional markers of kidney function, measurement of 
antibodies, etc.) and will be retained until completion of the final 
study report. 
 
IS: 
Serum and plasma samples will be collected and stored for 
follow-up exploration of laboratory findings and/or AEs (e.g., 
measurement of cytokine and/or chemokine levels, measurement 
of additional markers of kidney function, measurement of 
antibodies, etc.) and will be retained until completion of the final 
study report. 
There is no plan to archive 
urine from subjects in this 
trial. 
Appendix E 
footnote 
WAS: 
Not applicable 
 
IS: 
a 
There is a range for this visit, it should happen prior 
to and as close as possible to Day 1. 
Clarification 
Appendix E 
WAS: 
Post-prandial assessment for lipoproteins metabolism will be 
performed using a radiolabelled meal supplemented with a 
This change will allow 
documentation of kinetics for 
all apolipoprotein B containing 


ISIS 703802-CS3 
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13 
labeled tracer, 3H-palmitate (300µCi, 
 
 Canada), sonicated… 
A liquid meal (similar to a milkshake) containing a small amount 
(300µCi) of radiolabelled fatty acids (3H-palmitate) will be 
provided.  The liquid meal will provide about a third of the daily 
caloric requirements.  From 1 hr prior to 9 hrs after the ingestion 
of the meal, a constant infusion of [U 13 C] K palmitate (0.01 
µmol/kg/min in 100 mL 25% human albumin; 
 
) and a primed (1.6 mmol/kg) 
continuous (0.05 mmol/kg/min) infusion of [1,1,2,3,3-2H]-glycerol 
 will be administered as 
previously described (Normand-Lauziere et al. 2010).  Plasma 
palmitate and glycerol appearance rates will be calculated using 
Steele’s non-steady state equation assuming a volume of 
distribution of 90mL/kg and 230ml/kg, respectively 
(Gastaldelli et al. 1999).  
… 
The following will be measured: 
Plasma and CM fraction levels for 3H tracer 
Plasma [U 13C] K palmitate and [1,1,2,3,3 2H] glycerol 
appearance rates 
Plasma and CM fraction levels for TG, TC, and apoB 
Plasma, CM, and VLDL fraction levels for apo CIII, apo CII, and 
apo E 
Plasma levels for glucose and insulin 
 
IS: 
Post-prandial assessment for lipoproteins metabolism 
(lipoprotein kinetics: newly formed CM, VLDL, IDL, LDL and 
HDL) will be performed as follow.  A  radiolabelled meal 
supplemented with a labeled tracer, 3H-palmitate (300µCi, 
 
 Canada), will be sonicated 
A liquid meal (similar to a milkshake) containing a small amount 
(300µCi) of radiolabelled fatty acids (3H-palmitate) will be 
provided.  The liquid meal will provide about a third of the daily 
caloric requirements.  From 1 hr prior to 9 hrs after the ingestion 
of the meal, two stable isotope tracers will be continuously 
infused. A primed (1.6 mmol/kg) continuous (0.05 mmol/kg/min) 
infusion of [1,1,2,3,3-2H]-glycerol 
 
 will be administered as previously described 
(Normand-Lauziere et al. 2010).  To document VLDL, IDL, LDL 
and HDL kinetics, L-[5,5,5-D3] leucine (10 mmol/kg) will be 
injected as a bolus intravenously and then by continuous 
infusion (10 mmol·kg body weight-1·h-1) (Tremblay et al. 2006). 
Glycerol appearance rates will be calculated using Steele’s non-
steady state equation assuming a volume of distribution of 
230ml/kg, respectively (Gastaldelli et al. 1999). The isotopic 
enrichment of leucine in the apolipoproteins will be 
expressed as tracer/tracee ratio (%) using standardized 
formulas (Cobelli et al. 1987). 
lipoproteins. 
 
  


ISIS 703802-CS3 
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ISIS 703802-CS3 
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15 
PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2 Open-Label Study to Assess the Pharmacodynamics, 
Pharmacokinetics, Safety and Tolerability of AKCEA-ANGPTL3-LRX (ISIS 
703802) Administered Subcutaneously to Patients with Familial 
Chylomicronemia Syndrome (FCS) 
Study Phase 
2 
Indication 
Familial Chylomicronemia Syndrome 
Objectives 
 
The primary objective is to evaluate the efficacy of AKCEA-ANGPTL3-LRX for 
reduction of triglyceride (TG) levels in patients with FCS  
Secondary objectives are: 
To evaluate the effect of AKCEA-ANGPTL3-LRX on plasma angiopoietin-like 3 
(ANGPTL3) and other lipid parameters. 
To evaluate the effect of AKCEA-ANGPTL3-LRX on postprandial TG and 
lipoprotein kinetics: of CM, VLDL, IDL, LDL and HDL  
To evaluate the pharmacokinetics of AKCEA-ANGPTL3-LRX 
To evaluate safety and tolerability of AKCEA-ANGPTL3-LRX  
Study Design 
This is an, open-label study in 3 FCS patients. After confirming eligibility for 
the study during the screening period, patients will enter a 13-week treatment 
period.  Study drug (AKCEA-ANGPTL3-LRX) will be administered every week 
for 13 weeks during the treatment period.  The patients will then enter a 13 
week post-treatment evaluation follow-up period. 
Number of Subjects 
3 
Study Population 
Inclusion: 
1. 
Must have given written informed consent (signed and dated) and any 
authorizations required by local law and be able to comply with all 
study requirements. 
2. 
Males or females aged > 18 years old at the time of informed consent 
3. 
Genetically confirmed homozygote or compound heterozygote for 
known null loss-of-function mutations in the LPL gene. 
4. 
Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening. If the fasting TG 
< 750 mg/dL up to 2 additional tests may be performed in order to 
qualify. 
5. 
Willing to follow a diet comprising ≤ 20g fat per day during the study 
6.  Females:  must be non-pregnant and non-lactating and either;  
i. 
Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy); 
ii. 
Post-menopausal (defined as 12 months of spontaneous 
amenorrhea in females > 55 years of age or, in females ≤ 55 
years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal 
range for the laboratory involved); 
iii. Abstinent* or, 
iv. If engaged in sexual relations of child-bearing potential, agree to 


ISIS 703802-CS3 
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26 October 2017 
 
16 
use 2 highly effective contraceptive methods (refer to Section 
6.3.1) from the time of signing the informed consent form until at 
least 13 weeks after the last dose of Study Drug (AKCEA-
ANGPTL3-LRX) 
a. 
Males:  Surgically sterile or if engaged in sexual relations with a 
female of child-bearing potential, subject is utilizing an 
acceptable contraceptive method (refer to Section 6.3.1) from 
the time of signing the informed consent form until at least 13 
weeks after the last dose of Study Drug (AKCEA-ANGPTL3-
LRX) 
* Abstinence is only acceptable as true abstinence, i.e., when this is in line 
with the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a trial and withdrawal are not acceptable 
methods of contraception 
Exclusion: 
1. 
Diabetes mellitus with any of the following:  
b. 
Newly diagnosed within 12 weeks of screening  
c. 
HbA1c ≥ 9.0% at Screening  
d. 
Recent change in anti-diabetic pharmacotherapy (change in 
dosage or addition of new medication within 12 weeks of 
screening [with the exception of ± 10 units of insulin])  
e. 
Current use of GLP-1 agonists 
2.  Active pancreatitis within 2 weeks prior to screening 
3. 
History within 6 months of screening of acute or unstable cardiac 
ischemia (myocardial infarction, acute coronary syndrome, new onset 
angina, stroke, transient ischemic attack or unstable congestive 
cardiac failure requiring a change in medication) or major surgery 
within 3 months of screening 
4. 
Any of the following laboratory values at Screening  
f. 
Hepatic:  
g. 
Total bilirubin > upper limit of normal (ULN), unless prior 
diagnosis and documentation of Gilbert’s syndrome in which 
case total bilirubin must be ≤ 3 mg/dL  
h. 
ALT > 2.0 x ULN  
i. 
AST > 2.0 x ULN  
j. 
Renal:  
• 
Positive test (including trace) for blood on urinalysis.  In the 
event of a positive test, eligibility may be confirmed with urine 
microscopy showing ≤ 5 red blood cells per high power field 
• 
Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg. In the 
event of a UPCR above this threshold, eligibility may be 
confirmed by a quantitative total urine protein measurement of 
˂ 300 mg/24-hr 
k. 
Estimated creatinine clearance calculated according to the 
formula of Cockcroft and Gault < 60 mL/min (CKD-EPI 


ISIS 703802-CS3 
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17 
formulas can be used instead of Cockcroft-Gault for estimation 
of GFR in patients with low body weight after discussion with 
Sponsor Medical Monitor)  
l. 
Platelet count < 140,000 mm3    
m. Any other laboratory abnormalities which, in the opinion of the 
Investigator or the Sponsor, would make the patient unsuitable 
for inclusion 
5. 
Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg) 
6. 
History of bleeding diathesis or coagulopathy or clinically-significant 
abnormality in coagulation parameters at Screening 
7. 
History of heart failure with NYHA greater than Class II 
8. 
Active infection requiring systemic antiviral or antimicrobial therapy 
that will not be completed prior to Study Day 1 
9. 
Known history of or positive test for human immunodeficiency virus 
(HIV), hepatitis C or chronic hepatitis B 
10. Malignancy within 5 years, except for basal or squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix that has been 
successfully treated 
11. Treatment with another investigational drug, biological agent, or 
device within 1-month of screening, or 5 half-lives of investigational 
agent, whichever is longer 
12. Unwilling to comply with lifestyle requirements 
13. Use of any of the following:  
a. 
Statins, omega-3 fatty acids (prescription or OTC), or fibrates 
unless on a stable dose for at least 3 months prior to screening 
and dose and regimen expected to remain constant during the 
treatment period. Patients taking OTC omega-3 fatty acids 
should make every effort to remain on the same brand 
throughout the study.  
b. 
Nicotinic acid or derivatives of nicotinic acid within 4 weeks 
prior to screening  
c. 
Systemic corticosteroids or anabolic steroids within 6 weeks 
prior to screening unless approved by the Sponsor Medical 
Monitor  
d. 
Atypical antipsychotic medications (e.g., olanzapine and 
clozapine) unless on a stable dose for at least 3 months prior to 
screening and dose and regimen expected to remain stable 
throughout the study  
e. 
Antihypertensive medication unless on a stable dose for at 
least 4 weeks prior to screening and dose and regimen 
expected to remain constant during the treatment period  
f. 
Glybera gene therapy within 2 years prior to screening  
g. 
Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban,  
apixaban) unless on a stable dose for at least 4 weeks prior to 
screening and regular clinical monitoring is performed  
h. 
Tamoxifen, estrogens or progestins unless on a stable dose for 


ISIS 703802-CS3 
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18 
at least 4 months prior to screening and dose and regimen 
expected to remain constant during the treatment period  
i. 
Plasma apheresis within 4 weeks prior to screening or planned 
during the study  
j. 
Prior exposure to AKCEA-ANGPTL3-LRX  
k. 
Any other medication unless stable at least 4 weeks prior to 
screening (Occasional or intermittent use of over-the-counter 
medications will be allowed at Investigator’s discretion)  
14. Blood donation of 50 to 499 mL within 30 days of screening or of > 
499 mL within 60 days of screening  
15.  Known hypersensitivity to any of the excipients of the Study Drug  
16. Have any other conditions, which, in the opinion of the Investigator or 
the Sponsor would make the patient unsuitable for inclusion, or could 
interfere with the patient participating in or completing the study  
Treatment Groups 
Single group, open-label treatment with AKCEA-ANGPTL3-LRX by 
subcutaneous injection at 20 mg weekly 
Study Drug Dosage and 
Administration 
The Sponsor will provide AKCEA-ANGPTL3-LRX in a single use vial with a 
concentration of 100 mg/mL.  
The study dose of 20 mg (0.2 mL) of AKCEA-ANGPTL3-LRX will be 
administered every week during the treatment period. All doses will be given 
by SC injection.  Self-administration will be allowed after appropriate training 
of patient and/or caregiver. 
Rationale for Dose and Schedule 
Selection 
A 20 mg weekly dose was selected as being the lowest dose that provided 
maximum TG lowering of approximately 60%, based on the TG lowering 
effect of AKCEA-ANGPTL3-LRX observed in healthy volunteers with elevated 
TGs.  
Study Visit Schedule and 
Procedures 
Detailed information regarding the study procedures are outlined in Section 6, 
Appendices A and C. 
The study for an individual subject will consist of the following periods:  
An up to 8-week screening period, including a diet stabilization period of at 
least 6 weeks for subjects who are not already on a stable diet 
A 13 week treatment period during which Study Drug will be administered 
open label by SC injection 
A 13-week post-treatment follow-up period 
Patients will receive up to 13 SC doses of AKCEA-ANGPTL3-LRX weekly.  
Patients will return regularly for outpatient visits throughout the treatment and 
post-treatment follow-up periods according to the Schedule of Procedures 
(Appendix A).  
Blood and urine samples will be collected regularly throughout the study for 
safety, efficacy, and PK analysis.  Appendix B shows a list of analytes 
required for the study and Appendix C details the PK sample schedules. 
Pharmacodynamic and 
postprandial Evaluations 
Fasting TGs, plasma angiopoietin-like 3 (ANGPTL3), ANGPTL4, ANGPTL8, 
total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high 
density lipoprotein cholesterol (HDL-C), non-high density lipoprotein 
cholesterol (non-HDL-C), very low density lipoprotein cholesterol (VLDL-C). 
total apoC-III, apolipoprotein B-100 (apoB-100), apolipoprotein B-48 (apoB-


ISIS 703802-CS3 
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48), apolipoprotein A-1 (apoA-1), apolipoprotein A-2 (apoA-2), apolipoprotein 
E (apoE), very-low-density lipoprotein-triglyceride (VLDL-TG), chylomicron-
cholesterol (CM-C), chylomicron triglyceride (CM-TG), free fatty acids (FFA), 
and free glycerol levels 
Postprandial TGs and lipoprotein kinetics: of CM, VLDL, IDL, LDL and HDL 
prior and post dose by postprandial assessment  
Pharmacokinetic Evaluations 
The plasma PK of AKCEA-ANGPTL3-LRX (as total full length 
oligonucleotides, including, fully conjugated, partially conjugated, and 
unconjugated AKCEA-ANGPTL3-LRX) will be assessed following multiple-
dose SC administration.  The plasma trough levels of AKCEA-ANGPTL3-LRX 
during treatment period and those during post-treatment follow up period will 
be descriptively summarized with stratification by subject immunogenicity 
status if applicable. 
Safety and Tolerability 
Evaluations 
Safety and tolerability assessments include: adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, ECGs and use of 
concomitant medications.   
Statistical Considerations 
There is no statistical rationale for the selected sample size.  The sample size 
is based on prior experience with second generation and N-acetyl 
galactosamine (GalNAc)-modified antisense oligonucleotides (ASOs) in 
healthy volunteers and to ensure that the safety, tolerability, 
pharmacokinetics, and preliminary pharmacodynamics of AKCEA-ANGPTL3-
LRX will be adequately assessed while minimizing unnecessary subject 
exposure. 
Sponsor / Collaborator 
Ionis Pharmaceuticals/Akcea Therapeutics 
 
 


ISIS 703802-CS3 
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STUDY DESIGN AND TREATMENT SCHEMA 
 
 
TREATMENT PERIOD 
Weeks 1 to 13 
 
All Subjects will be receive 20 mg of 
AKCEA-ANGPTL3-LRX administered 
weekly by SC injection 
 
Routine safety assessments:  PK and 
PD assessments at specified time 
points per the Schedule of Procedures 
in Appendix A. 
POST-TREATMENT 
EVALUATIONS    
  Weeks 13 to 26 
4 clinical visits for safety,  
PK and PD assessments 
 
END-OF-STUDY 
PROCEDURES 
Early termination or Day 
Week 26 / Day 182 
 
EARLY 
TREATMENT 
TERMINATION 
Follow Week 14 
Schedule of 
Procedures at ET;  
 
Patient strongly 
encouraged to visit 
clinic for post-
treatment 
assessments 
 
SCREENING / DIET RUN-IN 
 
Weeks -8 to -1 (period may be reduced if the patient 
is following a stable low fat diet for a minimum of 6 
weeks) 


ISIS 703802-CS3 
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STUDY GLOSSARY 
Abbreviation/Acronym 
Definition 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
apoA-I 
Apolipoprotein A-I 
apoB 
Apolipoprotein B 
apoC-III 
Apolipoprotein C-III 
aPTT 
Activated partial thromboplastin time 
ASO 
Antisense oligonucleotide 
AST 
Aspartate aminotransferase 
AUCt 
Area under the plasma concentration-time curve from zero time (pre-
dose) to selected time (t) after Study Drug administration 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CHD 
Coronary heart disease 
CK 
Creatine kinase 
Cmax 
Maximum observed drug concentration 
Day 1 
Defined as the first day Study Drug product is administered to the 
subject 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FCS 
FH 
Familial Chylomicronemia Syndrome 
Familial hypercholesterolemia 
FHBL 
Familial hypobetalipoproteinemia  
FHBL2 
Familial combined hypolipidemia 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 


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Abbreviation/Acronym 
Definition 
HbA1c 
Glycated hemoglobin 
HDL-C 
High density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia 
HIV 
Human immunodeficiency virus 
HoFH 
Homozygous familial hypercholesterolemia 
HR 
Heart rate 
ICH 
International Conference on Harmonization 
INR 
International normalized ratio 
IRB 
Institutional review board 
LDL-C 
Low density lipoprotein cholesterol 
LDLR 
LDL receptor 
LLN 
Lower limit of normal 
Lp(a) 
Lipoprotein (a) 
LPL 
Lipoprotein lipase 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
MOE 
2′-O-(2-methoxyethyl) 
MRI 
Magnetic resonance imaging 
mRNA 
messenger ribonucleic acid (RNA) 
MTP 
Microsomal triglyceride transfer protein 
NCS 
Not clinically-significant 
NEFA 
Non-esterified fatty acids 
Non-HDL-C 
Non-high density lipoprotein cholesterol 
OTC 
Over-the-counter 
P/C 
Urine protein/creatinine 
PCSK9 
Proprotein convertase subtilisin kexin type 9 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Prothrombin time 


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Abbreviation/Acronym 
Definition 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SC 
Subcutaneous 
siRNA 
Small interfering RNA 
Study Drug 
AKCEA-ANGPTL3-LRX (ISIS 703802) 
SUSAR 
Suspected unexpected serious adverse reactions 
t 
Times 
t1/2λz 
Plasma terminal elimination half-life  
TC 
Total cholesterol 
TG 
Triglyceride 
Tmax 
Time to reach Cmax 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VLDL-C 
Very low density lipoprotein cholesterol 
 
 
 
 
 


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1. 
OBJECTIVES 
1.1 
Primary Objective(s) 
• 
The primary objective is to evaluate the efficacy of AKCEA-ANGPTL3-LRX (also known as ISIS 
703802 in this document) for reduction of triglyceride (TG) levels in patients with FCS  
1.2 
Secondary Objective(s) 
• 
To evaluate the effect of AKCEA-ANGPTL3-LRX on plasma angiopoietin-like 3 (ANGPTL3) 
and other lipid parameters. 
• 
To evaluate the effect of AKCEA-ANGPTL3-LRX on postprandial TG and lipoprotein kinetics: of 
CM, VLDL, IDL, LDL and HDL 
• 
To evaluate the pharmacokinetics of AKCEA-ANGPTL3-LRX  
• 
To evaluate safety and tolerance of AKCEA-ANGPTL3-LRX  
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Familial Chylomicronemia Syndrome (FCS) is an inherited disease characterized by severe 
hypertriglyceridemia and chylomicronemia. It is a rare autosomal recessive disease that can be diagnosed 
either in childhood or adulthood.  
FCS is characterized by frequent and severe abdominal pain, repetitive colicky pain, repeated episodes of 
potentially fatal acute pancreatitis, and in children, can result in a failure to thrive (Brunzell 1999-2011; 
Tremblay et al. 2011).  Physical examination frequently reveals eruptive xanthomas, lipemia retinalis and 
hepatosplenomegaly, and plasma from patients appears lactescent, interfering with determination of other 
laboratory parameters (Tremblay et al. 2011).  Fasting plasma triglyceride (TG) levels in FCS patients are 
typically 10-fold to 100-fold above normal (1,500 to 15,000 mg/dL), despite extreme dietary fat 
restriction (20 g or approximately 15-20% of daily calorie intake) (Brunzell 1999-2011).  
Patients with FCS often present in infancy or childhood with recurrent episodes of abdominal pain or 
pancreatitis, eruptive xanthomas or hepatomegaly.  The diagnosis of FCS is then established by 
genotyping or confirmation of very low or absent lipoprotein lipase (LPL) enzyme activity in post heparin 
plasma (Brunzell 1999-2011).  
Patients with FCS carry a heavy burden of medical complications, the most serious being an extreme risk 
of recurrent and potentially fatal pancreatitis.  Due to the recurrent episodes of acute pancreatitis, these 
patients may also develop chronic pancreatitis and signs of exocrine or endocrine pancreatic 
insufficiency, including diabetes mellitus (Gaudet et al. 2013).  While the pathophysiology underlying 
chylomicron-related pancreatitis has not been completely elucidated, one hypothesis is that large 
chylomicrons lodged in pancreatic capillaries are exposed to pancreatic lipase, with the subsequent 
release of free fatty acids through the hydrolysis of chylomicron-associated TGs.  High concentrations of 
free fatty acids are thought to damage pancreatic cells leading to emergent pancreatitis (Yang et al. 2009; 
Berglund et al. 2012).  
The etiology of extreme hypertriglyceridemia in FCS is considered to be ineffective triglyceride 
clearance, due to an extremely low level of LPL activity.  LPL normally functions to hydrolyze 


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triglycerides in chylomicrons along the luminal surface of capillaries, mainly in heart, skeletal muscle, 
and adipose tissue, promoting triglyceride clearance from the circulation.  LPL is regulated by a number 
of key genes, and loss-of-function mutations in one of these genes, or the LPL gene itself, results in FCS 
(Surendran et al. 2012).  In addition to loss of function mutations, null mutations, and nonsense mutations 
in the LPL gene, other genes currently identified in FCS patients, and known to directly influence LPL 
activity include: apolipoprotein C-II (APOC2) a cofactor for LPL (Schuster et al. 2011); apolipoprotein 
A-V (APOA5) (Schaap et al. 2004); lipase maturation Factor 1 (LMF1), a transmembrane protein 
involved in LPL maturation (Doolittle et al. 2009); glycosylphosphatidylinositol-anchored HDL-binding 
protein 1 (GPIHBP1), a capillary endothelial cell protein that provides a platform for LPL-mediated 
processing of chylomicrons (Beigneux et al. 2007). 
2.2 
Therapeutic Rationale 
The preclinical and human genetic studies strongly support a potential role for an ASO approach to lower 
plasma ANGPTL3 in humans to decrease elevated TG and LDL-C levels in patients that cannot be 
adequately managed by existing therapies.  
Numerous genome-wide association studies have been published in recent years confirming the 
association of mutations in human ANGPTL3 with reductions in serum lipids in human subjects 
(Minicocci et al. 2013).  The mechanism(s) by which ANGPTL3 affects lipoprotein metabolism appears 
to be complex, as loss of ANGPTL3 leads to a decrease in multiple atherogenic lipoprotein levels that is 
hard to ascribe to any 1 single mode of action.  ANGPTL3 deficiency in animals accelerates the clearance 
of VLDL particles from plasma because of increase in lipoprotein lipase (LPL) activity, whereas 
overexpression or intravenous injection of recombinant ANGPTL3 has opposite effects.  These and other 
observations support a possible role of the LPL enzyme.  However, a direct demonstration of this 
mechanism has not been provided.  Understanding the mechanism of action of ANGPTL3 is a present 
area of active research (Gusarova et al. 2015; Haridas et al 2015; Wang X et al. 2015; Wang Y et al. 
2015a; Wang Y et al. 2015b). 
The goal of the present protocol is to explore the effects of lowering ANGPTL3 in FCS patients using 
AKCEA-ANGPTL3-LRX (also known ISIS 703802), using a dose selected on the basis of results in 
healthy volunteers, to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of 
AKCEA-ANGPTL3-LRX in these patients. 
The known potential risks to study participants associated with AKCEA-ANGPTL3-LRX are further 
discussed in the Guidance to Investigator section of the Investigator’s Brochure. 
2.3 
AKCEA-ANGPTL3-LRX (ISIS 703802) 
2.3.1 
Mechanism of Action 
AKCEA-ANGPTL3-LRX is a second-generation ASO drug targeted to ANGPTL3 that has been 
covalently bonded to triantennary N-acetyl galactosamine (GalNAc), a high-affinity ligand for the 
hepatocyte-specific asialoglycoprotein receptor (ASGPR) to form an ASO-GalNAc conjugate.  This 
GalNAc-conjugate approach results in enhanced ASO delivery to hepatocytes versus non-parenchymal 
cells and has increased ASO potency by approximately 10-fold in mice (Prakash et al. 2014).  The ASO 
portion of AKCEA-ANGPTL3-LRX is complementary to a region within the ANGPTL3 messenger 
ribonucleic acid (RNA) (mRNA) coding sequence, and binds to the mRNA via Watson and Crick base 
pairing.  The hybridization (binding) of AKCEA-ANGPTL3-LRX to the cognate mRNA results in the 
Ribonuclease H1 (RNase H1)-mediated degradation of the ANGPTL3 mRNA, thus preventing 


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production of the ANGPTL3 protein.  Maximal antisense-mediated reduction of target mRNA levels is 
typically greater than 90% of control levels in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 
2010).  Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2 
Chemistry 
Chemically, AKCEA-ANGPTL3-LRX is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate and phosphodiester linkages (mixed backbone design).  The 
mixed backbone design reduces the total number of phosphorothioate linkages in the MOE-modified 
regions, which reduces non-specific interactions with proteins and further enhances potency of GalNAc 
conjugated ASOs.  The nucleotide sequence of AKCEA-ANGPTL3-LRX (Figure 1) is complementary to a 
20-nucleotide stretch within Exon 6 of the ANGPTL3 mRNA coding sequence at position 1169-1188 bp. 
Structurally, the oligonucleotide has 4 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 
nucleotides at the 3′ end, are composed of 2′-O-(2-methoxyethyl) (2′-MOE)-modified ribonucleotides.  
These MOE-modified nucleotides confer (1) increased affinity for the target mRNA (Altmann et al. 1996; 
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby increasing 
stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high dose toxicities thereby 
resulting in an improved safety profile compared to first generation antisense drugs containing 
phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  The third region, the 
central portion of the oligonucleotide, is composed of 10 oligodeoxynucleotides.  This chimeric design is 
called a MOE-Gapmer, and AKCEA-ANGPTL3-LRX employs this chimeric structure to enable use of the 
RNase H1 mechanism for antisense activity.  This is because while the 2′-MOE modification confers 
increased stability and affinity, it does not support RNase H1 catalyzed cleavage of RNA hybridized to 2′-
MOE-modified nucleotides (McKay et al. 1999).  This is caused by conformational changes induced in 
the heteroduplex by 2′-alkoxy:RNA hybrids that are not recognized by RNase H enzymes (Inoue et al. 
1987; Monia et al. 1993).  By limiting the 2′-MOE modification to nucleotides flanking the 
phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2′-MOE chemistry are 
preserved while also retaining RNase H1 recognition.  The fourth region is comprised of a triantennary 
cluster of N-acetyl galactosamine (GalNAc) sugars which is linked to the 5ʹ end of AKCEA-ANGPTL3-
LRX via a phosphodiester linkage.  The GalNAc cluster is a high affinity ligand for the asialoglycoprotein 
receptor (ASGPR), a receptor expressed primarily on the surface of liver hepatocytes (Stockert 1995).  
The GalNAc cluster enhances delivery of AKCEA-ANGPTL3-LRX to liver hepatocytes over other cell 
types and enhances potency.  After internalization into cells, the GalNAc cluster is metabolized to release 
‘free ASO’ inside the cell (Prakash et al. 2014). 




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with concomitant reductions in plasma TG and cholesterol.  Importantly, the potency and the lipid-
lowering effects of the ANGPTL3 ASO were independent of diet. 
Finally, administration of a mouse-specific ANGPTL3 ASO to western diet fed Ldlr-/-, a mouse model of 
FH, also led to significant reductions in hepatic ANGPTL3 mRNA and plasma ANGPTL3 protein with 
concomitant reductions in plasma TG and LDL-C that were similar to what was observed in wild type 
western diet fed mice, indicating that the absence of Ldlr does not affect the ASOs potency or lipid-
lowering effects.  This suggests that administration of ANGPTL3 ASO administration is a promising 
target for clinical study in familial hypercholesterolemia patients. 
While formal pharmacology studies have not been conducted in the monkey with the human ANGPTL3 
ASO, hepatic mRNA expression has been shown to be reduced by more than 60% in cynomolgus 
monkeys, the same model used to conduct the toxicology evaluation. 
2.3.3.2 
Preclinical Toxicology 
General toxicology studies for AKCEA-ANGPTL3-LRX consisted of sub-chronic (16-week) and chronic 
(26- or 39-week) toxicity studies CD-1 in mice and cynomolgus monkeys.  Since AKCEA-ANGPTL3-
LRX is not fully complementary to the mouse ANGPTL3 transcript, treatment group receiving a mouse-
specific inhibitor (ISIS 731875) was also included in the mouse study.  Please refer to the Investigator 
Brochure for a detailed description of the preclinical toxicology and pharmacokinetics with AKCEA-
ANGPTL3-LRX. 
Pharmacokinetic data confirmed continuous and dose-dependent exposure to AKCEA-ANGPTL3-LRX.  
An estimated liver and plasma elimination half-life values of approximately 1 week and 3-4 weeks for 
2 mg/kg and 35 mg/kg, respectively, were observed in monkeys.  The most noteworthy findings observed 
in mice and monkeys following AKCEA-ANGPTL3-LRX treatment were, in general, non-specific class 
effects related to the uptake and accumulation of ASO and no toxicologically relevant findings were 
considered related to the pharmacologic inhibition of hepatic ANGPTL3 expression, either with the 
present series of studies or with the former development candidate targeting ANGPTL3. There were no 
test-article related changes in PLT count in either mouse or monkey in both sub-chronic and chronic 
studies. 
The most noteworthy finding in the monkey was the kidney alteration (hypoalbuminemia and proteinuria) 
seen in one early-sacrifice animal from the 16-week study at 35 mg/kg/week, a dose equivalent to at least 
~190-fold of the 40 mg weekly clinical doses by plasma AUC.  Non-dose dependent increases in renal 
protein excretion (up to 2.2-fold in quantitative urine protein, protein/creatinine ratio or urine albumin) 
were also observed at 8 and/or 35 mg/kg/week (> ~ 30 to 190-fold of the 40 mg weekly clinical doses by 
plasma AUC) at the 16-week scheduled terminal necropsy. However, Similar kidney alterations were not 
seen at the 6-week interim at any doses or in the 39-week chronic monkey study up to 12 mg/kg/week (> 
~200-fold of the 20 mg weekly clinical dose by plasma AUC). 
Additional findings related to ASO liver accumulation included increased alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) at ≥ 8 mg/kg/week in the 16- 
and 26-week mouse studies, and were correlated with individual hepatocyte necrosis (minimal to mild) in 
mouse liver.  Those changes were most prominent in the high dose groups (50 and 24 mg/kg/week for the 
16- and 26-week studies, respectively). Conversely, no changes in liver enzymes were observed in 
monkeys from the 39-week toxicity study up to 12 mg/kg/week. In the 16-week monkeys study, increase 
in ALT was only evident in one early-sacrifice animal at 35 mg/kg/week, and non-statistically significant 


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increases in ALT (<2-fold of the pre-study baseline) were also observed in the interim- and terminal-
sacrifice animals at ≥ 8 mg/kg/week but showed no microscopic correlates or dose-dependency. 
Given the spectrum and severity of the test article-related clinicopathologic alterations present in 
monkeys at doses ≤ 12mg/kg/week (> ~100-fold of the 40 mg weekly clinical dose by plasma AUC) 
during the 39-week treatment phase, none would be regarded to represent an adverse effect (Dorato and 
Engelhardt 2005; Everds et al. 2013).  Considering the monkey to be the most relevant species, these data 
have characterized the safety profile and established appropriate therapeutic margins for the clinical 
evaluation of AKCEA-ANGPTL3-LRX in humans. 
2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with AKCEA-ANGPTL3-LRX can be 
found in the Investigator’s Brochure.  A summary is included below. 
The study drug, AKCEA-ANGPTL3-LRX, is being evaluated in Phase 1 in the clinical setting with single 
doses up to 120 mg and multiple doses up to 60 mg (once per week for 6 weeks). The parent drug 
ISIS 563580, an unconjugated 2′-MOE modified ASO that has the same base sequence as AKCEA-
ANGPTL3-LRX, was also evaluated in a blinded, placebo-controlled Phase 1 study. 
AKCEA-ANGPTL3-LRX Phase 1 SAD/MAD interim analysis of Study ISIS 703802-CS1 was performed 
in 44 subjects administered single ascending (20, 40 and 80 mg) or multiple ascending doses (10, 20, 40 
and 60 mg/week for 6 weeks). Twelve participants were randomly assigned to single-dose groups (9 to 
active-agent dose groups and 3 to the placebo group) and 32 were randomly assigned to multiple-dose 
groups (24 to active-agent dose groups and 8 to the placebo group). The main endpoints of the study were 
safety, tolerability, pharmacokinetics, pharmacodynamics and changes in lipids and lipoproteins. After 6 
weeks of treatment, persons in the multiple dose groups treated with AKCEA-ANGPTL3-LRX had dose-
dependent reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 
for all doses vs. placebo 1.6%) and in levels of triglycerides (reductions of 33.2 to 63.1% vs placebo 
11.4%), LDL cholesterol (1.3 to 32.9% vs placebo 13.6%), very-low-density lipoprotein cholesterol (27.9 
to 60.0% vs placebo 4.0%), non–high-density lipoprotein cholesterol (10.0 to 36.6% vs placebo 9.1%), 
apolipoprotein B (3.4 to 25.7% vs placebo 11.0%), and apolipoprotein C-III (18.9 to 58.8% vs placebo 
3.1%).  There were no serious adverse events documented during the trial. No protocol-defined injection-
site reactions were reported. Of those participants who received the multiple-dose regimen, three reported 
headache (one who received placebo and two who received ANGPTL3-LRx) and three reported dizziness 
(two who received placebo and one who received ANGPTL3-LRx). There was no clinical evidence of 
prothrombotic effects, bleeding episodes, significant decreases in platelet count or thrombocytopenia, or 
significant changes in liver or renal function. One subject in the 20 mg MAD group was lost to follow-up 
after 5 doses. There were no other discontinuations during the treatment period (Graham et al. 2017).  
The pharmacokinetics of AKCEA-ANGPTL3-LRX evaluated in Study ISIS 703802-CS1 showed rapid 
absorption following SC administration, with median time to maximum plasma concentrations (Tmax) 
ranging from 1 to 6 hours.  Similar Tmax values were observed at all dose levels.  After reaching Cmax, 
plasma concentrations of AKCEA-ANGPTL3-LRX declined in a multi-phasic fashion with a rapid 
disposition phase, followed by a slower elimination phase with terminal elimination half-life of 3 to 
5 weeks.  The peak (Cmax) and total exposure (AUC) after a single SC dose increased approximately dose 
proportionally from 20 to 40 mg, and greater than dose proportionally from 40 to 80 mg, suggesting more 
efficient tissue uptake at lower doses.  After single and multiple SC doses in the range of 10 to 60 mg, the 


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Cmax and AUC increased approximately dose proportionally.  No accumulation based on Cmax or AUC 
was observed after 6 weekly doses. 
2.3.4.1 
ISIS 563580-CS1 Phase 1 SAD/MAD  
In a Phase 1 study, ISIS 563580-CS1, healthy volunteers received subcutaneous administration of 
ISIS 563580 from 50 to 400 mg as a single dose, or 100 to 400 mg as multiple doses (8 doses in 36 days).  
Overall, the safety findings from this study suggest that ISIS 563580 was not associated with any safety 
concerns.  There were 383 adverse events (AE) reported in the ISIS 563580-treated subjects of which 363 
(95%) were mild in severity.  For the multiple-dose subjects, the most common treatment-emergent 
adverse events were AEs at the injection site.  There was 1 serious adverse event (SAE) in the study of 
periorbital cellulitis which was considered a medically important event by the Investigator and was also 
considered unlikely related to Study Drug by the Investigator.  Together, the above suggest that ISIS 
563580 was well-tolerated at the doses and regimen given, which exceed the dose levels and cumulative 
exposures to be tested in the current study.  There were no clinically-relevant changes in laboratory 
assessments and the heparin dose of 80 U/kg was well-tolerated in support of the post-heparin procedures.  
ISIS 563580 produced dose-dependent reductions in plasma ANGPTL3 (up to 93%; group means up to 
84%), TG (up to 63%; group means up to 49%) and TC (up to 46%; group means up to 28%) at Day 36 
(Brandt et al. 2015). 
2.4 
Rationale for Dose and Schedule of Administration 
Safety data from the available chronic mouse (26-week) and monkey (39-week) studies support 
once-weekly dosing for chronic administration.  The No Adverse Effect Level (NOAEL) for AKCEA-
ANGPTL3-LRX in chronic monkey study was determined to be 12 mg/kg/wk.    
Preclinical pharmacology experiments in Tg-mice and in non-human primates demonstrated that 
AKCEA-ANGPTL3-LRX achieved an equivalent reduction in ANGPTL3 plasma concentration to that of 
the unconjugated form, at 1/10th of the unconjugated ASO (ISIS 563580) dose.  The dose level planned 
for this study for AKCEA-ANGPTL3-LRX is 20 mg, which is the lowest dose that provided maximum TG 
lowering of approximately 60% in Study ISIS 703802-CS1 and is approximately 200-fold lower than 
NOAEL dose in monkey at 12 mg/kg/wk in the 39-week chronic monkey study up to terminal necropsy.  
An interim analysis of the phase 1 study completed for all but the 120 mg single dose cohort showed 
approximately 60% reduction of TG at 20 mg dose.  However, at 40 mg and 60 mg dose the TG reduction 
did not differ significantly from 20 mg dose.  Thus, the lower dose was selected for this study for optimal 
risk to benefit.  
2.5 
Benefit-Risk Assessment 
2.5.1 
Benefit Assessment 
The current study is designed to evaluate the safety and tolerance of AKCEA-ANGPTL3-LRX in FCS 
subjects.  The dose selected is expected to reduce ANGPTL3 and result in a reduction of the severe 
hypertriglyceridemia and chylomicronemia that afflicts FCS subjects.  Importantly, although we do not 
know if subjects participating in this study would necessarily benefit from the treatment, the increased 
understanding of AKCEA-ANGPTL3-LRX in this population is expected to result in improved treatment 
options that would ultimately benefit all FCS patients, including participants in the study.  Due to the 
short duration of this trial any benefit observed is not expected to persist beyond the end of the study.  


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2.5.2 
Risk Assessment 
The known potential risks to study participants associated with AKCEA-ANGPTL3-LRX are elaborated 
on in the Guidance to Investigator section of the Investigator’s Brochure.  
• 
In preclinical mouse studies, there were increases in ALT and AST and were correlated with 
increased incidence and/or severity of necrosis of individual hepatocytes (minimal to mild in 
severity).  Those changes were most prominent in the high dose groups and showed no clear 
progression over time. No increases in liver enzymes were observed in monkeys from the 39-
week toxicity study up to 12 mg/kg/week (~200-fold of the 20 mg clinical dose by plasma AUC).  
In the 16-week monkey study, increase in ALT was only evident in 1 early-sacrifice animal at 35 
mg/kg/week, no meaningful increase in ALT was observed in the schedule sacrificed animals. 
• 
There were no observed significant changes in ALT and liver function in an ongoing Phase 1 
human study (Graham et al. 2017).  The risk of observing significant ALT/AST changes in this 
clinical human study is expected to be relatively low with the proposed 20 mg dose.  However, to 
evaluate and mitigate the potential for liver enzyme abnormalities, regular liver chemistry 
monitoring and stopping rules are included in the study as specified in Sections 8.5 and 8.6.  
• 
Injection site adverse events, while not considered safety issues, may affect the ability of the 
patient to tolerate dosing.  Injection site adverse events are the most common side effects 
observed following SC administration of 2¢-MOE ASOs and are dose and concentration 
dependent.  Erythema is the most prevalent characteristic.  Generally, these events are mild and 
reversible, resolve spontaneously and do not worsen with time.  The histologic findings are 
consistent with a local inflammatory response.  While planned doses of AKCEA-ANGPTL3-LRX 
for clinical evaluation are generally below the doses that are historically associated with these 
effects, patients should be informed of the possibility of occurrence of injection site adverse 
events.  Symptomatic interventions such as icing of the injection site or administration of 
NSAIDs prior to and/or after the SC dosing have been utilized. 
While the long term consequences of reducing ANGPTL3 as a target with the study drug are not known at 
this time, there is evidence in literature in humans in whom ANGPTL3 is absent from plasma, due to 
homozygous or compound heterozygous ANGPTL3 mutations, present a pan-hypobetalipoproteinemia 
phenotype, with generalized and marked decreases (~50% to 70%) in all apoB-100 containing 
lipoproteins, including VLDL and LDL, as well as HDL.  This clinical phenotype has been termed 
familial combined hypolipidemia or FHBL2 (Romeo et al. 2009; Musunuru et al. 2010; Martin-Campos 
et al. 2012; Minicocci et al. 2012; Noto et al. 2012; Pisciotta et al. 2012; Wang et al. 2015).  Clinical 
studies in FHBL2 suggest a trend toward lower glucose and insulin levels and despite a reported decrease 
in VLDL production, there is no apparent difference in hepatic fat content compared to 
controls.  Remarkably, diabetes and cardiovascular disease are reportedly absent from those with 
homozygous FHBL2 and no adverse clinical phenotype has been reported to date. 
2.5.3 
Overall Assessment of Benefit:Risk 
Fasting plasma triglyceride (TG) levels in FCS patients are typically 10-fold to 100-fold above normal 
(1,500 to 15,000 mg/dL), despite extreme dietary fat restriction (20 g or approximately 15-20% of daily 
calorie intake) (Brunzell 1999-2011).  Given the unmet medical need for FCS patients, AKCEA-
ANGPTL3-LRX has demonstrated the ability to reduce TGs by 60% in the Phase 1/2 study in healthy 
volunteers.  The objective of this study is to assess the effect of TG lowering in FCS patients.  Although 
the FCS patients enrolled in this study will not derive long term benefits due to the short duration of the 


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study, the information obtained in the course of this study is critical to further development of AKCEA-
ANGPTL3-LRX for this disease with an extremely high unmet need.  Taking into account the measures 
taken to minimize risk to subjects participating in this study, the fact that potential risks identified in 
association with AKCEA-ANGPTL3-LRX are minimal and are manageable by routine monitoring 
exposure of FCS patients in this study is justified by the anticipated benefits that may be afforded to the 
wider population of FCS subjects by continued development of AKCEA-ANGPTL3-LRX.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This will be a Phase 2 open-label multiple-dose study of approximately 3 subjects with FCS and will be 
treated with AKCEA-ANGPTL3-LRX. 
Subject will receive 20 mg of AKCEA-ANGPTL3-LRX SC weekly. 
3.2 
Number of Study Centers 
This study will be conducted at a single center but could be expanded to more than one center. 
3.3 
Number of Subjects 
Approximately 3 subjects will be treated in this study.  
3.4 
Overall Study Duration and Follow-up 
The study will consist of a screen/ run-in period, study treatment, post-treatment and long term follow-up.  
Please refer to the Schedule of Procedures in Appendix A.  
Subjects may be required to attend additional visits for monitoring of adverse events or abnormal 
investigation results.  The frequency of additional monitoring will be determined by the Study Medical 
Monitor in consultation with the Investigator. 
The length of subjects’ participation in the study may be up to 34 weeks, including an up to 8-week 
screening period, that includes a 6-week diet stabilization / run-in period, a 13-week treatment period, and 
a 13-week post-treatment evaluation period.  Subjects will perform the first dosing at the site, with 
subsequent dosing occurring at home following training on how to dose.  The diet stabilization period 
may be reduced if the patient is following a stable low fat diet for optimal disease control and disease 
management prior to screening. 
3.4.1 
Screening 
Subject eligibility for the study will be determined within 56 days/8 weeks prior to study entry. 
3.4.2 
Treatment 
Eligible subjects will receive the first dose of study drug at the Study Center, at which time they will also 
be trained on self-administration of Study drug.  Subsequent administrations of study drug may occur at 
home or in the study center.  Eligible subjects will report to the Study Center for assessments at specified 
intervals throughout the 13-week treatment period as detailed in the Schedule of Procedures in Appendix 
A.    


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3.4.3 
Post-Treatment 
Subjects are to return to the Study Center for follow-up visits every four weeks (refer to the Schedule of 
Procedures in Appendix A).  The final study visit will be Study Week 26. 
3.5 
End-of-Study 
The End-of-Study is defined as the last subject’s last visit. 
4. 
SUBJECT ENROLLMENT 
4.1 
Screening 
Before subjects may be enrolled into the Study, the Sponsor or designee requires a copy of the Study 
Center’s written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other subject information and/or recruitment material. 
Subjects must sign the informed consent form before any screening tests or assessments are performed.  
At the time of consent, the subject will be considered enrolled into the Study and will be assigned a 
unique screening number before any Study procedures, including screening procedures, are performed.  
At the time of randomization or registration, subjects will be assigned a unique subject identification 
number.  This number will be used to identify the subject throughout the trial and must be used on all 
study documentation related to that subject.  The screening number and subject identification number 
must remain constant throughout the entire trial.  Screening numbers and subject identification numbers, 
once assigned, will not be reused. 
4.2 
Registration 
Patients will be registered after all screening assessments have been completed and after the Investigator 
has verified that they are eligible per criteria in Sections 5.1 and 5.2.  No subject may begin treatment 
prior to assignment of a unique subject identification number. 
4.3 
Replacement of Subjects 
Due to the small number of subjects participating in the study, subjects who withdraw from the study may 
be replaced by allowing a new subject to be screened and enrolled.  The subjects who withdrew for safety 
reasons will not be replaced.  
5. 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria within 56 
days of treatment day 1 or at the time point specified in the individual eligibility criterion listed. 
5.1 
Inclusion Criteria 
1. Must have given written informed consent (signed and dated) and any authorizations required by 
local law and be able to comply with all study requirements. 
2. Males or females aged > 18 years old at the time of informed consent. 
3. Genetically confirmed homozygote or compound heterozygote for known null loss-of-function 
mutations in the LPL gene. 
4. Fasting TG ≥ 750 mg/dL (8.4 mmol/L) at Screening. If the fasting TG < 750 mg/dL up to 2 
additional tests may be performed in order to qualify. 


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5. Willing to follow a diet comprising ≤ 20g fat per day during the study. 
6. Females:  must be non-pregnant and non-lactating and either;  
i. 
Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy); 
ii. 
Post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 years of 
age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved); 
iii. 
Abstinent* or, 
iv. 
If engaged in sexual relations of child-bearing potential, agree to use 2 highly effective 
contraceptive methods (refer to Section 6.3.1) from the time of signing the informed consent 
form until at least 13 weeks after the last dose of Study Drug (AKCEA-ANGPTL3-LRX). 
7. Males:  Surgically sterile or if engaged in sexual relations with a female of child-bearing 
potential, subject is utilizing an acceptable contraceptive method (refer to Section 6.3.1) from the 
time of signing the informed consent form until at least 13 weeks after the last dose of Study 
Drug (AKCEA-ANGPTL3-LRX). 
*  Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable 
methods of contraception. 
5.2 
Exclusion Criteria 
1. Diabetes mellitus with any of the following:  
a. 
Newly diagnosed within 12 weeks of screening  
b. 
HbA1c ≥ 9.0% at Screening  
c. 
Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of screening [with the exception of ± 10 units of insulin])  
d. 
Current use of GLP-1 agonists 
2. Active pancreatitis within 2 weeks prior to screening 
3. History within 6 months of screening of acute or unstable cardiac ischemia (myocardial 
infarction, acute coronary syndrome, new onset angina, stroke, transient ischemic attack or 
unstable congestive cardiac failure requiring a change in medication) or major surgery within 3 
months of screening 
4. Any of the following laboratory values at Screening  
a. 
Hepatic:  
• 
Total bilirubin > upper limit of normal (ULN), unless prior diagnosis and documentation 
of Gilbert’s syndrome in which case total bilirubin must be ≤ 3 mg/dL  
• 
ALT > 2.0 x ULN  
• 
AST > 2.0 x ULN  
b. 
Renal:  


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• 
Positive test (including trace) for blood on urinalysis.  In the event of a positive test, 
eligibility may be confirmed with urine microscopy showing ≤ 5 red blood cells per high 
power field 
• 
Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg. In the event of a UPCR above this 
threshold, eligibility may be confirmed by a quantitative total urine protein measurement 
of ˂ 300 mg/24-hr 
• 
Estimated creatinine clearance calculated according to the formula of Cockcroft and 
Gault < 60 mL/min (CKD-EPI formula can be used instead of Cockcroft-Gault for 
estimation of GFR in patients with low body weight after discussion with Sponsor 
Medical Monitor)  
c. 
Platelet count < 140,000 mm3    
d. 
Any other laboratory abnormalities which, in the opinion of the Investigator or the Sponsor, 
would make the patient unsuitable for inclusion 
5. Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg)  
6. History of bleeding diathesis or coagulopathy or clinically-significant abnormality in coagulation 
parameters at Screening 
7. History of heart failure with NYHA greater than Class II 
8. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed 
prior to Study Day 1 
9. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or 
chronic hepatitis B 
10. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma 
in situ of the cervix that has been successfully treated 
11. Treatment with another investigational drug, biological agent, or device within 1-month of 
screening, or 5 half-lives of investigational agent, whichever is longer 
12. Unwilling to comply with lifestyle requirements (Section 6.3) 
13. Use of any of the following:  
a. Statins, omega-3 fatty acids (prescription or OTC), or fibrates unless on a stable dose for at 
least 3 months prior to screening and dose and regimen expected to remain constant during 
the treatment period. Patients taking OTC omega-3 fatty acids should make every effort to 
remain on the same brand throughout the study.  
b. Nicotinic acid or derivatives of nicotinic acid within 4 weeks prior to screening  
c. Systemic corticosteroids or anabolic steroids within 6 weeks prior to screening unless 
approved by the Sponsor Medical Monitor  
d. Atypical antipsychotic medications (e.g., olanzapine and clozapine) unless on a stable dose 
for at least 3 months prior to screening and dose and regimen expected to remain stable 
throughout the study  
e. Antihypertensive medication unless on a stable dose for at least 4 weeks prior to screening 
and dose and regimen expected to remain constant during the treatment period  


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f. Glybera gene therapy within 2 years prior to screening  
g. Oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, and apixaban) unless on a stable 
dose for at least 4 weeks prior to screening and regular clinical monitoring is performed  
h. Tamoxifen, estrogens or progestins unless on a stable dose for at least 4 months prior to 
screening and dose and regimen expected to remain constant during the treatment period  
i. 
Plasma apheresis within 4 weeks prior to screening or planned during the study  
j. 
Prior exposure to AKCEA-ANGPTL3-LRX 
k. Any other medication unless stable at least 4 weeks prior to screening (Occasional or 
intermittent use of over-the-counter medications will be allowed at Investigator’s discretion)  
14. Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 60 days of 
screening  
15. Known hypersensitivity to any of the excipients of the Study Drug  
16. Have any other conditions, which, in the opinion of the Investigator or the Sponsor would make 
the patient unsuitable for inclusion, or could interfere with the patient participating in or 
completing the study  
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
The study will consist of a Screening period, a Treatment period and a Post-treatment period. These 
periods are described below. 
All required study procedures are outlined in Appendix A. 
6.1.1 
Screening 
Written informed consent for the study will be obtained prior to the performance of any study-related 
procedures including screening procedures.  An up to 8-week period is provided for completing screening 
assessments and determining subject eligibility for the study.  Subjects on stable diet known to the 
investigator and followed at the site may skip the 6-week diet run-in. Safety labs may be re-tested for 
determination of subject eligibility after consultation with the Sponsor Medical Monitor.  
During the screening period, subjects will undergo a medical history and physical examination including 
vital signs, 12-lead ECG, and have blood and urine samples taken for clinical laboratory testing.  Subjects 
will be screened for HIV, hepatitis B, and hepatitis C. 
Eligible subjects will be on a stable low-fat diet (according to local clinical guidelines) beginning at least 
6 weeks prior to the first dose of Study Drug.  The diet stabilization period may be reduced if the patient 
is following a stable low fat diet for optimal disease control and disease management prior to screening. 
Subjects meeting eligibility criteria at Screening will receive standardized meals in preparation for the 
pre-dose postprandial analysis to be performed on Day -1.  


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6.1.2 
Treatment Period 
Subjects will be managed on an outpatient basis.  Safety and clinical laboratory evaluations as well as 
blood sampling for PK analysis will be performed periodically throughout the treatment period.  Any AEs 
and concomitant medications will be recorded. 
Postprandial Assessment (Appendix E):  Postprandial assessments will be performed at Day -1 and at 
Week 14.  Subjects will consume standardized pre-cooked meals (lunches and dinners (provided) and 
instructions for breakfasts and snacks) for the 2 days prior to the post-prandial evaluations.  Patients will 
remain fasted after consuming the standardized pre-cooked meal for the dinner on the evening prior to 
their visit.  Alcohol consumption is not allowed for the 2 days prior to the post-prandial evaluations.  On 
each of the post-prandial evaluation days, following the first blood draw, patients will consume a 
standardized liquid meal (which represents about a third of the daily caloric requirements) containing a 
radioisotope tracer, followed by an 9 hour infusion of two stable isotope tracers and serial blood 
sampling.  Patients will receive a standardized pre-cooked meal 9 hrs after consuming the liquid meal, 
after which they will fast until the 24 hour blood draw the following day. 
6.1.4 
Post-Treatment Period 
Each subject will be followed for safety assessments for up to 13 weeks after the last dose of Study Drug.  
During the post-treatment evaluation period, subjects will return to the Study Center for outpatient visits 
on Days 119, 147 and 182 for safety and clinical laboratory evaluations.  A ± 3-day excursion from the 
scheduled visit date is permitted for this time period.  
6.2 
Study/Laboratory Assessments  
Laboratory analyte samples will be collected throughout the Study.  A list of these analytes is contained in 
Appendix B.  Blood chemistry and urine samples (excluding 24-hour urine collection) should be taken 
after fasting for approximately 10 hours.  During this time subjects can drink water and should ensure that 
they consume sufficient water to not become dehydrated. 
6.3 
Restriction on the Lifestyle of Subjects 
6.3.1 
Contraception Requirements 
All male subjects and women of childbearing potential must refrain from sperm/egg donation and either 
be abstinent† or practice effective contraception from the time of signing the informed consent form until 
at least a period of 13 weeks after their last dose of study treatment.  
Male subjects engaged in sexual relations with a female of child-bearing potential must also encourage 
their female partner to use effective contraception from the time of signing the informed consent until a 
period of 13 weeks after the subject’s last dose of study treatment. 
For the purposes of this study, women of childbearing potential are defined as any female who has 
experienced menarche, and who does not meet one of the following conditions: 
• 
Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, in 
females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative medical 
cause and FSH levels in the postmenopausal range for the laboratory involved 
• 
6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• 
Post hysterectomy 


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For the purposes of the study, effective contraception is defined as follows: 
For male subjects: 
• 
Effective male contraception includes a vasectomy with negative semen analysis at follow-up, or 
the use of condoms together with spermicidal foam/gel/film/cream/suppository 
• 
Male subjects with partners that are pregnant must use condoms as contraception to ensure that 
the fetus is not exposed to the Study Drug 
For female subjects and female partners of male subjects: 
• 
Using 1 or more of the following acceptable methods of contraception:  surgical sterilization 
(e.g., bilateral tubal ligation), hormonal contraception, intrauterine contraception/device, or any 2 
barrier methods (a combination of male or female condom* with diaphragm, sponge, or cervical 
cap) together with spermicidal foam/gel/film/cream/suppository 
†Note: Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception. 
*Note: A female condom and a male condom should not be used together as friction between the 
two can result in either or both products failing. 
6.3.2 
Other Requirements 
All subjects will be required to fast for approximately 10 hours before visits requiring fasted blood 
sampling.   
7. 
STUDY DRUG 
7.1 
Study Drug Description 
7.1.1 
AKCEA-ANGPTL3-LRX (ISIS 703802)  
Study Drug characteristics are listed in Table 1. 
A solution of Study Drug contained in stoppered glass vials will be provided.  The Study Drug and its 
storage and preparation instructions will be provided by the Sponsor or designee.  The Study Drug must 
be stored securely at 2° to 8° Celsius and be protected from light. 
Table 1 
Study Drug Characteristics 
Study Drug 
AKCEA-ANGPTL3-LRX 
(ISIS 703802) 
Strength 
100 mg/ mL  
Volume/Formulation 
0.8 mL/vial 
Route of Administration 
SC* 
* 
SC = subcutaneous 


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7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug labeled in accordance with specific 
country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug supplies 
provided by the Sponsor.  The Study Center must return all used and unused Study Drug to the Sponsor 
or designee. 
8. 
TREATMENT OF SUBJECTS 
8.1 
Study Drug Administration 
Vials are for single use only.  Study staff will administer the first dose of Study Drug.  Doses will be 
administered by SC injection, patients or their caregivers may self-administer the study drug following 
the training given by the study center staff.   
 
Volumes to be administered are shown in Table 2.  Please refer to the Study Drug Manual provided by the 
Sponsor or designee for more detailed instructions for Study Drug preparation and/or administration. 
Table 2 
Study Drug Dosing Information 
Volume to Administer 
Total Dose 
0.20 mL  
20 mg (open label) 
8.2 
Other Protocol-Required Drugs 
There are no other protocol-required drugs. 
Subjects will continue their stable lipid-lowering therapy through the end of the post-treatment evaluation 
period. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol-required treatment procedures other than those outlined in the schedule of 
procedures. 
8.4 
Treatment Precautions 
No specific treatment precautions are required. 
8.5 
Safety Monitoring Rules 
Please refer also to the Guidance for Investigator section of the Investigator’s Brochure. 
For the purposes of safety monitoring Baseline is defined as the average of the pre-dose test closest to 
Day 1 and Day 1. 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are provided 
for the monitoring of selected parameters chosen based on preclinical and clinical observations. 


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In case of discrepancy between the test results from 2 sources, safety-mandated action must be initiated 
based on the more critical (lower or higher, as relevant) of the 2 values. 
Confirmation Guidance:  At any time during the Study (Treatment or Post-Treatment Periods), the initial 
clinical laboratory results meeting the safety monitoring criteria presented below must be confirmed by 
performing measurements (ideally in the same laboratory that performed the initial measurement) on new 
specimens prior to administering the next dose of Study Drug.  All new specimen collections should take 
place as soon as possible (ideally within 3 days of the initial collection).   
Stopping Rule Guidance:  The Investigator may interrupt or permanently discontinue study treatment for 
any safety reason including clinically meaningful changes in clinical laboratory results.  The medical 
monitor should be informed. 
Re-dosing Guidance:  Subjects with initial laboratory test values that reach a stopping rule must not be re-
dosed until the re-test results are available.  In general, subjects who do not meet the stopping rules based 
upon retest may continue dosing.  However, the Investigator and the Sponsor Medical Monitor (or 
appropriately qualified designee) should confer as to whether additional close monitoring of the subject is 
appropriate.  If any of the stopping criteria described in Section 8.6 are met, the subject will be 
permanently discontinued from further treatment with Study Drug, evaluated fully as outlined below and 
in consultation with the Sponsor Medical Monitor or appropriately qualified designee, and will be entered 
into the post-treatment evaluation portion of the study. 
Additional Guidance:  If possible, a PK sample should be collected as soon as possible after an SAE has 
occurred (preferably within 2 weeks).  In addition, if a patient is asked to return to the clinic for additional 
evaluations due to an AE, then a PK sample should be taken at the time of the unscheduled visit.  
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the FDA guidance for industry, “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation,” issued by the U.S. Department of Health and Human Services, Food 
and Drug Administration, July 2009.  For a definition of Baseline, please refer to guidance in Section 8.5 
above. 
All patients will have liver chemistry tests monitored every 2 weeks during the treatment and follow-up 
Period. 
• 
In the event of appearance of symptoms or signs of hepatic injury (jaundice, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, abnormal bleeding or bruising, or 
eosinophilia > ULN) liver enzymes and bilirubin should be tested as soon as possible.  Testing at 
a lab that is local to the patient is permissible for this purpose. 
• 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (treatment or 
post-treatment period), the initial measurement(s) should be confirmed as described in Section 
8.5. 
• 
Patients with confirmed ALT or AST levels > 3 x ULN should have their liver chemistry tests 
(ALT, AST, ALP, international normalized ratio [INR] and total bilirubin) retested at least once 
weekly until ALT and AST levels become ≤ 1.2 x ULN. 


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• 
All results of liver function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per Section 
8.6.1.  Further Investigation into Liver Chemistry Elevations: For patients with confirmed ALT or 
AST levels > 3 x ULN, the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (hepatitis A virus [HAV] immunoglobulin M [IgM], hepatitis B 
surface antigen [HBsAg], hepatitis C virus [HCV] antibody, Cytomegalovirus [CMV] IgM, 
and EBV antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or MRI 
scans, may be performed at the discretion of the Investigator, in consultation with the Sponsor Medical 
Monitor. Repetition of the above evaluations should be considered if a patient’s ALT and/or AST levels 
reach 5 x ULN. 
All routine liver function test results will be reviewed on an ongoing basis at the weekly safety review by 
the Medical Monitor. 
All lab alerts for abnormal liver function tests must be promptly (within 48 hours of receipt) reviewed by 
the Investigator and Medical Monitors. 
Lab alerts for abnormal liver chemistry tests will be issued for:  
1. ALT or AST > 3 x ULN;  
2. ALT or AST > 2 x baseline;  
3. total bilirubin > ULN;  
4. ALP > ULN.  
These alert levels are set to anticipate the risk of a combined elevation of aminotransferases and bilirubin 
as per the FDA Guidance referenced in Section 8.5.1.  A more frequent liver function test monitoring may 
be recommended by the Investigator if warranted.  The Investigator should inform the Medical Monitor. 
All clinically significant lab alerts for monitoring/ stopping rules as described above are reviewed 
promptly by the Medical Monitor and communicated with the Investigator and/or the study personnel 
within 24 hours of receiving an actionable lab alert. 
8.5.2 
Safety Monitoring for Renal Function 
All patients will have renal function tests monitored every 4 weeks throughout the study. 
In the event of appearance of symptoms or signs consistent with renal dysfunction such as hematuria, 
polyuria, anuria, flank pain, new-onset hypertension, nausea and/or anorexia, renal function should be 
tested as soon as possible.  


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During the course of the study, urinary surveillance will include urinalysis to include urine 
albumin/creatinine ratio (UACR), urine protein/creatinine ratio (UPCR) and urinary red blood cells 
(RBCs), as well as serum creatinine and cystatin-C to estimate glomerular filtration rate (eGFR), which 
will be monitored every 4 weeks.  
All renal function test results will be reviewed on an ongoing basis at the safety review by the Medical 
Monitor. 
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per Section 8.6.2. 
Lab alerts for abnormal renal tests will be issued for:  
• 
Creatinine clearance (by CKD-EPI formula) decrease from baseline > 25%,  
• 
Urine albumin/creatinine ratio (UACR) > 250 mg/g, urine protein/creatinine ratio (UPCR) > 0.5 
mg/mg, or  
• 
An increase in serum creatinine from baseline > 0.3 mg/dL). 
These alert levels are set to anticipate and prevent the risk of a medically significant change in renal 
function while receiving Study Drug. 
In the event of a confirmed (as described in Section 8.5) laboratory result meeting one or more of the 
above criteria, dosing with the Study Drug should be interrupted and the Study Medical Monitor 
informed.  
In addition, the following supplemental renal tests should be immediately obtained: 
• 
Serum creatinine,  
• 
Urine culture,  
• 
24-hour urine sample for creatinine clearance, 
• 
Urine albumin and urine protein, 
• 
Urine microscopy sample with inspection of sediment. 
The Investigator should also review the patient’s concomitant medications for potentially nephrotoxic 
agents, and, with the results of these evaluations, review any decision to continue or discontinue the 
patient in consultation with the Study Medical Monitor. 
8.5.3 
Safety Monitoring Rules for Platelet Count Results 
All patients will have platelet counts monitored every 2 weeks for the duration of the study and must not 
receive Study Drug without an interpretable platelet count result in the prior 2 weeks. 
In addition, platelet function may be evaluated by aggregometry, using an approved point-of-care 
diagnostic device, in all patients at each study site visit. 
All platelet count results must be reviewed promptly (within 48 hours of receipt) by the Investigator or 
the designee to ensure that the result has not met the stopping rule and to determine whether the rate of 
decline is suggestive that the patient could be approaching the dose interruption rule of 75,000/mm3 as 
specified in Section 8.6.3. 


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Any case of a platelet count reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is considered an 
adverse event of special interest and should be reported in an expedited fashion to the Sponsor. 
Lab alerts related to platelet monitoring/stopping rules are issued when:  
1. Platelet counts are < 140,000 mm3;  
2. When platelet count is ≥ 30% decreased from baseline, or  
3. When the hematology sample is unreportable.  
Actions to be taken in the event of reduced platelet count are shown in Table 3 below.  In the event of a 
platelet count ˂ 100,000/mm3 the laboratory tests outlined should be performed as soon as possible.  
Additional lab tests will be determined by the Sponsor Medical Monitor or designee in consultation with 
the Investigator. 
 
 


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Table 3 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation: 
Monitor every week* 
75K-100K/mm3 
Permanently reduce as follows: 
Reduce to 10 mg every week 
Closer observation: 
Monitor every week* 
50K-75K/mm3 
Pause dosing 
When platelet count returns to > 100K/mm3 restart 
dosing as follows only if approved by Sponsor 
Medical Monitor: 
Reduce to 10 mg every week 
or 
Permanently discontinue Study Drug if it occurs 
while on already reduced dose  
Closer observation: 
Monitor every 2-3 days until 
2 successive values show 
improvement 
Consider discontinuation of 
antiplatelet agents/non-
steroidal anti-inflammatory 
drug (NSAIDS)/ anticoagulant 
medication 
25K-50K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 
2 successive values show 
improvement then monitor 
every 2-3 days until platelet 
count stable 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 
˂ 25K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 
2 successive values show 
improvement then monitor 
every 2-3 days until platelet 
count stable 
Steroids recommended** 
Consider need for 
hospitalization and referral to 
hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 
* 
Once a patient commences weekly monitoring this frequency of monitoring should continue irrespective of 
whether the platelet count rises into the normal range. 
** 
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after methylprednisolone). 
All clinically significant lab alerts for monitoring/stopping rules as described above are reviewed 
promptly by the Medical Monitor and communicated with the Investigator and/or the study personnel 
within 24 hours of receiving an actionable lab alert as described in Section 6.2. 


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8.5.4 
Safety Monitoring for Minor Bleeding Events 
Patients will be instructed to promptly report any signs or symptoms of bleeding.  Minor bleeding events 
are those that do not fulfill the criteria for major bleeding or clinically-relevant, non-major bleeding 
events (which are defined in Section 8.6.3), for example excess bruising, petechiae, or gingival bleeding 
on brushing teeth.  If a minor bleeding event occurs, the Investigator must notify the Sponsor Medical 
Monitor and additional testing of coagulation parameters activated partial thromboplastin time (aPTT), 
prothrombin time (PT), INR, hepatic enzymes, bilirubin and platelet count should be performed. 
8.6 
Stopping Rules  
For the purposes of the stopping rules, Baseline is defined as the average of the pre-dose test closest to 
Day 1 and Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of confirmed laboratory results meeting any of the following criteria, dosing of a patient with 
Study Drug will be stopped permanently: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x Baseline value or 3 x ULN if the Baseline value 
was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x Baseline value or 3 x ULN if the Baseline value 
was > ULN), which is confirmed, and the new appearance (i.e., onset coincides with the changes 
in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, or eosinophilia (> ULN) felt by the Investigator to be potentially related to hepatic 
inflammation. 
8.6.2 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules for Renal 
Function Test Results 
In the event of an estimated creatinine clearance (by CKD-EPI formula) meeting any of the following 
criteria, or any change in renal biomarkers deemed by the nephrologist to require further evaluation, a 
serum creatinine and 24-hour urine sample for creatinine clearance and protein should be obtained: 
1. CKD-EPI decrease of > 40% from Baseline 
2. CKD-EPI value < 45 mL/min/1.73 m2 
Dosing of a patient with Study Drug (AKCEA-ANGPTL3-LRX) will be stopped permanently if 24-hour 
urine testing confirms any of the following values in the absence of an alternative explanation: 
1. Urine protein is > 1.0 g 
2. Creatinine clearance decrease of > 40% from baseline 
3. Creatinine clearance < 45 mL/min/1.73 m2 
Irrespective of whether the stopping rule is confirmed or not, the follow-up schedule and frequency of 
renal function monitoring after the initial event will be determined by the Study Medical Monitor in 
consultation with the Investigator.  The Investigator should consider consulting a local nephrologist for 


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any change of renal function that presents a concern.  If a renal biopsy is performed, a sample specimen 
should be made available for examination by an independent renal pathologist who has been engaged by 
the Sponsor to review such specimens.  
8.6.3 
Stopping Rule for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3. 
In the event of any platelet count less than 50,000/mm3, or a platelet count less than 75,000/mm3 that 
occurs while the patient is already on reduced dose, dosing of the patient with Study Drug will be stopped 
permanently (Table 3).  
Platelet count will be monitored daily until 2 successive values show improvement then monitored every 
2-3 days until platelet count is stable. 
Administration of steroids is recommended for patients whose platelet count is less than 25,000/mm3.  
Recovery in platelet count may be accelerated by administration of high dose steroids.  Treatment 
guidelines for immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily 
for 4 days every 2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or 
methylprednisolone 30 mg/kg/day for 7 days (note: may require continuation with oral steroids after 
methylprednisolone). 
In the event of a platelet count ˂ 75,000/mm3 and > 50,000/mm3, and in the absence of major bleeding or 
clinically-relevant non-major bleeding (defined below; Schulman et al. 2005), dosing of a patient with 
Study Drug should be suspended temporarily until the platelet count has recovered to > 100,000/mm3.  If 
dosing is continued it must be at a reduced dose as shown in Table 3.  The suitability of the patient for 
continued dosing will be determined by the Investigator in consultation with the Study Medical Monitor 
and will be based on factors such as the original rate of decline in the patient’s platelet count, whether any 
bleeding events were experienced by the patient, and the speed of recovery of platelet count after 
interruption of dosing.  This will be documented in the patient by the investigator and filed in the 
TMF.rec. 
If, after reintroduction of Study Drug, the platelet count again falls below 75,000/mm3, then dosing of the 
patient with Study Drug will be stopped permanently. 
Once a patient commences weekly monitoring this frequency of monitoring should continue irrespective 
of whether the platelet count rises into the normal range. 
Any unreportable platelet count result must be rechecked and determined not to have met a stopping rule 
before dosing can continue. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• 
Fatal bleeding, and/or 
• 
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, 
retroperitoneal, intraarterial or pericardial, or intramuscular with compartment syndrome, and/or 
• 
Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 24 hours, or 
leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 


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1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis 
6. Bleeding after venipuncture for > 5 minutes 
8.7 
Adjustment of Dose and/or Treatment Schedule 
Dose frequency adjustments for platelet count reduction must be made in accordance with Section 8.6.3 
and Table 3 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose will be allowed for 
safety or tolerability in consultation with the Sponsor Medical Monitor.   
Patients may have their dose interrupted in response to AEs in consultation with Study Medical Monitor. 
8.8 
Discontinuation of Study Drug/Treatment 
A subject must permanently discontinue study treatment for any of the following: 
• 
The subject becomes pregnant.  Report the pregnancy according to instructions in Section 9.5.4 
• 
The subject withdraws consent 
• 
The subject experiences an adverse event (AE) that necessitates permanent discontinuation of 
Study Drug 
• 
The subject develops laboratory test abnormalities that meet any of the stopping rules listed in 
Sections 8.6.1 to 8.6.3 
The reason for discontinuation of Study Drug Treatment must be recorded in the electronic Case Report 
Form (eCRF) and source documentation. 
Subjects who discontinue treatment early should be entered into the post-treatment evaluation period.  
Every effort should be made to complete the early termination study procedures and observations at the 
time of withdrawal (see Appendix A). 
If a subject discontinues treatment after only 1 dose, then the post-treatment evaluation procedures 
cohorts should be followed.   
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from Post-Treatment 
Follow-up Period 
Any patient who discontinues early from the treatment period or from post-treatment follow-up period 
should be followed as per the platelet monitoring rules shown in Table 3, Section 8.6.3 for the first 6 
weeks after discontinuing Study Drug.  Following this period, if the platelet count is stable (at least 
3 consecutive values that are stable as determined by the Sponsor Medical Monitor and > 100,000/mm3), 
the next platelet count should be taken within at least 6 weeks so that patients are monitored for at least 12 
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If the patient declines or is unable to participate in the above, the early termination visit procedures should 
be performed at the time of withdrawal, at a minimum, and ideally within 2 weeks from the last dose of 
Study Drug.  
8.9 
Withdrawal of Subjects from the Study 
Subjects must be withdrawn from the Study for any of the following: 
• 
Withdrawal of consent 
• 
The subject is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of subjects from the Study might include: 
• 
At the discretion of the Investigator for medical reasons 
• 
At the discretion of the Investigator or Sponsor for noncompliance 
• 
Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to the date 
of withdrawal.  All information, including the reason for withdrawal from Study, must be recorded in the 
eCRF.  
Any subject who withdraws consent to participate in the Study will be removed from further treatment 
and study observation immediately upon the date of request.  These subjects should be encouraged to 
complete the early termination study procedures and observations at the time of withdrawal 
(Appendix A).   
For subjects withdrawn for reasons other than withdrawal of consent every effort should be made to 
complete the early termination study procedures and observations at the time of withdrawal (see 
Appendix A).  
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the subject’s eCRF.  
Adverse events related to administration of these therapies or procedures must also be documented on the 
appropriate eCRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-counter 
medications, herbal medications and vitamin supplements) administered between screening and the end of 
the post-treatment evaluation period.  All concomitant medications/treatments and significant non-drug 
therapies (including supplements and assistive devices) received by a subject, including changes in the 
subject’s current medications, must be recorded in the subject’s source documents and CRF.  Subjects 
taking over the counter (OTC) omega-3 fatty acids should make every effort to remain on the same brand 
throughout the study. 
Allowed Concomitant Therapy 
Ibuprofen may be used for symptomatic relief.  Any other therapy (including OTC medications) should be 
approved by the Sponsor Medical Monitor or designee. 


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Any medications deemed necessary by the Investigator are allowed except those listed in the disallowed 
concomitant therapy. 
Disallowed Concomitant Therapy 
The use of prescription and OTC medications including nonsteroidal anti-inflammatory drugs (with the 
exception of occasional ibuprofen) is prohibited during this study unless the occurrence of an AE requires 
a drug therapy.  In such cases, the Investigator must consult the Sponsor Medical Monitor to decide on 
subject continuation or withdrawal from the study. 
Disallowed concomitant therapy are identified in exclusion criteria, Section 5.2, and include the following 
as specified*: 
• 
Anti-obesity medications (e.g., orlistat, sibutramine), or has discontinued treatment < 12 weeks 
prior to screening 
• 
Systemic corticosteroids or anabolic agents within 6 weeks of screening* 
• 
Treatment with another investigational drug, biological agent, or device within 4 weeks of 
screening or 5 half-lives of study agent, whichever is longer 
• 
Prior treatment with gene therapy 
• 
No lipid lowering therapies (e.g., fibrates, niacin, fish oil or other products containing omega-3 
fatty acids [including OTC preparations]), glucagon-like peptide-1 (GLP-1) agonists, Glybera, or 
systemic corticosteroids may be started or adjusted after baseline qualification.   
• 
Doses of existing oral anti-diabetic medication, oral contraceptives, hormone replacement 
therapy, anticoagulants, or drugs or dietary supplements with potential lipid-altering effects 
should not be adjusted.   
• 
Study patients are prohibited from receiving other experimental agents during the study.  This 
includes marketed agents at experimental dosages that are being tested for the treatment of 
hypertriglyceridemia. 
• 
Other experimental agents during the study including investigational drug, biological agent, or 
device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer.  
This includes marketed agents at experimental dosages 
• 
Treatment with any non-Ionis oligonucleotide (including siRNA) at any time or prior treatment 
with an Ionis oligonucleotide or siRNA within 9 months of screening.  Patients that have 
previously received only 1 dose of an Ionis oligonucleotide as part of a clinical study may be 
included as long as ≥ 4 months has elapsed since dosing 
Patients should consult with the Site Investigator or designee prior to initiating any new medication, 
including non-prescription or herbal compounds or any other non-drug therapy. 
 
*Note:  Concomitant therapy with oral corticosteroids used as replacement therapy for 
pituitary/adrenal disease as well as inhaled steroid therapy (e.g., Pulmicort®), or 
intra-articular, or topical may be acceptable; however, the subject must be on a stable regimen 
for at least 4 weeks prior to screening.  All exceptions should be discussed with the Sponsor 
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8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) or 
diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between screening and 
the end of the post-treatment evaluation period. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded by Study Center staff.  The Study 
Center staff is required to document the receipt, dispensing, and return/destruction of study medication.  
Subjects that are self-administering study medication at home must record treatment in a dosing diary that 
will be reviewed periodically by Study Center staff and the Clinical Monitor. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING  
9.1 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee in accordance 
with the Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the Investigators of 
serious adverse events (SAEs) including suspected unexpected serious adverse reactions (SUSARs) per 
the International Conference on Harmonization (ICH) guidelines E2A and ICH E6.  Country-specific 
regulatory requirements will be followed in accordance with local country regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any SAE 
according to applicable regulations. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate the 
available information and perform an independent assessment of relatedness.  While the Sponsor may 
upgrade an Investigator’s decision it is not permissible to downgrade the Investigator’s opinion for the 
purposes of determining whether the SAE meets the definition of a SUSAR. 
For the purpose of regulatory reporting of SUSARs, there are no “expected” AEs in this study population. 
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the Study or use of 
investigational drug product, whether or not the AE is considered related to the investigational drug 
product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any AE caused by the Study Drug. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug caused the 
adverse event.  A suspected adverse reaction implies a lesser degree of certainty about causality than an 
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9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event that in the view of either the Investigator or Sponsor, meets 
any of the following criteria: 
• 
Results in death 
• 
Is life threatening: that is, poses an immediate risk of death at the time of the event 
• 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Hospitalization is defined as an admission of greater than 24 hours to a medical facility and does 
not always qualify as an AE (See Section 9.5.2) 
• 
Results in a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Results in a congenital anomaly or birth defect in the offspring of the subject (whether the subject 
is male or female) 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may also be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse. 
9.3.3.1 
Adverse Events of Special Interest 
For the purpose of this study severe reductions in platelet count < 50,000 mm3 are considered as an AE of 
special interest and should be subject to expediting reporting to the Sponsor following the same 
requirements as for SAE reporting (Section 9.4.1). 
9.4 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of the Study 
(i.e., before informed consent) should be recorded as Medical History and not recorded as AEs unless the 
pre-existing condition worsened.  The Investigator should always group signs and symptoms into a single 
term that constitutes a single unifying diagnosis if possible. 
9.4.1 
Serious Adverse Events 
In the interest of subject safety, and in order to fulfill regulatory requirements, all SAEs (regardless of 
their relationship to Study Drug) should be reported to the Sponsor or designee within 24 hours of the 
Study Center’s first knowledge of the event.  The collection of SAEs will begin after the subject signs the 
informed consent form and stop at the end of the subject’s follow-up period.  When the Investigator is 
reporting by telephone, it is important to speak to someone in person versus leaving a message.  An Initial 
Serious Adverse Event Form should be completed and a copy should be faxed to the Sponsor or designee.   


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The contact information for reporting SAEs is as follows: 
 
 – USA: 
Telephone: 
 or 
 
Facsimile: 
 or 
 
e-mail: 
 
Detailed information should be actively sought and included on Follow-Up Serious Adverse Event Forms 
as soon as additional information becomes available.  All SAEs will be followed until resolution.  SAEs 
that remain ongoing past the subject’s last protocol-specified follow-up visit will be evaluated by the 
Investigator and Sponsor.  If the Investigator and Sponsor agree the subject’s condition is unlikely to 
resolve, the Investigator and Sponsor will determine the follow-up requirement. 
9.4.2 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the informed consent form and will 
stop at the end of the subject’s follow-up period.  The Investigator will monitor each subject closely and 
record all observed or volunteered AEs on the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case Report 
Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (AKCEA-ANGPTL3-LRX or placebo) is characterized by 1 of 
the following: 
• 
Related:  There is clear evidence that the event is related to the use of Study Drug 
(e.g., confirmation by positive re-challenge test) 
• 
Possible:  The event cannot be explained by the subject’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event and 
Study Drug (AKCEA-ANGPTL3-LRX or placebo) administration 
• 
Unlikely/Remote:  An event for which an alternative explanation is more likely 
(e.g., concomitant medications or ongoing medical conditions) or the temporal relationship to 
Study Drug (AKCEA-ANGPTL3-LRX or placebo) administration and/or exposure suggests that a 
causal relationship is unlikely (For reporting purposes, Unlikely/Remote will be grouped together 
with Not Related) 
• 
Not Related:  The event can be readily explained by the subject’s underlying medical condition, 
concomitant therapy, or other causes, and therefore, the Investigator believes no relationship 
exists between the event and Study Drug 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D). 
Any AE not listed in Appendix D will be graded as follows: 


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• 
Mild:  The event is easily tolerated by the subject and does not affect the subject’s usual daily 
activities 
• 
Moderate:  The event causes the subject more discomfort and interrupts the subject’s usual daily 
activities 
• 
Severe:  The event is incapacitating and causes considerable interference with the subject’s usual 
daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Study Drug 
Action taken with Study Drug (AKCEA-ANGPTL3-LRX or placebo) due to the event is characterized by 
1 of the following. 
• 
None:  No changes were made to Study Drug (AKCEA-ANGPTL3-LRX or placebo) 
administration and dose 
• 
Permanently Discontinued:  Study drug was discontinued and not restarted 
• 
Temporarily Interrupted, Restarted – Same Dose:  Dosing was temporarily interrupted or 
delayed due to the AE and restarted at the same dose 
• 
Temporarily Interrupted, Restarted Reduced Dose:  Dosing was temporarily interrupted or 
delayed due to the AE and restarted at the next lower dose 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the Adverse 
Event Case Report Form.  Treatment should also be recorded on the concomitant treatment or ancillary 
procedures eCRF, as appropriate. 
9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE, then the event’s outcome is characterized by 1 of the following: 
• 
AE Persists:  Patient terminates from the trial and the AE continues 
• 
Recovered:  Patient recovered completely from the AE 
• 
Became Serious:  The event became serious (the date that the event became serious should be 
recorded as the Resolution Date of that AE and the Onset Date of the corresponding SAE) 
• 
Change in Severity (if applicable):  AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by 1 of the following: 
• 
Ongoing:  SAE continuing 
• 
Persists (as non-serious AE):  Patient has not fully recovered but the event no longer meets 
serious criteria and should be captured as an AE on the non-serious eCRF (the SAE resolution 
date should be entered as the date of onset of that AE) 


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• 
Recovered:  Patient recovered completely from the SAE (the date of recovery should be entered 
as the SAE resolution date) 
• 
Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, constitute or 
be associated with an AE.  Examples of these include abnormal laboratory results that are associated with 
symptoms, or require treatment (e.g., bleeding due to thrombocytopenia, tetany due to hypocalcemia, or 
cardiac arrhythmias due to hyperkalemia).  Whenever possible, the underlying diagnosis should be listed 
in preference to abnormal laboratory values as AEs.  Clinically-significant abnormalities will be 
monitored by the Investigator until the parameter returns to its baseline value or until agreement is 
reached between the Investigator and Sponsor Medical Monitor.  Laboratory abnormalities deemed not 
clinically-significant (NCS) by the Investigator should not be reported as AEs.  Similarly, laboratory 
abnormalities reported as AEs by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed clinical 
laboratory reports will serve as source documents and should include the Investigator’s assessment of 
clinical significance of out of range/abnormal laboratory values. 
All platelet count results must be reviewed promptly (within 48 hours of receipt) by the Investigator or 
the designee to ensure that the count has not met the stopping rule and to determine whether the rate of 
decline is suggestive that the patient could be approaching the dose interruption rule of 75,000/mm3 as 
specified in Section 8.6.3. 
Any case of a platelet count reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is considered an 
adverse event of special interest and should be reported in an expedited fashion to the Sponsor as per 
Sections 9.3.3.1 and 9.4.1). 
All results of liver function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per Section 8.6.1. 
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per Section 8.6.2. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered an SAE, 
even if the subject is hospitalized; the Study Center must document all of the following: 
• 
The prescheduled or elective procedure or routinely scheduled treatment was scheduled (or was 
on a waiting list to be scheduled) prior to obtaining the subject’s consent to participate in the 
Study 
• 
The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the Investigator 
between the subject’s consent to participate in the Study and the timing of the procedure or 
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• 
The prescheduled or elective procedure or routinely scheduled treatment is the sole reason for the 
intervention or hospital admission 
9.5.3 
Dosing Errors 
Study Drug (AKCEA-ANGPTL3-LRX) errors should be documented as Protocol Deviations.  A brief 
description should be provided in the deviation, including whether the subject was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing eCRF.  If the subject takes a dose of Study Drug that 
exceeds protocol specifications and the subject is symptomatic, then the symptom(s) should be 
documented as an AE and be reported per Section 9.4. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to Investigator’s 
section of the Investigator’s Brochure and contact the Sponsor or designee within 24 hours. 
9.5.4 
Contraception and Pregnancy 
Subjects must continue to use appropriate contraception with their partners, or refrain from sexual 
activity, as described in Section 6.3.1. 
If a subject becomes pregnant or a pregnancy is suspected, or if a male subject makes or believes that he 
has made someone pregnant during the Study, then the Study Center staff must be informed immediately.  
An Initial Pregnancy Form should be submitted to the Sponsor or designee within 24 hours of first 
learning of the occurrence of pregnancy.  Follow-up information including delivery or termination is 
reported by designating as ‘Follow-up’ on the Pregnancy Forms and reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the subject’s responsibility. 
Female subjects:  If a suspected pregnancy occurs while on the Study (including follow-up), a pregnancy 
test will be performed.  The subject with a confirmed pregnancy will be immediately withdrawn from 
treatment with Study Drug.  However, the subject will be encouraged to complete the post-treatment 
follow-up portion of the Study to the extent that study procedures do not interfere with the pregnancy.  
Regardless of continued study participation, the study physician will assist the subject in getting 
obstetrical care and the progress of the pregnancy will be followed until the outcome of the pregnancy is 
known (i.e., delivery, elective termination, or spontaneous abortion).  If the pregnancy results in the birth 
of a child, the Study Center and Sponsor may require access to the mother and infant’s medical records 
for an additional 8 weeks after birth.  Follow-up will be performed to the extent permitted by the 
applicable regulations and privacy considerations. 
Male subjects:  The progress of the pregnancy of a male subject’s partner should be followed until the 
outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous abortion).  If the 
pregnancy results in the birth of a child, the Study Center and Sponsor may request access to the 
mother and infant’s medical records for an additional 8 weeks after birth.  Follow-up will be 
performed to the extent permitted by the applicable regulations and privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Subsets, and Covariates 
For fasting lipid measurements, the values for the Month 3 analysis time point are defined as the average 
of Week 13 (Day 85) and Week 14 (Day 92) fasting assessments. 


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10.1.1 
Efficacy Endpoints 
• 
Percent change and absolute change from baseline in fasting TG 
• 
Percent change and absolute change from baseline in fasting ANGPTL3 
• 
Fasting lipid measurements, including:  non-HDL-C, apoB,  HDL-C, apoA-1, VLDL-C, and 
LDL-C 
• 
Percent change and change from baseline in other fasting lipid measurements including total 
cholesterol, non-HDL-C, apoB, HDL-C, apolipoprotein A-1 (apoA-1), VLDL-C, and LDL-C 
• 
Postprandial TG change from baseline 
• 
Frequency and severity of patient reported abdominal pain during the treatment period 
10.1.2 
Safety Endpoints  
• 
Adverse events 
• 
Vital signs and weight 
• 
Physical examinations  
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• 
Electrocardiograms (ECGs) 
• 
Use of concomitant medications 
10.2 
Sample Size Considerations 
There is no formal statistical justification for the selected sample size.  The sample size is selected based 
upon prior experience with AKCEA-ANGPTL3-LRX to ensure that the safety, tolerability and efficacy of 
AKCEA-ANGPTL3-LRX can be explored while minimizing unnecessary subject exposure.  In 6 healthy 
volunteers, AKCEA-ANGPTL3-LRX reported a 63% TG reduction after 6 weeks of administration. 
10.3 
Populations 
Safety Set:  All subjects who are enrolled and receive at least 1 dose of Study Drug. 
 
PK Set:  All subjects who receive at least 1 dose of Study Drug and have at least 1 evaluable PK sample. 
10.4 
Definition of Baseline 
Definitions of baseline are given below for the purposes of the final analysis. 
For fasting lipid measurements, the baseline is defined as the average of Day 1 pre-dose assessment and 
the last measurement prior to Day 1. 
For other measurements, baseline will be the last non-missing assessment prior to the first dose of 
Study Drug. 
10.5 
Interim Analysis and Early Stopping Guidelines 
Since the study is open labeled no interim analysis will be performed to inform early stopping guidelines.  


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10.6 
Planned Methods of Analysis 
Summary tabulations will be provided for disposition, demographic, baseline, efficacy, and safety data as 
noted in the following sections. 
All eCRF data, lab data, and any outcomes derived from the data will be provided in the patient data 
listings.  Patient data listings will be presented for all patients enrolled into the study.  Descriptive 
summary statistics including n, mean, median, standard deviation, standard error, interquartile range (25th 
percentile, 75th percentile), and range (minimum, maximum) for continuous variables, and counts and 
percentages for categorical variables will be used to summarize most data.   
10.6.1 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by treatment 
group.  All patients enrolled will be included in a summary of patient disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drug received will be summarized by treatment group and 
overall. 
Injection Site Reactions (ISRs) will be summarized by treatment group, MedDRA preferred term and 
severity. 
10.6.2.1 
Adverse Events 
Treatment duration and amount of Study Drug received will be summarized.  Patient incidence rates of all 
AEs will be tabulated by MedDRA system organ class, and by MedDRA preferred term.  Narratives of 
treatment-emergent deaths, serious and significant AEs, including early withdrawals due to AEs, will also 
be provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all treatment-
emergent serious AEs, and all treatment-emergent serious AEs potentially related to Study Drug will be 
summarized. 
10.6.2.2 
Clinical Laboratory Data 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) with 
differential, coagulation panel, complement, etc., will be summarized by study visit.  These safety 
variables will also be presented as change and percent change from baseline over time after Study Drug 
administration, as appropriate.  In addition, the number of patients who experience abnormalities in 
clinical laboratory evaluations will be listed. 
10.6.2.3 
Vital Signs and Examinations 
Vital signs, weight, and ECG measures will be tabulated by treatment group. 
10.6.3  
Efficacy Analysis 
Percent change and change from baseline to Month 3 in fasting TG will be summarized.  Response rate of 
patients with fasting serum TG < 750 mg/dL or achieving fasting TG ≥ 40% reduction from baseline at 
Month 3 will be summarized.  Response analysis will also be conducted using a range of fasting serum 
TG thresholds for determination of responder status. 


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Percent change and change from baseline to Month 3 will also be summarized by treatment group for 
other fasting lipid measures including ANGPTL3, non-HDL-C, apoB, HDL-C, apoA-1, VLDL-C, and 
LDL-C, total cholesterol, and fasting total apoC-III. 
10.6.4 
Pharmacokinetic Analysis 
The plasma PK of AKCEA-ANGPTL3-LRX (as total full length oligonucleotides, including, fully 
conjugated, partially conjugated, and unconjugated AKCEA-ANGPTL3-LRX) will be assessed following 
multiple-dose SC administration.  The plasma trough levels of AKCEA-ANGPTL3-LRX during treatment 
period and those during post-treatment follow up period will be descriptively summarized with 
stratification by subject immunogenicity status if applicable. 
10.6.5 
Pharmacodynamic Analysis 
The following parameters will be measured throughout the trial:  Fasting TGs, plasma angiopoietin-like 
3 (ANGPTL3), ANGPTL4, ANGPTL8, total cholesterol (TC), low density lipoprotein cholesterol (LDL-
C), high density lipoprotein cholesterol (HDL-C), non-high density lipoprotein cholesterol (non-HDL-C), 
very low density lipoprotein cholesterol (VLDL-C), total apoC-III, apolipoprotein B-100 (apoB-100), 
apolipoprotein B-48 (apoB-48), apolipoprotein A-1 (apoA-1), apolipoprotein A-2 (apoA-2), 
apolipoprotein E (apoE), very-low-density lipoprotein-triglyceride (VLDL-TG), chylomicron-cholesterol 
(CM-C), chylomicron triglyceride (CM-TG), free fatty acids (FFA), and free glycerol levels. 
10.6.6 
Immunogenicity Analysis 
Immunogenicity (IM) results (screen positive/negative, confirmed positive/negative or not evaluable, and 
when applicable, titer of anti-AKCEA-ANGPTL3-LRX antibodies) before, during, and after treatment with 
AKCEA-ANGPTL3-LRX will be listed.  Subject ADA status (positive/negative or not evaluable) for all 
evaluable patients, along with the study day associated with the first positive IM status emerged (Tfirst, i.e., 
onset of ADA development), the last positive IM status observed (Tlast), the last ADA sample collection 
day, and subject - peak titer if applicable, will be listed and study day. 
Additionally, the sample and subject IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated subjects with antibody negative, positive, and 
unknown status by treatment group.  Furthermore, onset and titer of the ADA response, if applicable, will 
be summarized as median, quartiles (25% and 75%), and range. 
10.6.7 
Additional Analyses 
Additional analyses may be performed not specified in this open label study protocol from the data 
available. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential patient 
population, based on an English version provided by the Sponsor or designee. 
Before a subject’s participation in the trial, the Investigator is responsible for obtaining written informed 
consent from the subject or legally acceptable representative after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or any Study Drug AKCEA-ANGPTL3-LRX are administered.  The subject or 


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legally acceptable representative must be given sufficient time to consider whether to participate in the 
study.   
The acquisition of informed consent and the subject’s agreement or refusal to notify his/her primary care 
physician should be documented in the subject’s medical records and the informed consent form should 
be signed and personally dated by the subject or a legally acceptable representative and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations required by 
institutional policy, and a copy of the signed consent form should be provided to the subject or legally 
acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally acceptable 
representative, the Investigator must provide an impartial witness to read the informed consent form to the 
subject and must allow for questions.  Thereafter, both the subject or legally acceptable representative and 
the witness must sign the informed consent form to attest that informed consent was freely given and 
understood. 
The sponsor shall maintain all records referred to in the applicable Regulations for a period of 25 years. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated October 2002, 
the applicable regulations and guidelines of current Good Clinical Practice (GCP), as well as the demands 
of national drug and data protection laws and other applicable regulatory requirements will be strictly 
followed.  The more recent Declaration of Helsinki version from 2013 is not being followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written subject information, and any 
proposed advertising material must be submitted to the IEC/IRB for written approval.  A copy of the 
written approval of the protocol and informed consent form must be received by the Sponsor or designee 
before recruitment of subjects into the study and shipment of Study Drug.  A copy of the written approval 
of any other items/materials that must be approved by the Study Center or IEC/IRB must also be received 
by the Sponsor or designee before recruitment of subjects into the study and shipment of Study Drug.  
The Investigator’s Brochure must be submitted to the IEC/IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The Investigator 
should notify the IEC/IRB of deviations from the protocol in accordance with ICH GCP Section 4.5.2.  
The Investigator should also notify the IEC/IRB of SAEs occurring at the Study Center and other AE 
reports received from the Sponsor or designee, in accordance with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout the 
duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the IEC/IRB 
continuance of approval must be sent to the Sponsor or designee. 
11.4 
Subject Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained.  On the case report forms or 
other documents submitted to the Sponsor or designee, subjects should be identified by initials (if 
permitted by local law) and a subject identification number only.  Documents that are not for submission 


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to the Sponsor or designee (e.g., signed informed consent forms) should be kept in strict confidence by 
the Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the Investigator 
and institution permit authorized representatives of the company, of the regulatory agency(s), and the 
IEC/IRB direct access to review the subject’s original medical records for verification of study-related 
procedures and data.  Direct access includes examining, analyzing, verifying, and reproducing any 
records and reports that are important to the evaluation of the study.  The Investigator is obligated to 
inform and obtain the consent of the subject to permit named representatives to have access to his/her 
study-related records without violating the confidentiality of the subject. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the informed 
consent document.  The regulatory authority and IEC/IRB must be informed of all amendments and give 
approval for any amendments likely to affect the safety of the subjects or the conduct of the trial.  The 
Investigator must send a copy of the approval letter from the IEC/IRB to the Sponsor or designee. 
12.2 
Study Termination 
The Sponsor or designee reserves the right to terminate the study.  The Investigator reserves the right to 
terminate their participation in the study, according to the terms of the site contract.  The 
Investigator/Sponsor or designee should notify the IEC/IRB in writing of the trial’s completion or early 
termination and send a copy of the notification to the Sponsor or designee. 
12.3 
Study Documentation and Storage 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application will be 
used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has delegated trial 
duties are recorded on a Sponsor-approved Delegation of Site Responsibilities Form. 
Source documents are original documents, data, and records from which the subject’s case report form 
data are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  Case report form entries may be 
considered source data if the case report form is the site of the original recording (i.e., there is no other 
written or electronic record of data).   
The Investigator and Study Center staff are responsible for maintaining a comprehensive and centralized 
filing system of all study-related (essential) documentation in accordance with Section 8 of the ICH 
Guidelines (E6), suitable for inspection at any time by representatives from the Sponsor or designee 
and/or applicable regulatory authorities.  Elements should include: 
• 
Subject files containing completed case report forms, informed consents, and supporting copies of 
source documentation 


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• 
Study files containing the protocol with all amendments, Investigator’s Brochure, copies of pre-
study documentation and all correspondence to and from the IEC/IRB and the Sponsor or 
designee 
• 
If drug supplies are maintained at the Study Center, proof of receipt, Study Drug Product 
Accountability Record, Return of Study Drug Product for Destruction, final Study Drug product 
reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the case report forms must be maintained 
and be readily available.  
No study document should be destroyed without prior written agreement between the Sponsor or designee 
and the Investigator.  Should the Investigator wish to assign the study records to another party or move 
them to another location, he/she must notify the Sponsor or designee. 
12.4 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and visiting 
the Investigator for the purpose of inspecting the facilities and, upon request, inspecting the various 
records of the trial (e.g., case report forms and other pertinent data) provided that subject confidentiality is 
respected. 
The Sponsor monitor or designee is responsible for inspecting the case report forms at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to local regulations on the conduct of clinical research.  The monitor should have 
access to subject medical records and other study-related records needed to verify the entries on the case 
report forms. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the course 
of these monitoring visits, including delays in completing case report forms, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit by 
representatives from the Sponsor’s Clinical Quality Assurance Department (or designees).  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study-related 
records will occur to evaluate the trial conduct and compliance with the protocol, ICH GCP, and 
applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on subject data 
received by the Sponsor or designee.  During this review, subject data will be checked for consistency, 
omissions, and any apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data management review process, 
data queries and/or Study Center notifications will be sent to the Study Center for completion and return 
to Sponsor or designee. 
The Principal Investigator will sign and date the indicated places on the case report form.  These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case report 
form, the data queries, and the Study Center notifications, and agrees with the content. 
12.5 
Language 
Case report forms must be completed in English.  Whenever possible, the trade name rather than the 
generic name for concomitant medications should be recorded and if possible, in English.  Generic names 


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are acceptable if the trade name is unknown.  Combination medications should be recorded using their 
trade name in English if possible. 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow applicable local 
compensation laws.  Subjects will be treated and/or compensated for any study-related illness/injury in 
accordance with the information provided in the Compensation for Injury section of the Informed Consent 
document. 
 
 


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13. 
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14. APPENDICES 
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Appendix A 
Schedule of Procedures 
 
 
 


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Appendix A 
Schedule of Procedures 
Study Period 
Screen/ 
Run-in a 
Treatment Period 
Post-treatment 
Follow-up 
Study Week 
-8 to -1 
1 
3 
5 
7 
9 
11 
13 
14/ET 
18 
22 
26 
Study Day 
-56 To -1 
1 b 
15 
29 
43 
57 
71 
85 
92 
94 
95 
120 
148 
176 
Visit and Testing Window +/- Days 
0 
0 
2 
2 
2 
2 
2 
2 
2 
0 
0 
3 
3 
3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height & Weight c 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
Vital Signs 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Physical Examination d 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
24-hour urine creatinine clearance and 
protein 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal Pain Assessment 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
Urinalysis 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Blood Draw e 
 
Chemistry Panel (+ CPK) f g  
X 
X 
X  
X 
X  
X 
X  
X  
 
 
 
X 
 
X 
CBC with Differential f g 
X 
X 
X  
X 
X  
X  
X  
X  
X  
 
 
X h 
X 
X 
Serum Lipid Panel  
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
PD Panel 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
Coagulation (aPTT, PT, INR) 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Complement Markers C5A, Bb 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
hsCRP  
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
Hepatitis B, C, HIV,  TSH,  Free 
T4  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK i 
 
X1 
 
X 1 
X 1 
X 1 
X 1 
 
X 
 
 
X 
X 
X 
Genetic Testing j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-ANGPTL3-LRX Antibodies 
 
X1 
 
X1 
 
X1 
 
 
X 
 
 
X 
 
X 
FSH (women only, if applicable) k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test k 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1  
Protocol 
 
26 October 2017 
 
70 
Appendix A 
Schedule of Procedures Continued 
 
All procedures and study samples are to be performed pre-dose at respective visits, unless specified 
a 
Subject starts the tightly controlled diet, if needed. 
b 
After 6 weeks on the controlled diet, patients will have baseline measurements and be assessed for qualification of enrollment.  
c 
Height is only required on Day 1. 
 
d 
Full physical exam to be given at Screening and abbreviated physical exam to be given during treatment and follow-up period as indicated to assess changes 
from screening. 
 
e 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours, unless tests are repeated for safety reasons. 
f 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) a repeat blood 
specimen should be re-drawn as soon as possible (ideally within 7 days).  All platelet count results will be reviewed promptly (within 48 hours of receipt) by the 
Investigator.  Any case of a platelet count ≤ 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
g 
If not done as part of a Study Center visit, assessments and procedures to be conducted by either a home healthcare service or the Study Center.  Subject 
Study Center visits must be no more than 4 weeks apart during the treatment period.  
h 
During follow-up period, hematology sampling for platelet values are taken every 14 days for 6 weeks after last dose of Study Drug, then at Week 22 and 
Week 26 Follow-up visits.  
i 
Refer to Appendix C for PK Sampling schedule. 
j 
Genetic testing will only be performed for eligibility if no documented genetic testing in medical history.  
k 
Women who are not surgically sterile or post-menopausal.  
 
Study Period 
Screen/ 
Run-in a 
Treatment Period 
Post-treatment 
Follow-up 
Study Week 
-8 to -1 
1 
3 
5 
7 
9 
11 
13 
14/ET 
18 
22 
26 
Study Day 
-56 To -1 
1 b 
15 
29 
43 
57 
71 
85 
92 
94 
95 
120 
148 
176 
Visit and Testing Window +/- Days 
0 
0 
2 
2 
2 
2 
2 
2 
2 
0 
0 
3 
3 
3 
 
HbA1C and delipidated free 
glycerol  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived Serum & Plasma m 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
Post-Prandial Assessment 
Xl 
 
 
 
 
 
 
 
Xl 
Xl 
Xl 
 
 
 
Platelet aggregation 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
Study Drug Administration 
 
WEEKLY SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG (Week 1 
through Week 13) 
 
 
 
 
 
 
Adverse Events 
TO BE COLLECTED FROM TIME OF INFORMED CONSENT TO END OF FOLLOW-UP PERIOD 
Concomitant Medication 
TO BE COLLECTED FROM TIME OF INFORMED CONSENT TO END OF FOLLOW-UP PERIOD 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1  
Protocol 
 
26 October 2017 
 
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Appendix A 
Schedule of Procedures Continued 
l 
The postprandial assessment for Screening will only be performed after other eligibility criteria are met. Subjects will be provided a standardized meal during 
Screening visit with instructions on when and how to consume and will return to the study center on Day -1 (2 days after consumption)  for pre-dose 
postprandial assessments.  Subjects will again be provided standardized meal at the Week 14 visit (Day 92) and will return to the site 2 days later (Day 94) 
plus one more day (Day 95) for post-dose postprandial assessments. 
m 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine and/or 
chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) and will be retained until completion of the final 
study report. 
  
Time (time is in reference to Study Drug administration): 
1 
Pre-dose


ISIS 703802-CS3 
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Amendment 1 
Protocol 
 
26 October 2017 
 
72 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
73 
Appendix B 
List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be performed on 
stored samples to better characterize the profile of AKCEA-ANGPTL3-LRX or other similar 
oligonucleotides. 
Clinical Chemistry 
Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
Insulin 
• 
BUN 
• 
Creatinine 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect 
(unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline 
phosphatase 
• 
Creatinine kinase 
• 
Cys-C 
 
Fasting Lipid Panel 
• 
Total cholesterol 
• 
Total ApoB 
• 
ApoB-100 
• 
ApoB-48 
• 
LDL cholesterol 
• 
HDL cholesterol 
• 
Total Triglycerides 
• 
CM triglycerides 
• 
VLDL cholesterol 
• 
VLDL triglycerides 
• 
Non-HDL 
cholesterol 
 
Screening Tests 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis C antibody 
• 
HIV antibody 
• 
FSH (women only) 
• 
Serum βhCG 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Complement 
• 
C5a 
• 
Bb 
 
PD Panel  
• 
ANGPTL3 
• 
ANGPTL4 
• 
ANGPTL8 
• 
ApoA-I 
• 
ApoB 
• 
ApoC-III 
 
 
Specialized Lipoprotein 
and post-prandial 
Analyses1 
• 
Lipoprotein particle 
analysis 
• 
Oxidized 
chylomicrons and 
VLDLs 
• 
Isoprostanes 
• 
HDL function and 
characterization 
• 
Lipoprotein 
subclass analysis 
• 
Newly formed CM 
and LDL, IDL, HDL 
kinetics 
• 
Post-prandial lipid 
panel 
• 
Post-prandial 
platelet count and 
function 
• 
Post-prandial 
glucose 
Hematology 
• 
Blood viscosity 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets count 
• 
Platelets function 
• 
White blood cells 
• 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
 
Thyroid Panel 
• 
TSH 
• 
Free T4 
 
 
Pharmacokinetics and 
Immunogenicity2 
• AKCEA-ANGPTL3-
LRX levels in plasma 
• Anti- AKCEA-
ANGPTL3-LRX 
antibodies in plasma 
 
Genetic Testing 
• 
Molecular 
confirmation of FCS 
• 
Genetic sequencing 
of FCS causing 
genes3 
 
 
Inflammatory 
• 
Hs-CRP  
• 
Cytokine panel  
o 
IL-1b,  
o 
IL-6,  
o 
IL-8 
 
 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination5 
• 
P/C Ratio (UPCR) 
• 
A/C Ratio (UACR) 
 
24 Hour Urine Test 
• 
Creatinine clearance 
• 
Protein 
• 
Albumin 
1 
Scope of specialized lipoprotein analyses will be determined based on results from fasting lipid panel 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
74 
2 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation, 
stability assessments, metabolite assessments, testing of additional exploratory pharmacodynamics markers, 
immunogenicity testing (or possibly for immunogenicity assay development and/or validation), or to assess other 
actions of AKCEA-ANGPTL3-LRX with plasma constituents 
Appendix B 
List of Laboratory Analytes Continued 
3 
If the genotype is not already available, blood will be collected to assess genetic evidence of null loss-of-function 
for LPL.  May not be collected if adequate genetic data are available in medical history or if patient does not 
consent to genetic testing 
4 
Will be performed on abnormal findings unless otherwise specified 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1 
Protocol 
 
26 October 2017 
 
75 
 
 
 
 
 
 
 
Appendix C 
PK Sampling Schedule  
 
 


ISIS 703802-CS3 
CONFIDENTIAL 
 Amendment 1 
Protocol 
 
 26 October 2017 
 
76 
Appendix C 
PK Sampling Schedule  
D1 
D29 
D43 
D57 
D71 
D92 
D120 
D148 
D176 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
Anytime 
Anytime 
Anytime 
Note:  D = Day 


ISIS 703802-CS3 
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 Amendment 1 
Protocol 
 
26 October 2017 
 
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Appendix D  
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 
 
 


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CONFIDENTIAL 
 Amendment 1 
Protocol 
 
26 October 2017 
 
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Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities  
The following grading recommendations for adverse events relating to lab test abnormalities are based 
upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, June 2010. 
 
 
 


ISIS 703802-CS3 
CONFIDENTIAL 
 Amendment 1 
Protocol 
 
26 October 2017 
 
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Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 
 
 


ISIS 703802-CS3 
CONFIDENTIAL 
 Amendment 1 
Protocol 
 
26 October 2017 
 
80 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities  
Continued 
 
 
 


ISIS 703802-CS3 
CONFIDENTIAL 
 Amendment 1 
Protocol 
 
26 October 2017 
 
81 
 
 
 
 
 
 
 
Appendix E 
Post-prandial Meal, Sampling Schedule, and 
Assessment 
 


ISIS 703802-CS3 
CONFIDENTIAL 
Amendment 1  
Protocol 
 
26 October 2017 
 
82 
Appendix E 
Post-prandial Meal, Sampling Schedule, and Assessment 
Post-prandial assessment for lipoproteins metabolism (lipoprotein kinetics: newly formed CM, VLDL, 
IDL, LDL and HDL) will be performed as follows. A radiolabelled meal supplemented with a labeled 
tracer, 3H-palmitate (300µCi, 
 Canada), will be sonicated into the 
liquid meal.  Palmitate is a fatty acid that is a common constituent of any diet.  The 3H-palmitate tracer 
emits weak radioactivity, equivalent to an X-ray.  Since dietary palmitate is incorporated into 
chylomicrons as they are formed in the enterocytes of the gut, this enables monitoring the appearance and 
clearance of newly-formed chylomicrons from circulation.  The methodology to be applied for studying 
post-prandial kinetics of chylomicrons appearance and clearance is well-established (Mittendorfer et al. 
2003; Bickerton et al. 2007; Normand-Lauziere et al. 2010). 
A liquid meal (similar to a milkshake) containing a small amount (300µCi) of radiolabelled fatty acids 
(3H-palmitate) will be provided.  The liquid meal will provide about a third of the daily caloric 
requirements.  From 1 hr prior to 9 hrs after the ingestion of the meal, two stable isotope tracers will be 
continuously infused. A primed (1.6 mmol/kg) continuous (0.05 mmol/kg/min) infusion of [1,1,2,3,3-2H]-
glycerol 
 will be administered as previously described (Normand-
Lauziere et al. 2010).  To document VLDL, IDL, LDL and HDL kinetics, L-[5,5,5-D3] leucine (10 
mmol/kg) will be injected as a bolus intravenously and then by continuous infusion (10 mmol·kg body 
weight-1·h-1) (Tremblay et al. 2006). Glycerol appearance rates will be calculated using Steele’s non-
steady state equation assuming a volume of distribution of 230ml/kg (Gastaldelli et al. 1999). The 
isotopic enrichment of leucine in the apolipoproteins will be expressed as tracer/tracee ratio (%) using 
standardized formulas (Cobelli et al. 1987). 
Blood samples will be drawn at intervals before and after the ingestion of the radiolabelled meal on days 
prior to and after the Treatment phase as noted in the table below.  A standardized meal will be given to 
the participants after the 9 hr blood draw.  Blood will be collected in tubes containing Na2EDTA and 
Orlistat (30 mg/ml, 
 Canada) to prevent in vitro triacylglycerol lipolysis and separate 
samples will be collected in NaF tubes for plasma glucose determination. 
Post-prandial Sampling (Blood) Schedule 
Study Day 
D -1a 
D1 
D94 
D95 
Visit Window 
+/- Days 
0 
0 
0 
0 
-1 hr pre-prandial, and 
0, 1, 2, 3, 4, 5, 6, 7, 8, 
and 9 hrs post prandial 
24 hrs post-prandial 
/pre SC injection 
-1 hr pre-prandial, and 
0, 1, 2, 3, 4, 5, 6, 7, 8, 
and 9 hrs post-prandial 
24 hrs post-prandial 
a 
There is a range for this visit, it should happen prior to and as close as possible to Day 1. 
Plasma samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability and metabolite assessments, or to assess other actions of AKCEA-ANGPTL3-LRX with 
plasma constituents.